Title of Invention	METHOD OF PRODUCING OPTICALLY ACTIVE ALCOHOL
Abstract	This invention relates to a process for preparing an optically active alcohol represented by formula (V): wherein, R1 and R2 are as described in the specification, which comprises: reducing aromatic ketones represented by formula (I): wherein R1 and R2 are as described in the specification, with sodium borohydride, chlorotrimethylsilane and optically active 2-[bis(4-methoxyphenyl)hydroxymethyl]pyrrolidine represented by formula (IV): to give optically active alcohol represented by formula (V).

Title of Invention

METHOD OF PRODUCING OPTICALLY ACTIVE ALCOHOL

Abstract

This invention relates to a process for preparing an optically active alcohol represented by formula (V): wherein, R1 and R2 are as described in the specification, which comprises: reducing aromatic ketones represented by formula (I): wherein R1 and R2 are as described in the specification, with sodium borohydride, chlorotrimethylsilane and optically active 2-[bis(4-methoxyphenyl)hydroxymethyl]pyrrolidine represented by formula (IV): to give optically active alcohol represented by formula (V).

Full Text	TECHNICAL FIELD This invention relates to a process for producing optically active alcohols using asymmetric reduction of aromatic ketones. BACKGROUND TECHNOLOGY Hydroxyalkyl substituted azetidinone derivatives, such as ezetimibe ([l-(4-fluorophenyl)-(3R)-[3-(4-fluorophenyl)-(3S)-hydroxypropyl]-(4S)-(4-hydroxyphenyl)azetidin-2-one]) represented by formula XII, are useful as hypochlesterolemic agents in the prevention and treatment of atherosclerosis. Several processes have been reported for the preparation of diphenylazetidinones. (Journal of Organic Chemistry, 1999, 64, 3714, Journal of Medicinal Chemistry, 1998,41 973, U.S Patent No. 5,631,365; 5,886,171; 6,207,822; 6,133,001; 5,856,473, WO2005/066120, JP 2002-531546, JP 2005-53931) . These processes involve that the β-lactam ring construction using 3-[(5S)-(4-fluorophenyl)-5-hydroxypentanoyl]-(4S)-phenyl-l ,3-oxazolidin-2-one (VII) (method 1) or asymmetric reduction of derivatives having carbonyl group in side chain at 3-position of β-lactam ring such as (4S)-(benzyloxyphenyl)-1-(4-fluorophenyl)-(3R)-[3-(4-fluorophenyl)-3- oxopropyl]azetidin-2-one (X) (method 2). In Method 1, the intermediate, the hydroxyl group of 3-[(5S)-(4- fluorophenyl)-5- hydroxypentanoyl]-(4S)-phenyl-l ,3-oxazolidin-2-one (VII) is protected with a suitable protecting group such as trimethylsilyl group or t-butyldimethylsilyl group, was used (U.S Patent No. 6,207,822, WO2005/066120, JP 2002-531546, JP2005-53931) . 3-[(5S)-(4- fluorophenyl)-5- hydroxypentanoyl]-(4S)-phenyl-l,3-oxazolidin-2-one (VII) is synthesized by stereoselective microbial reduction of 3-[5-(4- fluorophenyl)-5-oxopentanoyl]- (4S)-phenyl-l,3-oxazolidin-2-one (VI) (U.S.Patent No. 5,618,707). It is reported mat 3-[(5S)-(4- fluorophenyl)-5- hydroxypentanoyl] -(4S)- phenyl-l,3-oxazolidin-2-one (VII) is synthesized by asymmetric reduction of 3-[5-(4-fluorophenyl)-5-oxopentanoyl]-(4S)-phenyl-l,3-oxazolidin-2-one (VI) ( U.S Patent No. 6,207,822; 6,627,757, Tetrahedron Letters, 2003, 44, 801.) . These processes are reduction by borane-dimethylsulfide complex or borane-tetrahydrofuran complex using (R)-tetraydro)-1-methyl-3,3-diphenyl-1H,3H-pyrrolo(l,2-c)(l,2,3)-oxazaborolidine [(R)-MeCBS; XIII] as a catalyst to afford the corresponding alcohol in high enantioselectivity. However, the enatioselectivity of the reduction depends on rate and mode of addition of borane-complex, moisture sensitivity of the reaction medium and the reaction temperature. Moreover, the reduction using a chiral catalyst leads to problems associated with the formation of over reduced products, such as compound (XIV) (Tetrahedron Letters, 2003,44,801). Borane-dimethylsulfide complex and borane-tetrahydrofuran-complex are expensive and toxic. Furthermore, the handling of these reagents is not easy at large production due to borane is gas. (R)-MeCBS (XIII) is commercially available, but it is expensive. Moreover, the recycle process is required, since (R)-2-(diphenylhydroxymethyl)pyrrolidine (XV), the product that (R)-MeCBS ' (XIII) is decomposed by workup operations, is recovered. In this case, it is necessary expensive boron carrier such as trimethylboroxine to prepared (R)-MeCBS (XIII) . WO2005/066120 discloses the synthetic methods of 3-[(5S)-(4-fluorophenyl)- 5- hydroxypentanoyl]-(4S)-phenyl-l,3-oxazolidin-2-one (VII) and (5S)-(4-fluorophenyl)-5- hydroxypentanoic acid methyl ester (IX) using (-)-B-chlorodiisopinocampheylborane (XVI) as a reducing agent. (5S)-5-(4-fluorophenyl)-5- hydroxypentanoic acid methyl ester (IX) is converted to 3-[(5S)- (4- fluorophenyl)-5- hydroxypentanoyl]-(4S)- phenyl -l,3-oxazolidin-2-one (VII) in this patent This reaction also shows high selectivity, however a stoichiometric amount of reducing agent is necessary. In method 2 , (4S)-(4-benzyloxyphenyl)-l -(4-fluorophenyl)-(3R)-[(3S)-(4-fluorophenyl)- 3- hydroxypropyl]azetidin-2-one (XI) is produced in high stereoselectivity by borane-complex asymmetric reduction of (4S)-(4-benzyloxyphenyl)-l -(4-fluorophenyl)-(3R)-[3-(4- fluorophenyl)- 3-oxopropyl]azetidin-2-one (X) using (R>MeCBS (XIII) as a catalyst Compound (XI) is converted to ezetimibe (XII) by the removal of benzyl group (Journal of Organic Chemistry, 1999,64.3714) . However, this process is also used expensive (R)-MeCBS (XIII) and borane-complex. It is reported the asymmetric reduction of aromatic ketones by sodium borohydride, chlorotrimethylsilane and a catalytic amount of optically active 2-(diphenylhydroxymethyl)pylrolidine (XV) system (Tetrahedron Letters, 2000, 41. 10281). This reaction doesn't require low reaction temperature. Furthermore, cheep and low toxic reagents are used in this reduction system. Moreover, 2-(diphenylhydroxymethyl)pyrroIidine (XV) is easily recovered at workup operations in high yleld, and recyclable after purification such as recrystallization. Reduction of 3-[5-(4- fluorophenyl)-5-oxopentanoyl]-(4S)-phenyl-l ,3-oxazolidin- 2-one (VI) by this system gives 3-[(5S)-(4- fluorophenyl)-5-hydroxypentanoyl]-(4S)-phenyl- l,3-oxazolidin-2-one (VIII ) in high yleld and enantioselectivity [ 1 g scale ((R)-2-(diphenylhydroxymethyl)pyrrolidine 10 mol%) : de 87%) . However, Tendency of the decreased enantioselectivity of the product is observed at scale-up production [ 10 g scale ((R)-2-(diphenylhydroxymethyl)pyrrolidine 10 mol%) : de 74%) . Accordingly, the development of catalyst, which shows high enantioselectivity at large scale production, is desired. DISCLOSURE OF INVENTION This invention provides the synthetic method that shows high enantioselectivity at large scale production of optically active alcohols by asymmetric reduction of aromatic ketones. In the course of study on the development of a enantioselective method of preparing optically active alcohols, inventors found that use of optically active 2-[bis(4-methoxyphenyl)hydroxymethyl]pyrrolidine (IV) instead of optically active 2-(diphenylhydroxymethyl)pyrrolidine provides the alcohols in high enantioselectivity at large scale production. This invention relates to a process for producing optically active alcohols. Namely, this invention provides process that aromatic ketones represented by formula (I) [wherein, R1 are selected from hydrogen atom, halogen atom, lower alkyl group (1 to 5 carbon atom) , lower haloalkyl group (1 to 5 carbon atom) , lower alkoxycarbonyl group (1 to 5 carbon atom) , lower alkoxy group (1 to 5 carbon atom) , hydroxyl group, nitro group, cyano group, lower acyloxy group (1 to 5 carbon atom) , lower alkylthio group (1 to 5 carbon atom) , lower alkylsulfonyl group (1 to 5 carbon atom) , substituted and unsubstituted amino group, substituted and unsubstituted carbamoyl group, substituted and unsubstituted aromatic ring or heteroaromatic ring. R2 is -(CH2)n-R3 [wherein n is 1 to 5 integer. R3are selected from hydrogen atom, halogen atom, lower alkoxycarbonyl group (1 to 5 carbon atom), lower alkoxy group (1 to 5 carbon atom), lower alkylthio group (1 to 5 carbon atom) , lower alkylsulfonyl group (1 to 5 carbon atom) , substituted and unsubstituted amino group, unsubstituted carbamoyl group, substituted and unsubstituted aromatic ring or heteroaromatic ring and formula (II) : {wherein, R4 are selected from lower alkyl group (1 to 5 carbon atom) , substituted and unsubstituted aromatic ring, and substituted and unsubstituted benzyl group.} and formula (III) : {wherein, R5 and R6are the same or different and are selected from hydrogen atom, halogen atom, lower alky] group (1 to 5 carbon atom) , lower haloalkyl group (1 to 5 carbon atom) , lower alkoxycarbonyl group (1 to 5 carbon atom) , lower alkoxy group (1 to 5 carbon atom) , lower acyloxy group (1 to 5 carbon atom) , hydroxyl group, nitro group, cyano group, substituted and unsubstituted benzyloxy group, substituted silyloxy group, lower alkylthio group (1 to 5 carbon atom) , lower alkylsulfonyl group (1 to 5 carbon atom) , substituted and unsubstituted amino group, substituted and unsubstituted carbamoyl group, substituted and unsubstituted aromatic ring or heteraromatic ring, substituted and unsubstituted tetrahydropyranyl group, lower alkyl group containing substituted and unsubstituted tetrahydropyranyl group (1 to 5 carbon atom) , lower alkyl group containing amino group (1 to 5 carbon atom) }) ] are reduced by sodium borohydride, chlorotrimethylsilane and optically active (R)-2-[b is(4-memoxyphenyl)hydroxymethyl]pyrrelidine represented by formula (IV) to give optically active alcohol represented by formula (V) stereoselectively. (wherein, R1 and R2 are as defined above.) This invention also provides process that 3-[5-(4-fluorophenyl)-5-oxopentanoyl]-(4S)- phenyl- 1,3-oxazolidin-2-one represented by formula (VI) is reduced by sodium borohydride, chlorotrimethylsilane and optically active (R)-2-[bis(4-methoxyphenyl)hydroxymethyl]pyrrolidine represented by formula (IV) to give 3-[(5S)-(4-fluorophenyl)-5-hydroxypentanoyl]-(4S)-phenyl-1,3-oxazolidin-2-one represented by formula (VII) stereoselectively. This invention also provides process that 5-(4-fluoropheny1)-5-oxopentanoic acid methyl ester represented by formula (VIII) is reduced by sodium borohydride, chlorotrimethylsilane and optically active (R)-2-[bis(4-methoxyphenyl)hydroxymethyl]pyrrolidine represented by formula (IV) to give (5S)-(4-fluorophenyl)-5-oxopentanoic acid methyl ester represented by formula (IX) stereoselectively. This invention also provides process that (4S)-(4-benzyloxyphenyl)-1-(4- fluorophenyl)-(3R)-[3-(4- fluorophenyl)-3oxopropyl]azetidin-2-one represented by formula (X) is reduced by sodium borohydride, chlorotrimethylsilane and optically active (R) 2-[bis(4-methoxyphenyl)hydroxyme1hyl]pylTolidine represented by formula (IV) to give (4S)-(4-benzyloxyphenyl)-l -(4-fluorophenyl)-(3R)-[(3SH4-fluorophenylH3S)- 3-hydoxypropyl]azetidin-2-one represented by formula (XI) stereoselectively. BEST MODE FOR CARRYING OUT THE INVENTION Compounds represented by general formula (I) are defined herein. R1 are selected from hydrogen atom, halogen atom (e.g. fluorine atom, chlorine atom, bromine atom, iodine atom), alkyl group (e.g. methyl group, ethyl group, propyl group, butyl group, pentyl group, haloalkyl group (e.g. trifluoromethyl group, 2,2,2,-trifluoroethyl group), alkoxycarbonyl group (e.g. methylxycarbonyl group, ethoxycarbonyl group, propyloxycarbonyl group, butoxycarbonyl group, pentyloxycarbonyl group), alkoxy group (e.g. methoxy group, ethoxy group, propyloxy group, butoxy group, penryloxy group), hydroxyl group, nitro group, cyano group, acyloxy group (e.g. acetyloxy group, propionyloxy group), alkylthio group (e.g. methylthio group, ethylthio group, propylthio group, butylthio group, pentylthio group) , alkylsulfonyl group (e.g. methylsulfonyl group, ethylsulfonyl group, propylsulfonyl group, butylsulfonyl group, pentylsulfonyl group) , substituted or unsubstituted amino group (e.g. amino group, methylamino group, ethylamino group, propylamino group, butylamino group, pentylamino group, dimethylamino group, diethylamino group, dipropylamino group, dibutylamino group, dipentylamino group, acetylamino group, propionylamino group, methoxycarbonylamino group, ethoxycarbonylamino group, propionylcarbonylamino group, butoxycarbonylamino group, pentyloxycarbonylamino group, methylsulfonylamino group, ethylsulfonylamino group), substituted or unsubstituted carbamoyl group (e.g. carbamoyl group, methylaminocarbonyl group, ethylaminocarbonyl group, propylaminocarbonyl group, butylaminocarbony] group, pentylaminocarbonyl group, dimethylamino group, diethylamino group, diethylaminocarbonyl group, dipropylaminocarbonyl group, dibutylaminocarbonyl group, dipentylaminocarbonyl group), substituted or unsubstituted aromatic ring (e.g. phenyl group, fluorophenyl group, chlorophenyl group, bromophenyl group, iodophenyl group, methylphenyl group, methoxyphenyl group, aminophenyl group, cyanophenyl group, methylthiophenyl group, methylsulfamoylphenyl group, methylsulfonylphenyl group, naphtyl group, azulenyl group, biphenyl group, phenoxyphenyl group) or heteroaromatic ring (e.g. pyridine ring, furan ring, thiophene ring, imidazole ring, thiazole ring, benzofuran ring, benzothiophene ring, benzimidazole ring, benzothiazole ring) . R2 are selected from alkyl group (e.g. methyl group, ethyl group, propyl group, butyl group, pentyl group) , haloalkyl group (e.g. chloromethyl group, 2-chloroethyl group, 3-chloropropyl group, 4-chlorobutyl group, 5-chloropentyl group, bromomethyl group, 2-bromoethyl group, 3-bromopropyl group, 4-bromobutyl group, 5-bromopentyl group, iodomethyl group, 2-iodoethyl group, 3-iodopropyl group, 4-iodobutyl group, 5-iodopentyl group ) , alkyl group containing methoxycarbonyl group ( e.g. methoxycarbonylmethyl group, 2-methoxycarbonylethyl group, 3-methoxycarbonylpropyl group, 4-methoxycarbonylbutyl group, 5-methoxycarbonylpentyl group, 3-ethoxycarbonylpropyl group, 3-propyloxycarbonylpropyl group, 3-butoxycarbonylpropyl group, 3-penryloxycarbonylpropyl group) , alkyl group containing alkoxy group (e.g. methoxymethyl group, 2-methoxyemyl group, 3-methoxypropyl group, 4-methoxybutyl group, 5-methoxypentyl group, 4-ethoxybutyl group, 4-propyloxybutyl group, 4-butoxybutyl group, 4-pentyloxybutyl group) , hydroxyl group, alkyl group containing alkylthio group (e.g. methylthiomethyl group, 2-methylthioethyl group, 3-methylthiopropyl group, 4-methylthiobutyl group, 5-methylthiopenty group, 4-ethylthiobutyl group, 4-propylthiobutyl group, 4-pentylthiobutyl group) , alkyl group containing alkylsulfonyl group (e.g. methylsulfonylmethyl group, 2-methylsulfonylethyl group, 3-methylsulfonylpropyl group, 4-methylsulfonylbutyl group, 5-methylsuIfonylpentyl group, 4-ethylsulfonylbutyl group, 4-propylsulfonylbutyl group, 4-butylsulfonylbutyl group, 4-pentylsulfonylbutyl group) , alkyl group containing substituted or unsubstituted amino group (e.g. dimethylaminomethyl group, 2-dimethylaminoethyl group, 3-dimethylaminopropyl group, 4-dimethylaminobutyl group, 5-dimethylaminopentyl group, 4-diethylaminobutyl group, 4-dipropylaminobutyl group, 5-dipentylaminobutyl group, acetylaminomethyl group, 2-acetylaminoethyl group, 3-acetylaminopropyl group, 4-acetylaminobutyl group, 5-acetylaminopentyl group, 4-propionylaminobutyl group, methoxycarbonylaminomethyl group, 2-methoxycarbonylaminoethyl group, 3-methoxycarbonylaminopropyl group, 4-methoxycarbonylaminobutyl group, 5-methoxycarbonylaminopentyl group, 4-ethoxycarbonylaminobutyl group, 4-propyloxycarbonylaminobutyl group, 4-butoxycarbonylaminobuty group, 4-pentyloxycarbonylaminobutyl group, methylsulfonylaminomethyl group, 2-methylsulfonylaminoethyl group, 3-methylsulfonylaminopropyl group, 4-methylsulfonylaminobutyl group, S-methylsulfonylaminopentyl group, 4-ethylsulfonylaminobutyl group, 4-propylsulfonylaminobutyl group, 4-butylsulfonylaminobutyl group, 4-pentylsulfonylaminobutyl group, alkyl group containing substituted or unsubstituted carbamoyl group (e.g. carbamoylmethyl group, 2-carbamoylethyl group, 3-carbamoylpropyl group, 4-carbamoylbutyl group, 5-carbamoylpentyl group, 3-methylaminocarbonylpropyl group, 3-dimethylaminocarbamoylpropyl group, 3-ethylaminocarbonylpropyl group, 3-diethylaminocarbonylpropyl group, 3-propylaminocarbonylpropyl group, 3-dipropylaminocarbonylpropyl group, 3-butylaminocarbonylpropyl group, 3-propylaminocarbonylpropyl group, 3-butylaminocarbonylpropyl group, 3-dibutylaminocarbonylpropyl group, 3-pentylaminocarbonylpropyl group, 3-dipentylaminocarbonylpropyl group) , alkyl group containing substituted or unsubstituted aromatic ring [e.g. benzyl group, 2-phenylethyl group, 3-phenylpropyl group, 4-phenylbutyl group, 5-phenylpentyl group, 4-(fluorophenyl)butyl group, 4-(chlorophenyl)butyl group, 4-{bromophenyl)butyl group, 4-(iodophenyl)butyl group, 4-(methylphenyl)butyl group, 4-(methoxyphenyl)butyl group, 4-(aminophenyl)butyl group, 4-(cyanophenyl)butyl group, 4-(methylthiphenyl)butyl group, 4-(methylsulfonylphenyl)butyl group, 4-(naphtyl)phenyl, 4-(azulenyl)butyl group], alkyl group containing substituted or unsubstituted heteroaromatic ring [e.g. 4-(pyridyl)butyl group, 4-(furyl)butyl group, 4-(thiophenyl)butyl group, 4-(imidazolyl)butyl group, 4-(thiazolyl)butyl group, 4-(benzofuryl)butyl group, 4-(benzothiophenyl)butyl group, 4-(benzoimidazolyl ) butyl group, 4- and formula (XVIII) . R4 are selected from alky] group (e.g. methyl group, ethyl group, propyl group, butyl group, isobutyl group, t-butyl group, pentyl group) , substituted or unsubstituted aromatic ring (e.g. phenyl group, fluorophenyl group, chlorophenyl group, bromophenyl group, iodophenyl group, methylphenyl group, methoxyphenyl group, aminophenyl group, cyanophenyl group, methylthiophenyl group, methylsulfonylphenyl group, naphtyl group, azulenyl group, biphenyl group, phenoxyphenyl group) x substituted or unsubstituted benzyl group (e.g. benzyl group, fluorobenzyl group, chlorobenzyl group, bromobenzyl group, iodobenzyl group, methylbenzyl group, methoxybenzyl group, aminobenzyl group, cyanobenzyl group, methylthiobenzyl group, methylsulfonylbenzyl group, naphtylmethyl group, azulenylmethyl group, biphenylmethyl group, phenoxybenzyl group) . R5 and R6are the same or different and are selected from hydrogen atom, halogen atom (e.g. fluorine atom, chlorine atom, bromine atom, iodine atom) , alkyl group (e.g. methyl group, ethyl group, propyl group, butyl group, pentyl group, haloalkyl group (e.g. trifluoromethyl group, 2,2,2,-trifluoroethyl group, chloromethyl group, bromomethyl group, iodomethyl group, 2-bromoethyl group, 3-bromopropyl group, 4-bromobutyl group, 5-bromopentyl group,), lower alkoxycarbonyl group (e.g. methylxycarbonyl group, ethoxycarbonyl group, propyloxycarbonyl group, butoxycarbonyl group, pentyloxycarbonyl group), lower alkoxy group (e.g. methoxy group, ethoxy group, propyloxy group, butoxy group, pentyloxy group), lower acyloxy group (acetyloxy group, propionyloxy group), hydroxyl group, nitro group, cyano group, substituted or unsubstituted benzyloxy group (e.g. benzyloxy group, fluorobenzyloxy group, chlorobenzyloxy group, bromobenzyloxy group, iodobenzyloxy group, methylbenzyloxy group, methoxybenzyloxy group, aminobenzyloxy group, cyanobenzyloxy group, methylthiobenzyloxy group, methylsulfonylbenzyloxy group, naphtylmethyloxy group, azulenylmethyloxy group, biphenylmethyloxy group, phenoxybenzyloxy group) , substituted silyl group (e.g. trimethylsilyl group, triethylsilyl group, triisopropylsilyl group, t-butyldimethylsilyl group, t-butyldiphenylsilyl group), alkylthio group (e.g. methylthio group, ethylthio group, propylthio group, butylthio group, pentylthio group) , alkylsulfonyl group (e.g. methylsulfonyl group, ethylsulfonyl group, propylsulfonyl group, butylsulfonyl group, penrylsulfonyl group) , substituted or unsubstituted amino group (e.g. amino group, methylamino group, ethylamino group, propylamine* group, butylamino group, pentylamino group, dimethylamino group, diethylamino group, dipropylamino group, dibutylamino group, dipentylamino group, acetylamino group, propionylamino group, methoxycarbonylamino group, ethoxycarbonylamino group, propionylcarbonylamino group, butoxycarbonylamino group, pentyloxycarbonylamino group, methylsulfonylamino group, ethylsulfonylamino group), substituted or unsubstituted carbamoyl group (e.g. carbamoyl group, methylaminocarbonyl group, ethylaminocarbonyl group, propylaminocarbonyl group, butylaminocarbonyl group, pentylaminocarbonyl group, dimethylamino group, diethylamino group, diethylarriinocarbonyl group, dipropylaminocarbonyl group, dibutylaminocarbonyl group, dipentylaminocarbonyl group), substituted or unsubstituted aromatic ring (e.g. phenyl group, fluorophenyl group, chlorophenyl group, bromophenyl group, iodophenyl group, methylphenyl group, methoxyphenyl group, aminophenyl group, cyanophenyl group, methylthiophenyl group, methylsulfamoylphenyl group, methylsulfonylphenyl group, naphtyl group, azulenyl group, biphenyl group, phenoxyphenyl group) or heteroaromatic ring (e.g. pyridine ring, furan ring, thiophene ring, imidazole ring, thiazole ring, benzofuran ring, benzothiophene ring, benzimidazole ring, benzothiazole ring) , substituted or unsubstituted tetrahydropyranyl group ( e.g. tetrahydropyranyl group, fluorotetrahydropyranyl group, chloro tetrahydropyranyl group, methyltetrahydropyranyl group, methoxytetrahydropyranyl group, hydroxy tetrahydropyranyl group, acetoxytetrahydropyranyl group, benzyloxytetrahydropyranyl group, trimethylsilyloxytetrahydropyranyl group, methoxycarbonyltetrahydropyranyl group, alkyl group containing substituted or unsubstituted tetrahydropyranyl group [tetrahydropyranylmethyl group, 2-tetrahydropyranylethyl group, 3-tetrahydropyranylpropyl group, 4-tetrahydropyranylbutyl group, 5-tetrahydropyranylpenryl group, 2-{fluorotetrahydropyranyl)ethyl group, 2-(chlorotetrahydropyranyl)ethyl group, 2-(methyltetrahydropyranyl)ethyl group, 2-(methoxytetrahydropyranyl)ethyl group, 2-(hydroxytetrahydropyranyl)ethyl group, 2-(acetoxytetrahydropyranyl)ethyl group, 2-(benzyloxytetrahydropyranyl)ethyl group, 2-(trimethylsilyloxytetrahydropyranyl)ethyl group, 2-(methoxycarbonyltetrahydropyranyl)ethyl group], alkyl group containing amino group ( e.g. dimethylaminomethyl group, 2-dimethylaminoethyl group, 3-dimethylaminopropyl group, 4-dimethylaminobutyl group, 5-dimethylaminopentyl group, 4-diethylaminobutyl group, 4-dipropylaminobutyl group, 5-dipentylaminopentyl group) . This invention is a process for producing optically active alcohols by asymmetric reduction of aromatic ketones represented by general formula (I) using sodium borohydride, chlorotrimethylsilane and optically active 2-[bis(4-methoxyphenyl)hydroxymethyl]pyrrolidine (IV) . Optically active 2-[bis(4-methoxyphenyl)hydroxymethyl]pyrrolidine (IV) , which is used in this invention, can be synthesized from D- or L-proline according to the literatures (Journal of Chemical Society, Perkin Trans 1,1985, 2039; Journal of American Society, 1987,109,5551; Tetrahedron, 1993,42,5127; Synthesis, 2004,217) . The reaction is carried out in one-pot according to the method described in Tetrahedron Letters (2000, 41, 10281). This reaction is consisted with 3 steps operations. 1 step : The reaction of sodium borohyderide with chlorotrimethylsilane. 2 step : Preparation of asymmetric reducing agent by the addition of optically active 2-[bis(4-methoxyphenyl)hydroxymethyl]pyrrolidine into 1 step reaction mixture. 3 step : Aromatic ketone is reduced by the addition into 2 step reaction mixture to give optically active alcohol. 1 step : The amount of sodium borohyderide and chlorotrimethylsilene is 1 to 1.5-fold mol per aromatic ketone. Preferably amount is 1.2 to 1.4-fold mol. The reaction is carried out in inert solvent such as ethereal solvent (ether, isopropyl ether, t-butyl methyl ether, tetrahydrofuran, 1,4-dioxane) and halogenated solvent (dichloromethane, 1,2-dichloroethane). Preferably reaction solvent is tetrahydrofuran. The reaction is carried out under reflux temperature and reaction time is about 1 hr. 2 step : The mixture of sodium borohydride and chlorotrimethylsilane is reacted with 2-[bis(4-methoxyphenyl)hydroxymethyl]pyrrolidine by the dropwise addition. The reaction is carried out at 01 to 40 *C and reaction time is 0.5 hr. The amount of optically active 2-[bis(4-methoxyphenyl)hydroxymethyl]pyrrolidine is 5 mol% to 20 mol% per aromatic ketone. Preferably amount is 10 mol%. 3 step : Aromatic ketone is reduced by asymmetric reducing agent prepared in 1 step and 2 step. Aromatic ketone is added dropwise to reaction mixture. The reduction is carried out at 0oC to 40oC. Preferably reaction temperature is 15oC to 30oC. 3-[5-(4-Fluorophenyl)-5-oxopentanoyl]-(4S)-phenyl-1,3-oxazolidin-2-one ( VI ) and 5-(4-fluorophenyl)-5-oxopentanoic acid methyl ester (VIII) can be prepared in accordance with procedure in US Patent No. 6,207,822. (4S)-(4-Benzyloxyphenyl)-l -(4-fluoropheny])-(3R)-[3-{4-fluorophenyl)-3-oxopropyl]azetidin-2-one (X) can be synthesized as described in Journal of Organic Chemistry, 1999, 64, 3714 or Journal of Medicinal Chemistry, 1998,41, 973. 3-[(5S)-(4-Fluorophenyl)-5-hydroxypentanoyl]-(4S)-phenyl-1,3-oxazolidin-2-one (VII) , which is obtained by the asymmetric reduction of 3-[5-(4-fluorophenyl)-5-oxopentanoyl]-(4S)-phenyl- 1,3-oxazolidin-2-one (VI) , is available to produce ezetimibe by the β-lactam ring construction. On the other hand, (5S)-(4-fluorophenyl)-5-hydroxypentanoic acid methyl ester (IX), which is obtained by the asymmetric reduction of 5-(4-fluorophenyl>5-oxopentanoic acid methyl ester (VIll) , is utilized to produce 3-[(5S)-(4-fluorophenyl)-5-hydroxypentanoyl]-(4S)-phenyl-1,3- oxazolidin-2-one (VII) . Furthermore, (4S)-(4-benzyloxyphenyl)-1-{4-fluorophenyl)-(3R)- [(3S)- (4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one (XI) , which is obtained by the asymmetric reduction of (4S)-(4-benzyloxyphenyl)-1-(4-fluorophenyl)-(3R)-[3-(4-fluorophenyl)-3- oxopropyl]azetidin-2-one (X), is available to produce ezetimibe. [Example 1] Preparation-[(5S)-4-fluorophenyl)-5-hydroxypentanoyl]-(4S)-phenyl-1,3-oxazolidin-2-one Chlorotrimethylsilane (25.0 mL, 0.197 mol) was added to a suspension of sodium borohydride (7.45 g, 0.197 mol) in tetrahydrofuran (700.0 mL) at 24oC, and the reaction mixture was stirred under reflux for 1 hr. The reaction mixture was cooled to 24oC, and a solution of (R)-2- [bis(4-methoxyphenyl)hydroxymethyl]pyrrolidine (4.41 g, 0.014 mol) in tetrahydrofuran (280.0 mL) was added. After stirring for 0.5 hr, a solution of 3-[5-(4-fluorophenyl)-5-oxopentanoyl]- (4S)- phenyl-1,3-oxazolidin-2-one (50.00 g, 0.141 mol) in tetrahydrofuran (280.0 mL) was added dropwise during 80 min. After stirring for 10 min, the reaction mixture was cooled to A°C. 6N-HC1 was added to the reaction mixture, and water and toluene were added. After stirring for 30 min, the organic layer was separated. The organic layer was washed with water, aqueous saturated sodium bicarbonate and aqueous saturated sodium chloride, and dried over sodium sulfate. Filtration and evaporation gave 3-[(5S)-(4-fluorophenyl)-5-hydroxypentanoyl]-(4S)-phenyl-1,3-oxazolidin-2-one 48.71 g as colorless oil. 1H-NMR(CDC13)δ= 1.56-1.75 (m, 4H), 1.97 (d, J=3Hz, 1H), 2.96-2.99 (m, 2H), 4.28 (dd, J=3Hz, 9Hz, 1H), 4.56-4.66 (m, 1H), 4.68 (t, J=9Hz, 1H), 5.40 (dd, J=3Hz, 9 Hz, 1H), 6.98-7.02 (m, 2H), 7.25-7.37 (m, 7H). The de [diastereoselectivty de (%)=[(S,S)%-(R,R)%]] of the desired product was determined to be 93% by HPLC using a chiral column, [column: CHIRALCELL OD-H (DAICEL),mobile phase : ethanol/n-hexane= 1/5 (v/v)^ detection : UV at 258 nm]. [Example 2] The loading amount (mol%) of (R)-2-[bis(4-methoxyphenyl)hydroxymethyl]pyrrolidine and the reaction scale of 3-[5-(4-fluorophenyl)-5-oxopentanoyl]-(4S)-phenyl-1,3-oxazolidin-2-one (VI) were changed as shown in Table 1, and 3-[(5S)-4-fluorophenyl)-5-hydroxypentanoyl]-(4S)- phenyl-1,3- oxazolidin-2-one was synthesized using general procedure of Example 1 above. The de (%) of the desired product was determined by HPLC using a chiral column. The results are summarized in Table 1. In the reduction of using 3-[5-(4-fluorophenyl)-5-oxopentanoyl]-(4S)-phenyl-l ,3-oxazolidin-2-one as a catalyst, (R)-2-[bis(4-methoxyphenyl)hydroxymethyl]pyrrolidine was replaced with (R)-2- (diphenylhydroxymethyl)pyrrolidine in order to compare the de of the resulting product. As shown in Table 1, the loading amount (mol%) of (R)-2-(diphenylhydroxymethyl)pyrrolidine and the reaction scale of 3-[5-{4-fluorophenyl)-5-oxopentanoyl]-(4S)-phenyl-1,3-oxazolidin-2-one (VI) were changed. The de (%) of the desired product was determined by HPLC using a chiral column. The results are summarized in Table 1. In the reduction of using 3-[5-(4-fluorophenyl)-5-oxopentanoyl]-(4S)-phenyl-1,3-oxazolidin-2-one as a catalyst, (R)-2-[bis(4-methoxyphenyl)hydroxymethyl]pyrrolidine was replaced with (R)-2- [bis(4-trifluorophenyl)hydroxymethyl]pyrrolidine in order to compare the de of the resulting product The loading amount (mol%) of (R)-2-(diphenylhydroxymethyl)pylTolidine and the reaction scale of 3-[5-(4-fluorophenyl)-5-oxopentanoyl]-(4S)-phenyl-1,3-oxazolidin-2-one (VI) were shown in Table 1. The de (%) of the desired product was determined by HPLC using a chiral column. The results are summarized in Table 1. As shown in Table 1, when (R)-2-[bis(4-methoxyphenyl)hydroxymethyl]pyrrolidine is used as a catalyst at large scale production, the de of reaction product increased. In the case of usual (R)-2- (diphenylhydroxymethyl)pyrrolidine, the de of reaction product decreased at large scale production. When (R)-2- [bis(4-trifluorophenyl)hydroxymethyl]pyrrolidine was used as a catalyst, the de of reaction product dramatically decreased at small scale production. [Example 3] Preparation of (5S)-(4-fluorophenyl)-5-hydroxypentanoic acid methyl ester Chlorotrimethylsilane (2.0 mL, 0.01606 mol) was added to a suspension of sodium borohydride (0.61 g, 0.01606 mol) in tetrahydrofuran (63.0 mL) at 20oC, and the reaction mixture was stirred under reflux for 1 hr. The reaction mixture was cooled to 24oC, and a solution of (R)-2- [bis(4-methoxyphenyl)hydroxyme1hyl]pyrrolidine (0.42 g, 0.00134 mol) in tetrahydrofuran (10.0 mL) was added. After stirring for 0.5 hr, a solution of 5-(4-fluorophenyl)-5-oxopentanoic acid methyl ester (VIII) (3.00 g, 0.01338 mol) in tetrahydrofuran (10.0 mL) was added dropwise during 45 min. After stirring for 1.5 hr, the reaction mixture was cooled to 2oC. 6N-HC1 was added dropwise to the reaction mixture, and water and ethyl acetate were added. After stirring for 30 min, the organic layer was separated. The organic layer was washed with water, aqueous saturated sodium bicarbonate and aqueous saturated sodium chloride, and dried over sodium sulfate. Filtration and evaporation gave the crude product, which was purified by silica gel column chromatography (ethyl acetate/n-hexane) to give (5S)-(4-fluorophenyl)-5-hydroxypentanoic acid methyl ester 2.79 g as colorless oil. 1H-NMR(CDC13)δ= 1.59-1.80 (m, 4H), 2.21 (s, 1H), 2.32-2.36 (m, 2H), 3:65 (s, 3H), 4.63-4.68 (m, 1H), 7.00-7.04 (m, 2H), 7.26-7.32 (m, 2H). The ee [enantioselectivty ee (%)=[(S)%-(R)%]] of the desired product was determined by HPLC using a chiral column, [column : CHIRALPAK AD (DAICEL), mobile phase : ethanol/n-hexane= 1/20 (v/v), detection : UV at 258 nmj. The result is shown in Table 2. [Comparative Example 1] Chlorotrimethylsilane (0.86 mL, 0.005352 mol) was added to a suspension of sodium borohydride (0.202 g, 0.005352 mol) in tetrahydrofuran (21.0 mL) at 21oC, and the reaction mixture was stirred under reflux for 1 hr. The reaction mixture was cooled to 24oC, and a solution of (R)-2- (diphenylhydroxymethyl)pyrrolidine (0.114 g, 0.0004466 mol) in tetrahydrofuran (5.0 mL) was added. After stirring for 0.5 hr, a solution of 5-(4-fluorophenyl)-5-oxopentanoic acid methyl ester (VIII) (1.00 g, 0.00446 mol) in tetrahydrofuran (5.0 mL) was added dropwise during 48 min. After stirring for 0.5 hr, the reaction mixture was cooled to 2oC. 6N-HC1 was added dropwise to the reaction mixture, and water and ethyl acetate were added. After stirring for 30 min, the organic layer was separated. The organic layer was washed with water, aqueous saturated sodium bicarbonate and aqueous saturated sodium chloride, and dried over sodium sulfate. Filtration and evaporation gave the crude product, which was purified by silica gel column chromatography (ethyl acetate/n-hexane) to give (5S)-(4-fluorophenyl)-5-hydroxypentanoic acid methyl ester 0.90 g as colorless oil. The ee [enantioselectivty ee (%)=[(S)%-(R)%]] of the desired product was determined by HPLC using a chiral column, [column : CHIRALPAKAD (DAICELh mobile phase : ethanol/n-hexane=l/20(v/v)x detection '• UV at 258 nm]. The result is shown in Table 2. As shown in Table 2, when (R)-2-[bis(4-methoxyphenyl)hydroxymethyl]pyrrolidine was used as a catalyst at large scale production, the ee was larger than usual (R)-2- (diphenylhydroxymethyl)pyrrolidine. [Example 4] Preparation of (4S)-(4-ben2yloxyphenyl)-1-(4-fluorophenyl)-(3R)-[(3S)-(4-fluorophenyl)-3- hydroxypropyl]azetidin-2-one Chlorotrimethylsilane (0.33 mL, 0.02613 mol) was added to a suspension of sodium borohydride (0.099 g, 0.02613 mol) in tetrahydrofuran (15.1 mL) at 19oC, and the reaction mixture was stirred under reflux for 1 hr. The reaction mixture was cooled to 22oC, and , a solution of (R)-2- [bis(4-methoxyphenyl)hydroxymethyl]pyrro]idine (0.063 g, 0.000201 mol) in tetrahydrofuran (5.2 mL) was added. After stirring for 0.5 hr, a solution of (4S)-(4-benzyloxyphenyl)-l -(4- fluorophenyl)-(3R)-[3-(4-fluorophenyl)-3-oxopropyl]azetidin-2-one (l.00g, 0.00201 mol) in tetrahydrofuran (5.2 mL) was added dropwise during 8 min. After stirring for 1 hr, the reaction mixture was cooled to 2oC. 6N-HC1 was added dropwise to the reaction mixture, and water and toluene were added. After stirring for 30 min, the organic layer was separated. The organic layer was washed with water, aqueous saturated sodium bicarbonate and aqueous saturated sodium chloride, and dried over sodium sulfate. Filtration and evaporation gave the crude product, which was purified by silica gel column chromatography (ethyl acetate/n-hexane) (4SH4-benzyloxyphenyl)-1-(4-fluorophenyl)-(3R)-[(3S)-(4-fluorophenyl)-3- hydroxypropyl]azetidin-2-one 0.89 g as colorless crystals. 1H-NMR(CDCl3)δ= 1.88-2.01 (m, 4H), 2.19 (d, J=4Hz, 1H), 3.07 (dt, J=2Hz, 8Hz, 1H), 4.57 (d, J=2Hz, 1H), 4.71-4.73 (m, 1H), 5.29 (s, 2H), 6.90-7.03 (m, 6H), 7.21-7.43 (m, 11H). The ee [enantioselectivty ee (%)=[(S)%-(R)%]] of the desired product was determined by HPLC using a chiral column, [column : CHIRALPAKAD (DAICEL), mobile phase : ethanol/n-hexane= 1/9 (v/v), detection : UV at 258 ran]. The result is shown in Table 3. [Comparative Example 2] Chlorotrimethylsilane (0.33 mL, 0.02613 mol) was added to a suspension of sodium borohydride (0.099 g, 0.02613 mol) in tetrahydrofuran (15.1 mL) at 19oC, and the reaction mixture was stirred under reflux for 1 hr. The reaction mixture was cooled to 22t, and a solution of 2- (diphenylhydroxymethyl)pyrrolidine (0.051 g, 0.000201 mol) in tetrahydrofuran (5.2 mL) was added. After stirring for 0.5 hr, a solution of (4S)-(4-benzyloxyphenyl)-1-(4- fluorophenyl)-(3R)- [3-(4- fluorophenyl)-3-oxopropyl]azetidin-2-on (l.00g, 0.00201 mol) in tetrahydrofuran (5.2 mL) was added dropwise during 7 min. After stirring for 70 min, the reaction mixture was cooled to 2°C. 6N-HC1 was added dropwise to the reaction mixture, and water and toluene were added. After stirring for 30 min, the organic layer was separated. The organic layer was washed with water, aqueous saturated sodium bicarbonate and aqueous saturated sodium chloride, and dried over sodium sulfate. Filtration and evaporation gave the crude product, which was purified by silica gel column chromatography (ethyl acetate/n-hexane) (4S)-(4-benzyloxyphenyl)-l -(4-fluorophenyl)-(3R)-[(3S)- (4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one 0.92 g as colorless crystals. 1H-NMR(CDCl3)δ= 1.88-2.01 (m, 4H), 2.19 (d, J=4Hz, 1H), 3.07 (dt, J=2Hz, 8Hz, 1H), 4.57 (d, J=2Hz, 1H), 4.71-4.73 (m, 1H), 5.29 (s, 2H), 6.90-7.03 (m, 6H), 7.21-7.43 (m, 11H). The ee of the desired product was determined by HPLC using a chiral column, [column : CHIRALPAK AD (DAICEL, mobile phase : ethanol/n-hexane=1/9(v/v), detection : UV at 258 nm]. The result is shown in Table 3. As shown in Table 3, when (R)-2-[bis(4-niethoxyphenyl)hydroxymethyl]pyrrolidine was used as a catalyst at the same scale production, the ee was larger about 2-fold than usual (R)-2- (diphenylhydroxymethyl)pyrrolidine. FIELD OF INDUSTRIAL APPLICATION Aromatic ketones are reduced to optically active alcohols in high enantioselectivity by using of the reduction process in this invention at large scale production. This invention is useful for producing optically active alcohols such as ezetimibe: ([l-(4-fluorophenyl)-(3R)-[3-(4-fluorophenyl)-(3S)- hydroxypropyl]-(4S)-{4-hydroxyphenyl)azetidin-2-one]), which is useful as hypochlesterolemic agents in the prevention and treatment of atherosclerosis. The advantage of this process is that (R)-2-[bis(4-methoxyphenyl)hydroxymethyl]pylTolidine is recovered in high yleld at reaction end-point by simple operation such as extraction, and recyclable after purification such as recrystallization. Furthermore, this reaction proceeds at room temperature, and is not required low reaction temperature. We Claim: 1. A process for preparing an optically active alcohol represented by formula (V): wherein, R1 are selected from hydrogen atom, halogen atom, lower alkyl group (1 to 5 carbon atom), lower haloalkyl group (1 to 5 carbon atom), lower alkoxycarbonyl group (1 to 5 carbon atom), lower alkoxy group (1 to 5 carbon atom), hydroxyl group, nitro group, cyano group, lower acyloxy group (1 to 5 carbon atom), lower alkylthio group (1 to 5 carbon atom), lower alkylsulfonyl group (1 to 5 carbon atom), substituted and unsubstituted amino group, substituted and unsubstituted carbamoyl group, substituted and unsubstituted aromatic ring or heterocycle, and R2 is -(CH2)n-R3 wherein, n is 1 to 5 integer. R3 are selected from hydrogen atom, halogen atom, lower alkoxycarbonyl group (1 to 5 carbon atom), lower alkoxy group (1 to 5 carbon atom), lower alkylthio group (1 to 5 carbon atom), lower alkylsulfonyl group (1 to 5 carbon atom), substituted and unsubstituted amino group, unsubstituted carbamoyl group, substituted and unsubstituted aromatic ring or heteroaromatic ring and formula (II): {wherein, R4 are lower alkyl group (1 to 5 carbon atom), substituted and unsubstituted aromatic ring, and substituted and unsubstituted benzyl group.} and formula (III): {wherein, R5 and R6 are the same or different and are selected from hydrogen atom, halogen atom, lower alkyl group (1 to 5 carbon atom), lower haloalkyl group (1 to 5 carbon atom), lower alkoxycarbonyl group (1 to 5 carbon atom), lower alkoxy group (1 to 5 carbon atom), lower acyloxy group (1 to 5 carbon atom), hydroxyl group, nitro group, cyano group, substituted and unsubstituted benzyloxy group, substituted silyloxy group, lower alkylthio group (1 to 5 carbon atom), lower alkylsulfonyl group (1 to 5 carbon atom), substituted and unsubstituted amino group, substituted and unsubstituted carbamoyl group, substituted and unsubstituted aromatic ring or heteroaromatic ring, substituted and unsubstituted tetrahydropyranyl group, lower alkyl group containing substituted and unsubstituted tetrahydropyranyl group (1 to 5 carbon atom), lower alkyl group containing amino group (1 to 5 carbon atom)}, which comprises: reducing aromatic ketones represented by formula (I): wherein R1 and R2 are as defined above, with sodium borohydride, chlorotrimethylsilane and optically active 2-[bis(4- methoxyphenyl)hydroxymethyl]pyrrolidine represented by formula (IV): to give optically active alcohol represented by formula (V). 2. A process for stereoselectively preparing 3-[(5S)-(4-fluorophenyl)-5-hydroxypentanoyl]-(4S)-phenyl- l,3-oxazolidin-2-one represented by formula (VII): which comprises: reducing 3-[5-(4-fluorophenyl)-5-oxopentanoyl]-(4S)-phenyl-1,3-oxazolidin-2-one represented by formula (VI): with sodium borohydride, chlorotrimethylsilane and optically active (R)-2-[bis(4- methoxyphenyl)hydroxymethyl]pyrrolidine represented by formula (IV): to give 3-[(5S)-(4-fluorophenyl)-5-hydroxypentanoyl]-(4S)-phenyl-1,3-oxazolidin-2-one. 3. A process for preparing (5S)-(4-fluorophenyl)-5-oxopentanoic acid methyl ester represented by formula (IX): which comprises: reducing 5-(4-fluarophenyl)-5-oxopentanoic acid methyl ester represented by formula (VIII): with sodium borohydride, chlorotrimethylsilane and optically active (R)-2-[bis(4- methoxyphenyl)hydroxymethyl]pyrrolidine represented by formula (IV) to give (5S)-(4-fluorophenyl)-5-oxopentanoic acid methyl ester. 4. A process for preparing (4S)-(4-benzyloxyphenyl)-1-(4-fluorophenyl)-(3R)-[(3S)-(4-fluorophenyl)- (3S)-3-hydoxypropyl]azetidin-2-one represented by formula (XI): which comprises: reducing (4S)-(4-benzyloxyphenyl)-1-(4-fluorophenyl)-(3R)-[3-(4- fluorophenyl)-3- oxopropyl]azetidin-2-one represented by formula (X) with sodium borohydride, chlorotrimethylsilane and optically active (R)-2-[bis(4- methoxyphenyl)hydroxymethyl]pyrrolidine represented by formula (IV) to give (4S)-(4-benzyloxyphenyl)-1-(4-fluorophenyl)-(3R)-[(3S)-(4-fluorophenyl)- (3S)-3-hydoxypropyl]azetidin- 2-one. ABSTRACT METHOD OF PRODUCING OPTICALLY ACTIVE ALCOHOL This invention relates to a process for preparing an optically active alcohol represented by formula (V): wherein, R1 and R2 are as described in the specification, which comprises: reducing aromatic ketones represented by formula (I): wherein R1 and R2 are as described in the specification, with sodium borohydride, chlorotrimethylsilane and optically active 2-[bis(4-methoxyphenyl)hydroxymethyl]pyrrolidine represented by formula (IV): to give optically active alcohol represented by formula (V).

Full Text

TECHNICAL FIELD
This invention relates to a process for producing optically active alcohols using asymmetric reduction of
aromatic ketones.
BACKGROUND TECHNOLOGY
Hydroxyalkyl substituted azetidinone derivatives, such as ezetimibe
([l-(4-fluorophenyl)-(3R)-[3-(4-fluorophenyl)-(3S)-hydroxypropyl]-(4S)-(4-hydroxyphenyl)azetidin-2-one])
represented by formula XII, are useful as hypochlesterolemic agents in the prevention and treatment of
atherosclerosis.

Several processes have been reported for the preparation of diphenylazetidinones. (Journal of Organic Chemistry,
1999, 64, 3714, Journal of Medicinal Chemistry, 1998,41 973, U.S Patent No. 5,631,365; 5,886,171; 6,207,822;
6,133,001; 5,856,473, WO2005/066120, JP 2002-531546, JP 2005-53931) .
These processes involve that the β-lactam ring construction using
3-[(5S)-(4-fluorophenyl)-5-hydroxypentanoyl]-(4S)-phenyl-l ,3-oxazolidin-2-one (VII) (method 1) or asymmetric
reduction of derivatives having carbonyl group in side chain at 3-position of β-lactam ring such as
(4S)-(benzyloxyphenyl)-1-(4-fluorophenyl)-(3R)-[3-(4-fluorophenyl)-3-
oxopropyl]azetidin-2-one (X) (method 2).
In Method 1, the intermediate, the hydroxyl group of 3-[(5S)-(4- fluorophenyl)-5-
hydroxypentanoyl]-(4S)-phenyl-l ,3-oxazolidin-2-one (VII) is protected with a suitable protecting group such as
trimethylsilyl group or t-butyldimethylsilyl group, was used (U.S Patent No. 6,207,822, WO2005/066120, JP
2002-531546, JP2005-53931) . 3-[(5S)-(4- fluorophenyl)-5- hydroxypentanoyl]-(4S)-phenyl-l,3-oxazolidin-2-one
(VII) is synthesized by stereoselective microbial reduction of 3-[5-(4- fluorophenyl)-5-oxopentanoyl]-
(4S)-phenyl-l,3-oxazolidin-2-one (VI) (U.S.Patent No. 5,618,707).
It is reported mat 3-[(5S)-(4- fluorophenyl)-5- hydroxypentanoyl] -(4S)-
phenyl-l,3-oxazolidin-2-one (VII) is synthesized by asymmetric reduction of
3-[5-(4-fluorophenyl)-5-oxopentanoyl]-(4S)-phenyl-l,3-oxazolidin-2-one (VI) ( U.S Patent No. 6,207,822;
6,627,757, Tetrahedron Letters, 2003, 44, 801.) . These processes are reduction by borane-dimethylsulfide
complex or borane-tetrahydrofuran complex using
(R)-tetraydro)-1-methyl-3,3-diphenyl-1H,3H-pyrrolo(l,2-c)(l,2,3)-oxazaborolidine [(R)-MeCBS; XIII] as a
catalyst to afford the corresponding alcohol in high enantioselectivity.

However, the enatioselectivity of the reduction depends on rate and mode of addition of borane-complex, moisture
sensitivity of the reaction medium and the reaction temperature. Moreover, the reduction using a chiral catalyst
leads to problems associated with the formation of over reduced products, such as compound (XIV) (Tetrahedron
Letters, 2003,44,801).

Borane-dimethylsulfide complex and borane-tetrahydrofuran-complex are expensive and toxic.
Furthermore, the handling of these reagents is not easy at large production due to borane is gas.
(R)-MeCBS (XIII) is commercially available, but it is expensive. Moreover, the recycle process is
required, since (R)-2-(diphenylhydroxymethyl)pyrrolidine (XV), the product that (R)-MeCBS '
(XIII) is decomposed by workup operations, is recovered. In this case, it is necessary expensive
boron carrier such as trimethylboroxine to prepared (R)-MeCBS (XIII) .

WO2005/066120 discloses the synthetic methods of 3-[(5S)-(4-fluorophenyl)- 5-
hydroxypentanoyl]-(4S)-phenyl-l,3-oxazolidin-2-one (VII) and (5S)-(4-fluorophenyl)-5-
hydroxypentanoic acid methyl ester (IX) using (-)-B-chlorodiisopinocampheylborane (XVI) as a reducing agent.

(5S)-5-(4-fluorophenyl)-5- hydroxypentanoic acid methyl ester (IX) is converted to 3-[(5S)- (4-
fluorophenyl)-5- hydroxypentanoyl]-(4S)- phenyl -l,3-oxazolidin-2-one (VII) in this patent This reaction also
shows high selectivity, however a stoichiometric amount of reducing agent is necessary.
In method 2 , (4S)-(4-benzyloxyphenyl)-l -(4-fluorophenyl)-(3R)-[(3S)-(4-fluorophenyl)- 3-
hydroxypropyl]azetidin-2-one (XI) is produced in high stereoselectivity by borane-complex asymmetric reduction
of (4S)-(4-benzyloxyphenyl)-l -(4-fluorophenyl)-(3R)-[3-(4- fluorophenyl)-
3-oxopropyl]azetidin-2-one (X) using (R>MeCBS (XIII) as a catalyst Compound (XI) is converted
to ezetimibe (XII) by the removal of benzyl group (Journal of Organic Chemistry, 1999,64.3714) .
However, this process is also used expensive (R)-MeCBS (XIII) and borane-complex.
It is reported the asymmetric reduction of aromatic ketones by sodium borohydride, chlorotrimethylsilane and a

catalytic amount of optically active 2-(diphenylhydroxymethyl)pylrolidine (XV) system (Tetrahedron Letters,
2000, 41. 10281). This reaction doesn't require low reaction temperature. Furthermore, cheep and low toxic
reagents are used in this reduction system. Moreover, 2-(diphenylhydroxymethyl)pyrroIidine (XV) is easily
recovered at workup operations in high yleld, and recyclable after purification such as recrystallization.
Reduction of 3-[5-(4- fluorophenyl)-5-oxopentanoyl]-(4S)-phenyl-l ,3-oxazolidin-
2-one (VI) by this system gives 3-[(5S)-(4- fluorophenyl)-5-hydroxypentanoyl]-(4S)-phenyl-
l,3-oxazolidin-2-one (VIII ) in high yleld and enantioselectivity [ 1 g scale
((R)-2-(diphenylhydroxymethyl)pyrrolidine 10 mol%) : de 87%) . However, Tendency of the decreased
enantioselectivity of the product is observed at scale-up production [ 10 g scale
((R)-2-(diphenylhydroxymethyl)pyrrolidine 10 mol%) : de 74%) . Accordingly, the development of catalyst,
which shows high enantioselectivity at large scale production, is desired.
DISCLOSURE OF INVENTION
This invention provides the synthetic method that shows high enantioselectivity at large scale production of
optically active alcohols by asymmetric reduction of aromatic ketones. In the course of study on the development
of a enantioselective method of preparing optically active alcohols, inventors found that use of optically active
2-[bis(4-methoxyphenyl)hydroxymethyl]pyrrolidine (IV) instead of optically active
2-(diphenylhydroxymethyl)pyrrolidine provides the alcohols in high enantioselectivity at large scale production.
This invention relates to a process for producing optically active alcohols.
Namely, this invention provides process that aromatic ketones represented by formula (I)

[wherein, R1 are selected from hydrogen atom, halogen atom, lower alkyl group (1 to 5 carbon atom) , lower
haloalkyl group (1 to 5 carbon atom) , lower alkoxycarbonyl group (1 to 5 carbon atom) , lower alkoxy group
(1 to 5 carbon atom) , hydroxyl group, nitro group, cyano group, lower acyloxy group (1 to 5 carbon atom) ,
lower alkylthio group (1 to 5 carbon atom) , lower alkylsulfonyl group (1 to 5 carbon atom) , substituted and
unsubstituted amino group, substituted and unsubstituted carbamoyl group, substituted and unsubstituted aromatic
ring or heteroaromatic ring. R2 is -(CH2)n-R3 [wherein n is 1 to 5 integer. R3are selected from hydrogen atom,
halogen atom, lower alkoxycarbonyl group (1 to 5 carbon atom), lower alkoxy group (1 to 5 carbon atom), lower
alkylthio group (1 to 5 carbon atom) , lower alkylsulfonyl group (1 to 5 carbon atom) , substituted and
unsubstituted amino group, unsubstituted carbamoyl group, substituted and unsubstituted aromatic ring or
heteroaromatic ring and formula (II) :

{wherein, R4 are selected from lower alkyl group (1 to 5 carbon atom) , substituted and unsubstituted aromatic
ring, and substituted and unsubstituted benzyl group.}

and formula (III) :

{wherein, R5 and R6are the same or different and are selected from hydrogen atom, halogen atom, lower alky]
group (1 to 5 carbon atom) , lower haloalkyl group (1 to 5 carbon atom) , lower alkoxycarbonyl group (1 to 5
carbon atom) , lower alkoxy group (1 to 5 carbon atom) , lower acyloxy group (1 to 5 carbon atom) , hydroxyl
group, nitro group, cyano group, substituted and unsubstituted benzyloxy group, substituted silyloxy group, lower
alkylthio group (1 to 5 carbon atom) , lower alkylsulfonyl group (1 to 5 carbon atom) , substituted and
unsubstituted amino group, substituted and unsubstituted carbamoyl group, substituted and unsubstituted aromatic
ring or heteraromatic ring, substituted and unsubstituted tetrahydropyranyl group, lower alkyl group containing
substituted and unsubstituted tetrahydropyranyl group (1 to 5 carbon atom) , lower alkyl group containing amino
group (1 to 5 carbon atom) }) ] are reduced by sodium borohydride, chlorotrimethylsilane and optically active
(R)-2-[b is(4-memoxyphenyl)hydroxymethyl]pyrrelidine represented by formula (IV)

to give optically active alcohol represented by formula (V) stereoselectively.

(wherein, R1 and R2 are as defined above.)
This invention also provides process that 3-[5-(4-fluorophenyl)-5-oxopentanoyl]-(4S)- phenyl-
1,3-oxazolidin-2-one represented by formula (VI)

is reduced by sodium borohydride, chlorotrimethylsilane and optically active
(R)-2-[bis(4-methoxyphenyl)hydroxymethyl]pyrrolidine represented by formula (IV)

to give 3-[(5S)-(4-fluorophenyl)-5-hydroxypentanoyl]-(4S)-phenyl-1,3-oxazolidin-2-one represented by formula
(VII) stereoselectively.

This invention also provides process that 5-(4-fluoropheny1)-5-oxopentanoic acid methyl ester represented by
formula (VIII)

is reduced by sodium borohydride, chlorotrimethylsilane and optically active
(R)-2-[bis(4-methoxyphenyl)hydroxymethyl]pyrrolidine represented by formula (IV)

to give (5S)-(4-fluorophenyl)-5-oxopentanoic acid methyl ester represented by formula (IX) stereoselectively.

This invention also provides process that (4S)-(4-benzyloxyphenyl)-1-(4- fluorophenyl)-(3R)-[3-(4-
fluorophenyl)-3oxopropyl]azetidin-2-one represented by formula (X)

is reduced by sodium borohydride, chlorotrimethylsilane and optically active (R)
2-[bis(4-methoxyphenyl)hydroxyme1hyl]pylTolidine represented by formula (IV)

to give (4S)-(4-benzyloxyphenyl)-l -(4-fluorophenyl)-(3R)-[(3SH4-fluorophenylH3S)-
3-hydoxypropyl]azetidin-2-one represented by formula (XI) stereoselectively.

BEST MODE FOR CARRYING OUT THE INVENTION
Compounds represented by general formula (I) are defined herein. R1 are selected from hydrogen atom, halogen
atom (e.g. fluorine atom, chlorine atom, bromine atom, iodine atom), alkyl group (e.g. methyl group, ethyl group,
propyl group, butyl group, pentyl group, haloalkyl group (e.g. trifluoromethyl group, 2,2,2,-trifluoroethyl group),
alkoxycarbonyl group (e.g. methylxycarbonyl group, ethoxycarbonyl group, propyloxycarbonyl group,
butoxycarbonyl group, pentyloxycarbonyl group), alkoxy group (e.g. methoxy group, ethoxy group, propyloxy
group, butoxy group, penryloxy group), hydroxyl group, nitro group, cyano group, acyloxy group (e.g. acetyloxy
group, propionyloxy group), alkylthio group (e.g. methylthio group, ethylthio group, propylthio group, butylthio
group, pentylthio group) , alkylsulfonyl group (e.g. methylsulfonyl group, ethylsulfonyl group, propylsulfonyl
group, butylsulfonyl group, pentylsulfonyl group) , substituted or unsubstituted amino group (e.g. amino group,
methylamino group, ethylamino group, propylamino group, butylamino group, pentylamino group,
dimethylamino group, diethylamino group, dipropylamino group, dibutylamino group, dipentylamino group,
acetylamino group, propionylamino group, methoxycarbonylamino group, ethoxycarbonylamino group,
propionylcarbonylamino group, butoxycarbonylamino group, pentyloxycarbonylamino group,
methylsulfonylamino group, ethylsulfonylamino group), substituted or unsubstituted carbamoyl group (e.g.
carbamoyl group, methylaminocarbonyl group, ethylaminocarbonyl group, propylaminocarbonyl group,
butylaminocarbony] group, pentylaminocarbonyl group, dimethylamino group, diethylamino group,
diethylaminocarbonyl group, dipropylaminocarbonyl group, dibutylaminocarbonyl group, dipentylaminocarbonyl
group), substituted or unsubstituted aromatic ring (e.g. phenyl group, fluorophenyl group, chlorophenyl group,
bromophenyl group, iodophenyl group, methylphenyl group, methoxyphenyl group, aminophenyl group,
cyanophenyl group, methylthiophenyl group, methylsulfamoylphenyl group, methylsulfonylphenyl group, naphtyl
group, azulenyl group, biphenyl group, phenoxyphenyl group) or heteroaromatic ring (e.g. pyridine ring, furan
ring, thiophene ring, imidazole ring, thiazole ring, benzofuran ring, benzothiophene ring, benzimidazole ring,
benzothiazole ring) .
R2 are selected from alkyl group (e.g. methyl group, ethyl group, propyl group, butyl group, pentyl group) ,
haloalkyl group (e.g. chloromethyl group, 2-chloroethyl group, 3-chloropropyl group, 4-chlorobutyl group,
5-chloropentyl group, bromomethyl group, 2-bromoethyl group, 3-bromopropyl group, 4-bromobutyl group,
5-bromopentyl group, iodomethyl group, 2-iodoethyl group, 3-iodopropyl group, 4-iodobutyl group, 5-iodopentyl
group ) , alkyl group containing methoxycarbonyl group ( e.g. methoxycarbonylmethyl group,
2-methoxycarbonylethyl group, 3-methoxycarbonylpropyl group, 4-methoxycarbonylbutyl group,
5-methoxycarbonylpentyl group, 3-ethoxycarbonylpropyl group, 3-propyloxycarbonylpropyl group,
3-butoxycarbonylpropyl group, 3-penryloxycarbonylpropyl group) , alkyl group containing alkoxy group (e.g.
methoxymethyl group, 2-methoxyemyl group, 3-methoxypropyl group, 4-methoxybutyl group, 5-methoxypentyl
group, 4-ethoxybutyl group, 4-propyloxybutyl group, 4-butoxybutyl group, 4-pentyloxybutyl group) , hydroxyl

group, alkyl group containing alkylthio group (e.g. methylthiomethyl group, 2-methylthioethyl group,
3-methylthiopropyl group, 4-methylthiobutyl group, 5-methylthiopenty group, 4-ethylthiobutyl group,
4-propylthiobutyl group, 4-pentylthiobutyl group) , alkyl group containing alkylsulfonyl group (e.g.
methylsulfonylmethyl group, 2-methylsulfonylethyl group, 3-methylsulfonylpropyl group, 4-methylsulfonylbutyl
group, 5-methylsuIfonylpentyl group, 4-ethylsulfonylbutyl group, 4-propylsulfonylbutyl group,
4-butylsulfonylbutyl group, 4-pentylsulfonylbutyl group) , alkyl group containing substituted or unsubstituted
amino group (e.g. dimethylaminomethyl group, 2-dimethylaminoethyl group, 3-dimethylaminopropyl group,
4-dimethylaminobutyl group, 5-dimethylaminopentyl group, 4-diethylaminobutyl group,
4-dipropylaminobutyl group, 5-dipentylaminobutyl group, acetylaminomethyl group, 2-acetylaminoethyl
group, 3-acetylaminopropyl group, 4-acetylaminobutyl group, 5-acetylaminopentyl group,
4-propionylaminobutyl group, methoxycarbonylaminomethyl group, 2-methoxycarbonylaminoethyl group,
3-methoxycarbonylaminopropyl group, 4-methoxycarbonylaminobutyl group, 5-methoxycarbonylaminopentyl
group, 4-ethoxycarbonylaminobutyl group, 4-propyloxycarbonylaminobutyl group,
4-butoxycarbonylaminobuty group, 4-pentyloxycarbonylaminobutyl group, methylsulfonylaminomethyl group,
2-methylsulfonylaminoethyl group, 3-methylsulfonylaminopropyl group, 4-methylsulfonylaminobutyl group,
S-methylsulfonylaminopentyl group, 4-ethylsulfonylaminobutyl group, 4-propylsulfonylaminobutyl group,
4-butylsulfonylaminobutyl group, 4-pentylsulfonylaminobutyl group, alkyl group containing substituted or
unsubstituted carbamoyl group (e.g. carbamoylmethyl group, 2-carbamoylethyl group, 3-carbamoylpropyl
group, 4-carbamoylbutyl group, 5-carbamoylpentyl group, 3-methylaminocarbonylpropyl group,
3-dimethylaminocarbamoylpropyl group, 3-ethylaminocarbonylpropyl group, 3-diethylaminocarbonylpropyl
group, 3-propylaminocarbonylpropyl group, 3-dipropylaminocarbonylpropyl group,
3-butylaminocarbonylpropyl group, 3-propylaminocarbonylpropyl group, 3-butylaminocarbonylpropyl group,
3-dibutylaminocarbonylpropyl group, 3-pentylaminocarbonylpropyl group, 3-dipentylaminocarbonylpropyl
group) , alkyl group containing substituted or unsubstituted aromatic ring [e.g. benzyl group, 2-phenylethyl group,
3-phenylpropyl group, 4-phenylbutyl group, 5-phenylpentyl group, 4-(fluorophenyl)butyl group,
4-(chlorophenyl)butyl group, 4-{bromophenyl)butyl group, 4-(iodophenyl)butyl group, 4-(methylphenyl)butyl
group, 4-(methoxyphenyl)butyl group, 4-(aminophenyl)butyl group, 4-(cyanophenyl)butyl group,
4-(methylthiphenyl)butyl group, 4-(methylsulfonylphenyl)butyl group, 4-(naphtyl)phenyl, 4-(azulenyl)butyl
group], alkyl group containing substituted or unsubstituted heteroaromatic ring [e.g. 4-(pyridyl)butyl group,
4-(furyl)butyl group, 4-(thiophenyl)butyl group, 4-(imidazolyl)butyl group, 4-(thiazolyl)butyl group,
4-(benzofuryl)butyl group, 4-(benzothiophenyl)butyl group, 4-(benzoimidazolyl ) butyl group,
4-
and formula (XVIII) .

R4 are selected from alky] group (e.g. methyl group, ethyl group, propyl group, butyl group, isobutyl group,
t-butyl group, pentyl group) , substituted or unsubstituted aromatic ring (e.g. phenyl group, fluorophenyl group,
chlorophenyl group, bromophenyl group, iodophenyl group, methylphenyl group, methoxyphenyl group,
aminophenyl group, cyanophenyl group, methylthiophenyl group, methylsulfonylphenyl group, naphtyl group,
azulenyl group, biphenyl group, phenoxyphenyl group) x substituted or unsubstituted benzyl group (e.g. benzyl
group, fluorobenzyl group, chlorobenzyl group, bromobenzyl group, iodobenzyl group, methylbenzyl group,
methoxybenzyl group, aminobenzyl group, cyanobenzyl group, methylthiobenzyl group, methylsulfonylbenzyl
group, naphtylmethyl group, azulenylmethyl group, biphenylmethyl group, phenoxybenzyl group) .
R5 and R6are the same or different and are selected from hydrogen atom, halogen atom (e.g. fluorine atom,
chlorine atom, bromine atom, iodine atom) , alkyl group (e.g. methyl group, ethyl group, propyl group, butyl
group, pentyl group, haloalkyl group (e.g. trifluoromethyl group, 2,2,2,-trifluoroethyl group, chloromethyl group,
bromomethyl group, iodomethyl group, 2-bromoethyl group, 3-bromopropyl group, 4-bromobutyl group,
5-bromopentyl group,), lower alkoxycarbonyl group (e.g. methylxycarbonyl group, ethoxycarbonyl group,
propyloxycarbonyl group, butoxycarbonyl group, pentyloxycarbonyl group), lower alkoxy group (e.g. methoxy
group, ethoxy group, propyloxy group, butoxy group, pentyloxy group), lower acyloxy group (acetyloxy group,
propionyloxy group), hydroxyl group, nitro group, cyano group, substituted or unsubstituted benzyloxy group (e.g.
benzyloxy group, fluorobenzyloxy group, chlorobenzyloxy group, bromobenzyloxy group, iodobenzyloxy group,
methylbenzyloxy group, methoxybenzyloxy group, aminobenzyloxy group, cyanobenzyloxy group,
methylthiobenzyloxy group, methylsulfonylbenzyloxy group, naphtylmethyloxy group, azulenylmethyloxy group,
biphenylmethyloxy group, phenoxybenzyloxy group) , substituted silyl group (e.g. trimethylsilyl group,
triethylsilyl group, triisopropylsilyl group, t-butyldimethylsilyl group, t-butyldiphenylsilyl group), alkylthio group
(e.g. methylthio group, ethylthio group, propylthio group, butylthio group, pentylthio group) , alkylsulfonyl
group (e.g. methylsulfonyl group, ethylsulfonyl group, propylsulfonyl group, butylsulfonyl group, penrylsulfonyl
group) ,
substituted or unsubstituted amino group (e.g. amino group, methylamino group, ethylamino group, propylamine*
group, butylamino group, pentylamino group, dimethylamino group, diethylamino group, dipropylamino group,
dibutylamino group, dipentylamino group, acetylamino group, propionylamino group, methoxycarbonylamino
group, ethoxycarbonylamino group, propionylcarbonylamino group, butoxycarbonylamino group,
pentyloxycarbonylamino group, methylsulfonylamino group, ethylsulfonylamino group), substituted or
unsubstituted carbamoyl group (e.g. carbamoyl group, methylaminocarbonyl group, ethylaminocarbonyl group,
propylaminocarbonyl group, butylaminocarbonyl group, pentylaminocarbonyl group, dimethylamino group,
diethylamino group, diethylarriinocarbonyl group, dipropylaminocarbonyl group, dibutylaminocarbonyl group,
dipentylaminocarbonyl group), substituted or unsubstituted aromatic ring (e.g. phenyl group, fluorophenyl group,
chlorophenyl group, bromophenyl group, iodophenyl group, methylphenyl group, methoxyphenyl group,
aminophenyl group, cyanophenyl group, methylthiophenyl group, methylsulfamoylphenyl group,

methylsulfonylphenyl group, naphtyl group, azulenyl group, biphenyl group, phenoxyphenyl group) or
heteroaromatic ring (e.g. pyridine ring, furan ring, thiophene ring, imidazole ring, thiazole ring, benzofuran ring,
benzothiophene ring, benzimidazole ring, benzothiazole ring) , substituted or unsubstituted tetrahydropyranyl
group ( e.g. tetrahydropyranyl group, fluorotetrahydropyranyl group, chloro tetrahydropyranyl group,
methyltetrahydropyranyl group, methoxytetrahydropyranyl group, hydroxy tetrahydropyranyl group,
acetoxytetrahydropyranyl group, benzyloxytetrahydropyranyl group, trimethylsilyloxytetrahydropyranyl group,
methoxycarbonyltetrahydropyranyl group, alkyl group containing substituted or unsubstituted tetrahydropyranyl
group [tetrahydropyranylmethyl group, 2-tetrahydropyranylethyl group, 3-tetrahydropyranylpropyl group,
4-tetrahydropyranylbutyl group, 5-tetrahydropyranylpenryl group, 2-{fluorotetrahydropyranyl)ethyl group,
2-(chlorotetrahydropyranyl)ethyl group, 2-(methyltetrahydropyranyl)ethyl group,
2-(methoxytetrahydropyranyl)ethyl group, 2-(hydroxytetrahydropyranyl)ethyl group,
2-(acetoxytetrahydropyranyl)ethyl group, 2-(benzyloxytetrahydropyranyl)ethyl group,
2-(trimethylsilyloxytetrahydropyranyl)ethyl group, 2-(methoxycarbonyltetrahydropyranyl)ethyl group], alkyl
group containing amino group ( e.g. dimethylaminomethyl group, 2-dimethylaminoethyl group,
3-dimethylaminopropyl group, 4-dimethylaminobutyl group, 5-dimethylaminopentyl group, 4-diethylaminobutyl
group, 4-dipropylaminobutyl group, 5-dipentylaminopentyl group) .
This invention is a process for producing optically active alcohols by asymmetric reduction of aromatic ketones
represented by general formula (I) using sodium borohydride, chlorotrimethylsilane and optically active
2-[bis(4-methoxyphenyl)hydroxymethyl]pyrrolidine (IV) .
Optically active 2-[bis(4-methoxyphenyl)hydroxymethyl]pyrrolidine (IV) , which is used in this invention, can be
synthesized from D- or L-proline according to the literatures (Journal of Chemical Society, Perkin Trans 1,1985,
2039; Journal of American Society, 1987,109,5551; Tetrahedron, 1993,42,5127; Synthesis, 2004,217) .
The reaction is carried out in one-pot according to the method described in Tetrahedron Letters (2000, 41,
10281). This reaction is consisted with 3 steps operations.
1 step : The reaction of sodium borohyderide with chlorotrimethylsilane.
2 step : Preparation of asymmetric reducing agent by the addition of optically active
2-[bis(4-methoxyphenyl)hydroxymethyl]pyrrolidine into 1 step reaction mixture.
3 step : Aromatic ketone is reduced by the addition into 2 step reaction mixture to give optically active alcohol.
1 step : The amount of sodium borohyderide and chlorotrimethylsilene is 1 to 1.5-fold mol per aromatic ketone.
Preferably amount is 1.2 to 1.4-fold mol. The reaction is carried out in inert solvent such as ethereal
solvent (ether, isopropyl ether, t-butyl methyl ether, tetrahydrofuran, 1,4-dioxane) and halogenated
solvent (dichloromethane, 1,2-dichloroethane). Preferably reaction solvent is tetrahydrofuran. The
reaction is carried out under reflux temperature and reaction time is about 1 hr.
2 step : The mixture of sodium borohydride and chlorotrimethylsilane is reacted with
2-[bis(4-methoxyphenyl)hydroxymethyl]pyrrolidine by the dropwise addition. The reaction is carried
out at 01 to 40 *C and reaction time is 0.5 hr. The amount of optically active
2-[bis(4-methoxyphenyl)hydroxymethyl]pyrrolidine is 5 mol% to 20 mol% per aromatic ketone.
Preferably amount is 10 mol%.
3 step : Aromatic ketone is reduced by asymmetric reducing agent prepared in 1 step and 2 step. Aromatic ketone
is added dropwise to reaction mixture. The reduction is carried out at 0oC to 40oC. Preferably reaction

temperature is 15oC to 30oC.
3-[5-(4-Fluorophenyl)-5-oxopentanoyl]-(4S)-phenyl-1,3-oxazolidin-2-one ( VI ) and
5-(4-fluorophenyl)-5-oxopentanoic acid methyl ester (VIII) can be prepared in accordance with procedure in US
Patent No. 6,207,822.
(4S)-(4-Benzyloxyphenyl)-l -(4-fluoropheny])-(3R)-[3-{4-fluorophenyl)-3-oxopropyl]azetidin-2-one (X) can
be synthesized as described in Journal of Organic Chemistry, 1999, 64, 3714 or Journal of Medicinal Chemistry,
1998,41, 973.
3-[(5S)-(4-Fluorophenyl)-5-hydroxypentanoyl]-(4S)-phenyl-1,3-oxazolidin-2-one (VII) , which is
obtained by the asymmetric reduction of 3-[5-(4-fluorophenyl)-5-oxopentanoyl]-(4S)-phenyl-
1,3-oxazolidin-2-one (VI) , is available to produce ezetimibe by the β-lactam ring construction.
On the other hand, (5S)-(4-fluorophenyl)-5-hydroxypentanoic acid methyl ester (IX), which is obtained by the
asymmetric reduction of 5-(4-fluorophenyl>5-oxopentanoic acid methyl ester (VIll) , is utilized to produce
3-[(5S)-(4-fluorophenyl)-5-hydroxypentanoyl]-(4S)-phenyl-1,3-
oxazolidin-2-one (VII) . Furthermore, (4S)-(4-benzyloxyphenyl)-1-{4-fluorophenyl)-(3R)- [(3S)-
(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one (XI) , which is obtained by the asymmetric reduction of
(4S)-(4-benzyloxyphenyl)-1-(4-fluorophenyl)-(3R)-[3-(4-fluorophenyl)-3-
oxopropyl]azetidin-2-one (X), is available to produce ezetimibe.
[Example 1]
Preparation-[(5S)-4-fluorophenyl)-5-hydroxypentanoyl]-(4S)-phenyl-1,3-oxazolidin-2-one
Chlorotrimethylsilane (25.0 mL, 0.197 mol) was added to a suspension of sodium borohydride (7.45 g, 0.197 mol)
in tetrahydrofuran (700.0 mL) at 24oC, and the reaction mixture was stirred under reflux for 1 hr. The reaction
mixture was cooled to 24oC, and a solution of (R)-2-
[bis(4-methoxyphenyl)hydroxymethyl]pyrrolidine (4.41 g, 0.014 mol) in tetrahydrofuran (280.0 mL) was added.
After stirring for 0.5 hr, a solution of 3-[5-(4-fluorophenyl)-5-oxopentanoyl]- (4S)-
phenyl-1,3-oxazolidin-2-one (50.00 g, 0.141 mol) in tetrahydrofuran (280.0 mL) was added dropwise during 80
min. After stirring for 10 min, the reaction mixture was cooled to A°C. 6N-HC1 was added to the reaction mixture,
and water and toluene were added. After stirring for 30 min, the organic layer was separated. The organic layer
was washed with water, aqueous saturated sodium bicarbonate and aqueous saturated sodium chloride, and dried
over sodium sulfate. Filtration and evaporation gave
3-[(5S)-(4-fluorophenyl)-5-hydroxypentanoyl]-(4S)-phenyl-1,3-oxazolidin-2-one 48.71 g as colorless oil.
1H-NMR(CDC13)δ= 1.56-1.75 (m, 4H), 1.97 (d, J=3Hz, 1H), 2.96-2.99 (m, 2H), 4.28 (dd, J=3Hz, 9Hz, 1H),
4.56-4.66 (m, 1H), 4.68 (t, J=9Hz, 1H), 5.40 (dd, J=3Hz, 9 Hz, 1H), 6.98-7.02 (m, 2H), 7.25-7.37 (m, 7H).
The de [diastereoselectivty de (%)=[(S,S)%-(R,R)%]] of the desired product was determined to be 93% by HPLC
using a chiral column, [column: CHIRALCELL OD-H (DAICEL),mobile phase : ethanol/n-hexane= 1/5 (v/v)^
detection : UV at 258 nm].
[Example 2]
The loading amount (mol%) of (R)-2-[bis(4-methoxyphenyl)hydroxymethyl]pyrrolidine and the reaction scale of
3-[5-(4-fluorophenyl)-5-oxopentanoyl]-(4S)-phenyl-1,3-oxazolidin-2-one (VI) were changed as shown in Table 1,
and 3-[(5S)-4-fluorophenyl)-5-hydroxypentanoyl]-(4S)- phenyl-1,3-

oxazolidin-2-one was synthesized using general procedure of Example 1 above. The de (%) of the desired product
was determined by HPLC using a chiral column. The results are summarized in Table 1.
In the reduction of using 3-[5-(4-fluorophenyl)-5-oxopentanoyl]-(4S)-phenyl-l ,3-oxazolidin-2-one as a catalyst,
(R)-2-[bis(4-methoxyphenyl)hydroxymethyl]pyrrolidine was replaced with (R)-2-
(diphenylhydroxymethyl)pyrrolidine in order to compare the de of the resulting product. As shown in Table 1, the
loading amount (mol%) of (R)-2-(diphenylhydroxymethyl)pyrrolidine and the reaction scale of
3-[5-{4-fluorophenyl)-5-oxopentanoyl]-(4S)-phenyl-1,3-oxazolidin-2-one (VI) were changed. The de (%) of the
desired product was determined by HPLC using a chiral column. The results are summarized in Table 1.
In the reduction of using 3-[5-(4-fluorophenyl)-5-oxopentanoyl]-(4S)-phenyl-1,3-oxazolidin-2-one as a catalyst,
(R)-2-[bis(4-methoxyphenyl)hydroxymethyl]pyrrolidine was replaced with (R)-2-
[bis(4-trifluorophenyl)hydroxymethyl]pyrrolidine in order to compare the de of the resulting product The loading
amount (mol%) of (R)-2-(diphenylhydroxymethyl)pylTolidine and the reaction scale of
3-[5-(4-fluorophenyl)-5-oxopentanoyl]-(4S)-phenyl-1,3-oxazolidin-2-one (VI) were shown in Table 1. The de (%)
of the desired product was determined by HPLC using a chiral column. The results are summarized in Table 1.

As shown in Table 1, when (R)-2-[bis(4-methoxyphenyl)hydroxymethyl]pyrrolidine is used as a catalyst at large
scale production, the de of reaction product increased. In the case of usual (R)-2-
(diphenylhydroxymethyl)pyrrolidine, the de of reaction product decreased at large scale production. When (R)-2-
[bis(4-trifluorophenyl)hydroxymethyl]pyrrolidine was used as a catalyst, the de of reaction product dramatically
decreased at small scale production.
[Example 3]
Preparation of (5S)-(4-fluorophenyl)-5-hydroxypentanoic acid methyl ester
Chlorotrimethylsilane (2.0 mL, 0.01606 mol) was added to a suspension of sodium borohydride (0.61 g, 0.01606
mol) in tetrahydrofuran (63.0 mL) at 20oC, and the reaction mixture was stirred under reflux for 1 hr. The reaction
mixture was cooled to 24oC, and a solution of (R)-2-
[bis(4-methoxyphenyl)hydroxyme1hyl]pyrrolidine (0.42 g, 0.00134 mol) in tetrahydrofuran (10.0 mL) was added.

After stirring for 0.5 hr, a solution of 5-(4-fluorophenyl)-5-oxopentanoic acid methyl ester (VIII) (3.00 g, 0.01338
mol) in tetrahydrofuran (10.0 mL) was added dropwise during 45 min. After stirring for 1.5 hr, the reaction
mixture was cooled to 2oC. 6N-HC1 was added dropwise to the reaction mixture, and water and ethyl acetate were
added. After stirring for 30 min, the organic layer was separated. The organic layer was washed with water,
aqueous saturated sodium bicarbonate and aqueous saturated sodium chloride, and dried over sodium sulfate.
Filtration and evaporation gave the crude product, which was purified by silica gel column chromatography (ethyl
acetate/n-hexane) to give (5S)-(4-fluorophenyl)-5-hydroxypentanoic acid methyl ester 2.79 g as colorless oil.
1H-NMR(CDC13)δ= 1.59-1.80 (m, 4H), 2.21 (s, 1H), 2.32-2.36 (m, 2H), 3:65 (s, 3H), 4.63-4.68 (m, 1H),
7.00-7.04 (m, 2H), 7.26-7.32 (m, 2H).
The ee [enantioselectivty ee (%)=[(S)%-(R)%]] of the desired product was determined by HPLC using a chiral
column, [column : CHIRALPAK AD (DAICEL), mobile phase : ethanol/n-hexane= 1/20 (v/v), detection : UV
at 258 nmj. The result is shown in Table 2.
[Comparative Example 1]
Chlorotrimethylsilane (0.86 mL, 0.005352 mol) was added to a suspension of sodium borohydride (0.202 g,
0.005352 mol) in tetrahydrofuran (21.0 mL) at 21oC, and the reaction mixture was stirred under reflux for 1 hr.
The reaction mixture was cooled to 24oC, and a solution of (R)-2-
(diphenylhydroxymethyl)pyrrolidine (0.114 g, 0.0004466 mol) in tetrahydrofuran (5.0 mL) was added. After
stirring for 0.5 hr, a solution of 5-(4-fluorophenyl)-5-oxopentanoic acid methyl ester (VIII) (1.00 g, 0.00446 mol)
in tetrahydrofuran (5.0 mL) was added dropwise during 48 min. After stirring for 0.5 hr, the reaction mixture was
cooled to 2oC. 6N-HC1 was added dropwise to the reaction mixture, and water and ethyl acetate were added. After
stirring for 30 min, the organic layer was separated. The organic layer was washed with water, aqueous saturated
sodium bicarbonate and aqueous saturated sodium chloride, and dried over sodium sulfate. Filtration and
evaporation gave the crude product, which was purified by silica gel column chromatography (ethyl
acetate/n-hexane) to give (5S)-(4-fluorophenyl)-5-hydroxypentanoic acid methyl ester 0.90 g as colorless oil.
The ee [enantioselectivty ee (%)=[(S)%-(R)%]] of the desired product was determined by HPLC using a chiral
column, [column : CHIRALPAKAD (DAICELh mobile phase : ethanol/n-hexane=l/20(v/v)x detection '• UV
at 258 nm]. The result is shown in Table 2.

As shown in Table 2, when (R)-2-[bis(4-methoxyphenyl)hydroxymethyl]pyrrolidine was used as a catalyst at large
scale production, the ee was larger than usual (R)-2-

(diphenylhydroxymethyl)pyrrolidine.
[Example 4]
Preparation of (4S)-(4-ben2yloxyphenyl)-1-(4-fluorophenyl)-(3R)-[(3S)-(4-fluorophenyl)-3-
hydroxypropyl]azetidin-2-one
Chlorotrimethylsilane (0.33 mL, 0.02613 mol) was added to a suspension of sodium borohydride (0.099 g,
0.02613 mol) in tetrahydrofuran (15.1 mL) at 19oC, and the reaction mixture was stirred under reflux for 1 hr. The
reaction mixture was cooled to 22oC, and , a solution of (R)-2-
[bis(4-methoxyphenyl)hydroxymethyl]pyrro]idine (0.063 g, 0.000201 mol) in tetrahydrofuran (5.2 mL) was added.
After stirring for 0.5 hr, a solution of (4S)-(4-benzyloxyphenyl)-l -(4-
fluorophenyl)-(3R)-[3-(4-fluorophenyl)-3-oxopropyl]azetidin-2-one (l.00g, 0.00201 mol) in tetrahydrofuran (5.2
mL) was added dropwise during 8 min. After stirring for 1 hr, the reaction mixture was cooled to 2oC. 6N-HC1
was added dropwise to the reaction mixture, and water and toluene were added. After stirring for 30 min, the
organic layer was separated. The organic layer was washed with water, aqueous saturated sodium bicarbonate and
aqueous saturated sodium chloride, and dried over sodium sulfate. Filtration and evaporation gave the crude
product, which was purified by silica gel column chromatography (ethyl acetate/n-hexane)
(4SH4-benzyloxyphenyl)-1-(4-fluorophenyl)-(3R)-[(3S)-(4-fluorophenyl)-3-
hydroxypropyl]azetidin-2-one 0.89 g as colorless crystals.
1H-NMR(CDCl3)δ= 1.88-2.01 (m, 4H), 2.19 (d, J=4Hz, 1H), 3.07 (dt, J=2Hz, 8Hz, 1H), 4.57 (d, J=2Hz, 1H),
4.71-4.73 (m, 1H), 5.29 (s, 2H), 6.90-7.03 (m, 6H), 7.21-7.43 (m, 11H).
The ee [enantioselectivty ee (%)=[(S)%-(R)%]] of the desired product was determined by HPLC using a chiral
column, [column : CHIRALPAKAD (DAICEL), mobile phase : ethanol/n-hexane= 1/9 (v/v), detection : UV
at 258 ran]. The result is shown in Table 3.
[Comparative Example 2]
Chlorotrimethylsilane (0.33 mL, 0.02613 mol) was added to a suspension of sodium borohydride (0.099 g,
0.02613 mol) in tetrahydrofuran (15.1 mL) at 19oC, and the reaction mixture was stirred under reflux for 1 hr. The
reaction mixture was cooled to 22t, and a solution of 2-
(diphenylhydroxymethyl)pyrrolidine (0.051 g, 0.000201 mol) in tetrahydrofuran (5.2 mL) was added. After stirring
for 0.5 hr, a solution of (4S)-(4-benzyloxyphenyl)-1-(4- fluorophenyl)-(3R)- [3-(4-
fluorophenyl)-3-oxopropyl]azetidin-2-on (l.00g, 0.00201 mol) in tetrahydrofuran (5.2 mL) was added dropwise
during 7 min. After stirring for 70 min, the reaction mixture was cooled to 2°C. 6N-HC1 was added dropwise to
the reaction mixture, and water and toluene were added. After stirring for 30 min, the organic layer was separated.
The organic layer was washed with water, aqueous saturated sodium bicarbonate and aqueous saturated sodium
chloride, and dried over sodium sulfate. Filtration and evaporation gave the crude product, which was purified by
silica gel column chromatography (ethyl acetate/n-hexane)
(4S)-(4-benzyloxyphenyl)-l -(4-fluorophenyl)-(3R)-[(3S)-
(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one 0.92 g as colorless crystals.
1H-NMR(CDCl3)δ= 1.88-2.01 (m, 4H), 2.19 (d, J=4Hz, 1H), 3.07 (dt, J=2Hz, 8Hz, 1H), 4.57 (d, J=2Hz, 1H),
4.71-4.73 (m, 1H), 5.29 (s, 2H), 6.90-7.03 (m, 6H), 7.21-7.43 (m, 11H).
The ee of the desired product was determined by HPLC using a chiral column, [column : CHIRALPAK AD
(DAICEL, mobile phase : ethanol/n-hexane=1/9(v/v), detection : UV at 258 nm].

The result is shown in Table 3.

As shown in Table 3, when (R)-2-[bis(4-niethoxyphenyl)hydroxymethyl]pyrrolidine was used as a catalyst at the
same scale production, the ee was larger about 2-fold than usual (R)-2-
(diphenylhydroxymethyl)pyrrolidine.
FIELD OF INDUSTRIAL APPLICATION
Aromatic ketones are reduced to optically active alcohols in high enantioselectivity by using of the reduction
process in this invention at large scale production. This invention is useful for producing optically active alcohols
such as ezetimibe: ([l-(4-fluorophenyl)-(3R)-[3-(4-fluorophenyl)-(3S)-
hydroxypropyl]-(4S)-{4-hydroxyphenyl)azetidin-2-one]), which is useful as hypochlesterolemic agents in the
prevention and treatment of atherosclerosis. The advantage of this process is that
(R)-2-[bis(4-methoxyphenyl)hydroxymethyl]pylTolidine is recovered in high yleld at reaction end-point by simple
operation such as extraction, and recyclable after purification such as recrystallization. Furthermore, this reaction
proceeds at room temperature, and is not required low reaction temperature.

We Claim:
1. A process for preparing an optically active alcohol represented by formula (V):

wherein, R1 are selected from hydrogen atom, halogen atom, lower alkyl group (1 to 5 carbon atom), lower
haloalkyl group (1 to 5 carbon atom), lower alkoxycarbonyl group (1 to 5 carbon atom), lower alkoxy group (1 to
5 carbon atom), hydroxyl group, nitro group, cyano group, lower acyloxy group (1 to 5 carbon atom), lower
alkylthio group (1 to 5 carbon atom), lower alkylsulfonyl group (1 to 5 carbon atom), substituted and
unsubstituted amino group, substituted and unsubstituted carbamoyl group, substituted and unsubstituted aromatic
ring or heterocycle, and
R2 is -(CH2)n-R3 wherein, n is 1 to 5 integer. R3 are selected from hydrogen atom, halogen atom, lower
alkoxycarbonyl group (1 to 5 carbon atom), lower alkoxy group (1 to 5 carbon atom), lower alkylthio group (1 to
5 carbon atom), lower alkylsulfonyl group (1 to 5 carbon atom), substituted and unsubstituted amino group,
unsubstituted carbamoyl group, substituted and unsubstituted aromatic ring or heteroaromatic ring and formula
(II):

{wherein, R4 are lower alkyl group (1 to 5 carbon atom), substituted and unsubstituted aromatic
ring, and substituted and unsubstituted benzyl group.}
and formula (III):

{wherein, R5 and R6 are the same or different and are selected from hydrogen atom, halogen atom, lower alkyl
group (1 to 5 carbon atom), lower haloalkyl group (1 to 5 carbon atom), lower alkoxycarbonyl group (1 to 5
carbon atom), lower alkoxy group (1 to 5 carbon atom), lower acyloxy group (1 to 5 carbon atom), hydroxyl
group, nitro group, cyano group, substituted and unsubstituted benzyloxy group, substituted silyloxy group, lower
alkylthio group (1 to 5 carbon atom), lower alkylsulfonyl group (1 to 5 carbon atom), substituted and
unsubstituted amino group, substituted and unsubstituted carbamoyl group, substituted and unsubstituted aromatic
ring or heteroaromatic ring, substituted and unsubstituted tetrahydropyranyl group, lower alkyl group containing

substituted and unsubstituted tetrahydropyranyl group (1 to 5 carbon atom), lower alkyl group containing amino
group (1 to 5 carbon atom)},
which comprises: reducing aromatic ketones represented by formula (I):

wherein R1 and R2 are as defined above,
with sodium borohydride, chlorotrimethylsilane and optically active 2-[bis(4-
methoxyphenyl)hydroxymethyl]pyrrolidine represented by formula (IV):

to give optically active alcohol represented by formula (V).
2. A process for stereoselectively preparing 3-[(5S)-(4-fluorophenyl)-5-hydroxypentanoyl]-(4S)-phenyl-
l,3-oxazolidin-2-one represented by formula (VII):

which comprises: reducing 3-[5-(4-fluorophenyl)-5-oxopentanoyl]-(4S)-phenyl-1,3-oxazolidin-2-one
represented by formula (VI):

with sodium borohydride, chlorotrimethylsilane and optically active (R)-2-[bis(4-
methoxyphenyl)hydroxymethyl]pyrrolidine represented by formula (IV):

to give 3-[(5S)-(4-fluorophenyl)-5-hydroxypentanoyl]-(4S)-phenyl-1,3-oxazolidin-2-one.

3. A process for preparing (5S)-(4-fluorophenyl)-5-oxopentanoic acid methyl ester represented by formula
(IX):

which comprises: reducing 5-(4-fluarophenyl)-5-oxopentanoic acid methyl ester represented by formula
(VIII):

with sodium borohydride, chlorotrimethylsilane and optically active (R)-2-[bis(4-
methoxyphenyl)hydroxymethyl]pyrrolidine represented by formula (IV)

to give (5S)-(4-fluorophenyl)-5-oxopentanoic acid methyl ester.
4. A process for preparing (4S)-(4-benzyloxyphenyl)-1-(4-fluorophenyl)-(3R)-[(3S)-(4-fluorophenyl)-
(3S)-3-hydoxypropyl]azetidin-2-one represented by formula (XI):

which comprises: reducing (4S)-(4-benzyloxyphenyl)-1-(4-fluorophenyl)-(3R)-[3-(4- fluorophenyl)-3-
oxopropyl]azetidin-2-one represented by formula (X)

with sodium borohydride, chlorotrimethylsilane and optically active (R)-2-[bis(4-

methoxyphenyl)hydroxymethyl]pyrrolidine represented by formula (IV)

to give (4S)-(4-benzyloxyphenyl)-1-(4-fluorophenyl)-(3R)-[(3S)-(4-fluorophenyl)- (3S)-3-hydoxypropyl]azetidin-
2-one.

ABSTRACT

METHOD OF PRODUCING OPTICALLY ACTIVE ALCOHOL
This invention relates to a process for preparing an optically active alcohol represented by formula (V):

wherein, R1 and R2 are as described in the specification, which comprises: reducing aromatic ketones
represented by formula (I):

wherein R1 and R2 are as described in the specification, with sodium borohydride, chlorotrimethylsilane
and optically active 2-[bis(4-methoxyphenyl)hydroxymethyl]pyrrolidine represented by formula (IV):

to give optically active alcohol represented by formula (V).

Documents:

3363-KOLNP-2008-(16-10-2012)-CORRESPONDENCE.pdf

3363-KOLNP-2008-(16-10-2012)-OTHERS.pdf

3363-KOLNP-2008-(29-10-2012)-ABSTRACT.pdf

3363-KOLNP-2008-(29-10-2012)-ANNEXURE TO FORM 3.pdf

3363-KOLNP-2008-(29-10-2012)-CLAIMS.pdf

3363-KOLNP-2008-(29-10-2012)-CORRESPONDENCE.pdf

3363-KOLNP-2008-(29-10-2012)-DESCRIPTION (COMPLETE).pdf

3363-KOLNP-2008-(29-10-2012)-FORM-1.pdf

3363-KOLNP-2008-(29-10-2012)-FORM-2.pdf

3363-KOLNP-2008-(29-10-2012)-FORM-3.pdf

3363-KOLNP-2008-(29-10-2012)-FORM-5.pdf

3363-KOLNP-2008-(29-10-2012)-OTHERS.pdf

3363-KOLNP-2008-(29-10-2012)-PETITION UNDER RULE 137.pdf

3363-kolnp-2008-abstract.pdf

3363-KOLNP-2008-ASSIGNMENT 1.1.pdf

3363-kolnp-2008-assignment.pdf

3363-KOLNP-2008-CANCELLED PAGES.pdf

3363-kolnp-2008-claims.pdf

3363-KOLNP-2008-CORRESPONDENCE 1.1.pdf

3363-kolnp-2008-correspondence.pdf

3363-kolnp-2008-description (complete).pdf

3363-KOLNP-2008-EXAMINATION REPORT.pdf

3363-kolnp-2008-form 1.pdf

3363-kolnp-2008-form 18.pdf

3363-kolnp-2008-form 3.pdf

3363-kolnp-2008-form 5.pdf

3363-KOLNP-2008-GPA 1.1.pdf

3363-kolnp-2008-gpa.pdf

3363-KOLNP-2008-GRANTED-ABSTRACT.pdf

3363-KOLNP-2008-GRANTED-CLAIMS.pdf

3363-KOLNP-2008-GRANTED-DESCRIPTION (COMPLETE).pdf

3363-KOLNP-2008-GRANTED-FORM 1.pdf

3363-KOLNP-2008-GRANTED-FORM 2.pdf

3363-KOLNP-2008-GRANTED-FORM 3.pdf

3363-KOLNP-2008-GRANTED-FORM 5.pdf

3363-KOLNP-2008-GRANTED-SPECIFICATION-COMPLETE.pdf

3363-KOLNP-2008-INTERNATIONAL PUBLICATION 1.1.pdf

3363-kolnp-2008-international publication.pdf

3363-KOLNP-2008-INTERNATIONAL SEARCH REPORT & OTHERS.pdf

3363-kolnp-2008-international search report.pdf

3363-KOLNP-2008-OTHERS.pdf

3363-kolnp-2008-pct priority document notification.pdf

3363-kolnp-2008-pct request form.pdf

3363-KOLNP-2008-PETITION UNDER RULE 137.pdf

3363-KOLNP-2008-REPLY TO EXAMINATION REPORT.pdf

3363-kolnp-2008-specification.pdf

3363-KOLNP-2008-TRANSLATED COPY OF PRIORITY DOCUMENT.pdf

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Patent Number

256184

Indian Patent Application Number

3363/KOLNP/2008

PG Journal Number

20/2013

Publication Date

17-May-2013

Grant Date

13-May-2013

Date of Filing

18-Aug-2008

Name of Patentee

KOTOBUKI PHARMACEUTICAL CO., LTD.

Applicant Address

6351 OAZA-SAKAKI, SAKAKI-MACHI HANISHINA-GUN, NAGANO

Inventors:

#	Inventor's Name	Inventor's Address
1	YOKOTA, MASAYUKI	2671-10, YAWATA, CHIKUMA-SHI, NAGANO 387-0023
2	TOMIYAMA, HIROSHI	1113, OAZA-SAKAKI, SAKAKI-MACHI, HANISHINA-GUN, NAGANO 389-0601

PCT International Classification Number

C07C 29/143

PCT International Application Number

PCT/JP2007/052900

PCT International Filing date

2007-02-13

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	2006-038964	2006-02-16	Japan