FIELD OF THE INVENTION
The present invention relates to an improved process for the purification of ezetimibe of formula I.

(Formula Removed)
Formula-I
Specifically, the present invention relates to a process for the synthesis of enantiomerically and chemically pure ezetimibe which is substantially free of impurities.
BACKGROUND OF THE INVENTION
Ezetimibe of formula-I is indicated as monotherapy for the treatment of primary hypercholesterolemia and homozygous sitosterolemia and is chemically known as l-(4-fluorophenyl)-3-(R)-[3-(4-fliiorophenyl)-3(S)-hydroxypropyll-4(S)-(4-hydroxyphenyl)-2-azetidinone.
(Formula Removed)
Formula-1
Ezetimibe was first disclosed in US Patent 5,767,115 (RE 37,721) as a useful
hypocholesterolemic agent in the treatment and prevention of artherosclcrosis.
The patent discloses a process for the preparation of ezetimibe by initially
reducing l-(4-fiuorophenyl)-4(S)-(4-hydroxyphenyl)-3(R)-(3-oxo-3-phcnyl
propyl)-2-azetidinone with (R)-tetrahydro-l-methyl-3,3-diphenyl-1H.3H-pyrrolo-
[l,2-c][l,3,2]oxazaborole in the presence of borane dimethyl sulfide complex in tetrahydrofuran to obtain (S)-hydroxypropyl a/.etidinone; and subsequently deprotecting the benzyl group using palladium on carbon.
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 yield and low enantiomeric and chemical purity.
Several other processes for the preparation of e/etimibe are disclosed in I IS Patent Nos. 5,739,329, 5,886,171, 5,856,473, 6,207,822, 7,067,675; PCT application nos. WO 2004/099132, WO 2005/009955, WO 2005/066120 and in article, Journal of Medicinal Chemistry, 1998, 41(6), 977-980.
Like any synthetic compound, ezetimibe can contain extraneous compounds or impurities. These impurities may be, for example, starting materials, by-products of the reaction, products of side reactions, or degradation products. Impurities in ezetimibe, or any active pharmaceutical ingredient ("API"), are undesirable and, in extreme cases, might even be harmful to a patient being treated with a dosage form containing the API.
The purity of an API produced in a manufacturing process is critical for commercialization. The U.S. Food and Drug Administration ("FDA") requires that process impurities be maintained below set limits. For example, in its 1CII Q7A guidance for API manufacturers, the FDA specifies the quality of raw materials that may be used, as well as acceptable process conditions, such as temperature, pressure, time, and stoichiometric ratios, including purification steps, such as crystallization, distillation, and liquid-liquid extraction.
The product of a chemical reaction is rarely a single compound with sufficient purity to comply with pharmaceutical standards. Side products and by-products of the reaction and adjunct reagents used in the reaction will, in most cases, also be present in the product. At certain stages during processing of an API. such as ezetimibe, it must be analyzed for purity, typically, by high performance liquid chromatography ("I1PLC") or thin-layer chromatography ("TLC"). to determine if
it is suitable for continued processing and, ultimately, for use in a pharmaceutical product. The FDA requires that an API is as free of impurities as possible, so that it is as safe as possible for clinical use. For example, the FDA recommends that the amounts of some impurities be limited to less than 0.1 percent.
Prior art processes disclose several processes for the preparation of pure c/etimibe using crystallization with solvents like methanol, methyl tertiary-butyl ether, isopropyl alcohol, etc. But it was found by the present inventors that certain identified and unidentified impurities does not go away with the purification techniques reported in prior art.
There is a long-felt need for the industrially applicable and consistently reproducible process to prepare highly pure ezetimibe having acceptable levels of certain impurities, which complies with the requirements of pharmacopoeias.
The present invention is thus directed to an industrially advantageous process for the purification of ezetimibe. Further the present invention is thus directed to an impurity of ezetimibe. which was previously unidentified, as well as other known impurities, obtained in the preparation of ezetimibe and process for the elimination of such impurities using selective purification to yield highly pure ezetimibe. The present invention thus provides ezetimibe having improved chemical and/or enantiomeric purity.
SUMMARY OF THE INVENTION
In the first embodiment, the present invention provides a process for the purification of ezetimibe, comprising
a) dissolving ezetimibe in a suitable solvent specifically tertiary butanol.
b) admixing an anti-solvent specifically water with cooling to obtain a
precipitate,
c) filtering the product,
d) optionally repeating the steps a-c, and subsequently
c) isolating the highly pure ezetimibe there from.
Another embodiment of the present invention provides a process for purification of ezetimibe, comprising
a) providing a solution of ezetimibe in a suitable solvent specifically aqueous
tertiary butanol at reflux,
b) cooling the reaction mass to obtain a precipitate,
c) filtering the product,
d) optionally repeating the steps a-e, and subsequently
c) isolating the highly pure ezetimibe there from.
One another embodiment of this invention is directed to an isolated 'bis impurity' of following formula;
(Formula Removed)
whew in R ix selected from HOP benzyl
Yet one another embodiment of this invention is directed to ezetimibe containing less than about 0.15 percent area by I IPLC of lhe'(3R) isomer impurity' of following formula

(Formula Removed)
as well as less than 0.04 percent area by I IPLC of other known impurities such as the "bis impurity' and 'keto impurity' of following formulae,

(Formula Removed)
wherein R is selected from H or benzyl

(Formula Removed)
DETAILED DESCRIPTION OF THE INVENTION
As used herein, the term 'crude e/etimibe' refers to e/.etimibe containing more than about 1.0 percent area by 1IPLC of the 'bis impurity' and 'keto impurity' along with certain other known impurities; and more than about 1.0 percent area by HPLC of the '(3R) isomer impurity.'
As used herein, the term "chemically pure ezetimibe" refers to c/ctimibe, containing less than about 0.15 percent area by HPLC of the 'bis impurity', 'keto impurity7 and other unidentified impurities. Preferably, the level of these impurities is less than about 0.10 percent area by HPLC, and, most preferably, less than about 0.07 percent area by HPLC. A chemically pure c/etimibc in accordance with the invention may be substantially free of these impurities, such that the level of'bis impurity' and 'keto impurity' is below the detection limit.
As used herein, the term "cnantiomerically pure ezetimibe" refers to c/etimibc, containing less than about 0.15 percent area by HPLC of the '(3R) isomer impurity'. Preferably, the level of the '(3R) isomer impurity' is less than about 0.10 percent area by HPLC.
The chemical purity of e/etimibe in the present invention relates to the level of two impurities in the final product. These impurities include:
1. The impurity of following formula, referred to herein as 'bis impurity'

(Formula Removed)

wherein R is selected from If or benzyl
2. l-(4-Fluoro-phenyl)-3-|3-(4-fliioro-phcnyl)-3-oxo-propyl|-4-(4-hydroxy-phenyl)-a/etidin-2-one, referred herein as 'keto impurity' of following formula
(Formula Removed)
The bis impurity forms the inventive part of the present invention and contaminates e/etimibe of formula I.
Specific illustrations of the bis impurity includes:
3-[3,3-bis-(4-nuoro-phenyl)-3-hydroxy-propyl]-l-(4-fluoro-phcnyl)-4-(4-hydroxy-phenyl)-azetidin-2-one;
3-[3,3-bis-(4-fluoro-phenyl)-3-hydroxy-propyl]-l-(4-fluoro-phenyl)-4-(4-benzyloxy-phenyl)-azetidin-2-one.
As is mentioned hereinabovc, a major limitation associated with the prior art processes for obtaining ezetimibe from 3-[2-(4-benzyloxy-phenyl)-l-(4-fluorophenyl)-4-oxo-azctidin-3-yl]-propionic acid is the presence of'bis impurity' of following formula,
(Formula Removed)
wherein R is selected from H or benzyl
which is typically obtained during the synthesis of 4-(4-benzyloxy-phcnyl)-l-(4-fluoro-phenyl)-3-[3[(4-fluoro-phenyl)-3-oxo-propyl]-azetidin-2-one and is exceptionally difficult to remove from both the said intermediate and the crude ezetimibe obtained there from. Such crude e/etimibe typically contains by itscll'a substantial amount of this impurity that is difficult to remove from the final product.
'Keto impurity' is an intermediate, which may remain unreacted during the reduction step with borane dimethyl sulfide complex and get carry forward to final product as an impurity.
The enantiomeric purity in the present invention relates to the level of the (3R,4S)-1 -(4-fluoro-phenyl)-3-[(3R)-3-(4-nuoro-phenyl)-3-hydroxy-propyl |-4-(4-hydroxy-phenyl)-azetidin-2-one, referred herein as '(3R.) isomcr impurity1 of following formula
(Formula Removed)
'(3R) Isomer impurity' has been found to be present in substantial amounts i.e. about 5-10%, in crude ezetimibe which is difficult to remove using the prior art processes. This impurity may be generated due to non-selective reduction of 4-(4-hydroxy-phenyl)-l-(4-fluoro-phenyl)-3-[3[(4-fiuoro-phenyl)-3-oxo-propyl|-azetidin-2-one.
The progress of the purification process and the presence or absence of impurities can be monitored using HPLC analysis.
One embodiment of the present invention provides a process lor the purification of crude ezetimibe comprising heating a mixture of crude ezetimibc and an alcoholic solvent, specifically tertiary-butanol to a temperature of between about 70°C and above up to the reflux temperature of the solvent, and cooling the solution to a temperature of about 40°C to about 60°C. The process further includes combining the solution with an anti solvent that is a poor solvent for ezetimibe and which when mixed with a solution of ezetimibc, causes it to precipitate. Preferably the anti solvent is water. The reaction mass is further cooled to 0-5°C and maintained for a time sufficient to precipitate c/etimibe in high purity. The precipitated product can be isolated by the methods well known in the art like filtration, decantation, centrifugation and the like. Typically, this product is isolated by filtration.
It has been observed that although purification can be performed using other alcoholic solvents like isopropyl alcohol, methanol, ethanol, n-butanol and the like. However surprising results were obtained using tertiary butanol. Specific illustrations of the reduction of level of impurities using purification process with tertiary butanol can be had by the Example section that follows.
Another embodiment of the present invention provides a process for the preparation of e/etimibe by providing a solution of crude e/etimibc in a suitable solvent specifically aqueous tertiary butanol at reflux. This is followed by cooling the reaction mass initially to room temperature and finally at 0 to 5°C to induce precipitation and isolation of ezetimibe from the reaction mixture. Generally, the product can be isolated by any standard method known in the art such as by filtration, centrifugation or decantation. Typically, this product is isolated by filtration.
Preferably, the ezetimibe obtained after the crystallization is chemically and enantiomerically purer than the crude ezetimibe used as the starting material. To
exemplify, the obtained ezetimibe contains a lower level of the 'keto' and 'bis' impurity and a lower level of the '(3R) isomer impurity'.
The crystallization process may be repeated in order to increase the purification even further either with the same or a different solvent that was used for the first crystallization.
The crude ezetimibe can be prepared starting from 3-[2-(4-benzyloxy-phenyl)-l-(4-fluorophenyl)-4-oxo-azetidin-3-yl]-propionic acid by the processes well known in art or as described in our co-pending application 234/DHL/2007. Specifically. ezetimibe is prepared by reacting 3-[2-(4-benzyIoxy-phenyl)-l-(4-fiuorophenyl)-4-oxo-azetidin-3-yl]-propionic acid of following formula or its reactive derivative
(Formula Removed)

with 4-bromofluoro benzene in the presence of iron catalyst, Grignard reagent in suitable solvent and the resulting compound is converted to ezetimibe by performing hydrogenation and debenzylation.
Typically, 3-[2-(4-benzyIoxy-phenyl)-1 -(4-fluorophenyl)-4-oxo-azetidin-3-yl |-propionic acid is converted to 3-[2-(4-benzyloxy-phenyl)-l-(4-fluorophenyl)-4-oxo-azetidin-3-yl|-propionyl chloride of following formula.

(Formula Removed)
by reacting it with oxalyl chloride in a suitable halogenated solvent at a temperature of below 20°C under inert atmosphere. Preferably halogenated
solvent can be selected from dichloromethane, chloroform, carbon tetrachloridc. More preferably dichloromethane is used. The reaction can optionally be conducted in the presence of catalytic amount of jV,A-dimethylformamidc. The reaction mass is stirred at ambient temperature till completion of the reaction, which is monitored by HPLC. The solvent is then distilled off fully under vacuum at 50-70°C to obtain 3-[2-(4-benzyloxy-phenyl)-l-(4-fluorophenyl)-4-oxo-azetidin3-yl]-propionyl chloride.
Yet another aspect of the present in invention provides a process for the conversion of acid chloride to 4-(4-ben/yloxy-phenyl)-l-(4-fluoro-phenyl)-3-[3[(4-fluoro-phenyl)-3-oxo-propyl]-a/.etidin-2-one of following formula, yet another key intermediate for the preparation of ezetimibe, using non stringent reaction conditions and inexpensive reagents.

(Formula Removed)

To the above formed acid chloride, 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, xylcne. ethyl acetate and the like. Preferably tetrahydrofuran is used. To the reaction mass, catalytic amount of appropriate catalyst is added and the reaction mass is further stirred at a temperature of-95 to -70°C for few minutes. Catalyst can be selected from iron catalysts such as iron acetyl acctonate, 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 bcn/cne and tetrahydrofuran, optionally with catalytic amount of iodine. 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%. The reaction mass is then added to ice cold demineralized water followed by extraction with suitable organic solvent like methyl tertiary-butyl ether to obtain 4-(4-benzyIoxy-phenyl)-l-(4-fluoro-phenyl)-3-[3[(4-fluoro-phenyl)-3-oxo-propyl| -azetidin-2-one.
4-(4-Benzyloxy-phenyl)-l-(4-fluoro-phenyl)-3-[3|(4-fluoro-phenyl)-3-oxo-propyl] -azetidin-2-one can further be converted to ezetimibe by the methods well known in art by main two processes. In one aspect, it is reduced to 4-(4-benzyloxy-phenyl)-l-(4-fluoro-phenyl)-3-[3|(4-fluoro-phenyl)-3-hydoxy-propyl|-azetidin-2-one and then debenzylated to form ezetimibe. According to another aspect, 4-(4-benzyloxy-phenyl)-]-(4-fluoro-phenyl)-3-[3[(4-fluoro-phenyl)-3-oxo-propyl|-azetidin-2-one is debenzylated to form 4-(4-hydroxy-phenyl)-l-(4-fluoro-phenyl)-3-[3[(4-fIuoro-phenyl)-3-oxo-propyl|-azetidin-2-one and further reduced to form ezetimibe.
Typically, 4-(4-benzyloxy-phenyl)-l-(4-fluoro-phenyl)-3-|3f(4-fluoro-phcnyl)-3-oxo-propyT]-azetidin-2-one can be hydrolyzed to 4-(4-hydroxy-phcnyl)-l-(4-fluoro-phenyl)-3-[3[(4-fluoro-phenyl)-3-oxo-propyl]-azetidin-2-one of following formula,
(Formula Removed)
using conventional techniques known in the art or by the method described herein for reference. Typically, 4-(4-ben/,yloxy-phenyl)-l-(4-fluoro-phenyl)-3-[3|(4-fluoro-phenyl)-3-oxo-propyl]-azetidin-2-one is dissolved in a suitable solvent like ester such as ethyl acetate, alcoholic solvent such as C|-C4 alcohol; the like and mixtures thereof. This is followed by the addition of a suitable catalyst. Catalyst can be selected from platinum group metals, particularly platinum, palladium, rhodium and ruthenium are highly active catalysts. Non-precious metal catalysts, especially those based on nickel such as Raney nickel and Urushibara nickel can
also be employed. More preferably 10% by weight palladium supported on carbon is used. Reaction is conducted preferably in the presence of an additional compound, such as hydrogen. The reaction mixture is exposed to hydrogen gas under a pressure of 4.00-5.50 kg/cm" at a temperature of about 25-45°C till the reaction goes to completion. The catalyst is filtered through hyflo bed and product is extracted after work up with organic solvent like toluene. The product is found to contain 4,4'-difluoro-biphenyl as impurity which can be removed by treating the product with a suitable solvent like n-heptane at a temperature of 70-100°C and then cooling to 10-25°C. The impurity is isolated preferably by decanlation. This process can be repeated several times, preferably till the thin layer chromatography (TLC) shows the absence of biphenyl impurity.
The product can further optionally be purified of the undesired impurities by dissolving the product in suitable solvent like chloroform and passing it through a column packed with silica gel in chloroform. The column is then washed with chloroform. The eluted chloroform is distilled out at 50-55°C to obtain pure 4-(4-hydroxy-phenyl)-l-(4-nuoro-phenyl)-3-|3|(4-fiuoro-phenyl)-3-oxo-propyl|-azetidin-2-one.
4-(4-Hydroxy-phenyl)-l-(4-fluoro-phenyl)-3-[3|(4-fluoro-phenyl)-3-oxo-propyl]-azetidin-2-one so obtained, is further reduced to ezelimibe of formula 1 using suitable reducing agent and a suitable chiral promoter/catalyst. Typically, 4-(4-hydroxy-phenyl)-l-(4-fiuoro-phenyl)-3-|3|(4-nuoro-phcnyl)-3-oxo-propyl|-azetidin-2-onc in a suitable organic solvent is added slowly to a mixture of suitable reducing agent and a suitable chiral promoter/catalyst in catalytic or stochiometric amount at a temperature of below 5°C under inert atmosphere. Suitable anhydrous organic solvent can be selected from dichloromclhane, tetrahydrofuran, toluene, xylenc and the like. Reducing agent can be selected from borane dimethylsulfide complex, sodium borohydride, a substituted borohydride eg.| cbz-Proline'lsBHNa and the like, while the chiral promoter/catalyst can be selected from (R)-2-methyl-CBS-oxa/.aborolidine, (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 1.0%, preferably not more than 0.5%. Addition of hydrogen peroxide to affect the decomposition of borane complex followed by extraction with suitable organic solvent like diehloromethane gives crude e/.etimibc.
It is advantageous to remove the traces of borane complex from the final compound by taking the compound in methanol and distilling off the solvent under vacuum at a temperature of about 50-60°C. The process can be repeated with same solvent followed by treatment with toluene to remove the traces of methanol, if any to obtain crude ezctimibc
Although, the following examples illustrate the practice of the present invention in some of its embodiments, the examples should not be construed as limiting the scope of the invention. Other embodiments will be apparent to one skilled in the art from consideration of the specification and examples. It is intended that the specification, including the examples, is considered exemplary only, with the scope and spirit of the invention being indicated by the claims which follow.
EXAMPLES
Example 1; Preparation of 4-(4-benzyloxy-phenYl)-l-(4-fluoro-phcnyl)-3-|3|(4-fluoro-phenvl)-3-oxo-prQpvll-a/etidin-2-onc
3-[2-(4-Ben/yloxy-phenyl)-1 -(4-fluorophenyl)-4-oxo-a/etidin-3-yl ]-propionic acid (lOOg) was dissolved in diehloromethane (500 ml) and N,N-dimethylformamide (2 ml) under nitrogen and then cooled to 10°C. Oxalyl chloride (40 ml) was added slowly at 10-I5°C and then the reaction mass was stirred at ambient temperature till reaction completion. Solvent was then distilled off fully to get 3-[2-(4-benzyloxy-phenyl)-l-(4-fluorophenyl)-4-oxo-a/ctidin-3-yl]-propionyl chloride. Tctrahydrofuran (600 ml) was added to the same and the reaction mass was cooled to -78°C under nitrogen. Iron acetyl acetonate (3.75 g) was added and the reaction mass was further stirred at -90 to -78°C for 2 minutes. A freshly prepared Grignard solution (prepared by using 15.76 g of magnesium turnings, 114.9g of l-bromo-4-fluoro ben/ene, a pinch of iodine and 400 ml of
tetrahydrofuran) was added dropwise at -90 to -80°C. After complete addition, the reaction mass was stirred at same temperature till reaction completion (monitored by HPLC). The reaction mass was poured into cold deminerali/ed water (750 ml). Methyl tertiary butyl ether (400 ml) was added and the reaction mixture was stirred at ambient temperature for 15 minutes. The product was filtered through hyflo bed. The hyflo bed was washed with methyl tertiary-butyl ether (400ml). Organic layer was separated from the filtrate and then washed with brine. The organic layer was dried over sodium sulfatc. Solvent was distilled off fully under vacuum at 50-55°C to obtain 150 g of the title compound.
Example 2: Preparation of l-(4-fluoro-phenvl)-3-[3-(fluoro-phcnyl)-3-oxo-propvl|-4-(4-hvdroxy-phenyl)-azetidin-2-onc
1 -(4-Benzyloxy-phenyl)-1 -(4-fluoro-phenyl)-3-| 3-(fluoro-phenyl)-3-oxo-propyl]-azetidin-2-one (150 g) was dissolved in ethyl acetate (600 ml). Methanol (600 ml) and palladium-carbon (6.0 g) was added. Hydrogen gas pressure (4.0 to 4.5 kg/cm") was applied and maintained till reaction completion. Thereafter the reaction mass was filtered through hyflo bed to recover palladium carbon, which was washed with toluene (600 ml). To the filtrate. 25% aqueous sodium chloride solution (1.0 1.) and \N hydrochloric acid solution (500 ml) was added and stirred for 5 minutes. The layers were separated and the aqueous layer was extracted with toluene (400 ml). The organic layers were combined and washed twice with 25% aqueous sodium chloride solution (2x1.0 L). The organic layer was dried over sodium sulfate (50 g). The solvent was distilled off fully under vacuum, n-Heptane (250 ml) was added and the reaction was heated to 90°C and then cooled to 20°C. n-Heptane was decanted. This process was repeated several times; finally the traces of solvent were removed under vacuum at 60°C. The residue was dissolved in chloroform (150 ml) and passed through a column packed with silica gel (150 g) in chloroform (500 ml). The column was washed using 2.5 L chloroform. The eluted chloroform was distilled at 50-55°C to obtain l-(4-fluoro-phenyl)-3-[3-(fluoro-phenyl)-3-oxo-propyl|-4-(4-hydroxy-phcnyl)-a/.ctidin-2-onc
Example 3: Preparation of c/ctimibc
Borane dimethylsulfide complex (20.49 ml) and 1M solution of R-2-methyI-CBS-oxazaborolidine (10.78 ml) were added to a cooled solution of dichloromethane (616 ml) and tetrahydrofuran (88 ml) under nitrogen and the reaction mass was stirred at 0°C for 15 minutes. A solution of l-(4-fluoro-phenyl)-3-|3-(fluoro-phenyl)-3-oxo-propyl]-4-(4-hydroxy-phenyl)-azetidin-2-one in dichloromethane (264 ml) was added to the reaction mass at 0°C and the reaction mass was maintained at 0 to 5°C till reaction completion (monitored by HPLC). 5% Hydrogen peroxide solution (440 ml) was added slowly at 0-20°C and then the reaction mass was stirred at room temperature for 30 minutes. The layers were separated and the aqueous layer was extracted with dichloromethane (88 ml). The combined organic layer was washed with \N hydrochloric acid solution (440 ml) and 25% aqueous sodium chloride solution (1.0 L) respectively. The solvent was distilled off fully under vacuum at 5()-60°C. Methanol (88 ml) was added to the residue and then distilled off fully under vacuum 50-60°C. This process was repeated several times. Toluene (166 ml) was added and distilled off fully under vacuum at 50-60°C. This process was repeated several times. Slowly the reaction mass was cooled to room temperature, stirred for 2 hours. The reaction mass was filtered, washed with toluene (88 ml) and suck dried for 60 minutes under vacuum. The product was taken in toluene (450 ml) and heated to 90"C for 30 minutes. The reaction mass was slowly cooled to room temperature, stirred for 2 hours. The solid was filtered and washed with toluene (50 ml). The solid was dried under vacuum at 60-70°C to give crude ezetimibe. Relative purity 98.15% by HPLC (0.23% of 'koto impurity' and 0.48% of 'bis impurity') and -(3R) isomer impurity' by Chiral HPLC is 7.17%.
Example 4: Purification of crude ezctimibc
(i) Crude ezetimibe (47 g) obtained above, was added to tertiary-butanol (188 ml) and heated to 80-85°C for 15 minutes. This was followed by slow addition of dcmineralized water (47 ml). The reaction mass was cooled to ambient
temperature and stirred for 4 hours at same temperature. The reaction mass was then cooled to 0-5°C and stirred for further 4 hours. The solid, thus obtianed was filtered, washed with a mixture of tertiary-butanol and deminerali/ed water (45 ml, 4:1) and then dried at 60-65°C to get 36 g of ezetimibe. Relative purity: 99.28% by HPLC (0.10% of 'keto impurity' and 0.17% of 'bis impurity') and '(3R) isomer impurity' by Chiral HPLC: 2.58%
(ii) Fzetimibc (36 g) obtained above was added to tertiary-butanol (144 ml) and heated to 80-85°C to get a clear solution. This was followed by slow addition of demineralized water (36 ml). The reaction mass was cooled to ambient temperature and stirred for 4 hours at ambient temperature. The reaction mass was further cooled to 0-5°C and stirred for 4 hours. The solid was filtered and washed with a mixture of tertiary-butanol and demineralized water (35 ml, 4:1). The solid was dried at 60-65°C to get 30 g of ezetimibe. Relative purity: 99.61% by HPLC (0.06% of ;keto impurity' and 0.09% of 'bis impurity') and '(3R) isomer impurity' by Chiral HPLC: 1.17%.
(iii) Ezetimibe (30 g) obtained above was added to tertiary-butanol (120 ml) and heated to 80-85°C to get a clear solution. This was followed by slow addition of demineralized water (30 ml). The reaction mass was cooled to ambient temperature and stirred for 4 hours at ambient temperature The reaction mass was further cooled to 0-5°C and stirred for 4 hours. The solid was filtered, washed with a mixture of t-butanol and demineralized water (30 ml, 4:1). The solid was dried at 60-65°C to get 25 g of highly pure ezetimibe. Relative purity: 99.84% by HPLC ('kcto impurity' and 'bis impurity' are not detectable) and '(3R) isomer impurity' by Chiral HPLC: 0.14%.
Example 5: Purification of crude e/ctimibc
(i) Crude ezetimibe (50 g, relative purity: 98.32% (0.23 % of 'keto impurity' and 0.43% of'bis impurity') and'(3R) isomer impurity' by Chiral HPLC: 7.09%) was added to tertiary-butanol (200 ml) and heated to 80-85°C for 15 minutes. This was followed by slow addition of demineralized water (50 ml). The reaction mass
was cooled to ambient temperature and stirred for 4 hours at ambient temperature. The reaction mass was further cooled to 0-5°C and stirred for 4 hours. The solid was filtered, washed with a mixture of tertiary-butanol and deminerali/ed water (50 ml,4:l) and then dried at 60-65°C to get 35 g of ezetimibe. Relative purity: 99.20% by HPLC (0.12% of 'keto impurity' and 0.18% of 'bis impurity') and '(3R) isomer impurity' by Chiral HPLC: 2.91%
(ii) Ezetimibe (35 g) obtained above was added to tertiary-butanol (140 ml) and heated to 80-85°C to get a clear solution. This was followed by slow addition of demineralized water (35 ml). The reaction mass was cooled to ambient temperature and stirred for 4 hours at ambient temperature. The reaction mass was further cooled to 0-5°C and stirred for 4 hours. The solid was filtered and washed with a mixture of tertiary-butanol and demineralized water (35 ml,4:1). The solid was dried at 60-65°C to get 31 g of e/etimibe. Relative purity: 99.60% by HPLC (0.05 % of 'keto impurity' and 0.07% of 'bis impurity') and *(3R) isomer impurity' by Chiral HPLC: 1.17%
(iii) Ezetimibe (31 g) obtained above was added to tertiary-butanol (124 ml) and heated to 80-85°C to get a clear solution and to this demineralized water (31 ml) was added. The reaction mass was cooled to ambient temperature and stirred for 4 hours at ambient temperature The reaction mass was further cooled to ()-5°C and stirred for 4 hours. The solid was filtered, washed with a mixture of tertiary-butanol and demineralized water (30 ml). The solid was dried at 6()-65°C to get 26 g of highly pure ezetimibe. Relative purity: 99.81% by HPLC ('keto impurity' and 'bis impurity'are not detectable) and '(3R) isomer impurity' by Chiral HPLC: 0.12%.
Example 6: Purification of crude e/etimibc
Crude ezetimibe (10 g, relative purity: 98.48% by HPLC (0.20% of 'kcto impurity' and 0.39% of 'bis impurity') and '(3R) isomer impurity' by Chiral HPLC: 7.03% ) was charged in 20% aqueous tertiary-butanol (50 ml) and heated to 80-85°C for 15 minutes to get a solution. Thereafter, the reaction mass was
allowed to cool to room temperature and maintained under stirring for 4 hours. The reaction mass was further cooled to 0-5°C and stirred for 4 hours. The solid was filtered, washed with a mixture of tcrtiary-butanol and deminerali/cd water (10 ml) and then dried at 60-65°C to get 7 g of ezetimibe. Similar purification steps were repeated twice to get 5.20 g of highly pure ezetimibe. Relative purity: 99.86% by HPLC (0.02% of'keto impurity' and 'bis impurity' is not dctactablc) and b(3R) isomer impurity' by Chiral HPLC: 0.09%.

WE CLAIM
1. A process for the preparation of highly pure czctimibe having less than about 0.15 percent area by HPLC of '(3R) isomer impurity' of following formula,
(Formula Removed)
and having less than 0.10 percent area by HPLC of each of bis impurity' and 'keto impurity' of following formulae,
(Formula Removed)
wherein R is selected from H or benzyl
(Formula Removed)
comprising the steps of:
a) dissolving ezetimibe in a suitable solvent specifically tertiary butanol,
b) admixing an anti-solvent specifically water with cooling to "obtain a
precipitate,
c) filtering the product,
d) optionally repeating the steps a-c, and subsequently
c) isolating the highly pure ezetimibe there from.
2. The process according to claim 1, wherein highly pure e/etimibe is having less
than about 0.14 percent area by HPLC of the'(3R) isomcr impurity" and less
than 0.04 percent area by HPLC each of 'bis impurity' and 'kcto impurity.'
3. A process for the preparation of highly pure c/etimibe having less than about
0.15 percent area by 1IPLC of'(3R) isomer impurity' of following formula.

(Formula Removed)

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

(Formula Removed)
wherein R is selected from If or benzyl

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

4. The process according to claim 3, wherein highly pure ezetimibe is having less
than about 0.14 percent area by HPLC of the'(3R) isomer impurity' and less
than 0.04 percent area by HPLC each of 'bis impurity' and 'keto impurity.'
5. A process for the preparation of highly pure ezetimibe of formula 1
(Formula Removed)
which comprises:
a. reacting 3-[2-(4-benzyloxy-phenyl)-l-(4-fluorophenyl)-4-oxo-a/etidin-3-yl]-propionic acid of following formula

(Formula Removed)

with oxalyl chloride in halogenated solvent preferably dichloromcthanc, optionally with catalytic amount of MyV-dimethylformamide to form 3-|2-(4-benzyloxy-phenyl)-l-(4-fluorophenyl)-4-oxo-azetidin-3-yl]-propionyl chloride of following formula,
(Formula Removed)
b. reacting 3-| 2-(4-benzyloxy-phenyl)-1 -(4-fluorophenyl)-4-oxo-a/etidin-3-yl]-propionyl chloride with phenyl magnesium bromide in the presence of suitable solvent and catalyst to form 4-(4-benzyloxy-phenyl)-1-(4-fluoro-phenyl)-3-[3f(4-fluoro-phenyl)-3-oxo-propyl]-azetidin-2-one of following formula,

(Formula Removed)
c. debcn/ylating 4-(4-benzyloxy-phcnyl)-l-(4-fluoro-phenyl)-3-|3|(4-fluoro-phenyl)-3-oxo-propyl]-azetidin-2-one using palladium on carbon in the presence of suitable solvent to form 4-(4-hydroxy-phcnyl)-l-(4-fluoro-phenyl)-3-[3[(4-fluoro-phenyl)-3-oxo-propyl]-azetidin-2-one of following formula,
(Formula Removed)
d. reducing 4-(4-hydroxy-phenyl)-l-(4-fIuoro-phenyl)-3-f3f(4-fluoro-phenyl) -3-oxo-propyl|-azetidin-2-one with a suitable reducing agenl and a suitable chiral promoter/catalyst in a suitable organic solvent to form crude ezetimibe of formula I,

e. purifying crude e/etimibe with a suitable solvent like tertiary butanol,
f. optionally repeating step (e) to obtain highly pure ezetimibe and
g. isolating highly pure ezetimibe there from.
6. The process according to claim 5, wherein in step b, suitable organic solvent is
selected from tetrahydrofuran, toluene etc. and the catalyst is iron acetyl
acetonate, iron (III) chloride.
7. The process according to claim 5, wherein in step c, solvent is selected from
ester such as ethyl acetate; alcoholic solvent such as C|-C,t alcohol, the like
and mixtures thereof.
8. The process according to claim 5, wherein in step d, solvent is selected from
dichloromethane, tetrahydrofuran, toluene, xylcne and the like; reducing
agent is selected from borane dimethyl sulfide complex, sodium borohydride,
a substituted borohydride eg.f cbz-ProlinelsBHNa and the like; while the
chiral promoter/catalyst can be selected from (R)-2-methyl-CBS-
oxazaborolidine, (R)-butyl CBS, (R)-phenyl CBS.
9. An isolated bis impurity of following formula
(Formula Removed)
wherein R is selected from II or benzyl
24
10. Ezetimibe having less than about 0.15 percent area by UPLC of'(3R) isomer impurity' of following formula,
(Formula Removed)

and having less than 0.10 percent area by HPLC of each of bis impurity' and 'keto impurity' of following formulae,
(Formula Removed)
wherein R is selected from H or benzyl
(FORMULA REMOVED)