WO2009157019A2

WO2009157019A2 - Process for preparing ezetimibe using novel allyl intermediates

Info

Publication number: WO2009157019A2
Application number: PCT/IN2009/000358
Authority: WO
Inventors: Srinivasan Chidambaram Venkateswaran; Singh Sarin Gurdeep; Pranav Gupta; Lalit Wadhwa
Original assignee: Ind-Swift Laboratories Limited
Priority date: 2008-06-23
Filing date: 2009-06-23
Publication date: 2009-12-30
Also published as: WO2009157019A3

Abstract

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

Description

PROCESS FOR PREPARING EZETIMIBE USING NOVEL ALLYL INTERMEDIATES FIELD OF THE INVENTION

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

Formula-I

BACKGROUND OF THE INVENTION

Ezetimibe of formula-I is indicated as a monotherapy for the treatment of primary hypercholesterolemia and homozygous sitosterolemia and is chemically known as (3R,4S)-l-(4- fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(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, which is further condensed with 4-benzyloxybenzylidine-(4-fluoro)aniline in the presence of titanium isopropoxide and titanium tetrachloride to give an amide compound, that undergoes cyclization in the presence of tetrabutylammonium fluoride and bistrimethylsilyl acetamide to yield a protected lactam. The protected lactam so obtained is hydrolyzed to give the corresponding carboxylic acid, which is reacted with oxalyl chloride to give the corresponding acid chloride which is further reacted with p- fluorophenyl magnesium bromide in the presence of zinc chloride and tetrakis(triphenyl phosphine) palladium to give benzylated keto derivative of ezetimibe. It is then reduced selectively in the presence of a chiral catalyst to obtain a benzylated ezetimibe, which is debenzylated to yield ezetimibe of formula I. The aforementioned patent fails to mention the yield and purity of ezetimibe so obtained. However, following the above process, we obtained ezetimibe in very low yields and low purity. It has been observed that most of the intermediates of the above process are highly viscous oils or gummy materials and have to be purified using chromatographic technique, which is cumbersome and difficult to implement on an industrial scale. The critical condensation reaction between the acid chloride intermediate and p-fluorophenylzinc halide in presence of tetrakis(triphenyl phosphine)palladium as a catalyst yields the keto intermediate with a number of side products and the desired keto intermediate is formed in low yield, low purity and requires purification using chromatographic technique. All these drawbacks make the process unattractive from the industrial point of view. US Patent 5,739,321 discloses a process for preparing ezetimibe by reacting 4(S)-hydroxy butyrolactone and a benzyl protected imine in the presence of a base to give a chiral diol, which is then oxidized to the corresponding aldehyde. The aldehyde so formed is condensed with an enolether to give 4-(4-benzyloxy-phenyl)-l-(4-fluoro-phenyl)-3-[3-(4-fluoro-phenyl)-3-oxo-propenyl]- azetidin-2-one. The resulting intermediate is then hydrogenated followed by a chiral catalytic reduction and debenzylation to yield ezetimibe.

US Patent 5,856,473 discloses a process for preparing ezetimibe by initially alkylating l-(4- fluorophenyl)-4(S)-(4-benzyloxyphenyl)-2-azetidinone with 4-fluorocinnamyl bromide to give (3R,4S)-4-(4-benzyloxy-phenyl)-l-(4-fluorophenyl)-3 - [(E)-3 -(4-fluorophenyl)-allyl] -azetidin-2-one which is then successively oxidized to give corresponding ketone. The resulting intermediate is asymmetrically reduced and debenzylated to yield ezetimibe. The patent also discloses another process for the preparation of the intermediate, (3R,4S)-4-(4-benzyloxy-phenyl)-l-(4-fluorophenyl)- 3-[(E)-3-(4-fluorophenyl)-allyl]-azetidin-2-one by converting 4-fluorophenyl pentanoic acid to the corresponding acid chloride, which is then reacted with (S)-(+)-4-phenyl-2-oxazolidine. The product so formed is enolized with a base and condensed with a protected imine followed by intermolecular cyclization in the presence of a silylating agent and a fluoride ion catalyst. The key intermediate in the process, (3R,4S)- 1 -(4-fluorophenyl)-3-[3-oxo-3-(4-fluorophenyl)propyl)]-4-(4-benzyloxy- phenyl)-2-azetidinone is purified by preparative plate chromatography and making the whole process commercially unsuitable. US Patent 6,207,822 discloses a process for preparing ezetimibe by the reaction of p- fluorobenzoylbutyric acid with pivaloyl chloride followed by acylation of the obtained product with a chiral auxiliary to obtain a keto intermediate. The reduction of the keto intermediate in the presence of a chiral catalyst results in the formation of a corresponding chiral alcohol intermediate which is condensed with a suitable imine and silyl protecting agent to give β-(substituted-amino)amide compound. Cyclisation of β-(substituted-amino)amide compound followed by deprotection gives ezetimibe.

PCT publication WO 2007/17705 discloses a process for the preparation of ezetimibe which involves the protection of the hydroxy group of (5R)-5-(4-fluoro-phenyl)-5-hydroxy-pentanoic acid amide derivative followed by hydrolysis with a strong base to give corresponding carboxylic acid derivative, which is then condensed with a suitable imine derivative followed by deprotection of the hydroxy group to give ezetimibe.

PCT publication WO 2007/108007 discloses a process for the preparation of ezetimibe starting from 3-[2-(4-benzyloxy-phenyl)- 1 -(4-fluoro-phenyl)-4-oxo-azetidin-3-yl]-propionic acid, intermediate which is treated with an activating agent followed by treatment with N,O-dimethylhydroxylamine salt in presence of base to form corresponding amide derivative. The amide derivative thus formed is reacted with Grignard reagent to give keto intermediate, which is asymmetrically reduced to afford ezetimibe.

PCT publication WO 2007/072088 discloses a process for the preparation of ezetimibe, which involves intermediates in which the hydroxy group, is protected by silyl group and the keto group is protected by a diol compound.

PCT publication WO 2004/099132 discloses a process for the preparation of trans isomer of ezetimibe by the reaction of chiral delta-lactone with a suitable imine in presence of base to give protected ezetimibe. Further, the application discloses a process for the preparation of chiral delta lactone by the stereoselective reduction of benzoyl butyrate to form chiral hydroxyester which is hydrolysed followed by cyclisation in presence of an acid or a salt of a weak base to give chiral delta- lactone.

Most of the prior art processes, for the preparation of ezetimibe report the use of intermediates wherein the hydroxy group is benzyl protected. The hydrogenolysis of benzylated keto intermediate with palladium on carbon catalyst under hydrogen gas pressure involves the debenzylation as well as partial reduction of keto group to give some amount of racemic ezetimibe along with keto intermediate, increasing the amount of undesired isomer in the final product, thereby decreasing the overall efficiency of chiral reduction. Purification of the crude ezetimibe to remove undesired isomer requires several tedious purification steps, which decreases the overall yield of desired isomer of ezetimibe besides adding to the cost and is hence not advisable on an industrial scale. The protecting groups play a crucial role in multi step synthesis of organic molecules like ezetimibe having a variety of functional groups. It has now been discovered that the allyl group is useful as a protecting group of the hydroxy functionality as it can be easily introduced to protect hydroxy group under mild conditions, also the allyl group is relatively stable to acidic, basic conditions and to the selected reductive conditions. Such a synthetic method has the advantage that target allyl ether can be synthesized with a high chemical yield and be conveniently removed under non-hydrogenolytic conditions, thus minimizing the contamination of ezetimibe with its unwanted (R)-isomer. OBJECT OF THE INVENTION

It is the prime object of the present invention, which has been developed with a view to solve the problems pointed out above, to provide novel allyl intermediates of ezetimibe which serve as industrially useful intermediates for the efficient synthesis of ezetimibe.

Another object of the present invention is to provide a process for the synthesis of ezetimibe in overall high yield and purity.

Another object of the invention is to provide the use of allyl functionality as a hydroxy protecting group, which is easily cleaved under non-hydrogenolytic conditions circumventing the reduction of carbonyl functionality, thereby reducing the formation of impurities and increasing overall yield and purity of ezetimibe.

Another object of the present invention is to provide an industrially advantageous process for the preparation of ezetimibe using novel allyl intermediates that is cost effective, eco-friendly, commercially viable as well as reproducible on industrial scale and meets the needs of regulatory agencies.

Yet another object of the invention is to isolate and identify a novel impurity of ezetimibe and process for the preparation thereof. SUMMARY OF THE INVENTION The present invention provides a novel and industrially advantageous process for the preparation of ezetimibe of formula I,

Formula-I comprising the steps of: a. condensing the compound of formula II,

Formula- 11 wherein R_/ is selected from Cj.io alkyl group, aryl group, substituted aryl group, aryl alkyl or substituted aryl alkyl group, preferably Ri is ethyl, phenyl, substituted phenyl, benzyl, substituted benzyl, naphthyl, substituted naphthyl and the like with a Schiff base of formula III,

Formula-Ill wherein R₂, R₃ and R₄ can be individually selected from hydrogen, Ci^ alkyl, aryl, substituted aryl, Ci^ alkoxy group, preferably i?₂, R₃ ond R4 can be individually selected from hydrogen, methyl, ethyl, methoxy, ethoxy, phenyl, substituted phenyl and the like in the presence of a Lewis acid catalyst and a base in a suitable organic solvent to obtain a compound of formula IV;

Formula-IV wherein Ri, R₂, R₃ and R₄ are as defined above b. cyclizing the compound of formula FV in the presence of a silylating agent and a fluoride source in a suitable solvent to obtain a compound of formula V;

Formula-V wherein Ri, R₂, R₃ andR₄ are as defined above c. hydrolyzing the compound of formula V in the presence of a suitable base in a suitable solvent to obtain a compound of formula VI;

Formula-VI wherein R₂, R₃ and R₄ are as defined above d. optionally, reacting the compound of formula VI with a base to form its salt; e. reacting the compound of formula VI or salts thereof with an activating agent in a suitable solvent to obtain its reactive derivative of formula VII;

Formula-VII wherein R₂, R₃ and R₄ are as defined above and X is halogen or a good leaving group suitable for the Grignard or organometallic addition f. reacting the compound of formula VII with a suitable Grignard reagent or other organometallic reagent in the presence of a catalyst or ligand in a suitable solvent to obtain a compound of formula VIII; and

Formula-Viπ wherein R₂, R₃ and R₄ are as defined above g. converting the compound of formula VIII to ezetimibe of formula I.

In one aspect of the present invention, the compound of formula VIII is converted to ezetimibe by: a. reducing the carbonyl group of compound of formula VIII in presence of a chiral reducing agent or any reducing agent in presence of a chiral catalyst to obtain a compound of formula IX; and

Formula-IX wherein R₂, R₃ andR₄ are as defined above b. deallylating the compound of formula IX to give ezetimibe of formula I. In another aspect of the present invention, compound of formula VIII is converted to ezetimibe by: a. deallylating the compound of formula VIII to obtain a compound of formula X; and

Formula X b. reducing the carbonyl group of compound of formula X in presence of a chiral reducing agent or any reducing agent in presence of a chiral catalyst to form ezetimibe of formula I.

Another aspect of the present invention provides novel intermediates of formulae IV through IX for which the protection is sought which also include salts, solvates, isomers, hydrates and chiral isomers thereof. The compounds of formulae V through VIII may be represented by following common structural formula:

wherein when Z is ORj, it represents formula V, wherein Ri is selected from Cj.jo alkyl group, aryl group, substituted aryl group, aryl alkyl or substituted aryl alkyl group ; Z is OH, it represents formula VI; Z is X it represents formula VII, wherein X is halogen or a good leaving group suitable for the Grignard or organometallic addition; Z is 4-flourophenyl, it represents formula VIII; and wherein R₂, R₃ and R₄ can be individually selected from hydrogen, Ci^ alkyl, aryl, substituted aryl, C ₁.₆ alkoxy group; Ultimately, these intermediates can be converted to ezetimibe or its pharmaceutically acceptable salts thereof. Still another aspect of the present invention is to provide a novel impurity of formula XI,

Formula XI and process for the preparation thereof. DETAILED DESCRIPTION OF THE INVENTION

As described herein all the intermediates as well as the final product i.e. ezetimibe include salts, solvates, isomers, hydrates and chiral isomers thereof.

The present invention provides novel intermediates and a novel process for the preparation of ezetimibe of formula I.

According to one aspect of the present invention, the compound of formula II is condensed with Schiff base of formula III to form a compound of formula IV, a novel and key intermediate for the preparation of ezetimibe which further forms an inventive part of the present invention. Generally, the compound of formula II (preferably where R₁ is phenyl) is condensed with Schiff base of formula. Ill (preferably where R₂, R₃ and R₄ are hydrogen) in presence of a Lewis acid such as titanium tetrachloride and titanium isopropoxide and like or combination thereof, and suitable base in a suitable solvent at a temperature of about or below room temperature. Suitable solvents include aliphatic or aromatic hydrocarbon solvents, halogenated solvents, ethers or mixture thereof. Solvent can be selected from toluene, 1,2 or 1,4-xylene, dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, tetrahydrofuran, 2-methyl tetrahydrofuran, 1,2-diethoxyethane, 1,2- dimethoxyethane and the like or mixture thereof, preferably dichloromethane. Suitable base includes organic bases which can be a tertiary amine selected from trialkylamine such as N,N- diisopropylethylamine, triethylamine, tri-n-butylamine, tri-n-propylamine, tetramethylethylene diamine and the like is added to the reaction mass. The reaction is performed at a temperature of - 40⁰C to 25⁰C over a period of 1-20 hours. After completion, the reaction mixture is quenched with a suitable acid or acid in combination with a suitable solvent. Acids include carboxylic acids such as- acetic acid, inorganic acids such as sulfuric acid or combinations thereof. It is optional to isolate the compound of formula IV from the reaction mixture; it can be in situ processed for the next step. The compound of formula IV can be isolated from the reaction mixture by suitable techniques such as layer separation followed by solvent removal. The compound of formula FV, if desired, can be purified via a crystallization from a suitable solvent which includes alcoholic solvents such as methanol, ethanol; ethers such as methyl tertiary-butyl ether, isopropyl ether; esters such as ethyl acetate; aliphatic or aromatic hydrocarbons; and the like or mixture thereof. Specifically, the compound of formula IV in a suitable solvent is heated to a temperature of 2O⁰C to reflux temperature of the solvent followed by cooling of the solution. The purified compound of formula IV is isolated from the mixture by suitable techniques such as filtration, centrifugation and the like. According to another aspect of the present invention, the compound of formula IV is further cyclized to form a compound of formula V, yet another novel and key intermediate for the preparation of ezetimibe and further forms a part of the present invention. Generally, the compound of formula IV is cyclized in the presence of a silylating agent and a fluoride source in a suitable solvent at a temperature of 10-80⁰C till completion of reaction (1-12 hours). Fluoride sources include tetra n-butylammonium fluoride, cesium fluoride, potassium fluoride, benzyltriethyl ammoniumfluoride, benzyltrimethylammonium fluoride, phenyltriethyl ammonium fluoride, phenyltrimethylammonium fluoride or hydrates thereof. Preferably, tetra-n- butylammonium fluoride or its trihydrate is used. The silylating agents include N₁O- bis(trimethylsilyl)acetamide, 7V-methyl-O-trimethylsilyl acetamide, isopropenyloxy trimethyl silane , trimethylsilyl chloride and the like. Suitable solvents include ether such as alkyl or aryl or cyclic ethers, aliphatic or aromatic hydrocarbons, alkyl or allyl nitriles, alkyl or allyl esters, halogenated solvents or mixture thereof. Solvents can be selected from dichloromethane, toluene, 1,2 or 1,4- xylene, ethyl acetate, tetrahydrofuran, 2-methyl tetrahydrofuran, methyl tertiary-butyl ether, acetonitrile or mixture thereof, preferably methyl tertiary-butyl ether. After completion, the reaction mixture is quenched with a suitable acid such as hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, acetic acid or formic acid and the like. After quenching of the reaction mixture, the layers are separated and the organic layer is neutralized by washing with an aqueous solution of a suitable base such as alkali or alkaline metal hydroxide, carbonates, bicarbonates, or alkoxide thereof. Thereafter, the desired compound is isolated by removal of solvent by distillation. The compound of formula V is optionally isolated or can be used as such for the further reaction. It is advantageous to use the compound of formula V in situ to the next step of the reaction. According to yet another aspect of the present invention, compound of formula V is hydrolyzed to compound of formula VI, a novel and key intermediate in the preparation of ezetimibe and further forms a novel part of the present invention.

Generally, the reaction is performed in the presence of a suitable base in a suitable solvent at a temperature of 0-60⁰C till completion of the reaction. Suitable bases include alkali or alkaline metal hydroxides, carbonates/ bicarbonates, hydrates and alkoxide thereof. Preferably, the base can be selected from lithium hydroxide, lithium hydroxide monohydrate, sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide and the like. Suitable solvents include C_1-5 alcohols, ethers such as alkyl or aryl or cyclic ethers, dialkyl ethers, and C_3-6 ketones or mixture thereof. Preferably, the solvent can be selected from methanol, ethanol, isopropanol, tertiary butanol, tetrahydrofuran, 2-methyl tetrahydrofuran, acetone and methyl isobutyl ketone or mixture thereof. After completion of the reaction, water is added to the reaction mixture and further washed with a suitable solvent preferably ethyl acetate. Thereafter, pH of the reaction mixture is adjusted between 3 to 6, preferably about 5 to 6.0 and then the product is extracted from the aqueous layer using a suitable solvent. Solvents for extraction include esters such as methyl acetate, ethyl acetate, propyl acetate; halogenated solvents such as dichloromethane, 1,2-dichloroethane, chloroform; alkyl or aryl or cyclic ethers such as 2-methyl tetrahydrofuran or any water immiscible solvent or mixture thereof, preferably ethyl acetate. The organic layer is separated, dried and distilled off to give the desired compound. The compound of formula VI can optionally be isolated or can be used as such in the next stage of the sequence of reactions. The compound of formula VI is optionally purified to remove identified and unidentified impurities by crystallization from a suitable solvent that includes, but not limited to aliphatic or aromatic hydrocarbon solvents such as cyclohexane or mixture thereof or by converting the compound of formula VI to its salt. Generally, the process involves reacting the compound of formula VI with a suitable base in the presence of a suitable solvent at a temperature of 0⁰C to the reflux temperature of the solvent, preferably 0-100⁰C till complete formation of the corresponding salt of following formula Via or VIb.

Formula-VIa wherein R₂, R₃ and R₄ are as defined above and R₅, Re and Rγ can be independently selected from hydrogen, unsubstituted or monosubstituted or polysubstituted (Ci-Cβ)-alkyl; (Ci-Cs)cycloalkyl, alkenyl, alkynyl, alkaryl, aryl, aralkyl, alkoxy, aryloxy, aminoalkyl or aminoaryl or a three to six membered heterocyclic ring with one or more hetero atom selected from nitrogen, oxygen or sulphur. Preferably the organic base is selected from 1,2-dimethylpropylamine, 3-(2- aminoethylamino)-propylamine, butylamine, amylamine, cyclopentylamine, cyclohexylamine, cycloheptylamine, dicyclohexylamine, N-methylcyclo hexylamine, N,N'-diisopropylethylenediamine, N,N'-diethylene diamine, N-methyl-l,3-propanediamine, N-methylethylenediamine, N,N,N',N'- tetramethyl-l,2-diamino ethane, N,N,N',N'-tetramethyl-l-,4-diaminobutane, N,N,N',N'-tetramethyl- 1 ,6-diaminohexane, 1 ,2-dipiperidinethane, dipiperidine- methane, 2-amino-3,3-dimethylbutane, N,N- dimethylcyclohexyl amine, neopentyl amine, adamantly amine, N-methylcyclohexylamine, cyclobutylamine, N-isopropylccyclohexylamine, N-diethylcyclohexcylamine, cyclobutylamine and norborylamine and the like

Formula- VI b wherein R2, R₃, andR₄, are as defined above and M is alkali or alkaline earth metal. Base employed in the reaction can be organic or inorganic bases. Organic bases include primary, secondary or tertiary amines depending upon substitution such as NR₅RsR₇ wherein R_5j R₆ and R₇ are as defined above. Inorganic bases include alkali or alkaline earth metal hydroxides, carbonates, bicarbonates, alkoxides, hydrides thereof. Preferably, inorganic base can be sodium hydroxide, potassium hydroxide, lithium hydroxide and the like. Solvents include aliphatic C_1-8 alcohols, C_3-8 ketones, C_4-8 ethers, C_2-5 nitriles and C_3-8 esters or mixture thereof. Preferably, solvents can be selected from methanol, ethanol, isopropanol, acetone, diethyl ketone, methyl isobutyl ketone, tetrahydrofuran, 2-methyl tetrahydrofuran, acetonitrile, and ethyl acetate or mixture thereof. Preferably, the reaction mixture is heated to reflux temperature of solvent for about 1 to 5 hours. The salt can be isolated from the reaction mixture by inducing the precipitation either by adding an anti- solvent or by cooling. Anti solvent includes aliphatic or cyclic C_5-I0 alkanes, C_5-10 alkyl ethers, C_2-6 nitriles or mixture thereof, more preferably isopropyl ether. The compound of formula Via or VIb is optionally isolated from the reaction mixture or it can be proceeded as such for the further reaction. Most preferably, the dicyclohexylamine salt of the compound of formula VI is prepared. The compound of formula Via or VIb can optionally be purified using a suitable solvent. Suitable solvents include aliphatic ketones such as acetone, diethyl ketone, methyl isobutyl ketone; C₂^ nitriles; aliphatic or cyclic alkanes such as C_5-10 alkanes, C_5-I0 cycloalkanes; aromatic hydrocarbons or mixture thereof or their mixture with water in any suitable proportion. Specifically, the compound of formula Via or VIb in a suitable solvent is stirred at a temperature of 0 to 100⁰C for few minutes to few hours. Preferably, the mixture is stirred at a temperature of 55 to 7O⁰C for 1 to 2 hours. Thereafter the mixture is cooled to ambient temperature to a temperature of 35°C. The solid thus precipitated out, is filtered and washed with the same solvent. The purification process can be repeated to enhance the purity of the compound and to remove the undesired impurities to acceptable limits.

The salt so formed, with or without purification, may be further converted into corresponding highly pure acid compound of formula VI. Generally, the salt of compound of formula Via or VIb is hydrolyzed using a suitable acid or base in a suitable solvent at a temperature of 0-50⁰C. Acid employed in the reaction can be inorganic or organic acids. Inorganic acids include hydrochloric acid, hydrobromic acid; sulfuric acid and the like and organic acids include carboxylic acid such as formic acid, acetic acid, propionic acid, butyric acid and the like or combination thereof. Solvents for carrying hydrolysis include halogenated solvents, aliphatic or aromatic hydrocarbon solvents, aliphatic ethers, aliphatic esters or mixture thereof. Preferably, the solvents can be selected from chloroform, carbon tetrachloride, dichloromethane, toluene, 1,2 or 1,4-xylene, ethyl acetate or mixture thereof. The purified compound of formula VI can be isolated from the reaction mixture or reaction mixture can be used as such for the next stage of the reaction. In another embodiment of the present invention, compound of formula VI or salt thereof is directly converted to its reactive derivative of formula VII. The reactive derivatives include acid halides, organic acid anhydrides, mixed acid anhydride, cyclic carboxy-anhydrides, active amides or esters, triazole such as benzotriazole or other groups as described in "Comprehensive Organic Transformation by R.C. Larock". The reactive derivative of formula VII can be prepared by reaction with an activating agent like oxalyl chloride, phosphorous trihalide, phosphorous pentahalide, thionyl halide, organic acid halides like acetyl chloride, pivaolyl chloride, C_2-8 alkyl chloroformate or aryl chloroformate, Lewis acid like boric acid or 4-(4,6-dimethpxy-l,3,5-triazine-2-yl)-4- methylmoφholinium chloride and the like.

Preferably, the reaction is carried out using a suitable activating agent in suitable solvent at a temperature of 5-50⁰C. Suitable solvents include halogenated solvents, aliphatic esters, aliphatic or cyclic ethers, amide solvents, aliphatic or aromatic hydrocarbon solvents, or mixture thereof. Preferably the solvents can be selected from dichloromethane, chloroform, carbon tetrachloride, 1,2- dichloroethane, toluene, 1,2 or 1,4-xylene, ethyl acetate, dimethylformamide, tetrahydrofuran, 2- methyl tetrahydrofuran, 1,2-dimethoxyethane, 1,2-diethoxyethane or mixtures thereof. Preferably, dichloromethane with catalytic amount of dimethyl formamide is used. The compound of formula VII can be isolated from the reaction mixture by the removal of the solvent.

Yet another aspect of the present invention provides a process for the conversion of compound of formula VII to compound of formula VIII by condensing the compound of formula VIII with organometallic reagent derived from 4-fluorophenyl halide, preferably 4-fluorophenylmagnesium bromide. Compound of formula VIII is yet another key intermediate for the preparation of ezetimibe and further forms an inventive part of the present invention.

Generally, the reaction is performed in the presence of suitable catalyst in a suitable organic solvent at a temperature of -100 to 50⁰C for few minutes to few hours. Preferably, the reaction is carried out at a temperature of -80 to -90⁰C. Catalyst can be selected from transition metal salts or complexes thereof including metal such as palladium, zinc, cerium or iron metal; palladium salts, iron (III) salts, iron (III) acetyl acetonate, FeCl₂, FeCl₃, ZnCl₂, cerium (III) chloride, Pd (0) complexes, Cu (I) salts, tetrakis(triphenylphosphine) palladium and the like with or without additives. The above reaction can also be performed in the presence of ligands such as N-methylmorpholine, N,N,N',N'- tetramethylethylenediamine, N,N,N',N',N'-tettame\hy\ diethylene triamine and bis[2-(N,N- dimethylamine)ethyl]ether. Suitable organic solvents include aliphatic or aromatic hydrocarbon solvents, halogenated solvents and aliphatic or cyclic ethers or mixture thereof. Preferably solvents can be selected from toluene, 1,2 or 1,4-xylene, dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 2-methyl tetrahydrofuran, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like or mixture thereof, More preferably tetrahydrofuran is used. After completion of the reaction, the product is extracted from the reaction using suitable solvent. Solvent for extraction includes alkyl ethers such as diethyl ether, diisopropyl ether, methyl tertiary-butyl ether; alkyl esters such as ethyl acetate, propyl acetate; aliphatic or aromatic hydrocarbon solvents such as toluene and the like or mixture thereof. The product is isolated from the organic layer by distillation of the solvent. The isolated product, if desired, can be purified using a suitable solvent that include alcoholic solvents such as methanol, ethanol, isopropanol and the like or mixture thereof. Specifically, the resulting product in a suitable solvent is stirred at a temperature of 0 to 5O⁰C for 30 minutes to several hours. Thereafter, the solution was stirred and optionally, seeded with a pure compound followed by cooling of the solution. The product is isolated from the solution by suitable techniques like filtration or centrifugation. Thereafter, compound of formula VIII is converted to ezetimibe. In one aspect, the compound of formula VIII is reduced to a compound of formula IX, and then deprotected to form ezetimibe.

The compound of formula VIII is first reduced with a suitable chiral reducing agent or reducing agent in presence of chiral catalyst in a suitable organic solvent. Organic solvents used during reduction include halogenated solvents, aliphatic or aromatic hydrocarbon solvents, aliphatic or cyclic ethers or mixture thereof. Preferably solvents can be selected from dichloromethane, 1,2- dichloroethane, chloroform, tetrahydrofuran, 2-methyltetrahydrofuran, 1,2-dimethoxyethane, 1,2- diethoxyethane, toluene, 1,2 or 1,4-xylene or mixture thereof. The reducing agent can be selected from borane dimethyl sulfide complex, borane tetrahydrofuran complex, sodium borohydride, a substituted borohydride eg.[ CBZ-ProlinekBHNa and the like, while the chiral promoter/catalyst can be selected from (R)-2-methyl-CBS-oxazaborolidine, R-butyl CBS-oxazaborolidine, R-phenyl CBS- oxazaborolidine, β-chloro diisopino camphenyl borane and the like. The reaction is performed at a temperature of -40 to 40⁰C over a period of half hour to 24 hours to afford a compound of formula IX.

Compound of formula FX is then deprotected to give ezetimibe of formula I by any of the methods known in the prior art. The compound can be deallylated or deprotected by non- hydrogenolytic conditions as mentioned in "Protective Groups in Organic Synthesis" by Theodora W. Greene & Peter G.M. Wuts and also by Philip Kocienski. Particularly, the compound of formula EX can be deallylated using a nucleophile; 1,3-dicarbonyl compounds such as but not limited to N,N'- dimethylbarbituric acid, S^-dimethyl-l^-cyclohexanedione, diethyl malonate or other β-ketoester or 1,3-diketone; or substituted and unsubstituted amines like morpholine, pyrrolidine and the like or alkali metal carbamate in presence of suitable transition metal catalyst such as those derived from palladium salts in the presence of a suitable solvent. Preferably, the reaction is conducted at ambient temperature to reflux temperature of the solvent. Solvents for the reaction include C_1-8 alcohols, halogenated solvents, aliphatic or aromatic hydrocarbon solvents, aliphatic esters, aliphatic ethers and nitriles or mixture thereof. Preferably, the solvent can be selected from methanol, isoprρpanol, tertiary butanol, dichloromethane, 1,2-dichloroethane, chloroform, toluene, ethyl acetate, propyl acetate, tetrahydrofuran, 2-methyl tetrahydrofuran, di-n-butyl ether, 1,2-dimethoxy ethane 1,2- diethoxy ethane and the like or mixture thereof. Preferably, deallylation can be performed using 5,5- dimethyl-l,3-cyclohexanedione or morpholine in presence of tetrakis(triphenylphosphine)palladium in tetrahydrofuran or dichloromethane as a solvent. Alternatively, compound of formula EX can be deallylated in the presence of suitable catalyst to give ezetimibe of formula I. The catalyst can be selected from platinum oxide, palladium on carbon (PdVC), ruthenium on carbon (Ru/C), rhodium on carbon (Rh/C), copperchromiumoxide, tetrakis(triphenylphosphine) palladium, other palladium complexes and the like, preferably palladium on carbon (Pd/C). The above catalyst can be used in presence of an acid catalyst such as sulfonic acid selected from p-toluenesulfonic acid, benzene sulfonic acid or salts thereof, preferably p-toluenesulfonic acid or bases that includes alkali metal carbonates such as potassium carbonate, hi another embodiment, the compound of formula VIII can be first deallylated to form compound of formula X, and then reduced to form ezetimibe of formula I Compound of formula VIII may be deprotected/ deallylated to give compound of formula X by any of the methods known in the prior art for deprotection/ deallylation. The compound can be deallylated or deprotected by non- hydrogenolytic conditions as mentioned in "Protective Groups in Organic Synthesis" by Theodora W. Greene & Peter G.M. Wuts and also by Philip Kocienski. Particularly, the compound of formula IX can be deallylated using a nucleophile; 1,3-dicarbonyl compounds such as but not limited to ΛζiV'-dimethylbarbituric acid, 5,5-dimethyl-l,3- cyclohexanedione, diethyl malonate or other β-ketoester or 1,3-diketone; or substituted and unsubstituted amines like morpholine, pyrrolidine and the like or alkali metal carbamate in presence of suitable transition metal catalyst such as those derived from palladium salts in the presence of a suitable solvent. The reaction is performed at a temperature of about 25⁰C to reflux temperature of the solvent used for a period of 15 minutes to 24 hours, more preferably till the reaction goes to completion. Solvents for the reaction include C_1-8 alcohols, halogenated solvents, aliphatic or aromatic hydrocarbon solvents, aliphatic esters, aliphatic ethers and nitriles or mixture thereof. Preferably, the solvent can be selected from methanol, isopropanol, tertiary butanol, dichloromethane, 1,2-dichloroethane, chloroform, toluene, ethyl acetate, propyl acetate, tetrahydrofuran, 2-methyl tetrahydrofuran, di-n-butyl ether, 1,2-dimethoxy ethane 1,2-diethoxy ethane and the like or mixture thereof. Preferably, deallylation can be performed using 5,5-dimethyl- 1,3-cyclohexanedione or morpholine in presence of tetrakis(triphenyl phosphine)palladium in tetrahydrofuran or dichloromethane as a solvent.

Alternatively, the deprotection/deallylation can be performed in the presence of suitable catalyst in a suitable solvent. Catalyst includes platinum oxide, palladium on carbon (Pd/C), ruthenium on carbon (Ru/C), rhodium on carbon (Rh/C), copperchromiumoxide, tetrakis(triphenylphosphine) palladium, other palladium complexes and the like, preferably palladium on carbon (Pd/C). The above catalysts can be used in presence of an acid catalyst such as sulfonic acid catalyst selected from p- toluenesulfonic acid, benzene sulfonic acid or salts thereof, preferably p-toluenesulfonic acid or bases that includes alkali metal carbonates such as potassium carbonate. More preferably, 10% by weight palladium supported on carbon is used. l-(4-Fluoro-phenyl)-3-[3-(4-fluoro-phenyl)-3-oxo-propyl]-4-(4-hydroxy-phenyl)-azetidin-2-one of formula X so obtained, is further reduced to ezetimibe of formula I using suitable chiral reducing agent or reducing agent in presence of chiral catalyst in a suitable organic solvent. Organic solvents include halogenated solvents, aliphatic or aromatic hydrocarbon solvents, aliphatic or cyclic ether or mixture thereof. Preferably, solvent can be selected from dichloromethane, tetrahydrofuran, toluene, xylene or mixture thereof. Reducing agent can be selected from borane dimethyl sulfide complex, borane tetrahydrofuran complex, sodium borohydride, a substituted borohydride eg.[ CBZ- PrOlUIe]₃BHNa and the like, while the chiral promoter/catalyst can be selected from (R)-2-methyl- CBS-oxazaborolidine, R-butyl CBS-oxazaborolidine, R-phenyl CBS-oxazaborolidine, β-chloro diisopinocamphenyl borane and the like. After completion of the reaction, the reaction mixture is quenched with a suitable quenching agent, which includes alcoholic solvents or alcoholic solvents in combination with peroxide and the like. Preferably, the reaction mixture can be quenched by the addition of methanol and hydrogen peroxide. The product may be isolated from the reaction mixture by extraction with a suitable solvent. Suitable solvents for extraction include ethers such as halogenated solvents such as dichloromethane, chloroform, 1,2-dichloroethane; C_4-8 alkyl esters; C_3-8 dialkyl ethers; aliphatic or aromatic hydrocarbons such as benzene, toluene, 1,2 or 1,4-xylene, and the like or mixture thereof.

As is known in the art, the management of process impurities is greatly enhanced by understanding their chemical structures and by identifying the parameters that influence the formation of impurities in the final product. Moreover, it is important that an impurity present in a product must be identified by suitable techniques. Thus, the impurities may be characterized by suitable techniques like ¹H Nuclear magnetic resonance spectroscopy (¹H-NMR), ¹³C Nuclear magnetic resonance spectroscopy (¹³C NMR), infra-red spectroscopy (IR), ultra violet spectroscopy (UV), mass spectra (MS). Ezetimibe formed by the above process may contain compound of formula IX as an impurity, which may arise during the reduction of compound of formula X containing some amount of compound of formula VIII as an impurity that also gets reduced to compound of formula IX as an impurity in small amounts. The generation of this impurity in the final product can be minimized by controlling the amount of unreacted compound of formula VIII in the compound of formula X. According to another embodiment, the present invention provides a novel impurity of formula XI that may be present in the sample of ezetimibe. It is observed by the present inventors that during the reaction for the synthesis of compound of formula VIII from compound of formula VII, the compound of formula X is also formed in the reaction in smaller amounts along with the desired compound of formula VIII. The compound of formula X, in situ, then reacts with the unreacted compound of formula VII, present in the reaction mixture, and results in the generation of compound of formula XII.

Formula XII wherein R₂, R₃ andR.₄ are as defined above

If the presence of the compound of formula XII is not controlled at the intermediate stage of preparation of formula VIII, then compound of formula XII along with the compound of formula VIII will undergo successive deallylation and reduction resulting in ezetimibe containing impurity of formula XI. The main reason for the generation of impurity XI, in the final product, is the presence of impurity XII in the intermediate of formula VIII. However, the percentage of impurity in the final API can be controlled at the level of its precursor impurity of formula XII in the intermediate of formula VIII. According to another embodiment, the present invention provides a process for the removal of impurity of formula XII from the compound of formula VIII, if present. The compound of formula XII is removed by treating compound of formula VIII containing impurity of formula XII with a suitable base, which results in the cleavage of ester functionality in the compound of formula XII. Typically, the process involves the treatment of compound of formula VIII containing impurity of formula XII in a suitable solvent with organic or inorganic base at a temperature of 0 to 6O⁰C for few minutes to few hours. Preferably, the reaction mixture is stirred at a temperature of room temperature to 5O⁰C for 2 to 6 hours. The suitable base is inorganic base that include alkali or alkaline metal hydroxides, carbonates, bicarbonates, alkoxides, hydrides thereof such as potassium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium bicarbonate, sodium carbonate, sodium bicarbonate and the like. Preferably, potassium carbonate is used for the reaction. Suitable solvents for the removal of impurity of formula XI include alcohols such as methanol, ethanol, isopropanol and butanol or mixture thereof or their mixture with water in suitable proportion. The purified compound of formula VIII is isolated from the mixture by suitable techniques such as centrifugation or filtration. It is observed that the purification process is highly efficient to provide the compound of formula VIII having less than 0.1% of impurity of formula XII, preferably less than 0.06% or free from that impurity. The purification process can be repeated to minimize the level of impurity. The purified compound of formula VIII having impurity of formula XII in acceptable limits, is then converted to ezetimibe which may have impurity of formula XI either in acceptable amount or it may be free from impurity. The impurity of formula XI is characterized as follows:

¹H-NMR δ (CDCl₃, 400 MHz): 1.84-1.93 (4H, m, CH₂); 2.26-2.28 (2H, m, CH₂); 2.74-2.81 (2H, m, CH₂); 3.07-3.14 (2H, m, CH); 4.59-4.61 (IH, m, CH); 4.64-4.68 (2H, m, CH); 6.80-7.28 (2OH, m, aromatic H) MS (M-I) : 718.98 According to another embodiment, the present invention provides a process for the preparation of impurity of formula XI.

The process involves the reaction of compound of formula VII with the compound of formula X in the presence of a suitable base in an organic solvent at a temperature below ambient for 5 minutes to several hours. Preferably, the reaction takes place at a temperature of 0-10⁰C till completion of reaction. After completion of the reaction, the resulting product is deallylated and then asymmetrically reduced using the conditions similar to those described above for deallylation and reduction to provide impurity of formula XI. The impurity of formula XI, if desired, can be purified by suitable techniques like column chromatography or crystallization with suitable solvents or a combination thereof. The suitable solvents for the purification include aliphatic or aromatic hydrocarbon solvents such as n-hexane, n-heptane, hexane, heptane, cyclohexane; esters such as methyl acetate, ethyl acetate, propyl acetate and the like or mixture thereof in suitable proportions. The impurity of formula XI obtained by the process of present invention is highly pure, having purity of more than 95%, preferably more than 99% by HPLC. Ezetimibe obtained by the processes of the present invention, if desired, may be purified using suitable solvent. Suitable solvents include C₁^ alcoholic solvents such as methanol, ethanol, propanol, isopropanol; aliphatic ketones such as acetone, diethyl ketone, methyl isobutyl ketone; and the like or mixture thereof. The product is precipitated from the solution by the addition of suitable anti solvent that includes water or any other relatively non polar solvent that includes nitriles such as acetonitrile; ethers such as isopropyl ether, methyl tertiary butyl ether and the like or mixture thereof. Specifically, ezetimibe in a suitable solvent is stirred at a temperature of room temperature to reflux temperature of solvent until the clear solution is obtained. Then anti solvent is added to the solution to precipitate the pure product, which is isolated by suitable methods such as filtration or centrifugation and the like. The purification process may be repeated, if desired, to enhance the purity of ezetimibe and to remove the undesired impurities from the final product. Key intermediates of formula II and III can be prepared by the processes well known in prior art or as exemplified herein for reference.

Generally, the compound of formula II can be prepared by the reaction of glutaric acid or anhydride with an alcohol of general formula R₁OH (wherein Ri is as defined above) in presence of base to give an ester intermediate which is then reacted with pivaloyl chloride followed by reaction with chiral auxiliary. Specifically, 5-oxo-5-(2-oxo-phenyl-oxazolidin-3-yl)-pentanoic acid benzyl ester can be prepared by: (i) reaction of glutaric acid or anhydride with benzyl alcohol in the presence of sodium metal at a temperature of 25-90 ⁰C to form pentanedioic acid monobenzyl ester; (ii) it is further converted to its reactive derivative by reaction with pivaloyl chloride in the presence of a suitable organic or inorganic base at a temperature of 5-20 °C, followed by in situ condensation with a chiral auxiliary, preferably (S)-4-phenyl-2-oxazolidinone in the presence of a suitable base in a solvent. The condensation reaction is performed at a temperature of 40°C to the reflux temperature of the solvent. The solvents used in the reaction include highly polar aprotic solvent such as dimethylformamide, dimethylacetamide, dimethylsulfoxide; ethers such as tetrahydrofuran, 2- methyltetrahydrofuran, 1,2-diethoxyethane, 1,2-dimethoxyethane; aromatic solvents such as toluene, halogenated solvents such as dichloromethane, chloroform and the like or mixture thereof. The base used in condensation reaction can be selected from organic amines such as pyridine, Λ-N,N- dimethyaminopyridine, diisopropylethylamine, triethylamine, tributylamine and the like. After completion of the reaction, the resulting product is isolated from the reaction by acid base wash followed by water wash to the reaction mixture. Solvents are removed from the organic layer by distillation. The isolated product, if desired, can be purified with a suitable solvent, which include alcohols such as ethanol and the like or mixture thereof. The solution is optionally seeded with pure material and mixture is stirred, cooled and filtered to give highly pure compound of formula II. Schiff base of formula III can be prepared according to the process of the present invention. Generally, the Schiff base of formula III can be prepared by (i) the reaction of p- hydroxybenzaldehyde with substituted allyl halides, preferably allyl bromide in presence of a base and tetrabutylammonium bromide in a suitable solvent to give p-allyloxy benzaldehyde (where allyl group is substituted with R₂, R₃ and R₄ which are as defined above). The reaction mixture is preferably stirred for 2 to 12 hours, more preferably till the completion of the reaction. Solvents include halogenated solvents, preferably dichloromethane and bases includes alkali or alkaline metal hydroxide, carbonates, bicarbonates and hydrides thereof, preferably sodium hydroxide. The product can be isolated from the reaction mixture or in situ proceeded to further reaction, (ϋ) The above prepared intermediate, p-allyloxy benzaldehyde is then reacted with 4-fluoroaniline in a suitable solvent for 2 to 24 hours at temperature of 5-100⁰C to give Schiff base of formula III. Solvents for the reaction include C₁₄ alcohols, halogenated solvents, aliphatic ether, aliphatic or aromatic hydrocarbon or mixture thereof. Preferably the solvent is selected form ethanol, isopropanol, dichloromethane, 1,2-dichloroethane, chloroform, diethyl ether, diisopropyl ether, dibutyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, benzene, 1,2 or 1,4-toluene, xylene or mixture thereof. The Schiff base of formula III of the present invention can be isolated as solid or reaction mixture is used as such in the next step. The isolated intermediates are optionally purified. The order and manner of combining the reactants at any stage of the process are not important and may be varied. The reactants may be added to the reaction mixture as solids, or may be dissolved individually and combined as solutions. Further, any of the reactants may be dissolved together as sub-groups, and those solutions may be combined in any order. Wherever required, progress of the reaction is monitored by suitable chromatographic techniques such as High performance liquid chromatography (HPLC) or thin layer chromatography (TLC). Isolation and purification of final compound and intermediates described here in the present invention can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, derivatisation, slurry wash, salt preparation or combination of these procedures. However, other equivalent procedures such as acid-base treatment could, also be used, to purify the intermediates. The solvents used for the purification of final compound and intermediates of the present invention can be selected form water, C_1-6 alcohols, aliphatic C_3-6 ketones, aliphatic or aromatic hydrocarbons, aliphatic esters, C_3-6 ethers, C_2-4 nitrile, halogenated solvents and the like or mixture thereof in suitable proportion. Although, the following examples illustrate the present invention in more detail, but should not be construed as limiting the scope of the invention. EXAMPLES

Example 1: Preparation of 5-oxo-5-(2-oxo-4-phenyl-oxazolidin-3-yl)-pentanoic acid benzyl ester Benzyl alcohol (95.Og, 0.88mol) and sodium metal (2.01g, 0.087mol) were mixed and stirred for 30 minutes. Then, the reaction mixture was heated to 80-85⁰C and stirred to dissolve the sodium metal. Glutaric anhydride (10Og, 0.876mol) was added and stirred for further 2 hours at 80-85⁰C. The reaction mixture was cooled to 25-3O⁰C and to this dichloromethane (250ml) and demineralized water (1x25 OmI) were added. The layers were separated; organic layer was dried over sodium sulfate and concentrated at 40-45⁰C. The reaction mixture was cooled and dichloromethane (850ml) was added. The reaction mixture was cooled to 10-15⁰C under nitrogen atmosphere. Triethylamine (214ml, 1.535mol) was added followed by the slow addition of pivaloyl chloride (110 ml, 0.893mol). The reaction mixture was stirred at 25-3O⁰C for 90 minutes followed by addition of (S)-4-phenyl-2- oxazolidinone (86g, 0.527mol), N,iV-dimethyl formamide (92ml) and 4-dimethyl amino pyridine (15g, 0.123mol). The reaction mass was further refluxed for 6 hours and then cooled to 10-20⁰C. Dilute sulphuric acid was added to the reaction mixture and stirred for 15 minutes. The layers were separated; organic layer was washed with 10% aqueous sodium bicarbonate solution (500ml) and demineralized water (500ml). The organic layer was concentrated at atmospheric pressure and finally under reduced pressure at 40-50⁰C. Ethanol (600ml) was added to the reaction mixture and cooled to 20-30⁰C. Title compound (1.Og) was added as seeds to the reaction mixture and stirred for 60 minutes at 20-30⁰C. The reaction mixture was again cooled to 0-5⁰C, stirred for 2 hours, filtered and washed with ethanol (100ml) to afford 180g of the title compound having purity 99.41% by HPLC. Example 2: Preparation of(4-aUyloxy-benzylidene)-(4-fluoro-phenyl)-amine p-Hydroxy bezaldehyde (500.0g, 4.09mol) was added to a solution of sodium hydroxide (172g,4.30mol) in demineralized water (4.0L) and stirred. Dichloromethane (2.50L), terra butyl ammonium bromide (135.Og, 0.42 mol) were added to the above mixture and stirred at 25-30⁰C for 15 minutes. Allyl bromide (400ml, 4.62 mol) was added and the reaction mass was stirred for 8 hours at 20-30⁰C. The layers were separated; the aqueous layer was extracted with dichloromethane (1.0L). The combined organic layer was washed with a solution of sodium hydroxide (2x (15Og in 2.0L water)) and demineralized water (4.0 L). Organic layer was dried over sodium sulfate and concentrated at 40-50⁰C. Isopropyl alcohol (500ml) was added to the reaction mass and distilled out under reduced pressure. Isopropyl alcohol (1.25L) was again added and the reaction mass was heated to 6O⁰C followed by addition of 4-fluoroaniline (465ml, 4.90 mol) and then the reaction mass was maintained for 2 hours at 60-65⁰C. The reaction mixture was cooled at 0 to -1O⁰C, stirred for 2 hours, filtered and washed with n- hexane (1.0L) to afford 880g of the title compound having purity 96.55 % by HPLC.

Example 3: Preparation of 4-[(4-allyloxy-phenyl)-(4-fluoro-phenylamino)-methyl]-5-oxo-5-(2- oxo-4-phenyl-oxazolidin-3-yl)-pentanoic acid benzyl ester Titanium tetrachloride (149ml, 1.36 mol) and titanium (FV) isopropoxide (129ml, 0.44 mol) were added to pre cooled dichloromethane (3.50L) and stirred for 15 minutes at 0 to -1O⁰C under nitrogen atomosphere. 5-Oxo-5-(2-oxo-4-phenyl-oxazolidin-3-yl)-pentanoic acid benzyl ester (500g, 1.36 mol) in dichloromethane (1.50L) was added slowly to the above mixture and stirred for 30 minutes at 0 to -1O⁰C followed by addition of 7V,7V-diisopropylethylamine (663.50ml, 3.80 mol) at 0 to -1O⁰C and again stirred for 1 hour. The reaction mixture was cooled to -25⁰C and (4-allyloxy-benzylidene)- (4-fluoro-phenyl)-amine (415g, 1.63mol) was added to the reaction mass. The reaction mixture was maintained for 6 hours at -15 to -25°C and a mixture of dichloromethane (400ml) and acetic acid (400ml) was added at -25 to O⁰C. Thereafter dilute sulfuric acid (176ml cone. H₂SO₄ in 2.324L water) was added at 0-10⁰C and stirred for 1 hour at 0-10⁰C. The layers were separated. The aqueous layer was extracted with dichloromethane (500ml). The combined organic layer was washed with demineralized water (2x4.0L), dried over sodium sulfate, concentrated at 40 to 45°C. Ethanol (1.0L) was added to the reaction mass and distilled under reduced pressure. Ethanol (3.50L) was again added to the resulting residue, heated to reflux and maintained for 60 minutes. The mixture was cooled to 30-35⁰C, stirred for 2 hours, filtered and washed with ethanol (1.0L) to afford 501g of the title compound having purity 99.06 % by HPLC. Example 4: Preparation of 3-[2-(4-allyloxy-phenyl)-l-(4-fluoro-phenyl)-4-oxo-azetidin-3-yl]- propionic acid

To a mixture of 4-[(4-allyloxy-phenyl)-(4-fluoro-phenylamino)-methyl]-5-oxo-5-(2-oxo-4-phenyl- oxazolidin-3-yl)-pentanoic acid benzyl ester (50Og, 0.80mol) and tert butylmethyl ether (5.0L); N,O- bis(trimethylsilyl)acetamide (500ml, 2.04 mol), tetrabutylammonium fluoride trihydrate (10.0g, 0.03 mol) were added at 25 to 3O⁰C, and mixture was stirred at 35-45⁰C. After completion of the reaction (monitored by HPLC), the reaction mixture was cooled to ambient temperature and IN hydrochloric acid (5.0L) was added. The reaction mass was stirred for 15 minutes. The layers were separated and organic layer was washed with 10% aqueous sodium bicarbonate solution (5.0L) and then with brine solution (5.0L). Organic layer was dried over sodium sulfate and concentrated at 40-50⁰C under reduced pressure. The reaction mass was cooled to 25-3O⁰C, acetone (3.70L) was added, followed by addition of a solution of lithium hydroxide monohydrate (40.Og, 0.95mol) in demineralized water (1.285L) and stirred at 25-30⁰C till the reaction completion. After reaction completion demineralized water (7.40L) and ethyl acetate (3.70L) were added and stirred for 15 minutes. The aqueous layer was washed with ethyl acetate (1.85L) and then acidified to pH of 5.0-6.0 with IN hydrochloric acid. Ethyl acetate (1.85L) was added to the reaction mass and stirred for 15 minutes at ambient temperature. The organic layer was separated and dried over sodium sulphate. Solvent was distilled off under reduced pressure at 40-50⁰C to give 326 g of title compound.

Example 5: Preparation of 3-[2-(4-allyloxy-phenyl)-l-(4-fluoro-phenyl)-4-oxo-azetidin-3-yl]- propionic acid dicyclohexylamine salt Ethanol (590ml) and dicyclohexylamine (191.50ml) were added to the 3-[2-(4-allyloxy-phenyl)-l- (4-fluoro-phenyl)-4-oxo-azetidin-3-yl]-propionic acid (300 g) and heated to reflux for 60 minutes. Then the solvent was distilled off under reduced pressure at 40-50⁰C. Acetone (370ml) was added to the reaction mass and stirred at 60-65⁰C for 15 minutes to get a homogenous solution. Thereafter demineralized water (3.70L) was added slowly to the reaction mass at 50-60⁰C and cooled to 35- 40⁰C, stirred for 60 minutes. The solid material was filtered, washed with a mixture of acetone (50ml) and demineralized water (500ml) followed by demineralized water (5.0L). The resulting product was dried at 60-65⁰C until water content becomes less than 1.0% w/w to afford 318g of title compound. The compound thus obtained was again purified with a mixture of acetone (318ml) and demineralized water (3.18 L) to give 304g of title compound having purity 99.36 % by HPLC. Example 6: Preparation of 3-[2-(4-allyloxy-phenyl)-l-(4-fluoro-phenyl)-4-oxo-azetidin-3-yl]- propionic acid

To a solution of 3-[2-(4-allyloxy-phenyl)-l-(4-fluoro-phenyl)-4-oxo-azetidin-3-yl]-propionic acid ΛζiV-dicyclohexylamine salt (1Og) in ethyl acetate (50 ml), acetic acid (4 ml) was added to adjust the pH of the reaction mixture between 4 to 5 and stirred at room temperature for 15 minutes. The organic layer was washed with demineralized water (2 x 50 ml) and dried over sodium sulfate. The resulting layer was distilled off to remove the solvent to give 6.5g of the title compound. Example 7: Preparation of 4-(4-allyloxy-phenyl)-l-(4-fluoro-phenyl)-3-[3-(4-fluoro-phenyl)-3- oxo-propyl]-azetidin-2-one Step 1: Preparation of Grignard reagent

4-Bromofluoro benzene (34.47g, 0.197mol) was added to magnesium turnings (47.28g, 1.94mol) and iodine (15mg) under nitrogen atmosphere to intiate the reaction. A solution of 4-bromofluoro benzene (310.1 Ig, 1.77mol) in tetrahydrofuran (1.20L) was slowly added to the reaction mass while maintaining a gentle reflux. Then the reaction mass was stirred at RT for 60 minutes to give title compound.

Step 2: Preparation of 4-(4-allyloxy-phenyl)-l-(4-fluoro-phenyl)-3-[3-(4-fluoro-phenyl)-3-oxo- propy 1] -azetidin-2-one

Method A: A solution of 3-[2-(4-allyloxy-phenyl)-l-(4-fluoro-phenyl)-4-oxo-azetidin-3-yl]- propionic acid (1Og) in dichloromethane (50 ml) and Λ/,N-dimethylformamide (0.20ml) was cooled to 5-1O⁰C under nitrogen atmosphere. Oxalyl chloride (4.58ml) was added slowly at 5-15⁰C to the above mixture and stirred at 5-15⁰C. After completion of the reaction (monitored by TLC), the solvent was distilled off under reduced pressure. Tetrahydrofuran (10ml) was added to the resulting residue and distilled off under reduced pressure at 40-50⁰C. To the residue, tetrahydrofuran (60 ml) was added and mixture was cooled to -80° to -90⁰C. Iron (III) acetylacetonate (0.375 g) was added to the reaction mass followed by addition of freshly prepared Grignard reagent i.e.4- fluorophenylmagnesiumbromide solution (0.074 mol) at -80 to -90⁰C. After reaction completion, the reaction mass was slowly poured into ice cold water (50 ml). Thereafter, tertiary butylmethyl ether (40 ml) was added to the reaction mass and stirred at 25-3O⁰C for 15 minutes. The reaction mass was filtered through hyflo bed and the hyfio bed was washed with tertiary butylmethyl ether (40 ml). The organic layer was separated from the filtrate, washed twice with brine solution (2x 100 ml) and then dried over sodium sulphate. The solvent was distilled off under reduced pressure at 40-50⁰C. Ethanol (10ml) was added to the resulting residue and distilled off under reduced pressure at 40-50⁰C. The reaction mass was then cooled to 20-25⁰C and ethanol (20 ml) was added and stirred to dissolve the residue. Title compound (0.05 gm) was added as seeds to the reaction mass and stirred at 20-30⁰C for 60 minutes. Additional ethanol (10 ml) was added to the reaction mass, cooled to 0-5⁰C and stirred for 2 hours. The precipitated solid was filtered, washed with chilled ethanol (600ml) and dried at 40- 45⁰C to afford 5.0 g of the title compound.

Method B: A solution of 3-[2-(4-allyloxy-phenyl)-l-(4-fluoro-phenyl)-4-oxo-azetidin-3-yl]- propionic acid 7V,./V-dicyclohexylamine salt (300g, 0.545 mol) in dichloromethane (1.50L) and N,N- dimethylformamide (6ml) was cooled to 5-1O⁰C under nitrogen atmosphere. Oxalyl chloride (120ml, 1.42mol) was added slowly at 5-15⁰C to the above mixture and stirred at 5-15⁰C. After completion of the reaction (monitored by TLC/HPLC), the solvent was distilled off under reduced pressure. Tetrahydrofuran (300ml) was added to the resulting residue and distilled off under reduced pressure at 40-50⁰C. To the residue, tetrahydrofuran (1.80L) was added and mixture was cooled to -80° to - 9O⁰C. Iron (III) acetylacetonate (11.25g) was added to the reaction mass followed by addition of Grignard reagent at -80 to -9O⁰C. After reaction completion, the reaction mass was slowly poured into chilled water (1.50L). Thereafter, tertiary butylmethyl ether (1.20L) was added to the reaction mass and stirred at 25-3O⁰C for 15 minutes. The reaction mass was filtered through hyflo and the hyflo was washed with tert-butylmethyl ether (1.20L). The organic layer was separated from the filtrate, washed twice with brine solution (2x3.0L) and then dried over sodium sulphate. The solvent was distilled off under reduced pressure at 40-50⁰C. Ethanol (300ml) was added to the resulting residue and distilled off under reduced pressure at 40-50⁰C. The reaction mass was then cooled to 20- 25⁰C and ethanol (600ml) was added and stirred to dissolve the residue. Title compound (1.50g) was added as seeds to the reaction mass and stirred at 20-30⁰C for 60 minutes. Additional ethanol (300ml) was added to the reaction mass, cooled to 0-5⁰C and stirred for 2 hours. The precipitated solid was filtered, washed with chilled ethanol (600ml) and dried at 40-45⁰C to afford 181g of the title compound as a crystalline solid having purity 99.11% by HPLC. Example-8 Preparation of ezetimibe Step-I: Preparation of 4-(4-allyloxy-phenyl)-l-(4-fluoro-phenyl)-3-[(3S)-3-(4-fluoro-phenyl)-3- hydroxy-propyl]-azetidin-2-one: To a solution of boranedimethyl sulfide complex (2.10ml) and (R)-2-methyl-CBS-oxazoborolidine(1.12ml) in dichloromethane O⁰C under nitrogen atmosphere, 4- (4-allyloxy-phenyl)- 1 -(4-fluoro-phenyl)-3 -[3 -(4-fluoro-phenyl)-3 -oxo-propyl] -azetidin-2-one ( 1 Og, 0.022mol) in dichloromethane (30ml) was added slowly at 0-5⁰C and the reaction mixture was stirred till completion of the reaction (monitored by thin layer chromatography). Methanol (4ml) and 5% aqueous hydrogen peroxide solution (50ml) were added to the reaction mixture and stirred at 25- 3O⁰C for 15 minutes. The organic layer was separated, successively washed with 1 N hydrochloric acid solution (50ml) and brine (50ml), dried over sodium sulphate. The solvent was distilled off completely under reduced pressure to obtain the title compound. Step-II: Preparation of ezetimibe: To a solution of 4-(4-allyloxy-phenyl)-l-(4-fluoro-phenyl)-3- [(3S)-3-(4-fluoro-phenyl)-3-hydroxy-propyl]-azetidin-2-one (obtained above) and 5, 5 -dimethyl- 1,3- cyclohexanedione (6.2Og, 0.044 mol) in tetrahydrofuran (200ml), tetrakis (triphenyl- phosphine)palladium(O) (0.15g, 0.129 mmol) was added at 25-3O⁰C and the reaction mass was heated with vigorous refluxing under nitrogen gas atmosphere. After completion of the reaction (monitored by thin layer chromatography), the mixture was cooled to 25-3O⁰C and poured into 10% sodium carbonate solution (200ml) and extracted with ethyl acetate (200ml). The organic layer was separated and washed successively with 10% aqueous sodium carbonate solution (2 x 200ml), demineralized water (200ml) and dried over sodium sulphate. The solvent was distilled off completely under reduced pressure to obtain title compound. Example 9: Preparation of ezetimibe Step-I: Preparation of l-(4-fluoro-phenyl)-3-[3-(4-fluoro-phenyl)-3-oxopropyl]-4-(4-hydroxy- phenyl)-azetidin-2-one: To a solution of 4-(4-allyloxy-phenyl)-l-(4-fluoro-phenyl)-3-[3-(4-fluoro- phenyl)-3-oxo-propyl]-azetidin-2-one (25Og, 0.56 mol) in dichloromethane (625ml), morpholine (72.9Og, 0.84mol) and tetrakis(triphenylphosphine)palladium (1.25g,0.0011 mol) were added and heated to reflux. After reaction completion (monitored by TLC) the reaction mass was cooled to 20- 3O⁰C and washed with IN hydrochloric acid (3x1.25L), demineralized water (1.25L), with brine solution (1.25L) respectively. The organic layer was dried over sodium sulphate and distilled at 40- 5O⁰C under atmospheric pressure to afford title compound having purity 98.99 % by HPLC. Step-II: Preparation of ezetimibe: Boranedimethylsulfϊde complex (84.82ml, 0.89mol) and (R)-2- methyl-CBS-oxazo- borolidine (55.87ml, 0.056 mol) were added to pre cooled dichloromethane (500ml) and the reaction mass was stirred at 0-5⁰C for 15 minutes under nitrogen atmosphere. l-(4- Fluoro-phenyl)-3-[3-(4-fluoro-phenyl)-3-oxopropyl]-4-(4-hydroxy-phenyl)-azetidin-2-one (as obtained above) in dichloromethane (750ml) was added slowly at 0-5⁰C to the reaction mass and then maintained at same temperature till reaction completion (during reaction, dichloromethane (3 L) was added in lots). After reaction completion, methanol (250ml) was added to the reaction mixture at 0-5⁰C, followed successively by addition of 5% aqueous hydrogen peroxide solution (1.25L) and tetrahydrofuran (500ml) at 0-15⁰C, and stirred for 15 minutes at 20-30⁰C. The organic layer was separated, washed successively with 1 N hydrochloric acid (1.25L) and brine solution (2.50L). The organic layer was distilled off at 40-50 ° C and finally under reduced pressure to afford title compound as a residue. The residue was taken in isopropyl alcohol (500ml), heated and solvent was distilled off under reduced pressure. Isopropyl alcohol (375ml) was again added to the reaction mass and stirred at 65-7O⁰C to dissolve the residue, activated charcoal (25g) was added and the reaction mass was stirred at 65-7O⁰C for 30 minutes. The reaction mass was filtered through hyflo bed and washed with hot isopropyl alcohol (505ml); demineralized water was (220ml) was added to the filtrate at 25-3O⁰C under stirring. The reaction mixture thereafter cooled to 3O-35°C, stirred for 2 hours and then further cooled to 0-5⁰C and stirred for 2 hours. The resulting solid was filtered, washed successively with a chilled mixture of isopropyl alcohol (125ml) and demineralized water (25ml), demineralized water (1.25L) and finally dried at 60-65⁰C to afford 172g of title compound having purity 99.39 % and (R)-isomer impurity 1.70% by HPLC Example-10 Purification of ezetimibe Ezetimibe (17Og, having relative purity 99.39% and impurity (R)-isomer 1.70% by HPLC) in isopropyl alcohol (850ml) was stirred at 55-60⁰C to get a clear solution. The water bath was removed and demineralized water (170ml) was added into the reaction mass. The reaction mass was slowly cooled to 30-35⁰C and stirred for 2 hours. The reaction mass was further cooled to 0-5⁰C and stirred for 2 hours. The resulting purified product was filtered, washed with a chilled mixture of isopropyl alcohol (125ml) and demineralized water (25ml) followed by washing with demineralized water (500ml) and dried at 60-65⁰C to give 153g of the title compound having purity 99.62% and (R)- isomer impurity 0.65% by HPLC. The product was crystallized twice from isopropanol and water to give 119g of the title compound having purity 99.83% and (R)-isomer impurity 0.017 % by HPLC. Example 11: Purification of 4-(4-allyloxy-phenyl)-l-(4-fluoro-phenyl)-3-[3-(4-fluoro-phenyl)-3- oxo-propyl]-azetidin-2-one

To a solution of 4-(4-allyloxyphenyl)-l-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl]- azetidin-2-one (0.5Og , O.OOlmol having purity 98.55% and containing 0.65% impurity of formula XII where R₂, R₃ and R₄ are hydrogen) in methanol (10ml), potassium carbonate (0.3 Ig , 0.002mol) and demineralized water ( 1.0ml) were added and the reaction mixture was stirred at 35-45⁰C for 4 hours. The resulting solid was filtered, washed with demineralized water (5ml) and dried to give 0.45g of title compound having purity 99.61% and impurity of formula XII (where R₂, R₃ and R₄ are hydrogen) at the level of 0.06% by HPLC.

Example 12: Preparation of 3-[l-(4-fluoro-phenyl)-2-(4-hydroxy-phenyl)-4-oxo-azetidin-3-yl]- propionic acid 4-{l-(4-fluoro-phenyl)-3-[3-(4-fluoro-phenyl)-3- hydroxy-propyl] -4-oxo- azetidin-2-yl}-phenyl ester

To a solution of 3-[2-(4-allyloxyphenyl)-l-(4-fluorophenyl)-4-oxoazetidhi-3-yl]-propionic acid N,N- dicyclohexylamine salt (31.08g, 0.056mol) in dichloromethane (155ml) and N,N-dimethylformamide (0.62ml) at 5-1O⁰C under nitrogen atmosphere, oxalyl chloride (12.43ml, 0.14mol) was slowly added at 5-15°C and the mixture was stirred at 5-15°C. After reaction completion (monitored by TLC), the solvent was distilled off under reduced pressure at 60-65⁰C. The resulting residue was dissolved in dichloromethane (100ml) and slowly added to a stirred solution of l-(4-fluorophenyl)-3-[3-(4- fluorophenyl)-3-oxopropyl]-4-(4-hydroxy phenyl)-azetidin-2-one (23g, 0.056mol), triethylamine (9.44ml, 0.068mol) in dichloromethane (100ml) under nitrogen atmosphere at 0-5⁰C. After reaction completion, the reaction mass was successively washed with demineralized water (200ml), IN HCl solution (200ml) and finally with brine solution (200ml). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure at 40-50⁰C. Dichloromethane (107ml) was added to resulting residue under nitrogen atmosphere followed by addition of morpholine (7.38g, 0.085mol) and tetrakis(triphenylphosphene)palladium (261mg, 0.23 mmol) and the reaction mass was heated to reflux under stirring. After reaction completion, the reaction mass was cooled to 20- 3O⁰C, washed with IN HCl solution (200ml) and finally with brine solution (200ml). The organic layer was dried over sodium sulfate and concentrated under reduced pressure at 40-50⁰C. The residue thus obtained was dissolved in a mixture of tetrahydrofuran (200ml) and methanol (200ml), under nitrogen atmosphere and cooled to O⁰C and sodium borohydride (2.56g, 0.068mol) was added in small lots and the reaction mass was stirred at 0-5⁰C till reaction completion (by TLC). Demineralized water (400ml) and ethyl acetate (400ml) were added to reaction mass and stirred at room temperature for 15 minutes, the layers were separated and aqueous layer was extracted with ethyl acetate (200ml). The combined organic layer was washed with IN HCl solution (200ml) and brine solution (200ml), dried over sodium sulfate and then concentrated under reduced pressure at 40-50⁰C to give crude title compound, which was purified by column chromatography on silica gel and then crystallized from a mixture of hexane and ethyl acetate. The resulting product was filtered and dried to give 19g of title compound having purity 99.06 % by HPLC.

Example 13: Preparation of 4-(4-allyloxyphenyl)-l-(4-fluorophenyl)-3-[3-(4-fluorophenyI)-3- hydroxy-propyl] -azetidin-2-one To a solution of 4-(4-allyloxyphenyl)-l-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl]- azetidin-2-one (50g,0.11mol) in a mixture of tetrahydrofuran (250ml) and methanol (250ml) at 0- 5⁰C, sodium borohydride (2.10g,0.55mol) was added in small lots and the mixture was stirred at 0- 5⁰C. After completion of the reaction (monitored by TLC), demineralized water (250ml), ethyl acetate (250ml) were successively added to the reaction mass and stirred at room temperature for 15 minutes. The layers were separated; the organic layer was successively washed with IN HCl solution (250ml), demineralized water (250ml), dried over sodium sulfate and then concentrated under reduced pressure at 40-50⁰C. The resulting residue was purified by column chromatography on silica gel to obtain 2Og of pure title compound.

Claims

WE CLAIM

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

Formula-I comprising the steps of: a. condensing the compound of formula II,

Formula-II wherein Ri is selected from C wo alkyl group, aryl group, substituted aryl group, aryl alkyl or substituted aryl alkyl group with a Schiff base of formula III,

Formula-Ill wherein R₂, R₃ and R₄ can be individually selected from hydrogen, C ₁₄ alkyl group, aryl group, substituted aryl group, Ci^ alkoxy group in the presence of a Lewis acid catalyst and a base in a suitable organic solvent to obtain a compound of formula FV;

Formula-IV wherein Ri, R₂, R₃ and R₄ are as defined above b. cyclizing the compound of formula IV in the presence of a silylating agent, a fluoride source, in a suitable solvent to obtain a compound of formula V;

Formula-V wherein Ri, R2, R₃ andR4 are as defined above c. hydrolyzing the compound of formula V in the presence of a suitable base in a suitable solvent to obtain a compound of formula VI;

Formula-VI wherein R₂, R₃ andR₄ are as defined above d. optionally, reacting the compound of formula VI with a base to form its salt; e. reacting the compound of formula VI or salts thereof with an activating agent in a suitable solvent to obtain its reactive derivative of formula VII;

Formula-Vπ wherein R₂, R₃ andR₄ are as defined above and X is halogen or a good leaving group suitable for the Grignard or organometallic addition reaction f. reacting the compound of formula VII with a suitable Grignard reagent or another organometallic reagent in the presence of a catalyst or ligand in a suitable solvent to obtain a compound of formula VIII; and

Formula-Vm wherein R₂, R₃ andR₄ are as defined above g. converting the compound of formula VIII to ezetimibe of formula I. 2). The process according to claim 1, wherein in step a) Lewis acid catalyst includes titanium tetrachloride and titanium isopropoxide or combination thereof and bases includes organic base like tertiary amine selected from trialkylamine such as N,N-diisopropylethylamine, triethylamine, tri-n-butylamine, tri-n-propylamine, tetramethylethylenediamine and the like.

3). The process according to claim 1, wherein step a) suitable organic solvent includes aliphatic or aromatic hydrocarbon solvents such as toluene, 1,2 or 1,4-xylene; halogenated solvents such as dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride; ethers such as tetrahydrofuran, 2-methyl tetrahydrofuran, 1,2-dimethoxyethane, 1,2-diethoxyethane or mixture thereof.

4). The process according to claim 1, wherein in step b) silylating agents include N₁O- bis(trimethylsilyl)acetamide, N-methyl-O-trimethylsilylacetamide, isopropenyloxy trimethyl silane , trimethylsilyl chloride and the like and fluoride source includes tetra n-butylammonium fluoride, cesium fluoride, potassium fluoride, benzyltriethylammonium fluoride, benzyltrimethylammonium fluoride, phenyltriethylammonium fluoride, phenyltrimethyl- ammonium fluoride or hydrates thereof. 5). The process according to claim 1, wherein in step b) suitable solvent include ethers such as alkyl or aryl or cyclic ether such as tetrahydrofuran, 2-methyl tetrahydrofuran, methyl tert-butyl ether; aliphatic or aromatic hydrocarbons such as toluene, 1,2 or 1,4-xylene; alkyl or allyl nitrile such as acetonitrile; alkyl or allyl ester such as ethylacetate; halogenated solvent such as dichloromethane or mixture thereof. 6). The process according to claim 1, wherein in step c) suitable base includes alkali or alkaline metal hydroxides, alkali or alkaline metal carbonates/ bicarbonates, hydrates and alkoxide thereof such as lithium hydroxide, lithium hydroxide monohydrate, sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide and the like. T). The process according to claim 1, wherein in step c) suitable solvents include C_1-5 alcohols such as methanol, ethanol, isopropanol, tertiary butanol; alkyl or aryl or cyclic ethers such as tetrahydrofuran, 2-methyl tetrahydrofuran; dialkyl ethers; and C_3-6 ketones such as acetone, methyl isobutyl ketone or mixture thereof.

8). The process according to claim 1, wherein in step d) base is organic base which includes primary, secondary or tertiary amines depending upon substitution such as amine of general formula NR₅R₆R₇ wherein R^, Re and Rγ can be independently selected from hydrogen, unsubstituted or monosubstituted or polysubstituted (Cj-CgJ-alkyl; (Cι-Cs)cycloalkyl, alkenyl, alkynyl, alkaryl, aryl, aralkyl, alkoxy, aryloxy, aminoalkyl or aminoaryl or a three to six membered heterocyclic ring with one or more hetero atom selected from nitrogen, oxygen or sulfur 9). The process according to claim 1, wherein hi step d) base is inorganic bases that include alkali or alkaline earth metal hydroxide, carbonates, bicarbonate, alkoxide, hydride thereof. 10). The process according to claim 1, wherein in step e) activating agent includes oxalyl chloride, phosphorous trihalide, phosphorous pentahalide, thionyl halide, organic acid halide such as acetyl chloride, pivaolyl chloride, C_2-8alkyl chloroformate, aryl chloroformates, Lewis acid such as boric acid or 4-(4,6-dimethoxy-l,3,5-triazi-2-yl)-4-methylmorpholinium chloride, triazole such as benzotriazole and the like. 11). The process according to claim 1, wherein step e) suitable solvent includes halogenated solvents such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane; aliphatic esters such as ethyl acetate; aliphatic or cyclic ether such as tetrahydrofuran, 2-methyl tetrahydrofuran,

1,2-dimethoxyethane, 1,2-diethoxyethane; amide solvent such as dimethylformamide; aliphatic or aromatic hydrocarbon solvent such as toluene, 1,2 or 1,4-xylene; and the like or mixture thereof. 12). The process according to claim 1, wherein in step f) is carried out in presence of catalyst that includes transition metal salts or complex thereof including metal such as palladium, zinc, cerium or iron metal; palladium salts, iron (IΙI)salts; iron (III) acetyl acetonate, FeCl₂, FeCl₃, ZnCl₂, cerium (III) chloride, Pd (0) complexes, Cu (I) salts, tetrakis(triphenylphosphine) palladium and the like with or without additives; or ligands includes iV-methyl morpholine,

Λ^ΛζiV'.iV'-tetramethylethylene diamine, ΛζN.N'.N'.N'-tetramethyldiethylene triamine and bis[2- (ΛζiV-dimethyl amine)ethyl]ether and the like.

13). The process according to claim 1, wherein in step f) suitable solvent includes aliphatic or aromatic hydrocarbon solvent such as toluene, 1,2 or 1,4-xylene; halogenated solvent such as dichloromethane, 1,2-dichloroethane and aliphatic or cyclic ether such as tetrahydrofuran, 2- methyl tetrahydrofuran, 1,2-dimethoxyethane, 1,2-diethoxyethane and the like and mixture thereof.

14). The process according to claim 1 , wherein preferably, R] is phenyl; R₂, R₃ and R₄ are hydrogen.

15). The process according to claim 1, wherein the compound of formula VIII is converted to ezetimibe by, a. deallylating the compound of formula VIII to obtain a compound of formula X; and

Formula X b. reducing the carbonyl group of compound of formula X in presence of chiral reducing agent or reducing agent in presence of chiral catalyst to form ezetimibe of formula I. 16). The process according to claim 15, wherein in step a) deallylation is carried out in the presence of 1,3-dicarbonyl compounds; β-ketoesters; 1,3-diketones; substituted and unsubstituted amines such as morpholine or pyrrolidine and the like or alkali metal carbamate in presence of suitable transition metal catalyst; or using an acid catalyst such as sulfonic or sulfuric acid catalyst selected from p-toluenesulfonic acid, benzene sulfonic acid or salts thereof, preferably p- toluenesulfonic acid or bases that include alkali metal carbonate such as potassium carbonate and the like.

17). The process according to claim 15, wherein in step b) reducing agent includes borane dimethyl sulfide complex, borane tetrahydrofuran complex, sodium borohydride, a substituted borohydride eg.[ CBZ-Proline]₃BHNa and the like and chiral catalyst includes(R)-2-methyl- CBS-oxazaborolidine, R-butyl CBS-oxazaborolidine, R-phenyl CBS-oxazaborolidine, β-chloro diisopinocamphenyl borane and the like or by any known non-hydrogenolytic conditions. 18). A compound of formula FV including salts, solvates, isomers, hydrates and chiral isomers thereof,

Formula-IV wherein Ri is selected from Ci-io alkyl group, aryl group, substituted aryl group, aryl alkyl or substituted aryl alkyl group; R₂, R3 and R₄ can be individually selected from hydrogen, C_t-β alkyl, aryl, substituted aryl, C ).₆ alkoxy group.

19). A compound of following formula, including salts, solvates, isomers, hydrates and chiral isomers thereof:

when Z is ORu it represents formula V, wherein Ri is selected from C_/.yø alkyl group, aryl group, substituted aryl group, aryl alkyl or substituted aryl alkyl group ; when Z is OH, it represents formula VI; when Z is X it represents formula VII, wherein X is halogen or a good leaving group suitable for the Grignardor organometallic addition; when Z is 4-flourophenyl, it represents formula VIII; wherein R₂, Rs andR₄ can be individually selected from hydrogen, C ₁.₆ alkyl, aryl, substituted aryl, Ci^ alkoxy group.

20). A compound of formula XI,

Formula XI including salts, solvates, isomers, hydrates and chiral isomers thereof.