Title of Invention	NOVEL PROCESS FOR STEREOSELECTIVE REDUCTION OF β-KETOESTERS
Abstract	A novel process for the preparation of compounds of formula I where R<SUB>1</SUB>=CN or OP (P is any suitable protecting group) R<SUB>2</SUB> = alkyl or aryl by reacting a compound of formula II where R<SUB>1</SUB>=CN or OP (P is any suitable protecting group) R<SUB>2</SUB> = alkyl or aryl with a reducing agent, sodium borohydride in presence of metal halides.

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TITLE OF INVENTION Novel process for stereoselective reduction of P-ketoesters TECHNICAL FIELD The present invention relates to a novel stereoselective process for preparing optically active dihydroxy ester derivatives of formula I which are useful intermediates for the synthesis of HMG-CoA enzyme inhibitors like atorvastatin, cerivastatin, rosuvastatin, itavastatin, fluvastatin. BACKGROUND Esters derivatives of the formula I R1 = CN, OP (P=any suitable protecting group), alkyl, aryi or hetroaryl R2 = Alkyl oraryl Formula I are valuable chiral synthons for synthesizing compounds which are known anti-hyptercholesterolemic agents having an inhibitory effect on HMG-CoA reductase (Ref. US 5003080, US 5169857, WO 01 85702, US 5354772, EP 0304063) The most common approach for achieving stereoselective synthesis of compounds of formula I is the reduction of formula II R, = CN, OP (P=any suitable protecting group), alkyl, aryl or hetroaryl R2 = Alkyl or aryl Formula II using special borane reagents (ref. US 5273995, US 5470981, US 5489691). Reagents such as methoxydiethylborane are hazardous and expensive. US 6001615 describe an enzymatic route of synthesis. This process, however, suffers from the fact that the process is not industrially scalable and also involves large volumes. US 5399722 describe a process starting from commercially available ethyl-© -chloroacetoacetate or its benzyloxy derivative. The disadvantages of tins process is that a stereoselective reduction using a ruthenium-BlNAP catalyst in employed and the desired compound of formula I is obtained in six steps. US 5481009 describe a process starting from 4-phenyl-3-butenoic acid in about 5 steps. The process uses hazardous steps (ozonolysis) to obtain the desired product. The objective of the present invention is to provide a simple, industrially scalable process for the stereoselective reduction of compounds of formula n, leading to preparation of compounds of formula I employing inexpensive and non-hazardous reagents. The use of compounds of Formula I in synthesis of statins are illustrated in Schemes 1-6. The present invention has following advantages over known method: 1. Safe and non-hazardous 2. Cost-effective 3. Industrially scalable 4. Lesser number of steps 5. Commercially viable Summary of the invention The present invention details a novel process for the preparation of compounds of formula I R1 = CH, OP (P=any suitable protecting group), alkyl, aryl or hetroaryl R2 = Alkyl or aryl Formula I by reacting a compound of formula II R, = CN, OP (P=any suitable protecting group), alkyl, aryl or hetroaryl R2 = Alkyl or aryl Formula II with sodium borohydride in presence of metal halides, preferably CeCU or metal alkoxides, preferably Ti(OiPr)4 (Scheme I). The reagents used are non-hazardous, easily available and cheap. Detailed Description of the invention The compound of formula II is an important intermediate for the preparation of many drug molecules especially, HMG Co-A reductase inhibitors. The HMG Co-A reductase inhibitors are useful as inhibitors of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG CoA reductase) and are thus useful as hypolipidemic or hypocholesterolemic agents. The process of the present invention in its first aspect is a new, improved, non-hazardous, industrially scalable, economical, and commercially feasible method for preparing intermediates used for the preparation of HMG.C0A reductase inhibitors. The process of the present invention in its first aspect is outlined in Scheme I. The present invention details a novel process for the preparation of compounds of formula I R1 = CN, OP (P=any suitable protecting group), alkyl, aryi or hetroaryl R2 = Alkyl or aryl Formula I by reacting a compound of formula II R1 = CN, OP (P=any suitable protecting group), alkyl, aryl or hetroaryl R2 = Alkyl or aryl Formula II with 1) sodium borohydride in presence of metal halides, preferably anhydrous CeCl3 or 2) hydrated CeCl3 or 3) metal alkoxides, preferably Ti(OiPr)4 The reagents used are non-hazardous, easily available and economic. The compound of formula I arc important intermediates for Hxc preparation of HMG Co-A reductase inhibitors as shown in scheme 2 (Atorvastatin), scheme 3 (Cerivastatin), scheme 4 (Etavastatin), scheme 5 (Rosuvastatin) and scheme 6 (Fluvastatin). The following non-limiting examples illustrate the inventors' preferred method for preparing the compounds of the invention. EXAMPLES Example 1 Preparation of tert-butyl (3i?,5i?)-6-cyano-3,5-dihydroxyhexanoate: A solution of/erf-butyl (5#)-6-cyano-5-hydroxy-3-oxohexanoate (10 g, 0.044 mol) in THF (60 mL) was stirred under nitrogen and methanol (20 mL) was added. The reaction mixture was stirred for 15 min. and cooled to -50° C to -55° C. Anhydrous CeCl3 (10.8 g, 0.044 mol) was added and stirred for 30 min., mamteining temperature between -50 to -55 ° C. Sodium borohydride (2.5 g, 0.066 mol) was added in 6 portions mamtaining the temperature (-70 to -90° C ) and stirred for 1 h at the same temperature. After warming the reaction mixture to RT, it was concentrated to residue under vacuum at about 45° C. Methanol (60 mL) was added and concentrated completely. The residue was cooled to RT, water (50 mL) was added and extracted with ethyl acetate (100 rnL x 2). The-Gombined-organic layer was washed with brine solution (50 mL), concentrated to obtain title compound. Yield: 9 g. Preparation of tert-butyl (3i?,5#)-6-cyano-3,5-dihydroxyhexanoate: A solution of tert-butyl (5i?)-6-cyano-5-hydroxy-3-oxohexanoate (10 g, 0.044 mol) in THF (60 mL) was stirred under nitrogen and methanol (20 mL) was added. The reaction mixture was stirred for 15 min. and cooled to -50° C to -55 ° C. CeCl3.7H20 (16.4 g, 0.044 mol) was added and stirred for 30 min., maintaining temperature between -50 to -55 ° C. Sodium borohydride (2.5 g, 0.066 mol) was added in 6 portions maintaining the temperature (-70 to -90° C ) and stirred for 1 h at the same temperature. After warming the reaction mixture to RT, it was concentrated to residue under vacuum at about 45° C. Methanol (60 mL) was added and concentrated completely. The residue was cooled to RT, water (50 mL) was added and extracted with ethyl acetate (100 mL x 2). The combined organic layer was washed with brine solution (50 mL), concentrated to obtain title compound. Yield: 5 g. Example 3 Preparation of tert-butyl (3i?,5i?)-6-cyano-3,5-dihydroxyhexanoate: A solution of tert-butyl (5i?)-6-cyano-5-hydroxy-3-oxohexanoate (10 g, 0.044 mol) in THF (60 mL) was stirred under nitrogen and methanol (20 mL) was added. The reaction mixture was stirred for 15 min. Ti(IV)isopropoxide (12.5 g, 0.044 mol) was added and stirred for 30 min. at room temperature. After cooling the reaction mixture to -50° C to -55° C, sodium borohydride (1.67 g, 0.044 mol) was added in 4 portions maintaining the temperature (-50°-C-to—55° G)- and stirr-ed^or-l h at the same temperature. After warming the reaction mixture to RT, it was concentrated to residue under vacuum at about 45° C. Methanol (60 mL) was added and concentrated completely. The residue was cooled to RT, water (50 mL) was added and extracted with ethyl acetate (100 mL x 2). The combined organic layer was washed with saturated ammonium chloride solution (2 x 50 mL), water (50 mL) and brine solution (50 mL), concentrated to obtain title compound. Yield: 7.5 g. Example 4 Preparation of (3R,5S)-6-(tert-butyl-diphenyl-silanyloxy)-3,5-dihydroxy-hexanoic acid tert-butyl ester: A solution of (5S)-6-(tert-butyl-diphenyl-silanyloxy)-5-hydroxy-3-oxo-hexanoic acid tert-butyl ester (20 g, 0.044 mol) in THF (60 mL) was stirred under nitrogen and methanol (20 mL) was added. The reaction mixture was stirred for 15 min. and cooled to -50° C to -55° C. Anhydrous CeCl3 (10.8 g, 0.044 mol) was added and stirred for 30 min., mamtaining temperature between -50 to -55° C. Sodium borohydride (2.5 g, 0.066 mol) was added in 6 portions maintaining the temperature (-70 to -90° C ) and stirred for 6 h at the same temperature. After warming the reaction mixture to RT, it was concentrated to residue under vacuum at about 45° C. Methanol (60 mL) was added and concentrated completely. The residue was cooled to RT, water (50 mL) was added and extracted with ethyl acetate (100 mL x 2). The combined organic layer was washed with brine solution (50 mL), concentrated to obtain title compound. Yield: 17 g. Example 5 Preparation of (3R,5S)-3,5-dmydroxy-6-trityloxy- hexanoic acid tert- butyl ester: A solution of (5S)-5-dihydroxy-3-oxo-6-trilyloxy- hexanoic acid tert-butyl ester (20 g; 0.044 mol) in TRF (75 mT.) was stirred under nitrogen and methanol (20 mL) was added. Ti(IV)isopropoxide (12.5 g, 0.044 mol) was added and stirred for 30 min. at room temperature. After cooling the reaction mixture to -50° C to -55° C, sodium borohydride (1.67 g, 0.044 mol) was added in 4 portions maintaining the temperature (-50° C to -55° C) and stirred for 5 h at the same temperature. After warming the reaction mixture to RT, it was concentrated to residue under vacuum at about 45° C. Methanol (60 mL) was added and concentrated completely. The residue was cooled to RT, water (50 mL) was added and extracted with ethyl acetate (100 mL x 2). The combined organic layer was washed with saturated ammonium chloride solution (2 x 50 mL), water (50 mL) and brine solution (50 mL), concentrated to obtain title compound. Yield: 14.5 g. We claim: 1. A process for the preparation of compounds of formula I R, = CN, OP (P=any suitable protecting group), alkyl, aryl or hetroaryl R2 = Alkyl or aryl Formula I by reacting a compound of formula.Il R, = CN, OP (P=any suitable protecting group), alkyl, aryl or hetroaryl P*2 = Alkyl or aryl Formula II with a reducing agent, sodium borohydride in presence of metal halide. 2. A process in claim 1, wherein the metal halide is CeCl3 3. A process in claim 2, wherein the metal halide is replaced with a metal alkoxide. 4. A process in claim 3, wherein the metal alkoxide is Ti(OiPr)4. 5. A process in claim 1, wherein the compound of formula I is further used for production of HMG CoA Reductase inhibitors. 6. A process as in claim 1, wherein the HMG CoA Reductase inhibitor is selected from statin group comprising Atorvastatin, Rosuvastatin, Cerivastatin, Fluvastatin and Itavastatin.

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2702-2005.rtf

2702-chenp-2005-abstract.pdf

2702-chenp-2005-claims.pdf

2702-chenp-2005-correspondnece-others.pdf

2702-chenp-2005-description(complete).pdf

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