AN IMPROVED PROCESS FOR THE PREPARATION OF EZETIMIBE
INTERMEDIATE
Field of the Invention
The present invention relates to an improved process for the preparation of
3-[5-(4-tluorophenyl)-5-oxopentanoyl]-4(S)-phenyl"l,3-oxazoHdin-2-one of
formula (I),

which is a key intermediate for hydroxyalkyl substituted azetidinone derivatives,
such as Ezetimibe, i.e., l-(4-fluorophenyl)-3-(R)-[3-(4-fluorophenyl)-3(S)-
hydroxypropyl]-4(S)-(4-hydroxyphenyl)-2-azetidinone, is useful as
hypocholesterolemic agents in the prevention and treatment of atherosclerosis. US Patent No. RE 37721 (Reissue of US 5767115 patent) discloses hydroxy-substituted azetidinones as useful for hypocholesterolemic agents in the treatment or prevention of atherosclerosis.
Background of the invention
3-[5-(4-fluorophenyl)-5-oxopentanoyl]-4(S)-phenyl-l,3-oxazolidin-2-one
of formula (I) is a key starting material for most of the processes for the

preparation of Ezetimibe and the process available from the prior art for this compound involves the use of toxic chlorinated reagents like pivaloyloxy chloride and the yields that obtained are very low.

Synlett 2000, No, 3, 315-318, discloses the similar process for the preparation of (S)-l-(2-oxo-4-phenyloxazolidin-3-yl)hexane-l,5-dione by treating acetyl butyric acid with pivaloyl chloride and the resulting mixed anhydride treated with lithium azaenolate of (S)-phenyloxazolidinone to give required compound, the said process as shown below.

US 6207822 and US 2006/0135755 Al disclose the process for producing compound of formula (I) by reacting p-fluoro benzoyl butyric acid with pivaloyl chloride and acylation the product with a chiral auxiliary. WO 2006/127893 and WO 2000/034240 also disclose the process for producing the compound of formula I by using same method as described in the above references.
Most of the prior art processes involve the use of pivaloyl chloride, and dichloromethane in mixed anhydrous stage and dimethylformamide solvent in S-phenyloxazolidinone condensation. These processes involve the use of expensive solvents such as DMF and do not have in-process control to monitor the formation of the mixed anhydride intermediate stage for the condensation of p-fluoro benzoyl butyric acid with S-phenyloxazolidinone and the reaction was monitored by NMR.
There is a definite reason to develop an improved process for the preparation of compound of formula I with single solvent system, user friendly, easily scalable with high yields, better purity and simple equipment without any hazardous emissions in the process and most importantly to have better reaction monitoring conditions.

The present invention involves condensation of p-fluoro benzoyl butyric acid with S-phenyloxazolidinine in the presence of N,N'-dicyclohexylcarbodiimide (DCC) and catalytic amount of dimethylaminopyridine (DMAP) in single solvent dichloromethane and the reaction can be monitored by TLC.
Summary of the Invention
The main objective of the present invention is to provide a industrially robust process for the preparation of 3-[5-(4-fluorophenyl)-5-oxopentanoyl]-4(S)-
pacing 1-1.3-oxazolidin-2-one of formula I.

Yet another objective of the invention is to provide an improved process, with single solvent system, user friendly, easy scalable with high yields, better purity and simple equipment without any hazardous emissions in the process and most importantly to have better reaction monitoring conditions.
The present invention involves the condensation of p-fluoro benzoyl butyric acid of formula II with S-phenyloxazolidinine of formula III in the presence of N.N'-dicyclohexylcarbodiimide and catalytic amount of dimethylaminopyridine in


Detailed Description of the Invention
The present embodiment of the invention provides an improved method,
cost effective and robust process for the preparation of Ezetimibe intermediate of
3-[5-(4-fluorophenyl)-5-oxopentanoyl]-4(S)-phenyl-l,3-oxazolidin-2-one of
formula I, by condensation of p-fluorobenzoyl butyric acid with S-phenyloxazolidinine in the presence of N,N'-dicyclohexylcarbodiimide (DCC) with or without catalyst at optimum temperature, high yields are obtained in the presence of a catalyst using a single solvent and the reaction can be monitored by TLC.
The catalyst selected from the group of dimethylaminopyridine, imidazole, pyrrolidinopyridine, triethyl amine and pyridine. The solvent is selected from aromatic hydrocarbons like toluene and benzene; halogenated aliphatic hydrocarbons, such as dichloromethane, dichloroethane and chloroform; ethyl acetate; acetonitrile; tetrahydrofuran; methyl isobutylketone or mixtures thereof.
The optimum temperature ranges from room temperature to 60 , preferably at 25 to 50 , more preferably 45-50*^C. The optimum reaction maintenance time can be 1 to 10 hrs, preferably 2 to 2.5hrs.
The mole ratio of the condensing agent in the range of 0.8 to 3 with respect to p-fluorobenzoyl butyric acid, preferably 1.0 to 1.5, more preferably 1.0 to 1.1 equivalents. The catalyst used in the range of 0.1 to 0.2 equivalents, preferably
0.135 to 0J 75 equivalents.
Yet another embodiment of the present invention is that the byproduct
N,N'-dicyclohexylurea (DCU) can be converted to dicyclohexylcarbodiimide and
*
the same DCC can be reused for the same reaction, which will reduce the cost

tremendously. Conversion of DCU to DCC as Practical Organic Chemistry page 434, the process as describes below.
Phosphorous oxychloride was added drop wise to dicyclohexylurea with stirring in pyridine at 50^C and heated at 60-90^C for 1.5hrs. The reaction product was poured on to crushed ice, extracted with petroleum ether (b.p: 60-80^C) and the extract was dried over anhydrous sodium sulphate. The solvent was removed using a rotary evaporator and the residual oil was distilled under reduced pressure. The yield of diamide was about 68.0%; b.p 157-159V/15mmHg.
1 he starling material 4-tluorobenzoyl butyric acid can be prepared from the process disclosed in Tetrahedron; EN; 49; 15; 1993; 3193-3202 by reacting pentanedioicacid anhydride with fluorobenzene in the presence of AICI3 in dichloromethane.

The following examples are provided by way of illustration only and should not be limited to construe the scope of the invention


Equip a 3-necked 500 ml round bottom flask with a thermometer, an addition funnel and a nitrogen inlet. Add p-fluoro-benzoylbutyric acid (20 g, 95.15 mmol), CH2CI2 (100 mL) and TEA (23 mL, 165 mmol) and agitate the mixture at room imperator for 5 min. Add trimethylacetyl chloride (11.3 mL, 91.75 mmol) slowly over a period of 30 min. Check for complete formation of mixed anhydride by NMR.
Add the compound of formula III (10 g, 61.3 mmol), DMAP (1.6 g, 13 mmol) and dry DMF- (10 mL) and heat the mixture at reflux for about 7 h or until the reaction is complete (<3% compound III) by NMR. Cool to room temperature, transfer the batch to a flask containing 2N H2SO4 (80 ml) slowly with agitation and continue agitation for about 30 min. Separate the layers and wash the organic 5 (80 ml). Concentrate the organic layer and crystallize the product from isopropyl alcohol (100 ml) filter and dry, yield: 20 (92% molar); mp: 92-94


check for the clear solution. To this solution added dicyclohexylcarbodiimide (98.2 g; 1.0 mole) and dimethylamino pyridine (8.0 g; 0.138 moles). Reaction mass healed to reflux and maintained for 2-3 hrs. Check the TLC for the completion of the reaction, slowly reaction mass cooled to room temperature, filter the byproduct (DCU), and wash the organic layer with water followed by saturated sodium chloride solution. The combined organic layers were dried over anhydrous sodium sulphate and concentrate the solvent below 50 to yield crude compound of 3-[5-(4-fluorophenyl)-5-oxopentanoyl]-4(S)-phenyl-l, 3-oxazolidin-2-one.
Dissolve the crude compound in methanol(150 ml) at 25-30 , stir for 10-15 min. cool the solution to 0-5 stir for 1.0 hr at same temperature, filter the compound and wash with methanol (50 ml). Dry the material at 50-55 for 2-3 hrs to get 137.5gm (Yield: 81.0%; HPLC purity 99.21%) of title compound.
Further, this intermediate can be used for the preparation of Ezetimibe as per the known methods in the literature.

We claim:
1. A process for the preparation of 3-[5-(4-fluorophenyl)-5-oxopentanoyl]-4(S)-
phenyl-1. 3-oxazolidin-2-one of formula ,

Wherein the process comprises condensing 4-fluorobenzoyl butyric acid of a formula (II)

in the presence of a condensing agent and an organic solvent.
2. The process according to claim 1, wherein the condensing agent is
dicyclohexylcarbodiimide (DCC).
3. he process according to claim 1, wherein dicyclohexylcarbodiimide is used
along with a catalyst.

4. The process according to claim 3, where the catalyst is selected from
dimethylamino pyridine (DMAP). imidazole, pyrrolidinopyridine, triethyl amine
and pyridine.
5. The process according to claims 1 to 3, the condensing agent used in the molar ratio of 0.8 to 3.0 equivalents with respect to p-fluoro benzoyl butyric acid, preferably 1.0 to 1.5 equivalents, more preferably 1.0 to 1.1 equivalents. And the catalyst can be used in the ratio of 0.1 to 0.2 equivalents, preferably 0.135 to 0.175 equivalents.
6. The process according to claim 1, wherein the organic solvent is selected from aromatic hydrocarbons like toluene, benzene; halogenated aliphatic hydrocarbons, such as dichloromethane, dichloroethane and chloroform; ethyl acetate; acetonitrile; tetrahydrofuran; hexane; methyl isobutyiketone or mixtures thereof
7. The process according to claim 1, wherein the organic solvent is
dichloromethane
8. Hie process according to claim 1, wherein the process further comprises the
conversion of the byproduct of the reaction dicyclohexylurea to
dicyclohexylcarbodiimide for its reuse.