FIELD OF INVENTION
The present invention provides an industrially advantageous process for the preparation of ezetimibe of formula I, using novel intermediates.
BACKGROUND OF THE INVENTION
Ezetimibe of Formula-1 is indicated as monotherapy for the treatment of primary hypercholesterolemia and horaozygous sitosterolemia and is chemically known as l-(4-fluorophenyl)-3-(R)-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4(S)-(4-hydroxyphenyl)-2-azetidinone.
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,
(Figure Removed)
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,

HiCOOC.
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 tetraki's (triphenyl phosphine) palladium to give an aromatic ketone of formula.
(Figure Removed)

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 publication WO 2006/137080 discloses a process for the preparation of ezetimibe, wherein in 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-fluorophenylmagnesium 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 leads 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 qualities which results in lot of bye product and difficult to remove and not green chemistry. The sample of zinc chloride has to be protected from moisture and always freshly fused before use.
The above mentioned drawbacks calls for an alternative and novel process for the preparation of ezetimibe with novel intermediates that is cost effective, eco-friendly, commercially viable, reproducible on industrial scale and meets the needs of regulatory agencies.
It is, therefore, desirable to solve the problems associated with the prior art and to provide an efficient process for the preparation of ezetimibe which improves the economics by employing less expensive and less hazardous raw materials and is more productive. The process must be convenient to operate on a commercial scale and give the desired product in good yield and quality.
SUMMARY OF THE INVENTION
The present invention provides a novel and alternative process for the preparation of l-(4-fluorophenyl)-3(R)-[3-(4-fliiorophenyl)-3(S)-liydroxypropyl]-4(S)-(4-hydroxyphenyl)-2-azetidinone herein referred to as ezetimibe of formula I,
comprising:
a) condensing pentanedioic acid monobenzyl ester of formula II,

Formula-II
with (S)-(+)-4-phenyl-2-oxazolidinone in the presence of 4-dimethylaminopyridine and N,N-dimethylformamide to form 5-oxo-5-(2-oxo-4-phenyl-oxazolidin-3-yl)-pentanoic acid benzyl ester of formula III,
b) condensing 5-oxo-5-(2-oxo-4-phenyl-oxazolidin-3-yl)-pentanoic acid benzyl ester of formula III with (4-benzyloxy-benzylidine)-4-fluoro-phenyl)-amine of formula IV,
n the presence of lewis acid like titanium tetra chloride along with titanium isopropoxide and 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,
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 in the presence of a silylating agent, a fluoride anion source and a suitable solvent to form 3-[2-(4-benzyloxy-phenyl)-1 -(4-fluorophenyl)-4-oxo-azetidin-3-yl]-propionic acid benzyl ester of formula VI,
hydrolyzing 3-[2-(4-benzyloxy-phenyl)-l-(4-fluorophenyl)-4-oxo-azetidin-3-yl]-propionic acid benzyl ester of formula VI in the presence of base and suitable solvent to form 3-[2-(4-benzyloxy-phenyl)-] -(4-fluorophenyl)-4-oxo-azetidin-3-yl]-propionic acid of formula VII,
Formula-VII

d) 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 to form 3-[2-(4-benzyloxy-
phenyl)-1 -(4-fluorophenyl)-4-oxo-azetidin-3 -yl]-propionyl chloride of formula VIII,
e) reacting 3-[2-(4-benzyloxy-phenyl)-l-(4-fluorophenyl)-4-oxo-azetidin-3-yl]-propionyl
chloride of formula VIII with phenyl magnesium bromide in the presence of a suitable
solvent and iron catalyst to form 4-(4-benzyloxy-phenyl)-l-(4-fluoro-phenyl)-3-[3[(4-
fluoro-phenyl)-3-oxo-propyl]-azetidin-2-one of formula IX,
f) reducing 4-(4-benzyloxy-phenyl)- 1 -(4-fluoro-phenyl)-3-[3 [(4-fluoro-phenyl)-3-oxo-propyl]-azetidin-2-one of formula IX with borane dimethyl sulfide complex in the presence of (R)-2-methyl-CBS-oxazaborolidine in a suitable organic solvent to form 4-(4-benzyloxy-phenyl)-l-(4-fluoro-phenyl)-3-[3[(4-fluoro-phenyl)-3-hydroxy-propyl]-azetidin-2-one of formula X,
g) debenzylating the same with Pd/C in a suitable alcoholic solvent preferably alcoholic solvent to form ezetimibe of formula I.
Another aspect of the present invention provides novel intermediates and processes useful for the preparation of the same. Ultimately, these intermediates can be linked to provide a total synthesis of pharmaceutically acceptable ezetimibe.
DETAILED DESCRIPTION OF THE TNVENTTON
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,
One aspect of the present invention provides a process for the preparation of ezetimibe comprising condensing pentanedioic acid monobenzyl ester of 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,

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 methylene chloride, is added to the pentanedioic acid monobenzyl ester of formula II and the reaction mass is allowed to cool to a temperature of about 10-20°C. Preferably halogenated solvent used is methylene chloride. 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 aniine, diisopropyl ethylamine, tributylamine, triethylamine. Preferably triethyl amine is used. To the reaction mass, pivaloyl chloride is added slowly while maintaining the reaction temperature between 10-35°C. 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 N.N-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 45-65°C 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 10-25°C. To the reaction mass, sulphuric 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 40°C 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/gas chromatography.
Another aspect of the present invention is to provide a process for the preparation of pentanedioic acid monobenzyl ester of formula IT as given above. Typically, pentanedioic

acid monobenzyl ester can be prepared from glutaric acid. More particularly, glutaric acid alongwith benzyl alcohol, p-toluene sulphonic 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 or high performance liquid chromatography 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 monobenzyl 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-plienylamino)-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 0°C. Suitable solvent can be selected from methylene chloride, 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 -20°C and benzylated Schiff

base is added to it. The reaction is maintained at -15°C to -20°C for 6 hours. After 6 hours the reaction mass is further cooled to a temperature of below -20°C 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 5°C. 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 60°C and followed by the slow addition of hexane. The reaction mass is cooled to 0-5°C and the solid is filtered, washed with hexane and finally dried under vacuum at 50-55°C 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/gas 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-yr)pentanoic acid benzyl ester of formula V can be cyclized to 3-[2-(4-beiuyloxy-phenyl)-l-(4-fliiorophenyl)-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, nitrites, halogenated solvents. Preferably the solvent can be selected from amongst methyl tertiary butyl ether, toluene.

acetonitrile. Mild silylating agent preferably A/r,O-bis(trimethyl silyl)acetamide is added to the reaction mass with continuous stirring for few minutes. To the reaction mass, phase transfer catalyst is added and the temperature of reaction mass is raised to 40°C. The phase transfer catalyst can be fluoride anion source, selected from amongst tetra butyl ammonium bromide, tetra butyl ammonium fluoride, tetra butyl ammonium sulfate, cesium fluoride, potassium fluoride. Preferably tetra butyl ammonium 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 vacuum. Alcoholic solvent preferably etlianol 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 0°C 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 50-55°C to 3-[2-(4-benzyloxy-phenyl)-1 -(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/gas 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-pheiiyl)-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]-propionic 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 is selected from tetrahydrofuran, inethanol. ethanol, isopropyl alcohol, acetone, 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, HC1 solution is added (pH=5-6) then the product is extracted in ethyl acetate, layers are seperated and the solvent from organic layer is removed by distillation under vacuum at 50-55°C. The product is dissolved in ethylacetate by 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 25-30°C, stirred for few hours, filtered and washed with hexane and dried under vacuum at 50-55°C 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/gas chromatography. 3-[2-(4-benzyloxy-phenyl)-]-(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.
3-[2-(4-benzyloxy-phenyl)-1 -(4-fluorophenyl)-4-oxo-azetidm-3-yl]-propionic acid of formula VII is added to a suitable solvent and cooled to 10°C under nitrogen. Suitable solvent can be selected from halogenated solvent, aromatic hydrocarbons. Preferably halogenated solvent can be selected from methylene chloride, chloroform, carbon tetrachloride. More preferably methylene chloride is used. To the above solution, oxalyl chloride is added slowly at a temperature of below 20°C and then the reaction mass is stirred at ambient temperature till the reaction is complete. The solvent is distilled off fully under vacuum at 50°C to get 3-[2-(4-benzyloxy-phenyl)-1 -(4-fluorophenyl)-4-oxo-azetidin-3-yl]-propionyl chloride of formula VIII.
Yet another aspect of the present in invention provides a process for the conversion of acid chloride of formula VIII to 4-(4-benzyloxy-phenyl)-l-(4-fluoro-phenyl)-3-[3[(4-fIuoro-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 V11I, 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 or a mixture of both xylene, ethyl acetate etc.. To the reaction mass, catalytic amount of appropriate catalyst is added and the reaction mass is further stirred at a temperature of-70 to -95°C 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. 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%, Quenching with dilute acid like IN hydrochloric acid followed by extraction with suitable organic solvent like methyl tertiary butyl ether yields 4-(4-benzyloxy-phenyl)-l -(4-fluoro-phenyl)-3-[3[(4-fluoro-plienyl)-3-oxo-propyl]-azetidin-2-one of formula IX in high yield and having purity greater than 82% by high performance liquid chromatography/gas chromatography. 4-(4-benzyloxy-phenyl)-l-(4-fluoro-phenyl)-3-[3[(4-fluoro-phenyl)-3-oxo-propyl]-azetidin-2-one of formula IX can be reduced to form 4-(4-benzyloxy-phenyl)-l-(4-fluoro-phenyl)-3-[3[(4-fluoro-phenyl)-3-hydoxy-propyl]-azetidin-2-one of formula X.
Typically, 4-(4-benzyloxy-phenyl)-1 -(4-fluoro-phenyl)-3-[3 [(4-fluoro-phenyl)-3-oxo-
propyl]-azetidin-2-one 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 stochiometric amount at a temperature of below 5°C under inert atmosphere. Suitable anhydrous organic solvent can be selected from methylene chloride, 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 (R)-2-methyl-CBS-oxazaborolidine, R-butyl CBS, R-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 IN hydrochloric acid followed by extraction with suitable organic solvent like methanol yields 4-

(4-benzyloxy-phenyl)-l-(4-tliioro-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 high performance liquid chromatography/gas chromatography.
Compound of formula X can 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 C(-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/cm2 at a temperature of about 25-45°C till the reaction goes to completion. The ezetimibe so obtained can be crystallized further using alcoholic solvent and water to yield pure ezetimibe having purity greater than 95% by high performance liquid chromatography. The alcoholic solvent can be selected from Ci-C4 alcohols.
Major advantages realized in the present invention are:
1. Use of novel intermediates which are easy to prepare and purify without using colomn
chromatography. Novel intermediates have only minimal residual impurities and are
prepared in high yields.
2. No need of costly and time consuming purification techniques and tedious column
chromatography technique as reported in prior art processes.
3. Lesser reaction time and easily scalable process,
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 (R)-2-methyl-CBS oxazaborolidin (0.05 M eq.) as compared to
that reported in US 5,631,365 (0.22 M eq.), 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. Several variants of these examples would be evident to persons
EXAMPLES
Example 1
Preparation of pentanedioic acid monabenzyl ester
Glutaric acid (200 g) was taken alongwith benzyl alcohol (160 g), p-toluene sulphonic 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 sulphate. Solvent was distilled off fully under vacuum and then degassed to get the title compound as oil. Example 2
Preparation of 5-oxo-5-(2-oxo-4-phenyl-oxazolidin-3-vl)-pentanoic acid benzyl ester Methylene chloride (1.70 L) was added to the oil 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 15-20°C. After addition, the reaction mass was stirred for 60 minutes at 25-30°C. (S)-(+)-4-Phenyl-2-oxazolidinone (172 g), 4-dimethylaminopyridine (30 g) and /V,Ar-Dimethylformamide (184 ml) were added and the reaction mass was heated to 50-55°C and then maintained at this temperature for 5 hours. After 5 hours the reaction mass was cooled to 20°C, 2N sulphuric 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 bisulphite solution (1.0 L) and then with saturated sodium chloride solution (1.0 L). The organic layer was dried over sodium sulphate. 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 0-5°C and then maintained at 0-
5°C for 2 hours. The solid was filtered and washed with chilled ethanol (200 ml). Finally the
solid was dried at 40°C under vacuum to get 220 g of the title compound having purity of
98.16%byHPLC.
Example 3
Preparation of Benzylated Schiff Base
p-Hydroxy benzaldehyde (100 g) was charged alongwith demineralized water (1.0 L), Sodium hydroxide (34.40 g) and stirred at ambient temperature for 5 minutes. Methylene chloride (750 ml) and tetra butyl ammonium 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 25-30°C for 90 minutes. The two layers were separated. Aqueous layer was extracted with methylene chloride (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% aqueous sodium chloride solution (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 60°C to get a clear solution. 4-Fluoroaniline (156 g) was added dropwise and then the reaction mass was maintained at 60°C 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 50-60°C to get 230 g of benzylated Schiff base having purity of 95.97% by HPLC.
Example 4
Preparation of 4-f(4-benzyloxy-phenyl)-(4-fluoro-phenylainino)-methyl15-oxo-5-(2-oxo-
4-phenvl-oxazolidin-3-vl)pentanoic acid benzyl ester
Methylene chloride (1.532 L) was cooled to 0°C under nitrogen atmosphere, Titanium tetra chloride (37.53 ml) and Titanium isopropoxide (32.40 ml) was added. 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 dichloride (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 0 to -5°C and then the reaction mass was stirred at 0 to -5°C for 60 minutes. The reaction mass was cooled to -25°C and benzylated schiffbase (115 g) was added. The reaction mass was maintained at -15 to -20°C for 6 hours. After 6 hours the reaction mass was cooled to -30°C and then a solution of acetic acid (100 ml) and methylene dichloride (100 ml) was added slowly at -30 to -25°C. The reaction mass was poured into 7% aqueous tartaric acid solution (1.75 L) precooled to 0°C. 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 25-30°C for 30 minutes. The two layers were separated. Aqueous layer was extracted with methylene dichloride (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 60°C 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 0-5°C 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 50-55°C to get 186 g of the title compound having purity of 99.48 % by HPLC.
Example 5
Preparation of 3-f2-(4-benzvloxy-Dhenvl)-l-(4-fluorophenyl)-4-oxo-azetidin-3-vl|-
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 tertiary butyl ether (1.86 L) and stirred for 5 minutes at ambient temperature. W,0-bis(trimethyl silyl)acetamide (223 ml) was added and the reaction mass was stirred for 5 minutes. Terra butyl ammonium fluoride trihydrate (3.72 g) was added and the temperature of reaction mass was raised to 40°C. Reaction mass was maintained at 38-42°C and reaction completion was checked by TLC/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 (1.86L). and 25% aqueous sodium chloride solution (1.86 L) respectively. The organic layer was dried over sodium sulphate. Silica gel (55.8 g) and activated carbon (37.20 g) was 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 tertiary butyl 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 0°C and stirred at 0-5°C for 2 hours. The solid was filtered and washed with chilled ethanol (186 ml). Finally the solid was dried under vacuum at 50-55°C to get 102 g of the title compound having purity of 98.26% by HPLC. Example 6
Preparation of 3-f2-(4-betizyloxy-Dhenyl)-l-(4-fhioroptienyl)-4-oxo-azetidin-3-yl1-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 by TLC/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 (1.0 L). Solvent was removed by distillation under vacuum at 50-55°C. Ethylacetate (100ml) 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 25-30°C and maintained for 10 hours. The solid was filtered and washed with hexane (100 ml). The solid was dried under vacuum at 50-55°C to get 80 g of the title compound having purity of 96.87% by HPLC, Example 7
ration of 4-(4-benzvloxv-phenvl)-l-(4-fluoro-phenyl)-3-[3[(4-fluoro-phenvl)-3-oxo-propyll-azetidin-2-one
3-[2-(4-benzyloxy-phenyl)-l-(4-fluorophenyl)-4-oxo-azetidin-3-yl]-propionic acid (25 g) was dissolved in methylene dichloride (150 ml) and then cooled to 10°C under nitrogen. Oxalyl chloride (10 ml) was added dropwise at 10-15°C and then the reaction mass was stirred at ambient temperature till reaction completion. Solvent was distilled off fully under vacuum at 50°C to get 3-[2-(4-benzy1oxy-phenyl)-1 -(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 -85°C 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 tertiary butyl 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 tertiary butyl 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% aqueous sodium chloride solution (2x100 ml) respectively. The organic layer was dried over sodium sulfate. Solvent was distilled off fully under vacuum at 50-55°C and degassed to get 26g of the title compound having purity 82.39%. Example 8
Preparation of 4-(4-benzyloxy-phenyl)-l-(4-fluoro-phenyl)-3-[3[(4-fluoro-phenyl)-3-hvdoxY-propyll-azetidin-2-one
Methylene chloride (100 ml) was taken in RBF and borane dimethyl sulfide complex (5.04 ml) was added under nitrogen. The reaction mass was cooled to 0°C. (R)-2-methyl-CBS-oxazaborolidine (3.04 ml, 1M in toluene) was added and then the reaction mass was stirred for 30 minutes at 0°C under nitrogen. A solution of 4-(4-benzyloxy-phenyl)-l-(4-fluoro-phenyl)-3-[3[(4-fluoro-phenyl)-3-oxo-propyl]-azetidin-2-one in methylene dichloride
(100 ml) was added slowly at 0°C. After addition, the reaction mass was maintained at 0°C till reaction completion by TLC/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 methylene dichloride (100 ml). The two layers were separated from the filtrate. The organic layer was washed with 25% aqueous sodium chloride solution (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 50-55°C. Finally the oil was degassed under vacuum at 50°C.The residue was dissolved in acetonitrile (100 ml) and then this acetonitrile layer was washed six times with hexane (6x100 ml) to eliminate difluorobiphenyl purity. Finally the acetonitrile layer was collected. Solvent was removed under vacuum at 50-55°C to get title compound having purity 84.78%. Example 9
Preparation of Ezetimibe
4-(4-ben2yloxy-phenyl)-l-(4-fliioro-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. E2 pressure (5.00-5.50 Kg/cm2) was applied at 30-35°C. Reaction conditions were maintained till reaction got completed by TLC/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 50-55°C 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 50-60°C under vacuum to get 17.50 g of the title compound.

WE CLAIM;
1. A process for the preparation of ezetimibe of formula I,
which comprises:
a) condensing pentanedioic acid monobenzyl ester of formula II,
with a chiral auxiliary preferably (S)-(+)-4-phenyl-2-oxazolidinone in the presence of base preferably triethylamine, pivaloyl chloride, 4-dimethylamino pyridine and N.N-dimethylformamide to form 5-oxo-5-(2-oxo-4-phenyl-oxazolidin-3-yl)-pentanoic acid benzyl ester of formula III,
b) condensing 5-oxo-5-(2-oxo-4-phenyl-oxazolidin-3-yl)-pentanoic acid benzyl ester of
formula III with (4-benzyloxy-benzylidine)-4-fluoro-phenyl)-amine of formula IV,
in the presence of lewis acid like titanium tetra chloride along with titanium isopropoxide and suitable organic solvent selected from halogenated solvent preferably methylene chloride
to form 4-[(4-benzyloxy-phenyl)-(4-fliioro-phenylamino)-methyl]5-oxo-5-(2-oxo-4-phenyl-oxazolidine-3-yl)pentanoic acid benzyl ester of 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 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,
d) hydrolyzing 3-[2-(4-benzyloxy-phenyl)-]-(4-fluorophenyl)-4-oxo-azetidin-3-yl]-
propionic acid benzyl ester of formula VI in the presence of base and suitable solvent to
form 3-[2-(4-benzyloxy-phenyl)-l-(4-fluorophenyl)-4-oxo-azetidin-3-yl]-propionic acid
of formula VII,
e) reacting 3-[2-(4-benzyloxy-phenyl)- 1 -(4-fluorophenyl)-4-oxo-azetidin-3-yl]-propionic
acid of formula VII with oxalyl chloride in halogenated solvent preferably methylene
chloride to form 3-[2-(4-benzyloxy-phenyl)-l -(4-fluorophenyl)-4-oxo-azetidin-3-yl]-propionyl chloride of fomiula VIII,
f) reacting 3-[2-(4-benzyloxy-phenyl)-]-(4-fluorophenyl)-4-oxo-azetidin-3-yl]-propionyl chloride of formula VIII with phenyl magnesium bromide in the presence of suitable solvent and catalyst to form 4-(4-benzyloxy-phenyl)-l-(4-fliioro-phenyl)-3-[3[(4-fliioro-phenyl)-3-oxo-propyl]-azetidin-2-one of formula IX,
.v
g) reducing 4-(4-benzyloxy-phenyl)-l-(4-fluoro-phenyl)-3-[3[(4-fluoro-phenyl)-3-oxo-propyl]-azetidin-2-one of formula IX to form 4-(4-benzyloxy-phenyl)-l-(4-fluoro-phenyl)-3-[3 [(4-fluoro-phenyl)-3-hydroxy-propyl]-azetidin-2-one of formula X,
h) debenzylating 4-(4-benzyloxy-phenyl)-l-(4-fluoro-phenyl)-3-[3[(4-fliioro-phenyl)-3-hydroxy-propyl]-azetidin-2-one of formula X to form ezetimibe of formula I.
2. A process according to claim 1, step (c), wherein silylating agent is A/.O-bisltrimethyl silyl)acetamide, a fluoride anion source is tetra butyl ammonium bromide, tetra butyl
ammonium fluoride, tetra butyl ammonium sulfate,cesium fluoride, potassium fluoride and solvent is ethers, aromatic hydrocarbons, nitriles,halogenated solvents.
3. A process according to claim 1, step (d), wherein suitable base is selected from alkali
metal hydroxides, alkalimetal carbonates, preferably lithium hydroxide and solvent is
selected from tetrahydrofuraiynethanol, acetone.
4. A process according to claim 1, step (f), wherein suitable organic solvent is
tetrahydrofuran, toluene etc. and the catalyst is iron acetyl acetonate, iron (III) chloride.
5. A process for the preparation of pentanedioic acid monobenzyl ester of formula II,
by refluxing glutaric acid alongwith benzyl alcohol, p-toluene sulphonic acid and 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 formula II.
6. A compound of formula III,
8. A compound of formula VI,
9. A process for the preparation of ezetimibe of formula I,
(Figure Removed) which comprises:
a) reacting 3-[2-(4-benzyloxy-phenyl)-l-(4-fluorophenyl)-4-oxo-azetidin-3-yl]-propionic acid of formula VII with oxalyl chloride in halogenated solvent preferably methylene chloride to form 3-[2-(4-benzyloxy-phenyl)-l-(4-fluorophenyl)-4-oxo-azetidin-3-yl]-propionyl chloride of formula VIII,
b) reacting 3-[2-(4-benzyloxy-phenyl)-l-(4-fluorophenyl)-4-oxo-azetidin-3-yl]-propionyl chloride of formula VIII with phenyl magnesium bromide in the presence of suitable solvent and catalyst to form 4-(4-benzyloxy-phenyl)-l-(4-fluoro-phenyl)-3-[3[(4-fluoro-phenyl)-3-oxo-propyl]-azetidin-2-one of formula IX.
F
Formula IX
c) reducing 4-(4-benzyloxy-phenyl)-1-(4-fluoro-phenyl)-3-[3[(4-fluoro-phenyl)-3-oxo-propyl]-azetidin-2-one of formula IX to form 4-(4-benzyloxy-phenyl)-l-(4-fluoro-phenyl)-3-[3[(4-fluoro-phenyl)-3-liydroxy-propy]]-azetidin-2-one of formula X.
debenzylating4-(4-benzyloxy-phenyl)-l-(4-fluoro-phenyl)-3-[3[(4-fluoro-phenyl)-3-hydroxy-propyl]-azetidin-2-one of formula X to form ezetimibe.
10. A process for the preparation of 3-[2-(4-benzyloxy-phenyl)-l-(4-fluorophenyl)-4-oxo-azetidin-3-yl]-propionic acid of formula VII,
which comprises: a) condensing pentanedioic acid monobenzyl ester of forniula II,
hiral auxiliary preferably (S)-(+)-4-phenyl-2-oxazolidinone in the presence of base preferably triethylamine, pivaloyl chloride, 4-dimethylamino pyridine and N,N-dimethylformamide to form 5-oxo-5-(2-oxo-4-phenyl-oxazolidin-3-yl)-pentanoic acid benzyl ester of formula III,
zolidin-3-yl)-pentanoic acid benzyl ester of
formula III with (4-benzyloxy-benzylidine)-4-fluoro-phenyl)-amine of formula IV,
in the presence of lewis acid like titanium tetra chloride along with titanium isopropoxide and suitable organic solvent selected from halogenated solvent preferably methylene chloride 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,
c) cyclizing 4-[(4-benzyloxy-phenyl)-(4-fluoro-phenylaniino)-methyl]-5-oxo-5-(2-oxo-4-phenyl-oxazolidine-3-yl)pentanoic acid benzyl ester of formula V in the presence of 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,
mula VI
d) hydrolyzing 3-[2-(4-benzyloxy-phenyl)-l-(4-f1uorophenyl)-4-oxo-azetidin-3-yl]-propionic acid benz>'l ester of formula VI in the presence of base and suitable solvent to form 3-[2-(4-benzyloxy-phenyl)-] -(4-fluorophenyl)-4-oxo-azetidin-3-yl]-propionic acid .