WO2006023889A2 - A method for preparing irbesartan and intermediates thereof - Google Patents

A method for preparing irbesartan and intermediates thereof Download PDF

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Publication number
WO2006023889A2
WO2006023889A2 PCT/US2005/029879 US2005029879W WO2006023889A2 WO 2006023889 A2 WO2006023889 A2 WO 2006023889A2 US 2005029879 W US2005029879 W US 2005029879W WO 2006023889 A2 WO2006023889 A2 WO 2006023889A2
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Prior art keywords
formula
compound
phosphite
pharmaceutically acceptable
acceptable salt
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PCT/US2005/029879
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French (fr)
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WO2006023889A3 (en
Inventor
Edgar I. Miranda
Cornelis Vlaar
Jingyang Zhu
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Bristol-Myers Squibb Company
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Priority to DE602005024819T priority Critical patent/DE602005024819D1/en
Priority to EP05791492A priority patent/EP1781627B1/en
Priority to MX2007002030A priority patent/MX2007002030A/en
Priority to CA002578409A priority patent/CA2578409A1/en
Application filed by Bristol-Myers Squibb Company filed Critical Bristol-Myers Squibb Company
Priority to AU2005277162A priority patent/AU2005277162B2/en
Priority to AT05791492T priority patent/ATE488508T1/en
Priority to KR1020077004208A priority patent/KR101252309B1/en
Priority to CN2005800286578A priority patent/CN101006064B/en
Priority to JP2007530039A priority patent/JP5203703B2/en
Priority to BRPI0514584-8A priority patent/BRPI0514584A/en
Publication of WO2006023889A2 publication Critical patent/WO2006023889A2/en
Publication of WO2006023889A3 publication Critical patent/WO2006023889A3/en
Priority to IL181464A priority patent/IL181464A/en
Priority to NO20071254A priority patent/NO20071254L/en
Priority to HK07105816.4A priority patent/HK1098157A1/en

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D235/00Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D403/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings

Definitions

  • the invention relates to methods for preparing irbesartan and intermediates thereof.
  • Irbesartan is an. antagonist for angiotensin II receptor and is useful for treating angiotensin II-associated disorders.
  • Irbesartan is a potent, long-acting angiotensin II receptor antagonist that is especially useful in the treatment of cardiovascular ailments such as hypertension and heart failure. Irbesartan has the following structure:
  • This invention is directed to various methods for preparing irbesartan and intermediates thereof as recited in the claims appended hereto.
  • One aspect of the present invention provides a method for preparing a compound useful in the synthesis of irbesartan, having the formula ⁇ , or a pharmaceutically acceptable salt thereof, comprising reacting a mixture of a compound of formula IVa and a compound of formula IVb, and optionally a compound of formula FVc,
  • Another aspect of the present invention provides a method for preparing a compound of formula I (irbesartan), or a pharmaceutically acceptable salt thereof, from the compound of formula II.
  • a further aspect of the present invention provides a method for preparing a compound of formula II in substantially pure form
  • step (b) washing the compound of formula II in crystal form from step (a) with at least one solvent selected from methyl tert-butyl ether and wo-propanol to give the compound of formula II in substantially pure form; and
  • step (c) recycling the washed solvent collected from step (b) to crystallize a crude compound of formula II in the next batch as recited in step (a).
  • MTBAC methyl-77-tributhyl ammonium chloride
  • MTBE methyl tert-butyl ether
  • NBS N-bromosuccinimide
  • alkyl or "alk” refers to a straight or branched chain alkane
  • hydrocarbon radical containing from 1 to 12 carbon atoms, preferably 1 to 6 carbon atoms.
  • alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, t- butyl, isobutyl pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4- trimethylpentyl, nonyl, decyl, undecyl, dodecyl, and the like.
  • C 1 -C 6 alkyl refers to a straight or branched chain alkane (hydrocarbon) radical containing from 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, isopentyl, hexyl, and isohexyl.
  • phase transfer catalyst refers to a small quantity of a chemical agent that enhances the rate of a reaction between chemical species located in different phases (immiscible liquids or solid and liquid) by extracting one of the reactants, most commonly an anion, across the interface into the other phase so that reaction can proceed.
  • These catalysts include quaternary ammonium or phosphonium salts (e.g. fetraalkylammonium salts, wherein alkyl can be same or different), or agents that complex inorganic cations (e.g. crown ethers or other cryptands). The catalyst cation is not consumed in the reaction although an anion exchange does occur.
  • the compounds of present invention may form salts which are also within the scope of this invention.
  • Reference to compounds of the formula I through V herein is understood to include reference to salts thereof, unless otherwise indicated.
  • the term "salt(s)”, as employed herein, denotes acidic and/or basic salts formed with inorganic and/or organic acids and bases.
  • zwitterions inner salts
  • inner salts may be formed and are included within the term "salt(s)" as used herein.
  • Salts of the compounds may be formed, for example, by reacting those compounds with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
  • the compounds of present invention may form salts with a variety of organic and inorganic acids.
  • Exemplary acid addition salts include acetates (such as those formed with acetic acid or trihaloacetic acid, for example, trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides, hydroiodides, hydroxyethanesulfonates (e.g., 2- hydroxyethanesulfonates), lactates, maleates, methanesulfonates, naphthalenesulfonates (
  • the compounds of present invention may also form salts with a variety of organic and inorganic bases.
  • Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as benzathines, dicyclohexylamines, hydrabamines (formed with N,N- bis(dehydroabietyl) ethylenediamine), N-methyl-D-glucamines, N-methyl-D- glycamides, t-butyl amines, and salts with amino acids such as arginine, lysine and the like.
  • organic bases for example, organic amines
  • organic bases for example, organic amines
  • benzathines such as benzathines, dicyclohexylamines, hydrabamines (formed with N,N- bis(dehydroabietyl) ethylened
  • Basic nitrogen-containing groups may be quaternized with agents such as lower alkyl halides (e.g. methyl, ethyl, propyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g. dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g. decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides), aralkyl halides (e.g. benzyl and phenethyl bromides), and others.
  • lower alkyl halides e.g. methyl, ethyl, propyl, and butyl chlorides, bromides and iodides
  • dialkyl sulfates e.g. dimethyl, diethyl, dibutyl, and diamyl sulfates
  • prodrug denotes a compound that, upon administration to a subject, undergoes chemical conversion by metabolic or chemical processes to yield compounds of the formula I through V, or a salt and/or solvate thereof.
  • Solvates of the compounds of formula I through V include, for example, hydrates.
  • Compounds of the formula I through V, and salts thereof, may exist in their tautomeric form (for example, as an amide or imino ether). All such tautomeric forms are contemplated herein as part of the present invention.
  • All stereoisomers of the present compounds are contemplated within the scope of this invention.
  • Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers (e.g., as a pure or substantially pure optical isomer having a specified activity), or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers.
  • the chiral centers of the present invention may have the S or R configuration as defined by the IUPAC 1974 Recommendations.
  • racemic forms can be resolved by physical methods, such as, for example, fractional crystallization, separation or crystallization of diastereomeric derivatives or separation by chiral column chromatography.
  • the individual optical isomers can be obtained from the racemates by any suitable method, including without limitation, conventional methods, such as, for example, salt formation with an optically active acid followed by crystallization.
  • the compound of formula I (irbesartan) can be prepared according to
  • Compound 1 can be brominated to give a mixture of mono-brominated product FVa and di-brominated product IVb using a brominating reagent, such as Br 2 or NBS, in an organic solvent, such as CCl 4 , CHCl 3 or CH 2 Cl 2 , and optionally in the presence of UV light or a catalytic amount of benzoyl peroxide.
  • a tri-brominated product JVC may also be generated if a larger excess of bromine is used.
  • Br 2 can be generated in situ by reacting NaBrO 3 or H 2 O 2 with HBr in water.
  • the mixture of compounds IVa and IVb, and optionally IVc can be mono-alkylated upon treatment of compound V or a pharmaceutically acceptable salt thereof, in the presence of a base, such as NaH, and in the presence of a reducing reagent, such as dialkyl phosphite (i.e., diethyl phosphite) to provide the compound of formula H
  • a reducing reagent such as dialkyl phosphite (i.e., diethyl phosphite)
  • a phase transfer catalyst such as tetra-alkylammonium chloride is also used in addition to the reducing reagent such as dialkyl phosphite (i.e., diethyl phosphite).
  • the reducing regent selectively reduces di-brominated compound IVb (or tri-brominated compound IVc) into mono- brominated compound IVa while compound IVa is alkylated to provide the desired mono-alkylation product.
  • This method can be applied to a mixture of compounds IVa, IVb in any ratio, i.e., the ratio between IVa : IVb can vary from 1% : 99% to 99% : 1%.
  • this method also works in the presence of any amount of compound rVc.
  • compound II can be reacted with an azide reagent, such as NaN 3 , to give the compound of formula I.
  • IVa IVb optionally IVc
  • Solvent A Buffer solution A l.lg of heptanesulfonic acid in 1 liter of water and adjust the pH to 2.5;
  • Solvent B Methanol Flow rate: 1.2mL/min; Gradient Elution Condition: Time% A % %B
  • Injection volume 10 uL.
  • IVa IVb about 80-90% about 10-20%
  • a IL 3-neck flask was charged with Compound V (134.0 g), MTBAC (5.0 g) and CH 2 Cl 2 (170 mL) and cool to -5 to 5 0 C.
  • An aqueous solution of KOH (182.6 g in 212 mL water) was added slowly to the IL flask and the reaction temperature was kept at ⁇ 5 0 C.
  • the methylene chloride solution of Compound FVa and Compound IVb from Example 1 was added to the reaction mixture slowly, while maintaining the temperature at 0-10 0 C.
  • Diethyl phosphite 39.66g was added drop wise at 0-10 0 C. Check the reaction mixture for completion of the reduction reaction, and additional diethyl phosphite may be added.
  • reaction mixture was allowed to warm to ambient (20-30 0 C) and agitated until the reaction was deemed complete by HPLC. Water (150 mL) was added and the phases were separated. The organic layer was extracted with water (230 mL) and polish filtered.
  • the solvent i.e., MTBE or IPA
  • the solvent used to wash the crystals of Compound II above can be recycled and used to crystallize the crude Compound II in the next batch. Since the washed solvent contains Compound II as well as impurities, it was surprisingly found that the washed solvent can be recovered and used again in crystallizing the crude compound of formula II in the next batch without sacrificing its purity while increasing its yield.
  • Example 3
  • the aqueous phase was discarded and the organic phase was treated with toluene (1.73 kg) and water (5.0 kg), and stirred for about 0.5 hours at about 20 - about 30°C.
  • the toluene phase was discarded and the aqueous phase was washed with ethyl acetate (1.8 kg) and treated with aqueous HCl until pH was adjusted to about 4.8 - about 5.2.
  • the precipitation was collected and washed with water three times (1.0 kg x 3).
  • the crude wet product was recrystallized using a mixture of zsO-propanol (0.393 kg) and water (4.5 kg). HPLC retention time: 11.725 min.
  • the yield for Compound I was about 87%.

Abstract

A method for preparing irbesartan and intermediates thereof. Irbesartan has the structure of Formula (I).

Description

A METHOD FOR PREPARING IRBESART AN AND INTERMEDIATES THEREOF
RELATED APPLICATIONS [0001] This application claims priority benefit under Title 35 § 119(e) of United States Provisional Application No. 60/603,606, filed August 23, 2004, the contents of which are herein incorporated by reference.
FIELD OF THE INVENTION [0002] The invention relates to methods for preparing irbesartan and intermediates thereof. Irbesartan is an. antagonist for angiotensin II receptor and is useful for treating angiotensin II-associated disorders.
BACKGROUND OF THE INVENTION [0003] Irbesartan is a potent, long-acting angiotensin II receptor antagonist that is especially useful in the treatment of cardiovascular ailments such as hypertension and heart failure. Irbesartan has the following structure:
Figure imgf000002_0001
and is described by Bernhart et al., in U.S. Pat. No. 5,270,317, which is incorporated herein by reference.
SUMMARY OF THE INVENTION
[0004] This invention is directed to various methods for preparing irbesartan and intermediates thereof as recited in the claims appended hereto. [0005] One aspect of the present invention provides a method for preparing a compound useful in the synthesis of irbesartan, having the formula π, or a pharmaceutically acceptable salt thereof,
Figure imgf000003_0001
comprising reacting a mixture of a compound of formula IVa and a compound of formula IVb, and optionally a compound of formula FVc,
+ optionally
Figure imgf000003_0003
Figure imgf000003_0002
IVa IVb IVc with a compound of formula V, or a pharmaceutically acceptable salt thereof,
Figure imgf000003_0004
in the presence of a base and a reducing agent, and optionally in the presence of a phase transfer catalyst; and optionally, converting the compound of formula II into a pharmaceutically acceptable salt.
[0006] Another aspect of the present invention provides a method for preparing a compound of formula I (irbesartan), or a pharmaceutically acceptable salt thereof, from the compound of formula II.
Figure imgf000003_0005
[0007] A further aspect of the present invention provides a method for preparing a compound of formula II in substantially pure form,
Figure imgf000003_0006
comprising: (a) crystallizing a crude compound of formula II with at least one solvent selected from methyl tert-butyl ether and wo-propanol to give a compound of formula II in crystal form;
(b) washing the compound of formula II in crystal form from step (a) with at least one solvent selected from methyl tert-butyl ether and wo-propanol to give the compound of formula II in substantially pure form; and
(c) recycling the washed solvent collected from step (b) to crystallize a crude compound of formula II in the next batch as recited in step (a).
DETAILED DESCRIPTION OF THE INVENTION
ABBREVIATIONS
HPLC: High Pressure Liquid Chromatography
MTBAC: methyl-77-tributhyl ammonium chloride MTBE: methyl tert-butyl ether
IPA: /sopropyl alcohol
NBS: N-bromosuccinimide
DEFINITIONS [0008] The term "alkyl" or "alk" refers to a straight or branched chain alkane
(hydrocarbon) radical containing from 1 to 12 carbon atoms, preferably 1 to 6 carbon atoms. Exemplary "alkyl" groups include methyl, ethyl, propyl, isopropyl, n-butyl, t- butyl, isobutyl pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4- trimethylpentyl, nonyl, decyl, undecyl, dodecyl, and the like. The term "C1-C6 alkyl" refers to a straight or branched chain alkane (hydrocarbon) radical containing from 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, isopentyl, hexyl, and isohexyl.
[0009] The term "phase transfer catalyst" refers to a small quantity of a chemical agent that enhances the rate of a reaction between chemical species located in different phases (immiscible liquids or solid and liquid) by extracting one of the reactants, most commonly an anion, across the interface into the other phase so that reaction can proceed. These catalysts include quaternary ammonium or phosphonium salts (e.g. fetraalkylammonium salts, wherein alkyl can be same or different), or agents that complex inorganic cations (e.g. crown ethers or other cryptands). The catalyst cation is not consumed in the reaction although an anion exchange does occur. [0010] The compounds of present invention may form salts which are also within the scope of this invention. Reference to compounds of the formula I through V herein is understood to include reference to salts thereof, unless otherwise indicated. The term "salt(s)", as employed herein, denotes acidic and/or basic salts formed with inorganic and/or organic acids and bases. In addition, when a compound contains both a basic moiety, such as but not limited to a pyridine or imidazole, and an acidic moiety such as but not limited to a carboxylic acid, zwitterions ("inner salts") may be formed and are included within the term "salt(s)" as used herein. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful, e.g., in isolation or purification steps which may be employed during preparation. Salts of the compounds may be formed, for example, by reacting those compounds with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization. [0011] The compounds of present invention may form salts with a variety of organic and inorganic acids. Exemplary acid addition salts include acetates (such as those formed with acetic acid or trihaloacetic acid, for example, trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides, hydroiodides, hydroxyethanesulfonates (e.g., 2- hydroxyethanesulfonates), lactates, maleates, methanesulfonates, naphthalenesulfonates (e.g., 2-naphthalenesulfonates), nicotinates, nitrates, oxalates, pectinates, persulfates, phenylpropionates (e.g., 3-phenylpropionates), phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates (such as those formed with sulfuric acid), sulfonates, tartrates, thiocyanates, toluenesulfonates such as tosylates, undecanoates, and the like. [0012] The compounds of present invention may also form salts with a variety of organic and inorganic bases. Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as benzathines, dicyclohexylamines, hydrabamines (formed with N,N- bis(dehydroabietyl) ethylenediamine), N-methyl-D-glucamines, N-methyl-D- glycamides, t-butyl amines, and salts with amino acids such as arginine, lysine and the like. Basic nitrogen-containing groups may be quaternized with agents such as lower alkyl halides (e.g. methyl, ethyl, propyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g. dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g. decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides), aralkyl halides (e.g. benzyl and phenethyl bromides), and others. [0013] Prodrugs and solvates of the compounds of the invention are also contemplated herein. The term "prodrug" as employed herein denotes a compound that, upon administration to a subject, undergoes chemical conversion by metabolic or chemical processes to yield compounds of the formula I through V, or a salt and/or solvate thereof. Solvates of the compounds of formula I through V include, for example, hydrates. [0014] Compounds of the formula I through V, and salts thereof, may exist in their tautomeric form (for example, as an amide or imino ether). All such tautomeric forms are contemplated herein as part of the present invention. [0015] All stereoisomers of the present compounds (for example, those which may exist due to asymmetric carbons on various substituents), including enantiomeric forms and diastereomeric forms, are contemplated within the scope of this invention. Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers (e.g., as a pure or substantially pure optical isomer having a specified activity), or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. The chiral centers of the present invention may have the S or R configuration as defined by the IUPAC 1974 Recommendations. The racemic forms can be resolved by physical methods, such as, for example, fractional crystallization, separation or crystallization of diastereomeric derivatives or separation by chiral column chromatography. The individual optical isomers can be obtained from the racemates by any suitable method, including without limitation, conventional methods, such as, for example, salt formation with an optically active acid followed by crystallization.
[0016] All configurational isomers of the compounds of the present invention are contemplated, either in admixture or in pure or substantially pure form. The definition of compounds of the present invention embraces both cis (Z) and trans (E) alkene isomers, as well as cis and trans isomers of cyclic hydrocarbon or heterocyclic rings.
[0017] Throughout the specifications, groups and substituents thereof may be chosen to provide stable moieties and compounds.
METHODS OF PREPARATION
[0018] The methods for preparing compounds of formula I and II are illustrated in the following schemes. Solvents, temperatures, pressures, and other reaction conditions may readily be selected by one of ordinary skill in the art. Starting materials are commercially available or readily prepared by one of ordinary skill in the art.
[0019] The compound of formula I (irbesartan) can be prepared according to
Scheme 1. Compound 1 can be brominated to give a mixture of mono-brominated product FVa and di-brominated product IVb using a brominating reagent, such as Br2 or NBS, in an organic solvent, such as CCl4, CHCl3 or CH2Cl2, and optionally in the presence of UV light or a catalytic amount of benzoyl peroxide. A tri-brominated product JVC may also be generated if a larger excess of bromine is used. Br2 can be generated in situ by reacting NaBrO3 or H2O2 with HBr in water. The mixture of compounds IVa and IVb, and optionally IVc, can be mono-alkylated upon treatment of compound V or a pharmaceutically acceptable salt thereof, in the presence of a base, such as NaH, and in the presence of a reducing reagent, such as dialkyl phosphite (i.e., diethyl phosphite) to provide the compound of formula H When an aqueous base such as aq. KOH or aq. NaOH is used, a phase transfer catalyst such as tetra-alkylammonium chloride is also used in addition to the reducing reagent such as dialkyl phosphite (i.e., diethyl phosphite). Here, the reducing regent selectively reduces di-brominated compound IVb (or tri-brominated compound IVc) into mono- brominated compound IVa while compound IVa is alkylated to provide the desired mono-alkylation product. This method can be applied to a mixture of compounds IVa, IVb in any ratio, i.e., the ratio between IVa : IVb can vary from 1% : 99% to 99% : 1%. In addition, this method also works in the presence of any amount of compound rVc. Finally, compound II can be reacted with an azide reagent, such as NaN3, to give the compound of formula I.
Scheme 1
Bromination
Figure imgf000008_0002
Figure imgf000008_0001
IVa IVb optionally IVc
Simultaneous reduction and mono-alkylation
Figure imgf000008_0003
Figure imgf000008_0004
I [0020] The features and advantages of the present invention are more fully shown by the following examples which are provided for purposes of illustration, and are not to be construed as limiting the invention in anyway.
EXAMPLES HPLC condition:
Column: Alltima Cl 8 (Alltech 88050) 15.0cm in length x 4.6mm in internal diameter and 5 micron particle size; Column temperature: 40 C;
Solvent A: Buffer solution A l.lg of heptanesulfonic acid in 1 liter of water and adjust the pH to 2.5;
Solvent B: Methanol Flow rate: 1.2mL/min; Gradient Elution Condition: Time% A % %B
0 min 50 50
35 min 15 85
Detector: 240 nm;
Injection volume: 10 uL.
[0021] The above HPLC condition is used in the following examples unless otherwise noted.
Example 1 Preparation of Compounds of formula IVa and IVb:
Figure imgf000009_0001
1 IVa IVb about 80-90% about 10-20%
[0022] A jacketed 1 ,000 mL 3-neck flask was charged with 4'-methylbiphenyl-2- carbonitrile (Compound 1, 100.0 g) and CH2CI2 (500 mL) under nitrogen. To a 500 mL Erlenmeyer flask with magnetic stirrer, sodium bromate (NaBrO3; 31.2 g) was dissolved in water (170 mL). The NaBrO3 solution was transferred to the 1 ,000 mL flask and the reaction mixture was cooled to about 5 0C or less. Aqueous HBr solution (48 %, 105.0 g) was added to the 1,000 mL flask and the resulting reaction mixture was recycled though a UV lamp reactor. The reaction mixture was kept at 0- 20 0C and the recycling was continued until the reaction was deemed complete by HPLC. Optionally, additional sodium bromate and hydrogen bromide may be added. The relative amounts of Compound 2 and Compound 3 were about 80-90% and about 10-20% respectively. Aqueous sodium metabisulfite solution (2.0 g of in 10 mL water) was added to the reaction mixture. Allow the phases to settle and the methylene chloride phase was washed with water and used in the next step without further purification. Example 2 Preparation of Compound II:
Figure imgf000010_0001
[0023] A IL 3-neck flask was charged with Compound V (134.0 g), MTBAC (5.0 g) and CH2Cl2 (170 mL) and cool to -5 to 5 0C. An aqueous solution of KOH (182.6 g in 212 mL water) was added slowly to the IL flask and the reaction temperature was kept at < 5 0C. The methylene chloride solution of Compound FVa and Compound IVb from Example 1 was added to the reaction mixture slowly, while maintaining the temperature at 0-100C. Diethyl phosphite (39.66g) was added drop wise at 0-10 0C. Check the reaction mixture for completion of the reduction reaction, and additional diethyl phosphite may be added.
[0024] The reaction mixture was allowed to warm to ambient (20-30 0C) and agitated until the reaction was deemed complete by HPLC. Water (150 mL) was added and the phases were separated. The organic layer was extracted with water (230 mL) and polish filtered.
[0025] The methylene chloride (which contained the crude Compound II) was distilled off and exchanged with about 400 mL of methyl fert-butyl ether (MTBE) (optionally, the MTBE recycled from washing below can be used here). Upon cooling, crystallization occurred (optionally seeds were added) and after further cooling to below 250C, crystals of Compound II were isolated, washed with MTBE and dried in vacuum at a temperature of less than 600C. HPLC retention time: 18.126 min. Typically, the yield was about 85 to about 88%. Alternatively, IPA could be used as the crystallization and washing solvent. [0026] Optionally, the solvent (i.e., MTBE or IPA) used to wash the crystals of Compound II above can be recycled and used to crystallize the crude Compound II in the next batch. Since the washed solvent contains Compound II as well as impurities, it was surprisingly found that the washed solvent can be recovered and used again in crystallizing the crude compound of formula II in the next batch without sacrificing its purity while increasing its yield. Example 3
Preparation of Compound I:
Figure imgf000011_0001
π [0027] A reactor was charged with Compound II (1 kg), triethylamine chlorhydrate (0.713 kg), sodium azide (0.337 kg) andN-methyl pyrrolidinone (2.07 kg), and the reaction mixture was heated to about 122°C under stirring. After completion of the reaction as determined by HPLC, the reaction mixture was cooled to about 45°C, and an aqueous solution of sodium hydroxide (35%, 5.99 kg) and water (3.0 kg) were added, the resulting mixture was stirred at a temperature between about 20 and about 40°C for about 0.5 hours. The aqueous phase was discarded and the organic phase was treated with toluene (1.73 kg) and water (5.0 kg), and stirred for about 0.5 hours at about 20 - about 30°C. The toluene phase was discarded and the aqueous phase was washed with ethyl acetate (1.8 kg) and treated with aqueous HCl until pH was adjusted to about 4.8 - about 5.2. Precipitation occurred and the resulting suspension was stirred for about 1 hour at about 20 — about 25°C. The precipitation was collected and washed with water three times (1.0 kg x 3). The crude wet product was recrystallized using a mixture of zsO-propanol (0.393 kg) and water (4.5 kg). HPLC retention time: 11.725 min. The yield for Compound I was about 87%.

Claims

WE CLAIM:
1. A method for preparing a compound of formula II, or a pharmaceutically acceptable salt thereof,
Figure imgf000012_0001
comprising reacting a mixture of a compound of formula IVa and a compound of formula IVb, and optionally a compound of formula FVc,
Figure imgf000012_0002
with a compound of formula V, or a pharmaceutically acceptable salt thereof,
Figure imgf000012_0003
in the presence of a base and a reducing agent, and optionally in the presence of a phase transfer catalyst; and further optionally, converting the compound of formula II into a pharmaceutically acceptable salt.
2. The method of claim 1, wherein said reducing agent is dialkly phosphite.
3. The method of claim 1, wherein said pharmaceutically acceptable salt of formula V is HCl.
4. The method of claim 1, in which at least one aqueous base is used in the presence of said phase transfer catalyst.
5. The method of claim 4, wherein said aqueous base is aqueous KOH, aqueous NaOH, or aqueous LiOH, said phase transfer catalyst is tetra- alkylammonium chloride, said reducing agent is dialkly phosphite, and said pharmaceutically acceptable salt of formula V is HCl.
6. The method of claim 5, wherein said tetrø-all<ylammonium chloride is methyl-trz-H-butyl ammonium chloride, and said dialkly phosphite is diethyl phosphite.
7. The method of claim 1 , wherein the compound of formula II is crystallized from at least one solvent selected from methyl tert-butyl ether and iso- propanol.
8. The method of claim 5, wherein the compound of formula II is crystallized from at least one solvent selected from methyl tert-butyl ether and iso- propanol.
9. The method of claim 7, further comprising washing the compound of formula II with at least one solvent selected from methyl tert-butyl ether and iso- propanol, and recycling the washed solvent to crystallize the compound of formula II as recited in claim 7.
10 The method of claim 8, further comprising washing the compound of formula II with at least one solvent selected from methyl tert-butyl ether and iso- propanol, and recycling the washed solvent to crystallize the compound of formula II as recited in claim 8.
11. The method of claim 1 , further comprising converting the compound of formula II to a compound of formula I, or a pharmaceutically acceptable salt thereof,
Figure imgf000014_0001
12. The method of claim 11 , wherein said reducing agent is diakyl phosphite.
13. The method of claim 11, wherein said pharmaceutically acceptable salt offormula V is HCl.
14. The method of claim 11, in which at least one aqueous base is used in the presence of said phase transfer catalyst.
15. The method of claim 14, wherein said aqueous base is aqueous KOH, aqueous NaOH, or aqueous LiOH, said phase transfer catalyst is tetra- alkylammonium chloride, said reducing agent is dialkly phosphite, and said pharmaceutically acceptable salt of formula V is HCl.
16. The method of claim 15, wherein said fetrø-alkylammonium chloride is Hiethyl-fr7-7i-butyl ammonium chloride, and said dialkly phosphite is diethyl phosphite.
17. The method of claim 11, wherein the conversion is achieved by reacting the compound of formula II with sodium azide.
18. The method of claim 17, wherein said reducing agent is diakyl phosphite.
19. The method of claim 17 wherein said pharmaceutically acceptable salt offormula V is HCl.
20. The method of claim 17, in which at least one aqueous base is used in the presence of said phase transfer catalyst.
21. The method of claim 20, wherein said aqueous base is aqueous KOH, aqueous NaOH, or aqueous LiOH, said phase transfer catalyst is tefra- alkylammonium chloride, said reducing agent is dialkly phosphite, and said pharmaceutically acceptable salt of formula V is HCl.
22. The method of claim 21, wherein said teή-α-alkylammonium chloride is methyl-trz-π-butyl ammonium chloride, and said dialkly phosphite is diethyl phosphite.
23. A method for preparing a compound of formula II in substantially pure form,
Figure imgf000015_0001
comprising:
(a) crystallizing a crude compound of formula II with at least one solvent selected from methyl tert-bviy\ ether and /so-propanol to give a compound of formula II in crystal form; (b) washing the compound of formula II in crystal form from step (a) with at least one solvent selected from methyl tert-butyl ether and zso-propanol to give the compound of formula II in substantially pure form; and
(c) recycling the washed solvent collected from step (b) to crystallize a crude compound of formula II in the next batch as recited in step (a).
24. The method of claim 23, wherein said solvent in steps (a), (b) and (c) is methyl tert-butyl ether.
25. The method of claim 23, wherein said solvent in steps (a), (b) and (c) is iyø-propanol.
PCT/US2005/029879 2004-08-23 2005-08-23 A method for preparing irbesartan and intermediates thereof WO2006023889A2 (en)

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MX2007002030A MX2007002030A (en) 2004-08-23 2005-08-23 A method for preparing irbesartan and intermediates thereof.
CA002578409A CA2578409A1 (en) 2004-08-23 2005-08-23 A method for preparing irbesartan and intermediates thereof
CN2005800286578A CN101006064B (en) 2004-08-23 2005-08-23 Method for preparing irbesartan and intermediates thereof
AU2005277162A AU2005277162B2 (en) 2004-08-23 2005-08-23 A method for preparing irbesartan and intermediates thereof
EP05791492A EP1781627B1 (en) 2004-08-23 2005-08-23 A method for preparing irbesartan and intermediates thereof
KR1020077004208A KR101252309B1 (en) 2004-08-23 2005-08-23 A method for preparing irbesartan and intermediates thereof
DE602005024819T DE602005024819D1 (en) 2004-08-23 2005-08-23 METHOD FOR PRODUCING IRBESARTAN AND INTERMEDIATE PRODUCTS THEREOF
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IL181464A IL181464A (en) 2004-08-23 2007-02-20 Method for preparing irbesartan and intermediates thereof
NO20071254A NO20071254L (en) 2004-08-23 2007-03-07 Process for the preparation of irbesartan and its intermediates.
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