WO2008096372A2

WO2008096372A2 - Process for preparing highly pure ezetimibe using novel intermediates

Info

Publication number: WO2008096372A2
Application number: PCT/IN2008/000072
Authority: WO
Inventors: Chidambaram Venkateswaran Srinivasan; Rahul Saxena; Pranav Gupta; Lalit Wadhwa
Original assignee: Ind-Swift Laboratories Limited
Priority date: 2007-02-06
Filing date: 2008-02-06
Publication date: 2008-08-14
Also published as: WO2008096372A3

Abstract

The present invention relates to an industrially advantageous process for the preparation of ezetimibe of formula (I) in high yields by using novel benzyl ester intermediates. The present invention further provides a process for the purification of ezetimibe of formula (I).

Description

PROCESS FOR PREPARING HIGHLY PURE EZETIMIBE USING NOVEL INTERMEDIATES

FIELD OF INVENTION

The present invention provides an industrially advantageous process for the preparation of ezetimibe of formula I, using novel intermediates.

Formula-I

The present invention further relates to a purification process for preparing enantiomerically and chemically pure ezetimibe which is substantially free of impurities.

BACKGROUND OF THE INVENTION

Ezetimibe of Formula-I is indicated as monotherapy for the treatment of primary hypercholesterolemia and homozygous sitosterolemia and is chemically known as l-(4- fluorophenyl)-3-(R)-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4(S)-(4-hydroxyphenyl)-2- azetidinone.

Formula-I

Ezetimibe was first disclosed in US Patent 5,767,115 (RE 37,721) as a useful hypocholesterolemic agent in the treatment and prevention of artherosclerosis. The process comprises reacting (S)-4-phenyl-2-oxazolidinone with methyl-4-(chloroformyl) butyrate to obtain an ester of formula,

which is further condensed with 4-benzyloxybenzylidine-(4-fluoro)aniline in the presence of titanium isopropoxide and titanium tetrachloride to give an amide compound of formula,

which is further cyclized in the presence of tetrabutylammonium fluoride and bistrimethylsilyl acetamide to yield a protected lactam of formula,

The protected lactam so obtained is hydrolysed to give the corresponding carboxylic acid, which is further reacted with oxalyl chloride to give following compound of formula,

that is further reacted with p-fluorophenyl magnesium bromide and zinc chloride in the presence of tetrakis ( triphenyl phosphine) palladium to give an aromatic ketone of formula,

which is further reduced selectively in the presence of chiral catalyst to obtain a hydroxy compound, that is debenzylated to yield ezetimibe of formula-I.

The aforementioned patent fails to mention the yield and purity of ezetimibe so obtained. However, in our hands, we have found that the above process yields ezetimibe in very low yields and purity. It has been observed that most of the intermediates of the above process results in the formation of gummy material and are purified using chromatographic technique, which is cumbersome and difficult to utilize on an industrial scale.

PCT application WO 2006/137080 discloses a process for the preparation of ezetimibe, wherein the coupling reaction between acid chloride and p-fluorophenyl zinc chloride is carried out in the presence of palladium acetate.

In the prior art processes as described above during coupling reaction between acid chloride and p-fluorophenyl zinc chloride (prepared from p-fluorophenyl magnesium bromide and zinc chloride), the catalyst used is tetrakis(triphenylphosphine) palladium, which is quite irritant and is a highly expensive palladium catalyst. The reaction results in the formation of additional byproducts which lead to low overall yield and low purity that fails to comply with the pharmaceutical standards. In addition, the use of zinc chloride in the same step makes the reaction difficult to handle as zinc chloride is hygroscopic, corrosive and deliquescent. Further zinc chloride has to be used in equimolar quantities which results in lots of bye products and are difficult to remove. The sample of zinc chloride has to be protected from moisture and always freshly fused before use.

The above mentioned drawbacks call for an alternative and novel process for the preparation of ezetimibe that should be cost effective, eco-friendly, commercially viable, reproducible on industrial scale and meet the needs of regulatory agencies.

Like any synthetic compound, ezetimibe can contain extraneous compounds or impurities. These impurities may be, for example, starting materials, by-products of the reaction, products of side reactions, or degradation products. Impurities in ezetimibe, or any active pharmaceutical ingredient ("API"), are undesirable and, in extreme cases, might even be harmful to a patient being treated with a dosage form containing the API. At certain stages during processing of an

API, such as ezetimibe, it must be analyzed for purity, typically, by high performance liquid chromatography ("HPLC") or thin-layer chromatography ("TLC"), to determine if it is suitable for continued processing and, ultimately, for use in a pharmaceutical product.

The FDA requires that an API is as free of impurities as possible, so that it is as safe as possible for clinical use. For example, the FDA recommends that the amounts of some impurities be limited to less than 0.1 percent. In its ICH Q7A guidance for API manufacturers, the FDA specifies the quality of raw materials that may be used, as well as acceptable process conditions, such as temperature, pressure, time, and stoichiometric ratios, including purification steps, such as crystallization, distillation, and liquid-liquid extraction.

Prior art processes disclose several processes for the preparation of pure ezetimibe using crystallization with solvents like methanol, methyl tertiary-butyl ether, isopropyl alcohol, etc.

But it was found by the present inventors that certain identified and unidentified impurities does not go away with the purification techniques reported in prior art.

There is a long-felt need for the industrially applicable and consistently reproducible process to prepare highly pure ezetimibe having acceptable levels of certain impurities, which complies with the requirements of pharmacopoeias.

The present invention is thus directed to an industrially advantageous process for the preparation of ezetimibe which improves the economics by employing less expensive and less hazardous raw materials and is more productive. Further the present invention provides a process for the purification of ezetimibe to provide ezetimibe having improved chemical and/or enantiomeric purity.

SUMMARY OF THE INVENTION

The present invention provides a novel and alternative process for the preparation of l-(4- fluorophenyl)-3(R)-[3-(4-fluorophenyl)-3(S)-hydroxyρropyl]-4(S)-(4-hydroxyphenyl)-2- azetidinone herein referred to as ezetimibe of formula I,

Formula-I

comprising: a) reacting pentanedioic acid monobenzyl ester of formula II,

? ? Formula-II

with pivaloyl chloride in the presence of base like triethylamine and subsequent reaction with chiral auxiliary like (S)-(+)-4-phenyl-2-oxazolidinone to form 5-oxo-5-(2-oxo-4-phenyl- oxazolidin-3-yl)-pentanoic acid benzyl ester of formula III,

Formula-Ill

b) condensing 5-oxo-5-(2-oxo-4-phenyl-oxazolidin-3-yl)-pentanoic acid benzyl ester of formula III with (4-benzyloxy-benzylidine)-4-fiuoro-phenyl)-amine of formula IV,

Formula-IV

in the presence of lewis acid like titanium tetrachloride along with titanium isopropoxide in a suitable organic solvent to form 4-[(4-benzyloxy-phenyl)-(4-fluoro-phenylamino)-methyl]-5- oxo-5-(2-oxo-4-phenyl-oxazolidin-3-yl)pentanoic acid benzyl ester of formula V,

Formula-V

c) cyclizing 4-[(4-benzyloxy-phenyl)-(4-fluoro-phenylamino)-methyl]-5-oxo-5-(2-oxo-4- phenyl-oxazolidin-3-yl)pentanoic acid benzyl ester of formula V with a fluoride anion source and a silylating agent and in a suitable solvent to form 3-[2-(4-benzyloxy-phenyl)-l- (4-fluorophenyl)-4-oxo-azetidin-3-yl] -propionic acid benzyl ester of formula VI,

Formula-VI

d) hydro lyzing 3-[2-(4~benzyloxy-ρhenyl)- 1 -(4-fluorophenyl)-4-oxo-azetidin-3-yl]-propionic acid benzyl ester of formula VI with a base in a suitable solvent to form 3-[2-(4-benzyloxy- phenyl)-l-(4-fluorophenyl)-4-oxo-azetidin-3-yl]-propionic acid of formula VII,

Formula- VII

e) reacting 3-[2-(4-benzyloxy-phenyl)-l-(4-fluorophenyl)-4-oxo-azetidin-3-yl]-propionic acid of formula VII with oxalyl chloride in a suitable solvent, optionally with catalytic amount of ΛζN-dimethylformamide to form 3-[2-(4-benzyloxy-phenyl)-l-(4-fluorophenyl)-4-oxo- azetidin-3-ylJ-propionyl chloride of formula VIII,

Formula-VHI

f) reacting 3-[2-(4-benzyloxy-phenyl)-l -(4-fluorophenyl)-4-oxo-azetidin-3-yl]-propionyl chloride of formula VIII with 4-fluorophenyl magnesium bromide in the presence of iron catalyst in a suitable solvent to form 4-(4-benzyloxy-phenyl)-l-(4-fluoro-phenyl)-3-[3[(4- fluoro-phenyl)-3-oxo-propyl]-azetidin-2-one of formula IX, and

FormuIa-IX

g) converting the compound of formula IX to ezetimibe of formula I.

Another aspect of the present invention provides novel intermediates and processes useful for the preparation of ezetimibe.

In another embodiment, the present invention provides a process for the purification of ezetimibe, comprising a) dissolving ezetimibe in a suitable solvent specifically tertiary butanol, b) admixing an anti-solvent specifically water with cooling to obtain a precipitate, c) filtering the product, d) optionally repeating the steps a-c, and subsequently e) isolating the highly pure ezetimibe therefrom. Another embodiment of the present invention provides a process for purification of ezetimibe, comprising a) providing a solution of ezetimibe in a suitable solvent specifically aqueous tertiary butanol at reflux, b) cooling thexeaction mass to obtain a precipitate, c) filtering the product, d) optionally repeating the steps a-c, and subsequently e) isolating the highly pure ezetimibe therefrom.

One another embodiment of this invention is directed to an isolated 'bis impurity' of following formula:

wherein R is selected from H or benzyl

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides novel intermediates and novel process for the preparation of l-(4- fluorophenyl)-3(R)-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4(S)-(4-hydroxyphenyl)-2- azetidinone (Ezetimibe) of formula I,

Formula-I

One aspect of the present invention provides a process for the preparation of ezetimibe comprising condensing pentanedϊoic acid monobenzyl ester of formula II, Formula-II

with (S)-(+)-4-phenyl-2-oxazolidinone to form 5-oxo-5-(2-oxo-4-phenyl-oxazolidin-3-yl)- pentanoic acid benzyl ester of formula III,

Formula-Ill

a novel and key intermediate for the preparation of ezetimibe and further forms a part of the present invention. The starting materials can be procured from the market or can be prepared according to the process of the present invention disclosed further in this invention or by methods disclosed in any of the known processes.

More particularly, an inert organic solvent selected from halogenated solvents preferably dichloromethane, is added to the pentanedioic acid monobenzyl ester of formula II and the reaction mass is allowed to cool to a temperature of about 10-20⁰C. To the reaction mass a suitable base or acid trapping agent is added and the reaction mass is stirred for a period of about 5-20 minutes under inert atmosphere. Suitable base can be selected from tertiary amine such as diisopropyl ethylamine, tributylaniine, triethylamine. Preferably triethylamine is used. To the reaction mass, pivaloyl chloride is added slowly while maintaining the reaction temperature between 10-35⁰C. The reaction mass is further stirred for a period of about few minutes to few hours. Preferably the reaction mass is stirred for 60 minutes at ambient temperature. A chiral auxiliary particularly (S)-(+)-4-phenyl-2-oxazolidinone, a suitable base, and N₁N- dimethylformamide are added to the reaction mass. Suitable base can be selected from, but not limited to 4-dimethylaminopyridine, n-butyl lithium and the like. Preferably 4- dimethylaminopyridine is used. The reaction mass is further heated to a temperature of about 45- 65⁰C and is then maintained at this temperature for a period of about 4-7 hours. The reaction mass is then allowed to cool to a temperature of about 10-25⁰C. To the reaction mass, sulfuric acid solution is added while stirring the reaction mass for a period of about 10-30 minutes. The organic layer is separated and the solvent is distilled off fully under vacuum. To the reaction mass, alcoholic solvent is added followed by stirring at ambient temperature for 15 minutes. The reaction mixture may be slowly cooled, filtered, washed with alcoholic solvent and dried at 40⁰C under vacuum to obtain 5-oxo-5-(2-oxo-4-phenyl-oxazolidin-3-yl)-pentanoic acid benzyl ester of formula III in high yield and having purity greater than 98% by high performance liquid chromatography.

Another aspect of the present invention is to provide a process for the preparation of pentanedioic acid monobenzyl ester of formula II as given above. Typically, pentanedioic acid monobenzyl ester can be prepared from glutaric acid. More particularly, glutaric acid along with benzyl alcohol, p-toluene sulfonic acid and suitable solvent are added together and the reaction mass is heated to a reflux temperature. Suitable solvent can be selected from aromatic hydrocarbons, halogenated solvents. Preferably toluene is used. The reaction is further checked for completion by thin layer chromatography (TLC) or high performance liquid chromatography (HPLC) for the absence of benzyl alcohol. After completion of reaction, the reaction mass is cooled to ambient temperature, followed by the addition of demineralized water. The reaction mass is further stirred for a few minutes. The organic layer is separated and the solvent is distilled off completely under vacuum to get pentanedioic acid monobenzyl ester of formula II as oil.

According to another aspect of the present invention, novel and key intermediate, 5-oxo-5-(2- oxo-4-phenyl-oxazolidin-3-yl)-pentanoic acid benzyl ester of formula III can directly be prepared in one pot from glutaric acid without the isolation of pentanedioic acid mpnobenzyl ester of formula II.

According to yet another aspect of the present invention, 5-oxo-5-(2-oxo-4-phenyl-oxazolidin-3- yl)-pentanoic acid benzyl ester of formula III is condensed with (4-benzyloxy-benzylidine)-4- fluoro-phenyl)-amine, herein referred to as benzylated schiff base of formula IV as given above to form 4-[(4-benzyloxy-phenyl)-(4-fluoro-phenylamino)-methyl]-5-oxo-5-(2-oxo-4-phenyl- oxazolidine-3-yl)pentanoic acid benzyl ester of formula V, yet another novel and key intermediate for the preparation of ezetimibe and further forms a part of the present invention. According to the detailed aspect of the present invention, 5-oxo-5-(2-oxo-4-phenyl-oxazolidin-3- yl)-pentanoic acid benzyl ester of formula III in a suitable anhydrous solvent is added slowly to the precooled solution of Lewis acid preferably titanium tetrachloride and titanium isopropoxide in the same solvent at a temperature of below O⁰C. Suitable solvent can be selected from dichloromethane, chloroform, carbon tetrachloride etc. The reaction mass is stirred at same temperature for few minutes. Diisopropylethylamine is added slowly to the reaction mass with continuous stirring for about an hour at same temperature. The reaction mass is then further cooled to a temperature of below -2O⁰C and benzylated Schiff base is added to it. The reaction is maintained at -15⁰C to -20⁰C for 6 hours. After 6 hours the reaction mass is further cooled to a temperature of below -2O⁰C and then a solution of acetic acid and halogenated solvent is added slowly to the reaction mass. The reaction mass is then poured into aqueous tartaric acid solution precooled to a temperature of below 5⁰C. The temperature of reaction mass is then raised to 25°C and then maintained for few minutes. 20% aqueous sodium bisulfite solution is added and then the reaction mass is stirred at ambient temperature for few minutes. The organic layer is separated and the solvent is removed by distillation at atmospheric pressure. Ethyl acetate is added to the reaction mass and the reaction mass is heated to reflux temperature to get a clear solution. The reaction mass is cooled to 60⁰C and followed by the slow addition of hexane. The reaction mass is cooled to 0-5⁰C and the solid is filtered, washed with hexane and finally dried under vacuum at 50-55⁰C to get 4-[(4-benzyloxy-phenyl)-(4-fluoro-phenylamino)-methyl]-5- oxo-5-(2-oxo-4-phenyl-oxazolidine-3-yl)pentanoic acid benzyl ester of formula V having purity greater than 99% by high performance liquid chromatography. Benzylated schiff base can be procured from the market or can be prepared according to the process of the present invention disclosed further in this invention or by methods disclosed in any of the known processes.

According to yet another aspect of the present invention, 4-[(4-benzyloxy-phenyl)-(4-fluoro- phenylamino)-methyl]-5-oxo-5-(2-oxo-4-phenyl-oxazolidine-3-yl)pentanoic acid benzyl ester of formula V can be cyclized to 3-[2-(4-benzyloxy-phenyl)-l-(4-fluorophenyl)-4-oxo-azetidin-3- yl]-propionic acid benzyl ester of formula VI as given above, yet another novel and key intermediate for the preparation of ezetimibe and further forms a part of the present invention. According to the detailed aspect of the present invention, 4-[(4-benzyloxy-phenyl)-(4-fluoro- phenylamino)-methyl]-5-oxo-5-(2-oxo-4-phenyl-oxazolidine-3-yl)pentanoic acid benzyl ester of formula V in a suitable solvent is stirred for few minutes at ambient temperature. Suitable solvent can be selected from ethers, aromatic hydrocarbons, nitriles, halogenated solvents. Preferably the solvent can be selected from amongst methyl tertiarybutyl ether, toluene, acetonitrile. Mild silylating agent preferably N,O-bis(trimethyl silyl)acetamide is added to the reaction mass with continuous stirring for few minutes. To the reaction mass, fluoride ion catalyst is added and the temperature of reaction mass is raised to 4O⁰C. The fluoride ion catalyst can be selected from tetrabutylammonium fluoride, cesium fluoride and potassium fluoride. Preferably tetrabutylammonium fluoride trihydrate is used in the present invention. The reaction completion can be checked by thin layer chromatography or high performance liquid chromatography for the presence of starting material to be not more than 2%. After reaction completion the reaction mass is cooled to ambient temperature and hydrochloric acid solution is added with further stirring for few minutes. The organic layer is separated and the solvent is removed under yacuum. Alcoholic solvent preferably ethanol is added to the reaction mass and is heated to reflux temperature to get a clear solution. The reaction mass is then cooled to ambient temperature slowly and stirred for 2-4 hours. The reaction mass is then preferably cooled to 0⁰C and stirred at a temperature of below 5°C for few hours. The solid is filtered, washed with chilled alcoholic solvent and dried under vacuum at 50-55⁰C to 3-[2-(4-benzyloxy-phenyl)-l-(4- fluorophenyl)-4-oxo-azetidin-3-yl] -propionic acid benzyl ester of formula VI in high yield and having purity greater than 98% by high performance liquid chromatography. According to yet another aspect of the present invention, 3-[2-(4-benzyloxy-phenyl)-l-(4- fluorophenyl)-4-oxo-azetidin-3-yl] -propionic acid benzyl ester of formula VI can be hydrolysed to 3-[2-(4-benzyloxy-phenyl)-l-(4-fluorophenyl)-4-oxo-azetidin-3-yl]-propionic acid of formula VII as given above, a known and key intermediate in the preparation of ezetimibe using mild reaction conditions. More particularly, a suitable base is added to a solution of 3-[2-(4-benzyloxy-phenyl)-l-(4- fluorophenyl)-4-oxo-azetidin-3-yl]-ρropionic acid benzyl ester of formula VI in a suitable solvent at ambient temperature with continuous stirring. Suitable base is selected from alkali metal hydroxides, alkali metal carbonates/ bicarbonates. Preferably lithium hydroxide is used. Solvent can be selected from tetrahydrofuran, methanol, ethanol, isopropyl alcohol, acetone and methyl isobutyl ketone. The reaction completion can be checked by thin layer chromatography or high performance liquid chromatography for the absence of starting material. After reaction completion, demineralized water and ethyl acetate are added and the reaction mass is stirred for few minutes. The aqueous layer is separated, hydrochloric acid solution is added (pH— 5-6), then the product is extracted in ethyl acetate, layers are separated and the solvent from organic layer is removed by distillation under vacuum at 50-55⁰C. The product is dissolved in ethyl acetate by the addition of hexane and then the reaction mass is heated to get a clear solution and then crystallized. The reaction mass is slowly cooled to 25-3O⁰C, stirred for few hours, filtered and washed with hexane and dried under vacuum at 50-55⁰C to get 3-[2-(4-benzyloxy-phenyl)-l-(4- fluorophenyl)-4-oxo-azetidin-3-yl]-propionic acid of formula VII in high yield and having purity greater than 96% by high performance liquid chromatography (HPLC). 3-[2-(4-benzyloxy- phenyl)-l-(4-fluorophenyl)-4-oxo-azetidin-3-yl]-propionic acid of formula VII can be converted to ezetimibe by the processes known in prior art or according to the process of the present invention.

Specifically, ezetimibe is prepared by reacting 3-[2-(4-benzyloxy-phenyl)-l-(4-fluorophenyl)-4- oxo-azetidin-3-yl] -propionic acid of formula VII or its reactive derivative with Grignard reagent in the presence of iron catalyst in suitable solvent and the resulting compound is converted to ezetimibe by performing hydrogenation and debenzylation or vice versa.

3-[2-(4-Benzyloxy-phenyl)-l-(4-fluorophenyl)-4-oxo-azetidin-3-yl]-propionic acid of formula VII is converted to 3-[2-(4-benzyloxy-phenyl)-l-(4-fluorophenyl)-4-oxo-azetidin-3-yl]- propionyl chloride of formula VIII by reacting it with oxalyl chloride in a suitable solvent at a temperature of below 20⁰C under inert atmosphere. Suitable solvent can be selected from halogenated solvent, aromatic hydrocarbons. Preferably halogenated solvent can be selected from dichloromethane, chloroform, carbon tetrachloride. More preferably dichloromethane is used. The reaction can optionally be conducted in the presence of catalytic amount of N,N- dimethylformamide. The reaction mass is stirred at ambient temperature till completion of the reaction, which is monitored by HPLC. The solvent is then distilled off fully under vacuum at 50-70⁰C to obtain 3-[2-(4-benzyloxy-phenyl)-l-(4-fluorophenyl)-4-oxo-azetidin3-yl]-propionyl chloride of formula VIII. Yet another aspect of the present invention provides a process for the conversion of acid cnloriSe"' of formula VIII to. 4-(4-benzyloxy-phenyl)-l-(4-fluoro-phenyl)-3-[3[(4-fluoro-phenyl)-3-oxo- propyl]-azetidin-2-one of formula IX as shown above, yet another key intermediate for the preparation of ezetimibe, using non stringent reaction conditions and inexpensive reagents. To the above formed acid chloride of formula VIII, suitable organic solvent is added and the reaction mass is cooled to -78°C under inert atmosphere. Suitable organic solvent can be selected from, but not limited to tetrahydrofuran, toluene, xylene, ethyl acetate and mixtures thereof. To the reaction mass, catalytic amount of appropriate catalyst is added and the reaction mass is further stirred at a temperature of -95 to -7O⁰C for few minutes. Catalyst can be selected from iron catalysts such as iron acetyl acetonate, iron chloride and the like. A freshly prepared Grignard solution is added slowly at same temperature and the reaction mass is stirred further for few minutes to few hours. Grignard solution can be prepared by using magnesium turnings, 4- bromofluoro benzene and tetrahydrofuran, optionally with catalytic amount of iodine. The reaction completion can be checked by thin layer chromatography (TLC) or high performance liquid chromatography (HPLC) for the presence of starting material to be not more than 1%. Quenching with dilute acid like IN hydrochloric acid or ice cold demineralized water followed by extraction with suitable organic solvent like methyl tertiarybutyl ether yields 4-(4-benzyloxy- phenyl)-l-(4-fluoro-phenyl)-3-[3[(4-fluoro-phenyl)-3-oxo-propyl]-azetidin-2-one of formula IX in high yield and having purity greater than 82% by HPLC.

4-(4-Benzyloxy-phenyl)-l-(4-fluoro-phenyl)-3-[3[(4-fluoro-phenyl)-3-oxo-propyl]-azetidin-2- one of formula IX can further be converted to ezetimibe by the methods well known in art by main two processes. In one aspect, it is reduced to 4-(4-benzyloxy-phenyl)-l-(4-fluoro-phenyl)- 3-[3[(4-fluoro-phenyl)-3-hydoxy-propyl]-azetidin-2-one of formula X and then debenzylated to form ezetimibe. According to another aspect, 4-(4-berizyloxy-phenyl)-l-(4-fluoro-phenyl)-3- [3[(4-fluoro-phenyl)-3-oxo-propyl]-azetidin-2-one is debenzylated to form 4-(4-hydroxy- phenyl)-l-(4-fluoro-phenyl)-3-[3[(4-fluoro-phenyl)-3-oxo-propyl]-azetidin-2-one and further reduced to form ezetimibe.

In one aspect, 4-(4-benzyloxy-phenyl)-l-(4-fluoro-phenyl)-3-[3[(4-fiuoro-phenyl)-3-oxo- propyl]-azetidin-2-one of formula EX is reduced to 4-(4-benzyloxy-phenyl)-l-(4-fluoro-phenyl)- 3-[3[(4-fluoro-phenyl)-3-hydoxy-propyl]-azetidin-2-one of formula X and then debenzylated to form ezetimibe. Typically, compound of formula IX in a suitable anhydrous organic solvent is added slowly to a mixture of suitable reducing agent and a suitable chiral promoter/catalyst in catalytic or stoichiometric amount at a temperature of below 5⁰C under inert atmosphere. Suitable anhydrous organic solvent can be selected from dichloromethane, tetrahydrofuran, toluene, xylene and the like. Reducing agent can be selected from borane dimethyl sulfide complex, sodium borohydride, a substituted borohydride eg.[ cbz-Proline]₃BHNa and the like, while the chiral promoter/catalyst can be selected from (i?)-2-methyl-CBS-oxazaborolidine, R- butyl CBS, i?-phenyl CBS. The reaction completion can be checked by thin layer chromatography or high performance liquid chromatography for the presence of starting material to be not more than 0.5%. Addition of dilute acid like IiV hydrochloric acid followed by extraction with suitable organic solvent like methanol yields 4-(4-benzyloxy-phenyl)-l-(4- fluoro-phenyl)-3-[3[(4-fluoro-phenyl)-3-hydoxy-propyl]-azetidin-2-one of formula X residue. The residue is further dissolved in acetonitrile and washed with hexane to eliminate difluorobiphenyl impurity. Finally the acetonitrile layer is collected and the solvent is removed under vacuum to get the required compound in high yields and purity greater than 84% by HPLC.

Compound of formula X can further be debenzylated to ezetimibe of formula I using conventional techniques known in the art or by the method described herein. Compound of formula X is dissolved in suitable alcoholic solvent like C₁-C₄ alcohols and a hydrogenation catalyst is added. Hydrogenation catalyst can be selected from Palladium carbon. More preferably 10% by weight palladium on carbon is used. Reactions that use a palladium reagent to affect the conversion of a compound of formula X to ezetimibe should be conducted in the presence of an additional compound capable of acting as a reductant, such as hydrogen. The mixture is then exposed to hydrogen gas under a pressure of 5.00-5.50 kg/cm at a temperature of about 25-45°C till the reaction goes to completion to yield crude ezetimibe. In another aspect, 4-(4-benzyloxy-phenyl)-l-(4-fluoro-phenyl)-3-[3[(4-fluoro-phenyl)-3-oxo- propyl]-azetidin-2-one of formula IX can be hydrolyzed to 4-(4-hydroxy-phenyl)-l-(4-fiuoro- phenyl)-3-[3[(4-fluoro-phenyl)-3-oxo-propyl]-azetidin-2-one of following formula,

using conventional techniques known in the art or by the method described herein for reference. Typically, 4-(4-benzyloxy-phenyl)-l-(4-fluoro-phenyl)-3-[3[(4-fluoro-phenyl)-3-oxo-propyl]- azetidin-2-one is dissolved in a suitable solvent like ester such as ethyl acetate, alcoholic solvent such as C₁-C₄ alcohol; the like and mixtures thereof. This is followed by the addition of a suitable catalyst. Catalyst can be selected from platinum group metals, particularly platinum, palladium, rhodium and ruthenium are highly active catalysts. Non-precious metal catalysts, especially those based on nickel such as Raney nickel and "Urushibara nickel can also be employed. More preferably 10% by weight palladium supported on carbon is used. Reaction is conducted preferably in the presence of an additional compound, such as hydrogen. The reaction mixture is exposed to hydrogen gas under a pressure of 4.00-5.50 kg/cm² at a temperature of about 25-45°C till the reaction goes to completion. The catalyst is filtered through hyflo bed and product is extracted after work up with organic solvent like toluene. The product is found to contain 4,4'-difluoro-biphenyl as impurity which can be removed by treating the product with a suitable solvent like n-heptane at a temperature of 70-100⁰C and then cooling to 10-25⁰C. The impurity is isolated preferably by decantation. This process can be repeated several times, preferably till the thin layer chromatography (TLC) shows the absence of biphenyl impurity. The product can further optionally be purified of the undesired impurities by dissolving the product in suitable solvent like chloroform and passing it through a column packed with silica gel in chloroform. The column is then washed with chloroform. The eluted chloroform is distilled out at 50-55⁰C to obtain pure 4-(4-hydroxy-phenyl)-l-(4-fluoro-phenyl)-3-[3[(4-fluoro- phenyl)-3-oxo-propyl]-azetidin-2-one.

4-(4-Hydroxy-phenyl)-l-(4-fiuoro-phenyl)-3-[3[(4-fluoro-phenyl)-3-oxo-propyl]-azetidin-2-one so obtained, is further reduced to ezetimibe of formula I using suitable reducing agent and a suitable chiral promoter/catalyst. Typically, 4-(4-hydroxy-phenyl)-l-(4-fluoro-phenyl)-3-[3[(4- fluoro-phenyl)-3-oxo-propyl]-azetidin-2-one in a suitable organic solvent is added slowly to a mixture of suitable reducing agent and a suitable chiral promoter/catalyst in catalytic or stochiometric amount at a temperature of below 5⁰C under inert atmosphere. Suitable anhydrous organic solvent can be selected from dichloromethane, tetrahydrofuran, toluene, xylene and the like. Reducing agent can be selected from borane dimethylsulfide complex, sodium borohydride, a substituted borohydride eg.[ cbz-Proline]₃BHNa and the like, while the chiral promoter/catalyst can be selected from (i?)-2-methyl-CBS-oxazaborolidine, (i?)-butyl CBS, (2?)-phenyl CBS. The reaction completion can be checked by thin layer chromatography or high performance liquid chromatography for the presence of starting material to be not more than 1.0%, preferably not more than 0.5%. Addition of hydrogen peroxide to affect the decomposition of borane complex followed by extraction with suitable organic solvent like dichloromethane gives crude ezetimibe. It is advantageous to remove the traces of borane complex from the final compound by taking the compound in methanol and distilling off the solvent under vacuum at a temperature of about 50-60⁰C. The process can be repeated with same solvent followed by treatment with toluene to remove the traces of methanol, if any to obtain crude ezetimibe

One another embodiment of the present invention relates to a process for the synthesis of highly pure exetimibe by crystallizing crude ezetimibe so obtained by the processes of the present invention. As used herein, the term 'crude ezetimibe' refers to ezetimibe containing more than about 1.0 percent area by HPLC of the 'bis impurity' and 'keto impurity' along with certain other known impurities; and more than about 1.0 percent area by HPLC of the '(3R) isomer impurity.'

As used herein, the term "chemically pure ezetimibe" refers to ezetimibe, containing less than about 0.15 percent area by HPLC of the 'bis impurity', 'keto impurity' and other unidentified impurities. Preferably, the level of these impurities is less than about 0.10 percent area by HPLC, and, most preferably, less than about 0.07 percent area by HPLC. A chemically pure ezetimibe in accordance with the invention may be substantially free of these impurities, such that the level of

'bis impurity' and 'keto impurity' is below the detection limit.

As used herein, the term "enantiomerically pure ezetimibe" refers to ezetimibe, containing less than about 0.15 percent area by HPLC of the '(3R) isomer impurity'. Preferably, the level of the

'(3R) isomer impurity' is less than about 0.10 percent area by HPLC.

The chemical purity of ezetimibe in the present invention relates to the level of two impurities in the final product. These impurities include:

1. The impurity of following formula, referred to herein as 'bis impurity'

wherein R is selected from H or benzyl

2. l-(4-Fluoro-phenyl)-3-[3-(4-fluoro-phenyl)-3-oxo-propyl]-4-(4-hydroxy-phenyl)-azetidin-2- one, referred herein as 'keto impurity' of following formula

The bis impurity forms the inventive part of the present invention and contaminates ezetimibe of formula I.

Specific illustrations of the bis impurity includes:

3-[3,3-bis-(4-fluoro-phenyl)-3-hydroxy-propyl]-l-(4-fluoro-phenyl)-4-(4-hydroxy-phenyl)- azetidin-2-one;

3-[3,3-bis-(4-fluoro-phenyl)-3-hydroxy-propyl]-l-(4-fluoro-phenyl)-4-(4-benzyloxy-phenyl)- azetidin-2-one.

'Bis impurity' is typically obtained during the synthesis of 4-(4-benzyloxy-phenyl)-l-(4-fluoro- ρhenyl)-3-[3[(4-fluoro-phenyl)-3-oxo-propyl]-azetidin-2-one and is exceptionally difficult to remove from both the said intermediate and the crude ezetimibe obtained therefrom. 'Keto impurity' is an intermediate, which may remain unreacted during the reduction step with borane dimethyl sulfide complex and get carry forward to final product as an impurity.

The enantiomeric purity in the present invention relates to the level of the (3R,4S)-l-(4-fluoro- phenyl)-3-[(3R)-3-(4-fluoro-phenyl)-3-hydroxy-propyl]-4-(4-hydroxy-phenyl)-azetidin-2-one, referred herein as '(3R) isomer impurity' of following formula .

'(3R) Isomer impurity' has been found to be present in substantial amounts i.e. about 5-10%, in crude ezetimibe which is difficult to remove using the prior art processes. This impurity may be generated due to non-selective reduction of 4-(4-hydroxy-phenyl)-l-(4-fluoro-phenyl)-3-[3[(4- fluoro-phenyl)-3 -oxo-propyl] -azetidin-2-one.

The progress of the purification process and the presence or absence of impurities can be monitored using HPLC analysis.

One embodiment of the present invention provides a process for the purification of crude ezetimibe comprising heating a mixture of crude ezetimibe and an alcoholic solvent, specifically tertiary-butanol to a temperature of between about 70°C and above up to the reflux temperature of the solvent, and cooling the solution to a temperature of about 40°C to about 60°C. The process further includes combining the solution with an anti solvent that is a poor solvent for ezetimibe and which when mixed with a solution of ezetimibe, causes it to precipitate. Preferably the anti solvent is water. The reaction mass is further cooled to 0-5⁰C and maintained for a time sufficient to precipitate ezetimibe in high purity. The precipitated product can be isolated by the methods well known in the art like filtration, decantation, centrifugation and the like. Typically, this product is isolated by filtration.

It has been observed that although purification can be performed using other alcoholic solvents like isopropyl alcohol, methanol, ethanol, n-butanol and the like. However surprising results were obtained using tertiary butanol. Specific illustrations of the reduction of level of impurities using purification process with tertiary butanol can be had by the Example section that follows. Another embodiment of the present invention provides a process for the purification of ezetimibe by providing a solution of crude ezetimibe in a suitable solvent specifically aqueous tertiary butanol at reflux. This is followed by cooling the reaction mass initially to room temperature and finally at 0 to 5°C to induce precipitation and isolation of ezetimibe from the reaction mixture. Generally, the product can be isolated by any standard method known in the art such as by filtration, centrifugation or decantation. Typically, this product is isolated by filtration. Preferably, the ezetimibe obtained after the crystallization is chemically and enantiomerically purer than the crude ezetimibe used as the starting material. To exemplify, the obtained ezetimibe contains a lower level of the 'keto' and 'bis' impurity and a lower level of the '(3R) isomer impurity'. The crystallization process may be repeated in order to increase the purification even further either with the same or a different solvent that was used for the first crystallization.

Major advantages realized in the present invention are:

1. Use of novel intermediates which are easy to prepare and have only minimal residual impurities and are prepared in high yields.

2. No need of tedious column chromatography technique for purification

3. Lesser reaction time and easily scalable process to prepare highly pure ezetimibe.

4. Coupling reaction is carried out in the presence of cheap iron catalyst without using highly hygroscopic zinc chloride derivative, toxic and expensive tetrakis(triphenyl phosphonium) palladium, palladium acetate as reported in prior art.

5. Use of lesser quantity of (i?)-2-methyl-CBS oxazaborolidin as compared to that reported in US 5,631,365, resulting in reduced cost of the product.

In the following section, particular illustrative embodiments are described by way of examples to illustrate the process of invention. However, these do not limit the scope of the present invention.

EXAMPLES

Example 1: Preparation of pentanedioic acid monobenzyl ester

Glutaric acid (200 g) was taken along with benzyl alcohol (160 g), p-toluene sulfonic acid (30 g) and toluene (1.0 L). The reaction mass was heated to reflux temperature and water (^ 26 ml) was collected by azeotropic distillation. Reaction completion was checked by TLC/HPLC for absence of benzyl alcohol. After reaction completion, the reaction mass was cooled to ambient temperature and demineralized water (1.0 L) was added and the reaction mass was stirred for 15 minutes. The organic layer was separated and washed with demineralized water (1.0 L).The organic layer was dried over sodium sulfate. Solvent was distilled off fully under vacuum to get the title compound as oil.

Example 2: Preparation of 5-oxo-5-(2-oxo-4-phenyl-oxazolidin-3-yl)-pentanoic acid benzyl ester

Dichloromethane (1.70 L) was added to the oil obtained above and the reaction mass was cooled to 15°C. Triethylamine (428 ml) was added and the reaction mass was stirred for 5 minutes under nitrogen atmosphere. Pivaloyl chloride (220 ml) was added slowly while maintaining the reaction temperature between 15-2O⁰C. After addition, the reaction mass was stirred for 60 minutes at 25-30⁰C. (S)-(+)-4-Phenyl-2-oxazolidinone (172 g), 4-dimethylaminopyridine (30 g) and N,N-Dimethylformamide (184 ml) were added and the reaction mass was heated to 50-55⁰C and then maintained at this temperature for 5 hours. After 5 hours the reaction mass was cooled to 2O⁰C, 2Ν sulfuric acid solution (800 ml) was added and the reaction mass was stirred for 15 minutes. Organic layer was separated and washed with 5% aqueous sodium bisulfite solution (1.0 L) and then with brine (1.0 L). The organic layer was dried over sodium sulfate. Solvent was distilled off fully under vacuum. Ethanol (1.0 L) was added and the reaction mass was stirred at ambient temperature for 15 minutes and then a pinch of title compound was added. The reaction mass was stirred for 120 minutes at ambient temperature and then cooled to 0-5⁰C and then maintained at 0-5⁰C for 2 hours. The solid was filtered and washed with chilled ethanol (200 ml). Finally the solid was dried at 4O⁰C under vacuum to get 220 g of the title compound having purity of 98.16% by HPLC.

Example 3: Preparation of Benzylated Schiff Base p-Hydroxy benzaldehyde (100 g) was taken along with demineralized water (1.0 L), sodium hydroxide (34.40 g) and stirred at ambient temperature for 5 minutes. Dichloromethane (750 ml) and tetrabutylammonium bromide (26.40 g) were added and stirred for 10 minutes. Benzyl bromide (107 ml) was added and then the reaction mass was stirred at 25-3O⁰C for 90 minutes. The two layers were separated. Aqueous layer was extracted with dichloromethane (200 ml) and the extraction was added to the main organic layer. The combined organic layer was washed with 10% aqueous sodium hydroxide solution (2x500 ml), demineralized water (500 ml) and finally with 10% brine (1.0 L). Solvent was distilled out completely at atmospheric pressure. Isopropyl alcohol (1.20 L) was added and the reaction mass was heated to 60⁰C to get a clear solution. 4-Fluoroaniline (156 g) was added dropwise and then the reaction mass was maintained at 60⁰C for 2 hours. After 2 hours the reaction mass was cooled to ambient temperature and stirred for 30 minutes. The solid was filtered and washed with isopropyl alcohol (100 ml) and then with hexane (100 ml). Finally the solid was dried under vacuum at 50-60⁰C to get 230 g of benzylated Schiff base having purity of 95.97% by HPLC.

Example 4: Preparation of 44(4-benzyloxy-phenyl)-(4-fluoro-phenylaniino)-methyri-5-oxo- 5-(2-oxo-4-phenyl-oxazolidin-3-yl)pentanoic acid benzyl ester

Dichloromethane (1.532 L) was cooled to O⁰C under nitrogen atmosphere. Titanium tetrachloride (37.53 ml) and Titanium isopropoxide (32.40 ml) were added and the reaction mass was stirred at 0 to -5°C for 15 minutes. A solution of 5-oxo-5-(2-oxo-4-phenyl-oxazolidin-3-yl)-pentanoic acid benzyl ester (125 g) in methylene chloride (375 ml) was added slowly at 0 to -5°C. The reaction mass was stirred at 0 to -5°C for 30 minutes. Diisopropylethylamine (166.8 ml) was added dropwise at O to -5⁰C and then the reaction mass was stirred at 0 to -5⁰C for 60 minutes. The reaction mass was cooled to -25°C and benzylated schiff base (115 g) was added. The reaction mass was maintained at -15 to -2O⁰C for 6 hours. After 6 hours the reaction mass was cooled to -3O⁰C and then a solution of acetic acid (100 ml) and dichloromethane (100 ml) was added slowly at -30 to -25⁰C. The reaction mass was poured into 7% aqueous tartaric acid solution (1.75 L) precooled to 0⁰C. The temperature of reaction mass was raised to 25°C and then maintained for 30 minutes. 20% aqueous sodium bisulfite solution (625.50 ml) was added and then the reaction mass was stirred at 25-3O⁰C for 30 minutes. The two layers were separated. Aqueous layer was extracted with dichloromethane (250 ml) and added to the main organic layer. The combined organic layer was washed with demineralized water (2x800 ml). Solvent was removed by distillation at atmospheric pressure and finally degassed under^-vacuum. Ethyl acetate (375 ml) was added and the reaction mass was heated to reflux temperature to get a clear solution. The reaction mass was cooled to 6O⁰C and then hexane (750 ml) was added slowly. The reaction mass was cooled to ambient temperature and maintained for 2 hours. The reaction mass was cooled to 0-5⁰C and maintained at this temperature for 2 hours. The solid was filtered and washed with hexane (250 ml). Finally the solid was dried under vacuum at 50-55⁰C to get 186 g of the title compound having purity of 99.48 % by HPLC.

Example 5; Preparation of 3-f2-(4-benzyloxy-phenyl)-l-(4-fluorophenyl)-4-oxo-azetidin-3- yll -propionic acid benzyl ester

4-[(4-Benzyloxy-phenyl)-(4-fluoro-phenylamino)-methyl]-5-oxo-5-(2-oxo-4-phenyl- oxazolidine-3-yl)pentanoic acid benzyl ester (186 g) was taken in methyl tertiarybutyl ether (1.86 L) and stirred for 5 minutes at ambient temperature. N,0-bis(trimethyl silyl)acetamide (223 ml) was added and the reaction mass was stirred for 5 minutes. Tetrabutylammonium fluoride trihydrate (3.72 g) was added and the temperature of reaction mass was raised to 40⁰C. Reaction mass was maintained at 38-42°C and reaction completion was checked by HPLC. Thereafter the reaction mass was cooled to ambient temperature and IN hydrochloric acid solution (1.86 L) was added. The reaction mass was stirred for 15 minutes. The two layers were separated. Organic layer was washed with 10% aqueous sodium bicarbonate solution (1.86 L) and 25% brine (1.86 L) respectively. The organic layer was dried over sodium sulfate. Silica gel (55.8 g) and activated carbon (37.20 g) were added and the reaction mass was stirred at ambient temperature for 30 minutes. The reaction mass was filtered through hyflo and the hyflo bed was washed with methyl tertiarybutyl ether (186 ml). Solvent was distilled off fully under vacuum. Ethanol (1.116 L) was added and the reaction mass was heated to reflux temperature to get a clear solution. The reaction mass was cooled to ambient temperature slowly and stirred at ambient temperature for 2 hours. Then the reaction mass was cooled to 0⁰C and stirred at 0-5⁰C for 2 hours. The solid was filtered and washed with chilled ethanol (186 ml). Finally the solid was dried under vacuum at 50-55⁰C to get 102 g of the title compound having purity of 98.26% by HPLC. Example 6; Preparation of 342-(4-benzyloxy-phenylVl-(4-fluorophenylV4-oxo-azetidin-3- yU-propionic acid

3-[2-(4-Benzyloxy-phenyl)-l-(4-fluorophenyl)-4-oxo-azetidin-3-yl]-propionic acid benzyl ester (100 g) was taken in tetrahydrofuran (800 ml) at ambient temperature. A solution of lithium hydroxide (5.20 g) in demineralized water (350 ml) was added and the reaction mass was stirred at ambient temperature till reaction completion (monitored by HPLC). After reaction completion demineralized water (1.0 L) and ethyl acetate (500 ml) were added and stirred for 15 minutes. The two layers were separated. Organic layer was extracted with demineralized water (300 ml) and the aqueous layers were combined. IN hydrochloric acid solution (200 ml) and ethyl acetate (800 ml) were added to the combined aqueous layer and stirred for 15 minutes. The two layers were separated. Organic layer was washed with demineralized water (LO ₁ L). Solvent was removed by distillation under vacuum at 50-55⁰C. Ethyl acetate (lOOml) was added and then the reaction mass was heated to get a clear solution. Hexane (500ml) was added slowly and then the reaction mass was slowly cool to 25-30⁰C and maintained for 10 hours. The solid was filtered and washed with hexane (100 ml). The solid was dried under vacuum at 50-55⁰C to get 80 g of the title compound having purity of 96.87% by HPLC.

Example 7: Preparation of 4-(4-benzyloxy-phenyl)-l-(4-fluoro-phenyl)-3-f3[(4-fluoro- phenvD-3-oxo-propyl1-azetidin-2-one Method A:

3-[2-(4-Benzyloxy-phenyl)-l-(4-fluorophenyl)-4-oxo-azetidin-3-yl]-propionic acid (25 g) was dissolved in dichloromethane (150 ml) and then cooled to 1O⁰C under nitrogen. Oxalyl chloride (10 ml) was added dropwise at 10-15⁰C and then the reaction mass was stirred at ambient temperature till reaction completion. Solvent was distilled off fully under vacuum at 5O⁰C to obtain 3-[2-(4-benzyloxy-phenyl)-l-(4-fluorophenyl)-4-oxo-azetidin-3-yl]-propionyl chloride. Tetrahydrofuran (150 ml) was added to the same and the reaction mass was cooled to -78°C under nitrogen. Iron acetyl acetonate (0.84 g) was added and the reaction mass was further stirred at -78 to -85°C for 5 minutes. A freshly prepared Grignard solution (prepared by using 2.86 g magnesium turnings, 20.82 g 4-bromofluoro benzene and 100 ml tetrahydrofuran) was added dropwise at -78 to -85°C and after complete addition the reaction mass was stirred at -78 to -85⁰C for 60 minutes. Reaction completion was checked by TLC/HPLC. The reaction mass was poured into a solution of IN hydrochloric acid (30 ml) and ice cold demineralized water (200 ml). pH was adjusted to 5-6 using IN hydrochloric acid (^ 20 ml). Methyl tertiarybutyl ether (200 ml) was added and the reaction was stirred at ambient temperature for 15 minutes. Two layers were separated. The aqueous layer was extracted with methyl tertiarybutyl ether (100 ml) and the extraction was added to the main organic layer. The combined organic layer was washed with 0.5 N hydrochloric acid solution (2x100 ml), 1% aqueous sodium hydroxide solution (2x100 ml), 25% brine (2x100 ml) respectively. The organic layer was dried over sodium sulfate. Solvent was distilled off fully under vacuum at 50-55⁰C to get 26g of 4-(4- benzyloxy-phenyl)-l-(4-fluoro-phenyl)-3-[3[(4-fluoro-phenyl)-3-oxo-propyl]-azetidin-2-one having purity 82.39% by HPLC. Method B:

3-[2-(4-Benzyloxy-phenyl)-l-(4-fluorophenyl)-4-oxo-azetidin-3-yl]-propionic acid (10Og) was dissolved in dichloromethane (500 ml) and N,7V-dimethylformamide (2 ml) under nitrogen and then cooled to 1O⁰C. Oxalyl chloride (40 ml) was added slowly at 10-15⁰C and then the reaction mass was stirred at ambient temperature till reaction completion. Solvent was then distilled off fully to get 3-[2-(4-benzyloxy-phenyl)-l-(4-fluorophenyl)-4-oxo-azetidin-3-yl]-propionyl chloride. Tetrahydrofuran (600 ml) was added to the same and the reaction mass was cooled to - 78⁰C under nitrogen. Iron acetyl acetonate (3.75 g) was added and the reaction mass was further stirred at -90 to -78⁰C for 2 minutes. A freshly prepared Grignard solution (prepared by using 15.76 g of magnesium turnings, 114.9g of l-bromo-4-fluoro benzene, a pinch of iodine and 400 ml of tetrahydrofuran) was added dropwise at -90 to -80⁰C. After complete addition, the reaction mass was stirred at same temperature till reaction completion (monitored by HPLC). The reaction mass was poured into cold demineralized water (750 ml). Methyl tertiary butyl ether (400 ml) was added and the reaction mixture was stirred at ambient temperature for 15 minutes. The product was filtered through hyflo bed. The hyflo bed was washed with methyl tertiary-butyl ether (400ml). Organic layer was separated from the filtrate and then washed with brine. The organic layer was dried over sodium sulfate. Solvent was distilled off fully under vacuum at 50- 55⁰C to obtain 4-(4-benzyloxy-phenyl)-l-(4-fluoro-phenyl)-3-[3[(4-fluoro-phenyl)-3-oxo- propyl]-azetidin-2-one. Example 8: Preparation of ezetimibe Method A

Step-1: Preparation of 4-(4-benzyloxy-phenylVl-(4-fluoro-phenyl)-3-[3[(4-flttoro-phenvI)-3- hydoxy-propyH-azetidin-2-one

Dichloromethane (100 ml) and borane dimethylsulfide complex (5.04 ml) were added under nitrogen. The reaction mass was cooled to 0⁰C. (R)-2-methyl-CBS-oxazaborolidine (3.04 ml, IM in toluene) was added and then the reaction mass was stirred for 30 minutes at O⁰C under nitrogen. A solution of 4-(4-benzyloxy-phenyl)-l-(4-fluoro-phenyl)-3-[3[(4-fluoro-phenyl)-3- oxo-propyl]-azetidin-2-one (obtained in Example 7, Method A) in dichloromethane (100 ml) was added slowly at O⁰C. After addition, the reaction mass was maintained at 0°C till reaction completion by HPLC. Methanol (25 ml) was added slowly and stirred for 15 minutes. IN hydrochloric acid (250 ml) was added and the reaction mass was stirred for 30 minutes at ambient temperature. The reaction mass was filtered through hyflo and the hyflo bed was washed with dichloromethane (100 ml). The two layers were separated from the filtrate. The organic layer was washed with 25% brine (2x100 ml). The organic layer was dried over sodium sulfate and then the solvent was removed fully at atmospheric pressure. Methanol was added twice (2x100 ml) and then distilled off under vacuum each time at 50-55⁰C. The resulting residue was dissolved in acetonitrile (100 ml) and thereafter the acetonitrile layer was washed several times with hexane to eliminate difluorobiphenyl impurity. Finally the acetonitrile layer was collected and acetonitrile was removed under vacuum at 50-55⁰C to get the title compound having purity 84.78% by HPLC. Step-2; Preparation of Ezetimibe

4-(4-Benzyloxy-phenyl)- 1 -(4-fluoro-phenyl)-3 - [3 [(4-fluoro-phenyl)-3 -hydoxy-propyl] -azetidin- 2-one formed above was dissolved in ethanol (260 ml) and 10% palladium carbon (2.60 g) was added. Hydrogen pressure (5.00-5.50 Kg/cm ) was applied at 30-35⁰C. Reaction conditions were maintained till completion of reaction (monitored by HPLC). The reaction mass was filtered through hyflo and the hyflo bed was washed with ethanol (50 ml). Activated carbon (5.0 g) was added and the reaction mass was heated to reflux and maintained for 30 minutes. After 30 minutes refluxing, the reaction mass was filtered through hyflo and the hyflo bed was washed with hot ethanol (50 ml). Solvent was distilled off fully under vacuum at 50-55⁰C and then degassed to get solid. The solid was dissolved in ethanol (68 ml) and then slowly demineralized water (85 ml) was added at ambient temperature. The reaction mass was stirred for 2 hours and then filtered and washed with a mixture of ethanol and demineralized water (5 ml + 20 ml respectively). Finally the solid was dried at 50-60⁰C under vacuum to get 17.50 g of the title compound. Method B

Step-1: Preparation of l-(4-fluoro-phenyl)-3-f3-(fluoro-phenyl)-3-oxo-propyll-4-(4- hydroxy-phenyl)-azetidin-2-one l-(4-Benzyloxy-phenyl)-l-(4-fluoro-phenyl)-3-[3-(fluoro-phenyl)-3-oxo-propyl]-azetidin-2-one (obtained in Example 7, Method B) was dissolved in ethyl acetate (600 ml). Methanol (600 ml) and palladium-carbon (6.0 g) was added. Hydrogen gas pressure (4.0 to 4.5 kg/cm²) was applied and maintained till reaction completion. Thereafter the reaction mass was filtered through hyflo bed to recover palladium carbon, which was washed with toluene (600 ml). To the filtrate, 25% brine (1.0 L) and IN hydrochloric acid solution (500 ml) was added and stirred for 5 minutes. The layers were separated and the aqueous layer was extracted with toluene (400 ml). The organic layers were combined and washed twice with 25% brine (2x1.0 L). The organic layer was dried over sodium sulfate (50 g). The solvent was distilled off fully under vacuum, n- Heptane (250 ml) was added and the reaction was heated to 9O⁰C and then cooled to 2O⁰C. n- Heptane was decanted. This process was repeated several times; finally the traces of solvent were removed under vacuum at 6O⁰C. The residue was dissolved in chloroform (150 ml) and passed through a column packed with silica gel (150 g) in chloroform (500 ml). The column was washed using 2.5 L chloroform. The eluted chloroform was distilled at 50-55⁰C to obtain l-(4- fluoro-phenyl)-3-[3-(fluoro-phenyl)-3-oxo-propyl]-4-(4-hydroxy-phenyl)-azetidin-2-one.

Step-2: Preparation of ezetimibe

Borane dimethylsulfide complex (20.49 ml) and IM solution of R-2-methyl-CBS- oxazaborolidine (10.78 ml) were added to a cooled solution of dichloromethane (616 ml) and tetrahydrofuran (88 ml) under nitrogen and the reaction mass was stirred at 0⁰C for 15 minutes. A solution of l-(4-fluoro-phenyl)-3-[3-(fluoro-phenyl)-3-oxo-propyl]-4-(4-hydroxy-phenyl)- azetidin-2-one obtained above in dichloromethane (264 ml) was added to the reaction mass at 0⁰C and the reaction mass was maintained at 0 to 5°C till reaction completion (monitored by HPLC). 5% Hydrogen peroxide solution (440 ml) was added slowly at 0-20⁰C and then the reaction mass was stirred at room temperature for 30 minutes. The layers were separated and the aqueous layer was extracted with dichloromethane (88 ml). The combined organic layer was washed with IN hydrochloric acid solution (440 ml) and 25% brine (1.0 L) respectively. The solvent was distilled off fully under vacuum at 50-60⁰C. Methanol (88 ml) was added to the residue and then distilled off fully under vacuum 50-60⁰C. This process was repeated several times. Toluene (166 ml) was added and distilled off fully under vacuum at 50-60⁰C. This process was repeated several times. Slowly the reaction mass was cooled to room temperature, stirred for 2 hours. The reaction mass was filtered, washed with toluene (88 ml) and suck dried for 60 minutes under vacuum. The product was taken in toluene (450 ml) and heated to 90⁰C for 30 minutes. The reaction mass was slowly cooled to room temperature, stirred for 2 hours. The solid was filtered and washed with toluene (50 ml). The solid was dried under vacuum at 60- 7O⁰C to give crude ezetimibe. Relative purity 98.15% by HPLC (0.23% of 'keto impurity' and 0.48% of 'bis impurity') and '(3R) isomer impurity' by Chiral HPLC is 7.17%. Example 9; Purification of crude ezetimibe

(i) Crude ezetimibe (47 g) obtained above, was added to tertiary-butanol (188 ml) and heated to 80-85⁰C for 15 minutes. This was followed by slow addition of demineralized water (47 ml). The reaction mass was cooled to ambient temperature and stirred for 4 hours at same temperature. The reaction mass was then cooled to 0-5⁰C and stirred for further 4 hours. The solid, thus obtianed was filtered, washed with a mixture of tertiary-butanol and demineralized water (45 ml, 4:1) and then dried at 60-65⁰C to get 36 g of ezetimibe. Relative purity: 99.28% by HPLC (0.10% of 'keto impurity' and 0.17% of 'bis impurity') and '(3R) isomer impurity' by Chiral HPLC: 2.58%

(ii) Ezetimibe (36 g) obtained above .was added to tertiary-butanol (144 ml) and heated to 80- 85⁰C to get a clear solution. This was followed by slow addition of demineralized water (36 ml). The reaction mass was cooled to ambient temperature and stirred for 4 hours at ambient temperature. The reaction mass was further cooled to 0-5⁰C and stirred for 4 hours. The solid was filtered and washed with a mixture of tertiary-butanol and demineralized water (35 ml, 4:1). The solid was dried at 6O-65°C to get 30 g of ezetimibe. Relative purity: 99.61% by HPLC (0.06% of 'keto impurity' and 0.09% of 'bis impurity') and '(3R) isomer impurity' by Chiral HPLC: 1.17%.

(iii) Ezetimibe (30 g) obtained above was added to tertiary-butanol (120 ml) and heated to 80- 85⁰C to get a clear solution. This was followed by slow addition of demineralized water (30 ml). The reaction mass was cooled to ambient temperature and stirred for 4 hours at ambient temperature The reaction mass was further cooled to 0-5⁰C and stirred for 4 hours. The solid was filtered, washed with a mixture of t-butanol and demineralized water (30 ml, 4:1). The solid was dried at 60-65⁰C to get 25 g of highly pure ezetimibe. Relative purity: 99.84% by HPLC ('keto impurity' and 'bis impurity' are not detectable) and '(3R) isomer impurity' by Chiral HPLC: 0.14%.

Example 10; Purification of crude ezetimibe

(i) Crude ezetimibe (50 g, relative purity: 98.32% (0.23 % of 'keto impurity' and 0.43% of 'bis impurity') and'(3R) isomer impurity' by Chiral HPLC: 7.09%) was added to tertiary-butanol (200 ml) and heated to 80-85⁰C for 15 minutes. This was followed by slow addition of demineralized water (50 ml). The reaction mass was cooled to ambient temperature and stirred for 4 hours at ambient temperature. The reaction mass was further cooled to 0-5⁰C and stirred for 4 hours. The solid was filtered, washed with a mixture of tertiary-butanol and demineralized water (50 ml,4:l) and then dried at 60-65⁰C to get 35 g of ezetimibe. Relative purity: 99.20% by HPLC (0.12% of 'keto impurity' and 0.18% of 'bis impurity') and '(3R) isomer impurity' by Chiral HPLC: 2.91%

(ii) Ezetimibe (35 g) obtained above was added to tertiary-butanol (140 ml) and heated to 80- 85⁰C to get a clear solution. This was followed by slow addition of demineralized water (35 ml). The reaction mass was cooled to ambient temperature and stirred for 4 hours at ambient temperature. The reaction mass was further cooled to 0-5⁰C and stirred for 4 hours. The solid was filtered and washed with a mixture of tertiary-butanol and demineralized water (35 ml, 4:1). The solid was dried at 60-65⁰C to get 31 g of ezetimibe. Relative purity: 99.60% by HPLC (0.05 % of 'keto impurity' and 0.07% of 'bis impurity') and '(3R) isomer impurity' by Chiral HPLC: 1.17%

(iii) Ezetimibe (31 g) obtained above was added to tertiary-butanol (124 ml) and heated to 80- 85⁰C to get a clear solution and to this demineralized water (31 ml) was added. The reaction mass was cooled to ambient temperature and stirred for 4 hours at ambient temperature The reaction mass was further cooled to 0-5⁰C and stirred for 4 hours. The solid was filtered, washed with a mixture of tertiary-butanol and demineralized water (30 ml). The solid was dried at 60- 65⁰C to get 26 g of highly pure ezetimibe. Relative purity: 99.81% by HPLC ('keto impurity' and 'bis impurity' are not detectable) and '(3R) isomer impurity' by Chiral HPLC: 0.12%. Example 11: Purification of crude ezetimibe

Crude ezetimibe (10 g, relative purity: 98.48% by HPLC (0.20% of 'keto impurity' and 0.39% of 'bis impurity') and '(3R) isomer impurity' by Chiral HPLC: 7.03% ) was charged in 20% aqueous tertiary-butanol (50 ml) and heated to 80-85⁰C for 15 minutes to get a solution. Thereafter, the reaction mass was allowed to cool to room temperature and maintained under stirring for 4 hours. The reaction mass was further cooled to 0-5⁰C and stirred for 4 hours. The solid was filtered, washed with a mixture of tertiary-butanol and demineralized water (10 ml) and then dried at 60-65⁰C to get 7 g of ezetimibe. Similar purification steps were repeated twice to get 5.20 g of highly pure ezetimibe. Relative purity: 99.86% by HPLC (0.02% of 'keto impurity' and 'bis impurity' is not detectable) and '(3R) isomer impurity' by Chiral HPLC: 0.09%.

Claims

WE CLAIM:

1. A process for the preparation of ezetimibe of formula I,

Formula-I

which comprises: a) reacting pentanedioic acid monobenzyl ester of formula II, Formula-II

Formula-Ill

FormuIa-IV

in the presence of lewis acid like titanium tetra chloride along with titanium isopropoxide in suitable organic solvent selected from halogenated solvent preferably dichloromethane to form 4-[(4-benzyloxy-phenyl)-(4-fluoro-phenylamino)-methyl]-5-oxo-5-(2-oxo-4-phenyl- oxazolidine-3-yl)pentanoic acid benzyl ester of formula V,

Formula-V

c) cyclizing 4-[(4-benzyloxy-phenyl)-(4-fluoro-phenylamino)-methyl]-5-oxo-5-(2-oxo-4- phenyl-oxazolidine-3-yl)pentanoic acid benzyl ester of formula V in the presence of a fluoride ion source and silylating agent, in a suitable solvent to form 3-[2-(4-benzyloxy- phenyl)-l-(4-fluorophenyl)-4-oxo-azetidin-3-yl]-propionic acid benzyl ester of formula VI, Formula-VI

d) hydrolyzing 3 - [2-(4-benzyloxy-phenyl)- 1 -(4-fluorophenyl)-4-oxo-azetidin-3 -yl] - propionic acid benzyl ester of formula VI with a base in a suitable solvent to form 3-[2- (4-benzyloxy-phenyl)-l-(4-fluorophenyl)-4-oxo-azetidin-3-yl]-propionic acid of formula VII,

Formula-VII

e) reacting 3-[2-(4-benzyloxy-phenyl)-l-(4-fluorophenyl)-4-oxo-azetidin-3-yl]-propionic acid of formula VII with oxalyl chloride in a suitable solvent like halogenated solvent or aromatic hydrocarbons preferably dichloromethane, optionally with catalytic amount of N,N- dimethylformamide to form 3-[2-(4-benzyloxy-phenyl)-l-(4-fluorophenyi)-4-oxo-azetidin-3- yl]-propionyl chloride of formula VIII,

Formula-VIII

f) reacting 3 - [2-(4-benzyloxy-phenyl)- 1 -(4-fluorophenyl)-4-oxo-azetidin-3 -yl] -propionyl chloride of formula VIII with 4-fluorophenyl magnesium bromide in the presence of a catalyst in a suitable solvent to form 4-(4-benzyloxy-phenyl)-l-(4-fluoro-phenyl)-3-[3[(4- fluoro-phenyl)-3-oxo-propyl]-azetidin-2-one of formula IX,

Formula-IX

g) converting the compound of formula IX to ezetimibe of formula I.

2. The process according to claim 1, wherein in step c) silylating agent is N,O-bis(trimethyl silyl)acetamide; flouride ion source is selected from tetrabutylammonium fluoride, cesium fluoride, potassium fluoride and solvent is selected from ethers, aromatic hydrocarbons, nitriles and halogenated solvents.

3. The process according to claim 1, wherein in step d) the base is selected from alkali metal hydroxides, alkali metal carbonates/ bicarbonates and preferably lithium hydroxide; solvent is selected from tetrahydrofuran, methanol, ethanol, isopropyl alcohol, acetone, methyl isobutyl ketone.

4. The process according to claim 1, wherein in step f), the catalyst is iron acetyl acetonate or iron (III) chloride and suitable organic solvent is tetrahydrofuran, toluene, xylene, ethyl acetate and mixtures thereof.

5. The process according to claim 1, wherein 4-(4-benzyloxy-phenyl)-l-(4-tluoro-phenyl)-3- [3[(4-fluoro-phenyl)-3-oxo-propyl]-azetidin-2-one of formula IX is converted to ezetimibe of formula I comprises: a) reducing compound of formula IX in an organic solvent with a suitable reducing agent in the presence a chiral promoter/catalyst, to form 4-(4-benzyloxy-phenyl)-l-(4-fluoro- phenyl)-3-[3 [(4-fiuoro-phenyl)-3-hydroxy-propyl]-azetidin-2-one of formula X,

Formula-X

b) debenzylating 4-(4-benzyloxy-phenyl)- 1 -(4-fluoro-phenyl)-3 -[3 [(4-fluoro-phenyl)-3 - hydroxy-propyl] -azetidin-2-one of formula X with palladium on carbon in the presence of suitable alcoholic solvent like C₁-C₄ alcohols to form crude ezetimibe, and c) optionally purifying crude ezetimibe.

6. The process according to claim 5, wherein in step a) the reducing agent is selected from borane dimethyl sulfide complex, sodium borohydride, a substituted borohydride eg.[cbz- Proline]₃BHNa and the like; the chiral promoter/catalyst is selected from (R)-2-methyl-CBS- oxazaborolidine, R-butyl CBS or R-phenyl CBS and organic solvent is selected from dichloromethane, tetrahydrofuran, toluene, xylene and the like.

7. The process according to claim 1, wherein 4-(4-benzyloxy-phenyl)-l-(4-fluoro-phenyl)-3- [3[(4-fluoro-phenyl)-3-oxo-propyl]-azetidin-2-one of formula IX is converted to ezetimibe of formula I by the process which comprises: a. debenzylating 4-(4-benzyloxy-phenyl)- 1 -(4-fluoro-phenyl)-3 -[3 [(4-fluoro-phenyl)-3 -oxo- propyl] -azetidin-2-one using palladium on carbon in the presence of suitable solvent to form 4-(4-hydroxy-phenyl)-l-(4-fluoro-phenyl)-3-[3[(4-fluoro-phenyl)-3-oxo-propyl]- azetidin-2-one of following formula,

b. reducing ^' 4-(4-hydroxy-phenyl)-l-(4-fluoro-phenyl)-3-[3[(4-fluoro-ρhenyl) -3-oxo- propyl]-azetidin-2-one with a suitable reducing agent in the presence of chiral promoter/catalyst in an organic solvent to form crude ezetimibe of formula I, and c. optionally purifying crude ezetimibe.

8. The process according to claim 7, wherein in step a) solvent is selected from ester such as ethyl acetate; alcoholic solvent such as C₁-C₄ alcohol, the like and mixtures thereof.

9. The process according to claim 7, wherein in step b) reducing agent is selected from borane dimethyl sulfide complex, sodium borohydride, a substituted borohydride eg.[ cbz- Proline]₃BHNa and the like; the chiral promoter/catalyst is selected from (R)-2-methyl-CBS- oxazaborolidine, (R)-butyl CBS, (R)-phenyl CBS and organic solvent is selected from dichloromethane, tetrahydrofuran, toluene, xylene and the like.

10. A process for the preparation of pentanedioic acid monobenzyl ester of formula II,

_HσtJ_{r ~} Formula-II

by refluxing glutaric acid along with benzyl alcohol, p-toluene sulfonic acid in a suitable solvent selected from aromatic hydrocarbons, halogenated solvents, preferably toluene, cooling the reaction mass to ambient temperature, adding demineralized water, extracting and isolating pentanedioic acid monobenzyl ester of foπnula II.

11. A process for the preparation of 3-[2-(4-benzyloxy-phenyl)-l-(4-fluorophenyl)-4-oxo- azetidin-3-yl] -propionic acid of formula VII,

Formula-VII

Formula-Ill

b) condensing 5-oxo-5-(2-oxo-4-ρhenyl-oxazolidin-3-yl)-pentanoic acid benzyl ester of formula III with (4-benzyloxy-benzylidine)-4-fluoro-phenyl)-amine of formula IV,

Formula-IV

in the presence of lewis acid like titanium tetra chloride along with titanium isopropoxide in a suitable organic solvent selected from halogenated solvent preferably dichloromethane to form 4-[(4-benzyloxy-phenyl)-(4-fluoro-phenylamino)-methyl]-5-oxo-5-(2-oxo-4-phenyl- oxazolidine-3-yl)pentanoic acid benzyl ester of formula V,

Formula-V

c) cyclizing 4-[(4-benzyloxy-phenyl)-(4-fluoro-phenylamino)-methyl]-5-oxo-5-(2-oxo-4- phenyl-oxazolidine-3-yl)pentanoic acid benzyl ester of formula V in the presence of a fluoride ion source and a silylating agent in a suitable solvent to form 3-[2-(4-benzyloxy- phenyl)-l-(4-fluorophenyl)-4-oxo-azetidin-3-yl]-propionic acid benzyl ester of formula VI,

Formula-VI

d) hydrolyzing 3-[2-(4-benzyloxy-phenyl)-l-(4-fluorophenyl)-4-oxo-azetidin-3-yl]-propionic acid benzyl ester of formula VI with a base and suitable solvent to form 3-[2-(4-benzyloxy- ρhenyl)-l-(4-fluorophenyl)-4-oxo-azetidin-3-yl]-propionic acid.

12. The process according to claim 11, wherein in step (c) silylating agent is N, O-bis(trimethyl silyl)acetamide, a fluoride anion source is selected from tetrabutylammonium fluoride, cesium fluoride, potassium fluoride and solvent is selected from ethers, aromatic hydrocarbons, nitriles and halogenated solvents.

13. The process according to claim 11, wherein in step (d) suitable base is selected from alkali metal hydroxides, alkali metal carbonates/ bicarbonates, preferably lithium hydroxide and solvent is selected from tetrahydrofuran, methanol, ethanol, isopropyl alcohol, acetone, methyl isobutyl ketone.

14. A process for the preparation of ezetimibe of formula I, Formula-I

which comprises: a) reacting 3-[2-(4-benzyloxy-phenyl)-l -(4-fluofophenyl)-4-oxo-azetidin-3-yl]-propionic acid of formula VII

Formula- VII

with oxalyl chloride in a suitable solvent like halogenated solvent or aromatic hydrocarbons preferably dichloromethane, optionally with catalytic amount of N,Λ/-dimethylformamide to form 3 -[2-(4-benzyloxy-phenyl)- 1 -(4-fluorophenyl)-4-oxo-azetidin-3 -yl] -propionyl chloride of formula VIII,

Formula-VIII

b) reacting 3-[2-(4-benzyloxy-phenyl)-l -(4-fluorophenyl)-4-oxo-azetidin-3-yl]-propionyl chloride of formula VIII with 4-fluorophenyl magnesium bromide in the presence of catalyst in a suitable solvent to form 4-(4-benzyloxy-phenyl)-l-(4-fluoro-phenyl)-3-[3[(4-fluoro- phenyl)-3-oxo-propyl]-azetidin-2-one of formula IX,

■ Formula-DC

c) converting the compound of formula IX to ezetimibe of formula I.

15. The process according to claim 14, wherein in step b) the catalyst is iron acetyl acetonate, iron (III) chloride and suitable organic solvent is tetrahydrofuran, toluene, xylene, ethyl acetate and mixtures thereof.

16. A process for the preparation of highly pure ezetimibe having less than about 0.15 percent area by HPLC of '(3R) isomer impurity' of following formula,

and having less than 0.10 percent area by HPLC of each of 'bis impurity' and 'keto impurity' of folio wing formulae,

Bis impurity

wherein R is selected from H or benzyl

Keto impurity

comprising the steps of: a) dissolving ezetimibe in a suitable solvent specifically tertiary butanol, b) admixing an anti-solvent specifically water with cooling to obtain a precipitate, c) filtering the product, d) optionally repeating the steps a-c, and subsequently e) isolating the highly pure ezetimibe therefrom.

17. The process according to claim 16, wherein highly pure ezetimibe is having less than about 0.14 percent area by HPLC of the'(3i?) isomer impurity' and less than 0.04 percent area by HPLC each of 'bis impurity' and 'keto impurity.'

18. A process for the preparation of highly pure ezetimibe having less than about 0.15 percent area by HPLC x>f ' (3R) isomer impurity' of following formula,

and having less than 0.10 percent area by HPLC of each of 'bis impurity' and 'keto impurity' of following formulae,

Bis impurity

wherein R is selected from H or benzyl Keto impurity

comprising the steps of: a) providing a solution of ezetimibe in a suitable solvent specifically aqueous tertiary butanol at reflux, b) cooling the reaction mass to obtain a precipitate, c) filtering the product, d) optionally repeating the steps a-c, and subsequently e) isolating the highly pure ezetimibe therefrom.

19. A compound of formula III.

Formula-Ill