CN104327027B - One class novel C aryl glucoside SGLT2 inhibitor - Google Patents

One class novel C aryl glucoside SGLT2 inhibitor Download PDF

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CN104327027B
CN104327027B CN201410548765.9A CN201410548765A CN104327027B CN 104327027 B CN104327027 B CN 104327027B CN 201410548765 A CN201410548765 A CN 201410548765A CN 104327027 B CN104327027 B CN 104327027B
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compound
nmr
dmso
glucose
chloro
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CN104327027A (en
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黄文龙
钱海
李政
王学堃
焦磊
邱倩倩
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China Pharmaceutical University
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China Pharmaceutical University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/10—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing three or more hetero rings

Abstract

One class novel C aryl glucoside SGLT2 inhibitor, the present invention relates to the drug world related to diabetes, novel C aryl glucoside derivant shown in specifically related to a kind of logical formula (I), its preparation method, compositionss and their applications in hypoglycemic drug is prepared.There is described C aryl glucosides derivant extremely excellent rush glucose in urine to discharge effect and internal hypoglycemic activity, and therefrom filter out internal hypoglycemic activity even more excellent compound suitable with dapagliflozin, and which can be used for preventing or treats diabetes.

Description

One class novel C-aryl glucoside SGLT2 inhibitor
Technical field
The present invention relates to the field of pharmacology related to diabetes, and in particular to a class medicative to diabetes is new 2 type sodium-glucose transporter (SGLT2) inhibitor of type glucoside containing polyaryl structure, the invention also discloses its system Preparation Method, the pharmaceutical composition with such compound as active component, and their applications in hypoglycemic drug is prepared.
Background technology
Current whole world diabeticss about 3.7 hundred million, wherein great majority are 2 types (i.e. non-insulin-depending type) diabetes Patient.The medicine of traditional treatment diabetes mainly have insulin type, metformin class, sulfonylurea, thiazolidinedioneses and Alpha-glucosidase inhibitor, in recent years the medicine of the treatment diabetes of new listing have glucagon-like-peptide-1 (GLP-1) swash Dynamic agent, dipeptidyl peptidase-IV (DPP-IV) inhibitor etc..These medicines have good therapeutic effect, but long-term treatment is sugared There is safety issue in urine disease, such as：The problems such as liver toxicity, increased weight and hypoglycemia.
2 type sodium-glucose transporter (SGLT2) be discovered in recent years can be used to develop the new target of hypoglycemic drug Point, SGLT2 are mainly distributed on kidney, and its effect is the glucose that reabsorption Jing glomerular filtration is entered in renal tubules, maintains blood The balance of concentration of glucose in liquid.The activity of suppression SGLT2 can effectively reduce the reabsorption of glucose in kidney, increase glucose in urine dense Degree, reduces blood glucose.As the mechanism of this blood sugar lowering does not rely on insulin, can share with other hypoglycemic medicines, therefore, SGLT2 Inhibitor is very promising hypoglycemic medicine.
Although have been disclosed at present it is a series of for suppress SGLT2 compound such as dapagliflozin, Canagliflozin and Ipragliflozin etc., but remain a need for developing curative effect, medicine for property more preferably, the higher change of safety Compound is used for the treatment of diabetes, through being continually striving to, the invention discloses having for plasma glucose levels effectively can be reduced The SGLT2 inhibitor of logical formula (I) novel structure, and it was unexpectedly found that the compound with this class formation show it is excellent SGLT2 inhibitions and good internal hypoglycemic activity, and it is suitable with dapagliflozin therefrom to filter out internal hypoglycemic activity Even more excellent compound, with wide DEVELOPMENT PROSPECT.
The content of the invention
It is an object of the invention to provide the compound of the new logical formula (I) with medical value of a class and its pharmaceutically may be used The ester of acceptance.Which suppresses the effect of SGLT2, can be used to prepare new diabetes medicament.
The present invention also aims to provide the method for preparing the compound with logical formula (I).
Further object is that providing a kind of medicine system of compound containing logical formula (I) as effective ingredient Agent.
Detailed description content is as follows：
The present invention has synthesized a series of logical formula (I) compounds：
Wherein,
R1、R2It is respectively selected from：H、F、Cl、C1～C5Alkyl, C1～C5Alkoxyl ,-O- aryl ,-OC1-5- aryl, cycloalkyl；
Or R1And R2Formed together with the carbon atom being connected with them cycloalkyl or with 1-4 selected from N, O, S, SO and/or SO2The replacement of heteroatomic 5-12 units or unsubstituted aromatic heterocycle；
Wherein, described cycloalkyl, aryl, aromatic heterocycle further can be substituted by one or more substituents, described Substituent group includes halogen atom, hydroxyl, alkyl, the alkoxyl being substituted with halogen atoms, substituted or unsubstituted aryl or aralkyl Base.
It is preferred that below general formula (I) compound：
Wherein R1It preferably is selected from：C1～C5Alkyl, C1～C5Alkoxyl；
R2It preferably is selected from：F、Cl、C1～C5Alkyl；
Or R1And R2Formed together with the carbon atom being connected with them with 1-4 selected from N, O, S, SO and/or SO2Miscellaneous original The replacement of the 5-12 units of son or unsubstituted aromatic heterocycle；
Wherein, described aromatic heterocycle further can be substituted by one or more substituents, and described substituent group includes halogen Plain atom, hydroxyl, alkyl, alkoxyl or the alkoxyl being substituted with halogen atoms, substituted or unsubstituted aryl or aralkyl.
Preferably：
Wherein R1It is selected from：Methoxyl group, ethyoxyl, propoxyl group；
R2It is selected from：F, Cl, methyl, ethyl；
Or R1And R2With 1 oxygen atom 5 yuan of replacement or unsubstituted is formed together with the carbon atom being connected with them Aromatic heterocycle；
The preferred present invention has the compound and pharmaceutically acceptable ester of logical formula (I) as shown in the table：
Logical formula (I) compound of the present invention is synthesized by following steps：
As shown in flow process one, at -78 DEG C, Formula II compound n-BuLi is located in tetrahydrofuran/toluene Mixed Solvent Reason, is subsequently adding lactone II I, and question response adds methanesulfonic acid and methanol solution completely afterwards, is stirred overnight at room temperature and obtains formula IV chemical combination Thing；Lactone II I prepares reference literature R.Benhaddous, S.Czemecki etc., Carbohydr.Res., and 1994,260, 243-250。
At -20 DEG C, formula IV is reduced in acetonitrile/dichloromethane mixed solvent with triethyl silicane and boron trifluoride diethyl etherate Compound, can prepare Formula V compound, under room temperature, full acetylated under DMAP catalysis with pyridine, acetic anhydride, and Jing recrystallization split Formula IV compound is prepared, then Jing LiOH hydrolyze to obtain compound of formula I in tetrahydrofuran, methanol water mixed solvent；Wherein R1It is preferred that From：Methoxyl group, ethyoxyl, propoxyl group；R2It preferably is selected from：F, Cl, methyl, ethyl；Or R1And R2The carbon atom one being connected with them Act the replacement or unsubstituted aromatic heterocycle for forming 5 yuan with 1 oxygen atom.
The preparation method of Compounds of formula II is：
As shown in flow process two, phenol is dissolved in DMF, adds potassium carbonate room temperature reaction to obtain compound 2, with 2- under ice bath Chloro- 5- bromobenzoic acids Fu Ke is acylated and obtains compound 3, and Jing triethyl silicanes and boron trifluoride diethyl etherate obtain chemical combination in room temperature reduction Thing 4, is dissolved in trifluoracetic acid, is dividedly in some parts hexamethylenamine and flows back to obtain compound 5, and Jing potassium carbonate cyclizations obtain compound 6, are dissolved in Compound 7, Jing WILLIAMS-DARLING Tons ether synthesis compound II-a are obtained with sodium borohydride, Reduction of methanol in tetrahydrofuran；Wherein, R is selected from： C1～C5Alkyl, C1～C5Alkoxyl ,-O- aryl ,-OC1-5- aryl, substituted or unsubstituted cycloalkyl；II-a is with formula The compound of II.
As shown in flow process three, must change by the Fu Ke acylation reactions under aluminum chloride effect with compound 8 for the chloro- 5- bromobenzoic acids of 2- Compound 9, reduces to obtain compound II-b under triethyl silicane and boron trifluoride diethyl etherate effect；Wherein R1It preferably is selected from：Methoxyl group, second Epoxide, propoxyl group；R2It preferably is selected from：F, Cl, methyl, ethyl；Or R1And R2Formed together with the carbon atom being connected with them with 1 The replacement of 5 yuan of individual oxygen atom or unsubstituted aromatic heterocycle；II-b is with compounds of formula II.
The pharmaceutically acceptable ester of logical formula (I) compound of the present invention includes the 6-O positions hydroxyl of Fructus Vitis viniferae bglii fragment in molecule The pharmaceutically acceptable ester of the form such as base and acetyl group, formoxyl, methoxycarbonyl group and carbethoxyl group；Method shown in available following formula Prepare：
The R of compound I monovalents3COCl process, is esterified on the 6-O positions of the Fructus Vitis viniferae bglii fragment of compound I, is obtained Corresponding ester；Wherein, R3Selected from the pharmaceutically acceptable group such as Me, Et, MeO and EtO, preferred MeO and EtO.
Present invention additionally comprises pharmaceutical preparation, said preparation includes the logical formula (I) compound or its ester or pharmacy as activating agent Upper acceptable carrier.Above-mentioned pharmaceutically acceptable carrier refers to the conventional pharmaceutical carrier of pharmaceutical field, refers to a kind of or several Kind inert, atoxic solid or liquid filler material, diluent, auxiliary agent etc., they not inversely with reactive compound or patient Have an effect.
The dosage form of the present composition can be the dosage form commonly used on the pharmaceuticss such as tablet, capsule, pill, soft capsule.
Tablet for oral use and capsule contain traditional excipient such as implant, diluent, lubricant, dispersant and bonding Agent.
The various dosage forms of pharmaceutical composition of the present invention can be prepared according to well known method in pharmaceutical field.
The dosage of above activating agent will be different because of formula.
Usually, it has therefore proved that favourable amount, to reach results needed, per kilogram of formula (I) compound being administered per 24 hours Total amount be for about 0.01-200mg, preferred total amount be 0.1-100mg/kg；If necessary, given in the form of single dose several times Medicine.
However, if necessary, it is also possible to deviate above-mentioned consumption, i.e., this depends on the type and body of experimenter to be treated Weight, individual type and administration time and interval to the behavior of medicine, the property of disease and seriousness, preparation and administration.
In the present invention, the internal hypoglycemic activity of compound can be determined by using measurement system as described below.
Normal mouse oral glucose tolerance tests (OGTT)
10 week old Kunming kind cleaning grade mices, 18～22g of body weight, male are randomly divided into 11 groups, and blank control group is (blank Solvent), 1 (Dapagliflozin of positive drug control group：1.5mg/kg (3.7 μm of ol/kg)), (diformazan is double for positive drug control group 2 Guanidine：100mg/kg), test-compound group (3.7 μm of ol/kg), 8 per group.
Mice fasting before experiment can't help water 12 hours, and the equal oral administration gavage administration of each group, docking take blood, determine blood glucose value (note For -30min).Then 11 groups of mices gavage gives blank solvent, Dapagliflozin, metformin and tested chemical combination respectively Thing, determines blood glucose value and is designated as 0min after 30min, give the glucose that concentration is 3g/10ml by 10ml/kg gavages immediately afterwards molten Liquid, and blood glucose value (mmol/L) is determined in 15,30,45,60,120min.As a result such as following table.
Table 1：After normal mouse single-dose 2h blood glucose value changes (N=8).
Note：* P≤0.05, * * P≤0.01 is Student ' the s t assays relative to blank control group.
The test of normal mouse oral glucose tolerance shows that all test-compounds have certain hypoglycemic effect, wherein chemical combination Thing I-1 and I-5 can be obviously improved the carbohydrate tolerance of normal mouse, and internal hypoglycemic activity is suitable with Dapagliflozin, even more It is good, show excellent hypoglycemic activity.
In the present invention, the activity of the internal promotion glucose in urine of compound can be determined by using measurement system as described below.
10 week old Kunming kind cleaning grade mices, 18～22g of body weight, male are randomly divided into 11 groups, and blank control group is (blank Solvent), 1 (Dapagliflozin of positive drug control group：1.5mg/kg (3.7 μm of ol/kg)), (diformazan is double for positive drug control group 2 Guanidine：100mg/kg), test-compound group (3.7 μm of ol/kg), 8 per group.
Mice fasting before experiment can't help water 12 hours, the equal oral administration gavage administration of each group, determine glucose in urine (being designated as -30min).So Afterwards 11 groups of mices gavage gives blank solvent, Dapagliflozin, metformin and test-compound respectively, determine after 30min Urine sugar value is designated as 0min, gives the glucose solution that concentration is 3g/10ml by 10ml/kg gavages immediately afterwards, and in 15,30, 45,60,120min determine urine sugar value.
The measure of urine sugar value is Tes-Tape band to be immersed in urine, and drenched (about 1-2 second kinds) takes out afterwards；Along container edge Take out reagent paper to remove unnecessary urine；Reagent paper band color is observed within the 30-60 seconds and is compareed with color board, measure result.As a result Judge：(reagent paper by light blue to reddish brown color change representing testing result) is light blue to be indicated without glucose in urine, is represented with "-"；Brownish red Glucose in urine is indicated, the more, concentration of glucose is higher in urine for deeper "+" number.As a result such as following table.
Table 2：The glucose in urine value changes of 2h after normal mouse single-dose.
Note：-：Without glucose in urine； ±：100mg/dL； +：250mg/dL
++：500mg/dL +++：1000mg/dL ++++：2000mg/dL
Normal mouse urine glucose test shows, all test-compounds have certain glucose in urine effect, wherein compound I-1, I-5 and I-8 can be obviously promoted glucose in urine discharge, show which has preferable SGLT2 inhibitory activity.
Specific embodiment
With reference to embodiment, the invention will be further described.It should be noted that following embodiments are merely to illustrate, And it is not intended to limit the present invention.The various change that those skilled in the art's training centre of the invention is made all should be in this Shen Please be within the protection domain required by claim.
Embodiment 1
(the bromo- 2- chlorphenyls of 5-) (4- ethyoxyl -3- fluorophenyls) ketone (IIa-1)
It is equipped with the mono- neck bottles of 100ml of calcium chloride tube, the chloro- 5- bromobenzoic acids (5.0g, 21.23mmol) of 2- are suspended in 20ml dichloromethane, lower Deca oxalyl chloride (5.49ml, 63.69mmol) of stirring, drop are finished, with a drop DMF catalysis, room temperature reaction 3h, removes solvent and unnecessary oxalyl chloride under reduced pressure, and residue 25ml dichloromethane dissolves, put ice salt bath be cooled to -10 DEG C it is left The right side, is dividedly in some parts AlCl3(3.40g, 24.98mmol), finishes and is evenly stirred until that reactant liquor is changed into yellow thick liquid from yellow green, open Beginning Deca 2- fluorobenzene ether (2.84g, 20.84mmol), control interior temperature are less than 0 DEG C, and drop finishes, and react about 45min in 0 DEG C and have reacted Finish, be poured in cold 1N hydrochloric acid (100ml), stir to rufous reactant liquor and be changed near colourless, dichloromethane (25ml × 3) extraction Take, organic faciess are washed with 1N NaOH (30ml × 1), saturated aqueous common salt (50ml × 2) washing, anhydrous sodium sulfate drying are filtered, Remove solvent under reduced pressure, residual solid obtains the colourless column crystallizations of 5.3g, fusing point with ethyl alcohol recrystallization：136-138 DEG C, yield： 72.0%.
1H NMR (300MHz, DMSO-d6)δ：7.80-7.76 (m, 2H, Ar-H), 7.63-7.55 (m, 2H, Ar-H), 7.46-7.43 (m, 1H, Ar-H), 7.32-7.27 (m, 1H, Ar-H), 4.22 (q, J=6.96Hz, 2H, CH3 CH 2 - O), 1.38 (t, J=6.95Hz, 3H,CH 3 CH2-O)。
(the bromo- 2- chlorphenyls of 5-) (4- ethyoxyl -3- chlorphenyls) ketone (IIa-2)
The same IIa-1 of synthetic method, with 2- chlorophenetoles as raw material, is obtained colourless crystallization IIa-2 (4.7g), fusing point：126- 128 DEG C, yield：82.2%.
1H NMR (300MHz, DMSO-d6)δ：7.80-7.76 (m, 3H, Ar-H), 7.63-7.55 (m, 2H, Ar-H), 7.30 (d, J=8.58Hz, 1H, Ar-H), 4.25 (q, J=6.97Hz, 2H, CH3 CH 2 O), 1.39 (t, J=6.95Hz, 3H,CH 3 CH2- O)。
(the bromo- 2- chlorphenyls of 5-) (4- ethyoxyl -3- aminomethyl phenyls) ketone (IIa-3)
The same IIa-1 of synthetic method, with 2- tolyl ethyl ethers as raw material, is obtained colourless crystallization IIa-3 (5.6g), fusing point：93- 95 DEG C, yield：76.1%.
1H NMR (300MHz, DMSO-d6)δ：7.77-7.70 (m, 2H, Ar-H), 7.60-7.47 (m, 3H, Ar-H), 7.05 (d, J=8.64Hz, 1H, Ar-H), 4.15 (q, J=6.94Hz, 2H, CH3 CH 2 - O), 2.18 (s, 3H, Ar-CH 3 ), 1.39 (t, J =6.95Hz, 3H,CH 3 CH2-O)。
(the bromo- 2- chlorphenyls of 5-) (2- dibenzofurans) ketone (IIa-4)
The same IIa-1 of synthetic method, with dibenzofuran as raw material, is obtained colourless column crystallization IIa-4 (4.9g), fusing point：169-171 DEG C, yield：83.5%.
1H NMR (300MHz, DMSO-d6)δ：8.63 (d, J=1.32Hz, 1H, Ar-H), 8.32 (d, J=7.41Hz, 1H, Ar-H), 7.93-7.75 (m, 5H, Ar-H), 7.60 (d, J=8.46Hz, 2H, Ar-H), 7.47-7.42 (m, 1H, Ar-H).
Wherein, IIa-1～IIa-4 is the compound with formula 9.
Embodiment 2
The chloro- 2- of the bromo- 1- of 4- (4- ethyoxyl -3- luorobenzyls) benzene (II-1)
It is equipped with the mono- neck bottles of 100ml of anhydrous calcium chloride drying tube, raw material II a-1 (5.3g, 15.0mmol) is dissolved in 20ml The mixed solvent of dichloromethane and 20ml acetonitriles, puts ice salt bath and is cooled to -5 DEG C or so, lower Deca Et of stirring3SiH (5.3ml, 33.0mmol), Deca BF again after stirring3·Et2O (3.8ml, 30.0mmol), finishes, is warmed to room temperature in ice bath naturally, Be stirred overnight, solution PH is adjusted to Deca 2N NaOH in reactant liquor under ice-water bath cooling and is about 8-9, dilute, dichloromethane Alkane (25ml × 3) is extracted, and organic faciess are washed with 1N hydrochloric acid (30ml × 2), saturated aqueous common salt (40ml × 1) washing, anhydrous slufuric acid Sodium is dried, and filters, removes solvent under reduced pressure, and residue Jing column chromatography purification obtains 5.1g colourless oil liquids, yield：97.3%.
1H NMR (300MHz, DMSO-d6)δ：7.56 (d, J=2.16Hz, 1H, Ar-H), 7.48-7.38 (m, 2H, Ar- H), 7.10-7.04 (m, 2H, Ar-H), 6.95 (d, J=8.37Hz, 1H, ArH), 4.05 (q, J=6.97Hz, 2H, CH3 CH 2 - O), 3.99 (s, 2H, Ar-CH 2 - Ar), 1.33 (t, J=6.97Hz, 3H,CH 3 CH2-O)。
The chloro- 2- of the bromo- 1- of 4- (4- ethyoxyl -3- chlorobenzyls) benzene (II-2)
The same II-1 of synthetic method, obtains colorless oil, yield by raw material of IIa-2：93.7%.
1H NMR (300MHz, DMSO-d6)δ：7.58 (d, J=2.19Hz, 1H, Ar-H), 7.48-7.44 (m, 2H, Ar- H), 7.28 (d, J=1.80Hz, 1H, Ar-H), 7.13-7.04 (m, 2H, Ar-H), 4.06 (q, J=6.96Hz, 2H, CH3 CH 2 - O), 3.99 (s, 2H, Ar-CH 2 - Ar), 1.33 (t, J=6.96Hz, 3H,CH 3 CH2-O)。
The chloro- 2- of the bromo- 1- of 4- (3- methyl -4- ethoxy benzyls) benzene (II-3)
The same II-1 of synthetic method, obtains colorless oil, yield by raw material of IIa-3：95.6%.
1H NMR (300MHz, DMSO-d6)δ：7.48-7.37 (m, 3H, Ar-H), 6.98-6.81 (m, 3H, Ar-H), 3.96 (q, J=6.95Hz, 2H, CH3 CH 2 - O), 3.93 (s, 3H, Ar-CH 3 ), 2.10 (s, 2H, Ar-CH 2 - Ar), 1.31 (t, J= 6.95Hz, 3H,CH 3 CH2-O)。
2- (the bromo- 2- chlorobenzyls of 5-) dibenzofurans (II-4)
The same II-1 of synthetic method, obtains colourless column crystallization, fusing point by raw material of IIa-4：102-104 DEG C, yield： 83.2%.
1H NMR (300MHz, DMSO-d6)δ：8.12 (d, J=7.32Hz, 1H, Ar-H), 8.01 (s, 1H, Ar-H), 7.70-7.59 (m, 3H, Ar-H), 7.54-7.36 (m, 5H, Ar-H), 4.23 (s, 2H, Ar-CH 2 -Ar)。
Wherein, II-1～II-4 is the compound with formula II-b.
Embodiment 3
2- (4- (the chloro- 5- benzoyl bromides of 2-) phenoxy group) ethyl acetate (3)
In 100ml round-bottomed flasks, phenol (5.0g, 53.1mmol), ethyl chloroacetate (6.7mL, 63.8mmol) are dissolved in It is in 40mLDMF, disposable in stirring to add potassium carbonate (22.0g, 159.4mmol), 3h is stirred at room temperature.Add saturation in reactant liquor Sodium chloride solution to potassium carbonate dissolve, ethyl acetate (40ml × 3) extraction, organic faciess respectively to wash (30ml × 2), 1N hydrogen-oxygens Change sodium (20ml × 2) washing, saturated aqueous common salt (25ml × 2) washing, anhydrous sodium sulfate drying are filtered, and filtrate decompression is evaporated off molten Agent obtains 0.86g light yellow liquids.
It is equipped with the mono- neck bottles of 100ml of anhydrous calcium chloride drying tube, the chloro- 5- bromobenzoic acids (5g, 21.2mmol) of 2- suspend In 40mL dry methylene chlorides, add one to drip DMF catalysis, be slowly added dropwise the oxalyl chloride of 10mL dry methylene chlorides dissolving (7.3mL, 131.4mmol), drop is complete to be stirred at room temperature 3h.Stop stirring, remove solvent under reduced pressure and unnecessary oxalyl chloride obtains yellow oil Shape thing.Yellow oil is dissolved in 40mL dry methylene chlorides, ice bath is put and is cooled to 0 DEG C, be dividedly in some parts AlCl3(8.5g, 63.7mmol) keep interior temperature to be less than 5 DEG C, finish, stir and be slowly added dropwise the 2- phenoxy group second of dry methylene chloride dissolving again Acetoacetic ester (3.8g, 21.2mmol), drop finish 0 DEG C of stirring 5h, stop stirring, reactant liquor is poured in frozen water (100ml), stir 15min, dichloromethane extraction (40ml × 3), organic faciess are washed with 1N hydrochloric acid (20ml × 2), and saturated aqueous common salt (25ml × 2) is washed Wash, anhydrous sodium sulfate drying, filter, filtrate reduced in volume, gained solid Jing ethyl alcohol recrystallizations obtain 4.7g white crystals, fusing point： 78-79 DEG C, yield：55.6%.
1H NMR (300MHz, DMSO-d6)δ：7.78 (t, J=4.92Hz, 2H, Ar-H), 7.68 (d, J=8.7Hz, 2H, Ar-H), 7.55 (d, J=8.37Hz, 1H, Ar-H), 7.08 (d, J=8.73Hz, 2H, Ar-H), 4.92 (s, 2H, O-CH 2 - CO), 4.17 (q, J=7.08Hz, 2H ,-COOCH 2 -), 1.21 (t, 3H, J=7.08Hz ,-CH2 CH 3 )。
Embodiment 4
2- (4- (the chloro- 5- bromobenzyls of 2-) phenoxy group) ethyl acetate (4)
Compound 3 (4g, 10.0mmol) is dissolved in into 20mL dry methylene chlorides and 20mL is dried in acetonitrile, add Et3SiH (6.0mL, 37.4mmol), puts frozen water and is cooled to 0 DEG C, is slowly added dropwise the BF of 5ml dry methylene chlorides dissolving3·Et2O (5.0mL, 39.5mmol), 12h is stirred at room temperature after adding.Add 20mL 1N potassium hydroxide solutions in reactant liquor, stir 15min, acetic acid second Ester (30ml × 3) is extracted, and 1N sodium hydroxide (15ml × 2) washing, saturated aqueous common salt (20ml × 2) washing, anhydrous sodium sulfate are done It is dry, filter, concentrating under reduced pressure, Jing column chromatography purification obtain 2.8g colourless oil liquids, yield 72.5%.
1HNMR (300MHz, CDCl3)δ：7.30 (m, 3H), 7.11 (d, J=8.62Hz, 2H), 6.97 (d, J=8.63Hz, 2H), 4.60 (s, 2H), 4.30 (q, J=7.12Hz, 2H), 3.99 (s, 2H), 1.29 (t, J=7.13Hz, 3H).
Embodiment 5
2- (4- (the chloro- 5- bromobenzyls of 2-) -2- formvlphenoxvs) ethyl acetate (5)
Under ice bath cooling, hexamethylenamine (1g, 6.26mmol) is mixed with 10ml trifluoracetic acids, is added toward said mixture Compound 4 (2g, 5.20mmol) reactant liquor is in light red, puts oil bath heating backflow about 1h, stops stirring, be cooled to room temperature hypsokinesis Enter in frozen water, stir, it is 8-9 that sodium carbonate carefully alkalizes to PH, and Jing ethyl acetate (20ml × 3) extraction, organic faciess are eaten with saturation Saline (20ml × 2) is washed, anhydrous sodium sulfate drying, is filtered, and filtrate decompression is evaporated off solvent and obtains yellow oil, column chromatography purification Obtain 0.6g white plates crystals, fusing point：68-70 DEG C, yield：23.4%.
1H NMR (300MHz, DMSO-d6)δ：10.39 (s, 1H, CHO), 7.64 (d, J=2.25Hz, 1H, Ar-H), 7.51 (d, J=7.98Hz, 1H, Ar-H), 7.48 (t, J=3.12Hz, 2H, Ar-H), 7.41 (d, J=8.52Hz, 1H, Ar-H), 7.13 (d, J=8.43Hz, 1H, Ar-H), 4.96 (s, 2H, O-CH 2 - CO), 4.19 (q, J=7.10Hz, 2H ,-COOCH 2 -), 4.05 (s, 2H, Ar-CH 2 - Ar), 1.21 (t, J=7.10Hz, 3H ,-CH2 CH 3 )。
Embodiment 6
5- (the bromo- 2- chlorobenzyls of 5-) coumarilic acid ethyl ester (6)
Compound 5 (2.0g, 4.9mmol) is dissolved in 10ml DMF, adds Anhydrous potassium carbonate (0.9g, 6.3mmol), heating 92-94 DEG C of stirring 4h, has reacted, has been poured in ice-cold saturated aqueous common salt (30ml), and ethyl acetate (20ml × 3) extraction is organic Mutually washed with 1N hydrochloric acid (20ml × 1) successively, saturated aqueous common salt (25ml × 2) washing, anhydrous sodium sulfate drying are filtered, decompression Solvent is evaporated off and obtains 1.6g white solids, fusing point：115-117 DEG C, yield：80.8%.
1H NMR (300MHz, DMSO-d6)δ：7.72 (s, 1H, Ar-H), 7.67 (d, J=8.61Hz, 1H, Ar-H), 7.62 (d, J=2.22Hz, 1H, Ar-H), 7.58 (s, 1H, Ar-H), 7.47 (d, J=2.31Hz, 1H, Ar-H), 7.42 (m, 2H, Ar- H), 4.36 (q, J=7.10Hz, 2H ,-COOCH 2 -), 4.18 (s, 2H, Ar-CH 2 - Ar), 1.32 (t, J=7.10Hz, 3H ,- CH2 CH 3 )。
Embodiment 7
5- (the bromo- 2- chlorobenzyls of 5-) benzofuran -2- methanol (7)
In the mono- neck bottles of 50ml of configuration anhydrous calcium chloride drying tube, compound 6 (0.54g, 1.37mmol) is dissolved in 5ml THF, is placed in ice-water bath and is cooled to 0 DEG C or so, is dividedly in some parts NaBH4 (0.11g, 2.74mmol), finishes, and adds after stirring To flowing back, dropwise Deca methanol 0.5ml, reacts and acutely produces a large amount of bubbles heat, and drop finishes back flow reaction 0.5h, has reacted, has been poured into In frozen water, stirring, ethyl acetate (20ml × 3) extraction, organic faciess are washed with saturated aqueous common salt (25ml × 2), anhydrous sodium sulfate It is dried, filters, remove solvent under reduced pressure and obtain 0.47g white solids, fusing point：98-100 DEG C, yield 97.5%.
1H NMR (300MHz, DMSO-d6)δ：7.54 (d, J=2.13Hz, 1H, Ar-H), 7.47 (d, 1H, Ar-H), 7.44 (d, J=2.31Hz, 1H, Ar-H), 7.42 (s, 1H, Ar-H), 7.40 (m, J=1.96Hz, 1H, Ar-H), 7.13 (m, 1H, Ar- H), 6.70 (s, 1H, Ar-H), 5.48 (t, J=5.82Hz, 1H, OH), 4.54 (d, J=5.61Hz, 2H, Ar-CH 2 - O), 4.13 (s, 2H, Ar-CH 2 -Ar)。
Embodiment 8
5- (the bromo- 2- chlorobenzyls of 5-) -2- ethoxymethyl benzofurans (II-5)
Under ice bath cooling, NaH (0.15g, 3.13mmol) adds the THF (5ml) to compound 7 (0.5g, 1.4mmol) molten In liquid, ice bath is removed, be stirred at room temperature to reactant liquor bubble-free and emerge (about 1h), add catalytic amount TBAB, Deca bromoethane (0.17g, 1.57mmol), drop finish temperature rising reflux 1h, have reacted, have been poured in frozen water, ethyl acetate (25ml × 3) extraction, saturation Saline solution (25ml × 2) is washed, anhydrous sodium sulfate drying, is filtered, and decompression boils off solvent and obtains 0.53g yellow oils II-5, is received Rate 80.1%.
1H NMR (300MHz, DMSO-d6)δ：7.51 (d, J=2.07Hz, 1H, Ar-H), 7.47 (d, 1H, Ar-H), 7.44 (d, J=2.07Hz, 1H, Ar-H), 7.42 (s, 1H, Ar-H), 7.40 (m, 1H, Ar-H), 7.13 (m, 1H, Ar-H), 6.78 (s, 1H, Ar-H), 4.51 (s, 2H, Ar-CH 2 - O), 4.10 (s, 2H, Ar-CH 2 - Ar), 3.48 (q, J=6.99Hz, 2H, OCH 2 CH3), 1.10 (t, J=7.00Hz, 3H, OCH2 CH 3 )。
5- (the bromo- 2- chlorobenzyls of 5-) -2- benzyloxymethyl benzofurans (II-6)
The same II-5 of synthetic method, it is raw materials used for bromobenzyl, obtain white solid 2g, fusing point：74-76 DEG C, yield：96.3%.
1H NMR (300MHz, CDCl3)δ：7.43 (d, J=8.43Hz, 1H, Ar-H), 7.31 (s, 1H, Ar-H), 7.27- 7.20 (m, 8H, Ar-H), 7.11-7.08 (m, 1H, Ar-H), 6.64 (s, 1H, Ar-H), 4.63 (s, 2H, Ar-CH 2 - O), 4.62 (s, 2H, Ph-CH 2 - O), 4.13 (s, 2H, Ar-CH 2 -Ar)。
5- (the bromo- 2- chlorobenzyls of 5-) -2- (2- tetrahydrofuran methoxyl methyls) benzofuran (II-7)
The same II-5 of synthetic method, colourless oil liquid 1.5g, yield：80.2%.
1H NMR (300MHz, CDCl3)δ：7.41 (d, J=8.43Hz, 1H, Ar-H), 7.33 (s, 1H, Ar-H), 7.30- 7.22 (m, 3H, Ar-H), 7.11-7.08 (m, 1H, Ar-H), 6.63 (s, 1H, Ar-H), 4.67 (s, 2H, Ar-CH 2 - O), 4.12 (s, 2H, Ar-CH 2 - Ar), 4.10-4.06 (m, 1H, OCHCH2CH2), 3.92-3.75 (m, 2H, OCH 2 CHO), 3.58-3.50 (m, 2H, OCH 2 CH2), 1.96-1.58 (m, 4H, CHCH 2 CH 2 CH2)。
Wherein, II-5～II-7 is the compound with formula II-a.
Embodiment 9
The chloro- 3- of 4- (4- ethyoxyl -3- luorobenzyls) benzene -1- bases-α/β-D- methoxyl group pyranglucoside (IV-1)
It is equipped with the 100ml three-necked bottles of -100 DEG C of thermometeies and plug, compound II-1 (0.54g, 1.42mmol) is dissolved in 5mL dry tetrahydrofurans and 5mL dry toluenes, nitrogen protection, be cooled to -78 DEG C, be slowly added dropwise n-BuLi (1.04mL, 1.56mmol, 1.6M), -78 DEG C of reaction 0.5h after adding, then it is slowly added dropwise the trim,ethylchlorosilane guarantor of 5mL dry toluenes dissolving The gluconolactone (1g, 2.13mmol) of shield, reacts 3h after adding at -78 DEG C, adds the Loprazolam of 2mL methanol dissolving 0.3mL, is warmed to room temperature reaction 16h after adding, after reaction terminates, in reactant liquor, Deca saturated sodium bicarbonate is emerged to bubble-free, Ethyl acetate (50mL × 3) is extracted, and merges organic faciess, is washed with saturated sodium bicarbonate solution (25mL × 2) successively, saturated common salt Water (25mL × 2) is washed, anhydrous sodium sulfate drying, is filtered, is removed solvent under reduced pressure and obtain yellow oil, column chromatographic isolation and purification (dichloromethane：Methanol=30: 1) obtain white solid 0.3g (mixture of two kinds of configurations), fusing point：60-62 DEG C, yield： 42.9%.
1H NMR (300MHz, DMSO-d6)δ：7.52-7.40 (m, 3H, Ar-H), 7.05-6.88 (m, 3H, Ar-H), 4.99 (d, J=5.46Hz, 2H ,-OCH 2 -), 4.54 (t, J=5.68Hz, 1H ,-OCH-), 4.07-3.99 (m, 5H, Ar-CH 2 - Ar ,- OCH- ,-OCH 2 CH3), 3.73-3.68 (m, 1H ,-OCH-), 3.49-3.42 (m, 1H ,-OCH), 3.31-3.08 (m, 4H ,-OH), 2.92 (s, 3H ,-OCH 3 ), 1.31 (t, J=6.96Hz, 3H ,-OCH2 CH 3 )。
Embodiment 10
The chloro- 3- of 4- (4- ethyoxyl -3- luorobenzyls) benzene -1- base-β-D-2,3,4,6,-four-O- acetyl group Glucopyranose .s Glycosides (VI-1)
Compound IV-1 (0.3g, 0.61mmol) is dissolved in 5mL dichloromethane and 5mL acetonitriles, adds Et3SiH (0.27mL, 1.71mmol), is cooled to -15 DEG C, is slowly added dropwise the BF of dchloromethane3·Et2O (0.11mL, 0.85mmol), drop finishes and reacts overnight at -10 DEG C.Reaction adds saturated sodium bicarbonate to bubble-free in terminating backward reactant liquor Emerge, ethyl acetate extraction merges organic faciess, and saturated aqueous common salt (20mL × 2) is washed, and anhydrous sodium sulfate drying, sucking filtration are obtained 0.2g faint yellow solids.Above-mentioned crude product (0.2g, 0.43mmol) is dissolved in 5ml dichloromethane, sequentially adds pyridine under ice bath The DMAP of (0.42mL, 4.32mmol), acetic anhydride (0.5mL, 4.32mmol) and catalytic amount, adds rear room temperature reaction 2h.Reaction 20ml water, dichloromethane (30mL × 3) extraction is added to merge organic faciess, respectively with 1N hydrochloric acid (20mL in terminating backward reactant liquor × 2), and saturated aqueous common salt (20mL × 2) washing, anhydrous Na2SO4It is dried, sucking filtration removes solvent, gained solid Jing ethanol weights under reduced pressure Crystallization obtains white powdery solids 0.18g, fusing point：132-134 DEG C, yield：48.9%.
1H NMR (300MHz, DMSO-d6)δ：7.44-7.25 (m, 3H, Ar-H), 7.08-6.89 (m, 3H, Ar-H), 5.35 (t, J=9.48Hz, 1H ,-OCH-), 5.07 (t, J=9.45Hz, 1H ,-OCH-), 4.96 (t, J=9.64Hz, 1H ,-OCH-), 4.66 (d, J=9.69Hz, 1H ,-O-CH-Ar), 4.10-3.98 (m, 7H, Ar-CH 2 - Ar ,-OCH- ,-OCH 2 - ,-OCH 2 CH3), 2.01 (s, 3H,CH 3 CO), 1.99 (s, 3H,CH 3 CO), 1.92 (s, 3H,CH 3 CO), 1.70 (s, 3H,CH 3 CO), 1.31 (t, J =6.96Hz, 3H ,-OCH2 CH 3 )。
Embodiment 11
The chloro- 3- of 4- (4- ethyoxyl -3- luorobenzyls) benzene -1- base-β-D- pyranglucoside (I-1)
Compound VI-1 (0.18g, 0.30mmol) is dissolved in 4mL tetrahydrofurans, in 6mL methanol and 2mL water, adds hydronium(ion) Lithium oxide (0.07g, 1.7mmol), overnight, question response terminates rear concentrating under reduced pressure to room temperature reaction, and residual liquid is with 30ml acetic acid second Ester dissolve, respectively with 5% potassium hydrogen sulfate solution (10mL × 2), saturated aqueous common salt (15mL × 2) washing, anhydrous sodium sulfate do It is dry, filter, concentrating under reduced pressure obtains colorless oil, column chromatographic isolation and purification (dichloromethane：Methanol=30: 1) obtain white solid 0.1g, fusing point：66-68 DEG C, yield：76.9%.
1H NMR (300MHz, DMSO-d6)δ：7.39-7.35 (m, 2H, Ar-H), 7.27-7.23 (m, 1H, Ar-H), 7.07-6.98 (m, 2H, Ar-H), 6.94-6.91 (m, 1H, Ar-H), 4.96 (d, J=5.53Hz, 2H ,-OCH 2 -), 4.84 (d, J=5.67Hz, 1H ,-OCHAr), 4.50 (t, J=5.68Hz, 1H ,-OCH-), 4.08-3.99 (m, 5H, Ar-CH 2 - Ar ,- OCH- ,-OCH 2 CH3), 3.73-3.68 (m, 1H ,-OCH-), 3.49-3.42 (m, 1H ,-OCH), 3.31-3.08 (m, 4H ,-OH), 1.31 (t, J=6.96Hz, 3H ,-OCH2 CH 3 )；
13C NMR (75MHz, DMSO-d6)δ：153.0,149.8,139.7,137.1,131.8,130.8,128.6, 127.5,124.5,116.1,115.8,114.8,81.1,80.6,78.2,74.6,70.2,64.2,61.3,59.7,37.4, 14.5；
MS (ESI, m/z)：449.8[M+Na]+。
Embodiment 12
The chloro- 3- of 4- (4- ethyoxyl -3- chlorobenzyls) benzene -1- base-β-D- pyranglucoside (I-2)
The same I-1 of synthetic method, obtains white solid 0.30g, fusing point：78-79 DEG C, yield：91.3%.
1H NMR (300MHz, DMSO-d6)δ：7.36 (d, J=8.19Hz, 1H, Ar-H), 7.31-7.30 (m, 1H, Ar- H), 7.25-7.21 (m, 1H, Ar-H), 6.97-6.92 (m, 2H, Ar-H), 6.80 (d, J=8.28Hz, 1H, Ar-H), 4.96 (d, J=5.48Hz, 2H ,-OCH 2 -), 4.83 (d, J=5.55Hz, 1H ,-O-CH- Ar), 4.50 (t, J=5.68Hz, 1H ,- OCH-), 4.06-3.92 (m, 5H, ArCH 2 Ar ,-OCH- ,-OCH 2 CH3), 3.73-3.68 (m, 1H ,-OCH-), 3.49-3.43 (m, 1H ,-OCH), 3.30-3.07 (m, 4H ,-OH), 1.30 (t, J=6.93Hz, 3H ,-OCH2 CH 3 )；
13C NMR (75MHz, DMSO-d6)δ：152.1,139.7,137.1,132.6,131.8,130.8,129.7, 128.7,128.2,127.5,121.0,113.7,81.1,80.6,78.2,74.6,70.2,64.2,61.3,37.2,14.5；
MS (ESI, m/z)：466.3[M+Na]+。
Embodiment 13
The chloro- 3- of 4- (4- ethyoxyl -3- methyl-benzyls) benzene -1- base-β-D- pyranglucoside (I-3)
The same I-1 of synthetic method, white solid 0.31g, 75-76 DEG C of fusing point, yield：90.2%.
1H NMR (300MHz, DMSO-d6)δ：7.39-7.36 (m, 2H, Ar-H), 7.27-7.22 (m, 2H, Ar-H), 7.11-7.01 (m, 2H, Ar-H), 4.96 (d, J=5.66Hz, 2H ,-OCH 2 -), 4.84 (d, J=5.55Hz, 1H ,-O-CH- Ar), 4.44 (t, J=5.60Hz, 1H ,-OCH-), 4.06-3.99 (m, 5H, Ar-CH 2 - Ar ,-OCH- ,-OCH 2 CH3), 3.73- 3.68 (m, 1H ,-OCH-), 3.47-3.44 (m, 1H ,-OCH), 3.23-3.11 (m, 4H ,-OH), 2.09 (s, 3H, ArCH 3 ), 1.32 (t, J=6.94Hz, 3H ,-OCH2 CH 3 )；
13C NMR (75MHz, DMSO-d6)δ：154.9,139.5,137.8,131.8,130.8,130.7,130.6, 128.6,127.1,126.8,125.4,111.1,81.1,80.6,78.2,74.6,70.2,63.0,61.3,37.6,16.0, 14.7；
MS (ESI, m/z)：445.9[M+Na]+。
Embodiment 14
The chloro- 3- of 4- (dibenzofurans -2- methyl) benzene -1- base-β-D- pyranglucoside (I-4)
The same I-1 of synthetic method, obtains white solid 0.45g, 88-90 DEG C of fusing point, yield：95.7%.
1H NMR (300MHz, DMSO-d6)δ：8.10 (d, J=7.53Hz, 1H, Ar-H), 7.96 (s, 1H, Ar-H), 7.69-7.60 (m, 3H, Ar-H), 7.53-7.25 (m, 5H, Ar-H), 4.94 (d, J=5.72Hz, 2H ,-OCH 2 ), 4.85 (d, J =5.67Hz, 1H ,-OCHAr), 4.43 (t, J=5.76Hz, 1H ,-OCH), 4.23 (s, 2H, ArCH 2 Ar), 4.02-3.99 (m, 1H ,-OCH-), 3.71-3.66 (m, 1H ,-OCH), 3.47-3.42 (m, 1H ,-OCH), 3.26-3.08 (m, 4H ,-OH)；
13C NMR (75MHz, DMSO-d6)δ：155.7,154.0,139.7,137.5,134.3,131.9,130.9, 128.7,128.1,127.5,127.4,123.5,123.4,122.9,121.0,120.8,111.5,111.4,81.1,80.6, 78.2,74.7,70.2,61.3,38.3；
MS (ESI, m/z)：477.8[M+Na]+。
Embodiment 15
The chloro- 3- of 4- (2- ethoxymethyl benzofuran -5- methyl) benzene -1- base-β-D- pyranglucoside (I-5)
The same I-1 of synthetic method, obtains white solid 0.11g, fusing point：64-65 DEG C, yield：80.9%.
1H NMR (300MHz, DMSO-d6)δ：7.48 (d, J=8.49Hz, 1H, Ar-H), 7.40-7.36 (m, 3H, Ar- H), 7.26-7.23 (m, 1H, Ar-H), 7.17-7.13 (m, 1H, Ar-H), 6.81 (s, 1H, Ar-H), 4.95 (d, J= 5.64Hz, 2H ,-OCH 2 ), 4.84 (d, J=5.64Hz, 1H ,-O-CH-Ar), 4.53 (s, 2H, Ar-CH-O), 4.44 (t, J= 5.62Hz, 1H ,-OCH), 4.14 (s, 2H, Ar-CH 2 - Ar), 4.01-3.98 (m, 3H ,-OCH- ,-OCH 2 ), 3.72-3.66 (m, 1H ,-OCH), 3.54-3.40 (m, 3H ,-OCH, OCH 2 CH3), 3.26-3.10 (m, 4H ,-OH), 1.12 (t, J=6.99Hz, 3H,CH 3 )；
13C NMR (75MHz, DMSO-d6)δ：154.9,153.1,137.7,134.1,131.9,130.9,128.6, 127.8,127.3,125.2,120.7,110.8,105.5,81.1,80.6,78.2,75.6,74.6,71.3,70.2,69.4, 38.3,14.2；
MS (ESI, m/z)：485.9[M+Na]+。
Embodiment 16
The chloro- 3- of 4- (2- benzyloxymethyl benzofuran -5- methyl) benzene -1- base-β-D- pyranglucoside (I-6)
The same I-1 of synthetic method, obtains white solid 0.23g, 57-58 DEG C of fusing point, yield：87.1%.
1H NMR (300MHz, DMSO-d6)δ：7.49 (d, J=8.43Hz, 1H, Ar-H), 7.31 (s, 1H, Ar-H), 7.27-7.20 (m, 8H, Ar-H), 7.11-7.08 (d, J=8.37Hz, 1H, Ar-H), 6.64 (s, 1H, Ar-H), 4.98 (d, J =5.52Hz, 2H ,-OCH 2 -), 4.87 (d, J=5.52Hz, 1H ,-O-CH-Ar), 4.62 (s, 2H, Ar-CH 2 - O), 4.55 (s, 2H, Ph-CH 2 - O), 4.46 (t, J=5.22Hz, HOCH 2 CH-O), 4.14 (s, 2H, Ar-CH 2 - Ar), 4.01 (t, J= 7.32Hz, 1H ,-OCH-), 3.71 (t, J=6.3Hz, 1H ,-OCH-), 3.38 (t, J=4.5Hz, 1H ,-OCH), 3.26-3.16 (m, 4H ,-OH)；
13C NMR (75MHz, DMSO-d6)δ：154.7,153.2,139.7,137.8,137.7,134.1,131.1, 130.9,128.7,128.2,127.8,127.6,127.5,127.3,125.3,120.8,110.8,105.8,81.1,80.6, 78.2,74.6,71.3,70.2,63.9,61.3,59.7,38.3；
MS (ESI, m/z)：548.1[M+Na]+。
Embodiment 17
The chloro- 3- of 4- (2- (2- tetrahydrofuran methoxyl methyls) benzofuran -5- methyl) benzene -1- base-β-D- Glucopyranose .s Glycosides (I-7)
The same I-1 of synthetic method, obtains white solid 0.19g, 52-54 DEG C of fusing point, yield：77.2%.
1H NMR (300MHz, DMSO-d6)δ：7.47 (d, J=8.34Hz, 1H, Ar-H), 7.38-7.16 (m, 5H, Ar- H), 6.82 (d, J=8.36Hz, 1H, Ar-H), 4.58 (d, J=5.43Hz, 2H ,-OCH 2 ), 4.48 (d, J=6.52Hz, 1H ,- O-CH-Ar), 4.23 (s, 2H, Ar-CH-O), 4.08 (s, 2H, Ar-CH 2 - Ar), 4.01-3.92 (m, 2H, CH2 CH-O), 3.82- 3.69 (m, 3H, OCH 2 CHO ,-OCH), 3.60-3.5 (m, 3H ,-OCH- ,-OCH 2 ), 3.43 (t, J=4.50Hz, 1H ,-OCH), 3.28-3.19 (m, 4H ,-OH), 1.98-1.76 (m, 4H, CHCH 2 CH 2 CH2)；
13C NMR (75MHz, DMSO-d6)δ：154.9,153.1,137.7,134.1,131.9,130.9,128.6, 127.8,127.3,125.2,120.7,110.8,105.5,78.2,77.1,74.6,72.3,70.2,69.4,67.2,64.7, 61.3,59.7,38.3,27.6,25.1；
MS (ESI, m/z)：541.9[M+Na]+。
Embodiment 18
The chloro- 3- of 4- (4- ethyoxyl -3- luorobenzyls) benzene -1- bases -6-O- methoxycarbonyl group-β-D- pyranglucoside (I-8)
Compound I-1 (0.5g, 1.20mmol), triethylamine (0.11g, 1.20mmol) are dissolved in 20ml dichloromethane, are put Cool down in ice-water bath, Deca 0.11g ethyl chloroformate, drop finishes, and mixture is stirred overnight at room temperature, reaction system is eaten with 30ml saturations Saline is quenched, ethyl acetate (20mL × 3) extraction, merges organic faciess, saturated aqueous common salt (10mL × 2) washing, anhydrous sodium sulfate It is dried, sucking filtration removes solvent under reduced pressure, and gained residue Jing column chromatography purification obtains I-8 sterlings, clear crystal 0.4g, yield 68.7%.
MS (ESI, m/z)：485.9[M+H]+。
Embodiment 19
Tablet containing activating agent I-1：
Active component, pregelatinized Starch and Microcrystalline Cellulose are sieved, is sufficiently mixed, add polyvinylpyrrolidone molten Liquid, mixing, soft material processed sieve, wet granular processed, in 50-60 DEG C of drying, by Sodium carboxymethyl starch, magnesium stearate and Pulvis Talci Addition sieve to compression molding in above-mentioned granule.
Also there is good promotion glucose in urine to discharge effect and internal hypoglycemic activity for empirical tests, above-mentioned composition.

Claims (3)

1. compound is selected from：
The chloro- 3- of 4- (2- ethoxymethyl benzofuran -5- methyl) benzene -1- base-β-D- pyranglucoside；
The chloro- 3- of 4- (2- benzyloxymethyl benzofuran -5- methyl) benzene -1- base-β-D- pyranglucoside；
The chloro- 3- of 4- (2- (2- tetrahydrofuran methoxyl methyls) benzofuran -5- methyl) benzene -1- base-β-D- pyranglucoside.
2. application of the compound defined in claim 1 in terms of preparing prevention or treating diabetes medicament.
3. a kind of pharmaceutical composition, containing compound defined in claim 1 and appropriate carrier or excipient.
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US10696662B2 (en) 2017-08-21 2020-06-30 Janssen Pharmaceutica Nv 5-fluoro-C-(aryl or heterocyclyl)-glycoside derivatives useful as dual SGLT1 / SGLT2 modulators
CN107556276B (en) * 2017-10-12 2019-05-14 广州医科大学 C- triaryl glucoside compounds and its preparation method and application
CN112094254B (en) * 2019-06-17 2023-05-05 中国医学科学院药物研究所 Carbonoside compounds, and preparation and application thereof

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001027128A1 (en) * 1999-10-12 2001-04-19 Bristol-Myers Squibb Company C-aryl glucoside sglt2 inhibitors
CN1653075A (en) * 2002-05-20 2005-08-10 百时美施贵宝公司 C-aryl glucoside SGLT2 inhibitors and method
CN101384576A (en) * 2006-02-15 2009-03-11 贝林格尔.英格海姆国际有限公司 Glucopyranosyl-substituted benzonitrile derivatives, pharmaceutical compositions containing such compounds, their use and process for their manufacture
CN101503399A (en) * 2008-02-04 2009-08-12 白鹭医药技术（上海）有限公司 C-aryl glucoside SGLT2 inhibitor
CN102863417A (en) * 2011-07-09 2013-01-09 山东轩竹医药科技有限公司 C-indican derivative
CN103596564A (en) * 2011-06-01 2014-02-19 株式会社绿十字 Novel diphenylmethane derivatives as SGLT2 inhibitors
CN104109179A (en) * 2013-04-16 2014-10-22 杭州华东医药集团生物工程研究所有限公司 C-aryl glucoside derivatives, preparation method and application thereof

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001027128A1 (en) * 1999-10-12 2001-04-19 Bristol-Myers Squibb Company C-aryl glucoside sglt2 inhibitors
CN1653075A (en) * 2002-05-20 2005-08-10 百时美施贵宝公司 C-aryl glucoside SGLT2 inhibitors and method
CN101384576A (en) * 2006-02-15 2009-03-11 贝林格尔.英格海姆国际有限公司 Glucopyranosyl-substituted benzonitrile derivatives, pharmaceutical compositions containing such compounds, their use and process for their manufacture
CN101503399A (en) * 2008-02-04 2009-08-12 白鹭医药技术（上海）有限公司 C-aryl glucoside SGLT2 inhibitor
CN103596564A (en) * 2011-06-01 2014-02-19 株式会社绿十字 Novel diphenylmethane derivatives as SGLT2 inhibitors
CN102863417A (en) * 2011-07-09 2013-01-09 山东轩竹医药科技有限公司 C-indican derivative
CN104109179A (en) * 2013-04-16 2014-10-22 杭州华东医药集团生物工程研究所有限公司 C-aryl glucoside derivatives, preparation method and application thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Design, Synthesis and in vivo Evaluation of Novel C-Aryl Glucosides as Potent Sodium-Dependent Glucose Cotransporters Inhibitors for the Treatment of Diabetes;Zheng Li et al.;《Chem. Biol. Drug Des.》;20150320;第86卷(第4期);第764-775页 *

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