WO2012025857A1 - Cycloalkyl methoxybenzyl phenyl pyran derivatives as sodium dependent glucose co transporter (sglt2) inhibitors - Google Patents

Cycloalkyl methoxybenzyl phenyl pyran derivatives as sodium dependent glucose co transporter (sglt2) inhibitors Download PDF

Info

Publication number
WO2012025857A1
WO2012025857A1 PCT/IB2011/053641 IB2011053641W WO2012025857A1 WO 2012025857 A1 WO2012025857 A1 WO 2012025857A1 IB 2011053641 W IB2011053641 W IB 2011053641W WO 2012025857 A1 WO2012025857 A1 WO 2012025857A1
Authority
WO
WIPO (PCT)
Prior art keywords
benzyl
methoxy
substituted
tetrahydro
pyran
Prior art date
Application number
PCT/IB2011/053641
Other languages
French (fr)
Inventor
Bandi Parthasaradhi Reddy
Vedula Manohar Sharma
Kura Rathnakar Reddy
Lanka Vl Subrahmanyam
Neela Sudhakar
Original Assignee
Hetero Research Foundation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Hetero Research Foundation filed Critical Hetero Research Foundation
Publication of WO2012025857A1 publication Critical patent/WO2012025857A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D201/00—Preparation, separation, purification or stabilisation of unsubstituted lactams
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • the present invention relates to cycloalkyl methoxybenzyl phenyl pyran derivatives, which are SGLT2 inhibitors and are useful as therapeutic agents to treat metabolic disorders more particularly diabetes by stimulating excretion of glucose in the urine.
  • Type 2 diabetes is characterized by impaired insulin secretion in response to glucose, increased hepatic glucose production and decreased insulin dependent glucose uptake in the peripheral tissues or insulin resistance.
  • the burden of diabetes is driven by vascular complications such as cardiovascular disease, stroke, nephropathy, retinopathy, renal failure, and amputations of the extremities. Although these complications result from multiple metabolic derangements, hyper glycemia is central to both the vascular consequences of diabetes and progressive nature of the disease itself.
  • Hyperglycemia can be controlled in Individuals by healthy life style changes that increase activity and reduce weight and or by using current non insulin therapies. These therapies target the liver to reduce glucose output, small intestine to decrease glucose absorption, adipose deposits, or muscle to elevate glucose cellular uptake or to promote glucose metabolism, serum proteases to prolong incretion action, and the pancreas to enhance insulin release.
  • Patent applications were published describing C-glucosides for which one of the aryl rings in aglycone part had been replaced with heterocycles, primarily benzothiophene (US 7202350; WO 2004/080990, US 2007/0197450, and WO 2005/085237), azulene moiety (WO 2004/013118), N-benzylated indoles (WO 2006/054629), and thiophene (WO 2008/013321).
  • Thiaglucosides (WO 2006/073197), compounds arising from modifications of the glucose moiety, replacing the glucosyl hydroxyl methyl moiety with OH, loweralkoxy, SMe and S0 2 Me or replacement of the pyranosil oxygen with acylated nitrogen (US 2008/0221164) were published.
  • SGLT2 inhibitors may be relevant with respect to diabetes, diabetic complications or obesity.
  • WO 09/026537 describes benzyl-benzene derivatives and methods of use; US 2005/209166 describes glucopyranosyl substituted phenyl derivatives, medicaments containing such compounds, their use and process for their manufacture; WO 2008/055940 describes combination therapy with SGLT2 inhibitors and their pharmaceutical compositions; WO 2007/00445 describes glucopyranosyl substituted benzyl-benzene derivatives, medicaments containing such compounds, their use and process for their manufacture; and US 2003/0114390 describes C-aryl glucoside SGLT2 inhibitors and method.
  • Dapagliflozin is in phase III clinical trails in where as Canagliflozin is in phase HI.
  • the present invention relates to compounds of the formula (1):
  • R can be substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkoxy, or substituted or unsubstituted heterocyclic group and preferably methyl, ethyl, propyl, methoxy, ethoxy, isopropoxy, t-butoxy, and the R can be substituted by R a ;
  • each R' is independent and can be either the same or a different group and is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted acyl group, or substituted or unsubstituted alkoxy carbonyl group;
  • X can be CRiR 2 , O, NR l5 or S;
  • a, b, c, d, e, and f is independent and can be selected from hydrogen, hydroxyl group, halogen, substituted or unsubstituted alkyl, C(0)-R 3 , -C(0)0-R 3 , or -C(0)NR 3 R 4 ; and a and b; or c and d; or e and f can be together with their attached carbon to form Spiro ring or R and one of the a or b; or c and one of the e or f; or d and one of the e or f can be together with their attached carbon atoms to form bicyclic ring.
  • Z and Z' is independent and can be selected from hydrogen, hydroxyl group, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy group, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkyloxy, -C(0)-R 3 , -C(0)0-R 3 , or -C(0)NR 3 R4;
  • R a can be hydrogen, hydroxyl group, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy group, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkyloxy, R 3 R 4 , -C(0)-R 3 , -C(0)0- R 3 , -C(0)NR 3 R4, S(0) p NR 3 R 4 , or S(0) p R 3 ;
  • each R ⁇ and R 2 can be independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted cycloalkyl;
  • each R 3 and R 4 can be independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, or substituted or unsubstituted heterocyclylalkyl;
  • 'p' can be an integer ranging from 0 to 2.
  • prodrugs of the compounds of the formula (1) including ester prodrugs.
  • R is substituted or unsubstituted alkyl.
  • R is methyl, trifluoro-methyl, ethyl and ethoxy-methyl.
  • a compound of formula (1) wherein Z' is halogen or substituted or unsubstituted alkyl.
  • Z' is chlorine, fluorine and methyl.
  • each a, b, c, d, e and f are independently hydrogen or halogen.
  • a pharmaceutical preparation which comprises any one of the above cycloalkyl methoxybenzyl phenyl pyran compounds or a pharmaceutically acceptable salt thereof, a solvate thereof, or a hydrate thereof as an active ingredient.
  • such a pharmaceutical preparation which is an inhibitor of sodium-dependent glucose transporter 2 activity.
  • such a pharmaceutical preparation which is a prophylactic or therapeutic agent for diabetes, diabetes- related diseases or diabetic complications.
  • the present invention also provides a pharmaceutical composition that includes at least one compound as described herein and at least one pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent).
  • the pharmaceutical composition comprises a therapeutically effective amount of at least one compound described herein.
  • the compound(s) present in the composition may be associated with a pharmaceutically acceptable excipient (such as a carrier or a diluent) or may be diluted by a carrier, or enclosed within a carrier which may be in the form of a capsule, sachet, paper or other container.
  • the compounds and pharmaceutical compositions described herein are useful in the treatment of diseases, conditions and/or disorders mediated by SGLT2 inhibitors.
  • the present invention further provides a method of treating diabetes, disease condition and/or disorder mediated by stimulation of glucose excretion in urea/ inhibition of SGLT2 in a subject in need thereof by administering to the subject one or more compounds described herein in the amount effective to cause inhibition of such receptor.
  • the present invention provides cycloalkyl methoxybenzyl phenyl pyran derivatives, which may be used as SGLT2 inhibitors and processes for the synthesis of these compounds.
  • Pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers, polymorphs of these compounds that may have the same type of activity are also provided.
  • Pharmaceutical compositions containing the described compounds together with pharmaceutically acceptable carriers, excipients or diluents, which can be used for the treatment of diseases, condition and/or disorders mediated by SGLT2 inhibitors are further provided.
  • halogen or halo includes fluorine, chlorine, bromine, or iodine.
  • alkyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to eight carbon atoms, and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n- pentyl, and 1,1-dimethylethyl (t-butyl).
  • alkenyl refers to an aliphatic hydrocarbon group containing a carbon-carbon double bond and which may be a straight or branched chain having from 2 to about 10 carbon atoms, e.g., ethenyl, 1-propenyl, 2-propenyl (allyl), iso- propenyl, 2 -methyl- 1-propenyl, 1-butenyl, and 2-butenyl.
  • haloalkyl is used to denote a group comprised of an alkyl group substituted with halogen atom, where alkyl group is as defined above and halogen is used to denote fluorine, chlorine, bromine or iodine, an example of such group is trifluoromethyl, difluoromethyl.
  • acyl group is used to denote a linear or branched aliphatic acyl group (preferably a C 2-6 alkanoyl group) or an aromatic acyl group, which contains 2 to 10 carbon atoms.
  • examples include an acetyl group, a propionyl group, a pivaloyl group, a butyryl group, an isobutyryl group, a valeryl group and a benzoyl group, with an acetyl group being preferred.
  • alkoxy group is used to denote a linear or branched alkoxy group containing 1 to 6 carbon atoms. Preferred are C 1-4 alkoxy groups including a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a n-butoxy group, an isobutoxy group and a tert-butoxy group.
  • alkoxycarbonyl group isused to denote a structure composed of a linear or branched C 1-5 alkoxy group and a carbonyl group.
  • C 2-5 alkoxycarbonyl groups including a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group and a butoxycarbonyl group.
  • a methoxycarbonyl group is preferred.
  • cycloalkyl denotes a non-aromatic mono or multicyclic ring system of from 3 to about 12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • multicyclic cycloalkyl groups include, but are not limited to, perhydronapththyl, adamantyl and norbornyl groups, bridged cyclic groups and spirobicyclic groups, e.g., spiro (4,4) non-2-yl.
  • bicyclic ring denotes a aromatic or non-aromatic bicyclic ring system of from 3 to about 12 carbon atoms, such as benzofused or simple fused.
  • bicyclic ring groups include, but are not limited to, benzoisoxazole, benzoxazole, cyclopenta[c]furan, octahydropentalene, or the like.
  • cycloalkylalkyl refers to a cyclic ring-containing radical having from 3 to about 8 carbon atoms directly attached to an alkyl group.
  • the cycloalkylalkyl group may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure.
  • Non-limiting examples of such groups include cyclopropylmethyl, cyclobutylethyl, and cyclopentylethyl.
  • cycloalkenyl refers to a cyclic ring-containing radical having from 3 to about 8 carbon atoms with at least one carbon-carbon double bond, such as cyclopropenyl, cyclobutenyl, and cyclopentenyl.
  • aryl refers to an aromatic radical having from 6 to 14 carbon atoms such as phenyl, naphthyl, tetrahydronapthyl, indanyl, and biphenyl.
  • arylalkyl refers to an aryl group as defined above directly bonded to an alkyl group as defined above, e.g., -CH 2 C 6 H 5 and -C2H 5 C 6 H 5 .
  • heterocyclyl and “heterocyclic ring” refer to a stable 3- to 15- membered ring radical which consists of carbon atoms and from one to five heteroatoms selected from nitrogen, phosphorus, oxygen and sulfur.
  • the heterocyclic ring radical may be a monocyclic, bicyclic or tricyclic ring system, which may include fused, bridged or spiro ring systems, and the nitrogen, phosphorus, carbon, oxygen or sulfur atoms in the heterocyclic ring radical may be optionally oxidized to various oxidation states.
  • the nitrogen atom may be optionally quaternized; and the ring radical may be partially or fully saturated (i.e., heterocyclic or heteroaryl).
  • heterocyclic ring radicals include, but are not limited to, azetidinyl, acridinyl, benzodioxolyl, benzodioxinyl benzodioxanyl, benzofuranyl, carbazolyl, cinnolinyl, dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pyridyl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrazoyl, imidazolyl, tetrahydroisouinolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-o
  • heterocyclylalkyl refers to a heterocyclic ring radical directly bonded to an alkyl group.
  • the heterocyclylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure.
  • heteroaryl refers to an aromatic heterocyclic ring radical.
  • the heteroaryl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.
  • heteroarylalkyl refers to a heteroaryl ring radical directly bonded to an alkyl group.
  • the heteroarylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure.
  • prodrug means a compound that is transformed in vivo to yield a compound of Formula (1) or a pharmaceutically acceptable salt, hydrate or solvate of the compound. The transformation may occur by various mechanisms, such as through hydrolysis in blood.
  • a discussion of the use of prodrugs is provided by T. Higuchi and W. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the
  • treating or “treatment” of a state, disease, disorder or condition includes:
  • the benefit to a subject receiving treatment is either statistically significant or at least perceptible to the subject or to the physician.
  • subject includes mammals (especially humans) and other animals, such as domestic animals (e.g., household pets including cats and dogs) and non-domestic animals (such as wildlife).
  • domestic animals e.g., household pets including cats and dogs
  • non-domestic animals such as wildlife.
  • a “therapeutically effective amount” means the amount of a compound that, when administered to a subject for treating a state, disease, disorder or condition, is sufficient to effect such treatment.
  • the “therapeutically effective amount” will vary depending on the compound, the state, disease, disorder or condition and its severity and the age, weight, physical condition and responsiveness of the subject receiving treatment.
  • diabetes encompasses type I diabetes, type II diabetes, and other types of diabetes with specific etiology.
  • diabetes-related diseases includes adiposis, hyperinsulinemia, abnormal carbohydrate metabolism, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, abnormal lipid metabolism, hypertension, congestive heart failure, edema, hyperuricemia and gout.
  • diabetic complications can be classified into acute complications and chronic complications.
  • hyperglycemia e.g., ketoacidosis
  • infections e.g., skin, soft tissue, biliary system, respiratory system and urinary tract infections
  • chronic complications includes microangiopathy (e.g., nephropathy, retinopathy), arteriosclerosis (e.g., atherosclerosis, heart infarction, brain infarction, or lower extremity arterial occlusion), neuropathy (e.g., sensory nerves, motor nerves, or autonomic nerves), foot gangrene, etc.
  • microangiopathy e.g., nephropathy, retinopathy
  • arteriosclerosis e.g., atherosclerosis, heart infarction, brain infarction, or lower extremity arterial occlusion
  • neuropathy e.g., sensory nerves, motor nerves, or autonomic nerves
  • foot gangrene e.g., foot gangrene, etc.
  • Major complications are diabetic retinopathy, diabetic nephropathy and diabetic neuropathy.
  • the compound of the invention may form salts.
  • pharmaceutically acceptable salts forming part of this patent application include salts derived from inorganic bases salts of organic bases salts of chiral bases, salts of natural amino acids and salts of non-natural amino acids.
  • Certain compounds of present patent application are capable of existing in stereoisomeric forms (e.g. diastereomers and enantiomers). With respect to the overall compounds described by the Formula (1), the present patent application extends to these stereoisomeric forms and to mixtures thereof.
  • solvates includes hydrates and other solvents of crystallization (such as alcohols).
  • the compounds of the present invention may form solvates with low molecular weight solvents by methods known in the art.
  • compositions provided in the present invention include at least one compound described herein and at least one pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent).
  • the contemplated pharmaceutical compositions include a compound(s) described herein in an amount sufficient to excrete glucose in urine or inhibit SGLT2 in a subject.
  • the subjects contemplated include, for example, a living cell and a mammal, including human mammal.
  • the compound of the present invention may be associated with a pharmaceutically acceptable excipient (such as a carrier or a diluent) and can be formulated in to preparations in solid, semi-solid, liquid or gaseous forms.
  • suitable carriers include, but are not limited to, water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone.
  • the carrier or diluent may include a sustained release material, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
  • the pharmaceutical composition may also include one or more pharmaceutically acceptable auxiliary agents, wetting agents, emulsifying agents, suspending agents, preserving agents, salts for influencing osmotic pressure, buffers, sweetening agents, flavoring agents, colorants, or any combination of the foregoing.
  • the pharmaceutical composition of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the subject by employing procedures known in the art.
  • compositions described herein may be prepared, e.g., as described in Remington: The Science and Practice of Pharmacy, 20 th Ed., 2003 (Lippincott Williams & Wilkins).
  • the active compound can be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier, which may be in the form of an ampoule, capsule, or sachet.
  • the carrier serves as a diluent, it may be a solid, semi-solid, or liquid material that acts as a vehicle, excipient, or medium for the active compound.
  • the active compound can be adsorbed on a granular solid container, for example, in a sachet.
  • compositions may be, for example, capsules, tablets, aerosols, solutions, suspensions or products for topical application.
  • the route of administration may be any route which effectively transports the active compound to the appropriate or desired site of action.
  • Suitable routes of administration include, but are not limited to, oral, nasal, pulmonary, buccal, subdermal, intradermal, transdermal, parenteral, rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic (such as with an ophthalmic solution) or topical (such as with a topical ointment).
  • the oral route is preferred.
  • Solid oral formulations include, but are not limited to, tablets, capsules (soft or hard gelatin), dragees (containing the active ingredient in powder or pellet form), troches and lozenges. Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application. Preferable carriers for tablets, dragees, or capsules include lactose, cornstarch, and/or potato starch. A syrup or elixir can be used in cases where a sweetened vehicle can be employed.
  • a typical tablet that may be prepared by conventional tabletting techniques may contain: (1) Core: Active compound (as free compound or salt thereof), 250 mg colloidal silicon dioxide (Aerosil®), 1.5 mg microcrystalline cellulose (Avicel®), 70 mg modified cellulose gum (Ac-Di-Sol®), and 7.5 mg magnesium stearate; (2) Coating: HPMC, approx. 9 mg Mywacett 9-40 T and approx. 0.9 mg acylated monoglyceride
  • Liquid formulations include, but are not limited to, syrups, emulsions, soft gelatin and sterile injectable liquids, such as aqueous or non-aqueous liquid suspensions or solutions.
  • injectable solutions or suspensions preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.
  • the present invention provides compounds and pharmaceutical formulations thereof that are useful in the treatment of diseases, conditions and/or disorders mediated by SGLT2 inhibitors.
  • the connection between therapeutic effect and inhibition of SGLT2 is illustrated.
  • PCT publication Nos. WO 01//016147, WO 02/08306, or WO 03/020737 J. Clin. Invest. Vol. 79, pp. 1510- 1515 (1987); J.Clin. Invest., Vol. 93, pp. 397-404 (1994); Diabetes; 57, 1723-1729, 2008 and references cited therein, all of which are incorporated herein by reference in their entirety and for the purpose stated.
  • the present patent application further provides a method of treating a disease, condition and/or disorder mediated by SGLT2 inhibitors in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound or a pharmaceutical composition of the present invention.
  • Diseases, conditions, and/or disorders that are mediated by SGLT2 inhibitors are believed to include, but are not limited to, diabetes, especially type I and type 11 diabetes, including complications of diabetes such as retinopathy, neuropathy, nephropathy and delayed wound healing, and related diseases such as insulin resistance and impaired glucose homeostasis (IGH), hyperglycemia, hyperinsulinemia, elevated blood levels of fatty acids or glycerol, obesity, hyperlipidemia including hypertriglyceridemia, Syndrome X, hypertension, atherosclerosis and related diseases, and for increasing high density lipid levels.
  • IGH insulin resistance and impaired glucose homeostasis
  • Syndrome X also known as Metabolic Syndrome
  • the compounds of the present invention can obtain more advantageous effects than additive effects in the prevention or treatment of the above diseases when using suitably in combination with the above drugs. Also, the administration dose can be decreased in comparison with administration of either drug alone, or adverse effects of co administrated drugs other than SGLT2 inhibitors can be avoided or declined.
  • the compounds described herein may be prepared by techniques known in the art.
  • the compounds described herein may be prepared by following the reaction sequence as depicted in Scheme- 1 to 2. Further, in the following schemes, where specific bases, acids, reagents, solvents, coupling agents, etc., are mentioned, it is understood that other bases, acids, reagents, solvents, coupling agents etc., known in the art may also be used and are therefore included within the present invention. Variations in reaction conditions, for example, temperature and/or duration of the reaction, which may be used as known in the art, are also within the scope of the present invention. All the stereo isomers of the compounds in these schemes, unless otherwise specified, are also encompassed within the scope of this invention.
  • the deprotonation can be carried out under an inert atmosphere at a temperature from -70° C to room temperature and in suitable aprotic organic solvent, for example, tetrahydrofuran or the like, and then R-X can be reacted with the salts of formula 3 or 2 at an initial temperature from -80 °C to- 10 °C either using one or two equivalent of strong base like potassium diisopropylamide, lithium hexamethyl disilazide and preferably, lithium disopropylamide or the like. After a period of stirring at -15°C, the reaction was quenched then the resulted compounds of formula 4 can be isolated and purified by conventional techniques.
  • suitable aprotic organic solvent for example, tetrahydrofuran or the like
  • Compounds of formula 4 can be reduced to give hydroxyl compounds of formula 5 by a suitable reducing agent for example, lithium aluminum hydride or the like. Converting the hydroxy compounds of formula 5 to compounds of intermediate of formula 6 by the methods known in the art for example, reacting hydroxyl group with sulfonyl halides in the presence of a base such as, potassium carbonate, triethylamine, dimethylaminopyridine or the like.
  • a suitable reducing agent for example, lithium aluminum hydride or the like.
  • Converting the hydroxy compounds of formula 5 to compounds of intermediate of formula 6 by the methods known in the art for example, reacting hydroxyl group with sulfonyl halides in the presence of a base such as, potassium carbonate, triethylamine, dimethylaminopyridine or the like.
  • Compounds of formula 11 can be prepared according to the reaction sequences as shown in scheme-2.
  • Compounds of formula 7 can be prepared by following the method described in patent publication US 7,393,836 (as exemplified in the experimental section).
  • benzoyl halides either commercially available or prepared insitu from benzoic acid can be coupled with alkoxyaryl compound using a Lewis acid, typically A1C1 3 or the like to give corresponding benzophenone product.
  • Reduction of ketone function of benzophenone can be accomplished by trialkyl silane and an appropriate protic or Lewis acid, like trifluoroacetic acid or borontrifluoride etherate, followed by alkyl ether cleavage, using BBr 3 or A1C1 3 to give compounds of formula 7.
  • Alkylation of phenol compounds of formula 7 with intermediate compounds of formula 6 can be obtained in the presence of base such as K 2 C0 3 , CsC0 3 , NaOH or the like to give compounds of formula 8 in the solvents such as, dimethyl formamide, dimethyl sulfoxide or the like.
  • Compounds of formula 8 can be treated with a base like t-BuLi, n-BuLi to exchange halogen to lithium followed by addition of nascent lithiated aromatic to silyl sugar compounds of formula 9 (as described in Journal of Medicinal Chemistry, 2008, 51, 1 145-1149) in solvents such as, toluene, methane sulfonic acid or the like to give the diastereomeric mixture of lactol compounds, which were converted insitu to the desilylated O-methyl lactol compounds of formula 10 by treatment with methane sulfonicacid in methanol (J. Org. Chem. 1989, 54, 610-612).
  • the desired diastereoisomer of compounds of formula 11 can be separated by either column chromatography or peracetylation by the methods known in the art for example, acetic anhydride with catalytic amount of dimethylamino pyridine or the like and recrystallization in a suitable solvent by the methods known in the art for example, 20% methanolic ammonia or the like.
  • 5-bromo-2-chlorobenzoic acid 50 g was suspended in dichloromethane (100 ml) and dimethylformamide then it was cooled to 0 °C and to this mixture SOCl 2 (92.2 ml) was added slowly. The reaction mixture was slowly allowed to attain room temperature and stirred for about 12 hours. The solvent was removed under reduced pressure to give 5-bromo-2-chlorobenzoyl chloride as oil.
  • step 1 Ethoxybenzene (step 1, 25.8 g) was suspended in dichloromethane (50 ml) and cooled to -5 °C then A1C1 3 (42.3 g) was added slowly by portion wise and above 5- bromo-2-chlorobenzoyl chloride (53.8 g) in dichloromethane (150 ml ) was added drop wise and stirred for about 1 hour at 0 °C. After completion of the reaction (monitored by TLC), the reaction mixture was poured into ice- water. The organic layer was separated and aqueous layer was extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulphate and concentrated to give the crude compound.
  • A1C1 3 (42.3 g) was added slowly by portion wise and above 5- bromo-2-chlorobenzoyl chloride (53.8 g) in dichloromethane (150 ml ) was added drop wise and stirred for about 1 hour at 0 °
  • step 2 To a stirred solution of (5-bromo-2-chlorophenyl)(4- ethoxyphenyl)methanone (step 2, 48 g) in dichloromethane (150 ml) at 0°C, A1C1 3 (188.8 g) was added under N 2 atmosphere by portion wise over 30 minutes. Subsequently, the reaction mixture was stirred at room temperature for about 12 hours. After completion of the reaction (monitored by TLC), the reaction mixture was poured into ice- water. The organic layer was separated and aqueous layer was extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulphate and concentrated to give the crude compound.
  • step 3 To a stirred solution of (5-bromo-2-chlorophenyl)(4- hydroxyphenyl)methanone (step 3, 41 g) in dichloromethane (150 ml) and acetylnitrile (1: 1), Et 3 SiH (53 ml) was added at 0 °C under N 2 atmosphere followed by BF 3 : Et 2 0 (25 ml) and the reaction was stirred for about 16 hours at room temperature. After completion of the reaction (monitored by TLC), volatiles were concentrated under reduced pressure. Then the reaction mixture was cooled to 0 °C and neutralized by cautious addition of saturated aq. NaHC0 3 Solution. The reaction mixture was extracted with EtOAc.
  • Step 2 Synthesis of Ethyl 1 -ethylcyclopentanecarboxylate: To a solution of diisopropylamine (93.6 ml, 0.688 mol) in tetrahydrafuran (200 ml), n-BuLi (2.5M, 213.7 ml, 0.534 mol) in hexane was added at 0°C and the reaction mixture was allowed to stir at same temperature for about 10-15 minutes. The reaction mixture was stirred at room temperature for about 45 minutes.
  • Ethyl cyclohexanecarboxylate (step 1, 38 g, 0.267 mol) in tetrahydrafuran (150 ml) was added drop-wise at -78°C to LDA (reaction mixture).
  • the reaction mixture was stirred at same temperature for about 2 hours and then ethyl iodide (32.06 ml, 0.400 mol) was added drop-wise.
  • the reaction mixture was maintained at -78°C for an hour and allowed to attain room temperature.
  • Reaction mixture was stirred overnight at room temperature and quenched at 0°C with saturated NH 4 C1 solution. The solvent was concentrated over vaccum and the compound was extracted with ethyl acetate.
  • Ethyl 1-ethylcyclopentanecarboxylate (step 2, 32 g, 0.187 mol) in tetrahydrafuran (120 ml) was added to a suspension of LiAlH 4 (21.4 g, 0.563 mol) in tetrahydrafuran (200 ml) at 0°C and the reaction mixture was allowed to stir at same temperature for about 30 minutes. The reaction mixture was stirred overnight at room temperature. After completion of the reaction, the reaction mixture was quenched with ice cold water at 0°C and filtered over celite.
  • step 3 To a solution of (l-ethylcyclopentyl)methanol (step 3, 26 g, 0.202 mol) in dichloromethane (400 ml), triethyl amine (141.3 ml, 1.01 mol) was added followed by tosyl chloride (77.3 g, 0.405 mol) at 0°C. After addition of catalytic amount of DMAP (2.47 g, 0.020 mol), the reaction mixture was allowed to stir overnight at room temperature. After completion of the reaction, the reaction mixture was washed with water, saturated brine solution and the organic layer was dried over anhydrous Na 2 S0 4 and concentrated. The obtained product was purified by column chromatographic technique. Yield: 27 gm, 47 %.
  • Step 5 Synthesis of4-bromo-l-chloro-2-(4-((l-ethylcyclopentyl) methoxy)benzyl) benzene:
  • T-BuLi (1.7 M, 17.4 ml, 29.42 mmol) was added drop-wise at -78°C to a solution of intermediate 3 (6 g, 14.71 mmol) in tetrahydrafuran: toluene (90 ml) (1:2). After 20 minutes, the lithiated derivative was added drop- wise to a pre-cooled solution (at -78°C) of silyl sugar (Intermediate 2, 6.88 g, 14.71 mmol) in toluene (30 ml). The reaction mixture was maintained at the same temperature for about 2 hours and quenched with methane sulfonic acid (6 % in MeOH, 90 ml).
  • the reaction mixture was stirred at room temperature for an hour, then the reaction mixture was quenched with saturated NaHC0 3 solution and diluted with ethyl acetate. The organic layer was washed with saturated brine solution. The organic layer was dried over anhydrous Na 2 S0 4 and concentrated. The obtained diastereomeric products were separated by column chromatographic technique.
  • Step 1 Synthesis of Methyl cyclobutanecarboxylate: Concentrated H 2 S0 4 (39.2 ml, 1.0 eq) was added drop-wise to a solution of cyclobutanecarboxylic acid (40 g, 0.438 mol) in MeOH (200 ml) at 0°C and the reaction mixture was refluxed for about 36 hours. After completion of the reaction as monitored by TLC, the solvent was removed and the reaction mixture was dissolved in dichloromethane. The dichloromethane layer was washed with saturated NaHC0 3 solution and the organic layer was dried over anhydrous magnesium sulphate, dichloromethane was removed over rotary evaporator. The residue was used directly for the next step.
  • Step 3 Synthesis of (l-ethylcyclobutyl)methanol: Methyl 1-ethylcyclopentanecarboxylate (step 2, 25 g, 0.176 mol) in tetrahydrafuran (120 ml) was added to a suspension of L1AIH 4 (21.4 g, 0.563 mol) in tetrahydrafuran (200 ml) at 0°C and the reaction mixture was allowed to stir at the same temperature for about 30 minutes. The reaction mixture was stirred overnight at room temperature. After completion of the reaction, the reaction mixture was quenched with ice cold water at 0°C and filtered over celite. The residue was washed with hot ethyl acetate.
  • step 3 To a solution of (l-ethylcyclobutyl)methanol (step 3, 15 g, 0.131 mol) in dichloromethane (300 ml), triethyl amine (73.2 ml, 0.526 mol) was added followed by tosyl chloride (49.9 g, 0.26 mol) at 0°C. After addition of catalytic amount of DMAP (1.6 g, 0.0131 mol), the reaction mixture was allowed to stir overnight at room temperature. After completion of the reaction, the reaction mixture was washed with water, saturated brine solution and the organic layer was dried over anhydrous Na 2 S0 4 and concentrated then the obtained product was purified by column chromatographic technique. Yield: 27 gm, 47 %.
  • Step 5 Synthesis of 4-bromo-l-chloro-2-(4-((l-ethylcyclobutyl)methoxy)benzyl) benzene:
  • T-BuLi (1.7 M, 15.6 ml, 0.0265 mol) was added drop-wise at -78°C to a solution of Intermediate 5 (5.2 g, 0.0132mol) in tetrahydrafuran: toluene (90 ml) (1:2). After 20 minutes, the lithiated derivative was added drop- wise to a pre-cooled solution (at -78°C) of silyl sugar (Intermediate 2, 4.94 g, 0.0106 mol) in toluene (30 ml). The reaction mixture was maintained at the same temperature for about 2 hours and quenched with methane sulfonic acid (6 % in MeOH, 78 ml).
  • reaction mixture was stirred at room temperature for three hours then the reaction mixture was quenched with saturated NaHC0 3 solution and diluted with ethyl acetate. The organic layer was washed with brine solution, dried over anhydrous Na 2 S0 4 and concentrated. The obtained product was separated by column chromatographic technique.
  • Step 1 Synthesis of methyl cyclohexanecarboxylate:
  • Step 2 Synthesis of methyl 1-ethylcyclohexanecarboxylate:
  • Methyl 1-ethylcyclohexanecarboxylate (step 2, 10 g, 0.0588 mol) in tetrahydrafuran (120 ml) was added to a suspension of L1AIH 4 (6.7 g, 0.1764 mol) in tetrahydrafuran (200 ml) at 0°C and the reaction mixture was allowed to stir at the same temperature for about 30 min. The reaction mixture was stirred overnight at room temperature. After completion of the reaction, the reaction mixture was quenched with ice cold water at 0°C and filtered over celite. The residue was washed with hot ethyl acetate. The organic layer was washed with saturated brine solution, dried over anhydrous Na 2 S0 4 and concentrated.
  • step 3 To a solution of (l-ethylcyclohexyl)methanol (step 3, 8 g, 0.0563 mol) in dichloromethane (200 ml), triethyl amine (31.3 ml, 0.2253 mol) was added followed by tosyl chloride (21.4 g, 0.1126 mol) at 0°C. After addition of catalytic amount of DMAP (0.567 g, 0.0056 mol), the reaction mixture was allowed to stir for overnight at room temperature. After completion of reaction, the reaction mixture was washed with water, saturated brine solution; the organic layer was dried over anhydrous Na 2 S0 4 and concentrated. The obtained product was purified by column chromatographic technique. Yield: 8 gm.
  • T-BuLi (1.7 M, 23.8 ml, 0.0404mol) was added drop-wise to a solution of 4- bromo- 1 -chloro-2-(4-(( 1 -ethylcyclohexyl)methoxy)benzyl)benzene (Intermediate 7, 8.5 g, 0.0202 mol) in tetrahydrafuran: toluene (150 ml, 1:2) at -78°C. After 20 minutes, the lithiated derivative was added drop- wise to a pre-cooled solution (at - 78°C) of silyl sugar (Intermediate 2, 7.54 g, 0.0161mol) in toluene (70 ml).
  • reaction was maintained at the same temperature for about 2 hours then it was quenched with methane sulfonic acid (6 % in MeOH, 127.5 ml).
  • methane sulfonic acid (6 % in MeOH, 127.5 ml).
  • the reaction mixture was stirred at room temperature for an hour then the reaction mixture was quenched with saturated NaHC0 3 solution and diluted with ethyl acetate.
  • the organic layer was washed with saturated brine solution, dried over anhydrous Na 2 S0 4 and concentrated. Diastereomeric products were separated by column chromatographic technique.
  • Step 1 Synthesis of methyl cyclohexanecarboxylate:
  • Step 2 Synthesis of methyl 1 -methylcyclohexanecarboxylate:
  • Methyl 1-methylcyclohexanecarboxylate 3 (15 g, 0.0961 mol) in tetrahydrafuran (100 ml) was added to a suspension of LiAlH 4 (7.3 g, 0.1923 mol) in tetrahydrafuran (100 ml) at 0°C and the reaction mixture was allowed to stir at same temperature for about 30 minutes. The reaction mixture was stirred overnight at room temperature. After completion of reaction, the reaction mixture was quenched with ice cold water at 0°C and filtered over celite. The residue was washed with hot ethyl acetate. The organic layer was washed with saturated brine solution, dried over anhydrous Na 2 S0 4 and concentrated.
  • step 3 To a solution of (l-methylcyclohexyl)methanol (step 3, 9 g, 0.0775 mol) in dichloromethane (100 ml), triethyl amine (64.7 ml, 0.2253 mol) was added followed by tosyl chloride (36.85 g, 0.1939 mol) at 0°C. After addition of catalytic amount of DMAP (0.71 g, 0.00703 mol), the reaction mixture was allowed to stir for overnight at room temperature. After completion of the reaction, the reaction mixture was washed with water, saturated brine solution, and the organic layer was dried over anhydrous Na 2 S0 4 and concentrated. The obtained product was purified by column chromatographic technique. Yield: 15 gm.
  • Step 5 Synthesis of 4-bromo-l-chloro-2-(4-((l- methylcyclohexyl )methoxy )benzyl )benzene:
  • T-BuLi (1.7 M, 20.2 ml, 0.0344mol) was added drop-wise to a solution of 4- bromo- 1 -chloro-2-(4-(( 1 -methylcyclohexyl)methoxy)benzyl)benzene (Intermediate 9, 7 g, 0.0172mol) in tetrahydrafuran: toluene (90 ml) (1:2) at -78°C. After 20 minutes, the lithiated derivative was added drop-wise to a pre-cooled solution (at - 78°C) of silyl sugar (Intermediate 2, 6.4 g, 0.0137mol) in toluene (70 ml).
  • reaction mixture was maintained at the same temperature for about 2 hours then quenched with methane sulfonic acid (6 % in MeOH, 105 ml).
  • the reaction mixture was stirred at room temperature for an hour then quenched with saturated NaHC0 3 solution and diluted with ethyl acetate.
  • the organic layer was washed with brine solution, dried over anhydrous Na 2 S0 4 and concentrated.
  • the obtained product was separated by column chromatographic technique.
  • Step 1 Synthesis of (3-ethyloxetan-3-yl)methyl 4 -methylbenzene sulfonate:
  • Step 2 Synthesis of3-((4-(5-bromo-2-chlorobenzyl)phenoxy)methyl)-3- ethyloxetane:
  • T-BuLi (1.7 M, 23.8 ml, 0.0406mol) was added drop-wise to a solution of 3- ((4-(5-bromo-2-chlorobenzyl)phenoxy)methyl)-3-ethyloxetane (Intermediate 11, 8 g, 0.0203mol) in tetrahydrafuran: toluene (90 ml) (1:2) at -78°C. After 20 minutes, the lithiated derivative was added drop-wise to a pre-cooled solution (at -78°C) of silyl sugar (Intermediate 2, 7.6 g, 0.0162 mol) in toluene (60 ml).
  • the reaction mixture was maintained at the same temperature for about 2 hours then quenched with methane sulfonic acid (6 % in MeOH, 120 ml). The reaction mixture was stirred at room temperature for three hours then it was quenched with saturated NaHC0 3 solution and diluted with ethyl acetate. The organic layer was washed with saturated brine solution. The organic layer was dried over anhydrous Na 2 S0 4 and concentrated. The obtained product was separated by column chromatographic technique.
  • Step 1 Synthesis of(5-bromo-2-methylphenyl)(4-ethoxyphenyl)methanone:
  • step 1 To a stirred solution of (5-bromo-2-methylphenyl)(4- ethoxyphenyl)methanone (step 1, 15 g) in dichloromethane (200 ml), AICI 3 (62.5 g) was added at 0 °C under N 2 atmosphere by portion wise over 30 minutes. Subsequently, the reaction mixture was stirred at room temperature for about 12 hours. After completion of the reaction (monitored by TLC), reaction mixture was poured into ice- water. The organic layer was separated and aqueous layer was extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulphate and concentrated to give the crude compound.
  • dichloromethane 200 ml
  • step 2 To a stirred solution of (5-bromo-2-methylphenyl)(4- hydroxyphenyl)methanone (step 2, 14 g) in dichloromethane (100 ml) and acetylnitrile (1: 1), Et 3 SiH (39 ml) was added at 0 °C under N 2 atmosphere followed by BF 3 : Et 2 0 (15 ml) then reaction mixture was continued for about 16 hours at room temperature. After completion of the reaction (monitored by TLC), volatiles were concentrated under reduced pressure. Then the reaction mixture was cooled to 0 °C and neutralized by cautious addition of saturated aq. NaHC0 3 Solution. The reaction mixture was extracted with EtOAc.
  • Step 4 Synthesis of4-bromo-2-( -(methoxymethoxy)benzyl)-l-methylbenzene:
  • Step 5 Synthesis of (3R,4S,5S,6R) ⁇ 2-(3-(4-hydroxybenzyl)-4-methylphenyl)-6- ( hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3, 4, 5-triol:
  • step 4 To a stirred solution of 4-bromo-2-(4-(methoxymethoxy)benzyl)-l- methylbenzene (step 4, 11.6 g) in dry tetrahydrafuran (70 ml) and toluene (60 ml, 1: 1 ), n-BuLi (2.3 M in hexane) was added at -78 °C under N 2 atmosphere and stirred for about 30 minutes.
  • Step 6 Synthesis of (3R,4R,5S,6R)-2-(3-(4-hydroxybenzyl)-4-methylphenyl)-6- (hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol:
  • reaction mixture was cooled to 0 °C and neutralized by cautious addition of saturated aq. NaHC0 3 Solution.
  • the reaction mixture was extracted with EtOAc.
  • the combined organic layers were washed with water, brine, dried over anhydrous sodium sulphate and concentrated to afford the residue.
  • the crude product was purified by silica gel column chromatography with MeOH and dichloromethane (1:24) to give mixture compound (mixture of ⁇ & ⁇ isomers) as white solid (3 g).
  • Step 7 Synthesis of (2S,3S,4R,5R,6R)-2-(3-(4-acetoxybenzyl)-4-methylphenyl)-6- (acetoxymethyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate ( ⁇ - isomer):
  • Step 8 Synthesis of (2S,3R,4R,5S,6R)-2-(3-(4-hydroxybenzyl)-4-methylphenyl)-6- ( hydroxymethyl )tetrahydro-2H-pyran-3, 4, 5-triol:
  • Step 2 Synthesis of (l-(trifluoromethyl)cyclopropyl)methyl 4- methylbenzenesulfonate:
  • step 1 To a stirred solution of (l-(trifluoromethyl)cyclopropyl)methanol (step 1, 4.5 g) in dichloromethane (50 ml), Et 3 N (13.5 ml) was added at 0 °C under N 2 atmosphere followed by TsCl (9.1 g) and catalytic amount of DMAP. The reaction mixture was allowed to room temperature and stirred for about 12 hours. After completion of the reaction (monitored by 1H- NMR), reaction mixture was diluted with dichloromethane and organic layer was washed with saturated aq. NHUC1 solution, brine and dried over anhydrous sodium sulphate and concentrated to give the residue.
  • Step 1 Synthesis of ( 1 -(trifluoromethyl)cyclobutyl)methanol:
  • step 1 To a stirred solution of (l-(trifluoromethyl)cyclobutyl)methanol (step 1, 5.5 g) in dichloromethane (50 ml), Et 3 N (15 ml) was added at 0 °C under N 2 atmosphere followed by TsCl (10 g) and catalytic amount of DMAP. The reaction mixture was allowed to room temperature and stirred for about 12 hours. After completion of the reaction (monitored by 1H- NMR), reaction mixture was diluted with dichloromethane and organic layer was washed with saturated aq. NH 4 C1 solution, brine and dried over anhydrous sodium sulphate and concentrated to afford the residue.
  • step 2 To a stirred solution of (l-(trifluoromethyl)cyclobutyl)methanol (step 1, 5.5 g) in dichloromethane (50 ml), Et 3 N (15 ml) was added at 0 °C under N 2 atmosphere followed by TsCl (10 g) and catalytic amount of
  • Step 1 Synthesis of methyl 4,4-difluorocyclohexanecarboxylate:
  • Step 2 Synthesis of methyl 4,4-difluoro-l-methylcyclohexanecarboxylate:
  • Methyl 4,4-difluoro-l -methylcyclohexanecarboxylate (step 2, 5.7 g) in tetrahydrafuran (20 ml) was added to a suspension of LiAlH 4 (2.25 g) in tetrahydrafuran (50 ml) at 0 °C and the reaction mixture was allowed to stir at the same temperature for about 30 minutes. The reaction mixture was stirred overnight at room temperature. After completion of the reaction (monitored by TLC), the reaction mixture was quenched by cautious addition of water (3.5 ml), 15 % aq. NaOH solution (3.5 ml) and again water (11 ml) at 0 °C and stirred for about 30 minutes.
  • Step 4 Synthesis of (4,4-difluoro-l-methylcyclohexyl)methyl 4- methylbenzenesulfonate:
  • step 3 To a solution of (4,4-difluoro-l-methylcyclohexyl)methanol (step 3, 4.8 g) in dichloromethane (60 ml), triethyl amine (12.2 ml) was added followed by tosyl chloride (8.3 g) at 0 °C. After addition of catalytic amount of DMAP (2.47 g, 0.020 mol), the reaction mixture was allowed to stir overnight at room temperature. After completion of reaction, the reaction mixture was washed with water, saturated brine solution, dried over anhydrous Na 2 SC1 ⁇ 4 and concentrated. The product was purified by column chromatographic technique to afford the title compound as solid (5 g).
  • step 1 4-bromo-l-chloro-2-(4-((l- (trifluoromethyl)cyclobutyl)methoxy)benzyl)benzene (step 1, 6.2 g) in dry tetrahydrafuran (40 ml) and toulene (60 ml, 1:1 ), n-BuLi (2.3 M, 16.8 ml) was added at -78 °C under N 2 atmosphere and stirred for about 30 minutes at -78°C. To this solution (3R,4S,5R,6R)-3,4,5-tris(trimethylsilyloxy)-6-
  • Methyl 1-methylcyclopentanecarboxylate (step 1, 26 g) in tetrahydrafuran (200 ml) was added to a suspension of LiAlH 4 (14 g) in tetrahydrafuran (150 ml) at 0 °C and the reaction mixture was allowed to stir at same temperature for about 30 minutes. The reaction mixture was stirred overnight at room temperature. After completion of the reaction (monitored by 1 H-NMR), reaction mixture was quenched by cautious addition of water (14 ml), 15 % aq. NaOH solution (14 ml) and again water (42 ml) at 0 °C and stirred for about 1 hour.
  • step 2 To a solution of (l-methylcyclopentyl)methanol (step 2, 20 g) in dichloromethane (250 ml), triethyl amine (74 ml) was added followed by tosyl chloride (66.6 g) at 0°C. After addition of catalytic amount of DMAP (Cat), the reaction mixture was allowed to stir overnight at room temperature. After completion of the reaction, the reaction mixture was washed with water and brine solution, dried over anhydrous Na 2 S0 and concentrated then purified by column chromatographic technique to afford the title compound as liquid (14 g).
  • DMAP catalytic amount
  • Step 2 Synthesis of (3R,4S,5S,6R)-2-(4-chloro-3-(4-((l- methylcyclopentyl )methoxy )benzyl )phenyl )-6-( hydroxymethyl )-2-methoxytetrahydro- 2H-pyran-3, 4, 5-triol:
  • Step 3 Synthesis of (3R,4R,5S,6R)-2-(4-chloro-3-(4-((l- methylcyclopentyl )methoxy )benzyl )phenyl )-6-(hydroxymethyl )tetrahydro-2H-pyran- 3,4,5-triol:
  • step 2 3R,4S,5S,6R)-2-(4-chloro-3-(4-((l- methylcyclopentyl)methoxy)benzyl)phenyl)-6-(hydroxymethyl)-2- methoxytetrahydro-2H-pyran-3,4,5-triol (step 2, 3 g) in dichloromethane (30 ml) and acetylnitrile (30 ml, 1: 1), Et 3 SiH (1.9 ml) was added at 0° C under N 2 atmosphere followed by BF 3 : Et 2 0 (1.1 ml) and stirred for about 6 hours. After completion of the reaction (monitored by TLC), volatiles were concentrated under reduced pressure.
  • reaction mixture was cooled to 0° C and neutralized by cautious addition of saturated aq. NaHC0 3 Solution.
  • the reaction mixture was extracted with EtOAc.
  • the combined organic layers were washed with water and brine, dried over anhydrous sodium sulphate and concentrated to get the residue.
  • the crude product was purified via silica gel column chromatography with MeOH and dichloromethane (1:24) to give mixture compound (mixture of ⁇ & ⁇ isomers) as white solid (1.8 g).
  • step 1 4-bromo-l-chloro-2-(4-((l- (trifluoromethyl)cyclopropyl)methoxy)benzyl)benzene (step 1, 3.8 g) in dry tetrahydrafuran (40 ml) and toulene (40 ml, 1: 1), n-BuLi (2.3 M in hexane, 10.7 ml) was added at -78 °C under N 2 atmosphere and stirred for about 30 minutes at -78°C.
  • step 2 To a stirred solution of (3R,4S,5S,6R)-2-(4-chloro-3-(4-((l- (trifluoromethyl)cyclopropyl)methoxy)benzyl)phenyl)-6-(hydroxymethyl)-2- methoxytetrahydro-2H-pyran-3,4,5-triol (step 2, 2.5 g) in dichloromethane (20 ml) and acetylnitrile (20 ml, 1: 1), Et 3 SiH (1.5 ml) was added at 0 °C under N 2 atmosphere followed by BF 3 : Et 2 0 (0.8 ml) and stirred for about 6 hours at room temperature.
  • Step 1 Synthesis of 4-bromo-l-chloro-2-(4-((4,4-difluoro-l- methylcyclohexyl )methoxy )benzyl )benzene:
  • Step 2 Synthesis of (3R,4S,5S,6R)-2-(4-chloro-3-(4-((4,4-difluoro-l- methylcyclohexyl )methoxy )benzyl )phenyl)-6-(hydroxymethyl )-2-methoxytetrahydro- 2H-pyran-3, 4, 5-triol:
  • step 1 4-bromo-l-chloro-2-(4-((4,4-difluoro-l- methylcyclohexyl)methoxy)benzyl)benzene (step 1)) in dry tetrahydrafuran (40 ml) and toulene (40 ml, 1 : 1 ), n-BuLi (2.3 M in hexane) was added at -78 °C under N 2 atmosphere stirred for about 30 minutes.
  • Step 3 Synthesis of (3R,4R,5S,6R)-2-(4-chloro-3-(4-((4,4-difluoro-l- methylcyclohexyl )methoxy )benzyl )phenyl )-6-(hydroxymethyl )tetrahydro-2H-pyran- 3,4,5-triol:
  • step 2 1.2 g) in dichloromethane (15 ml) and acetylnitrile (15 ml, 1:1), Et 3 SiH (0.7 ml) was added at 0° C under N 2 atmosphere followed by BF 3 : Et 2 0 (0.4 ml) and reaction was stirred for about 6 hours.
  • step 1 To a stirred solution of Mg (9.5 g) in dry tetrahydrafuran (50 ml), 1-bromo- 4-ethoxybenzene (step 1, 53.4 g) in tetrahydrafuran (150 ml) was added under N 2 atmosphere at room temperature slowly by drop wise and stirred for about 1 hour. Then 5-bromo-2-fluorobenzaldehyde (11 ml) was added slowly to the above reaction mixture and the reaction mixture was allowed to stir for over night. After completion of the reaction (monitored by TLC), the reaction mixture was poured into saturated NH 4 C1 solution at 0 °C and extracted with ethyl acetate.
  • step 2 To a stirred solution of (5-bromo-2-fluorophenyl)(4-ethoxyphenyl)methanol (step 2, 24 g) in dichloromethane (150 ml) and acetylnitrile (150 ml, 1: 1), Et 3 SiH (24 ml) was added at 0 °C under N 2 atmosphere followed by BF 3 : Et 2 0 (14 ml) and the reaction mixture was stirred for about 12 hours at room temperature. After completion of the reaction (monitored by TLC), volatiles were concentrated under reduced pressure. Then the reaction mixture was cooled to 0 °C and neutralized by cautious addition of saturated aq. NaHC0 3 Solution. The reaction mixture was extracted with EtOAc.
  • step 3 To a stirred solution of 4-bromo-2-(4-ethoxybenzyl)-l-fluorobenzene (step 3, 15 g) in dichloromethane (80 ml), BBr 3 (53.3 ml, 1M solution in dichloromethane (50 ml)) was added slowly under N 2 atmosphere at 0 °C and stirred for. over night at room temperature. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to 0 °C and neutralized by cautious addition of saturated aq. NaHC0 3 solution. The reaction mixture was extracted with dichloromethane .
  • Step 2 Synthesis of (3R,4S,5S,6R)-2-(4-fluoro-.
  • step 1 4-bromo-l-fluoro-2-(4-((l- (trifluoromethyl)cyclobutyl)methoxy)benzyl)benzene (step 1, 5.7 g) in dry tetrahydrafuran (50 ml) and toulene (50 ml, 1: 1), t-BuLi (16 ml, 1.7 M in toluene (30 ml)) was added at -78 °C under N 2 atmosphere and stirred for about 30 minutes at - 78 °C.
  • step 2 3R,4S,5S,6R)-2-(4-fluoro-3-(4-((l- (trifluoromethyl)cyclobutyl)methoxy)benzyl)phenyl)-6-(hydroxymethyl)-2- methoxytetrahydro-2H-pyran-3,4,5-triol (step 2, 3g) in dichloromethane (20 ml) and acetylnitrile (20 ml, 1:1) Et 3 SiH (1.8 ml) was added at 0 °C under N 2 atmosphere followed by BF 3 : Et 2 0 (1 ml) and stirred for about 6 hours at room temperature. After completion of the reaction (monitored by TLC), volatiles were concentrated under reduced pressure.
  • reaction mixture was cooled to 0 °C and neutralized by cautious addition of saturated aq. NaHC0 3 solution.
  • the reaction mixture was extracted with EtOAc.
  • the combined organic layers were washed with water and brine, dried over anhydrous sodium sulphate and concentrated to get the residue.
  • the crude product was purified via silica gel column chromatography with MeOH and dichloromethane (1:24) to give mixture compound (mixture of ⁇ & ⁇ isomers) as white solid (2.3 g).
  • step 1 To a stirred solution of 4-bromo-l-fluoro-2-(4-((l- (trifluoromethyl)cyclopropyl)methoxy)benzyl)benzene (step 1, 5.3 g) in dry tetrahydrafuran (40 ml) and toulene (40 ml, 1: 1), t-BuLi (2.3 M in hexane, 15.5 ml) was added at -78 °C under N 2 atmosphere and stirred for about 30 minutes.
  • step 2 To a stirred solution of (3R,4S,5S,6R)-2-(4-fluoro-3-(4-((l- (trifluoromethyl)cyclopropyl)methoxy)benzyl)phenyl)-6-(hydroxymethyl)-2- methoxytetrahydro-2H-pyran-3,4,5-triol (step 2, 2.8 g) in dichloromethane (20 ml) and acetylnitrile (20 ml, 1: 1), Et 3 SiH (1.7 ml) was added at 0 °C under N 2 atmosphere followed by BF 3 : Et 2 0 (1 ml) and stirred for about 4 hours at room temperature.
  • Step 1 Synthesis of 4-bromo-2-(4-((4,4-difluoro-l- methylcyclohexyl)methoxy)benzyl)-l-fluorobenzene:
  • Step 2 Synthesis of (3R,4S,5S,6R)-2-(3-(4-((4,4-difluoro-l- methylcyclohexyl )methoxy )benzyl)-4-fluorophenyl)-6- ( hydroxymethyl )-2- methoxytetrahydro-2H-pyran-3,4,5-triol:
  • step 1 4-bromo-2-(4-((4,4-difluoro-l- methylcyclohexyl)methoxy)benzyl)-l-fluorobenzene (step 1, 2.6 g) in dry tetrahydrafuran (30 ml) and toluene (30 ml, 1: 1 ), t-BuLi (6 ml, 1.7 M in toluene) was added under N 2 atmosphere at -78 °C and stirred for about 30 minutes.
  • Step 3 Synthesis of (3R,4R,5S,6R)-2-(3-(4-((4,4-difluoro-l- methylcyclohexyl)methoxy )benzyl)-4-fluorophenyl )-6-(hydroxymethyl )tetrahydro- 2H-pyran-3, 4, 5-triol:
  • step 2 1.6 g) in dichloromethane (15 ml) and acetylnitrile (15 ml, 1 : 1), Et 3 SiH (0.9 ml) was added at 0°C under N 2 atmosphere followed by BF 3 : Et 2 0 (0.5 ml) and reaction was stirred for about 6 hours.
  • Step 1 Synthesis of methyl cyclopentanecarboxylate:
  • Step 2 Synthesis of methyl l-(ethoxymethyl)cyclopentanecarboxylate:
  • Methyl l-(ethoxymethyl)cyclopentanecarboxylate (step 2, 10 g, 0.0588 mol) in tetrahydrafuran (120 ml) was added to a suspension of L1AIH 4 (6.7 g, 0.1764 mol) in tetrahydrafuran (200 ml) at 0°C and the reaction mixture was allowed to stir at same temperature for about 30 minutes. The reaction mixture was stirred overnight at room temperature. After completion of reaction, the reaction mixture was quenched with ice cold water at 0°C and filtered over celite. The residue was washed with hot ethyl acetate. The organic layer was washed with saturated brine solution, dried over anhydrous Na 2 S0 4 and concentrated.
  • Step 4 Synthesis of 1 -(ethoxymethyl)cyclopentyl)methyl 4-methylbenzenesulfonate:
  • step 3 To a solution of (l-(ethoxymethyl)cyclopentyl)methanol (step 3, 8 g, 0.0563 mol) in dichloromethane (200 ml), triethyl amine (31.3 ml, 0.2253 mol) was added followed by tosyl chloride (21.4 g, 0.1126 mol) at 0°C. After addition of catalytic amount of DMAP (0.567 g, 0.0056 mol), the reaction mixture was allowed to stir for overnight at room temperature. After completion of reaction, the reaction mixture was washed with water and brine solution, dried over anhydrous Na 2 S0 4 and concentrated. The obtained product was purified by column chromatographic technique. Yield: 8 gm.
  • Step 1 Synthesis of (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-((l- ethylcyclopentyl )methoxy )benzyl )phenyl )-6-(hydroxymethyl )tetrahydro-2H-pyran- 3,4,5-triol ( ⁇ -isomer):
  • Triethylsilane (1.36 ml, 8.46 mmol) was added to a solution of (2S,3R,4R,5S,6R)-2-(4-cMoro-3-(4-((l-ethylcyclopentyl)methoxy)benzyl)phenyl)- 6-(hydroxymethyl)-tetrahydro-2H-pyran-3,4,5-triol (Intermediate 4-P-isomer, 2.2 g, 4.23 mmol) in dichloromethane:MeCN (40:40 ml) at -10°C. The reaction mixture was allowed to stir at same temperature for 10 minutes then BF 3 .OEt 2 (0.79 ml, 6.34 mmol) was added.
  • reaction mixture was stirred for about 30 minutes at -10°C and an hour at room temperature. After completion of reaction as monitored by TLC, the reaction mixture was quenched with 10% NaHC0 3 solution. The reaction mixture was washed with water, saturated brine solution and the organic layer was dried over anhydrous Na 2 S0 4 and concentrated. The obtained product was purified by column chromatographic technique.
  • Step 2 Synthesis of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4-((l- ethylcyclopentyl )methoxy )benzyl )phenyl )tetrahydro-2H-pyran-3,4, 5-triyl triacetate:
  • step 1 (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4-((l- ethylcyclo-pentyl)methoxy)benzyl)phenyl)-tetrahydro-2H-pyran-3,4,5-triyl triacetate (step 1, 1.3 g) in dichloromethane (50 ml) at 0°C was added pyridine (2.1 ml), acetic anhydride (2.5 ml) and catalytic amount of DMAP. The reaction mixture was stirred at room temperature for about an hour.
  • reaction mixture was diluted with dichloromethane, washed with water, 1% HC1 solution followed by saturated brine solution. The organic layer was dried over anhydrous Na 2 S0 4 and concentrated. Product was purified by flash column chromatographic technique to remove unreacted Ac 2 0. Recrystallisation of the obtained mixture in ethanol crystallized the desired isomer as white solid.
  • Step 3 Synthesis of (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-((l- ethylcyclopentyl )methoxy )benzyl )phenyl )-6-(hydroxymethyl )tetrahydro-2H-pyran- 3,4,5-triol:
  • Step 1 Synthesis of (2R,3R,4R,5S,6R)-2-(4-chloro-3-(4-((l- ethylcyclopentyl)methoxy )benzyl )phenyl )-6-(hydroxymethyl )tetrahydro-2H-pyran- 3,4,5-triol ( ⁇ -isomer):
  • Step 2 Synthesis of (2R,3R,4R,5S,6R)-2-(acetoxymethyl)-6-(4-chloro-3-(4-((l- ethylcyclopentyl)methoxy jbenzyl )phenyl )tetrahydro-2H-pyran-3, 4, 5-triyl triacetate:
  • Step 3 Synthesis of (2R,3R,4R5S,6R)-2-(4-chloro-3-(4-((l- ethylcyclopentyl)methoxy )benzyl )phenyl)-6-(hydroxymethyl )tetrahydro-2H-pyran- 3,4,5-triol:
  • Step 1 Synthesis of (2S,3R,4R5S,6R)-2-(4-chloro-3-(4-((l- ethylcyclobutyl )methoxy )benzyl )phenyl)-6-(hydroxymethyl )-tetrahydro-2H-pyran- 3,4,5-triol:
  • Triethylsilane (3.9ml, 0.0242mol) was added to a solution of (2S,3R,4S,5S,6R)-2-(4-cMoro-3-(4-((l-ethylcyclobutyl)methoxy)benzyl)phenyl)-6- (hydroxymethyl)-2-methoxy-tetrahydro-2H-pyran-3,4,5-triol (Intermediate 6, 3.5 g, 0.00691 mol) in dichloromethane: MeCN (40:40 ml) at -10°C. The reaction mixture was allowed to stir at same temperature for 10 minutes then BF 3 .OEt 2 (3.9 ml, 0.0172 mol) was added.
  • reaction mixture was stirred at -10°C for about 30 minutes and at room temperature for an hour. After completion of reaction as monitored by TLC, the reaction mixture was quenched with saturated NaHC0 3 solution. The reaction mixture was washed with saturated brine solution; the organic layer was dried over anhydrous Na 2 S0 4 and concentrated. The obtained product was purified by column chromatographic technique.
  • Step 2 Synthesis of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4-((l- ethylcyclobutyl)methoxy)benzyl)phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate:
  • step 1 To a solution of (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-((l- ethylcyclobutyl)methoxy)benzyl)phenyl)-6-(hydroxymethyl)-tetrahydro-2H-pyran- 3,4,5-triol (step 1, 3 g) in dichloromethane (50 ml) at 0°C was added pyridine (5.08 ml), acetic anhydride (5.95 ml) and 76 mg of DMAP. The reaction mixture was stirred at room temperature for about an hour.
  • reaction mixture was diluted with dichloromethane, washed with water, 1% HC1 solution, water followed by saturated brine solution. The organic layer was dried over anhydrous Na 2 S0 4 and concentrated. Product was purified by flash column chromatographic technique to remove unreacted Ac 2 0. Recrystallisation of the obtained mixture in ethanol gives the desired isomer as white solid.
  • Step 3 Synthesis of (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-((l- ethylcyclobutyl jmethoxy )benzyl )phenyl )-6-( hydroxymethyl )tetrahydro-2H-pyran- 3,4,5-triol:
  • Step 1 Synthesis of (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-((l- ethylcyclohexyl jmethoxy )benzyl )phenyl )-6-(hydroxymethyl )tetr hydro-2H-pyran- 3,4,5-triol:
  • Triethylsilane (1.5 ml, 0.00963 mol) was added to a solution of (2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-((l-ethylcyclohexyl)methoxy)benzyl)phenyl)-6- (hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (Intermediate 8, 2.5 g, 0.0046 mol) in dichloromethane:MeCN (40:40 ml) at -10°C and the reaction mixture was allowed to stir for 10 minutes at same temperature then BF 3 .OEt 2 (0.882 ml, 0.00702 mol) was added.
  • reaction mixture was stirred for about 30 minutes at - 10°C and for an hour at room temperature. After completion of reaction as monitored by TLC, the reaction mixture was quenched with 10% NaHC0 3 solution. The reaction mixture was washed with saturated brine solution and the organic layer was dried over anhydrous Na 2 S0 4 and concentrated. The obtained product was purified by column chromatographic technique.
  • Step 2 Synthesis of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4-((l- ethylcyclohexyl)methoxy)benzyl)phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate:
  • step 1 To a solution of (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-((l- ethylcyclohexyl)methoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran- 3,4,5-triol (step 1, 1.8 g) in dichloromethane (20 ml) at 0°C was added pyridine (2.87 ml), acetic anhydride (3.37 ml) and catalytic amount of DMAP. The reaction mixture was stirred at room temperature for about an hour.
  • reaction mixture was diluted with dichloromethane, washed with water, 1% HCl solution followed by saturated brine solution. The organic layer was dried over anhydrous Na 2 S0 4 and concentrated. The obtained product was purified by flash column chromatographic technique to remove unreacted Ac 2 0. Recrystallisation of the obtained mixture in ethanol gives the desired isomer as white solid.
  • Step 3 Synthesis of (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-((l- ethylcyclohexyl )methoxy )benzyl )phenyl)-6-(hydroxymethyl )tetrahydro-2H-pyran- 3,4,5-triol:
  • Step 1 Synthesis of (2S,3R,4R,5S,6R)-2-(4-chbro-3-(4-((l- methylcyclohexyl )methoxy )benzyl)phenyl )-6-(hydroxymethyl )tetrahydro-2H-pyran- 3,4,5-triol:
  • Triethylsilane (0.76 ml, 0.0048 mol) was added at -10°C to a solution of (2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-((l-methylcyclohexyl)methoxy)benzyl)phenyl)- 6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (Intermediate 10, 1 g, 0.0019 mol) in dichloromethane:MeCN (10: 10 ml). The reaction mixture was allowed to stir at same temperature for 10 min and then BF 3 .OEt 2 (0.365 ml, 0.0028 mol) was added.
  • reaction mixture was stirred for about 30 minutes at -10°C and at room temperature for an hour. After completion of reaction as monitored by TLC, reaction mixture was quenched with 10% NaHC0 3 solution. The reaction mixture was washed with saturated brine solution; the organic layer was dried over anhydrous Na 2 S0 4 and concentrated. The obtained product was purified by column chromatographic technique.
  • Step 2 Synthesis of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4-((l- methylcyclohexyl )methoxy )benzyl )phenyl )tetrahydro-2H-pyran-3, 4, 5-triyl triacetate:
  • step 1 (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-((l- methylcyclohexyl)methoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran- 3,4,5-triol (step 1, 0.6 g) in dichloromethane (10 ml), pyridine (0.98 ml), acetic anhydride (1.15 ml) and a catalytic amount of DMAP were added at 0°C. The reaction mixture was stirred at room temperature for about an hour.
  • reaction mixture was diluted with dichloromethane, washed with water, 1% HCl solution followed by saturated brine solution. The organic layer was dried over anhydrous Na 2 S0 4 and concentrated. Product was purified by flash column chromatographic technique to remove unreacted Ac 2 0. Recrystallisation of the obtained mixture in ethanol gives the desired isomer as white solid.
  • Step 3 Synthesis of (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-((l- methylcyclohexyl )methoxy )benzyl )phenyl)-6-(hydroxymethyl )tetrahydro-2H-pyran- 3,4,5-triol: A solution of 20% methanolic ammonia (15 ml) was added to (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4-((l- methylcyclohexyl)methoxy)benzyl)phenyl) tetrahydro-2H-pyran-3,4,5-triyl triacetate (step 2, 0.35g, 0.0005mol) at 0°C and the reaction mixture was stirred for overnight at room temperature.
  • Step 1 Synthesis of (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-((3-ethyloxetan-3- yl)methoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H ⁇
  • Triethylsilane (0.32ml, 0.00196mol) was added to a solution of (2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-((3-ethyloxetan-3-yl)methoxy)benzyl)phenyl)-6- (hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (Intermediate 12, 0.5 g, 0.0098 mol) in dichloromethane:MeCN (10: 10 ml) at -10°C. The reaction mixture was allowed to stir at same temperature for 10 minutes then BF 3 :OEt 2 (0.19 ml, 0.00147 mol) was added.
  • Step 2 Synthesis of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4-((3- ethyloxetan-3-yl)methoxy)benzyl)phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate:
  • Step 3 Synthesis of (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-((3-ethyloxetan-3- yl jmethoxy jbenzyl )phenyl )-6-(hydroxymethyl )tetrahydro-2H-pyran-3, 4, 5-triol: A solution of 20% methanolic ammonia (10 ml) was added to (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4-((3-ethyloxetan-3- yl)methoxy)benzyl)phenyl) tetrahydro-2H-pyran-3,4,5-triyl triacetate (step 2, 0.4 g, 0.000619 mol) at 0°C and the reaction mixture was stirred overnight at room temperature.
  • reaction mixture was cooled to room temperature and partitioned between water and EtOAc. Two layers were separated and aqueous layer was again extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulphate and concentrated to give the residue.
  • the crude product was purified via silica gel column chromatography with MeOH and dichloromethane (1: 25) to afford the title compound as white solid (198 mg).
  • Example 8 Preparation of ( , 2R,3S.4R.5R,6S)-2-( , hvdroxymethyl)-6-(4-methyl-3-(4- ((1 -(trifluoromethyl)cyclobutyl)methoxy)benzyl)phenyl)tetrahydro-2H-pyr an-3 ,4,5- triol:
  • Step 1 Synthesis of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4-((l- ( trifluoromethyl jcyclobutyl jmethoxy )benzyl )phenyl )tetrahydro-2H-pyran-3, 4, 5-triyl triacetate ( ⁇ isomer):
  • Step 2 Synthesis of (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-((l- ( trifluoromethyl )cyclobutyl )methoxy )benzyl )phenyl)-6- ( hydroxymethyl )tetrahydro- 2H-pyran-3,4,5-triol: NH 3 in MeOH (70 ml) was added to (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6- (4-chloro-3-(4-((l-(trifluoromethyl)cyclobutyl)methoxy)benzyl)phenyl)tetrahydro- 2H-pyran-3,4,5-triyl triacetate ( ⁇ isomer, step 1, 0.8 g) at room temperature and stirred for over night.
  • Step 1 Synthesis of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4-((l- methylcyclopentyljmethoxy )benzyl jphenyl )tetrahydro-2H-pyran-3, 4, 5-triyl triacetate ( ⁇ - isomer):
  • Step 2 Synthesis of (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-((l- methylcyclopentyl)methoxy jbenzyl )phenyl )-6-(hydroxymethyl )tetrahydro-2H-pyran- 3,4,5-triol:
  • Step 1 Synthesis of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4-((l- ( trifluoromethyl )cyclopropyl )methoxy )benzyl )phenyl )tetrahydro-2H-pyran-3, 4, 5- triyl triacetate ( ⁇ - isomer):
  • Step 2 Synthesis of (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-((l- (trifluoromethyl)cyclopropyl)methoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro- 2H-pyran-3, 4, 5-triol: NH 3 in MeOH (60 ml) was added to(2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6- (4-chloro-3-(4-((l-(trifluoromethyl)cyclopropyl)methoxy)benzyl)phenyl)tetrahydro- 2H-pyran-3,4,5-triyl triacetate ( ⁇ - isomer, step 1, 1.5 g) at room temperature and stirred over night.
  • Step 1 Synthesis of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4-((4,4- difluoro-l-methylcyclohexyl)methoxy)benzyl)phenyl)tetraty
  • reaction mixture was extracted with dichloromethane. The combined organic layers were washed with 3N HC1 solution and brine, dried over anhydrous sodium sulphate and concentrated to give the crude compound.
  • the crude product was purified via silica gel column chromatography with EtOAc and Hexane (2: 4) to afford the title compound ( ⁇ - isomer) as white solid (690 mg).
  • Step 2 Synthesis of (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-((4,4-difluoro-l- methylcyclohexyl )methoxy )benzyl )phenyl)-6-(hydroxymethyl )tetrahydro-2H-pyran- 3,4,5-triol:
  • Step 1 Synthesis of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-fluoro-3-(4-((l- ( trifluoromethyl )cyclobutyl )methoxy )benzyl )phenyl )tetrahydro-2H-pyran-3, 4, 5-triyl triacetate ( ⁇ - isomer):
  • Step 1 Synthesis of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-fluoro-3-(4-((l- ( trifluoromethyl jcyclopropyl )methoxy )benzyl jphenyl )tetrahydro-2H-pyran-3, 4, 5- triyl triacetate ( ⁇ - isomer):
  • Step 2 Synthesis of (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-((l- ( trifluoromethyl jcyclopropyl )methoxy jbenzyl )phenyl)-6- ( hydroxymethyl )tetrahydro- 2H-pyran-3,4,5-triol:
  • Step 1 Synthesis of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(3-(4-((4,4-difluoro-l- methylcyclohexyl )methoxy )benzyl)-4-fluorophenyl )tetrahydro-2H-pyran-3, 4, 5-triyl triacetate ( ⁇ - isomer):
  • Step 2 Synthesis of (2S,3R4R5S,6R)-2-(3-(4-((4,4-difluoro-l- methylcyclohexyl )methoxy )benzyl)-4-fluorophenyl )-6-(hydroxymethyl )tetrahydro- 2H-pyran-3,4,5-triol: NH 3 in MeOH (4 ml) was added to (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6- (3-(4-((4,4-difluoro-l-methylcyclohexyl)methoxy)benzyl)-4- fluorophenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate ( ⁇ - isomer, step 1, 0.79 g) at room temperature and stirred for over night.
  • Step 2 Synthesis of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4-((l- ( ethoxymethyl )cyclopentyl)methoxy )benzyl )phenyl )tetrahydro-2H-pyran-3, 4, 5-triyl triacetate:
  • step 1 To a solution of (3R,4R,5S,6R)-2-(4-chloro-3-(4-((l- (ethoxymethyl)cyclopentyl)methoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro- 2H-pyran-3,4,5-triol (step 1, 1.0 g) in dichloromethane (30 ml), pyridine (0.67 ml), acetic anhydride (0.79 ml) and 0.0 lg of DMAP were added at 0°C. The reaction mixture was stirred at room temperature for about an hour.
  • reaction mixture was diluted with dichloromethane, washed with water, 1% HC1 solution, water followed by saturated brine solution. The organic layer was dried over anhydrous Na 2 S0 4 and concentrated. Obtained product was purified by flash column chromatographic technique to remove unreacted Ac 2 0. Recrystallisation of the obtained mixture in ethanol gives the desired isomer as white solid (900 mg).
  • Step 3 Synthesis of (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-((l- ( ethoxymethyl )cyclopentyl )methoxy )benzyl )phenyl)-6-(hydroxymethyl )tetrahydro- 2H-pyran-3, 4, 5-triol:
  • the compounds described herein can be tested for their activity for SGLT2 inhibition following procedures known to a person of ordinary skill in the art. For example, the following protocols may be employed for testing the compounds. These protocols are illustrative and do not limit to the scope of the invention.
  • Stable cells CHO expressing h SGLT gene were seeded in 24 well plates.
  • Cells were washed with KRH Na buffer, followed by addition of test compound in KRH Na to the micro plate in defined format.
  • the final concentration of vehicle (DMSO) is not more than 1%.
  • Incubation was carried out for 10-15 minutes at 37° C in an incubator.
  • the radiolabel glucose analogue 14 C AMG was added to each well at 0.5 ⁇ Ci concentration. After lhr incubation plates were washed with ice cold KRH Na buffer containing 0.5 Mm phlorizin. Cells were solubilized with 0.2 N NaOH before transferring them to pico plate for radiolabel count.
  • Example 19 Effect of compounds on urinary glucose excretion in normal animal:
  • Example 20 Effect of compounds on STZ induced diabetic rats:
  • test item was administered at the specified dose mentioned above for 14 consecutive days.
  • the control group received vehicle during treatment period.
  • GTT was conducted in overnight fasted rats.
  • Glucose load of 2 g/kg was administered followed by compound dosing. Blood samples were drawn at time intervals for plasma glucose estimation. Effect of the test compound was assessed by comparing the AUC's plasma glucose of control with treated group.

Abstract

The invention relates to the cycloalkyl methoxybenzyl phenyl pyran derivatives as Sodium dependent glucose co transporter (SGLT) inhibitors, particularly SGLT2 and method of treating diseases, conditions and/or disorders inhibited by SGLT2 with them, and processes for preparing them.

Description

CYCLOALKYL METHOXYBENZYL PHENYL PYRAN
DERIVATIVES AS SODIUM DEPENDENT GLUCOSE CO TRANSPORTER (SGLT2) INHIBITORS
This application claims the benefit of Indian Provisional Patent Application No. 2434/CHE/2010 filed on 23rd August 2010, which is incorporated herein by reference.
Field of the Invention
The present invention relates to cycloalkyl methoxybenzyl phenyl pyran derivatives, which are SGLT2 inhibitors and are useful as therapeutic agents to treat metabolic disorders more particularly diabetes by stimulating excretion of glucose in the urine.
Background of the Invention
Diabetes is growing public health problem in developed and developing nations alike. In 2007, the number of people world wide with diabetes was estimated to be 246 million, and this number is estimated to reach 380 million by 2025. Type 2 diabetes is characterized by impaired insulin secretion in response to glucose, increased hepatic glucose production and decreased insulin dependent glucose uptake in the peripheral tissues or insulin resistance. The burden of diabetes is driven by vascular complications such as cardiovascular disease, stroke, nephropathy, retinopathy, renal failure, and amputations of the extremities. Although these complications result from multiple metabolic derangements, hyper glycemia is central to both the vascular consequences of diabetes and progressive nature of the disease itself. Chronically elevated blood glucose levels have been shown to result in higher protein glycation, reduced insulin secretion, beta cell apoptosis, increased oxidative stress, and heightened insulin resistance (Endocrinology 2002, 143, 339- 342). These effects can be reduced by tight glycemic control. Hyperglycemia can be controlled in Individuals by healthy life style changes that increase activity and reduce weight and or by using current non insulin therapies. These therapies target the liver to reduce glucose output, small intestine to decrease glucose absorption, adipose deposits, or muscle to elevate glucose cellular uptake or to promote glucose metabolism, serum proteases to prolong incretion action, and the pancreas to enhance insulin release. Despite the wide range of anti-hyperglycemic agents, achieving glycemic control is difficult for many patients. Since all of these oral therapies ultimately depend on insulin to regulate blood glucose levels. Patients with type 2 diabetes will eventually require insulin therapy because of an inevitable decline in beta cell function.
The obvious need for new approaches to treat patients with uncontrolled type 2 diabetes has prompted continued exploration of alternative targets in organs involved in maintenance of glucose homeostasis. In the context of type2 diabetes, renal glucose reabsorption contributes to elevated plasma glucose and the attendant micro vascular complications. Evaluation of molecular targets available in the kidney stimulated interest in the development of a new class of anti hyperglycemic agents that promote urinary glucose excretion. Inhibitors of the sodium glucose co transporter (SGLT2) prevent renal glucose reabsorption from the glomerular filtrate and provide an insulin independent means of controlling hyper glcemia ((7. Clin. Invest. Vol. 79, pp. 1510-1515 (1987), (7. Clin. Invest. Vol. 93, pp. 397-404 (1994)).
A good number of patent applications describing O-benzyl phenolic O- glucosides as SGLT2 inhibitors (WO 01/74834; WO 02/28872; WO 01/16147; and US 6414126) were published during 2000-2003. Subsequent applications from other groups reported the successful utilization of heteroaryl aglycone components or modification of the glucose moiety. Hydrolytically more stable C-glycosides were disclosed in US 641426; WO 2001/027128; WO 2002/083066; WO 2008/002824; WO 2003/099836; WO 2004/063209 and WO 2006/034489.
Patent applications were published describing C-glucosides for which one of the aryl rings in aglycone part had been replaced with heterocycles, primarily benzothiophene (US 7202350; WO 2004/080990, US 2007/0197450, and WO 2005/085237), azulene moiety (WO 2004/013118), N-benzylated indoles (WO 2006/054629), and thiophene (WO 2008/013321). Thiaglucosides (WO 2006/073197), compounds arising from modifications of the glucose moiety, replacing the glucosyl hydroxyl methyl moiety with OH, loweralkoxy, SMe and S02Me or replacement of the pyranosil oxygen with acylated nitrogen (US 2008/0221164) were published.
It is thus believed that SGLT2 inhibitors may be relevant with respect to diabetes, diabetic complications or obesity. PCT Publications Nos. WO 01//016147, WO 01/074835, WO 02/068439, WO 02/083066, WO 03/020737, WO 03/080635, WO 04/063209, WO 04/089967, WO 06//034489, WO 08/072726, WO 08/116195, WO 08/122014, WO 08/101939 and WO 08/144346; US patent application/patent Nos. US 7,476,671, US 7,439,232, US 2006/0194809 and US 2008/0132563; EP patent application/patent Nos. EP 1506211B1, EP 1224195B1, EP 1268502B1, EP 1268503A1, EP 1581543A4 and EP 1685147A4 disclose SGLT2 inhibitors, for treatment diseases mediated by SGLT2 inhibitors.
WO 09/026537 describes benzyl-benzene derivatives and methods of use; US 2005/209166 describes glucopyranosyl substituted phenyl derivatives, medicaments containing such compounds, their use and process for their manufacture; WO 2008/055940 describes combination therapy with SGLT2 inhibitors and their pharmaceutical compositions; WO 2007/00445 describes glucopyranosyl substituted benzyl-benzene derivatives, medicaments containing such compounds, their use and process for their manufacture; and US 2003/0114390 describes C-aryl glucoside SGLT2 inhibitors and method.
Also many of the SGLT2 inhibitors have entered in to the clinical studies. For example, Dapagliflozin is in phase III clinical trails in where as Canagliflozin is in phase HI.
In view of the above, we focused primarily on the identification of new glucosides by exploring chemical space available in this class of compounds, with focus on substituents attached to C4 or C4> of the diaryl methane aglycone in an effort to synthesize novel chemical entities which stimulate significant excretion of glucose in the urine and inhibit SGLT2 for treatment of diabetes or treating diseases and/or disorders related to diabetes.
Summary of the Invention
The present invention relates to compounds of the formula (1):
Figure imgf000004_0001
wherein,
R can be substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkoxy, or substituted or unsubstituted heterocyclic group and preferably methyl, ethyl, propyl, methoxy, ethoxy, isopropoxy, t-butoxy, and the R can be substituted by Ra;
each R' is independent and can be either the same or a different group and is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted acyl group, or substituted or unsubstituted alkoxy carbonyl group;
X can be CRiR2, O, NRl5 or S;
a, b, c, d, e, and f is independent and can be selected from hydrogen, hydroxyl group, halogen, substituted or unsubstituted alkyl, C(0)-R3, -C(0)0-R3, or -C(0)NR3R4; and a and b; or c and d; or e and f can be together with their attached carbon to form Spiro ring or R and one of the a or b; or c and one of the e or f; or d and one of the e or f can be together with their attached carbon atoms to form bicyclic ring.
Z and Z' is independent and can be selected from hydrogen, hydroxyl group, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy group, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkyloxy, -C(0)-R3, -C(0)0-R3, or -C(0)NR3R4;
Ra can be hydrogen, hydroxyl group, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy group, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkyloxy, R3R4, -C(0)-R3, -C(0)0- R3, -C(0)NR3R4, S(0)pNR3R4, or S(0)pR3;
each R\ and R2 can be independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted cycloalkyl;
each R3 and R4 can be independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, or substituted or unsubstituted heterocyclylalkyl;
'p' can be an integer ranging from 0 to 2.
Pharmaceutically acceptable salts of the compounds of the formula (1) are also contemplated. Likewise, pharmaceutically acceptable solvates, including hydrates, of the compounds of the formula (1) are contemplated. It should be understood that the formula (1) structurally encompasses all stereoisomers, including enatiomers and diastereomers, which may be contemplated from the chemical structure of the genus described herein.
Also contemplated are prodrugs of the compounds of the formula (1), including ester prodrugs.
According to another embodiment, there is provided a compound of formula (1), wherein R is substituted or unsubstituted alkyl. In this embodiment, preferably, R is methyl, trifluoro-methyl, ethyl and ethoxy-methyl.
According to another embodiment, there is provided a compound of formula (1), wherein X is O and CH2.
According to one embodiment, there is provided a compound of formula (1), wherein Z is hydrogen.
According to one embodiment, there is provided a compound of formula (1), wherein Z' is halogen or substituted or unsubstituted alkyl. In this embodiment, preferably, Z' is chlorine, fluorine and methyl.
According to one embodiment, there is provided a compound of formula (1), wherein R' is hydrogen.
According to one embodiment, there is provided a compound of formula (1), wherein R' is substituted or unsubstituted acetyl.
According to another embodiment, there is provided a compound of formula (1), wherein each a, b, c, d, e and f are independently hydrogen or halogen.
According to another embodiment, there is provided a pharmaceutical preparation, which comprises any one of the above cycloalkyl methoxybenzyl phenyl pyran compounds or a pharmaceutically acceptable salt thereof, a solvate thereof, or a hydrate thereof as an active ingredient.
According to another embodiment, there is provided such a pharmaceutical preparation which is an inhibitor of sodium-dependent glucose transporter 2 activity.
According to another embodiment, there is provided such a pharmaceutical preparation which is a prophylactic or therapeutic agent for diabetes, diabetes- related diseases or diabetic complications.
Below are the representative compounds, which are illustrative in nature only and are not intended to limit to the scope of the invention (Nomenclature has been generated from Chem. Draw Ultra 11.0 version): (2S,3R,4R,5S ,6R)-2-(4-chloro-3-(4-(( 1 - ethylcyclopentyl)methoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran- 3,4,5-triol (Compound 1),
(2R,3R,4R,5S,6R)-2-(4-chloro-3-(4-((l- ethylcyclopentyl)methoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran- 3,4,5-triol (Compound 2),
(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(( 1 - ethylcyclobutyl)methoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran- 3,4,5-triol (Compound 3),
(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-((l- ethylcyclohexyl)methoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran- 3,4,5-triol (Compound 4),
(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-((l- methylcyclohexyl)methoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran- 3,4,5-triol (Compound 5),
(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-((3-ethyloxetan-3- yl)methoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (Compound 6),
(2R,3S,4R,5R,6S)-2-(hydroxymethyl)-6-(4-methyl-3-(4-((l- (trifluoromethyl)cyclopropyl)methoxy)benzyl)phenyl)tetrahydro-2H-pyran-3,4,5- triol (Compound 7),
(2R,3S,4R,5R,6S)-2-(hydroxymethyl)-6-(4-methyl-3-(4-((l- (trifluoromethyl)cyclobutyl)methoxy)benzyl)phenyl)tetrahydro-2H-pyran-3,4,5-triol (Compound 8),
(2S,3R,4R,5S,6R)-2-(3-(4-((4,4-difluoro-l- methylcyclohexyl)methoxy)benzyl)-4-methylphenyl)-6-(hydroxymethyl)tetrahydro- 2H-pyran-3,4,5-triol (Compound 9),
(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-((l- (trifluoromethyl)cyclobutyl)methoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro- 2H-pyran-3,4,5-triol (Compound 10),
(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-((l- methylcyclopentyl)methoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H- pyran-3,4,5-triol (Compound 11), (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-((l- (trifluoromethyl)cyclopropyl)methoxy)benzyl)phenyl)-6- (hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (Compound 12),
(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-((4,4-difluoro-l- methylcyclohexyl)methoxy)benzyl)phenyl)-6-(hydroxymethyl)tetraliydro-2H-pyran- 3,4,5-triol (Compound 13),
(2S,3R,4R,5S,6R)-2-(4-fluoro-3-(4-((l- (trifluoromethyl)cyclobutyl)methoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro- 2H-pyran-3,4,5-triol (Compound 14),
(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-((l- (trifluoromethyl)cyclopropyl)methoxy)benzyl)phenyl)-6- (hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (Compound 15),
(2S,3R,4R,5S,6R)-2-(3-(4-((4,4-difluoro-l- methylcyclohexyl)methoxy)benzyl)-4-fluorophenyl)-6-(hydroxymethyl)tetrahydro- 2H-pyran-3,4,5-triol (Compound 16),
(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-((l- (ethoxymethyl)cyclopentyl)methoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro- 2H-pyran-3,4,5-triol (Compound 17), or
pharmaceutically acceptable salts, solvates, including hydrates and prodrugs of compounds are also contemplated.
The present invention also provides a pharmaceutical composition that includes at least one compound as described herein and at least one pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent). Preferably, the pharmaceutical composition comprises a therapeutically effective amount of at least one compound described herein. The compound(s) present in the composition may be associated with a pharmaceutically acceptable excipient (such as a carrier or a diluent) or may be diluted by a carrier, or enclosed within a carrier which may be in the form of a capsule, sachet, paper or other container.
The compounds and pharmaceutical compositions described herein are useful in the treatment of diseases, conditions and/or disorders mediated by SGLT2 inhibitors.
The present invention further provides a method of treating diabetes, disease condition and/or disorder mediated by stimulation of glucose excretion in urea/ inhibition of SGLT2 in a subject in need thereof by administering to the subject one or more compounds described herein in the amount effective to cause inhibition of such receptor.
Also provided herein are processes for preparing compounds of the present invention.
Detailed Description of the Invention
The present invention provides cycloalkyl methoxybenzyl phenyl pyran derivatives, which may be used as SGLT2 inhibitors and processes for the synthesis of these compounds. Pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers, polymorphs of these compounds that may have the same type of activity are also provided. Pharmaceutical compositions containing the described compounds together with pharmaceutically acceptable carriers, excipients or diluents, which can be used for the treatment of diseases, condition and/or disorders mediated by SGLT2 inhibitors are further provided.
The following definitions apply to the terms as used herein:
The terms "halogen" or "halo" includes fluorine, chlorine, bromine, or iodine.
The term "alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to eight carbon atoms, and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n- pentyl, and 1,1-dimethylethyl (t-butyl).
The term "alkenyl" refers to an aliphatic hydrocarbon group containing a carbon-carbon double bond and which may be a straight or branched chain having from 2 to about 10 carbon atoms, e.g., ethenyl, 1-propenyl, 2-propenyl (allyl), iso- propenyl, 2 -methyl- 1-propenyl, 1-butenyl, and 2-butenyl.
The term "haloalkyl" is used to denote a group comprised of an alkyl group substituted with halogen atom, where alkyl group is as defined above and halogen is used to denote fluorine, chlorine, bromine or iodine, an example of such group is trifluoromethyl, difluoromethyl.
The term "acyl group" is used to denote a linear or branched aliphatic acyl group (preferably a C2-6 alkanoyl group) or an aromatic acyl group, which contains 2 to 10 carbon atoms. Examples include an acetyl group, a propionyl group, a pivaloyl group, a butyryl group, an isobutyryl group, a valeryl group and a benzoyl group, with an acetyl group being preferred.
The term "alkoxy group" is used to denote a linear or branched alkoxy group containing 1 to 6 carbon atoms. Preferred are C1-4 alkoxy groups including a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a n-butoxy group, an isobutoxy group and a tert-butoxy group.
The term "alkoxycarbonyl group" isused to denote a structure composed of a linear or branched C1-5 alkoxy group and a carbonyl group. Preferred are C2-5 alkoxycarbonyl groups including a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group and a butoxycarbonyl group. Among them, a methoxycarbonyl group is preferred.
The term "cycloalkyl" denotes a non-aromatic mono or multicyclic ring system of from 3 to about 12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of multicyclic cycloalkyl groups include, but are not limited to, perhydronapththyl, adamantyl and norbornyl groups, bridged cyclic groups and spirobicyclic groups, e.g., spiro (4,4) non-2-yl.
The term "bicyclic ring" denotes a aromatic or non-aromatic bicyclic ring system of from 3 to about 12 carbon atoms, such as benzofused or simple fused. Examples of bicyclic ring groups include, but are not limited to, benzoisoxazole, benzoxazole, cyclopenta[c]furan, octahydropentalene, or the like.
The term "cycloalkylalkyl" refers to a cyclic ring-containing radical having from 3 to about 8 carbon atoms directly attached to an alkyl group. The cycloalkylalkyl group may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure. Non-limiting examples of such groups include cyclopropylmethyl, cyclobutylethyl, and cyclopentylethyl.
The term "cycloalkenyl" refers to a cyclic ring-containing radical having from 3 to about 8 carbon atoms with at least one carbon-carbon double bond, such as cyclopropenyl, cyclobutenyl, and cyclopentenyl.
The term "aryl" refers to an aromatic radical having from 6 to 14 carbon atoms such as phenyl, naphthyl, tetrahydronapthyl, indanyl, and biphenyl.
The term "arylalkyl" refers to an aryl group as defined above directly bonded to an alkyl group as defined above, e.g., -CH2C6H5 and -C2H5C6H5. The terms "heterocyclyl" and "heterocyclic ring" refer to a stable 3- to 15- membered ring radical which consists of carbon atoms and from one to five heteroatoms selected from nitrogen, phosphorus, oxygen and sulfur. For purposes of this invention, the heterocyclic ring radical may be a monocyclic, bicyclic or tricyclic ring system, which may include fused, bridged or spiro ring systems, and the nitrogen, phosphorus, carbon, oxygen or sulfur atoms in the heterocyclic ring radical may be optionally oxidized to various oxidation states. In addition, the nitrogen atom may be optionally quaternized; and the ring radical may be partially or fully saturated (i.e., heterocyclic or heteroaryl). Examples of such heterocyclic ring radicals include, but are not limited to, azetidinyl, acridinyl, benzodioxolyl, benzodioxinyl benzodioxanyl, benzofuranyl, carbazolyl, cinnolinyl, dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pyridyl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrazoyl, imidazolyl, tetrahydroisouinolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl, oxazolidinyl, triazolyl, indanyl, isoxazolyl, isoxasolidinyl, morpholinyl, thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, isoindolyl, indolinyl, isoindolinyl, octahydroindolyl, octahydroisoindolyl, quinolyl, isoquinolyl, decahydroisoquinolyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzooxazolyl, furyl, tetrahydrofurtyl, tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, dioxaphospholanyl, oxadiazolyl, chromanyl, and isochromanyl. The heterocyclic ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.
The term "heterocyclylalkyl" refers to a heterocyclic ring radical directly bonded to an alkyl group. The heterocyclylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure.
The term "heteroaryl" refers to an aromatic heterocyclic ring radical. The heteroaryl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure. The term "heteroarylalkyl" refers to a heteroaryl ring radical directly bonded to an alkyl group. The heteroarylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure.
Unless otherwise specified, the term "substituted" as used herein refers to substitution with any one or any combination of the following substituents: hydroxy, halogen, carboxyl, cyano, nitro, oxo (=0), thio (=S), substituted or unsubstituted alkyl, haloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclylalkyl ring, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic ring, substituted or unsubstiuted guanidine, -COORx, -C(0)Rx, -C(S)RX, -C(0)NRxRy, -C(0)ONRxRy, -NRxCONRyRz, -N(Rx)SORy, -N(Rx)S02Ry, -(=N- N(Rx)Ry), -NRxC(0)OR , -NRxRy, -NRxC(0)Ry, -NRxC(S)Ry, -NRxC(S)NRyRz, - SONRxRy, -S02NRxRy, -ORx, -ORxC(0)NRyRz, -ORxC(0)ORy, -OC(0)Rx, - OC(0)NRxRy, -RxNRyC(0)Rz, -RxORy, -RxC(0)ORy, -RxC(0)NRyRz, -RxC(0)Ry, - RxOC(0)Ry, -SRX, -SORx, -S02Rx, and -ON02, wherein Rx, Ry and Rz are independently selected from hydrogen, substituted or unsubstituted alkyl, haloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted heterocyclylalkyl ring, substituted or unsubstituted heteroarylalkyl, or substituted or unsubstituted heterocyclic ring. The substituents in the aforementioned "substituted" groups cannot be further substituted. For example, when the substituent on "substituted alkyl" is "substituted aryl", the substituent on "substituted aryl" cannot be "substituted alkenyl".
The term "prodrug" means a compound that is transformed in vivo to yield a compound of Formula (1) or a pharmaceutically acceptable salt, hydrate or solvate of the compound. The transformation may occur by various mechanisms, such as through hydrolysis in blood. A discussion of the use of prodrugs is provided by T. Higuchi and W. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the
A. C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward
B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.
The term "treating" or "treatment" of a state, disease, disorder or condition includes:
(1) preventing or delaying the appearance of clinical symptoms of the state, disease, disorder or condition developing in a subject that may be afflicted with or predisposed to the state, disease, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disease, disorder or condition;
(2) inhibiting the state, disease, disorder or condition, i.e., arresting or reducing the development of the state, disease, disorder or condition or at least one clinical or subclinical symptom thereof; or
(3) relieving the state, disease, disorder or condition, i.e., causing regression of the state, disease, disorder or condition or at least one of its clinical or subclinical symptoms.
The benefit to a subject receiving treatment is either statistically significant or at least perceptible to the subject or to the physician.
The term "subject" includes mammals (especially humans) and other animals, such as domestic animals (e.g., household pets including cats and dogs) and non-domestic animals (such as wildlife).
A "therapeutically effective amount" means the amount of a compound that, when administered to a subject for treating a state, disease, disorder or condition, is sufficient to effect such treatment. The "therapeutically effective amount" will vary depending on the compound, the state, disease, disorder or condition and its severity and the age, weight, physical condition and responsiveness of the subject receiving treatment.
The term "diabetes" encompasses type I diabetes, type II diabetes, and other types of diabetes with specific etiology.
The term "diabetes-related diseases" includes adiposis, hyperinsulinemia, abnormal carbohydrate metabolism, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, abnormal lipid metabolism, hypertension, congestive heart failure, edema, hyperuricemia and gout. The term "diabetic complications" can be classified into acute complications and chronic complications.
The term "acute complications" includes hyperglycemia (e.g., ketoacidosis), infections (e.g., skin, soft tissue, biliary system, respiratory system and urinary tract infections), etc.
The term "chronic complications" includes microangiopathy (e.g., nephropathy, retinopathy), arteriosclerosis (e.g., atherosclerosis, heart infarction, brain infarction, or lower extremity arterial occlusion), neuropathy (e.g., sensory nerves, motor nerves, or autonomic nerves), foot gangrene, etc. Major complications are diabetic retinopathy, diabetic nephropathy and diabetic neuropathy.
The compound of the invention may form salts. Non-limiting examples of pharmaceutically acceptable salts forming part of this patent application include salts derived from inorganic bases salts of organic bases salts of chiral bases, salts of natural amino acids and salts of non-natural amino acids. Certain compounds of present patent application are capable of existing in stereoisomeric forms (e.g. diastereomers and enantiomers). With respect to the overall compounds described by the Formula (1), the present patent application extends to these stereoisomeric forms and to mixtures thereof. To the extent prior art teaches synthesis or separation of particular stereoisomers, the different stereoisomeric forms of the present patent application may be separated from one another by the method known in the art, or a given isomer may be obtained by stereospecific or asymmetric synthesis. Tautomeric forms and mixtures of compounds described herein are also contemplated.
Pharmaceutically acceptable solvates includes hydrates and other solvents of crystallization (such as alcohols). The compounds of the present invention may form solvates with low molecular weight solvents by methods known in the art.
Pharmaceutical Compositions
The pharmaceutical compositions provided in the present invention include at least one compound described herein and at least one pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent). Preferably, the contemplated pharmaceutical compositions include a compound(s) described herein in an amount sufficient to excrete glucose in urine or inhibit SGLT2 in a subject.
The subjects contemplated include, for example, a living cell and a mammal, including human mammal. The compound of the present invention may be associated with a pharmaceutically acceptable excipient (such as a carrier or a diluent) and can be formulated in to preparations in solid, semi-solid, liquid or gaseous forms.
Examples of suitable carriers include, but are not limited to, water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone.
The carrier or diluent may include a sustained release material, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
The pharmaceutical composition may also include one or more pharmaceutically acceptable auxiliary agents, wetting agents, emulsifying agents, suspending agents, preserving agents, salts for influencing osmotic pressure, buffers, sweetening agents, flavoring agents, colorants, or any combination of the foregoing. The pharmaceutical composition of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the subject by employing procedures known in the art.
The pharmaceutical compositions described herein may be prepared, e.g., as described in Remington: The Science and Practice of Pharmacy, 20th Ed., 2003 (Lippincott Williams & Wilkins). For example, the active compound can be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier, which may be in the form of an ampoule, capsule, or sachet. When the carrier serves as a diluent, it may be a solid, semi-solid, or liquid material that acts as a vehicle, excipient, or medium for the active compound. The active compound can be adsorbed on a granular solid container, for example, in a sachet.
The pharmaceutical compositions may be, for example, capsules, tablets, aerosols, solutions, suspensions or products for topical application.
The route of administration may be any route which effectively transports the active compound to the appropriate or desired site of action. Suitable routes of administration include, but are not limited to, oral, nasal, pulmonary, buccal, subdermal, intradermal, transdermal, parenteral, rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic (such as with an ophthalmic solution) or topical (such as with a topical ointment). The oral route is preferred.
Solid oral formulations include, but are not limited to, tablets, capsules (soft or hard gelatin), dragees (containing the active ingredient in powder or pellet form), troches and lozenges. Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application. Preferable carriers for tablets, dragees, or capsules include lactose, cornstarch, and/or potato starch. A syrup or elixir can be used in cases where a sweetened vehicle can be employed.
A typical tablet that may be prepared by conventional tabletting techniques may contain: (1) Core: Active compound (as free compound or salt thereof), 250 mg colloidal silicon dioxide (Aerosil®), 1.5 mg microcrystalline cellulose (Avicel®), 70 mg modified cellulose gum (Ac-Di-Sol®), and 7.5 mg magnesium stearate; (2) Coating: HPMC, approx. 9 mg Mywacett 9-40 T and approx. 0.9 mg acylated monoglyceride
Liquid formulations include, but are not limited to, syrups, emulsions, soft gelatin and sterile injectable liquids, such as aqueous or non-aqueous liquid suspensions or solutions.
For parenteral application, particularly suitable are injectable solutions or suspensions, preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.
Methods of Treatment
The present invention provides compounds and pharmaceutical formulations thereof that are useful in the treatment of diseases, conditions and/or disorders mediated by SGLT2 inhibitors. The connection between therapeutic effect and inhibition of SGLT2 is illustrated. For example in PCT publication Nos. WO 01//016147, WO 02/08306, or WO 03/020737; J. Clin. Invest. Vol. 79, pp. 1510- 1515 (1987); J.Clin. Invest., Vol. 93, pp. 397-404 (1994); Diabetes; 57, 1723-1729, 2008 and references cited therein, all of which are incorporated herein by reference in their entirety and for the purpose stated.
The present patent application further provides a method of treating a disease, condition and/or disorder mediated by SGLT2 inhibitors in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound or a pharmaceutical composition of the present invention. Diseases, conditions, and/or disorders that are mediated by SGLT2 inhibitors are believed to include, but are not limited to, diabetes, especially type I and type 11 diabetes, including complications of diabetes such as retinopathy, neuropathy, nephropathy and delayed wound healing, and related diseases such as insulin resistance and impaired glucose homeostasis (IGH), hyperglycemia, hyperinsulinemia, elevated blood levels of fatty acids or glycerol, obesity, hyperlipidemia including hypertriglyceridemia, Syndrome X, hypertension, atherosclerosis and related diseases, and for increasing high density lipid levels. The conditions, diseases, and maladies collectively referred to as" Syndrome X" (also known as Metabolic Syndrome) are detailed in Johannsson, J. Clin. Endrocrinol. Metab. , 82, 727-34 (1997) incorporated herein by reference.
The compounds of the present invention can obtain more advantageous effects than additive effects in the prevention or treatment of the above diseases when using suitably in combination with the above drugs. Also, the administration dose can be decreased in comparison with administration of either drug alone, or adverse effects of co administrated drugs other than SGLT2 inhibitors can be avoided or declined.
General Synthesis Methods
The compounds described herein may be prepared by techniques known in the art. In addition, the compounds described herein may be prepared by following the reaction sequence as depicted in Scheme- 1 to 2. Further, in the following schemes, where specific bases, acids, reagents, solvents, coupling agents, etc., are mentioned, it is understood that other bases, acids, reagents, solvents, coupling agents etc., known in the art may also be used and are therefore included within the present invention. Variations in reaction conditions, for example, temperature and/or duration of the reaction, which may be used as known in the art, are also within the scope of the present invention. All the stereo isomers of the compounds in these schemes, unless otherwise specified, are also encompassed within the scope of this invention. Scheme 1
Figure imgf000018_0001
6
5
Compounds of intermediate 6 (wherein, L is leaving group, for example, halo, methyl sulfonyl, tolyl sulfonyl, 4-nitrobenzyl sulfonyl or the like, a, b, c, d, e, f, R and X are same as defined above) can be prepared as shown in the scheme 1. Cycloalkyl carboxylic acids of formula 2 can be converted to esters of formula 3 by conventional methods. The deprotonation can be carried out under an inert atmosphere at a temperature from -70° C to room temperature and in suitable aprotic organic solvent, for example, tetrahydrofuran or the like, and then R-X can be reacted with the salts of formula 3 or 2 at an initial temperature from -80 °C to- 10 °C either using one or two equivalent of strong base like potassium diisopropylamide, lithium hexamethyl disilazide and preferably, lithium disopropylamide or the like. After a period of stirring at -15°C, the reaction was quenched then the resulted compounds of formula 4 can be isolated and purified by conventional techniques. Compounds of formula 4 can be reduced to give hydroxyl compounds of formula 5 by a suitable reducing agent for example, lithium aluminum hydride or the like. Converting the hydroxy compounds of formula 5 to compounds of intermediate of formula 6 by the methods known in the art for example, reacting hydroxyl group with sulfonyl halides in the presence of a base such as, potassium carbonate, triethylamine, dimethylaminopyridine or the like.
Figure imgf000019_0001
Figure imgf000019_0002
Compounds of formula 11 (formula 1, when R' is H; wherein, a, b, c, d, e, f, R, Z, Z' and X are same as defined above) can be prepared according to the reaction sequences as shown in scheme-2. Compounds of formula 7 can be prepared by following the method described in patent publication US 7,393,836 (as exemplified in the experimental section). For example, benzoyl halides either commercially available or prepared insitu from benzoic acid can be coupled with alkoxyaryl compound using a Lewis acid, typically A1C13 or the like to give corresponding benzophenone product. Reduction of ketone function of benzophenone can be accomplished by trialkyl silane and an appropriate protic or Lewis acid, like trifluoroacetic acid or borontrifluoride etherate, followed by alkyl ether cleavage, using BBr3 or A1C13 to give compounds of formula 7. Alkylation of phenol compounds of formula 7 with intermediate compounds of formula 6 can be obtained in the presence of base such as K2C03, CsC03, NaOH or the like to give compounds of formula 8 in the solvents such as, dimethyl formamide, dimethyl sulfoxide or the like. Compounds of formula 8 can be treated with a base like t-BuLi, n-BuLi to exchange halogen to lithium followed by addition of nascent lithiated aromatic to silyl sugar compounds of formula 9 (as described in Journal of Medicinal Chemistry, 2008, 51, 1 145-1149) in solvents such as, toluene, methane sulfonic acid or the like to give the diastereomeric mixture of lactol compounds, which were converted insitu to the desilylated O-methyl lactol compounds of formula 10 by treatment with methane sulfonicacid in methanol (J. Org. Chem. 1989, 54, 610-612). Reduction of anomeric methoxy group of the desilylated O-methyl lactols compounds of formula 10 using a reducing agent such as alky silane, for example, triethyl silane or the like in the presence of acid such as BF3.0Et2, trifluroacetic acid, methane sulfonic acid or the like to give the inventive compounds of formula 11 (Formula 1, when R' is H). Finally, the desired diastereoisomer of compounds of formula 11 can be separated by either column chromatography or peracetylation by the methods known in the art for example, acetic anhydride with catalytic amount of dimethylamino pyridine or the like and recrystallization in a suitable solvent by the methods known in the art for example, 20% methanolic ammonia or the like.
Experimental
The present invention is further illustrated by the following examples, which are not to be construed in any way as imposing limitations upon the scope of this disclosure, but rather are intended to be illustrative only. On the contrary, it is to be clearly understood that resort may be had to various other embodiments, modifications, and equivalents thereof which, after reading the description herein, may suggest themselves to one of ordinary skill in the art without departing from the spirit of the present invention. Thus, the skilled artisan will appreciate how the experiments and Examples may be further implemented as disclosed by variously altering the following examples, substituents, reagents, or conditions.
Intermediates
Intermediate 1: Preparation of 4-(5-bromo-2-chlorobenzyl)phenol:
Figure imgf000020_0001
Step 1: Synthesis ofethoxy benzene
Figure imgf000020_0002
Potassium carbonate (264 g, 0.95 mol) was added to a solution of Phenol (60 g, 0.63 mol) in acetone (350 ml) and allowed to stir at room temperature for about 30 minutes then ethyl iodide (77 ml, 0.95 mol) was added drop wise. The reaction mixture was refluxed for about 3 hours and completion of reaction was monitored by TLC. The reaction mixture was filtered and acetone was removed over rotary evaporator. The residue was dissolved in ethyl acetate and washed with 10% NaOH solution to remove any unreacted phenol. The organic layer was washed with saturated brine solution, dried over anhydrous Na2S04 and concentrated and filtered to yield the title compound. Yield: 38 g, 48 %. 1H NMR (CDC13, 300 MHz): 6 7.30- 7.25 (m, 2H); 6.95-6.88 (m, 3H); 4.02 (q, 2H, J = 6.9 Hz); 1.41 (t, 3H, J = 6.9 Hz).
Step 2: Synthesis of(5-bromo-2-chlorophenyl)(4-ethoxyphenyl)methanone:
Figure imgf000021_0001
5-bromo-2-chlorobenzoic acid (50 g) was suspended in dichloromethane (100 ml) and dimethylformamide then it was cooled to 0 °C and to this mixture SOCl2 (92.2 ml) was added slowly. The reaction mixture was slowly allowed to attain room temperature and stirred for about 12 hours. The solvent was removed under reduced pressure to give 5-bromo-2-chlorobenzoyl chloride as oil. Ethoxybenzene (step 1, 25.8 g) was suspended in dichloromethane (50 ml) and cooled to -5 °C then A1C13 (42.3 g) was added slowly by portion wise and above 5- bromo-2-chlorobenzoyl chloride (53.8 g) in dichloromethane (150 ml ) was added drop wise and stirred for about 1 hour at 0 °C. After completion of the reaction (monitored by TLC), the reaction mixture was poured into ice- water. The organic layer was separated and aqueous layer was extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulphate and concentrated to give the crude compound. Ethanol was added to the crude compound at 0 °C and stirred for about 30 minutes. White solid was formed, then filtered off and washed with cold EtOH to afford the title compound as white solid (48 g). Yield: 67.6 ; 1H NMR (CDC13, 300 MHz): δ 7.76 (dd, J = 1.5, 6.9 Hz, 2H), 7.55- 7.47 (m, 2H), 7.32 (d, J = 8.4 Hz, 1H), 6.93 (d, J = 9 Hz, 2H), 4.11 (q, / = 6.9 Hz, 2H), 1.45 (t, J = 6.9 Hz, 3H).
Step 3: Synthesis of(5-bromo-2-chlorophenyl)(4-hydroxyphenyl)methanone:
Figure imgf000021_0002
To a stirred solution of (5-bromo-2-chlorophenyl)(4- ethoxyphenyl)methanone (step 2, 48 g) in dichloromethane (150 ml) at 0°C, A1C13 (188.8 g) was added under N2 atmosphere by portion wise over 30 minutes. Subsequently, the reaction mixture was stirred at room temperature for about 12 hours. After completion of the reaction (monitored by TLC), the reaction mixture was poured into ice- water. The organic layer was separated and aqueous layer was extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulphate and concentrated to give the crude compound. Ethanol was added to the crude compound at 0 °C and stirred for about 30 minutes. White solid was formed, then filtered off and washed with cold EtOH to afford the title compound as white solid (41 g). Yield: 93 %; 1H NMR (CDC13, 300 MHz): δ 8.50 (s, 1H), 6.43 (d, J = 8.7 Hz, 2H), 6.28- 6.20 (m, 2H), 6.06 (d, J = 8.4 Hz, 1H), 5.64 (d, J = 8.7 Hz, 2H); ES Mass: (M+H) 310.85.
Step 4: Synthesis of 4-(5-bromo-2-chlorobenzyl)phenol:
To a stirred solution of (5-bromo-2-chlorophenyl)(4- hydroxyphenyl)methanone (step 3, 41 g) in dichloromethane (150 ml) and acetylnitrile (1: 1), Et3SiH (53 ml) was added at 0 °C under N2 atmosphere followed by BF3: Et20 (25 ml) and the reaction was stirred for about 16 hours at room temperature. After completion of the reaction (monitored by TLC), volatiles were concentrated under reduced pressure. Then the reaction mixture was cooled to 0 °C and neutralized by cautious addition of saturated aq. NaHC03 Solution. The reaction mixture was extracted with EtOAc. The combined organic layers were washed with water, brine, dried over anhydrous sodium sulphate and concentrated to give the crude compound. Hexane was added to the crude compound at 0 °C and stirred for about 30 minutes. White solid was formed and filtered off to afford the title compound as white solid (37 g). Yield: 94.8 ; 1H NMR (CDC13, 300 MHz): δ 7.27- 7.24 (m, 3H), 7.06 (d, J = 8.4 Hz, 2H), 6.78 (d, / = 8.4 Hz, 2H), 4.69 (s, 1H), 3.98 (s, 2H); ES Mass: (M+H) 296.85
Intermediate 2: Preparation of (3R,4S,5R,6R)-3,4,5-tris(trimethylsilyloxy)-6-
Figure imgf000022_0001
To a stirred solution of (3R,4S,5S,6R)-3,4,5-trihydroxy-6- (hydroxymethyl)tetrahydro-2H-pyran-2-one (50 g) in tetrahydrafuran (1.3 L), NMM (N-methyl morpholine, 214 ml) and TMSC1 (trimethyl silyl chloride, 247 ml) were added at 0 °C under N2 atmosphere and the reaction mixture temperature was slowly raised to about 50 °C and stirred for about 5 to 6 hours. After completion of the reaction (monitored by TLC), toluene and water were added to the reaction mixture and organic layer was separated. Aqueous layer was again extracted with toluene. The combined organic layers were washed with potassium dihydrogen phosphate, water and brine, dried over anhydrous sodium sulphate and concentrated to give the title compound as liquid (120 g). Yield: 91.6 ; 1H NMR (CDC13, 300 MHz): δ 4.19- 4.15 (m, 1H), 3.99 (d, J = 8.1 Hz, 1H), 3.91 (dd, J = 7.5, 7.5 Hz, 1H ), 3.84- 3.72 (m, 3H), 0.20- 0.13 (m, 36H); ES Mass: (M+ Na) 489.
Intermediate 3: Preparation of 4-bromo-l-chloro-2-(4-((l-ethylcvclopentyl) methoxy)benzyl) benzene:
Figure imgf000023_0001
Step-1: Synthesis of Ethyl cyclopentanecarboxylate:
Figure imgf000023_0002
Concentrated H2S04 (43 ml, 1.0 equalent) was added drop-wise to a solution of cyclopentanecarboxylic acid (50 g, 0.438 mol) in EtOH (500 ml) at 0°C and the reaction mixture was refluxed for about 48 hours. After the completion of the reaction, the solvent was removed and the reaction mixture was dissolved in dichloromethane. The dichloromethane layer was washed with saturated NaHC03 solution and the organic layer was dried over anhydrous magnesium sulphate. Dichloromethane was removed over rotary evaporator without vaccum and the resulting residue of the title compound was used directly for the next step. Yield: 38 gm, 61 ; 1H NMR (CDC13, 300 MHz): δ 4.11 (q, 2H, J = 7.2 Hz); 2.75-2.65 (m, 1H); 1.89-1.56 (m, 8 H); 1.25 (t, 3H, J = 7.2 Hz). ESI Mass: 143 (M+l).
Step 2: Synthesis of Ethyl 1 -ethylcyclopentanecarboxylate:
Figure imgf000023_0003
To a solution of diisopropylamine (93.6 ml, 0.688 mol) in tetrahydrafuran (200 ml), n-BuLi (2.5M, 213.7 ml, 0.534 mol) in hexane was added at 0°C and the reaction mixture was allowed to stir at same temperature for about 10-15 minutes. The reaction mixture was stirred at room temperature for about 45 minutes. Ethyl cyclohexanecarboxylate (step 1, 38 g, 0.267 mol) in tetrahydrafuran (150 ml) was added drop-wise at -78°C to LDA (reaction mixture). The reaction mixture was stirred at same temperature for about 2 hours and then ethyl iodide (32.06 ml, 0.400 mol) was added drop-wise. The reaction mixture was maintained at -78°C for an hour and allowed to attain room temperature. Reaction mixture was stirred overnight at room temperature and quenched at 0°C with saturated NH4C1 solution. The solvent was concentrated over vaccum and the compound was extracted with ethyl acetate. The organic layer was washed with saturated brine solution, dried over anhydrous Na2S04 then concentrated and the resulted crude product of title compound was directly used for the next step. Crude yield: 32 gm, 70 %; 1H NMR (CDC13, 300 MHz): δ 4.11 (q, 2H, J = 7.2 Hz); 2.13-1.41 (m, 13H); 1.21 (t, 3H, J = 7.2 Hz); 0.81 (t, 3H, J = 7.5 Hz). ESI Mass: 171 (M+l).
Step 3: Synthesis of (l-ethylcyclopentyl)methanol:
Figure imgf000024_0001
Ethyl 1-ethylcyclopentanecarboxylate (step 2, 32 g, 0.187 mol) in tetrahydrafuran (120 ml) was added to a suspension of LiAlH4 (21.4 g, 0.563 mol) in tetrahydrafuran (200 ml) at 0°C and the reaction mixture was allowed to stir at same temperature for about 30 minutes. The reaction mixture was stirred overnight at room temperature. After completion of the reaction, the reaction mixture was quenched with ice cold water at 0°C and filtered over celite. The residue was washed with hot ethyl acetate and the organic layer was washed with saturated brine solution, dried over anhydrous Na2S04 then concentrated and the resulted crude product of title compound was directly used for the next step. Crude yield: 24 gm, 100 %. 1H NMR (CDC13, 300 MHz): δ 3.93 (s, 2H); 1.59-1.36 (m, 10H); 0.85 (t, 3H, J = 7.5 Hz).
Step 4: Synthesis of (l-ethylcyclopentyl)methyl 4-methylbenzenesulfonate:
Figure imgf000025_0001
To a solution of (l-ethylcyclopentyl)methanol (step 3, 26 g, 0.202 mol) in dichloromethane (400 ml), triethyl amine (141.3 ml, 1.01 mol) was added followed by tosyl chloride (77.3 g, 0.405 mol) at 0°C. After addition of catalytic amount of DMAP (2.47 g, 0.020 mol), the reaction mixture was allowed to stir overnight at room temperature. After completion of the reaction, the reaction mixture was washed with water, saturated brine solution and the organic layer was dried over anhydrous Na2S04 and concentrated. The obtained product was purified by column chromatographic technique. Yield: 27 gm, 47 %. 1H NMR (CDC13, 300 MHz): δ 7.79 (d, 2H, J = 8.1 Hz); 7.35 (d, 2H, J = 8.1 Hz); 3.76 (s, 2H); 2.45 (s, 3H); 1.54- 1.35 (m, 10H); 0.72 (t, 3H, / = 7.5 Hz).
Step 5: Synthesis of4-bromo-l-chloro-2-(4-((l-ethylcyclopentyl) methoxy)benzyl) benzene:
To a suspension of Cs2C03 (89.20 g, 0.273 mol) in dimethylformamide (300 ml) 4-(5-bromo-2-chlorobenzyl)phenol (Intermediate 1, 27 g, 0.091 mol) in dimethylformamide (100 ml) was added followed by (l-ethylcyclopentyl)methyl 4- methylbenzenesulfonate (step 4, 38.5 g, 0.136 mol) in dimethylformamide (100 ml) and the reaction mixture was stirred overnight at 120°C. After completion of the reaction as monitored by TLC, the reaction mixture was acidified with 10% HC1 solution. Compound was extracted with ether and washed with saturated brine solution. The organic layer was dried over anhydrous Na2S04 and concentrated then the obtained product was purified by column chromatographic technique. Yield: 28 gm, 75 %. 1H NMR (CDC13, 300 MHz): δ 7.37-7.24 (m, 3H); 7.02-6.98 (m, 2H); 6.78-6.49 (m, 2H); 4.17-4.15 (m, 1H); 3.90 (m, 2H); 3.76-3.74 (m, 1H); 3.56 (s, 3H); 3.48-3.43 (m, 1H); 2.86 (s, 2H); 2.81 (s, 1H); 1.48-1.31 (m, 10H); 0.71 (t, 3H, J = 7.2 Hz). ESI Mass: 543.20 (M+Na).
Intermediate 4: Preparation of (2S.3Rt4S,5S,6RV2-(4-chloro-3-(4-(f l- ethylcyclopentyl)methoxy)benzyl)phenyl)-6-(hvdroxymethyl)-2-methoxytetrahvdro- 2H-pyran-3.4,5-triol (β-isomer and (2R,3R,4S,5S,6R -2-(4-chloro-3-(4-((l- emylcyclopentyl)methoxy)benzyl)phenyl)-6-(hydro^
2H-pyran-3,4,5-tri -isomer):
Figure imgf000026_0001
T-BuLi (1.7 M, 17.4 ml, 29.42 mmol) was added drop-wise at -78°C to a solution of intermediate 3 (6 g, 14.71 mmol) in tetrahydrafuran: toluene (90 ml) (1:2). After 20 minutes, the lithiated derivative was added drop- wise to a pre-cooled solution (at -78°C) of silyl sugar (Intermediate 2, 6.88 g, 14.71 mmol) in toluene (30 ml). The reaction mixture was maintained at the same temperature for about 2 hours and quenched with methane sulfonic acid (6 % in MeOH, 90 ml). The reaction mixture was stirred at room temperature for an hour, then the reaction mixture was quenched with saturated NaHC03 solution and diluted with ethyl acetate. The organic layer was washed with saturated brine solution. The organic layer was dried over anhydrous Na2S04 and concentrated. The obtained diastereomeric products were separated by column chromatographic technique. 1H NMR (CDC13, 300 MHz): β-isomer: δ 7.33-7.28 (m, 3H); 7.05 (d, 2H, J = 8.4 Hz); 6.79 (d, 2H, J = 8.7 Hz); 4.10-3.88 (m, 7H); 3.62 (s, 4H); 3.21-3.18 (m, 2H); 2.99 (s, 2H); 2.53 (bs, 1H); 1.74-1.40 (m, 13H); 0.83 (t, 3H, J = 7.5 Hz). ESI Mass: 543.30 (M+Na).
oc-isomer: 6 7.40-7.29 (m, 3H); 7.08 (d, 2H, J = 8.4 Hz); 6.86-6.82 (m, 2H); 4.49 (t, 1H, / = 5.7 Hz); 4.18-4.14 (m, 1H); 4.04-3.77 (m, 7H); 3.66 (s, 3H); 3.31 (bs, 1H); 3.18 (bs, 1H); 3.08 (s, 2H); 2.94-2.91 (m, 1H); 2.30 (bs, 1H); 2.21 (bs, 1H); 1.64- 1.44 (m, 10H); 0.85 (t, 3H, J = 7.2 Hz).
Intermediate 5j Preparation of 4-bromo- 1 -chloro-2-( 4-(( 1 - ethylcvclobutyl)methoxy)benzyl) benzene:
Figure imgf000026_0002
Step 1: Synthesis of Methyl cyclobutanecarboxylate:
Figure imgf000026_0003
Concentrated H2S04 (39.2 ml, 1.0 eq) was added drop-wise to a solution of cyclobutanecarboxylic acid (40 g, 0.438 mol) in MeOH (200 ml) at 0°C and the reaction mixture was refluxed for about 36 hours. After completion of the reaction as monitored by TLC, the solvent was removed and the reaction mixture was dissolved in dichloromethane. The dichloromethane layer was washed with saturated NaHC03 solution and the organic layer was dried over anhydrous magnesium sulphate, dichloromethane was removed over rotary evaporator. The residue was used directly for the next step. Yield: 30 gm, 61.2 %. 1H NMR (CDC13, 300 MHz): δ 3.67 (s, 3H),17-3.11 (m, 1H) 2.32-2.16 (m, 4H), 1.92-1.90 (m, 2H).
Step 2: Synthesis of methyl 1-ethylcyclobutanecarboxylate:
Figure imgf000027_0001
To a solution of diisopropylamine (110.6ml) and tetrahydrafuran (200ml), was added n-BuLi (2.5M, 263.7 ml, 0.6578 mol) in hexane at 0°C and the reaction mixture was allowed to stir at same temperature for about 10-15 minutes. The reaction mixture was stirred at room temperature for about 45 minutes. Methyl cyclobutanecarboxylate (step 1, 30 g, 0.263 mol) in tetrahydrafuran (150 ml) was added drop-wise at -78°C to LDA (reaction mixture). The reaction mixture was stirred at same temperature for about 2 hours then neat ethyl iodide (31.56 ml, 0.3947 mol) was added drop-wise. The reaction was maintained at -78°C for an hour and allowed to attain room temperature. Reaction mixture was stirred overnight at room temperature and quenched at 0°C with saturated NH4C1 solution. The solvent was concentrated over vaccum and the compound was extracted with ethyl acetate. The organic layer was washed with saturated brine solution and then dried over anhydrous Na2S04 and concentrated then the obtained crude product was directly used for the next step. Crude yield: 32 gm, 70 %. 1H NMR (CDC13, 300 MHz): 6 3.67 (s, 3H); 2.40-2.36 (q, 2H); 1.89-1.74 (m, 6H); 0.81- 0.76(t, 3H, J = 7.5 Hz).
Step 3: Synthesis of (l-ethylcyclobutyl)methanol:
Figure imgf000027_0002
Methyl 1-ethylcyclopentanecarboxylate (step 2, 25 g, 0.176 mol) in tetrahydrafuran (120 ml) was added to a suspension of L1AIH4 (21.4 g, 0.563 mol) in tetrahydrafuran (200 ml) at 0°C and the reaction mixture was allowed to stir at the same temperature for about 30 minutes. The reaction mixture was stirred overnight at room temperature. After completion of the reaction, the reaction mixture was quenched with ice cold water at 0°C and filtered over celite. The residue was washed with hot ethyl acetate. Compound was extracted with ethyl acetate. The organic layer was washed with saturated brine solution, dried over anhydrous Na2S04 and concentrated. The obtained crude product was directly used for the next step. Crude yield: 24 gm, 100 %. 1H NMR (CDC13, 300 MHz): 6 3.77-3.72 (t, 1H); 3.53(s, 2H) 1.87-1.68 (m, 4H); 1.55-1.48 (q, 2H, J=7.5Hz), 0.84-0.79 (t, 3H, J=7.5 Hz). ESI Mass: (M-l) 113.
Step 4: Synthesis of (l-ethylcyclobutyl)methyl 4-methylbenzenesulfonate:
Figure imgf000028_0001
To a solution of (l-ethylcyclobutyl)methanol (step 3, 15 g, 0.131 mol) in dichloromethane (300 ml), triethyl amine (73.2 ml, 0.526 mol) was added followed by tosyl chloride (49.9 g, 0.26 mol) at 0°C. After addition of catalytic amount of DMAP (1.6 g, 0.0131 mol), the reaction mixture was allowed to stir overnight at room temperature. After completion of the reaction, the reaction mixture was washed with water, saturated brine solution and the organic layer was dried over anhydrous Na2S04 and concentrated then the obtained product was purified by column chromatographic technique. Yield: 27 gm, 47 %. 1H NMR (CDC13, 300 MHz): δ 7.81-7.79 (d, 2H, J = 8.4 Hz); 7.36 (d, 2H, J = 8.4 Hz); 3.9 (s, 2H); 2.45 (s, 3H); 1.80-1.71 (m, 6H); 1.53-1.45 (q, 2H), 0.70-0.65 (t, 3H, J=l .5 Hz).
Step 5: Synthesis of 4-bromo-l-chloro-2-(4-((l-ethylcyclobutyl)methoxy)benzyl) benzene:
To a suspension of intermediate 1 (8g, 0.027 mol) in dimethylformamide (60 ml), Cs2C03 (26.4 g, 0.081 mol) was added followed by (l-ethylcyclobutyl)methyl 4- methylbenzene sulfonate (step 4, 10.8 g, 0.0405 mol) in dimethylformamide (60 ml). The reaction mixture was stirred overnight at 120°C. After completion of the reaction as monitored by TLC, the reaction mixture was acidified with 10% HC1 solution. Compound was extracted with ether and washed with saturated brine solution. The organic layer was dried over anhydrous Na2S04 and concentrated. The obtained product was purified by column chromatographic technique. Yield: 28 gm, 75 . %. 1H NMR (CDC13, 300 MHz): 6 7.26-7.24 (m, 3H); 7.11-7.08 (d, 2H, J=8.7Hz); 6.89-6.86 (d, 2H, 8.7Hz); 4.00 (s, 2H), 3.82 (s, 2H), 1.95-1.85 (m, 6H); 1.82-1.80 (m, 2H); 1.68-1.61 (q, 2H, J=7.5Hz); 0.86-0.81 (t, 3H, 7 = 7.2 Hz).
Intermediate 6: Preparation of (2S.3R,4S.5S,6R -2-(,4-chloro-3-('4-(('l- ethylcyclobutyl methoxy)benzyl)phenyl)-6-(hvdroxymethyl)-2-methoxy-tetrahydro- 2H-pyran-3,4,5-triol:
Figure imgf000029_0001
T-BuLi (1.7 M, 15.6 ml, 0.0265 mol) was added drop-wise at -78°C to a solution of Intermediate 5 (5.2 g, 0.0132mol) in tetrahydrafuran: toluene (90 ml) (1:2). After 20 minutes, the lithiated derivative was added drop- wise to a pre-cooled solution (at -78°C) of silyl sugar (Intermediate 2, 4.94 g, 0.0106 mol) in toluene (30 ml). The reaction mixture was maintained at the same temperature for about 2 hours and quenched with methane sulfonic acid (6 % in MeOH, 78 ml). The reaction mixture was stirred at room temperature for three hours then the reaction mixture was quenched with saturated NaHC03 solution and diluted with ethyl acetate. The organic layer was washed with brine solution, dried over anhydrous Na2S04 and concentrated. The obtained product was separated by column chromatographic technique. 1H NMR (CDCI3, 300 MHz): δ 7.52 (s, 1H), 7.39 (s, 2H); 7.09-7.06 (d, 2H, J=8.4Hz); 6.87 -6.85 (d, 2H, 7=8.4 Hz); 5.00-4.98 (d, 1H, 7 = 5.4 Hz); 4.81-4.75 (m, 2H), 4.57-4.53 (m, 1H), 4.57-4.53 (q, 2H, J=6.3Hz), 4.01 (s, 2H), 3.98 (m, 1H); 3.80-3.73 (m, 3H), 3.23-3.21 (m, 1H), 2.92 (s, 3H), 2.88-2.85 (m, 1H); 1.86-1.73 (m, 6H); 1.60-1.53 (q, 2H, J=7.5Hz); 0.80-0.75 (t, 3H, 7=7.5 Hz). ESI Mass: 529 (M+Na).
Intermediate 7: Preparation of 4-bromo- 1 -chloro-2-(4-(( 1 - ethylcyclohexyl)methoxy)benzyl)benzene:
Figure imgf000030_0001
Step 1: Synthesis of methyl cyclohexanecarboxylate:
Figure imgf000030_0002
Concentrated H2S04 (19.1 ml, 1.0 eq) was added drop- wise to a solution of cyclohexanecarboxylic acid (25 g, 0.1953 mol) in MeOH (125 ml) at 0°C and the reaction mixture was refluxed for about 48 hours. After completion of the reaction, the solvent was removed and the reaction mixture was dissolved in dichloromethane. The organic layer was washed with saturated NaHC03 solution and the organic layer was dried over anhydrous magnesium sulphate. Dichloromethane was removed over rotary evaporator. The obtained residue with least moisture content (mc) was used directly for the next step. Yield: 16 gm.
Step 2: Synthesis of methyl 1-ethylcyclohexanecarboxylate:
Figure imgf000030_0003
To a solution of diisopropylamine (44.4 ml, 0.3169 mol) in tetrahydrafuran (200 ml), was added n-BuLi (2.5M, 105.6 ml, 0.264 mol) in hexane at 0°C and the reaction mixture was allowed to stir at same temperature for about 10-15 min. The reaction mixture was stirred at room temperature for about 45 min. methyl cyclohexanecarboxylate (step 1, 15 g, 0.15067 mol) in tetrahydrafuran (150 ml) was added drop-wise at -78°C to LDA (reaction mixture). The reaction mixture was stirred at same temperature for about 2 h and then neat ethyl iodide (12.67 ml, 0.1584 mol) was added drop-wise. The reaction was maintained at -78°C for an hour and allowed to attain room temperature. The reaction mixture was stirred overnight at room temperature and quenched at 0°C with saturated NH4C1 solution. The solvent was concentrated over vaccum and the compound was extracted with ethyl acetate. The organic layer was washed with saturated brine solution, dried over anhydrous Na2S04 and concentrated. The obtained crude product was directly used for the next step. Crude yield: 10 gm. Ή NMR (CDC13, 300 MHz): δ 4.11 (q, 2H, J = 7.2 Hz); 2.13-1.41 (m, 13H); 1.21 (t, 3H, J = 7.2 Hz); 0.81 (t, 3H, 7 = 7.5 Hz). ESI Mass: 171 (M+l).
Step 3: Synthesis of (l-ethylcyclohexyl)methanol:
Figure imgf000031_0001
Methyl 1-ethylcyclohexanecarboxylate (step 2, 10 g, 0.0588 mol) in tetrahydrafuran (120 ml) was added to a suspension of L1AIH4 (6.7 g, 0.1764 mol) in tetrahydrafuran (200 ml) at 0°C and the reaction mixture was allowed to stir at the same temperature for about 30 min. The reaction mixture was stirred overnight at room temperature. After completion of the reaction, the reaction mixture was quenched with ice cold water at 0°C and filtered over celite. The residue was washed with hot ethyl acetate. The organic layer was washed with saturated brine solution, dried over anhydrous Na2S04 and concentrated. The obtained crude product was directly used for the next step. Crude yield: 8 gm. 1H NMR (CDC13, 300 MHz): 6 3.41 (s, 2H); 1.42-1.36 (m, 12H); 1.30-1.26 (t, 3H).
Step 4: Synthesis of (l-ethylcyclohexyl)methyl 4-methylbenzenesulfonate:
Figure imgf000031_0002
To a solution of (l-ethylcyclohexyl)methanol (step 3, 8 g, 0.0563 mol) in dichloromethane (200 ml), triethyl amine (31.3 ml, 0.2253 mol) was added followed by tosyl chloride (21.4 g, 0.1126 mol) at 0°C. After addition of catalytic amount of DMAP (0.567 g, 0.0056 mol), the reaction mixture was allowed to stir for overnight at room temperature. After completion of reaction, the reaction mixture was washed with water, saturated brine solution; the organic layer was dried over anhydrous Na2S04 and concentrated. The obtained product was purified by column chromatographic technique. Yield: 8 gm. 1H NMR (CDC13, 300 MHz): δ 7.80-7.77 (d, 2H, J = 8.1 Hz); 7.35-7.33 (d, 2H, J = 8.1 Hz); 3.78 (s, 2H); 2.45 (s, 3H); 1.39- 1.27 (m, 12H); 0.68-0.63 (t, 3H, J = 7.5 Hz). ESI Mass: 319.17 (M+Na). Step 5: Synthesis of4-bromo-l-chloro-2-(4-((l- ethylcyclohexyl )methoxy )benzyl )benzene:
Figure imgf000032_0001
To a suspension of Cs2C03 (39.6 g, 0.1216 mol) in dimethylformamide (150 ml), Intermediate 1 (12 g, 0.0405 mol) in dimethylformamide (100 ml) was added followed by (l-ethylcyclohexyl)methyl 4-methylbenzenesulfonate (step 4, 17.9 g, 0.0608 mol) in dimethylformamide (50 ml) then the reaction mixture was stirred for overnight at 120°C. After completion of the reaction as monitored by TLC, the reaction mixture was extracted with ether and washed with saturated brine solution. The organic layer was dried over anhydrous Na2S04 and concentrated. The obtained product was purified by column chromatographic technique. Yield: 8.5 gm. 1H NMR (CDC13, 300 MHz): δ 7.27-7.23 (m, 3H); 7.09-7.06 (d, 2H, J=8.7Hz); 6.86- 6.83 (d, 2H, J=8.7Hz); 3.98 (s, 3H); 3.67 (s, 2H), 1.45-1.40 (m, 12H); 0.88-0.77 (t, 3H, J = 7.8 Hz).
Intermediate 8: Preparation of (2S.3R.4S.5S,6R)-2-(4-chloro-3-(4-((l- ethylcyclohexyl)methoxy benzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro- 2H-pyran-3A5-triol (β-isomer) & (2R,3R.4S,5S.6R)-2-(4-chloro-3-(4-(il- ethylcvclohexyl)methoxy benzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro- 2H-pyran-3A5-triol oc-isomer):
Figure imgf000032_0002
T-BuLi (1.7 M, 23.8 ml, 0.0404mol) was added drop-wise to a solution of 4- bromo- 1 -chloro-2-(4-(( 1 -ethylcyclohexyl)methoxy)benzyl)benzene (Intermediate 7, 8.5 g, 0.0202 mol) in tetrahydrafuran: toluene (150 ml, 1:2) at -78°C. After 20 minutes, the lithiated derivative was added drop- wise to a pre-cooled solution (at - 78°C) of silyl sugar (Intermediate 2, 7.54 g, 0.0161mol) in toluene (70 ml). The reaction was maintained at the same temperature for about 2 hours then it was quenched with methane sulfonic acid (6 % in MeOH, 127.5 ml). The reaction mixture was stirred at room temperature for an hour then the reaction mixture was quenched with saturated NaHC03 solution and diluted with ethyl acetate. The organic layer was washed with saturated brine solution, dried over anhydrous Na2S04 and concentrated. Diastereomeric products were separated by column chromatographic technique. 1H NMR (CDC13, 300 MHz): oc-isomer: 6 7.39-7.29 (m, 3H); 7.08 -7.06 (m, 2H); 6.85-6.81 (m, 2H); 4.49-4.17 (m, 3H); 4.16-3.97 (m, 6H); 3.67 (s, 2H); 3.11-2.93 (d, 2H); 1.51-1.36 (m, 10H), 0.81-0.76 (t, 3H).
β-isomer: 5 7.48 (s, 1H), 7.34 (s, 3H), 7.04-7.01 (d, 2H, J=8.7Hz); 6.82- 6.79 (d, 2H, J = 8.7 Hz); 4.96-4.94 (d, 2H, J=5.4Hz), 4.77-4.72 (m, 1H), 4.54-4.50 (m, 1H), 4.01- 3.88 (q, 2H); 3.71 (m, 1H), 3.67 (s, 2H); 3.56-3.45 (m, 3H); 3.19-3.13 (m, 1H); 2.88 (s, 3H); 2.85-2.82 (m, 1H), 1.40 -1.27 (m, 10H); 0.73-0.68 (t, 3H, J = 7.2 Hz). ESI Mass: 557.30 (M+Na).
Intermediate 9j Preparation of 4-bromo- 1 -chloro-2-(4-(( 1 - methylcyclohexyI)methoxy)benzyl)benzene:
Figure imgf000033_0001
Step 1: Synthesis of methyl cyclohexanecarboxylate:
Figure imgf000033_0002
Concentrated H2S04 (19.1 ml, 1.0 eq) was added drop-wise to a solution of cyclohexanecarboxylic acid (25 g, 0.1953 mol) in MeOH (125 ml) at 0°C and the reaction mixture was refluxed for about 48 hours. After completion of the reaction, the solvent was removed and the reaction mixture was dissolved in dichloromethane. The organic layer was washed with saturated NaHC03 solution and the organic layer was dried over anhydrous magnesium sulphate. The obtained residue with least moisture content (mc) was used directly for the next step. Yield: 16gm.
Step 2: Synthesis of methyl 1 -methylcyclohexanecarboxylate:
O
OMe To a solution of diisopropylamine (44.3 ml, 0.3169 mol) in tetrahydrafuran (200 ml), n-BuLi (2.5M, 106 ml, 0.264 mol) in hexane was added at 0°C and the reaction mixture was allowed to stir at same temperature for about 10-15 min. The reaction mixture was stirred at room temperature for about 45 minutes; methyl cyclohexanecarboxylate (step 1, 15 g, 0.15067 mol) in tetrahydrafuran (150 ml) was added drop-wise at -78°C to LDA (reaction mixture). The reaction mixture was stirred at same temperature for about 2 h and then neat methyl iodide (13.6 ml, 0.2112 mol) was added drop-wise. The reaction was maintained at -78°C for an hour and allowed to attain room temperature. Reaction mixture was stirred overnight at room temperature and quenched at 0°C with saturated NH4C1 solution. The solvent was concentrated over vaccum and the compound was extracted with ethyl acetate. The organic layer was washed with saturated brine solution and then dried over anhydrous Na2S04 and concentrated. The obtained crude product was directly used for the next step. Crude yield: 15 gm. Ή NMR (CDC13, 300 MHz): 3.65 (s, 3H); 2.33-2.26 (m, 1H); 1.91-1.87 (m, 2H, / = 7.2 Hz); 1.76-1.65 (m, 3H), 1.45-1.30 (m, 3H), 1.13 (s, 3H).
Step 3: Synthesis of (l-methylcyclohexyl)methanol:
Figure imgf000034_0001
Methyl 1-methylcyclohexanecarboxylate 3 (15 g, 0.0961 mol) in tetrahydrafuran (100 ml) was added to a suspension of LiAlH4 (7.3 g, 0.1923 mol) in tetrahydrafuran (100 ml) at 0°C and the reaction mixture was allowed to stir at same temperature for about 30 minutes. The reaction mixture was stirred overnight at room temperature. After completion of reaction, the reaction mixture was quenched with ice cold water at 0°C and filtered over celite. The residue was washed with hot ethyl acetate. The organic layer was washed with saturated brine solution, dried over anhydrous Na2S04 and concentrated. The obtained crude product was directly used for the next step. Crude yield: 9 gm. Ή NMR (CDC13, 300 MHz): δ 3.34 (s, 2H); 1.49-1.44 (m, 4H); 1.31-1.25 (m, 6H), 0.91 (s, 3H).
Step 4: Synthesis of (l-methylcyclohexyl)methyl 4-methylbenzenesulfonate :
Figure imgf000035_0001
To a solution of (l-methylcyclohexyl)methanol (step 3, 9 g, 0.0775 mol) in dichloromethane (100 ml), triethyl amine (64.7 ml, 0.2253 mol) was added followed by tosyl chloride (36.85 g, 0.1939 mol) at 0°C. After addition of catalytic amount of DMAP (0.71 g, 0.00703 mol), the reaction mixture was allowed to stir for overnight at room temperature. After completion of the reaction, the reaction mixture was washed with water, saturated brine solution, and the organic layer was dried over anhydrous Na2S04 and concentrated. The obtained product was purified by column chromatographic technique. Yield: 15 gm. 1H NMR (CDC13, 300 MHz): δ 7.80-7.77 (d, 2H, J = 7.8 Hz); 7.36-7.33 (d, 2H, J = 8.1 Hz); 3.72 (s, 2H); 2.45 (s, 3H); 1.40- 1.34 (m, 6H); 1.28-1.24 (m, 4H), 0.88 (s, 3H).
Step 5: Synthesis of 4-bromo-l-chloro-2-(4-((l- methylcyclohexyl )methoxy )benzyl )benzene:
Figure imgf000035_0002
To a suspension of Cs2C03 (36.5 g, 0.112 mol) in dimethylformamide (150 ml), Intermediate 1 (11.05 g, 0.037 mol) in dimethylformamide (100 ml) was added followed by (l-methylcyclohexyl)methyl 4-methylbenzenesulfonate (step 4, 15.8 g, 0.056 mol) in dimethylformamide (50 ml) and the reaction mixture was stirred overnight at 120°C. After completion of reaction as monitored by TLC, the reaction mixture was extracted with ether and washed with saturated brine solution. The organic layer was dried over anhydrous Na2S04 and concentrated. The obtained product was purified by column chromatographic technique. Yield: 4 gm. Ή NMR
(CDC13, 300 MHz): 6 7.23-7.22 (m, 3H); 7.09-7.06 (d, 2H, J=8.7Hz); 6.83 (d, 2H, J=8.7Hz); 3.97 (s, 2H); 3.62 (s, 2H), 1.49-1.36 (m, 10H); 1.02 (s, 3H).
Intermediate 10: Preparation of (2S,3R,4S.5S.6R)-2-(4-chloro-3-(4-((l- methylcvclohexyl)methoxy)benzyl phenyl)-6-(hydroxymethyl)-2- methoxytetrahvdro-2H-pyran-3,4,5-triol:
Figure imgf000036_0001
T-BuLi (1.7 M, 20.2 ml, 0.0344mol) was added drop-wise to a solution of 4- bromo- 1 -chloro-2-(4-(( 1 -methylcyclohexyl)methoxy)benzyl)benzene (Intermediate 9, 7 g, 0.0172mol) in tetrahydrafuran: toluene (90 ml) (1:2) at -78°C. After 20 minutes, the lithiated derivative was added drop-wise to a pre-cooled solution (at - 78°C) of silyl sugar (Intermediate 2, 6.4 g, 0.0137mol) in toluene (70 ml). The reaction mixture was maintained at the same temperature for about 2 hours then quenched with methane sulfonic acid (6 % in MeOH, 105 ml). The reaction mixture was stirred at room temperature for an hour then quenched with saturated NaHC03 solution and diluted with ethyl acetate. The organic layer was washed with brine solution, dried over anhydrous Na2S04 and concentrated. The obtained product was separated by column chromatographic technique. Ή NMR (CDC13, 300 MHz): δ 7.48 (s, 1H), 7.34 (s, 2H), 7.04-7.01 (d, 2H, J=8.4Hz); 6.81- 6.78 (d, 2H, / = 8.7Hz); 5.06 (bs, 1H), 4.82 (bs, 2H), 4.57 (bs, 1H), 3.96-3.93 (q, 2H); 3.67 (m, 1H), 3.62 (s, 3H); 3.58-3.50 (m, 2H); 3.18-2.87 (m, 3H); 1.40-1.25 (m, 6H); 1.19-1.16 (m, 4H), 0.9 (s, 3H); ESI Mass: 543.30 (M+Na).
Intermediate 11: Preparation of 3-((4-(5-bromo-2-chlorobenzyl)phenoxy)methyl)-3- ethyloxetane:
Figure imgf000036_0002
Step 1: Synthesis of (3-ethyloxetan-3-yl)methyl 4 -methylbenzene sulfonate:
Figure imgf000036_0003
To a solution of (3-ethyloxetan-3-yl)methanol (15 g, 0.129 mol) in dichloromethane (300 ml), triethyl amine (144 ml, 1.0344 mol) followed by tosyl chloride (123 g, 0.646 mol) was added at 0°C. After addition of catalytic amount of DMAP (16 g, 0131 mol), the reaction mixture was allowed to stir overnight at room temperature. After completion of the reaction as monitored by TLC, the reaction mixture was washed with water, saturated brine solution; the organic layer was dried over anhydrous Na2S04 and concentrated. The obtained product was purified by column chromatographic technique. Yield: 15 gm. 1H NMR (CDC13, 300 MHz): δ 7.83-7.80 (d, 2H, J = 8.4 Hz); 7.39- 7.36 (d, 2H, J = 8.4 Hz); 4.38-4.36 (d, 2H, J=6.3Hz), 4.31-4.29 (d, 2H, J=6.3Hz), 4.17 (s, 2H), 2.47 (s, 3H), 1.78-1.71 (q, 2H), 0.83-0.78 (t, 3H).
Step 2: Synthesis of3-((4-(5-bromo-2-chlorobenzyl)phenoxy)methyl)-3- ethyloxetane:
Figure imgf000037_0001
To a suspension of Cs2C03 (32.8 g, 0.1010 mol) in dimethylformamide (60 ml), Intermediate 1 (10 g, 0.033 mol) in dimethylformamide (100 ml) was added followed by (3-ethyloxetan-3-yl)methyl 4-methylbenzenesulfonate (step 1, 9 g, 0.033 mol) in dimethylformamide (50 ml) and the reaction mixture was stirred for overnight at 100°C. After completion of reaction as monitored by TLC, the reaction mixture was extracted with ether and washed with saturated brine solution. The organic layer was dried over anhydrous Na2S04 and concentrated. The obtained product was purified by column chromatographic technique. Yield: 8 gm. !H NMR (CDC13, 300 MHz): δ 7.30-7.21 (m, 3H); 7.12-7.09 (d, 2H, J=8.4Hz); 6.90-6.87 (d, 2H, 8.4Hz); 4.58-4.56 (d, 2H, J=5.7Hz), 4.49-4.47 (d, 2H, J=5.7), 4.06 (s, 2H), 4.00 (s, 2H), 1.91-1.84 (q, 2H); 0.95-0.90 (t, 3H).
Intermediate 12: Preparation of (2S,3R.4S.5S.6R)-2-(4-chloro-3-(4-((3-ethyloxetan-
3-yl)methoxy)benzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahvdro-2H-pyran-
3A5-triol:
Figure imgf000037_0002
T-BuLi (1.7 M, 23.8 ml, 0.0406mol) was added drop-wise to a solution of 3- ((4-(5-bromo-2-chlorobenzyl)phenoxy)methyl)-3-ethyloxetane (Intermediate 11, 8 g, 0.0203mol) in tetrahydrafuran: toluene (90 ml) (1:2) at -78°C. After 20 minutes, the lithiated derivative was added drop-wise to a pre-cooled solution (at -78°C) of silyl sugar (Intermediate 2, 7.6 g, 0.0162 mol) in toluene (60 ml). The reaction mixture was maintained at the same temperature for about 2 hours then quenched with methane sulfonic acid (6 % in MeOH, 120 ml). The reaction mixture was stirred at room temperature for three hours then it was quenched with saturated NaHC03 solution and diluted with ethyl acetate. The organic layer was washed with saturated brine solution. The organic layer was dried over anhydrous Na2S04 and concentrated. The obtained product was separated by column chromatographic technique. 1H NMR (DMSO-D6, 300 MHz): δ 7.48 (s, 1H), 7.35 (s, 2H), 7.05-7.02 (d, 2H, J=8.7Hz); 6.83-6.80 (d, 2H, J = 8.7Hz); 4.96-4.95 (d, 1H, J = 5.4 Hz); 4.79- 4.52 (m, 3H), 3.97 (m, 1H); 3.94-3.70 (m, 4H), 3.67-3.46 (m, 3H), 3.41 (s, 1H), 3.21-3.16 (m, 1H), 2.87-2.81 (m, 3H); 1.40-1.38 (q, 2H); 0.82-0.77 (t, 3H, J = 7.5 Hz). ESI Mass: 531 (M+Na).
Intermediate 13: Preparation of (2S,3R,4R,5S,6R)-2-(3-(4-hvdroxybenzyl)-4- methylphenyl)-6-(hvdroxymethyl)tetrahydro-2H-pyran-3,4,5-triol:
Figure imgf000038_0001
Step 1: Synthesis of(5-bromo-2-methylphenyl)(4-ethoxyphenyl)methanone:
Figure imgf000038_0002
5-bromo-2-methylbenzoic acid (13 g) was suspended in dichloromethane (100 ml) and dimethylformamide (100 ml) then it was cooled to 0 °C and SOCl2 (26.5 ml) was added slowly. The reaction mixture was slowly allowed to room temperature and stirred for about 12 hours. The solvent was removed under reduced pressure to give 5-bromo-2-methylbenzoyl chloride as oil. Ethoxybenzene (7 ml) was suspended in dichloromethane and cooled to -5 °C then the mixture was added slowly to A1C13 (10.4 g) by portion wise and the above acid chloride in dichloromethane (— ) was added drop wise and stirred for about 1 hour at 0 °C. After completion of the reaction (monitored by TLC), the reaction mixture was poured into ice- water. The organic layer was separated and aqueous layer was extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulphate and concentrated to give the crude compound. The crude product was purified via silica gel column chromatography with EtOAc and n- Hexane (1: 7) to afford the title compound as light yellow solid (15 g). Yield: 77.8 %; 1H NMR (CDCI3, 300 MHz): δ 7.76 (d, J = 8.7 Hz, 2H), 7.48 (dd, J = 2.1, 8.1 Hz, 1H), 7.40 (d, J = 2.1 Hz, 1H), 7.15 (d, / = 8.1 Hz, 1H), 6.92 (d, J = 8.7 Hz, 2H), 4.11 (q, J = 6.9 Hz, 2H), 2.22 (s, 3H), 1.45 (t, J = 6.9 Hz, 3H).
Step 2: Synthesis of (5-bromo-2-methylphenyl)(4-hydroxyphenyl)methanone:
Figure imgf000039_0001
To a stirred solution of (5-bromo-2-methylphenyl)(4- ethoxyphenyl)methanone (step 1, 15 g) in dichloromethane (200 ml), AICI3 (62.5 g) was added at 0 °C under N2 atmosphere by portion wise over 30 minutes. Subsequently, the reaction mixture was stirred at room temperature for about 12 hours. After completion of the reaction (monitored by TLC), reaction mixture was poured into ice- water. The organic layer was separated and aqueous layer was extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulphate and concentrated to give the crude compound. The crude product was purified via silica gel column chromatography with EtOAc and n-Hexane (1 : 5) to afford title compound as pale yellow solid (14 g). Yield: 81.3 %; 1H NMR (CDC13, 300 MHz): δ 7.74 (d, J = 8.7 Hz, 2H), 7.48 (dd, J = 2.1, 8.4 Hz, 1H), 7.40 (d, J = 2.1 Hz, 1H), 7.15 ( d, J = 8.4 Hz, 1H), 6.88 (d, J = 8.7 Hz, 2H), 5.53 (s, 1H), 2.23 (s, 3H).
Step 3: Synthesis of4-(5-bromo- -methylbenzyl)phenol:
Figure imgf000039_0002
To a stirred solution of (5-bromo-2-methylphenyl)(4- hydroxyphenyl)methanone (step 2, 14 g) in dichloromethane (100 ml) and acetylnitrile (1: 1), Et3SiH (39 ml) was added at 0 °C under N2 atmosphere followed by BF3: Et20 (15 ml) then reaction mixture was continued for about 16 hours at room temperature. After completion of the reaction (monitored by TLC), volatiles were concentrated under reduced pressure. Then the reaction mixture was cooled to 0 °C and neutralized by cautious addition of saturated aq. NaHC03 Solution. The reaction mixture was extracted with EtOAc. The combined organic layers were washed with water, brine, dried over anhydrous sodium sulphate and concentrated to give the crude compound. The crude product was purified via silica gel column chromatography with EtOAc and n-Hexane (1: 5) to afford the title compound as liquid (12.2 g). Yield: 92.3 %; 1H NMR (CDC13, 300 MHz): 6 7.25- 7.24 (m, 1H), 7.20 (d, J = 1.8 Hz, 1H), 7.03- 6.96 (m, 3H), 6.75 (dd, J = 1.8, 6.6 Hz, 2H), 4.63 (s, 1H), 3.85 (s, 2H), 2.17 (s, 3H); ES Mass: (M+ H) 276.90 (100 %).
Step 4: Synthesis of4-bromo-2-( -(methoxymethoxy)benzyl)-l-methylbenzene:
Figure imgf000040_0001
To a stirred solution of NaH (3.1 g) in dimethylformamide (110 ml), 4-(5- bromo-2-methylbenzyl)phenol (step 3, 12.2 g) was added under N2 atmosphere at 0 °C then. MOM-C1 (4.3 ml) was added after 30 minutes at 0 °C. The reaction mixture was slowly allowed to attain to room temperature and continued for over night. After completion of the reaction (monitored by TLC), reaction mixture was cooled to 0 °C and quenched with by cautious addition of sat. aq. NH4C1 solution. The reaction mixture was extracted with EtOAc twice and combined organic layers were washed with brine, dried over anhydrous sodium sulphate and concentrated to give the residue. The crude product was purified via silica gel column chromatography with EtOAc and n-Hexane (1:49) to afford compound as liquid (11.6 g). Yield: 82 %; 1H NMR (CDCI3, 300 MHz): δ 7.27- 7.21 (m, 2H), 7.03- 6.94 (m,5H), 5.15 (s,2H), 3.87 (s, 2H), 3.47 (s, 3H), 2.18 (s, 3H).
Step 5: Synthesis of (3R,4S,5S,6R)~2-(3-(4-hydroxybenzyl)-4-methylphenyl)-6- ( hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3, 4, 5-triol:
Figure imgf000041_0001
To a stirred solution of 4-bromo-2-(4-(methoxymethoxy)benzyl)-l- methylbenzene (step 4, 11.6 g) in dry tetrahydrafuran (70 ml) and toluene (60 ml, 1: 1 ), n-BuLi (2.3 M in hexane) was added at -78 °C under N2 atmosphere and stirred for about 30 minutes. To this solution (3R,4S,5R,6R)-3,4,5- tris(trimethylsilyloxy)-6-((trimethylsilyloxy)methyl)tetrahydro-2H-pyran-2-one (Intermediate2, 13.4 g) and stirred for about 2 hours at -78 °C then 6 % CH3S02H in MeOH (150 ml) was added slowly at same temperature then the reaction was allowed to room temperature and continued for about 12 hours. After completion of the reaction (monitored by TLC), reaction mixture was cooled to 0 °C and neutralized by cautious addition of saturated aq. NaHC03 Solution. The reaction mixture was extracted with EtOAc. The combined organic layers were washed with water, brine, dried over anhydrous sodium sulphate and concentrated to get the residue. The crude product was purified via silica gel column chromatography with MeOH and dichloromethane (1:24) to afford the title compound as White solid and Hygroscopic (5.2 g). Yield: 36.8 %; 1H NMR (DMSO- D6, 300 MHz): δ 9.14 (s, 1H), 7.32 (s, 1H), 7.27 (d, / = 7.8 Hz, 1H), 7.08 (d, J = 7.8 Hz, 1H), 6.89 (d, J = 8.4 Hz, 2H), 6.64 (d, J = 8.4 Hz, 2H), 4.93 (d, J = 5.4 Hz, 1H), 4.68 (d, J = 5.1 Hz, 1H), 4.62 (d, J = 7.5 Hz, 1H), 4.50 (dd, J = 6.0, 6.0 Hz, 1H), 3.83- 3.81 (m, 2H), 3.76- 3.71 (m, lH), 3.59- 3.50 (m, 3H), 3.26- 3.16 (m, 1H), 2.93 (s, 3H), 2.90- 2.87 (m, 1H), 2.13 (s, 3H); ES Mass: (M+ Na) 413.20 (100 %).
Step 6: Synthesis of (3R,4R,5S,6R)-2-(3-(4-hydroxybenzyl)-4-methylphenyl)-6- (hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol:
Figure imgf000041_0002
To a stirred solution of (3R,4S,5S,6R)-2-(3-(4-hydroxybenzyl)-4- methylphenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (step 5, 5.2 g) in dichloromethane (30 ml) and AcCN (30 ml) (1:1), Et3SiH (8.5 ml) was added at 0 °C under N2 atmosphere followed by BF3: Et20 (3.3 ml) then reaction mixture was stirred for about 6 hours. After completion of the reaction (monitored by TLC), volatiles were concentrated under reduced pressure. Then the reaction mixture was cooled to 0 °C and neutralized by cautious addition of saturated aq. NaHC03 Solution. The reaction mixture was extracted with EtOAc. The combined organic layers were washed with water, brine, dried over anhydrous sodium sulphate and concentrated to afford the residue. The crude product was purified by silica gel column chromatography with MeOH and dichloromethane (1:24) to give mixture compound (mixture of α & β isomers) as white solid (3 g). Yield: 62.5 %; HPLC: 83 %; 1H NMR (DMSO- D6, 300 MHz): δ 9.15 (s, 1H), 7.10- 7.07 (m, 3H), 6.91 (d, J = 8.4 Hz, 2H), 6.65 (d, J = 8.4 Hz, 2H), 4.91- 4.90 (m, 2H), 4.70 (d, J = 5.7 Hz, 1H), 4.42 (dd, J = 5.7, 5.7 Hz, 1H), 3.93 (d, J = 9.0 Hz, 1H), 3.81 (s, 2H), 3.75- 3.66 (m, 1H), 3.46- 3.38 (m, 1H), 3.23- 3.14 (m, 4H), 2.15 (s, 3H); ES Mass: (M+Na) 383.11
Step 7: Synthesis of (2S,3S,4R,5R,6R)-2-(3-(4-acetoxybenzyl)-4-methylphenyl)-6- (acetoxymethyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (β- isomer):
Figure imgf000042_0001
To a stirred solution of (3R,4R,5S,6R)-2-(3-(4-hydroxybenzyl)-4- methylphenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (step 6, 3 g) in dichloromethane (70 ml), Et3N was added at 0 °C under N2 atmosphere followed by AC20 (9.4 ml) and DMAP then the reaction temperature was slowly raised to room temperature and stirred for over night. After completion of the reaction (monitored by TLC), reaction mixture was diluted with dichloromethane and organic layer was washed with 3N HC1 solution, brine and dried over anhydrous sodium sulphate and concentrated to give the residue. The crude product was purified via silica gel column chromatography with EtOAc and Hexane (2: 4) to afford the title compound (β- isomer) as white solid (6 g). Yield: 96 %; 1H NMR (CDC13, 300 MHz): δ 7.15 (s, 2H), 7.07- 7.05 (m, 3H), 6.97 (d, J = 8.4 Hz, 2H), 5.34- 5.10 (m, 3H), 4.34 (d, J = 9.9 Hz, 1H), 4.30- 4.25 (m, 1H), 4.17- 4.11 (m, 1H), 3.95 (s, 2H), 3.84- 3.78 (m, 1H), 2.27 (s, 3H), 2.20 (s, 3H), 2.07 (s, 3H), 2.05 (s, 3H), 1.99 (s, 3H), 1.74 (s, 3H); ES Mass: (M+ Na) 592.98
Step 8: Synthesis of (2S,3R,4R,5S,6R)-2-(3-(4-hydroxybenzyl)-4-methylphenyl)-6- ( hydroxymethyl )tetrahydro-2H-pyran-3, 4, 5-triol:
NH3 in MeOH (120 ml) was added to (2S,3S,4R,5R,6R)-2-(3-(4- acetoxybenzyl)-4-methylphenyl)-6-(acetoxymethyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (β- isomer, step 7, 6g) at room temperature and stirred for over night. After completion of the reaction (monitored by TLC), volatiles were concentrated under reduced pressure to give residue. The crude product was purified via silica gel column chromatography with MeOH and dichloromethane (1: 19) to afford the title product as white solid (2.8 g). Yield: 93 %; 1H NMR (DMSO- D6, 300 MHz): δ 9.15 (s, 1H), 7.10- 7.07 (m, 3H), 6.91 (d, J = 8.4 Hz, 2H), 6.65 (d, J = 8.4 Hz, 2H), 4.91- 4.90 (m, 2H), 4.70 (d, J = 5.7 Hz, 1H), 4.42 (dd, J = 5.7, 5.7 Hz, 1H), 3.93 (d, / = 9.0 Hz, 1H), 3.81 (s, 2H), 3.75- 3.66 (m, 1H), 3.46- 3.38 (m, 1H), 3.23- 3.14 (m, 4H), 2.15 (s, 3H); ES Mass: (M+ Na) 383.10; HPLC: 96.3 %
Intermediate 14: Preparation of (l-(trifluoromethyl)cvclopropyl)methyl 4- methylbenzenesulf onate :
Figure imgf000043_0001
Step 1: Synthesis of (l-(trtfluoromethyl)cyclopropyl)methanol:
Figure imgf000043_0002
To a stirred solution of Lithium aluminium hydride (2.4 g) in dry ether (70 ml) l-(trifluoromethyl)cyclopropanecarboxylic acid (5 g) was added at 0 °C under N2 atmosphere and the reaction mixture was stirred for about 1 hour. After completion of the reaction (monitored by Ή- NMR), the reaction mixture was quenched by cautious addition of water (1 ml), 15 % aq. NaOH solution (1 ml) and again water (3 ml) and stirred for 30 minutes. The reaction mixture was filtered and cake was washed with ether twice. Due to volatile nature of the compound, only half of the ether volume was reduced on hot water both using without any vacuum and next reaction was proceeded as such. 1H NMR (CDC13, 300 MHz): δ 3.73 (s, 2H), 1.83 (br s, 1H), 1.05- 1.01 (m, 2H), 0.80- 0.76 (m, 2H); ES Mass: (M- H) 138.91
Step 2: Synthesis of (l-(trifluoromethyl)cyclopropyl)methyl 4- methylbenzenesulfonate:
To a stirred solution of (l-(trifluoromethyl)cyclopropyl)methanol (step 1, 4.5 g) in dichloromethane (50 ml), Et3N (13.5 ml) was added at 0 °C under N2 atmosphere followed by TsCl (9.1 g) and catalytic amount of DMAP. The reaction mixture was allowed to room temperature and stirred for about 12 hours. After completion of the reaction (monitored by 1H- NMR), reaction mixture was diluted with dichloromethane and organic layer was washed with saturated aq. NHUC1 solution, brine and dried over anhydrous sodium sulphate and concentrated to give the residue. The crude product was purified via silica gel column chromatography with EtOAc and n-Hexane (1:39) to afford the title compound as liquid (8.2 g). Yield: 86 %; 1H NMR (CDC13, 300 MHz): δ 7.79 (d, J = 8.4 Hz, 2H), 7.36 (d, J = 8.4 Hz, 2H), 4.09 (s, 2H), 2.46 (s, 2H), 1.14- 1.10 (m, 2H), 0.85- 0.84 (m, 2H); ES Mass: (M+ Na) 317.08.
Intermediate 15: Preparation of (l-(trifluoromethyl)cyclobutyl)methyl 4- methylbenzenesulfonate:
Figure imgf000044_0001
Step 1: Synthesis of ( 1 -(trifluoromethyl)cyclobutyl)methanol:
Figure imgf000044_0002
To a stirred solution of Lithium aluminium hydride (2.7 g) in dry ether (80 ml), l-(trifluoromethyl)cyclobutanecarboxylic acid (6 g) was added at 0 °C under N2 atmosphere and the reaction mixture was stirred for about 1 h at 0 °C. After completion of the reaction (monitored by !H- NMR), the reaction mixture was quenched by cautious addition of water (1 ml), 15 % aq. NaOH solution (1 ml) and again water (3 ml), with stirring continued for 30 min. The reaction mixture was filtered and cake was washed with ether twice. Due to volatile nature of the compound, only half of the ether volume was reduced on hot water both using without any vacuum and next reaction was proceeded as such. 1H NMR (CDC13, 300 MHz): δ 3.81 (s, 2H), 2.30- 2.26 (m, 2H), 2.06- 1.91 (m, 4H), 1.71 (br s, 1H); ES Mass: (M- H) 152.95.
Step 2: Synthesis of (l-(trifluoromethyl)cyclobutyl)methyl 4-methylbenzenesulfonate:
To a stirred solution of (l-(trifluoromethyl)cyclobutyl)methanol (step 1, 5.5 g) in dichloromethane (50 ml), Et3N (15 ml) was added at 0 °C under N2 atmosphere followed by TsCl (10 g) and catalytic amount of DMAP. The reaction mixture was allowed to room temperature and stirred for about 12 hours. After completion of the reaction (monitored by 1H- NMR), reaction mixture was diluted with dichloromethane and organic layer was washed with saturated aq. NH4C1 solution, brine and dried over anhydrous sodium sulphate and concentrated to afford the residue. The crude product was purified via silica gel column chromatography with EtOAc and n-Hexane (1:39) to afford the title compound as liquid (7 g). Yield: 63 ; 1H NMR (CDC13, 300 MHz): δ 7.81 (d, J = 8.4 Hz, 2H), 7.37 (d, / = 8.4 Hz, 2H), 4.13 (s, 2H), 2.46 (s, 3H), 2.32- 2.27 (m, 2H), 2.03- 1.96 (m, 4H); ES Mass: (M+ Na) 331.
Intermediate 16: Preparation of (4,4-difluoro-l-methylcyclohexyl)methyl 4- methylbenzenesulfonate:
Figure imgf000045_0001
Step 1: Synthesis of methyl 4,4-difluorocyclohexanecarboxylate:
e
Figure imgf000045_0002
Cone. H2S04 was added drop-wise to a solution of 4,4- difluorocyclohexanecarboxylic acid (6 g) in MeOH (50 ml) at 0 °C and the reaction mixture was refluxed for about 16 hours. After the completion of reaction, the solvent was removed and the reaction mixture was dissolved in dichloromethane. The organic layer was washed with saturated NaHC03 solution and the organic layer was dried over anhydrous sodium sulphate. The solvent was removed over rotary evaporator without vacuum to give the crude compound (7.4 g) which was used directly for the next step. 1H NMR (CDC13, 300 MHz): δ 3.69 (s, 3H), 2.42 (m, 1H), 2.10- 1.97 (m, 4H), 1.91- 1.72 (m, 4H).
Step 2: Synthesis of methyl 4,4-difluoro-l-methylcyclohexanecarboxylate:
Figure imgf000046_0001
To a solution of diisopropylamine (11 ml) in tetrahydrafuran (50 ml), n-BuLi (26 ml) was added at 0 °C and the reaction mixture was allowed to stir at same temperature for about 10-15 minutes. The reaction mixture was stirred at room temperature for about 45 minutes. Methyl 4,4-difluorocyclohexanecarboxylate (step 1, 5.3 g) in tetrahydrafuran (40 ml) was added drop-wise to above mixture at -78 °C. The reaction mixture was stirred at same temperature for about 2 hours and then methyl iodide was added drop-wise. The reaction was maintained at -78 °C for an hour and allowed to attain room temperature. Reaction mixture was stirred overnight at room temperature and quenched at 0 °C with saturated aq. NH4C1 solution and the compound was extracted with ethyl acetate. The organic layer was washed with saturated brine solution, dried over anhydrous Na2S04 and concentrated then crude product was directly used for the next step. 1H NMR (CDC13, 300 MHz): δ 3.71 (s, 3H), 2.20- 2.16 (m, 2H), 1.96- 1.71 (m, 4H), 1.57- 1.47 (m, 2H), 1.22 (s, 3H).
Step 3: Synthesis of (4,4-difluoro-l -methylcyclohexyl)methanol:
Figure imgf000046_0002
Methyl 4,4-difluoro-l -methylcyclohexanecarboxylate (step 2, 5.7 g) in tetrahydrafuran (20 ml) was added to a suspension of LiAlH4 (2.25 g) in tetrahydrafuran (50 ml) at 0 °C and the reaction mixture was allowed to stir at the same temperature for about 30 minutes. The reaction mixture was stirred overnight at room temperature. After completion of the reaction (monitored by TLC), the reaction mixture was quenched by cautious addition of water (3.5 ml), 15 % aq. NaOH solution (3.5 ml) and again water (11 ml) at 0 °C and stirred for about 30 minutes. The reaction mixture was filtered and the residue was washed with diisopropylether. The organic layer was washed with saturated brine solution, dried over anhydrous Na2S04 and concentrated. Crude product was directly used for the next step. 1H NMR (CDC13, 300 MHz): δ 3.41 (s, 2H), 1.96- 1.86 (m, 4H), 1.62- 1.54 (m, 2H), 1.46- 1.41 (m, 2H), 0.98 (s, 3H).
Step 4: Synthesis of (4,4-difluoro-l-methylcyclohexyl)methyl 4- methylbenzenesulfonate:
To a solution of (4,4-difluoro-l-methylcyclohexyl)methanol (step 3, 4.8 g) in dichloromethane (60 ml), triethyl amine (12.2 ml) was added followed by tosyl chloride (8.3 g) at 0 °C. After addition of catalytic amount of DMAP (2.47 g, 0.020 mol), the reaction mixture was allowed to stir overnight at room temperature. After completion of reaction, the reaction mixture was washed with water, saturated brine solution, dried over anhydrous Na2SC¼ and concentrated. The product was purified by column chromatographic technique to afford the title compound as solid (5 g). Yield: 51.11 %; 1H NMR (CDC13, 300 MHz): δ 7.78 (d, J = 7.8 Hz, 2H), 7.36 (d, J = 7.8 Hz, 2H), 3.75 (s, 2H), 2.46 (s, 3H), 1.88-1.80 (m, 4H), 1.50- 1.45 (m, 4H), 0.97 (s, 3H); ES Mass: (M+ Na) 340.95.
Intermediate 17: Preparation of (3R,4R,5S,6R)-2-(4-chloro-3-(4-((l-
(trifluoromethyl)cvclobutyl)methoxy)benzyl)phenyl)-6-(hvdroxymethyl)tetrahydro-
2H-pyran-3,4,5-triol:
Figure imgf000047_0001
Step 1: Synthesis of 4-bromo-l-chloro-2-(4-((l-
( trifluoromethyl )cyclobutyl )methoxy )benzyl )benzene:
Figure imgf000048_0001
To a stirred solution of 4-(5-bromo-2-chlorobenzyl)phenol (Intermediate 1, 5.4 g) in dimethylformamide (100 ml), Cs2C03 (17.8 g) was added under N2 atmosphere followed by (l-(trifluoromethyl)cyclobutyl)methyl 4- methylbenzenesulfonate (Intermediate 15, 6.8 g) at room temperature and the reaction mixture was heated to 110 °C then stirred for about 5 hours. After completion of the reaction (monitored by TLC), reaction mixture was cooled to room temperature and filtered through celite and the cake was washed with EtOAc. The filtrate was washed with water and brine, dried over anhydrous sodium sulphate and concentrated to give the residue. The crude product was purified via silica gel column chromatography with EtOAc and n-Hexane (1:49) to afford the title compound as white solid (6.2 g). Yield: 79.4 %; 1H NMR (CDC13, 300 MHz): δ 7.30- 7.21 (m, 3H), 7.11 (d, 7 = 8.7 Hz, 2H), 6.89 (d, 7 = 8.7 Hz, 2H), 4.05 (s, 2H), 4.00 (s, 2H), 2.38- 2.31 (m, 2H), 2.26- 2.17 (m, 2H), 2.07- 1.99 (m, 2H).
Step 2: Synthesis of (3R,4S,5S,6R)-2-(4-chloro-3-(4-((l-
( trifluoromethyl )cyclobutyl )methoxy )benzyl )phenyl )-6-(hydroxymethyl )-2- methoxytetrahydro-2H-pyran-3, 4, 5-triol:
Figure imgf000048_0002
To a stirred solution of 4-bromo-l-chloro-2-(4-((l- (trifluoromethyl)cyclobutyl)methoxy)benzyl)benzene (step 1, 6.2 g) in dry tetrahydrafuran (40 ml) and toulene (60 ml, 1:1 ), n-BuLi (2.3 M, 16.8 ml) was added at -78 °C under N2 atmosphere and stirred for about 30 minutes at -78°C. To this solution (3R,4S,5R,6R)-3,4,5-tris(trimethylsilyloxy)-6-
((trimethylsilyloxy)methyl)tetrahydro-2H-pyran-2-one (Intermediate 2, 5.3 g) in toluene was added at -78 °C and stirred for about 2 hours at same temperature then 6 % CH3S02H in MeOH (105 ml) was added slowly. The reaction mixture was allowed to room temperature and stirred for about 12 hours. After completion of the reaction (monitored by TLC), reaction mixture was cooled to 0 °C and neutralized by cautious addition of saturated aq. NaHC03 Solution. The reaction mixture was extracted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulphate and concentrated to get the residue. The crude product was purified via silica gel column chromatography with MeOH and dichloromethane (1:24) to afford the title compound as White solid (3.6 g). Yield: 46 %; 1H NMR (DMSO- D6, 300 MHz): δ 7.52 (s, 1H), 7.39 (s, 2H), 7.10 (d, / = 8.4 Hz, 2H), 6.90 (d, J = 8.4 Hz, 2H), 4.99 (d, J = 5.4 Hz, 1H), 4.81- 4.76 (m, 2H), 4.56 (dd, / = 5.7, 5.7 Hz, 1H), 4.15 (s, 2H), 4.00 (ABq, 7 = 14.7 Hz, 2H ), 3.76- 3.71 (m, 1H), 3.60- 3.48 (m, 2H), 3.35- 3.32 (m, 1H), 3.27- 3.17 (1H), 2.91 (s, 3H), 2.88- 2.85 (m, 1H), 2.31- 2.20 (m, 2H), 2.09- 1.89 (m, 4H); ES Mass: (M+Na) 469.
Step 3: Synthesis of (3R,4R,5S,6R)-2-(4-chloro-3-(4-((l-
( trifluoromethyl )cyclobutyl)methoxy )benzyl )phenyl)-6-(hydroxymethyl )tetrahydro- 2H-pyran-3,4,5-triol:
To a stirred solution of (3R,4S,5S,6R)-2-(4-chloro-3-(4-((l- (trifluoromethyl)cyclobutyl)methoxy)benzyl)phenyl)-6-(hydroxymethyl)-2- methoxytetrahydro-2H-pyran-3,4,5-triol (step 2, 3.6 g) in dichloromethane (25 ml) and acetylnitrile (25 ml, 1: 1), Et3SiH (2.1 ml) was added at 0 °C under N2 atmosphere followed by BF3: Et20 (1.2 ml) and stirred for about 6 hours at room temperature. After completion of the reaction (monitored by TLC), volatiles were concentrated under reduced pressure. Then the reaction mixture was cooled to 0 °C and neutralized by cautious addition of saturated aq. NaHC03 solution. The reaction mixture was extracted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulphate and concentrated to get the residue. The crude product was purified via silica gel column chromatography with MeOH and dichloromethane (1:24) to give mixture compound (mixture of two α, β isomers) as White solid (3 g). Yield: 88.2 %; HPLC: 79.88 ; 1H NMR (DMSO- D6, 300 MHz): δ 7.38-7.32 (m, 2H), 7.24- 7.14 (m, 1H), 7.12 (d, J = 8.5 Hz, 2H), 6.90 (d, J = 8.5 Hz, 2H), 4.97- 4.95 (m, 2H), 4.84 (d, J = 5.7 Hz, 1H), 4.46 (dd, J = 5.7 Hz, 5.7 Hz, 1H), 4.15 (s, 2H), 4.00-3.97 (m, 3H), 3.71- 3.66 (m, 1H), 3.45-3.40 (m, 1H), 3.26- 3.09 (m, 4H), 2.29- 2.24 (m, 2H), 2.10- 1.93 (m, 4H); ES Mass: (M+Na) 539.
Intermediate 18: Preparation of (l-methylcyclopentyl)methyl 4- methylbenzenesulfonate:
Figure imgf000050_0001
Step 1: Synthesis of methyl 1-methylcyclopentanecarboxylate:
Figure imgf000050_0002
To a solution of di-isopropylamine (69 ml) in tetrahydrafuran (100 ml), n- BuLi (166 ml) in hexane was added at 0 °C and the reaction mixture was allowed to stir at same temperature for about 10-15 minutes. The reaction mixture was stirred at room temperature for about 45 minutes. Methyl cyclopentanecarboxylate (25 g) in tetrahydrafuran (200 ml) was added drop-wise at -78 °C to above reaction mixture. The reaction mixture was stirred at same temperature for about 2 hours and then methyl iodide was added drop-wise. The reaction was maintained at -78°C for an hour and allowed to attain room temperature. The reaction mixture was stirred overnight at room temperature and quenched at 0 °C with saturated aq. NH4C1 solution and the compound was extracted with ethyl acetate. The organic layer was washed with saturated brine solution, dried over anhydrous Na2S04 and concentrated. Crude product was directly used for the next step. 1H NMR (CDC13, 300 MHz):™ 3.66 (s, 3H), 2.10- 2.03 (m, 2H), 1.69- 1.64 (m, 4H), 1.50- 1.42 (m, 2H), 1.23 (s, 3H).
Step 2: Synthesis of (l-methylcyclopentyl)methanol:
Figure imgf000050_0003
Methyl 1-methylcyclopentanecarboxylate (step 1, 26 g) in tetrahydrafuran (200 ml) was added to a suspension of LiAlH4 (14 g) in tetrahydrafuran (150 ml) at 0 °C and the reaction mixture was allowed to stir at same temperature for about 30 minutes. The reaction mixture was stirred overnight at room temperature. After completion of the reaction (monitored by 1 H-NMR), reaction mixture was quenched by cautious addition of water (14 ml), 15 % aq. NaOH solution (14 ml) and again water (42 ml) at 0 °C and stirred for about 1 hour. The reaction mixture was filtered and the residue was washed with diisopropylether. The organic layer was washed with saturated brine solution, dried over anhydrous Na2S04 and concentrated. Crude product was directly used for the next step. 1H NMR (CDC13, 300 MHz):™ 3.37 (s, 2H), 1.68- 1.46 (m, 7H), 1.35- 1.98 (m, 2H), 1.05 (s; 3H).
Step 3: Synthesis of (l-methylcyclopentyl)methyl 4-methylbenzenesulfonate:
To a solution of (l-methylcyclopentyl)methanol (step 2, 20 g) in dichloromethane (250 ml), triethyl amine (74 ml) was added followed by tosyl chloride (66.6 g) at 0°C. After addition of catalytic amount of DMAP (Cat), the reaction mixture was allowed to stir overnight at room temperature. After completion of the reaction, the reaction mixture was washed with water and brine solution, dried over anhydrous Na2S0 and concentrated then purified by column chromatographic technique to afford the title compound as liquid (14 g). Yield: 27 %; 1H NMR (CDC13, 300 MHz):™ 7.78 (d, J = 8.1 Hz, 2H), 7.34 (d, J = 8.1 Hz, 2H), 3.74 (s, 2H), 2.44 (s, 3H), 1.60-1.41 (m, 6H), 1.31- 1.29 (m, 2H), 0.96 (s, 3H).
Intermediate 19: Preparation of (3R,4R,5S,6R)-2-(4-chloro-3-(4-((l- methylcyclopentyl)methoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H- pyran-3A5-triol:
Figure imgf000051_0001
Step 1: Synthesis
methylcyclopentyl )methoxy )benzyl )benzene:
Figure imgf000052_0001
To a stirred solution of 4-(5-bromo-2-chlorobenzyl)phenol (Intermediate 1, 10 g) in dimethylformamide (100 ml), Cs2C03 (33 g) was added under N2 atmosphere followed by (l-methylcyclopentyl)methyl 4-methylbenzenesulfonate (Intermediate 18, 13.6 g) at room temperature. The reaction mixture was heated to 120 °C and stirred for about 5 hours. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature and filtered through celite and the cake was washed with EtOAc. The filtrate was washed with water and brine, dried over anhydrous sodium sulphate and concentrated to give the residue. The crude product was purified via silica gel column chromatography with EtOAc and n-Hexane (1:49) to afford the title compound as liquid (7 g). Yield: 53.8 %; 1H NMR (CDCI3, 300 MHz): δ 7.28- 7.22 (m, 3H), 7.08 (d, J = 8.5 Hz, 2H), 6.84 (d, J = 8.5 Hz, 2H), 3.98 (s, 2H), 3.65 (s, 2H), 1.72- 1.59 (m, 64H), 1.42- 1.37 (m, 2H), 1.11 (s, 3H).
Step 2: Synthesis of (3R,4S,5S,6R)-2-(4-chloro-3-(4-((l- methylcyclopentyl )methoxy )benzyl )phenyl )-6-( hydroxymethyl )-2-methoxytetrahydro- 2H-pyran-3, 4, 5-triol:
Figure imgf000052_0002
To a stirred solution of 4-bromo-l-chloro-2-(4-((l- methylcyclopentyl)methoxy)benzyl)benzene (step 1, 7 g) in dry tetrahydrafuran (40 ml) and toulene (80 ml, 1 : 1 ), t-BuLi (1.7 M in toluene, 24 ml) was added at -78 °C under N2 atmosphere and stirred for about 30 minutes. To this solution (3R,4S,5R,6R)-3,4,5-tris(trimethylsilyloxy)-6-
((trimethylsilyloxy)methyl)tetrahydro-2H-pyran-2-one (Intermediate 2, 6.6 g) in toluene (80 ml) was added at -78 °C and stirred for about 2 hours then 6 % CH3S02H in MeOH (105 ml) was added slowly at same temperature. Then the reaction was allowed to attain room temperature and stirred for about 12 hours. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to 0°C and neutralized by cautious addition of saturated aq. NaHC03 Solution. The reaction mixture was extracted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulphate and concentrated to get the residue. The crude product was purified via silica gel column chromatography with MeOH and dichloromethane (1:24) to afford the title compound as white solid (3 g). Yield: 33.3 %; 1H NMR (DMSO- D6, 300 MHz): δ 7.51 (s, 1H), 7.38 (s, 2H), 7.06 (d, J = 8.4 Hz, 2H), 6.83 (d, J = 8.4 Hz, 2H), 4.98 (d, J = 5.4 Hz, 1H), 4.80- 4.74 (m, 2H), 4.54 (dd, J = 6.3 Hz, 1H), 3.98 (ABq, / = 15.0 Hz, 2H), 3.76- 3.71 (m, 1H), 3.64 (s, 2H), 3.56- 3.48 (m, 2H), 3.40- 3.34 (m, 1H), 3.25- 3.20 (m, 1H), 2.91 (s, 3H), 2.88- 2.85 (m, 1H), 1.68- 1.55 (m, 6H), 1.34- 1.32 (m, 2H), 1.05 (s, 3H); ES Mass: (M+Na) 529.
Step 3: Synthesis of (3R,4R,5S,6R)-2-(4-chloro-3-(4-((l- methylcyclopentyl )methoxy )benzyl )phenyl )-6-(hydroxymethyl )tetrahydro-2H-pyran- 3,4,5-triol:
To a stirred solution of (3R,4S,5S,6R)-2-(4-chloro-3-(4-((l- methylcyclopentyl)methoxy)benzyl)phenyl)-6-(hydroxymethyl)-2- methoxytetrahydro-2H-pyran-3,4,5-triol (step 2, 3 g) in dichloromethane (30 ml) and acetylnitrile (30 ml, 1: 1), Et3SiH (1.9 ml) was added at 0° C under N2 atmosphere followed by BF3: Et20 (1.1 ml) and stirred for about 6 hours. After completion of the reaction (monitored by TLC), volatiles were concentrated under reduced pressure. Then the reaction mixture was cooled to 0° C and neutralized by cautious addition of saturated aq. NaHC03 Solution. The reaction mixture was extracted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulphate and concentrated to get the residue. The crude product was purified via silica gel column chromatography with MeOH and dichloromethane (1:24) to give mixture compound (mixture of α & β isomers) as white solid (1.8 g). Yield: 64.2 ; HPLC: 88.16 ; 1H NMR (DMSO- D6, 300 MHz): δ 7.36 (d, 7 = 8.1 Hz, 1H), 7.31 (d, 7 = 1.8 Hz, 1H), 7.22 (dd, J = 1.8, 8.1 Hz, 1H), 7.08 (d, J = 8.7 Hz, 2H), 6.83 (d, J = 8.7 Hz, 2H), 4.97- 4.95 (m, 2H), 4.83 (d, J = 5.7 Hz, 1H), 4.45 (dd, J = 6.0 Hz, 1H), 3.99- 3.96 (m, 3H), 3.71- 3.69 (m, 1H), 3.65 (s, 2H), 3.45- 3.41 (m, 1H), 3.29- 3.05 (m, 4H), 1.62- 1.58 (m, 6H), 1.34- 1.32 (m, 2H), 1.05 (s, 3H); ES Mass: (M+Na) 499.
Intermediate 20: Preparation of (3R.4R.5S.6R)-2-(4-chloro-3-(4-((l-
(trifluoromethyl)cyclopropyl)methoxy)benzyl)phenyl)-6-
(hvdroxymethyl)tetrahvdro-2 -pyran-3A5-triol:
Figure imgf000054_0001
Step 1: Synthesis of 4-bromo-l-chloro-2-(4-((l-
( trifluoromethyl )cyclopropyl j :
Figure imgf000054_0002
To a stirred solution of 4-(5-bromo-2-chlorobenzyl)phenol (Intermediate 1, 6 g) in dimethylformamide (50 ml), Cs2C03 (19.82 g) was added under N2 atmosphere followed by (l-(trifluoromethyl)cyclopropyl)methyl 4-methylbenzenesulfonate (Intermediate 14, 7.2 g) at room temperature. The reaction mixture was heated to 120 °C and stirred for about 5 hours. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature and filtered through celite then the cake was washed with EtOAc. The filtrate was washed with water and brine, dried over anhydrous sodium sulphate and concentrated to give the residue. The crude product was purified via silica gel column chromatography with EtOAc and n-Hexane (1:49) to afford the title compound as liquid (7.4 g). Yield: 88 %; Ή NMR (CDC13, 300 MHz): δ 7.29- 7.20 (m, 3H), 7.09 (d, J = 8.5 Hz, 2H), 6.83(d, J = 8.5 Hz, 2H), 4.06 (s, 2H), 3.98 (s, 2H), 1.14- 1.10 (m, 2H), 0.91- 0.90 (m, 2H).
Step 2: Synthesis of (3R,4S,5S,6R)-2-(4-chloro-3-(4-((l-
( trifluoromethyl )cyclopropyl )methoxy )benzyl )phenyl )-6-(hydroxymethyl )-2- methoxytetrahydro-2H-pyran-3,4,5-triol:
Figure imgf000055_0001
To a stirred solution of 4-bromo-l-chloro-2-(4-((l- (trifluoromethyl)cyclopropyl)methoxy)benzyl)benzene (step 1, 3.8 g) in dry tetrahydrafuran (40 ml) and toulene (40 ml, 1: 1), n-BuLi (2.3 M in hexane, 10.7 ml) was added at -78 °C under N2 atmosphere and stirred for about 30 minutes at -78°C. To this solution (3R,4S,5R,6R) -3,4,5- tris (trimethylsilyloxy) -6- ((trimethylsilyloxy) methyl)tetrahydro-2H-pyran-2-one (Intermediate 2, 3.4 g) in toluene (20 ml) was added at -78 °C and stirred for about 2 hours at -78 °C then 6 % CH3S02H in MeOH (57 ml) was added slowly at same temperature. Then the reaction was allowed to room temperature and continued for over night. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to 0 °C and neutralized by cautious addition of saturated aq. NaHC03 solution. The reaction mixture was extracted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulphate and concentrated to get the residue. The crude product was purified via silica gel column chromatography with MeOH and dichloromethane (1:24) to afford the title compound as white solid (2.5 g). Yield: 52 %; 1H NMR (DMSO- D6, 300 MHz): δ 7.52 (s, 1H), 7.39 (s, 2H), 7.08 (d, J = 8.4 Hz, 2H), 6.85 (d, J = 8.4 Hz, 2H), 4.97 (d, J = 5.4 Hz, 1H), 4.78- 4.73 (m, 2H), 4.53 (dd, J = 5.7 Hz, 1H), 4.05- 3.93 (m, 4H), 3.77- 3.72 (m, 1H), 3.60- 3.52 (m, 2H), 3.39 (m, 1H), 3.25- 3.18 (m, 1H), 2.92 (s, 3H), 2.92- 2.85 (m, 1H), 1.06 (m, 2H), 0.97 (m, 2H); ES Mass: (M+Na) 555.
Step 3: Synthesis of (3R,4R,5S,6R)-2-(4-chloro-3-(4-((l-
( trifluoromethyljcyclopropyl )methoxy )benzyl )phenyl)-6-(hydroxymethyl )tetrahydro- 2H-pyran-3, 4, 5-triol:
To a stirred solution of (3R,4S,5S,6R)-2-(4-chloro-3-(4-((l- (trifluoromethyl)cyclopropyl)methoxy)benzyl)phenyl)-6-(hydroxymethyl)-2- methoxytetrahydro-2H-pyran-3,4,5-triol (step 2, 2.5 g) in dichloromethane (20 ml) and acetylnitrile (20 ml, 1: 1), Et3SiH (1.5 ml) was added at 0 °C under N2 atmosphere followed by BF3: Et20 (0.8 ml) and stirred for about 6 hours at room temperature. After completion of the reaction (monitored by TLC), volatiles were concentrated under reduced pressure. Then the reaction mixture was cooled to 0 °C and neutralized by cautious addition of saturated aq. NaHC03 solution. The reaction mixture was extracted with EtOAc twice and the combined organic layers were washed with water and brine, dried over anhydrous sodium sulphate and concentrated to get the residue. The crude product was purified via silica gel column chromatography with MeOH and dichloromethane (1:24) to give mixture compound (mixture of α & β isomers) as white solid (1.8 g). Yield: 76 %; HPLC: 60.38 %; 1H NMR (DMSO- D6, 300 MHz): δ 7.36 (d, J = 8.1 Hz, 1H), 7.32 (d, J = 1.8 Hz, 1H), 7.22 (dd, J - 1.8, 8.1 Hz, 1H), 7.10 (d, J = 8.4 Hz, 2H), 6.85 (d, J = 8.4 Hz, 2H), 4.97- 4.95 (m, 2H), 4.84 (d, J = 5.7 Hz, 1H), 4.46 (dd, J = 5.7 Hz, 5.7 Hz, 1H), 4.06 (s, 2H), 3.99-3.97 (m, 3H), 3.71- 3.66 (m, 1H), 3.45-3.39 (m, 1H), 3.24- 3.10 (m, 4H), 1.07- 1.05 (m, 2H), 0.97 (m, 2H); ES Mass: (M-H) 501.
Intermediate 21: Preparation of (3R,4R,5S,6R)-2-(4-chloro-3-(4-((4.4-difluoro-l- methylcyclohexyl)methoxy)benzyl phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran- 3A5-triol:
Figure imgf000056_0001
Step 1: Synthesis of 4-bromo-l-chloro-2-(4-((4,4-difluoro-l- methylcyclohexyl )methoxy )benzyl )benzene:
Figure imgf000056_0002
To a stirred solution of 4-(5-bromo-2-chlorobenzyl)phenol (Intermediate 1 , 4 g) in dimethylformamide (50 ml), Cs2C03 (13.2 g) was added under N2 atmosphere followed by (4,4-difluoro-l-methylcyclohexyl)methyl 4-methylbenzenesulfonate (Intermediate 16, 4.7 g) at room temperature. The reaction mixture was heated to 120 °C and stirred for about 5 hours. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature and filtered through celite and the cake was washed with EtOAc. The filtrate was washed with water and brine, dried over anhydrous sodium sulphate and concentrated to give the residue. The crude product was purified via silica gel column chromatography with EtOAc and n-Hexane (1:49) to afford the title compound as solid (4.6 g). Yield: 77.9 %; 1H NMR (CDC13, 300 MHz): δ 7.23- 7.20 (m, 3H), 7.09 (d, J = 8.4 Hz, 2H), 6.84 (d, J = 8.4 Hz, 2H), 3.98 (s, 2H), 3.67 (s, 2H), 1.99- 1.89 (m, 4H), 1.79- 1.70 (m, 2H), 1.58 (m, 2H), 1.09 (s, 3H).
Step 2: Synthesis of (3R,4S,5S,6R)-2-(4-chloro-3-(4-((4,4-difluoro-l- methylcyclohexyl )methoxy )benzyl )phenyl)-6-(hydroxymethyl )-2-methoxytetrahydro- 2H-pyran-3, 4, 5-triol:
Figure imgf000057_0001
To a stirred solution of 4-bromo-l-chloro-2-(4-((4,4-difluoro-l- methylcyclohexyl)methoxy)benzyl)benzene (step 1, 10.4 g) in dry tetrahydrafuran (40 ml) and toulene (40 ml, 1 : 1 ), n-BuLi (2.3 M in hexane) was added at -78 °C under N2 atmosphere stirred for about 30 minutes. To this solution (3R,4S,5R,6R)- 3,4,5-tris(trimethylsilyloxy)-6-((trimethylsilyloxy)methyl)tetrahydro-2H-pyran-2- one (Intermediate 2, 3.9 g) in toluene (30 ml) was added at -78 °C and stirred for about 2 hours at same temperature then 6 % CH3SO3H in MeOH (69 ml) was added slowly. Then the reaction mixture was allowed to room temperature and stirred for about 12 hours. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to 0°C and neutralized by cautious addition of saturated aq. NaHC03 solution. The reaction mixture was extracted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulphate and concentrated to get the residue. The crude product was purified via silica gel column chromatography with MeOH and dichloromethane (1:24) to afford the title compound as white solid (1.2 g). Yield: 21 %; 1H NMR (DMSO- D6, 300
MHz): 5 7.52 (s, 1H), 7.38 (s, 2H), 7.07 (d, J = 8.1 Hz, 2H), 6.85 (d, J = 8.1 Hz, 2H), 4.96 (d, J = 5.4 Hz, 1H), 4.78- 4.72 (m, 2H), 4.52 (dd, J = 6.3, 6.3 Hz, 1H), 3.99 (ABq, J = 15.3 Hz, 2H), 3.70 (m, 3H), 3.60- 3.51 (m, 2H), 3.25- 3.20 (m, 2H), 2.91 (s, 3H), 2.88- 2.85 (m, 1H), 1.96- 1.87 (m, 4H), 1.67- 1.63 (m, 2H), 1.48- 1.44 (m, 2H), 1.03 (s, 3H); ES Mass: (M+Na) 579.1.
Step 3: Synthesis of (3R,4R,5S,6R)-2-(4-chloro-3-(4-((4,4-difluoro-l- methylcyclohexyl )methoxy )benzyl )phenyl )-6-(hydroxymethyl )tetrahydro-2H-pyran- 3,4,5-triol:
To a stirred solution of (3R,4S,5S,6R)-2-(4-chloro-3-(4-((4,4-difluoro-l- methylcyclohexyl)methoxy)benzyl)phenyl)-6-(hydroxymethyl)-2- methoxytetrahydro-2H-pyran-3,4,5-triol (step 2, 1.2 g) in dichloromethane (15 ml) and acetylnitrile (15 ml, 1:1), Et3SiH (0.7 ml) was added at 0° C under N2 atmosphere followed by BF3: Et20 (0.4 ml) and reaction was stirred for about 6 hours. After completion of the reaction (monitored by 1H-NMR), volatiles were concentrated under reduced pressure. Then the reaction mixture was cooled to 0 °C and neutralized by cautious addition of saturated aq. NaHC03 Solution. The reaction mixture was extracted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulphate and concentrated to get the residue. The crude product was purified via silica gel column chromatography with MeOH and dichloromethane (1:24) to give mixture compound (mixture of α & β isomers) as white solid (670 mg). Yield: 61 %; HPLC: 88.61 %; 1H NMR (DMSO- D6, 300 MHz): δ 7.37 (d, / = 8.4 Hz, 1H), 7.31 (s, 1H), 7.22 (d, J = 8.4 Hz, 1H), 7.10 (d, J = 8.4 Hz, 2H), 6.86 (d, J = 8.4 Hz; 2H), 4.98- 4.95 (m, 2H), 4.84 (d, J = 5.7 Hz, 1H), 4.44 (dd, J = 5.7 Hz, 5.7 Hz, 1H), 3.99- 3.97 (m, 3H), 3.71- 3.66 (m, 3H), 3.47- 3.06 (m, 5H), 1.97- 1.87 (m, 4H), 1.70- 1.61 (m, 2H), 1.49- 1.44 (m, 2H), 1.03 (s, 3H); ES Mass: (M+Na) 549.
Intermediate 22: Preparation of 4-(5-bromo-2-fluorobenzyl)phenol:
Figure imgf000058_0001
Step 1: Synthesis of l-bromo-4-ethoxybenzene:
Figure imgf000059_0001
Potassium carbonate (118 g) was added to a solution of 4-bromophenol (50 g) in acetone (250 ml) and allowed to stir at room temperature for about 30 minutes then ethyl iodide (67.6 g) was added drop wise. The reaction mixture was refluxed for about 10 hours and completion of reaction was confirmed by TLC. The reaction mixture was filtered and acetone was removed over rotary evaporator. The residue was dissolved in ethyl acetate and washed with water and brine solution, dried over anhydrous Na2S04 and concentrated then filtered and product was purified via silica gel column chromatography with EtOAc and n-Hexane (1: 7) to afford the title compound as liquid (57 g). Yield: 98.27 ; 1H NMR (CDC13, 300 MHz): δ 7.35 (d, / = 8.7 Hz, 2H), 6.76 (d, J = 8.7 Hz, 2H), 3.99 (q, J = 6.9 Hz, 2H), 1.40 (t, J = 6.9 Hz, 3H).
Step 2: Synthesis of (5-bromo-2-fluorophenyl)(4-ethoxyphenyl)methanol:
Figure imgf000059_0002
To a stirred solution of Mg (9.5 g) in dry tetrahydrafuran (50 ml), 1-bromo- 4-ethoxybenzene (step 1, 53.4 g) in tetrahydrafuran (150 ml) was added under N2 atmosphere at room temperature slowly by drop wise and stirred for about 1 hour. Then 5-bromo-2-fluorobenzaldehyde (11 ml) was added slowly to the above reaction mixture and the reaction mixture was allowed to stir for over night. After completion of the reaction (monitored by TLC), the reaction mixture was poured into saturated NH4C1 solution at 0 °C and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulphate and concentrated to give the residue. The crude product was purified via silica gel column chromatography with EtOAc and n-Hexane to afford the title compound as liquid (24 g). Yield: 85.7 ; Ή NMR (CDC13, 300 MHz): δ 7.745- 7.71 (m, 1H), 7.37- 7.27 (m, 3H), 6.91- 6.84 (m, 3H), 6.02 (d, J = 3.3 Hz, 1H), 4.01 (q, J = 7.2 Hz, 2H), 2.20 (d, J = 3.3 Hz, 1H), 1.39 (t, J = 7.2 Hz, 3H). Step 3: Synthesis of4-bromo-2-(4-ethoxybenzyl)-l-fl orobenzene:
Figure imgf000060_0001
To a stirred solution of (5-bromo-2-fluorophenyl)(4-ethoxyphenyl)methanol (step 2, 24 g) in dichloromethane (150 ml) and acetylnitrile (150 ml, 1: 1), Et3SiH (24 ml) was added at 0 °C under N2 atmosphere followed by BF3: Et20 (14 ml) and the reaction mixture was stirred for about 12 hours at room temperature. After completion of the reaction (monitored by TLC), volatiles were concentrated under reduced pressure. Then the reaction mixture was cooled to 0 °C and neutralized by cautious addition of saturated aq. NaHC03 Solution. The reaction mixture was extracted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulphate and concentrated to give the crude compound and purified by silica gel column chromatography with EtOAc and n- Hexane to afford the title compound as liquid (15 g). Yield: 65.7 %; !H NMR (CDC13, 300 MHz): δ 7.29- 7.21 (m, 2H), 7.10 (d, J = 8.4 Hz, 2H), 6.91 (dd, / = 9.0, 9.0 Hz, 1H), 6.83 (d, J = 8.4 Hz, 2H), 4.00 (q, J = 6.9 Hz, 2H), 3.88 (s, 2H), 1.39 (t, J = 6.9 Hz, 3H).
Step 4: Synthesis of 4-(5-bromo-2-fluorobenzyl)phenol:
To a stirred solution of 4-bromo-2-(4-ethoxybenzyl)-l-fluorobenzene (step 3, 15 g) in dichloromethane (80 ml), BBr3 (53.3 ml, 1M solution in dichloromethane (50 ml)) was added slowly under N2 atmosphere at 0 °C and stirred for. over night at room temperature. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to 0 °C and neutralized by cautious addition of saturated aq. NaHC03 solution. The reaction mixture was extracted with dichloromethane. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulphate and concentrated to give the crude compound and purified via silica gel column chromatography with EtOAc and n-Hexane to afford the title compound as solid (12 g). Yield: 88.2 %; 1H NMR (CDC13, 300 MHz): 6 7.29- 7.21 (m, 2H), 7.07 (d, J = 8.4 Hz, 2H), 6.91 (dd, J = 9.0, 9.0 Hz, 1H), 6.77 (d, J = 8.4 Hz, 2H), 4.68 (s, 1H), 3.87 (s, 2H); ES Mass: (M-H) 278.90. Intermediate 23: Preparation of (3R^R.5S.6RV2-(4-fluoro-3-(4-((l-
(trifluoromethyl)cvclobutyl)methoxy)benzyl)phenyl)-6-(hvdroxymethyl tetrahydro-
2H-pyran-3.4.5-triol:
4-bromo-l-fluoro-2-(4-((l-
Figure imgf000061_0001
To a stirred solution of 4-(5-bromo-2-fluorobenzyl)phenol (Intermediate 22, 4 g) in dimethylformamide (60 ml), Cs2C03 (13.9 g) was added under N2 atmosphere followed by (l-(trifluoromethyl)cyclobutyl)methyl 4- methylbenzenesulfonate (Intermediate 15, 15.6 g) at room temperature. The reaction mixture was heated to 120 °C and stirred for about 6 hours. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature and filtered through celite then the cake was washed with EtOAc. The filtrate was washed with water and brine, dried over anhydrous sodium sulphate and concentrated to give the residue. The crude product was purified via silica gel column chromatography with EtOAc and n-Hexane (1:49) to afford the title compound as liquid (5.7 g). Yield: 96.6 %; 1H NMR (CDC13, 300 MHz): δ 7.30- 7.22 (m, 2H), 7.13 (d, J = 8.1 Hz, 2H), 6.94- 6.87 (m, 3H), 4.04 (s, 2H), 3.90 (s, 2H), 2.41- 2.31 (m, 2H), 2.25- 2.16 (m, 2H), 2.07- 1.99 (m, 2H).
Step 2: Synthesis of (3R,4S,5S,6R)-2-(4-fluoro-.
( trifluoromethyl )cyclobutyl )methoxy )benzyl )phenyl )-6-( hydroxymethyl )-2 - methoxytetrahydro-2H-pyran-3,4,5-triol:
Figure imgf000062_0001
To a stirred solution of 4-bromo-l-fluoro-2-(4-((l- (trifluoromethyl)cyclobutyl)methoxy)benzyl)benzene (step 1, 5.7 g) in dry tetrahydrafuran (50 ml) and toulene (50 ml, 1: 1), t-BuLi (16 ml, 1.7 M in toluene (30 ml)) was added at -78 °C under N2 atmosphere and stirred for about 30 minutes at - 78 °C. To this solution (3R,4S,5R,6R)- 3,4,5-tris (trimethylsilyloxy)- 6- ((trimethylsilyloxy)methyl) tetrahydro-2H-pyran-2-one (Intermediate 2, 5.1 g) in toluene was added at -78 °C and stirred for about 2 hours at same temperature then 6 % CH3SO3H in MeOH (90 ml) was added slowly at -78 °C. Then the reaction mixture was allowed to attain room temperature and stirred for about 12 hours. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to 0 °C and neutralized by cautious addition of saturated aq. NaHC03 Solution. The reaction mixture was extracted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulphate and concentrated to get the residue. The crude product was purified via silica gel column chromatography with MeOH and dichloromethane (1:24) to afford the title compound as white solid (3 g). Yield: 41.6 %; Ή NMR (DMSO- D6, 300 MHz): δ 7.48 (d, J = 7.2 Hz, 1H), 7.39 (m, 1H), 7.14- 7.08 (m, 3H), 6.91 (d, J = 7.8 Hz, 2H), 4.99 (d, J = 5.1 Hz, 1H), 4.79- 4.76 (m, 2H), 4.56 (dd, J = 5.7, 5.7 Hz, 1H), 4.15 (s, 2H), 3.91 (ABq, 7 = 15 Hz, 2H ), 3.75- 3.73 (m, 1H), 3.60- 3.48 (m, 2H), 3.38 (m, 1H), 3.25- 3.20 (m, 1H), 2.91 (s, 3H), 2.91- 2.84 (m, 1H), 2.26 (m, 2H), 2.07- 1.92 (m, 4H); ES Mass: (M+Na) 553.3.
Step 3: Synthesis of (3R,4R,5S,6R)-2-(4-fluoro-3-(4-((l-
( trifluoromethyl )cyclobutyl )methoxy )benzyl )phenyl )-6-(hydroxymethyl )tetrahydro- 2H-pyran-3, 4, 5-triol:
To a stirred solution of (3R,4S,5S,6R)-2-(4-fluoro-3-(4-((l- (trifluoromethyl)cyclobutyl)methoxy)benzyl)phenyl)-6-(hydroxymethyl)-2- methoxytetrahydro-2H-pyran-3,4,5-triol (step 2, 3g) in dichloromethane (20 ml) and acetylnitrile (20 ml, 1:1) Et3SiH (1.8 ml) was added at 0 °C under N2 atmosphere followed by BF3: Et20 (1 ml) and stirred for about 6 hours at room temperature. After completion of the reaction (monitored by TLC), volatiles were concentrated under reduced pressure. Then the reaction mixture was cooled to 0 °C and neutralized by cautious addition of saturated aq. NaHC03 solution. The reaction mixture was extracted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulphate and concentrated to get the residue. The crude product was purified via silica gel column chromatography with MeOH and dichloromethane (1:24) to give mixture compound (mixture of α & β isomers) as white solid (2.3 g). Yield: 82.1 %; 1H NMR (DMSO- D6, 300 MHz): 6 7.28-7.20 (m, 2H), 7.16- 7.06 (m, 3H), 6.91 (d, J = 8.4 Hz, 2H), 4.96 (d, 7 = 2.1 Hz, 2H), 4.80 (d, 7 = 5.4 Hz, 1H), 4.46 (dd, 7 = 5.7 Hz, 5.7 Hz, 1H), 4.15 (s, 2H), 3.97 (d, 7 = 9.3 Hz, 1H), 3.89- 3.88 (m, 2H), 3.71-3.65 (m, 1H), 3.51- 3.11 (m, 5H), 2.26- 2.24 (m, 2H), 2.10- 1.89 (m, 4H); ES Mass: (M+Na) 523.15.
Intermediate 24: Preparation of (3R,4R,5S,6R -2-(4-fluoro-3-(4-((l-
(trifluoromethyl)cyclopropyl)methoxy)benzyl)phenyl)-6-
(hydroxymethyl)tetrahvdro-2H-pyran-3A5-triol:
4-bromo-l-fluoro-2-(4-( (1-
Figure imgf000063_0001
To a stirred solution of 4-(5-bromo-2-fiuorobenzyl)phenol (Intermediate 22, 4 g) in dimethylformamide (50 ml), Cs2C03 (13.9 g) was added under N2 atmosphere followed by (l-(trifluoromethyl)cyclopropyl)methyl 4- methylbenzenesulfonate (Intermediate 14, 4.6 g) at room temperature. The reaction mixture temperature was raised to 120 °C and stirred for about 6 hours. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature and filtered through celite then the cake was washed with EtOAc. The filtrate was washed with water and brine, dried over anhydrous sodium sulphate and concentrated to give the residue. The crude product was purified via silica gel column chromatography with EtOAc and n-Hexane (1:49) to afford the title compound as liquid (5.3 g). Yield: 92.7 %; 1H NMR (CDC13, 300 MHz): δ 7.29- 7.21 (m, 2H), 7.11 (d, 7 = 8.1 Hz, 2H), 6.91 (dd, J = 9.0, 9.0 Hz, 1H), 6.82 (d, J = 8.1 Hz, 2H), 4.05 (s, 2H), 3.88 (s, 2H), 1.13- 1.10 (m, 2H), 0.93- 0.88 (m, 2H).
Step 2: Synthesis of (3R,4S,5S,6R)-2-(4-fluoro-3-(4-((l-
( trifluoromethyl)cyclopropyl)methoxy jbenzyl )phenyl )-6-(hydroxymethyl)-2- methoxytetrahydro-2H-pyran-3, 4, 5-triol:
Figure imgf000064_0001
To a stirred solution of 4-bromo-l-fluoro-2-(4-((l- (trifluoromethyl)cyclopropyl)methoxy)benzyl)benzene (step 1, 5.3 g) in dry tetrahydrafuran (40 ml) and toulene (40 ml, 1: 1), t-BuLi (2.3 M in hexane, 15.5 ml) was added at -78 °C under N2 atmosphere and stirred for about 30 minutes. To this solution (3R,4S,5R,6R)-3,4,5-tris(trimethylsilyloxy)-6- ((trimethylsilyloxy)methyl)tetrahydro-2H-pyran-2-one (Intermediate 2, 4.9 g) in toluene (30 ml) was added at -78 °C and stirred for about 2 hours then 6 % CH3S03H in MeOH (80 ml) was added slowly at -78 °C. The reaction mixture was allowed to room temperature and stirred for over night. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to 0°C and neutralized by cautious addition of saturated aq. NaHC03 solution. The reaction mixture was extracted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulphate and concentrated to get the residue. The crude product was purified via silica gel column chromatography with MeOH and dichloromethane (1 :24) to afford the title compound as white solid (2.8 g). Yield: 41.7 %; 1H NMR (DMSO- D6, 300 MHz): 6 7.47 (d, J = 7.5 Hz, 1H), 7.39 (m, 1H), 7.11- 7.09 (m, 3H), 6.85 (d, J = 8.1 Hz, 2H), 4.99 (d, J = 5.1 Hz, 1H), 4.78- 4.76 (m, 2H), 4.55 (dd, J = 5.4, 5.4 Hz, 1H), 4.05 (s, 2H), 3.89 (Abq, J = 15 Hz, 2H), 3.74- 3.72 (m, 1H), 3.60- 3.47 (m, 2H), 3.24- 3.19 (m, 2H), 2.90 (s, 3H), 2.90- 2.84 (m, 1H), 1.06 (m, 2H), 0.97 (m, 2H); ES Mass: (M+Na) 539.15.
Step 3: Synthesis of (3R,4R,5S,6R)-2-(4-fluoro-3-(4-((l-
(trifluoromethyl)cyclopropyl)methoxy)benzyl)phenyl)-6-(hydroxy
2H-pyran-3, 4, 5-triol:
To a stirred solution of (3R,4S,5S,6R)-2-(4-fluoro-3-(4-((l- (trifluoromethyl)cyclopropyl)methoxy)benzyl)phenyl)-6-(hydroxymethyl)-2- methoxytetrahydro-2H-pyran-3,4,5-triol (step 2, 2.8 g) in dichloromethane (20 ml) and acetylnitrile (20 ml, 1: 1), Et3SiH (1.7 ml) was added at 0 °C under N2 atmosphere followed by BF3: Et20 (1 ml) and stirred for about 4 hours at room temperature. After completion of the reaction (monitored by TLC), volatiles were concentrated under reduced pressure. Then the reaction mixture was cooled to 0 °C and neutralized by cautious addition of saturated aq. NaHC03 solution. The reaction mixture was extracted with EtOAc and the combined organic layers were washed with water and brine, dried over anhydrous sodium sulphate and concentrated to get the residue. The crude product was purified via silica gel column chromatography with MeOH and dichloromethane (1:24) to give mixture compound (mixture of a & β isomers) as white solid (2 g). Yield: 77 %; 1H NMR (DMSO- D6, 300 MHz): δ 7.27- 7.21 (m, 2H), 7.13- 7.05 (m, 3H), 6.85 (d, J = 8.4 Hz, 2H), 4.96 (d, J = 2.1 Hz, 2H), 4.80 (d, J = 5.7 Hz, 1H), 4.46 (dd, J = 5.7 Hz, 5.7 Hz, lH), 4.05 (s, 2H), 3.96 (d, J = 9.3 Hz, 1H), 3.88- 3.87 (m, 2H), 3.71-3.65 (m, 1H), 3.51- 3.13 (m, 5H), 1.06 (m, 2H), 0.97 (m, 2H); ES Mass: (M+Na) 509.25.
Intermediate 25: Preparation of (3R.4R.5S.6R -2-(3-(4-((4.4-difluoro-l- methylcyclohexyl)methoxy)benzyl)-4-fluorophenyl)-6-(hydroxymethyl)tetrahydro-
2H-pyran-3,4.5-triol:
Figure imgf000066_0001
Step 1: Synthesis of 4-bromo-2-(4-((4,4-difluoro-l- methylcyclohexyl)methoxy)benzyl)-l-fluorobenzene:
Figure imgf000066_0002
To a stirred solution of 4-(5-bromo-2-fluorobenzyl)phenol (Intermediate 22, 2.6 g) in dimethylformamide (40 ml), Cs2C03 (9 g) was added under N2 atmosphere followed by (4,4-difluoro-l-methylcyclohexyl)methyl 4-methylbenzenesulfonate (Intermediate 16, 3.2 g) at room temperature. The reaction temperature was raised to 120 °C and stirred for about 6 hours. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature and filtered through celite then the cake was washed with EtOAc. The filtrate was washed with water and brine, dried over anhydrous sodium sulphate and concentrated to give the residue. The crude product was purified via silica gel column chromatography with EtOAc and n-Hexane (1:49) to afford the title compound as liquid (2.6 g). Yield: 66.6 %; 1H NMR (CDC13, 300 MHz): δ 7.23- 7.21 (m, 2H), 7.10 (d, J = 8.1 Hz, 2H), 6.90 (dd, J = 8.7, 8.7 Hz, 1H), 6.83 (d, J = 8.1 Hz, 2H), 3.88 (s, 2H), 3.66 (s, 2H), 1.99- 1.86 (m, 4H), 1.78- 1.69 (m, 2H), 1.58 (m, 2H), 1.09 (s, 3H).
Step 2: Synthesis of (3R,4S,5S,6R)-2-(3-(4-((4,4-difluoro-l- methylcyclohexyl )methoxy )benzyl)-4-fluorophenyl)-6- ( hydroxymethyl )-2- methoxytetrahydro-2H-pyran-3,4,5-triol:
Figure imgf000066_0003
To a stirred solution of 4-bromo-2-(4-((4,4-difluoro-l- methylcyclohexyl)methoxy)benzyl)-l-fluorobenzene (step 1, 2.6 g) in dry tetrahydrafuran (30 ml) and toluene (30 ml, 1: 1 ), t-BuLi (6 ml, 1.7 M in toluene) was added under N2 atmosphere at -78 °C and stirred for about 30 minutes. To this solution (3R,4S,5R,6R)-3,4,5-tris(trimethylsilyloxy)-6- ((trimethylsilyloxy)methyl)tetrahydro-2H-pyran-2-one (Intermediate 2, 2.3 g) in toluene (40 ml) was added at -78 °C and stirred for about 2 hours then 6 % CH3S03H in MeOH (39 ml) was added slowly at -78 °C. Then the reaction mixture was allowed to room temperature and stirred for about 12 hours. After completion of the reaction (monitored by TLC), reaction mixture was cooled to 0 °C and neutralized by cautious addition of saturated aq. NaHC03 solution. The reaction mixture was extracted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulphate and concentrated to get the residue. The crude product was purified via silica gel column chromatography with MeOH and dichloromethane (1:24) to afford the title compound as white solid (1.6 g). Yield: 50 %; 1H NMR (DMSO- D6, 300 MHz): δ 7.47 (d, J = 6.3 Hz, 1H), 7.39 (m, 1H), 7.13- 7.08 (m, 3H), 6.86 (d, J = 8.4 Hz, 2H), 4.95 (d, J = 5.4 Hz, 1H), 4.73- 4.71 (m, 2H), 4.52 (dd, J = 5.7, 5.7 Hz, 1H), 3.89 (ABq, J = 15 Hz, 2H), 3.70 (m, 3H), 3.60- 3.51 (m, 2H), 3.25- 3.20 (m, 2H), 2.91 (s, 3H), 2.88- 2.85 (m, 1H), 1.96- 1.87 (m, 4H), 1.69- 1.63 (m, 2H), 1.48- 1.44 (m, 2H), 1.03 (s, 3H); ES Mass: (M+Na) 563.15.
Step 3: Synthesis of (3R,4R,5S,6R)-2-(3-(4-((4,4-difluoro-l- methylcyclohexyl)methoxy )benzyl)-4-fluorophenyl )-6-(hydroxymethyl )tetrahydro- 2H-pyran-3, 4, 5-triol:
To a stirred solution of (3R,4S,5S,6R)-2-(3-(4-((4,4-difluoro-l- methylcyclohexyl)methoxy)benzyl)-4-fluorophenyl)-6-(hydroxymethyl)-2- methoxytetrahydro-2H-pyran-3,4,5-triol (step 2, 1.6 g) in dichloromethane (15 ml) and acetylnitrile (15 ml, 1 : 1), Et3SiH (0.9 ml) was added at 0°C under N2 atmosphere followed by BF3: Et20 (0.5 ml) and reaction was stirred for about 6 hours. After completion of the reaction (monitored by Ή-NMR), volatiles were concentrated under reduced pressure. The reaction mixture was cooled to 0 °C and neutralized by cautious addition of saturated aq. NaHC03 Solution. The reaction mixture was extracted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulphate and concentrated to get the residue. The crude product was purified via silica gel column chromatography with MeOH and dichloromethane (1:24) to give mixture compound (mixture of α & β isomers) as white solid (890 mg). Yield: 59.3 %; HPLC: 87.06 %; 1H NMR (DMSO- D6, 300 MHz): δ 7.27- 7.19 (m, 2H), 7.13- 7.05 (m, 3H), 6.86 (d, J = 8.7 Hz, 2H), 4.96- 4.94 (m, 2H), 4.79 (d, J = 5.7 Hz, 1H), 4.45 (dd, J = 5.7 Hz, 5.7 Hz, 1H), 3.96 (d, J = 9.0 Hz, 1H), 3.93- 3.87 (m, 2H), 3.71- 3.65 (m, 3H), 3.44- 3.11 (m, 5H), 1.96- 1.87 (m, 4H), 1.67- 1.63 (m, 2H), 1.48- 1.46 (m, 2H), 1.03 (s, 3H); ES Mass: (M+Na) 533.10.
Intermediate 26: Preparation of Synthesis of l-(ethoxymethyl)cvclopentyl)methyl 4- methylbenzenesulfonate:
Figure imgf000068_0001
Step 1: Synthesis of methyl cyclopentanecarboxylate:
OMe
Figure imgf000068_0002
Concentrated H2S04 (19.1 ml, 1.0 eq) was added drop-wise to a solution of cyclopentanecarboxylic acid (25 g, 0.1953 mol) in MeOH (125 ml) at 0°C and the reaction mixture was refluxed for about 48 hours. After completion of the reaction, the solvent was removed and the reaction mixture was dissolved in dichloromethane. The dichloromethane layer was washed with saturated NaHC03 solution and the organic layer was dried over anhydrous magnesium sulphate. The solvent was removed over rotary evaporator. The obtained residue with least moisture content was used directly for the next step. Yield: 16 gm.
Step 2: Synthesis of methyl l-(ethoxymethyl)cyclopentanecarboxylate:
Figure imgf000068_0003
To a solution of diisopropylamine (44.4 ml, 0.3169 mol) in tetrahydrafuran (200 ml), n-BuLi (2.5M, 105.6 ml, 0.264 mol) was added in hexane at 0°C and the reaction mixture was allowed to stir at same temperature for about 10-15 minutes. The reaction mixture was stirred at room temperature for about 45 minutes. Methyl cyclopentanecarboxylate (step 1, 15 g, 0.15067 mol) in tetrahydrafuran (150 ml) was added drop-wise at -78°C to reaction mixture. The reaction mixture was stirred at same temperature for about 2 hours and then (iodomethoxy)ethane (12.67 ml, 0.1584 mol) was added drop- wise. The reaction was maintained at -78°C for an hour and allowed to attain room temperature. Reaction rnixture was stirred overnight at room temperature and quenched at 0°C with saturated NH4C1 solution. Tetrahydrafuran was concentrated over vaccum and the compound was extracted with ethyl acetate. The organic layer was washed with saturated brine solution, dried over anhydrous Na2S04 and concentrated. The obtained crude product was directly used for the next step. Crude yield: 10 gm. 1H NMR (CDC13, 300 MHz): δ 4.11 (q, 2H, J = 7.2 Hz); 2.13-1.41 (m, 13H); 1.21 (t, 3H, J = 7.2 Hz); 0.81 (t, 3H, J = 7.5 Hz). ESI Mass: 187 (M+l)
Step 3: Synthesis of ( 1 -(ethoxymethyl)cyclopentyl)methanol:
Figure imgf000069_0001
Methyl l-(ethoxymethyl)cyclopentanecarboxylate (step 2, 10 g, 0.0588 mol) in tetrahydrafuran (120 ml) was added to a suspension of L1AIH4 (6.7 g, 0.1764 mol) in tetrahydrafuran (200 ml) at 0°C and the reaction mixture was allowed to stir at same temperature for about 30 minutes. The reaction mixture was stirred overnight at room temperature. After completion of reaction, the reaction mixture was quenched with ice cold water at 0°C and filtered over celite. The residue was washed with hot ethyl acetate. The organic layer was washed with saturated brine solution, dried over anhydrous Na2S04 and concentrated. The obtained crude product was directly used for the next step. Crude yield: 8 gm. 1H NMR (CDC13, 300 MHz): δ 3.41 (s, 2H); 1.42-1.36 (m, 12H); 1.30-1.26 (t, 3H).
Step 4: Synthesis of 1 -(ethoxymethyl)cyclopentyl)methyl 4-methylbenzenesulfonate:
To a solution of (l-(ethoxymethyl)cyclopentyl)methanol (step 3, 8 g, 0.0563 mol) in dichloromethane (200 ml), triethyl amine (31.3 ml, 0.2253 mol) was added followed by tosyl chloride (21.4 g, 0.1126 mol) at 0°C. After addition of catalytic amount of DMAP (0.567 g, 0.0056 mol), the reaction mixture was allowed to stir for overnight at room temperature. After completion of reaction, the reaction mixture was washed with water and brine solution, dried over anhydrous Na2S04 and concentrated. The obtained product was purified by column chromatographic technique. Yield: 8 gm. 1H NMR (CDC13, 300 MHz): 5 7.80-7.77 (d, 2H, J = 8.1 Hz); 7.35-7.33 (d, 2H, J = 8.1 Hz); 3.78 (s, 2H); 2.45 (s, 3H); 1.39-1.27 (m, 12H); 0.68-0.63 (t, 3H, 7 = 7.5 Hz). ESI Mass: 313 (M+l).
Intermediate 27: Preparation of (3R,4S.5S.6R)-2-(4-chloro-3-(4-((l-
(ethoxymethyl)cvclopentyl methoxy)benzyl)phenyl)-6-(hvdroxymethyl)-2- methoxytetrahydro-2H-pyr -3,4,5-triol:
Figure imgf000070_0001
Step 1: Synthesis of 4-bromo-l -chloro-2-( 4-((l-
( ethoxymethyl )cyclopentyl )methoxy )benzyl jbenzene:
Figure imgf000070_0002
To a suspension of Cs2C03 (39.6 g, 0.1216 mol) in dimethylformamide (150 ml), 4-(5-bromo-2-chlorobenzyl)phenol (Intermediate 1, 12 g, 0.0405 mol) in dimethylformamide (100 ml) was added followed by 1- (ethoxymethyl)cyclopentyl)methyl 4-methylbenzenesulfonate (Intermediate 26, 17.9 g, 0.0608 mol) in dimethylformamide (50 ml) then the reaction mixture was stirred for overnight at 120°C. After completion of the reaction as monitored by TLC, the reaction mixture was extracted with ether and washed with saturated brine solution. The organic layer was dried over anhydrous Na2S04 and concentrated. The obtained product was purified by column chromatographic technique. Yield: 8.5 gm. 1H NMR (CDC13, 300 MHz): δ 7.27-7.23 (m, 3H); 7.09-7.06 (d, 2H, J=8.7Hz); 6.86- 6.83 (d, 2H, J=8.7Hz); 3.98 (s, 3H); 3.67 (s, 2H), 1.45-1.40 (m, 12H); 0.88-0.77 (t, 3H, J = 7.8 Hz).
Step 2: Synthesis of (3R,4S,5S,6R)-2-(4-chloro-3-(4-((l-
( ethoxymethyl )cyclopentyl )methoxy )benzyl )phenyl)-6-(hydroxymethyl )-2- methoxytetrahydro-2H-pyran-3,4,5-triol:
T-BuLi (1.7 M, 20.2 ml, 0.0344mol) was added drop-wise to a solution of 4- bromo- 1 -chloro-2-(4-(( 1 -(ethoxymethyl)cyclopentyl)methoxy)benzyl)benzene (Step 1, 7 g, 0.0172mol) in tetrahydrafuran: toluene (90 ml) (1:2) at -78°C. After 20 minutes, to this solution (3R,4S,5R,6R)-3,4,5-tris(trimethylsilyloxy)-6- ((trimethylsilyloxy)methyl) tetrahydro-2H-pyran-2-one (Intermediate 2, 6.4 g, 0.0137mol) in toluene (70 ml) was added at -78°C. The reaction mixture was maintained at the same temperature for about 2 hours then quenched with methane sulfonic acid (6 % in MeOH, 105 ml). The reaction mixture was stirred at room temperature for an hour then quenched with saturated NaHC03 solution and diluted with ethyl acetate. The organic layer was washed with brine solution, dried over anhydrous Na2S04 and concentrated. The obtained product was separated by column chromatographic technique. 1H NMR (CDC13, 300 MHz): δ 7.48 (s, 1H), 7.34 (s, 2H), 7.04-7.01 (d, 2H, J=8.4Hz); 6.81- 6.78 (d, 2H, J = 8.7Hz); 5.06 (bs, 1H), 4.82 (bs, 2H), 4.57 (bs, 1H), 3.96-3.93 (q, 2H); 3.67 (m, 1H), 3.62 (s, 3H); 3.58-3.50 (m, 2H); 3.18-2.87 (m, 3H); 1.40-1.25 (m, 6H); 1.19-1.16 (m, 4H), 0.9 (s, 3H); ESI Mass: 552 (M+l).
Examples
Example 1: Preparation of (2S.3R,4R,5S,6R)-2-(4-chloro-3-(4-((l- ethylcvclopentyl)methoxy)benzyl)phenyl)-6-(hvdroxymethyl)tetrahydro-2H-pyran- 3 ,4,5-triol (β-isomer):
Figure imgf000071_0001
Step 1: Synthesis of (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-((l- ethylcyclopentyl )methoxy )benzyl )phenyl )-6-(hydroxymethyl )tetrahydro-2H-pyran- 3,4,5-triol (β-isomer):
Figure imgf000072_0001
Triethylsilane (1.36 ml, 8.46 mmol) was added to a solution of (2S,3R,4R,5S,6R)-2-(4-cMoro-3-(4-((l-ethylcyclopentyl)methoxy)benzyl)phenyl)- 6-(hydroxymethyl)-tetrahydro-2H-pyran-3,4,5-triol (Intermediate 4-P-isomer, 2.2 g, 4.23 mmol) in dichloromethane:MeCN (40:40 ml) at -10°C. The reaction mixture was allowed to stir at same temperature for 10 minutes then BF3.OEt2 (0.79 ml, 6.34 mmol) was added. The reaction mixture was stirred for about 30 minutes at -10°C and an hour at room temperature. After completion of reaction as monitored by TLC, the reaction mixture was quenched with 10% NaHC03 solution. The reaction mixture was washed with water, saturated brine solution and the organic layer was dried over anhydrous Na2S04 and concentrated. The obtained product was purified by column chromatographic technique. (DMSO-D6+D20, 300 MHz): β-isomer: 6 7.35-7.28 (m, 2H); 7.23-7.16 (m, 1H); 7.08-7.05 (m, 2H); 6.81-6.79 (m, 2H); 4.09- 3.11 (m, 10H); 1.53-1.33 (m, 10H); 0.75 (t, 3H, J = 7.2 Hz). ESI Mass: 513.05 (M+Na).
Step 2: Synthesis of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4-((l- ethylcyclopentyl )methoxy )benzyl )phenyl )tetrahydro-2H-pyran-3,4, 5-triyl triacetate:
Figure imgf000072_0002
To a solution of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4-((l- ethylcyclo-pentyl)methoxy)benzyl)phenyl)-tetrahydro-2H-pyran-3,4,5-triyl triacetate (step 1, 1.3 g) in dichloromethane (50 ml) at 0°C was added pyridine (2.1 ml), acetic anhydride (2.5 ml) and catalytic amount of DMAP. The reaction mixture was stirred at room temperature for about an hour. After completion of reaction as indicated by TLC, reaction mixture was diluted with dichloromethane, washed with water, 1% HC1 solution followed by saturated brine solution. The organic layer was dried over anhydrous Na2S04 and concentrated. Product was purified by flash column chromatographic technique to remove unreacted Ac20. Recrystallisation of the obtained mixture in ethanol crystallized the desired isomer as white solid. 1H NMR (CDC13, 300 MHz): β-isomer: δ 7.37-7.25 (m, 1H); 7.20-7.17 (m, 1H); 7.07- 7.04 (m, 3H); 6.84-6.81 (m, 2H); 5.32-5.17 (m, 3H); 5.08-5.02 (m, 1H); 4.33-3.77 (m, 6H); 3.64 (m, 2H); 2.07 (s, 3H); 2.05 (s, 3H); 1.99 (s, 3H); 1.71 (s, 3H); 1.63- 1.45 (m, 10H); 0.85 (t, 3H, / = 7.2 Hz); ESI Mass: 681.25 (M+Na).
Step 3: Synthesis of (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-((l- ethylcyclopentyl )methoxy )benzyl )phenyl )-6-(hydroxymethyl )tetrahydro-2H-pyran- 3,4,5-triol:
A solution of 20% methanolic ammonia (10 ml) was added to (2R,3R,4R,5S)-2-(acetoxymethyl)-6-(4-chloro-3-(4-((l- ethylcyclopentyl)methoxy)benzyl)phenyl)-tetrahydro-2H-pyran-3,4,5-triyl triacetate (step 2, 600 mg, 0.91 mmol) at 0°C and the reaction mixture was stirred overnight at room temperature. After completion of the reaction as indicated by TLC, solvent was removed over a rotary evaporator and the residue was dissolved in ethyl acetate. The organic layer was washed with saturated brine solution and dried over anhydrous Na2S04 and concentrated. The obtained title product was purified by column chromatographic technique. 1H NMR (DMSO-D6+D20, 300 MHz): β- isomer: 6 7.38-7.32 (m, 2H); 7.23 (d, 1H, J = 8.1 Hz); 7.08 (d, 2H, J = 8.4 Hz); 6.84 (d, 2H, J = 8.4 Hz); 4.96 (t, 2H, J = 4.2 Hz); 4.83 (d, 1H, J = 5.7 Hz); 4.45 (t, 1H, J = 5.7 Hz); 3.99-3.98 (m, 3H); 3.72-3.64 (m, 3H); 3.21-3.06 (m, 5H); 1.57-1.37 (m, 10H); 0.80 (t, 3H, J = 7.5 Hz); ESI Mass: 513.10 (M+Na);
Example 2: Preparation of (2R,3R.4R,5S.6R)-2-(4-chloro-3-(4-((l- ethylcvclopentyl)methoxy)benzyl)phenyl -6-(hydroxymethyl)tetrahvdro-2H-pyran- 3 A5-triol (oc-isomer):
Figure imgf000073_0001
Step 1: Synthesis of (2R,3R,4R,5S,6R)-2-(4-chloro-3-(4-((l- ethylcyclopentyl)methoxy )benzyl )phenyl )-6-(hydroxymethyl )tetrahydro-2H-pyran- 3,4,5-triol ( ^-isomer):
Figure imgf000074_0001
The experimental procedure similarly as described in Example 1-step 1. H NMR (CDC13, 300 MHz): °c-isomer: δ 7.32-7.29 (m, IH); 7.16-7.10 (m, 2H); 7.05- 7.02 (m, 2H); 6.81-6.76 (m, 2H); 4.52-3.33 (m, 14H); 1.96-1.89 (m, 3H); 1.58-1.38 (m, 10H); 0.83 (t, 3H, J = 7.2 Hz).
Step 2: Synthesis of (2R,3R,4R,5S,6R)-2-(acetoxymethyl)-6-(4-chloro-3-(4-((l- ethylcyclopentyl)methoxy jbenzyl )phenyl )tetrahydro-2H-pyran-3, 4, 5-triyl triacetate:
Figure imgf000074_0002
The experimental procedure similarly as described in Example 1-step 2 1H NMR (CDCI3, 300 MHz): ^-isomer: a gummy substance, δ 7.36-7.30 (m, IH); 7.25- 7.11 (m, IH); 7.08-7.05 (m, 3H); 6.85-6.81 (m, 2H); 5.36-5.26 (m, 2H); 4.92-4.88 (m, IH); 4.66-4.61 (m, IH); 4.58-4.50 (m, IH); 4.40-4.36 (m, IH); 4.18-3.97 (m, 3H); 3.64 (s, 2H); 2.14-2.09 (m, 9H); 1.83 (s, 2H); 1.58-1.41 (m, 10H); 0.84 (t, 3H, J = 12 Hz).
Step 3: Synthesis of (2R,3R,4R5S,6R)-2-(4-chloro-3-(4-((l- ethylcyclopentyl)methoxy )benzyl )phenyl)-6-(hydroxymethyl )tetrahydro-2H-pyran- 3,4,5-triol:
The experimental procedure similarly as described in Example 1-step 3' !H NMR (DMSO-D6+D20, 300 MHz): °c-isomer 5 7.32-7.20 (m, 3H); 7.03 (d, 2H, J = 8.4 Hz); 6.78 (d, 2H, J = 8.7 Hz); 4.45-4.44 (m, IH); 3.93-3.89 (m, 3H); 3.78-3.74 (m, 3H); 3.58 (s, 2H); 3.39-3.34 (m, IH); 3.11 (s, 4H); 1.51-1.33 (m, 10H); 0.74 (t, 3H, J = 7.5 Hz). Example 3: Preparation of (2S,3R,4R,5S,6R -2-(4-chloro-3-(4-(q- ethylcvclobuty methoxy)benzyl)phenyl -6-(hvdroxwethyl)tetrahydro-2H-pyran-
3.4.5-triol:
Figure imgf000075_0001
Step 1: Synthesis of (2S,3R,4R5S,6R)-2-(4-chloro-3-(4-((l- ethylcyclobutyl )methoxy )benzyl )phenyl)-6-(hydroxymethyl )-tetrahydro-2H-pyran- 3,4,5-triol:
Figure imgf000075_0002
Triethylsilane (3.9ml, 0.0242mol) was added to a solution of (2S,3R,4S,5S,6R)-2-(4-cMoro-3-(4-((l-ethylcyclobutyl)methoxy)benzyl)phenyl)-6- (hydroxymethyl)-2-methoxy-tetrahydro-2H-pyran-3,4,5-triol (Intermediate 6, 3.5 g, 0.00691 mol) in dichloromethane: MeCN (40:40 ml) at -10°C. The reaction mixture was allowed to stir at same temperature for 10 minutes then BF3.OEt2 (3.9 ml, 0.0172 mol) was added. The reaction mixture was stirred at -10°C for about 30 minutes and at room temperature for an hour. After completion of reaction as monitored by TLC, the reaction mixture was quenched with saturated NaHC03 solution. The reaction mixture was washed with saturated brine solution; the organic layer was dried over anhydrous Na2S04 and concentrated. The obtained product was purified by column chromatographic technique. 1H NMR (DMSO-D6, 300 MHz): δ 7.38-7.31 (m, 1H); 7.24-7.23 (m, 1H); 7.10-7.08 (d, 2H, J=8.7); 6.87-6.85 (d, 2H, J=8.7Hz); 4.98-4.96 (m, 2H); 4.86-4.84 (d, lH,J=5.7Hz); 4.49-4.45(m, 1H), 3.99- 3.96 (m, 1H), 3.80 (s, 3H), 3.71 (s, 2H), 3.70-3.66 (m, 1H), 3.21-3.08 (m, 5H), 1.86- 1.73 (m, 6H), 1.60-1.53 (q, 2H, J=7.5Hz), 0.80-0.75 (t, 3H); ESI Mass: 499.04 (M+Na).
Step 2: Synthesis of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4-((l- ethylcyclobutyl)methoxy)benzyl)phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate:
Figure imgf000076_0001
To a solution of (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-((l- ethylcyclobutyl)methoxy)benzyl)phenyl)-6-(hydroxymethyl)-tetrahydro-2H-pyran- 3,4,5-triol (step 1, 3 g) in dichloromethane (50 ml) at 0°C was added pyridine (5.08 ml), acetic anhydride (5.95 ml) and 76 mg of DMAP. The reaction mixture was stirred at room temperature for about an hour. After completion of the reaction as monitored by TLC, reaction mixture was diluted with dichloromethane, washed with water, 1% HC1 solution, water followed by saturated brine solution. The organic layer was dried over anhydrous Na2S04 and concentrated. Product was purified by flash column chromatographic technique to remove unreacted Ac20. Recrystallisation of the obtained mixture in ethanol gives the desired isomer as white solid. 1H NMR (CDC13, 300 MHz): δ 7.37-7.34 (m, 1H); 7.20-7.19 (m, 1H); 7.08-7.04 (m, 3H); 6.86-6.83 (m, 2H); 5.31-5.17 (m, 2H); 5.08-5.02 (m, 1H); 4.33- 4.23 (m, 3H); 4.16-4.15(m, 1H), 4.03-4.00 (q, 2H), 3.81 (s, 2H); 3.79-3.76 (m, 1H), 2.08 (s, 2H), 2.05 (s, 2H), 1.99 (s, 3H), 1.92-1.90 (m, 4H), 1.90-1.86 (m, 2H), 1.84- 1.59 (m, 5H), 0.85-0.80 (t, 3H, J=7.5Hz). ESI Mass: 667.2 (M+Na).
Step 3: Synthesis of (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-((l- ethylcyclobutyl jmethoxy )benzyl )phenyl )-6-( hydroxymethyl )tetrahydro-2H-pyran- 3,4,5-triol:
A solution of 20% methanolic ammonia (30 ml) was added to (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4-((l- ethylcyclobutyl)methoxy)benzyl)phenyl) tetrahydro-2H-pyran-3,4,5-triyl triacetate (step 2, 2.5 g, 0.0038 mol) at 0°C and the reaction mixture was stirred overnight at room temperature. After completion of the reaction as monitored by TLC, solvent was removed over rotary evaporator and the residue was dissolved in ethyl acetate. The organic layer was washed with saturated brine solution, dried over anhydrous Na2S04 and concentrated. The obtained product was purified by column chromatographic technique. 1H NMR (DMSO-D6+D20, 300 MHz): δ 7.34-7.28 (m, 2H); 7.20-7.18 (m, 1H); 7.07-7.04 (d, 2H, J=8.7Hz); 6.84-6.81 (d, 2H, J=8.7 Hz); 4.95-4.93 (m, 2H); 4.82-4.80 (d, 1H, 7=5.7 Hz); 4.45-4.41 (t, 1H, 7=5.7 Hz); 3.96- 3.93 (m, 3H); 3.76 (s, 2H); 3.68-3.62 (m, 1H), 3.15-3.13 (m, 5H); 1.83-1.69 (m, 6H); 1.54-1.52 (q, 2H), 0.77-0.72 (t, 3H, J=7.2Hz); 0.80 (t, 3H, J = 7.5 Hz); ESI Mass: 513.10 (M+Na).
Example 4: Preparation of (2S R,4R,5S,6R)-2-(4-chloro-3-(4-(q- ethylcyclohexyl)methoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-
3,4.5-triol:
Figure imgf000077_0001
Step 1: Synthesis of (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-((l- ethylcyclohexyl jmethoxy )benzyl )phenyl )-6-(hydroxymethyl )tetr hydro-2H-pyran- 3,4,5-triol:
Figure imgf000077_0002
Triethylsilane (1.5 ml, 0.00963 mol) was added to a solution of (2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-((l-ethylcyclohexyl)methoxy)benzyl)phenyl)-6- (hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (Intermediate 8, 2.5 g, 0.0046 mol) in dichloromethane:MeCN (40:40 ml) at -10°C and the reaction mixture was allowed to stir for 10 minutes at same temperature then BF3.OEt2 (0.882 ml, 0.00702 mol) was added. The reaction mixture was stirred for about 30 minutes at - 10°C and for an hour at room temperature. After completion of reaction as monitored by TLC, the reaction mixture was quenched with 10% NaHC03 solution. The reaction mixture was washed with saturated brine solution and the organic layer was dried over anhydrous Na2S04 and concentrated. The obtained product was purified by column chromatographic technique. 1H NMR (CDC13, 300 MHz): (DMSO-D6+D20, 300 MHz): 6 7.38-7.32 (m, 3H); 7.24-7.20 (m, 2H); 7.10-7.07 (d, 2H, J=8.4Hz); 6.86-6.83 (d, 2H, J=8.4Hz); 6.18 (bs, 1H), 4.98-4.96 (m, 1H); 4.85- 4.83 (d, 1H, J=5.7Hz); 4.48-4.44 (m, 4H), 4.04-3.97 (m, 3H), 3.66 (s, 2H), 3.21-3.15 (m, 4H), 2.66-2.60 (m, 1H), 1.44-1.31 (m, 12H), 0.77-0.75 (t, 3H). ESI Mass: 527.25 (M+Na).
Step 2: Synthesis of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4-((l- ethylcyclohexyl)methoxy)benzyl)phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate:
Figure imgf000078_0001
To a solution of (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-((l- ethylcyclohexyl)methoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran- 3,4,5-triol (step 1, 1.8 g) in dichloromethane (20 ml) at 0°C was added pyridine (2.87 ml), acetic anhydride (3.37 ml) and catalytic amount of DMAP. The reaction mixture was stirred at room temperature for about an hour. After completion of the reaction as monitored by TLC, the reaction mixture was diluted with dichloromethane, washed with water, 1% HCl solution followed by saturated brine solution. The organic layer was dried over anhydrous Na2S04 and concentrated. The obtained product was purified by flash column chromatographic technique to remove unreacted Ac20. Recrystallisation of the obtained mixture in ethanol gives the desired isomer as white solid. 1H NMR (CDC13, 300 MHz): δ 7.37-7.34 (d, 1H); 7.20-7.08 (m, 1H); 7.07-7.04 (m, 3H); 6.84-6.81 (d, 2H); 5.32-5.17 (m, 2H); 5.09- 5.02 (m, 1H); 4.33-4.24 (m, 2H), 4.16-3.94 (m, 3H), 3.82-3.77 (m, 1H); 3.66 (s, 2H); 2.08-2.05 (d, 6H); 1.99 (s, 3H); 1.70 (s, 3H); 1.51-1.44 (m, 12H); 0.82-0.77 (t, 3H, J = 7.5 Hz). ESI Mass: 695.2 (M+Na).
Step 3: Synthesis of (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-((l- ethylcyclohexyl )methoxy )benzyl )phenyl)-6-(hydroxymethyl )tetrahydro-2H-pyran- 3,4,5-triol:
A solution of 20% methanolic ammonia (10 ml) was added to (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4-((l-ethylcyclohexyl) methoxy)benzyl) phenyl) tetrahydro-2H-pyran-3,4,5-triyl triacetate (step 2, 0.8g, 0.0011 mol) at 0°C and the reaction mixture was stirred overnight at room temperature. After completion of reaction as monitored by TLC, solvent was removed over rotary evaporator and the residue was dissolved in ethyl acetate. The organic layer was washed with saturated brine solution, dried over anhydrous Na2S04 and concentrated. The obtained product was purified by column chromatographic technique. 1H NMR (DMSO-D6+D20, 300 MHz): δ 7.38-7.32 (m, 2H); 7.24-7.21 (m, 1H); 7.09 (d, 2H, / = 8.4 Hz); 6.85 (d, 2H, J = 8.7 Hz); 4.98-4.95 (m, 2H, J = 4.2 Hz); 4.84 (d, 1H, J = 6.0 Hz); 4.46 (t, 1H, J = 6.0 Hz); 4.00-3.97 (m, 3H); 3.75-3.67 (m, 3H); 3.45-3.43 (m, 1H); 3.24-3.08 (m, 4H), 1.45-1.31 (m, 12H), 0.75 (t, 3H, J = 7.2 Hz). ESI Mass: 527.25 (M+Na).
Example 5: Preparation of (2S,3R.4R,5S.6R)-2-(4-chloro-3-(,4-(('l- methylcvclohexyl)methoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran- 3,4.5-triol:
Figure imgf000079_0001
Step 1: Synthesis of (2S,3R,4R,5S,6R)-2-(4-chbro-3-(4-((l- methylcyclohexyl )methoxy )benzyl)phenyl )-6-(hydroxymethyl )tetrahydro-2H-pyran- 3,4,5-triol:
Figure imgf000079_0002
Triethylsilane (0.76 ml, 0.0048 mol) was added at -10°C to a solution of (2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-((l-methylcyclohexyl)methoxy)benzyl)phenyl)- 6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (Intermediate 10, 1 g, 0.0019 mol) in dichloromethane:MeCN (10: 10 ml). The reaction mixture was allowed to stir at same temperature for 10 min and then BF3.OEt2 (0.365 ml, 0.0028 mol) was added. The reaction mixture was stirred for about 30 minutes at -10°C and at room temperature for an hour. After completion of reaction as monitored by TLC, reaction mixture was quenched with 10% NaHC03 solution. The reaction mixture was washed with saturated brine solution; the organic layer was dried over anhydrous Na2S04 and concentrated. The obtained product was purified by column chromatographic technique. 1H NMR (CDC13, 300 MHz): δ 7.38-7.35 (m, 2H); 7.31 (m, 1H); 7.24-7.21 (d, 2HJ=8.4Hz); 6.85-6.83 (d, 2H, J=8.4Hz); 6.17 (bs, 1H), 4.97- 4.96 (m, 1H); 4.85-4.83 (d, 2H, J=5.7Hz); 4.48-4.44 (m, 1H), 3.98-3.96 (m, 2H), 3.62 (s, 2H), 3.23-3.19 (m, 4H), 2.62-2.60 (m, 2H), 1.44-1.29 (m, 10H), 1.11-1.06 (m, 3H), 0.97 (s, 3H); ESI Mass: 527.25 (M+Na).
Step 2: Synthesis of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4-((l- methylcyclohexyl )methoxy )benzyl )phenyl )tetrahydro-2H-pyran-3, 4, 5-triyl triacetate:
Figure imgf000080_0001
To a solution of (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-((l- methylcyclohexyl)methoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran- 3,4,5-triol (step 1, 0.6 g) in dichloromethane (10 ml), pyridine (0.98 ml), acetic anhydride (1.15 ml) and a catalytic amount of DMAP were added at 0°C. The reaction mixture was stirred at room temperature for about an hour. After completion of the reaction as monitored by TLC, the reaction mixture was diluted with dichloromethane, washed with water, 1% HCl solution followed by saturated brine solution. The organic layer was dried over anhydrous Na2S04 and concentrated. Product was purified by flash column chromatographic technique to remove unreacted Ac20. Recrystallisation of the obtained mixture in ethanol gives the desired isomer as white solid. 1H NMR (CDC13, 300 MHz): δ 7.36-7.34 (d, 1H, J=8.1Hz); 7.20-7.16 (m, 1H); 7.06-7.03 (d, 3H); 6.83-6.81 (d, 2H, J=8.7Hz); 5.31- 5.17 (m, 2H); 5.08-5.02 (m, 1H); 4.32-4.23 (m, 3H), 4.16-3.99 (m, 2H), 3.81-3.77 (m, 1H); 3.60 (s, 2H); 2.07 (s, 3H); 2.05(s, 3H), 1.99 (s, 3H); 1.71 (s, 3H); 1.49-1.35 (m, 10H); 1.01 (s, 3H). ESI Mass: 680.92 (M+Na).
Step 3: Synthesis of (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-((l- methylcyclohexyl )methoxy )benzyl )phenyl)-6-(hydroxymethyl )tetrahydro-2H-pyran- 3,4,5-triol: A solution of 20% methanolic ammonia (15 ml) was added to (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4-((l- methylcyclohexyl)methoxy)benzyl)phenyl) tetrahydro-2H-pyran-3,4,5-triyl triacetate (step 2, 0.35g, 0.0005mol) at 0°C and the reaction mixture was stirred for overnight at room temperature. After completion of reaction as monitored by TLC, solvent was removed over rotary evaporator and the residue was dissolved in ethyl acetate. The organic layer was washed with saturated brine solution, dried over anhydrous Na2S04 and concentrated. The obtained product was purified by column chromatographic technique. 1H NMR (DMSO-D6+D20, 300 MHz): 6 7.34-7.27 (m, 2H); 7.20-7.17 (m, 1H); 7.06-7.03 (d, 2H, J = 8.7 Hz); 6.82-6.79 (d, 2H, J = 8.7 Hz); 4.95-4.92 (m, 2H, ); 4.82-4.80 (d, 1H, J = 5.7 Hz); 4.45-4.41 (t, 1H, J = 6.0 Hz); 3.99-3.93 (m, 3H); 3.66-3.62 (m, 1H); 3.58 (s, 2H), 3.15 (m, 5H); 1.40-1.25 (m, 10H), 0.93 (s, 3H). ESI Mass: 513.25 (M+Na).
Example 6: Preparation of (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-((3-ethyloxetan-3- yl)methoxy)benzyl)phenyl)-6-(hvdroxymethyl)tetrahydro-2H-pyran-3,4,5-triol:
Figure imgf000081_0001
Step 1: Synthesis of (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-((3-ethyloxetan-3- yl)methoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H^
Figure imgf000081_0002
Triethylsilane (0.32ml, 0.00196mol) was added to a solution of (2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-((3-ethyloxetan-3-yl)methoxy)benzyl)phenyl)-6- (hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (Intermediate 12, 0.5 g, 0.0098 mol) in dichloromethane:MeCN (10: 10 ml) at -10°C. The reaction mixture was allowed to stir at same temperature for 10 minutes then BF3:OEt2 (0.19 ml, 0.00147 mol) was added. The reaction mixture was stirred for about 30 minutes at - 10°C and at room temperature for an hour. After completion of reaction as monitored by TLC, the reaction mixture was quenched with saturated NaHC03 solution. The reaction mixture was washed with saturated brine solution; the organic layer was dried over anhydrous Na2S04 and concentrated. The obtained product was purified by column chromatographic technique. 1H NMR (DMSO-D6, 300 MHz): δ
7.37-7.31 (m, 1H); 7.23-7.20 (m, 1H); 7.10-7.08 (d, 2H, J=8.4); 6.87-6.84 (d, 2H, J=8.4Hz); 4.98-4.96 (m, 2H); 4.85-4.81 (m, 2H,J=5.7Hz); 4.47 (m, 1H), 3.99-3.96 (m, 3H), 3.74-3.67 (m, 2H), 3.65 (s, 2H), 3.20-3.16 (m, 4H), 1.44-1.39 (q, 2H), 1.13- 1.02 (m, 2H), 0.85-0.80 (t, 3H).
Step 2: Synthesis of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4-((3- ethyloxetan-3-yl)methoxy)benzyl)phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate:
Figure imgf000082_0001
To a solution of (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-((3-ethyloxetan-3- yl)methoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (step 1, 0.4 g) in dichloromethane (50 ml), pyridine (0.67 ml), acetic anhydride (0.79 ml) and O.Olg of DMAP were added at 0°C. The reaction mixture was stirred at room temperature for about an hour. After completion of reaction as monitored by TLC, the reaction mixture was diluted with dichloromethane, washed with water, 1% HC1 solution, water followed by saturated brine solution. The organic layer was dried over anhydrous Na2S04 and concentrated. Obtained product was purified by flash column chromatographic technique to remove unreacted Ac20. Recrystallisation of the obtained mixture in ethanol gives the desired isomer as white solid. Ή NMR
(CDC13, 300 MHz): δ 7.37-7.34 (m, 1H); 7.20-7.19 (m, 1H); 7.08-7.04 (m, 3H); 6.86-6.83 (m, 2H); 5.31-5.17 (m, 2H); 5.08-5.02 (m, 1H); 4.33-4.23 (m, 3H); 4.16- 4.15 (m, 1H), 4.03-4.00 (q, 2H), 3.81 (s, 2H); 3.79-3.76 (m, 1H), 2.08 (s, 2H), 2.05 (s, 2H), 1.99 (s, 3H), 1.92-1.90 (m, 4H), 1.90-1.86 (m, 2H), 1.84-1.59 (m, 5H), 0.85- 0.80 (t, 3H, J=7.5Hz); ESI Mass: 667.2 (M+Na).
Step 3: Synthesis of (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-((3-ethyloxetan-3- yl jmethoxy jbenzyl )phenyl )-6-(hydroxymethyl )tetrahydro-2H-pyran-3, 4, 5-triol: A solution of 20% methanolic ammonia (10 ml) was added to (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4-((3-ethyloxetan-3- yl)methoxy)benzyl)phenyl) tetrahydro-2H-pyran-3,4,5-triyl triacetate (step 2, 0.4 g, 0.000619 mol) at 0°C and the reaction mixture was stirred overnight at room temperature. After completion of the reaction as monitored by TLC, the solvent was removed over rotary evaporator and the residue was dissolved in ethyl acetate. The organic layer was washed with saturated brine solution, dried over anhydrous Na2S04 and concentrated. The obtained product was purified by column chromatographic technique. 1H NMR (DMSO-D6+D20, 300 MHz): δ 7.34-7.28 (m, 2H); 7.20-7.18 (m, 1H, ); 7.07-7.04 (d, 2H, J=8.7Hz); 6.84-6.81 (d, 2H, J = 8.7 Hz); 4.95-4.93 (m, 2H); 4.82-4.80 (d, 1H, J = 5.7 Hz); 4.45-4.41 (t, 1H, /=5.7Hz); 3.96- 3.93 (m, 3H); 3.76 (s, 2H); 3.68-3.62 (m, 1H), 3.15-3.13 (m, 5H); 1.83-1.69 (m, 6H); 1.54-1.52 (q, 2H), 0.77-0.72 (t, 3H, J=7.2Hz), 0.80 (t, 3H, J = 7.5 Hz); ESI Mass: 513.10 (M+Na).
Example 7: Preparation of (2R.3S.4R.5R.6S)-2-(hydroxymethyl)-6-(4-methyl-3-(4-
((l-(trifluoromethyl)cyclopropyl)methoxy)benzyl)phenyl)tetrahydro-2H-pyran-
3A5-triol:
Figure imgf000083_0001
To a stirred solution of (2S,3R,4R,5S,6R)-2-(3-(4-hydroxybenzyl)-4- methylphenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (intermediate 13, 0.3 g) in dimethylformamide (10 ml), Cs2C03 (0.81 g) and (1- (trifluoromethyl)cyclopropyl)methyl 4-methylbenzenesulfonate (intermediate 14, 0.31 g) were added under N2 atmosphere at room temperature. The reaction mixture was heated to 120 °C and stirred for about 8 hours. After completion of the reaction (monitored by TLC), reaction mixture was cooled to room temperature and partitioned between water and EtOAc. Two layers were separated and aqueous layer was again extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulphate and concentrated to give the residue. The crude product was purified via silica gel column chromatography with MeOH and dichloromethane (1: 25) to afford the title compound as white solid (198 mg). Yield: 49.2 %; 1H NMR (DMSO- D6, 300 MHz): δ 7.11- 7.08 (m, 3H), 7.03 (d, J = 8.7 Hz, 2H), 6.84 (d, J = 8.7 Hz, 2H), 4.92 (d, J = 4.5 Hz, 2H), 4.72 (d, J = 5.7 Hz, 1H), 4.43 (dd, J = 5.7, 5.7 Hz, 1H), 4.05 (s, 2H), 3.93 (d, J = 9.3 Hz, 1H), 3.86 (s, 2H), 3.71- 3.66 (m, 1H), 3.46- 3.38 (m, 1H), 3.25- 3.12 (m, 4H), 2.14 (s, 3H), 1.09- 1.05 (m, 2H), 1.00- 0.97 (m, 2H); ES Mass: (M+ Na) 505.11.
Example 8: Preparation of (,2R,3S.4R.5R,6S)-2-(,hvdroxymethyl)-6-(4-methyl-3-(4- ((1 -(trifluoromethyl)cyclobutyl)methoxy)benzyl)phenyl)tetrahydro-2H-pyr an-3 ,4,5- triol:
Figure imgf000084_0001
To a stirred solution of (2S,3R,4R,5S,6R)-2-(3-(4-hydroxybenzyl)-4- methylphenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3 ,4,5-triol (intermediate 13 , 0.3 g) in dimethylformamide (10 ml), Cs2C03 (0.81 g) and (1- (trifluoromethyl)cyclobutyl)methyl 4-methylbenzenesulfonate (intermediate 15, 0.33 g) were added under N2 atmosphere at room temperature. The reaction mixture was heated to 120 °C and stirred for about 12 hours. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature and partitioned between water and EtOAc. Two layers were separated and aqueous layer was again extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulphate and concentrated to give the residue. The crude product was purified via silica gel column chromatography with MeOH and dichloromethane (1 : 25) to afford the title compound as white solid (160 mg).
Yield: 41 %; 1H NMR (DMSO- D6, 300 MHz): δ 7.12- 7.04 (m, 5H), 6.89 (d, J = 8.9 Hz, 2H), 4.92 (d, J = 4.8 Hz, 2H), 4.72 (d, J = 5.7 Hz, 1H), 4.43 (dd, J = 5.7, 5.7 Hz, 1H), 4.15 (s, 2H), 3.93 (d, J = 9.3 Hz, 1H), 3.87 (s, 2H), 3.72- 3.66 (m, 1H), 3.44- 3.40 (m, 1H), 3.26- 3.15 (m, 4H), 2.32- 2.21 (m, 4H), 2.15 (s, 3H), 2.10- 2.07 (m, 2H); ES Mass: (M+ Na) 519.10. Example 9: Preparation of (2S R lR.5S,6R)-2-(3-(4-((4^-difluoro-l- methylcyclohexyl)methoxy)benzyl)-4-methylphenylV6-(hvdroxymethyl)tetrahy
2H-pyran-3A5-triol:
Figure imgf000085_0001
To a stirred solution of (2S,3R,4R,5S,6R)-2-(3-(4-hydroxybenzyl)-4- methylphenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3 ,4,5-triol (intermediate 13 , 0.2 g) in dimethylformamide (8 ml), Cs2C03 (0.54 g) and (4,4-difluoro-l- methylcyclohexyl)methyl 4-methylbenzenesulfonate (intermediate 16, 0.22 g) were added under N2 atmosphere at room temperature. The reaction mixture was heated to 120 °C and stirred for about 12 hours. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature and partitioned between water and EtOAc. Two layers were separated and aqueous layer was again extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulphate and concentrated to give the residue. The crude product was purified via silica gel column chromatography with MeOH and dichloromethane (1 : 25) to afford the title compound as white solid (1 19 mg). Yield: 42.5 %; 1H NMR (DMSO- D6, 300 MHz): 5 7.11- 7.08 (m, 3H), 7.03 (d, J = 8.4 Hz, 2H), 6.85 (d, J = 8.4 Hz, 2H), 4.92 (d, / = 4.5 Hz, 2H), 4.71 (d, J = 5.7 Hz, 1H), 4.43 (dd, J = 5.7, 5.7 Hz, 1H), 3.93 (d, J = 9.0 Hz, 1H), 3.86 (s, 2H), 3.71 (s, 2H), 3.68- 3.66 (m, 1H), 3.46- 3.38 (m, 1H), 3.26- 3.12 (m, 4H), 2.15 (s, 3H), 1.97- 1.85 (m, 4H), 1.70- 1.61 (m, 2H), 1.49- 1.44 (m, 2H), 1.03 (s, 3H); ES Mass: (M+ Na) 529.20.
Example 10: Preparation of (2S.3R.4R,5S,6R)-2-(4-chloro-3-(4-((l-
(trifluoromethyl)cvclobutyl)methoxy)benzyl)phenyl)-6-(hvdroxymethyl)tetrahydro-
2H-pyran-3,4,5-triol:
Figure imgf000086_0001
Step 1: Synthesis of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4-((l- ( trifluoromethyl jcyclobutyl jmethoxy )benzyl )phenyl )tetrahydro-2H-pyran-3, 4, 5-triyl triacetate (β isomer):
Figure imgf000086_0002
To a stirred solution of (3R,4R,5S,6R)-2-(4-chloro-3-(4-((l- (trifluoromethyl)cyclobutyl)rnethoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro- 2H-pyran-3,4,5-triol (Intermediate 17, 3 g, mixture of α & β isomers ) in dichloromethane (80 ml), pyridine (4.7 ml) and AC20 (5.5 ml) followed by DMAP (catalytic) were added at 0° C under N2 atmosphere. The reaction temperature was slowly raised to room temperature and stirred for over night. After completion of the reaction (monitored by TLC), the reaction mixture was extracted with dichloromethane. The combined organic layers were washed with saturated 2N HC1 solution and brine, dried over anhydrous sodium sulphate and concentrated to give the residue. The crude product was purified via silica gel column chromatography with EtOAc and Hexane (2: 4) to afford the title compound (β- isomer) as white solid (3.8 g). HPLC: 97.97 %; H NMR (CDC13, 300 MHz): δ 7.36 (d, / = 8.1 Hz, 1H), 7.19 (dd, / = 1.8, 8.1 Hz, 1H), 7.17- 7.07 (m, 3H), 6.87 (d, / = 8.7 Hz, 2H), 5.32- 5.17 (m, 2H), 5.06 (dd, J = 9.6 Hz, 1H), 4.34-4.24 (m, 2H), 4.17- 4.02 (m, 5H), 3.83- 3.78 (m, 1H), 2.38- 2.31 (m, 2H), 2.23- 2.19 (m, 2H), 2.08 (s, 3H), 2.05 (s, 3H), 1.99 (s, 3H), 2.08- 1.99 (m, 2H), 1.72 (s, 3H); ES Mass: (M+Na) 707.
Step 2: Synthesis of (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-((l- ( trifluoromethyl )cyclobutyl )methoxy )benzyl )phenyl)-6- ( hydroxymethyl )tetrahydro- 2H-pyran-3,4,5-triol: NH3 in MeOH (70 ml) was added to (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6- (4-chloro-3-(4-((l-(trifluoromethyl)cyclobutyl)methoxy)benzyl)phenyl)tetrahydro- 2H-pyran-3,4,5-triyl triacetate (β isomer, step 1, 0.8 g) at room temperature and stirred for over night. After completion of the reaction (monitored by TLC), volatiles were concentrated under reduced pressure to give residue. The crude product was purified via silica gel column chromatography with MeOH and dichloromethane (1: 19) to afford the title compound as white solid (470 mg). Yield: 78.1 %; 1H NMR (DMSO- D6, 300 MHz): 5 7.38-7.32 (m, 2H), 7.24- 7.14 (m, 1H), 7.12 (d, / = 8.5 Hz, 2H), 6.90 (d, / = 8.5 Hz, 2H), 4.97- 4.95 (m, 2H), 4.84 (d, J = 5.7 Hz, 1H), 4.46(dd, 7 = 5.7 Hz, 5.7 Hz, 1H), 4.15 (s, 2H), 4.00-3.97 (m, 3H), 3.71- 3.66 (m, 1H), 3.45-3.40 (m, 1H), 3.26- 3.09 (m, 4H), 2.29- 2.24 (m, 2H), 2.10- 1.93 (m, 4H); ES Mass: (M+Na) 539; HPLC: 96.63 .
Example 11: Preparation of (2S.3R.4R,5S,6R)-2-(4-chloro-3-(4-((l- methylcyclopentyl)methoxy)benzyl)phenyl)-6-(hvdroxymethyl)tetrahydro-2H- pyran-3A5-triol:
Figure imgf000087_0001
Step 1: Synthesis of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4-((l- methylcyclopentyljmethoxy )benzyl jphenyl )tetrahydro-2H-pyran-3, 4, 5-triyl triacetate (β- isomer):
Figure imgf000087_0002
To a stirred solution of (3R,4R,5S,6R)-2-(4-chloro-3-(4-((l- methylcyclopentyl)methoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H- pyran-3,4,5-triol (Intermediate 19, mixture of α & β isomers, 1.8 g) in dichloromethane (40 ml), pyridine (3.6 ml) was added at 0°C under N2 atmosphere followed by AC20 (3.6 ml) and DMAP (catalytic). The reaction temperature was slowly raised to room temperature and stirred for over night. After completion of the reaction (monitored by TLC), the reaction mixture was extracted with dichloromethane. The combined organic layers were washed with 3N HC1 solution and brine, dried over anhydrous sodium sulphate and concentrated to give the residue. The crude product was purified via silica gel column chromatography with EtOAc and Hexane (2: 4) to afford the title compound (β- isomer) as white solid (1.2 g). Yield: 50 %; HPLC: 97.57 ; 1H NMR (CDC13, 300 MHz) of compound 15: 6 7.35 (d, J = 8.1 Hz, 1H), 7.18 (dd, 7 = 2.1, 8.1 Hz, 1H), 7.07- 7.04 (m, 3H), 6.83 (d, J = 8.4 Hz, 2H), 5.32- 5.17 (m, 2H), 5.05 (dd, J = 9.3 Hz, 1H), 4.33- 4.24 (m, 2H), 4.14 (dd, J = 2.1, 12.34 Hz, 1H), 4.02- 4.0 (m, 2H), 3.82- 3.77 (m, 1H), 3.64 (s, 2H), 2.08 (s, 3H), 2.05 (s, 3H), 1.99 (s, 3H), 1.71 (s, 3H), 1.62- 1.56 (m, 6H), 1.41- 1.39 (m, 2H), 1.11 (s, 3H); ES Mass: (M+Na) 667.
Step 2: Synthesis of (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-((l- methylcyclopentyl)methoxy jbenzyl )phenyl )-6-(hydroxymethyl )tetrahydro-2H-pyran- 3,4,5-triol:
NH3 in MeOH (100 ml) was added to (2R,3R,4R,5S,6S)-2-(acetoxymethyl)- 6-(4-chloro-3-(4-((l-methylcyclopentyl)methoxy)benzyl)phenyl)tetrahydro-2H- pyran-3,4,5-triyl triacetate (β- isomer, Step 1, 1.2 g) at room temperature and stirred over night. After completion of the reaction (monitored by TLC), volatiles were concentrated under reduced pressure to give residue. The crude product was purified via silica gel column chromatography with MeOH and dichloromethane (1 : 19) to afford the title compound as white solid (700 mg). Yield: 79 %; HPLC: 93.16 %; 1H NMR (DMSO- D6, 300 MHz): δ 7.36 (d, J = 8.1 Hz, 1H), 7.31 (d, J = 1.8 Hz, 1H), 7.22 (dd, J = 1.8, 8.1 Hz, 1H), 7.08 (d, J = 8.7 Hz, 2H), 6.83 (d, J = 8.7 Hz, 2H), 4.97- 4.95 (m, 2H), 4.83 (d, J = 5.7 Hz, 1H), 4.45 (dd, J = 6.0 Hz, 1H), 3.99- 3.96 (m, 3H), 3.71- 3.69 (m, 1H), 3.65 (s, 2H), 3.45- 3.41 (m, 1H), 3.29- 3.05 (m, 4H), 1.62- 1.58 (m, 6H), 1.34- 1.32 (m, 2H), 1.05 (s, 3H); ES Mass: (M+Na) 499.
Example 12: Preparation of (,2S.3R.4R.5S.6R -2-(4-chloro-3-(,4-f('l-
(trifluoromethyl)cvclopropyl)methoxy)benzyl)phenyl)-6-
(hvdroxymethyl)tetrahydro-2H-pyran-3A5-triol:
Figure imgf000089_0001
Step 1: Synthesis of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4-((l- ( trifluoromethyl )cyclopropyl )methoxy )benzyl )phenyl )tetrahydro-2H-pyran-3, 4, 5- triyl triacetate (β- isomer):
Figure imgf000089_0002
To a stirred solution of (3R,4R,5S,6R)-2-(4-chloro-3-(4-((l- (trifluoromethyl)cyclopropyl)methoxy)benzyl)phenyl)-6-
(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (Intermediate 20, mixture of α & β isomers, 1.8 g) in dichloromethane (40 ml), pyridine (2.9 ml) was added at 0 °C under N2 atmosphere followed by AC20 (3.4 ml) and DMAP (catalytic). The reaction temperature was slowly raised to room temperature and stirred over night. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with dichloromethane and the organic layer was washed with 3N HCl solution and brine, dried over anhydrous sodium sulphate and concentrated to give the residue. The crude product was purified via silica gel column chromatography with EtOAc and Hexane (2: 4) to afford the title compound (β- isomer) as white solid (1.5 g). Yield: 62.5 %; 1H NMR (CDC13, 300 MHz): δ 7.34 (d, J = 8.4 Hz, 1H), 7.17 (d, J = 8.4 Hz, 1H), 7.06- 7.03 (m, 3H), 6.80 (d, J = 8.4 Hz, 2H), 5.30- 5.15 (m, 2H), 5.04 (dd, J = 9.4 Hz, 1H), 4.31-4.22 (m, 2H), 4.15- 3.94 (m, 5H), 3.80- 3.77 (m, 1H), 2.06 (s, 3H), 2.03 (s, 3H), 1.97 (s, 3H), 1.69 (s, 3H), 1.10- 1.08 (m, 2H), 0.90 (m, 2H); ES Mass: (M+Na) 693.
Step 2: Synthesis of (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-((l- (trifluoromethyl)cyclopropyl)methoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro- 2H-pyran-3, 4, 5-triol: NH3 in MeOH (60 ml) was added to(2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6- (4-chloro-3-(4-((l-(trifluoromethyl)cyclopropyl)methoxy)benzyl)phenyl)tetrahydro- 2H-pyran-3,4,5-triyl triacetate (β- isomer, step 1, 1.5 g) at room temperature and stirred over night. After completion of the reaction (monitored by TLC), volatiles were concentrated under reduced pressure to give residue. The crude product was purified via silica gel column chromatography with MeOH and dichloromethane (1: 19) to afford the title compound as white solid (0.70 g). Yield: 63.6 %; 1H NMR (DMSO- D6, 300 MHz): 6 7.36 (d, J = 8.1 Hz, 1H), 7.32 (d, J = 1.8 Hz, 1H), 7.22 (dd, J = 1.8, 8.1 Hz, 1H), 7.10 (d, J = 8.4 Hz, 2H), 6.85 (d, / = 8.4 Hz, 2H), 4.97- 4.95 (m, 2H), 4.84 (d, J = 5.7 Hz, 1H), 4.46(dd, J = 5.7 Hz, 5.7 Hz, 1H), 4.06 (s, 2H), 3.99-3.97 (m, 3H), 3.71- 3.66 (m, 1H), 3.45-3.39 (m, 1H), 3.24- 3.10 (m, 4H), 1.07- 1.05 (m, 2H), 0.97 (m, 2H); ES Mass: (M+Na) 525; HPLC: 97.31 %.
Example 13: Preparation of (2S.3R.4R.5S.6R)-2-(4-chloro-3-(4-((4<4-difluoro-l- methylcyclohexyl)methoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran- 3A5-triol:
Figure imgf000090_0001
Step 1: Synthesis of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4-((4,4- difluoro-l-methylcyclohexyl)methoxy)benzyl)phenyl)tetraty
triacetate (β- isomer):
Figure imgf000090_0002
To a stirred solution of (3R,4R,5S,6R)-2-(4-chloro-3-(4-((4,4-difluoro-l- methylcyclohexyl)methoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran- 3,4,5-triol (Intermediate 21, mixture of α & β isomers, 0.67 g) in dichloromethane (20 ml), Pyridine (1 ml) was added at 0 °C under N2 atmosphere followed by AC20 (1.2 ml) and DMAP (catalytic). The reaction temperature was slowly raised to room temperature and stirred for over night. After completion of the reaction (monitored by TLC), reaction mixture was extracted with dichloromethane. The combined organic layers were washed with 3N HC1 solution and brine, dried over anhydrous sodium sulphate and concentrated to give the crude compound. The crude product was purified via silica gel column chromatography with EtOAc and Hexane (2: 4) to afford the title compound (β- isomer) as white solid (690 mg). Yield: 78.1 %; 1H NMR (CDCI3, 300 MHz) of compound: δ 7.35 (d, J = 8.4 Hz, 1H), 7.18 (dd, J = 1.5, 8.4 Hz, 1H), 7.08- 7.04 (m, 3H), 6.81 (d, J = 8.7 Hz, 2H), 5.31- 5.17 (m, 2H), 5.05 (dd, J = 9.6 Hz, 1H), 4.33-4.23 (m, 2H), 4.15- 4.11 (m, 1H), 4.02- 4.00 (m, 2H), 3.82- 3.77 (m, 1H), 3.66 (s, 2H), 2.07 (s, 3H), 2.05 (s, 3H), 1.99 (s, 3H), 1.69 (s, 3H), 2.07- 1.70 (m, 6H), 1.60- 1.58 (m, 2H), 1.09 (s, 3H); HPLC: 91.18 %; ES Mass: (M+Na) 717.
Step 2: Synthesis of (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-((4,4-difluoro-l- methylcyclohexyl )methoxy )benzyl )phenyl)-6-(hydroxymethyl )tetrahydro-2H-pyran- 3,4,5-triol:
NH3 in MeOH (20 ml) was added to (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6- (4-chloro-3-(4-((4,4-difluoro- 1 - methylcyclohexyl)methoxy)benzyl)phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (β- isomer, step 1, 0.69 g) at room temperature and stirred for over night. After completion of the reaction (monitored by TLC), volatiles were concentrated under reduced pressure to give residue. The crude product was purified via silica gel column chromatography with MeOH and dichloromethane (1: 19) to afford the title compound as white solid (270 mg). Yield: 51.7 %; HPLC: 91.03%; 1H NMR (DMSO- D6, 300 MHz): 6 7.37 (d, J = 8.4 Hz, 1H), 7.31 (s, 1H), 7.22 (d, J = 8.4 Hz, 1H), 7.10 (d, J = 8.4 Hz, 2H), 6.86 (d, / = 8.4 Hz, 2H), 4.98- 4.95 (m, 2H), 4.84 (d, J = 5.7 Hz, 1H), 4.44 (dd, J = 5.7 Hz, 5.7 Hz, 1H), 3.99- 3.97 (m, 3H), 3.71- 3.66 (m, 3H), 3.47- 3.06 (m, 5H), 1.97- 1.87 (m, 4H), 1.70- 1.61 (m, 2H)( 1.49- 1.44 (m, 2H), 1.03 (s, 3H); ES Mass: (M+Na) 549.
Example 14: Preparation of (2S.3R.4R.5S.6R)-2-(4-fluoro-3-r4-('il- (trifluoromethyl)cvclobutyl methoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-
2H-pyran-3.4.5-triol:
Figure imgf000092_0001
Step 1: Synthesis of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-fluoro-3-(4-((l- ( trifluoromethyl )cyclobutyl )methoxy )benzyl )phenyl )tetrahydro-2H-pyran-3, 4, 5-triyl triacetate (β- isomer):
Figure imgf000092_0002
To a stirred solution of (3R,4R,5S,6R)-2-(4-fluoro-3-(4-((l- (trifluoromethyl)cyclobutyl)methoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro- 2H-pyran-3,4,5-triol (Intermediate 23, mixture of α & β isomers, 2.3 g) in dichloromethane 960 ml), pyridine (3.9 ml) was added at 0°C under N2 atmosphere followed by AC20 (4.3 ml) and DMAP (catalytic). The reaction temperature was slowly raised to room temperature and stirred for over night. After completion of the reaction (monitored by TLC), the reaction mixture was extracted with dichloromethane. The combined organic layers were washed with saturated 2N HC1 solution and brine, dried over anhydrous sodium sulphate and concentrated to give the residue. The crude product was purified via silica gel column chromatography with EtOAc and Hexane (2: 4) to afford the title compound (β- isomer) as white solid (1.2 g). Yield: 40 %; HPLC: 99.91 %; lR NMR (CDC13, 300 MHz) of compound 16: δ 7.20 (m, 1H), 7.12- 6.98 (m, 4H), 6.86 (d, / = 8.4 Hz, 2H), 5.31- 5.17 (m, 2H), 5.06 (dd, J = 9.6, 9.6 Hz, 1H), 4.33- 4.23 (m, 2H), 4.15- 4.10 (m, 2H), 4.02 (s, 2H), 3.92- 3.91 (m, 2H), 3.81- 3.78 (1H), 2.36- 2.30 (m, 2H), 2.22- 2.19 (m, 2H), 2.07 (s, 3H), 2.05 (s, 3H), 1.99 (s, 3H), 2.07- 1.99 (m, 2H), 1.70 (s, 3H); ES Mass: (M+Na) 691.20.
Step 2: Synthesis of (2S,3R,4R,5S,6R)-2-(4-fluoro-3-(4-((l-
( trifluoromethyl )cyclobutyl )methoxy )benzyl )phenyl )-6-( hydroxymethyl )tetrahydro- 2H-pyran-3,4,5-triol: NH3 in MeOH (70 ml) was added to (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6- (4-fluoro-3-(4-((l-(trifluoromethyl)cyclobutyl)methoxy)benzyl)phenyl)tetrahydro- 2H-pyran-3,4,5-triyl triacetate (β- isomer, step 1, 1.2 g) at room temperature and stirred for over night. After completion of the reaction (monitored by TLC), volatiles were concentrated under reduced pressure to give residue. The crude product was purified via silica gel column chromatography with MeOH and dichloromethane (1: 19) to afford the title compound as white solid (810 mg). Yield: 90.2 %; HPLC: 99.45 %; 1H NMR (DMSO- D6, 300 MHz): δ 7.28-7.20 (m, 2H), 7.16- 7.06 (m, 3H), 6.91 (d, J = 8.4 Hz, 2H), 4.96 (d, J = 2.1 Hz, 2H), 4.80 (d, J = 5.4 Hz, 1H), 4.46 (dd, J = 5.7 Hz, 5.7 Hz, 1H), 4.15 (s, 2H), 3.97 (d, J = 9.3 Hz, 1H), 3.89- 3.88 (m, 2H), 3.71-3.65 (m, 1H), 3.51- 3.11 (m, 5H), 2.26- 2.24 (m, 2H), 2.10- 1.89 (m, 4H); ES Mass: (M+Na) 523.20.
Example 15: Preparation of (2S,3R,4R.5S,6RV2-(4-chloro-3-(4-((l-
(trifluoromethyl)cvclopropyl)methoxy')benzyl)phenyl)-6-
(hvdroxvmethvl tetrahvdro-2H-pvran-3,4,5-triol:
Figure imgf000093_0001
Step 1: Synthesis of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-fluoro-3-(4-((l- ( trifluoromethyl jcyclopropyl )methoxy )benzyl jphenyl )tetrahydro-2H-pyran-3, 4, 5- triyl triacetate (β- isomer):
Figure imgf000093_0002
To a stirred solution of (3R,4R,5S,6R)-2-(4-fluoro-3-(4-((l- (trifluoromethyl)cyclopropyl)methoxy)benzyl)phenyl)-6-
(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (Intermediate 24, mixture of α & β isomers, 2 g) in dichloromethane (20 ml), pyridine (3.3 ml) was added at 0°C under N2 atmosphere followed by AC20 (3.9 ml) and DMAP (catalytic). The reaction temperature was slowly raised to room temperature and stirred for over night. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with dichloromethane and the organic layer was washed with 3N HCl solution and brine, dried over anhydrous sodium sulphate and concentrated to give the residue. The crude product was purified via silica gel column chromatography with EtOAc and Hexane (2: 4) to afford the title compound (β- isomer) as white solid (1.8 g). Yield: 66.9 %; HPLC: 96.70 ; 1H NMR (CDC13, 300 MHz): δ 7.22- 7.20 (m, IH), 7.10- 6.98 (m, 4H), 6.81 (d, J = 8.1 Hz, 2H), 5.32- 5.17 (m, 2H), 5.05 (dd, J = 9.3 Hz, IH), 4.33- 4.23 (m, 2H), 4.16- 4.11 (m, IH), 4.04 (s, 2H), 3.91- 3.84 (m, 2H), 3.81- 3.78 (m, IH), 2.07 (s, 3H), 2.05 (s, 3H), 1.99 (s, 3H), 1.69 (s, 3H), 1.13- 1.10 (m, 2H), 0.93- 0.88 (m, 2H); ES Mass: (M+Na) 677.15.
Step 2: Synthesis of (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-((l- ( trifluoromethyl jcyclopropyl )methoxy jbenzyl )phenyl)-6- ( hydroxymethyl )tetrahydro- 2H-pyran-3,4,5-triol:
NH3 in MeOH (100 ml) was added to (2R,3R,4R,5S,6S)-2-(acetoxymethyl)- 6-(4-fluoro-3-(4-((l-
(trifluoromethyl)cyclopropyl)methoxy)benzyl)phenyl)tetrahydro-2H-pyran-3,4,5- triyl triacetate (β- isomer, step 1, 1.8 g) at room temperature and stirred over night. After completion of the reaction (monitored by TLC), volatiles were concentrated under reduced pressure to give residue. The crude product was purified via silica gel column chromatography with MeOH and dichloromethane (1: 19) to afford the title compound as white solid (0.90 g). Yield: 69.2 %; HPLC: 98.21 %; 1H NMR (DMSO- D6, 300 MHz): δ 7.27- 7.21 (m, 2H), 7.13- 7.05 (m, 3H), 6.85 (d, J = 8.4 Hz, 2H), 4.96 (d, J = 2.1 Hz, 2H), 4.80 (d, J = 5.7 Hz, IH), 4.46 (dd, J = 5.7 Hz, 5.7 Hz, IH), 4.05 (s, 2H), 3.96 (d, J = 9.3 Hz, IH), 3.88- 3.87 (m, 2H), 3.71-3.65 (m, IH), 3.51- 3.13 (m, 5H), 1.06 (m, 2H), 0.97 (m, 2H); ES Mass: (M+Na) 509.05.
Example 16: Preparation of (2S,3R,4R,5S,6R)-2-(3-(4-((4,4-difluoro-l- methylcvclohexyl)methoxy)benzyl)-4-fluorophenyl)-6-(hvdroxymethyl)tetrahydro-
2H-pyran-3,4,5-triol:
Figure imgf000095_0001
Step 1: Synthesis of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(3-(4-((4,4-difluoro-l- methylcyclohexyl )methoxy )benzyl)-4-fluorophenyl )tetrahydro-2H-pyran-3, 4, 5-triyl triacetate (β- isomer):
Figure imgf000095_0002
To a stirred solution of (3R,4R,5S,6R)-2-(3-(4-((4,4-difluoro-l- methylcyclohexyl)methoxy)benzyl)-4-fluorophenyl)-6-(hydroxymethyl)tetrahydro- 2H-pyran-3,4,5-triol (Intermediate 25, mixture of α & β isomers, 0.89 g) in dichloromethane (20 ml), pyridine (1.4 ml) was added at 0 °C under N2 atmosphere followed by AC20 (1.5 ml) and DMAP (catalytic). The reaction temperature was slowly raised to room temperature and stirred for over night. After completion of the reaction (monitored by TLC), the reaction mixture was extracted with dichloromethane. The combined organic layers were washed with 3N HC1 solution and brine, dried over anhydrous sodium sulphate and concentrated to give the crude compounds. The crude product was purified via silica gel column chromatography with EtOAc and Hexane (2: 4) to afford the title compound (β- isomer) as white solid (790 mg). Yield: 71.8 %; HPLC: 96.20 %; 1H NMR (CDC13, 300 MHz): δ 7.24- 7.18 (m, 1H), 7.10- 6.98 (m, 4H), 6.81 (d, J = 8.7 Hz, 2H), 5.32- 5.17 (m, 2H), 5.06 (dd, J = 9.6, 9.6 Hz, 1H), 4.33- 4.23 (m, 2H), 4.19- 4.11 (m, 1H), 3.91- 3.90 (m, 2H), 3.82- 3.77 (m, 1H), 3.65 (s, 2H), 2.07 (s, 3H), 2.05 (s, 3H), 2.02 (s, 3H), 2.02- 1.83 (m, 4H), 1.78- 1.70 (m, 2H), 1.70 (s, 3H), 1.59- 1.53 (m, 2H), 1.08 (s, 3H); ES Mass: (M+Na) 701.15.
Step 2: Synthesis of (2S,3R4R5S,6R)-2-(3-(4-((4,4-difluoro-l- methylcyclohexyl )methoxy )benzyl)-4-fluorophenyl )-6-(hydroxymethyl )tetrahydro- 2H-pyran-3,4,5-triol: NH3 in MeOH (4 ml) was added to (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6- (3-(4-((4,4-difluoro-l-methylcyclohexyl)methoxy)benzyl)-4- fluorophenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (β- isomer, step 1, 0.79 g) at room temperature and stirred for over night. After completion of the reaction (monitored by TLC), volatiles were concentrated under reduced pressure to give residue. The crude product was purified via silica gel column chromatography with MeOH and dichloromethane (1: 19) to afford the title compound as white solid (270 mg). Yield: 51.7 %; HPLC: 93.16%; JH NMR (DMSO- D6, 300 MHz): δ 7.27- 7.19 (m, 2H), 7.13- 7.05 (m, 3H), 6.86 (d, J = 8.7 Hz, 2H), 4.96- 4.94 (m, 2H), 4.79 (d, J = 5.7 Hz, 1H), 4.45 (dd, J = 5.7 Hz, 5.7 Hz, 1H), 3.96 (d, J = 9.0 Hz, 1H), 3.93- 3.87 (m, 2H), 3.71- 3.65 (m, 3H), 3.44- 3.11 (m, 5H), 1.96- 1.87 (m, 4H), 1.67- 1.63 (m, 2H), 1.48- 1.46 (m, 2H), 1.03 (s, 3H); ES Mass: (M+Na) 533.15.
Example 17: Preparation of (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-((l-
(ethoxymethyl)cyclopentyl)methoxy)benzyl)phenyl)-6-(hvdroxymethyl)tetrahydro-
2H-pyran-3,4.5-triol:
Figure imgf000096_0001
Step 1: (3R,4R,5S,6R)-2-(4-chloro-3-(4-((l-
( ethoxymethyl )cyclopentyl )methoxy )benzyl )phenyl )-6-( hydroxymethyl )tetrahydro- 2H-pyran-3, 4, 5-triol:
Figure imgf000096_0002
To a stirred solution of (3R,4S,5S,6R)-2-(4-chloro-3-(4-((l- (ethoxymethyl)cyclopentyl)methoxy)benzyl)phenyl)-6-(hydroxymethyl)-2- methoxytetrahydro-2H-pyran-3,4,5-triol (Intermediate 27, 2.8 g) in dichloromethane (20 ml) and acetylnitrile (20 ml, 1: 1), Et3SiH (1.7 ml) was added at 0 °C under N2 atmosphere followed by BF3: Et20 (1 ml) and stirred for about 4 hours at room temperature. After completion of the reaction (monitored by TLC), volatiles were concentrated under reduced pressure. Then the reaction mixture was cooled to 0 °C and neutralized by cautious addition of saturated aq. NaHC03 solution. The reaction mixture was extracted with EtOAc and the combined organic layers were washed with water and brine, dried over anhydrous sodium sulphate and concentrated to get the residue. The crude product was purified via silica gel column chromatography with MeOH and dichloromethane (1:24) to give mixture compound (mixture of a & P isomers) as white solid (1.3 g). !H NMR (DMSO- D6, 300 MHz): 5 0.70-0.84 (t, 3H); 1.38-1.50 (m, 10H); 1.95-1.98 (m, 3H); 2.91 (s, 1H); 3.27-3.30 (m, 2H); 3.37- 3.54 (m, 5H); 3.75 (s, 2H); 3.95-4.02 (m, 3H); 4.53 (s, 1H); 6.75-6.78 (d, J=9Htz, 2H); 7.01-7.04 (d, J=9Htz, 2H); 7.13 (s, 2H); 7.31 (s, 1H); ESI Mass: 522 (M+l).
Step 2: Synthesis of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4-((l- ( ethoxymethyl )cyclopentyl)methoxy )benzyl )phenyl )tetrahydro-2H-pyran-3, 4, 5-triyl triacetate:
Figure imgf000097_0001
To a solution of (3R,4R,5S,6R)-2-(4-chloro-3-(4-((l- (ethoxymethyl)cyclopentyl)methoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro- 2H-pyran-3,4,5-triol (step 1, 1.0 g) in dichloromethane (30 ml), pyridine (0.67 ml), acetic anhydride (0.79 ml) and 0.0 lg of DMAP were added at 0°C. The reaction mixture was stirred at room temperature for about an hour. After completion of reaction as monitored by TLC, the reaction mixture was diluted with dichloromethane, washed with water, 1% HC1 solution, water followed by saturated brine solution. The organic layer was dried over anhydrous Na2S04 and concentrated. Obtained product was purified by flash column chromatographic technique to remove unreacted Ac20. Recrystallisation of the obtained mixture in ethanol gives the desired isomer as white solid (900 mg). ]H NMR (CDC13, 300 MHz): δ 0.70-0.84 (t, 3H) ; 1.38-1.50 (m, 10H); 1.95-1.98 (m, 3H); 2.91 (s, 1H); 3.27-3.30 (m, 2H); 3.37-3.54 (m, 5H); 3.75 (s, 2H); 3.95-4.02 (m, 3H); 4.53 (s, 1H); 6.75-6.78 (d, J=9Htz, 2H); 7.01-7.04 (d, J=9Htz, 2H); 7.13 (s, 2H); 7.31 (s, 1H); 1.90-1.86 (m, 2H), 1.84-1.59 (m, 5H), 0.85-0.80 (t, 3H, J=7.5Hz); ESI Mass: 712 (M+Na).
Step 3: Synthesis of (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-((l- ( ethoxymethyl )cyclopentyl )methoxy )benzyl )phenyl)-6-(hydroxymethyl )tetrahydro- 2H-pyran-3, 4, 5-triol:
NH3 in MeOH (100 ml) was added to (2R,3R,4R,5S,6S)-2-(acetoxymethyl)- 6-(4-chloro-3 -(4-(( 1 -(ethoxymethyl)cyclopentyl)methoxy)benzyl)phenyl)tetrahydro- 2H-pyran-3,4,5-triyl triacetate (β- isomer, step 2, 900 mg) at room temperature and stirred for over night. After completion of the reaction (monitored by TLC), volatiles were concentrated under reduced pressure to give residue. The crude product was purified via silica gel column chromatography with MeOH and dichloromethane (1: 19) to afford the title compound as white solid (350 mg). HPLC: 95 %; 1H MR (DMSO- D6, 300 MHz): 8 0.70-0.84 (t, 3H); 1.38-1.50 (m, 10H); 1.95-1.98 (m, 3H); 2.91 (s, 1H); 3.27-3.30 (m, 2H); 3.37-3.54 (m, 5H); 3.75 (s, 2H); 3.95-4.02 (m, 3H); 4.53 (s, 1H); 6.75-6.78 (d, J=9Htz, 2H); 7.01-7.04 (d, J=9Htz, 2H); 7.13 (s, 2H); 7.31 (s, 1H); ESI Mass: 522 (M+l).
Pharmacological activity
The compounds described herein can be tested for their activity for SGLT2 inhibition following procedures known to a person of ordinary skill in the art. For example, the following protocols may be employed for testing the compounds. These protocols are illustrative and do not limit to the scope of the invention.
Example 18: Effect of compounds on SGLT inhibitory activity:
Stable cells (CHO) expressing h SGLT gene were seeded in 24 well plates. Cells were washed with KRH Na buffer, followed by addition of test compound in KRH Na to the micro plate in defined format. The final concentration of vehicle (DMSO) is not more than 1%. Incubation was carried out for 10-15 minutes at 37° C in an incubator. The radiolabel glucose analogue (14C AMG) was added to each well at 0.5μ Ci concentration. After lhr incubation plates were washed with ice cold KRH Na buffer containing 0.5 Mm phlorizin. Cells were solubilized with 0.2 N NaOH before transferring them to pico plate for radiolabel count.
Compound preparation:
10 Mm stock was made by dissolving test compound in DMSO. Subsequent dilutions were made with DMSO to make necessary working stocks (10X) and the results are in the following table 1.
Table 1
Figure imgf000099_0001
Example 19: Effect of compounds on urinary glucose excretion in normal animal:
Animals: SD rats, male Age: 8-9 weeks, n=4
Route of administration: Oral
Dose volume: lOml/kg
Vehicle: 0.5% Tween-20+0.25%CMC.
For glucoseuria assessment, overnight fasted SD rats (12 weeks of ages) were placed into metabolism cages for baseline urine collection over 24 hours. Rats were weighted, randomized into experimental groups and orally administered with aqueous glucose solution (2g/kg) and drug in 0.25% CMC. Rats were returned to metabolism cages for 24 hours urine collection. Urine samples were tested for glucose concentration at 6, 24 and 48 hour post dosing and urine volume was measured at the end of 6, 24 and 48 hours. The efficacies of the compounds were evaluated based on glucose excretion in urine and the obtained results were shown in the following table 2.
Table 2
Example Total glucose excretion(mg/200gm body weight) Dose (mg/kg) 24 hrs 48 hrs
3 30 111.65 —
6 30 205 —
7 30 262 265
8 30 234 285
9 30 277 285
11 30 249 —
12 30 358 605
13 30 387 713
Example 20: Effect of compounds on STZ induced diabetic rats:
Male Sprague Dawley rats were made diabetic by single intra peritoneal injection of streptozotocin at 45 mg kg dose, prepared in 0.1M citrate buffer. Induction of diabetes was confirmed by measuring the random blood glucose levels after 48 hours of STZ administration. Animals with more than 300 mg/dl of plasma glucose were considered as diabetic.
One week after induction of diabetes animals were grouped based on fasting plasma glucose levels. The test item was administered at the specified dose mentioned above for 14 consecutive days. The control group received vehicle during treatment period. On day 14 GTT was conducted in overnight fasted rats. Glucose load of 2 g/kg was administered followed by compound dosing. Blood samples were drawn at time intervals for plasma glucose estimation. Effect of the test compound was assessed by comparing the AUC's plasma glucose of control with treated group.
Table3 - Glucose concentration (mg/dl)
Figure imgf000100_0001
Although the invention herein has been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and applications of the present invention. It is therefore to be understood that numerous modifications may be made to the illustrative embodiments and that other arrangements may be devised without departing from the spirit and scope of the present invention as described above. All publications and patent applications cited in this application are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated herein by reference.

Claims

attorney Docket No. HI 089/20117 CLAIM:
1. A compound of the formula (1):
Figure imgf000102_0001
'herein,
R is substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, abstituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkoxy, or abstituted or unsubstituted heterocyclic group and preferably methyl, ethyl, propyl, lethoxy, ethoxy, isopropoxy, t-butoxy, and the R is optionally substituted by Ra;
each R' is independent and either the same or a different group and is selected om hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted acyl group, tid substituted or unsubstituted alkoxy carbonyl group;
X is CRiR2, O, NR], or S;
a, b, c, d, e, and f is independently selected from hydrogen, hydroxyl group, alogen, substituted or unsubstituted alkyl, C(0)-R3, -C(0)0-R3, or -C(0)NR3R4; and a tid b; or c and d; or e and f can be together with their attached carbon to form Spiro ring r R and one of the a or b; or c and one of the e or f; or d and one of the e or f can be )gether with their attached carbon atoms to form bicyclic ring.
Z and Z' is independently selected from hydrogen, hydroxyl group, halogen, abstituted or unsubstituted alkyl, substituted or unsubstituted alkoxy group, substituted r unsubstituted cycloalkyl, substituted or unsubstituted cycloalkyloxy, -C(0)-R3, - !(0)0-R3, or -C(0)NR3R4;
Ra is hydrogen, hydroxyl group, halogen, substituted or unsubstituted alkyl, abstituted or unsubstituted alkoxy group, substituted or unsubstituted cycloalkyl,
.ttorney Docket No. HI 089/20117 lbstituted or unsubstituted cycloalkyloxy, NR3ILt, -C(0)-R3, -C(0)0-R3, -C(0)NR3R4, (0)pNR3R4, or S(0)pR3;
each R] and R2 is independently selected from hydrogen, substituted or tisubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted cloalkyl;
each R3 and ^ is independently selected from hydrogen, substituted or tisubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted cloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted y'cloalkenyl substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, ibstituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, lbstituted or unsubstituted heterocyclic group, or substituted or unsubstituted sterocyclylalkyl;
'p' is an integer ranging from 0 to 2, a pharmaceutically acceptable salt thereof, a tiarmaceutically acceptable solvate thereof, a pharmaceutically acceptable hydrate lereof, an N-oxide thereof, a tautomer thereof, a regioisomer thereof, a stereoisomer lereof, a prodrug thereof or a polymorph thereof.
. A compound selected from the group consisting of:
(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(( 1 - :hylqyclopentyl)methoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5- iol (Compound 1),
(2R,3R,4R,5S,6R)-2-(4-chloro-3-(4-(( 1 - :hylcyclopentyl)methoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5- iol (Compound 2),
(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-((l-ethylcyclobutyl)methoxy)benzyl)phenyl)- -(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (Compound 3),
(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-((l-ethylcyclohexyl)methoxy)benzyl)phenyl)- -(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (Compound 4),
(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(( 1 - iethylcyclohexyl)methoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran- ,4,5-triol (Compound 5),
.ttorney Docket No. HI 089/20117
(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-((3-ethyloxetan-3- [)methoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol
Compound 6),
(2R,3S,4R,5R,6S)-2-(hydroxymethyl)-6-(4-methyl-3-(4-((l- rifluoromethyl)cyclopropyl)methoxy)benzyl)phenyl)tetrahydro-2H-pyran-3,4,5-triol Compound 7),
(2R,3S,4R,5R,6S)-2-(hydroxymethyl)-6-(4-methyl-3-(4-((l- rifluoromethyl)cyclobutyl)methoxy)benzyl)phenyl)tetrahydro-2H-pyran-3,4,5-triol Compound 8),
(2S,3R,4R,5S,6R)-2-(3-(4-((4,4-difluoro-l-methylcyclohexyl)methoxy)benzyl)- -methylphenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3 ,4,5-triol (Compound 9),
(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-((l- rifluoromethyl)cyclobutyl)methoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H- yran-3,4,5-triol (Compound 10),
(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-((l- iethylcyclopentyl)methoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran- ,4,5-triol (Compound 11),
(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-((l- rifluoromethyl)cyclopropyl)methoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H- yran-3,4,5-triol (Compound 12),
(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-((4,4-difluoro-l- iethylcyclohexyl)methoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran- ,4,5-triol (Compound 13),
(2S,3R,4R,5S,6R)-2-(4-fluoro-3-(4-((l- rifluoromethyl)cyclobutyl)methoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H- yran-3,4,5-triol (Compound 14),
(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-((l- rifluoromethyl)cyclopropyl)methoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H- yran-3,4,5-triol (Compound 15),
(2S,3R,4R,5S,6R)-2-(3-(4-((4,4-difluoro-l-methylcyclohexyl)methoxy)benzyl)- -fluorophenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (Compound 16), attorney Docket No. H1089/20117
(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-((l- ;thoxymethyl)cyclopentyl)methoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H- yran-3,4,5-triol (Compound 17),
isomers thereof, and pharmaceutically acceptable salts thereof.
3. A pharmaceutical composition comprising a compound according to any one of laims 1-2, and a pharmaceutically acceptable excipient.
4. The pharmaceutical composition according to claim 3, wherein the harmaceutically acceptable excipient is a carrier or diluent.
5. A method for preventing, ameliorating or treating an SGLT2 mediated disease, isorder or syndrome in a subject in need thereof comprising administering to the subject therapeutically effective amount of a compound according to any one of claims 1-2.
6. The method according to claim 5, wherein the disease, disorder or syndrome is sleeted from the group consisting of type I diabetes, type II diabetes, including omplications of diabetes such as retinopathy, neuropathy, nephropathy, and delayed Ound healing.
7. The method according to claim 5, wherein the disease, disorder or syndrome is sleeted from the group consisting of diabetes, diabetes type I, diabetes type II, omplications of diabetes, retinopathy, neuropathy, nephropathy, delayed wound healing, lsulin resistance, impaired glucose homeostasis (IGH), hyperglycemia, yperinsulinemia, elevated blood levels of fatty acids or glycerol, obesity, hyperlipidemia lcluding hypertriglyceridemia, Syndrome X, hypertension, and atherosclerosis.
8. A method of treating type I diabetes in a subject in need thereof comprising dministering to the subject a therapeutically effective amount of a compound according ) any one of claims 1-2.
9. A method of treating type II diabetes in a subject in need thereof comprising dministering to the subject a therapeutically effective amount of a compound according ) any one of claims 1-2.
10. A method of treating diabetes complications such as retinopathy, neuropathy, ephropathy and delayed wound healing in a subject in need thereof comprising dministering to the subject a therapeutically effective amount of a compound according ) any one of claims 1-2.
PCT/IB2011/053641 2010-08-23 2011-08-17 Cycloalkyl methoxybenzyl phenyl pyran derivatives as sodium dependent glucose co transporter (sglt2) inhibitors WO2012025857A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN2434CH2010 2010-08-23
IN2434/CHE/2010 2010-08-23

Publications (1)

Publication Number Publication Date
WO2012025857A1 true WO2012025857A1 (en) 2012-03-01

Family

ID=44653379

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2011/053641 WO2012025857A1 (en) 2010-08-23 2011-08-17 Cycloalkyl methoxybenzyl phenyl pyran derivatives as sodium dependent glucose co transporter (sglt2) inhibitors

Country Status (1)

Country Link
WO (1) WO2012025857A1 (en)

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012109996A1 (en) * 2011-02-18 2012-08-23 上海璎黎科技有限公司 Aryl glycoside compound, preparation method and use thereof
WO2013177224A1 (en) 2012-05-22 2013-11-28 Genentech, Inc. N-substituted benzamides and their use in the treatment of pain
WO2015044849A1 (en) * 2013-09-27 2015-04-02 Ranbaxy Laboratories Limited Process for the purification of dapagliflozin
JP2015129106A (en) * 2014-01-03 2015-07-16 山東軒竹医薬科技有限公司 Optically pure benzyl-4-chlorophenyl-c-glucoside derivative
WO2015158206A1 (en) * 2014-04-14 2015-10-22 上海迪诺医药科技有限公司 C-aryl indican derivative, and pharmaceutical composition thereof, preparation method therefor and uses thereof
US9243022B2 (en) 2012-12-21 2016-01-26 Alios Biopharma, Inc. Substituted nucleosides, nucleotides and analogs thereof
US9315438B2 (en) 2014-01-03 2016-04-19 Xuanzhu Pharma Co., Ltd Optically pure benzyl-4-chlorophenyl-C-glucoside derivative
US9394329B2 (en) 2013-09-27 2016-07-19 Sunshine Lake Pharma Co., Ltd. Glucopyranosyl derivatives and their uses in medicine
US9422323B2 (en) 2012-05-25 2016-08-23 Janssen Sciences Ireland Uc Uracyl spirooxetane nucleosides
JP2016533357A (en) * 2013-10-12 2016-10-27 セラコス サブ，リミティド ライアビリティ カンパニー Preparation of hydroxy-benzylbenzene derivatives
US9562029B2 (en) 2011-06-25 2017-02-07 Xuanzhu Pharma Co., Ltd. C-glycoside derivatives
CN106892948A (en) * 2015-12-17 2017-06-27 广东东阳光药业有限公司 Glucopyranosyl derivatives and its in application pharmaceutically
US11198699B2 (en) 2019-04-02 2021-12-14 Aligos Therapeutics, Inc. Compounds targeting PRMT5
CN115417836A (en) * 2022-09-21 2022-12-02 安庆奇创药业有限公司 Method for synthesizing lean hypoglycemic drug intermediate by using continuous flow

Citations (39)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US641426A (en) 1897-06-16 1900-01-16 Arthur M Allen Tricycle.
WO2001016147A1 (en) 1999-08-31 2001-03-08 Kissei Pharmaceutical Co., Ltd. Glucopyranosyloxypyrazole derivatives, medicinal compositions containing the same and intermediates in the production thereof
WO2001027128A1 (en) 1999-10-12 2001-04-19 Bristol-Myers Squibb Company C-aryl glucoside sglt2 inhibitors
WO2001074834A1 (en) 2000-03-30 2001-10-11 Bristol-Myers Squibb Company O-aryl glucoside sglt2 inhibitors and method
WO2001074835A1 (en) 2000-03-30 2001-10-11 Bristol-Myers Squibb Company O-glucosylated benzamide sglt2 inhibitors and method
WO2002008306A1 (en) 2000-07-26 2002-01-31 Mitsui Chemicals, Inc. Polymer and process for producing the same
WO2002028872A1 (en) 2000-09-29 2002-04-11 Kissei Pharmaceutical Co., Ltd. Glucopyranosyloxybenzylbenzene derivatives and medicinal compositions containing the same
WO2002068439A1 (en) 2001-02-26 2002-09-06 Kissei Pharmaceutical Co., Ltd. Glycopyranosyloxypyrazole derivatives and medicinal use thereof
WO2002083066A2 (en) 2001-04-11 2002-10-24 Bristol-Myers Squibb Company Amino acid complexes of c-aryl glucosides for treatment of diabetes and method
WO2003020737A1 (en) 2001-09-05 2003-03-13 Bristol-Myers Squibb Company O-pyrazole glucoside sglt2 inhibitors and method of use
US20030114390A1 (en) 2001-03-13 2003-06-19 Washburn William N. C-aryl glucoside SGLT2 inhibitors and method
WO2003080635A1 (en) 2002-03-22 2003-10-02 Kissei Pharmaceutical Co., Ltd. Crystals of glucopyranosyloxybenzyl benzene derivative
WO2003099836A1 (en) 2002-05-20 2003-12-04 Bristol-Myers Squibb Company C-aryl glucoside sglt2 inhibitors and method
WO2004013118A1 (en) 2002-08-05 2004-02-12 Yamanouchi Pharmaceutical Co., Ltd. Azulene derivatives and salts thereof
WO2004063209A2 (en) 2003-01-03 2004-07-29 Bristol-Myers Squibb Company Methods of producing c-aryl glucoside sglt2 inhibitors
WO2004080990A1 (en) 2003-03-14 2004-09-23 Astellas Pharma Inc. C-glycoside derivatives and salts thereof
WO2004089967A1 (en) 2003-04-01 2004-10-21 Taisho Pharmaceutical Co., Ltd. HETEROARYL 5-THIO-β-D-GLUCOPYRANOSIDE DERIVATIVES AND REMEDIES FOR DIABETES CONTAINING THE SAME
WO2005085237A1 (en) 2004-03-04 2005-09-15 Kissei Pharmaceutical Co., Ltd. Fused heterocycle derivative, medicinal composition containing the same, and medicinal use thereof
US20050209166A1 (en) 2004-03-16 2005-09-22 Boehringer Ingelheim International Gmbh Glucopyranosyl-substituted phenyl derivatives, medicaments containing such compounds, their use and process for their manufacture
WO2006034489A2 (en) 2004-09-23 2006-03-30 Bristol-Myers Squibb Company C-aryl glucoside sglt2 inhibitors and method for their production
WO2006054629A1 (en) 2004-11-18 2006-05-26 Kissei Pharmaceutical Co., Ltd. 1-SUBSTITUTED-3-β-D-GLUCOPYRANOSYLATED NITROGENOUS HETERO- CYCLIC COMPOUNDS AND MEDICINES CONTAINING THE SAME
WO2006073197A1 (en) 2005-01-07 2006-07-13 Taisho Pharmaceutical Co., Ltd. 1-thio-d-glucitol derivatives
EP1685147A2 (en) 2003-11-03 2006-08-02 Isis Pharmaceuticals, Inc. Modulation of sglt2 expression
US20060194809A1 (en) 2003-04-01 2006-08-31 Hiroyuki Kakinuma Heteroaryl 5-thio-beta-d-gucopyranoside derivatives and therapeutic agents for diabetes containing the same
WO2007000445A1 (en) 2005-06-29 2007-01-04 Boehringer Ingelheim International Gmbh Glucopyranosyl-substituted benzyl-benzene derivatives, medicaments containing such compounds, their use and process for their manufacture
WO2008002824A1 (en) 2006-06-28 2008-01-03 Bristol-Myers Squibb Company Crystalline solvates and complexes of (is) -1, 5-anhydro-l-c- (3- ( (phenyl) methyl) phenyl) -d-glucitol derivatives with amino acids as sglt2 inhibitors for the treatment of diabetes
WO2008013321A1 (en) 2006-07-28 2008-01-31 Mitsubishi Tanabe Pharma Corporation Novel sglt inhibitors
WO2008042688A2 (en) * 2006-09-29 2008-04-10 Lexicon Pharmaceuticals, Inc. Phlorizin analogs as inhibitors of sodium glucose co-transporter 2
WO2008055940A2 (en) 2006-11-09 2008-05-15 Boehringer Ingelheim International Gmbh Combination therapy with sglt-2 inhibitors and their pharmaceutical compositions
WO2008072726A1 (en) 2006-12-14 2008-06-19 Taisho Pharmaceutical Co., Ltd. 1-phenyl 1-thio-d-glucitol derivative
US7393836B2 (en) 2004-07-06 2008-07-01 Boehringer Ingelheim International Gmbh D-xylopyranosyl-substituted phenyl derivatives, medicaments containing such compounds, their use and process for their manufacture
WO2008101939A1 (en) 2007-02-21 2008-08-28 Boehringer Ingelheim International Gmbh Tetrasubstituted glucopyranosylated benzene derivatives, medicaments containing such compounds, their use and process for their manufacture
US20080221164A1 (en) 2007-03-08 2008-09-11 Goodwin Nicole C Inhibitors of Sodium Glucose Co-Transporter 2 and Methods of Their Use
WO2008116195A2 (en) 2007-03-22 2008-09-25 Bristol-Myers Squibb Compositions comprising an sglt2 ingibitor for treating obesity
WO2008122014A1 (en) 2007-04-02 2008-10-09 Theracos, Inc. Benzylic glycoside derivatives and methods of use
WO2008144346A2 (en) 2007-05-18 2008-11-27 Bristol-Myers Squibb Company Crystal structures of sglt2 inhibitors and processes for their preparation
US7476671B2 (en) 2004-04-10 2009-01-13 Boehringer Ingelheim International Gmbh 2-amino-imidazo[4,5-d]pyridazin-4-ones, their preparation and their use as pharmaceutical compositions
WO2009026537A1 (en) 2007-08-23 2009-02-26 Theracos, Inc. Benzylbenzene derivatives and methods of use
WO2010092125A1 (en) * 2009-02-13 2010-08-19 Boehringer Ingelheim International Gmbh Pharmaceutical composition comprising a sglt2 inhibitor, a dpp-iv inhibitor and optionally a further antidiabetic agent and uses thereof

Patent Citations (49)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US641426A (en) 1897-06-16 1900-01-16 Arthur M Allen Tricycle.
WO2001016147A1 (en) 1999-08-31 2001-03-08 Kissei Pharmaceutical Co., Ltd. Glucopyranosyloxypyrazole derivatives, medicinal compositions containing the same and intermediates in the production thereof
EP1224195B1 (en) 1999-10-12 2005-05-18 Bristol-Myers Squibb Company C-aryl glucoside sglt2 inhibitors
WO2001027128A1 (en) 1999-10-12 2001-04-19 Bristol-Myers Squibb Company C-aryl glucoside sglt2 inhibitors
US6414126B1 (en) 1999-10-12 2002-07-02 Bristol-Myers Squibb Company C-aryl glucoside SGLT2 inhibitors and method
WO2001074834A1 (en) 2000-03-30 2001-10-11 Bristol-Myers Squibb Company O-aryl glucoside sglt2 inhibitors and method
WO2001074835A1 (en) 2000-03-30 2001-10-11 Bristol-Myers Squibb Company O-glucosylated benzamide sglt2 inhibitors and method
EP1268502B1 (en) 2000-03-30 2006-02-01 Bristol-Myers Squibb Company O-aryl glucoside sglt2 inhibitors and method
EP1268503A1 (en) 2000-03-30 2003-01-02 Bristol-Myers Squibb Company O-glucosylated benzamide sglt2 inhibitors and method
WO2002008306A1 (en) 2000-07-26 2002-01-31 Mitsui Chemicals, Inc. Polymer and process for producing the same
WO2002028872A1 (en) 2000-09-29 2002-04-11 Kissei Pharmaceutical Co., Ltd. Glucopyranosyloxybenzylbenzene derivatives and medicinal compositions containing the same
WO2002068439A1 (en) 2001-02-26 2002-09-06 Kissei Pharmaceutical Co., Ltd. Glycopyranosyloxypyrazole derivatives and medicinal use thereof
US20030114390A1 (en) 2001-03-13 2003-06-19 Washburn William N. C-aryl glucoside SGLT2 inhibitors and method
WO2002083066A2 (en) 2001-04-11 2002-10-24 Bristol-Myers Squibb Company Amino acid complexes of c-aryl glucosides for treatment of diabetes and method
WO2003020737A1 (en) 2001-09-05 2003-03-13 Bristol-Myers Squibb Company O-pyrazole glucoside sglt2 inhibitors and method of use
WO2003080635A1 (en) 2002-03-22 2003-10-02 Kissei Pharmaceutical Co., Ltd. Crystals of glucopyranosyloxybenzyl benzene derivative
WO2003099836A1 (en) 2002-05-20 2003-12-04 Bristol-Myers Squibb Company C-aryl glucoside sglt2 inhibitors and method
EP1506211B1 (en) 2002-05-20 2007-02-07 Bristol-Myers Squibb Company C-aryl glucoside sglt2 inhibitors and method
WO2004013118A1 (en) 2002-08-05 2004-02-12 Yamanouchi Pharmaceutical Co., Ltd. Azulene derivatives and salts thereof
EP1581543A2 (en) 2003-01-03 2005-10-05 Bristol-Myers Squibb Company Methods of producing c-aryl glucoside sglt2 inhibitors
WO2004063209A2 (en) 2003-01-03 2004-07-29 Bristol-Myers Squibb Company Methods of producing c-aryl glucoside sglt2 inhibitors
WO2004080990A1 (en) 2003-03-14 2004-09-23 Astellas Pharma Inc. C-glycoside derivatives and salts thereof
US7202350B2 (en) 2003-03-14 2007-04-10 Astellas Pharma Inc. C-glycoside derivatives and salts thereof
US7439232B2 (en) 2003-04-01 2008-10-21 Taisho Pharmaceutical Co., Ltd. Heteroaryl 5-thio-β-D-glucopyranoside derivatives and therapeutic agents for diabetes containing the same
US20060194809A1 (en) 2003-04-01 2006-08-31 Hiroyuki Kakinuma Heteroaryl 5-thio-beta-d-gucopyranoside derivatives and therapeutic agents for diabetes containing the same
WO2004089967A1 (en) 2003-04-01 2004-10-21 Taisho Pharmaceutical Co., Ltd. HETEROARYL 5-THIO-β-D-GLUCOPYRANOSIDE DERIVATIVES AND REMEDIES FOR DIABETES CONTAINING THE SAME
EP1685147A2 (en) 2003-11-03 2006-08-02 Isis Pharmaceuticals, Inc. Modulation of sglt2 expression
WO2005085237A1 (en) 2004-03-04 2005-09-15 Kissei Pharmaceutical Co., Ltd. Fused heterocycle derivative, medicinal composition containing the same, and medicinal use thereof
US20070197450A1 (en) 2004-03-04 2007-08-23 Kissei Pharmaceutical Co., Ltd. Fused heterocycle derivative, medicinal composition containing the same, and medicinal use thereof
US20050209166A1 (en) 2004-03-16 2005-09-22 Boehringer Ingelheim International Gmbh Glucopyranosyl-substituted phenyl derivatives, medicaments containing such compounds, their use and process for their manufacture
US7476671B2 (en) 2004-04-10 2009-01-13 Boehringer Ingelheim International Gmbh 2-amino-imidazo[4,5-d]pyridazin-4-ones, their preparation and their use as pharmaceutical compositions
US7393836B2 (en) 2004-07-06 2008-07-01 Boehringer Ingelheim International Gmbh D-xylopyranosyl-substituted phenyl derivatives, medicaments containing such compounds, their use and process for their manufacture
WO2006034489A2 (en) 2004-09-23 2006-03-30 Bristol-Myers Squibb Company C-aryl glucoside sglt2 inhibitors and method for their production
WO2006054629A1 (en) 2004-11-18 2006-05-26 Kissei Pharmaceutical Co., Ltd. 1-SUBSTITUTED-3-β-D-GLUCOPYRANOSYLATED NITROGENOUS HETERO- CYCLIC COMPOUNDS AND MEDICINES CONTAINING THE SAME
WO2006073197A1 (en) 2005-01-07 2006-07-13 Taisho Pharmaceutical Co., Ltd. 1-thio-d-glucitol derivatives
US20080132563A1 (en) 2005-01-07 2008-06-05 Hiroyuki Kakinuma 1-Thio-D-Glucitol Derivatives
WO2007000445A1 (en) 2005-06-29 2007-01-04 Boehringer Ingelheim International Gmbh Glucopyranosyl-substituted benzyl-benzene derivatives, medicaments containing such compounds, their use and process for their manufacture
WO2008002824A1 (en) 2006-06-28 2008-01-03 Bristol-Myers Squibb Company Crystalline solvates and complexes of (is) -1, 5-anhydro-l-c- (3- ( (phenyl) methyl) phenyl) -d-glucitol derivatives with amino acids as sglt2 inhibitors for the treatment of diabetes
WO2008013321A1 (en) 2006-07-28 2008-01-31 Mitsubishi Tanabe Pharma Corporation Novel sglt inhibitors
WO2008042688A2 (en) * 2006-09-29 2008-04-10 Lexicon Pharmaceuticals, Inc. Phlorizin analogs as inhibitors of sodium glucose co-transporter 2
WO2008055940A2 (en) 2006-11-09 2008-05-15 Boehringer Ingelheim International Gmbh Combination therapy with sglt-2 inhibitors and their pharmaceutical compositions
WO2008072726A1 (en) 2006-12-14 2008-06-19 Taisho Pharmaceutical Co., Ltd. 1-phenyl 1-thio-d-glucitol derivative
WO2008101939A1 (en) 2007-02-21 2008-08-28 Boehringer Ingelheim International Gmbh Tetrasubstituted glucopyranosylated benzene derivatives, medicaments containing such compounds, their use and process for their manufacture
US20080221164A1 (en) 2007-03-08 2008-09-11 Goodwin Nicole C Inhibitors of Sodium Glucose Co-Transporter 2 and Methods of Their Use
WO2008116195A2 (en) 2007-03-22 2008-09-25 Bristol-Myers Squibb Compositions comprising an sglt2 ingibitor for treating obesity
WO2008122014A1 (en) 2007-04-02 2008-10-09 Theracos, Inc. Benzylic glycoside derivatives and methods of use
WO2008144346A2 (en) 2007-05-18 2008-11-27 Bristol-Myers Squibb Company Crystal structures of sglt2 inhibitors and processes for their preparation
WO2009026537A1 (en) 2007-08-23 2009-02-26 Theracos, Inc. Benzylbenzene derivatives and methods of use
WO2010092125A1 (en) * 2009-02-13 2010-08-19 Boehringer Ingelheim International Gmbh Pharmaceutical composition comprising a sglt2 inhibitor, a dpp-iv inhibitor and optionally a further antidiabetic agent and uses thereof

Non-Patent Citations (11)

* Cited by examiner, † Cited by third party
Title
"Remington: The Science and Practice of Pharmacy", 2003, LIPPINCOTT WILLIAMS & WILKINS
BAIHUA XU ET. AL.: "Ortho-Substituted C-aryl Glucosides as Highly Potent and Selective Renal Sodium-dependent Glucose Co-transporter (SGLT2) Inhibitors.", BIOORGANIC AND MEDICINAL CHEMISTRY, vol. 18, no. 12, 29 April 2010 (2010-04-29), pages 4422 - 4432, XP027072360, DOI: 10.1016/j.bmc.2010.04.088 *
DIABETES, vol. 57, 2008, pages 1723 - 1729
ENDOCRINOLOGY, vol. 143, 2002, pages 339 - 342
J. CLIN. INVEST., vol. 79, 1987, pages 1510 - 1515
J. CLIN. INVEST., vol. 93, 1994, pages 397 - 404
J. ORG. CHEM., vol. 54, 1989, pages 610 - 612
JOHANNSSON, J. CLIN. ENDROCRINOL. METAB., vol. 82, 1997, pages 727 - 734
JOURNAL OF MEDICINAL CHEMISTRY, vol. 51, 2008, pages 1145 - 1149
T. HIGUCHI, W. STELLA: "Bioreversible Carriers in Drug Design", vol. 14, 1987, AMERICAN PHARMACEUTICAL ASSOCIATION AND PERGAMON PRESS, article "Pro-drugs as Novel Delivery Systems"
WEI MENG ET. AL.: "Discovery of Dapagliflozin: A Potent, Selective Renal Sodium-Dependent Glucose Cotransporter 2 (SGLT2) Inhibitor for the Treatment of Type 2 Diabetes.", JOURNAL OF MEDICINAL CHEMISTRY, vol. 51, 2 September 2008 (2008-09-02), pages 1145 - 1149, XP002491733, DOI: 10.1021/jm701272q *

Cited By (32)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2014505709A (en) * 2011-02-18 2014-03-06 シャンハイ インリ サイエンス アンド テクノロジー カンパニー，リミティド Aryl glucoside compounds, their preparation and use
US8980829B2 (en) 2011-02-18 2015-03-17 Shanghai Yingli Science And Technology Co., Ltd Aryl glycoside compound, preparation method and use thereof
WO2012109996A1 (en) * 2011-02-18 2012-08-23 上海璎黎科技有限公司 Aryl glycoside compound, preparation method and use thereof
US9562029B2 (en) 2011-06-25 2017-02-07 Xuanzhu Pharma Co., Ltd. C-glycoside derivatives
US10253010B2 (en) 2011-06-25 2019-04-09 Sihuan Pharmaceutical Holdings Group Ltd. C-glycoside derivative
WO2013177224A1 (en) 2012-05-22 2013-11-28 Genentech, Inc. N-substituted benzamides and their use in the treatment of pain
US10774106B2 (en) 2012-05-25 2020-09-15 Janssen Sciences Ireland Unlimited Company Uracyl spirooxetane nucleosides
US10544184B2 (en) 2012-05-25 2020-01-28 Janssen Sciences Ireland Unlimited Company Uracyl spirooxetane nucleosides
US10301347B2 (en) 2012-05-25 2019-05-28 Janssen Sciences Ireland Unlimited Company Uracyl spirooxetane nucleosides
US10040814B2 (en) 2012-05-25 2018-08-07 Janssen Sciences Ireland Uc Uracyl spirooxetane nucleosides
US9845336B2 (en) 2012-05-25 2017-12-19 Janssen Sciences Ireland Uc Uracyl spirooxetane nucleosides
US9422323B2 (en) 2012-05-25 2016-08-23 Janssen Sciences Ireland Uc Uracyl spirooxetane nucleosides
US9249174B2 (en) 2012-12-21 2016-02-02 Alios Biopharma, Inc. Substituted nucleosides, nucleotides and analogs thereof
US10487104B2 (en) 2012-12-21 2019-11-26 Janssen Biopharma, Inc. Substituted nucleosides, nucleotides and analogs thereof
US11485753B2 (en) 2012-12-21 2022-11-01 Janssen Pharmaceutica Nv Substituted nucleosides, nucleotides and analogs thereof
US10793591B2 (en) 2012-12-21 2020-10-06 Janssen Biopharma, Inc. Substituted nucleosides, nucleotides and analogs thereof
US10683320B2 (en) 2012-12-21 2020-06-16 Janssen Biopharma, Inc. Substituted nucleosides, nucleotides and analogs thereof
US10112966B2 (en) 2012-12-21 2018-10-30 Alios Biopharma, Inc. Substituted nucleosides, nucleotides and analogs thereof
US10144755B2 (en) 2012-12-21 2018-12-04 Alios Biopharma, Inc. Substituted nucleosides, nucleotides and analogs thereof
US9243022B2 (en) 2012-12-21 2016-01-26 Alios Biopharma, Inc. Substituted nucleosides, nucleotides and analogs thereof
US9394329B2 (en) 2013-09-27 2016-07-19 Sunshine Lake Pharma Co., Ltd. Glucopyranosyl derivatives and their uses in medicine
WO2015044849A1 (en) * 2013-09-27 2015-04-02 Ranbaxy Laboratories Limited Process for the purification of dapagliflozin
JP2016533357A (en) * 2013-10-12 2016-10-27 セラコス サブ，リミティド ライアビリティ カンパニー Preparation of hydroxy-benzylbenzene derivatives
US9914688B2 (en) 2014-01-03 2018-03-13 Sihuan Pharmaceutical Holdings Group Ltd. Optically pure benzyl-4-chlorophenyl-C-glucoside derivative
JP2015129106A (en) * 2014-01-03 2015-07-16 山東軒竹医薬科技有限公司 Optically pure benzyl-4-chlorophenyl-c-glucoside derivative
US9315438B2 (en) 2014-01-03 2016-04-19 Xuanzhu Pharma Co., Ltd Optically pure benzyl-4-chlorophenyl-C-glucoside derivative
WO2015158206A1 (en) * 2014-04-14 2015-10-22 上海迪诺医药科技有限公司 C-aryl indican derivative, and pharmaceutical composition thereof, preparation method therefor and uses thereof
US9914724B2 (en) 2014-04-14 2018-03-13 Shanghai De Novo Pharmatech Co., Ltd. C-aryl glycosid derivatives, pharmaceutical composition, preparation process and uses thereof
JP2017511383A (en) * 2014-04-14 2017-04-20 上海▲ディー▼▲ノア▼医▲薬▼科技有限公司 C-aryl glycoside derivative, drug composition, preparation method and application thereof
CN106892948A (en) * 2015-12-17 2017-06-27 广东东阳光药业有限公司 Glucopyranosyl derivatives and its in application pharmaceutically
US11198699B2 (en) 2019-04-02 2021-12-14 Aligos Therapeutics, Inc. Compounds targeting PRMT5
CN115417836A (en) * 2022-09-21 2022-12-02 安庆奇创药业有限公司 Method for synthesizing lean hypoglycemic drug intermediate by using continuous flow

Similar Documents

Publication Publication Date Title
WO2012025857A1 (en) Cycloalkyl methoxybenzyl phenyl pyran derivatives as sodium dependent glucose co transporter (sglt2) inhibitors
AU2005265772B2 (en) Novel cyclohexane derivative, prodrug thereof and salt thereof, and therapeutic agent containing the same for diabetes
RU2156247C2 (en) Propiophenone derivatives and methods of preparation thereof
EP3056507B1 (en) C-aryl glucoside derivative, preparation method for same, and medical applications thereof
JP5833011B2 (en) Process for preparing compounds useful as inhibitors of SGLT2
CA2189603C (en) Propiophenone derivative and processes for preparing the same
CN102482290A (en) C-aryl glucoside derivatives, preparation rpocess and pharmaceutical use thereof
BRPI0717156B1 (en) sodium glucose co-transporter 2 inhibitors and pharmaceutical composition comprising them
WO2006080421A1 (en) Spiroketal derivative and use thereof as diabetic medicine
EP1783122A1 (en) Process for production of azulene derivatives and intermediates for the synthesis of the same
FR2929615A1 (en) C-ARYL GLYCOSIDE COMPOUNDS FOR THE TREATMENT OF DIABETES AND OBESITY
AU616335B2 (en) Derivatives of alpha, d-glucofuranose or alpha d-allofuranose and intermediates for preparing these derivatives
RU2678327C2 (en) Mannose derivatives for treating bacterial infections
JP2014517032A (en) Novel SGLT inhibitor
JP2009528299A (en) Glucosidase inhibitor and synthesis method thereof
CN108699098B (en) C-glucoside derivative having fused benzene ring or pharmaceutically acceptable salt thereof, preparation method thereof, and pharmaceutical composition comprising same
KR920000646B1 (en) Fluoro-substituted epipodophyllo-toxin glucosides
KR100556335B1 (en) 6r-3,6-dideoxy-l-arabino-hexopyranosyl heptanoic acid, preparation process for the same and dauer effect thereof
JP5801723B2 (en) Method for producing neoponcoranols
FR2699535A1 (en) Etoposide derivatives, process for their preparation, their use as a medicament and their use for the preparation of a medicament for anticancer treatment
CN108774274B (en) Sialylmethyl ester methyl glycoside derivative and synthesis method and application thereof
FR2903698A1 (en) NOVEL 5-THIOXYLOPYRANOSE DERIVATIVES.
HU208019B (en) Process for producing alkoxy-methyliden-epi-podofillotoxin-glucosides and pharmaceutical compositions containing them
CN115003661A (en) Aryl glucoside derivatives and their use in medicine
FR2906247A1 (en) NEW 5-THIOXYLOPYRANOSE DERIVATIVES

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 11757948

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 11757948

Country of ref document: EP

Kind code of ref document: A1