Title of Invention	A METHOD FOR PRODUCING AN OPTICALLY ACTIVE CHRYSANTHEMIC ACID
Abstract	This invention relates to a method for producing an optically active chrysanthemic acid with improved trans isomer ratio and optical purity, the said method comprises the steps of reacting chrysanthemic acid having a trans isomer ratio of not less than 50% and an optical purity of not less than 10% e.e with an optically active amine of the formula (A-2) wherein RI and R2 respectively represent a hydrogen atom, an alkyl group, an aralkyl group or an aryl group, RJ represents an alkyl group having 1 to 6 carbon atoms; and an asymmetric carbon atom represented by "" is either in S-configuration or R- configuration; to optically resolve said chrysanthemic acid and recovering the said optically active chrysanthemic acid in "a known manner. 57) Abstract:- This invention relates to a method for producing an optically active chrysanthemic acid with improved trans isomer ratio and optical purity, the said method comprises the steps of reacting chrysanthemic acid having a trans isomer ratio of not less than 50% and an optical purity of not less than 10% e.e with an optically active amine of the formula (A-2) wherein R1 and R2 respectively represent a hydrogen atom, an alkyl group, an aralkyl group or an aryl group, R3 represents an alkyl group having 1 to 6 carbon atoms; and an asymmetric carbon atom represented by " " is either in S-configuration or R- configuration; to optically resolve said chrysanthemic acid and recovering the said optically active chrysanthemic acid in a known manner. PRICE: THIRTY RUPEES

Title of Invention

A METHOD FOR PRODUCING AN OPTICALLY ACTIVE CHRYSANTHEMIC ACID

Abstract

This invention relates to a method for producing an optically active chrysanthemic acid with improved trans isomer ratio and optical purity, the said method comprises the steps of reacting chrysanthemic acid having a trans isomer ratio of not less than 50% and an optical purity of not less than 10% e.e with an optically active amine of the formula (A-2) wherein RI and R2 respectively represent a hydrogen atom, an alkyl group, an aralkyl group or an aryl group, RJ represents an alkyl group having 1 to 6 carbon atoms; and an asymmetric carbon atom represented by "*" is either in S-configuration or R- configuration; to optically resolve said chrysanthemic acid and recovering the said optically active chrysanthemic acid in "a known manner. 57) Abstract:- This invention relates to a method for producing an optically active chrysanthemic acid with improved trans isomer ratio and optical purity, the said method comprises the steps of reacting chrysanthemic acid having a trans isomer ratio of not less than 50% and an optical purity of not less than 10% e.e with an optically active amine of the formula (A-2) wherein R1 and R2 respectively represent a hydrogen atom, an alkyl group, an aralkyl group or an aryl group, R3 represents an alkyl group having 1 to 6 carbon atoms; and an asymmetric carbon atom represented by " * " is either in S-configuration or R- configuration; to optically resolve said chrysanthemic acid and recovering the said optically active chrysanthemic acid in a known manner. PRICE: THIRTY RUPEES

Full Text	The. present invention relates to a mutinied for producing an optically, active chrysantliemic acid , . DescR1ption of the Related Art Optically active cyclopropanecarboxylic acid deR1vatives are important intermediates for drugs and pesticides. For example, (+)-2,2-dimethyl-3-(2-methyl-1-propenyi)cyclopropanecarboxylic acid known as chrysanthemum mono-carboxylic acid constitutes an acid component of synthetic parathyroid insecticide. The insecticidal activity of a trans-pyrethroid ester is usually higher than that of a cis-isomer. Particularly, pyrethroid esters of (+)-trans-chrysanthemum mono-carboxylic acid(hereinafter referred to as "chrysanthemic acid") or chrysanthemic acid enR1ched with the (+)-trans-chrysanthemic acid have exhibited excellent insecticidal activity. Accordingly, an industR1ally advantageous method to produce (+)-trans-chrysanthemic acid or chrysanthemic acid enR1ched with the (+)-trans-chrysanthemic acid has been desired. As a method of producing an optically active chrysanthemic acid deR1vative by using a synthetic technique, there has been known a method of reacting a (±)-trans-chrysanthemum mono-carboxylic acid or trans R1ch (±)-chrysanthemum mono-carboxylic acid with an optical resolution agent, which are an optically active amine, to obtain an optically active chrysanthemic acid (JP46-20382B/1971, JP54-37130B/1979, JP49-109344A/1974 and JP51-23497B/1976). However, these optical resolution methods were not always satisfactory, because of low yield of the desired optically active chrysanthemic acid. Therefore, the present inventors have intensively studied. As a result, they - . have found that, when chrysanthemic acid optically enR1ched with one isomer, e.g. ;+)-:trans-chrysanthemic acid can be puR1fied by crystallization using an optical active amine in the production of an optically active chrysanthemic acid, whereby (+)-trans-chrysanthemic acid having excellent optical puR1ty can be obtained with surpR1singly good efficiency compared with the case of using racemes chrysanthemic acid, and trans isomer ratio of the chrysanthemic acid can also be improved efficiently when trans isomer having not less than 50% trans-isomer ratio are applied. SUMMARY OF THE INVENTION The present invention provides: 1. a method for producing an optically active chrysanthemic acid whose trans isomer ratio and optical puR1ty are improved, which compR1ses: reacting chrysanthemic acid having a trans isomer ratio of not less than 50% and an optical puR1ty of not less than 10% e.e. with an optically active organic amine to optically resolve said chrysanthemic acid; and 2. a method for producing an optically active chrysanthemic acid whose trans isomer ratio and optical puR1ty are improved, which compR1ses: reacting 2,5-dimethyl-2,4-hexadiene with diazoacetates of the formula (I): N2CHCO2R7 (1) wherein R7 represents an alky! group having 1 to 6 carbon atoms or a cycioalkyI group, in the presence of an asymmetR1c copper complex to produce an optically active chrysanthemic acid ester (cyclopropanation step), contacting chrysanthemic acid esters with an acid or base to form chrysanthemic acid (hydrolysis step); and optically resolving chrysanthemic acid using at least one optically active organic amine selected from those of the formulas (A-1), (A-2), (A^S) and (A"4i) shown below (optical resolution step). DESCR1PTION OF THE PREFERRED EMBODIMENTS First, a descR1ption will be made to the method for producing an optically active chrysanthemic acid of which trans isomer ratio and optical puR1ty are improved, which compR1ses: reacting chrysanthemic acid having a trans isomer ratio of not less than 50% and an optical puR1ty of not less than 10% e.e. with an optically active organic amine to optically resolve said chrysanthemic acid. Chrysanthemic acid having a trans isomer ratio of not less than 50% and an optical puR1ty of not less than 10% e.e can be obtained by any method, for example, it can be produced in the following manner. In the present invention, the "optical puR1ty" or e.e.% of (+)-trans-chrysanthemic acid in the trans isomer is calculated based on the analysis using optically active column and is defined, for example, by the following equation: 100 X {[(+)-trans-chrysanthemic acid - (-)-trans-chrysanthemic acid] / [(+)-trans-chryeanthemic acid + (-)-trans-chrysanthemic acid]}. The optically active chrysanthemic acid can be obtained by reacting 2,5-dimethyl-2,4-hexadiene with diazoacetate of the formula (I): N2CHCO2R7 (I) wherein R7 represents an alkyl group having 1 to 6 carbon.atoms or a cycioalkyI group, in the presence of an asymmetR1c copper complex to produce optically active chrysanthemic acid esters (cyclopropanation step); and decomposing chrysanthemic acid esters with an alkali or acid (hydrolysis step). In this method trans isomer ratio of not less than 50% and optical puR1ty of not less than 20% e.e is preferably employed, more preferably, chrysanthemic acid having trans isomer ratio of from 60%e.e. to 95% e.e. and optical puR1ty of from 30% e.e. to 90% e.e is employed. The optically active organic amine for optically resolving the optically active chrysanthemic acid includes, for example, an optically active organic amine of the formula (A-1 ): wherein R1 and R2 respectively represent a hydrogen atom, an alkyl group, an orally group or an aryl group; R3 represents an alkyl group having 1 to 6 carbon atoms, and ^. * represents an asymmetR1c carbon atom; or an Spatially active organic amine of the formula (A-3): R4—CH—R, I NH-CK-Rg ^ ^ (A-3) wherein R4 represents a naphthalene group, a cydohexyl group, or a phenyl group which may be substituted with halogen, nitro, lower alkyl or lower alloys; R5 represents a lower alkyl group, or a benzyl group which may be substituted with a lower alkyl group; Re represents a p-hydroxyphenyl group or a 2-hydroxy-3-lower alkoxyphenyl group when R5 is a lower alkyl group, and Re represents a p-hydroxyphenyl group when R5 is a benzyl group which may be substituted with a lower alkyl group, and * represents an asymmetR1c carbon atom, or an optically active organic amine of the formula (A-4): (^R,R2 CHjOH (A-4) wherein R1 and R2 respectively represent a hydrogen atom, an alkyl group,’ an aurally group or an aryl group, and * represents an asymmetR1c carbon atom. The optically active amine includes, for example, optically active compounds such as 1 -phenyl-2-(p-tolyl)ethylamine, ex -(1 -naphthyl)-ethylamine. a-(2-naphthyl)-ethylamine, 1-phenyiethylamine, erythrism- a, α biphenyl-^ -hydroxyethylamine, N-methylephedR1ne, N-(2,2,2-tR1chloro-1-formamideethyl)pipeR1r)in£, 2-benzylamino-1-butanol, ephedR1ne, cis-N-benzyl-2-(hydroxymethyl)cyGlohexylamine, N-(p-hydroxybenzyl)-1-phenylethylamine, N-(p-hydroxybenzyl)-1-(p-tolyl)ethylamine, N-(p-hydroxybenzyl)-1-(p-isopropylphenyl)ethylamine, N-(p-hydroxybenzyl)-1-(p-nitrophenyl)ethylamine, N-(p-hydroxybenzyl)-1-(p-bromophenyl)ethylamine, N-(p-hydroxybenzyl)-1-(1-naphthyl)ethylamine, N-(p-hydroxybenzyl)-1-cyclohexylethylamine, N-(p-hydroxybenzyl)-1-(p-methoxyphenyl)ethylamine, N-(p-hydroxybenzyl)-1-phenylpropylamtne, N-(p-hydroxybenzyl)-2-methyl-1-phenylpropylamine, N-(2-hydroxy-3-methoxybenzyl)-1-phenylethylamine, N-(2-hydroxy-3-methoxybenzyl)-1-(p-tolyl)ethylamine, M-(2-hydroxy-3-methoxybenzyl)-1-(p-isopropylphenyl)ethylamine, N-(2-hydroxy-3-methoxybenzyl)-1-(p-nitrophenyl)ethylamine, N-{2-hydroxy-3-methoxybenzyl)-1-(p-bromophenyl)ethylamine, N-(2-hydroxy-3-methoxybenzyl)-1-(1-naphthyl)ethylamine, N-(2-hydroxy-3-methoxybenzyl)-1-cyciohexylethylamine, N-(2-hydroxy-3-methoxybenzyl)-1-(p-methoxyphenyl)ethylamine, N-(2-hydroxy-3-methoxybenzyl)-1-phenylpropylamine, N-(2-hydroxy-3-methoxybenzyl)-2-methyl-1-phenylpropylamine, N-p-hydroxybenzyl- a -phenyl- /S -paratolylethylamine, erythro-1-p-nitrophenyl-2-N,N-dimethylamJnopropane-1,3-diol, and thre0-1-prnitrophenyl-2-N,N-dimethylaminopropane-1,3-diol. Optical resolution is performed by reacting the optically active chrysanthemic acid with an optically active amine (optical resolution agent) of the formula (A-1), (A^2).- (A-3) or (A-4). The optical resolution is usually performed in a solvent. As the solvent, there can be used aromatic hydrocarbons such as benzene, toluene and xylems; aliphatic hydrocarbons such as hexane and heptane; alcohols such as water, methanol and ethanol; ketones such as acetone and methyl isobutyl ketone; and ethers such as dioxane and tetrahydrofuran. These solvents may be used alone or in combination thereof. The amount of the solvent vaR1es depending on the solvent and conditions of the post treatments and is not specifically limited, and an optimum amount is optionally set according to the respective conditions. The amount of the optical resolution agent is usually from about 0.2 to 1.2 mol, and preferably from about 0.3 to 1.1 mol, per mol of chrysanthemic acid. The optical resolution agent and chrysanthemic acid are usually dissolved in the solvent above under stirR1ng or standing. The mixture may be heated to dissolve, if necessary. A diastereomer crystal compR1sing an optical resolution agent and optically active chrysanthemic acid is usually formed tcdeposit from the solution on standing at an ambient temperature or by cooling the solution. The deposited crystal may be collected as it is, or alternatively, it may be totally or partially dissolved by heating and then cooled to deposit the crystal, if necessary. The dissolution and deposition is usually conducted at a temperature ranging from -20 to 150°C, and preferably from -TO to 100°C. The deposited diastereomer crystal is usualiy separated by filtration. The diastereomer salt separated as a crystal is then decomposed with an acid or alkali and extracted to obtain the optically native chrysanthemic acid with higher trans ratio and optical puR1ty. The used optical resolution agent can be recovered. For example, an optically active chrysanthemic acid is obtained by recomposing the diastereomer salt, obtained by means of the above method, with hydrochloR1c acid or sulfuR1c acid and extracting the resultant with an organic solvent. Furthermore, the agent for optical resolution is recovered by making the aqueous layer weak alkali and extracting it. Alternatively, the optical resolution agent can be recovered by decomposing the disatereomer salt, obtained by means of the above method, with a base such as sodium hydroxide, and extracting the resultant with an organic solvent in the weak alkali condition. Thereafter, the aqueous layer is acidified and extracted, thereby making it possible to obtain an optically active chrysanthemic acid. The optical resolution agent recovered by these methods can be reused. Next a descR1ption will be made to the method for producing an optically active chrysanthemic acid, which compR1ses reacting 2,5-dimethyl-2,4-hexadiene with diazoacetates of the formula (I) as defined above, in the presence of an asymmetR1c copper complex to produce optically active chrysanthemic acid esters (cyclopropanation step); and contacting the chrysanthemic acid ester with an alkali or acid (hydrolysis step). t ■ The alkyl group of diazoacetate used in the above cyclopropanation step includes, for example, methyl, ethyl, n-propyi, iso-propyl, n-butyl, iso-butyl, t-butyl, phenyl, hexyl and cyclohexyl groups. The asyTifTTetR1c copper complex used in the above cyclopropanation step Is )repaired from a copper compound and an optically active organic compound hereinafter referred to as "an optically active ligand") (Pure & Appl. Chem., Vol. 57, No. 12,1839,1985, Tetrahedron Lett., 32, 7373 (1991), Tetrahedron Lett., 35, 7985(1994)). The copper compound includes, for example, mono- or divalent copper compounds such as copper naphthenate, copper tR1fluoromethanesulfonate, copper acetate, copper bromide and copper chloR1de. These compounds may be used alone or in combination thereof. The optically active ligand includes, for example, optically active bisoxazoline compound, optically active salicylideneamino alcohol compound, optically active diamine compound, optically active semicorR1n compound and optically active camphor compound. Preferred examples thereof include optically active salicylideneamino alcohol compound, optically active bisoxazoline compound and optically active ethylenediamine compound. The optically active bisoxazoline compound is of the formula (L-1): wherein R5 and R8are different and represent an optionally substituted phenyl group or a hydrogen atom. R1o and R11 represent a hydrogen atom, an alkyl group, a cycioalkyI group, an optionally substituted phenyl group or an aralkyi qroup,.Dr R10 and R11 may be combined to form a Syndic alKyiene group; and R12 represents a hydrogen atom or an alkyl group. The optically active bisoxazoline compound (L-1) includes, for example, 2,2' -methylenebis[(4R)-phenyl-5,5-dimethyloxazoline], 2,2' -methyienebis[(4R)-phenyl-5,5-diethyloxazoline], 2,2' -methylenebis[(4R)-phenyl-5,5-di-n-propyloxazoline], 2,2' -methylenebis[(4R)-phenyl-5,5-di-i-propyloxazoline], 2,2' -methylenebis[(4R)-phenyl-5,5-dicyclohexyloxazoline], 2,2' -methylenebis[(4R)-phenyl-5,5-diphenyloxazoline], 2,2' -methylenebis[(4R)-phenyl-5,5-di-(2-methylphenyl) oxazoline], 2,2'-methylenebis[{4R)-phenyl-5,5-di-(3-methylphenyl)oxazoline], 2,2'-methylenebis[(4R)-phenyl-5,5-di-(4-methylphenyl) oxazoline], 2,2'-methylenebis[(4R)-phenyl-5,5-di-(2-methoxyphenyl)oxazoline], 2,2'-methylenebis[(4R)-phenyl-5,5-di-(3-methoxyphenyl)oxazoline], 2,2'-methylenebis[(4R)-phenyl-5,5-di-(4-methoxyphenyl)oxazoline], 2,2' -methylenebis[spiro{(4R)-phenyloxazoline-5,1' -cyclobutane}], 2,2' -methylenebis[spiro{(4R)-phenyloxazoline-5,1' -cyclopentane}], 2,2' -methylenebis[spiro{(4R)-phenyloxazoline-5,1' -cyclohexane}], 2,2' -methylenebis[spiro{(4R)-phenyloxazoline-5,1' -cycloheptane}] and compounds wherein (4R) in the-above respective compounds is replaced by (4S). The optically active salicylideneamino alcohol compound includes a compound of the formula (L-2): (L-2) wherein R13 and Ru respectively represent an alkyl group, an aralkyi group or an aryl group, Z represents a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, an aralkyi group or an aryl group, and * represents an asymmetR1c carbon atom. R13 of the optically active salicylideneamino alcohol compound (L-2) includes, for example, methyl, ethyl, iso-propyl, iso-butyl, t-butyl, benzyl and phenyl groups. R14 includes, for example, methyl, ethyl, iso-propyl, iso-butyl, t-butyl and benzyl groups, and phenyl group which may be substituted with an alkyl group, a halogen atom or an alkoxy group. Specific examples of the compound of the formula (L-2) includes (R) isomer or (S) isomer of the following compounds: N-salicylidene-2-amino-1,1-diphenyl-1-propanol, N-salicyiidene-2-amino-1,1-di(3-methylphenyl)-1-propanol, N-salicylidene-2-amino-1,1-di(4-methylphenyl)-1-propanol, N-salicylidene-2-amino-1,1-di(2-methoxyphenyl)-1-propanol, -N-salicylidene-2-amino-1,1-di(2-ethoxyphenyl)-1-propanol, N-salicylidene-2-amino-1,1 -di(2-isopropoxyphenyl)-1 -propanol, N-salicylidene-2-amino-1,1 -di(2-n-butoxy-5-t-butylphenyl)-1 -propanol, N-salicylidene-2-amino-1,1-diphenyl-3-methyl-1-butanol, N-salicylidene-2-amino-N-salicylidene-2-amino-N- salicylidene-2-amino-N-salicylidene-2-amino-. N-saliGylidene-2-amino-N-salicylidene-2-amino- butane, N-salicylidene-2-amino- N-salicylidene-2-amino- N-salicylidene-2-amino- N-salicylidene-2-amino- N-salicylidene-2-amino N-salicylidene-2-amino N-salicylidene-2-amino pentanol, N-salicylidene-2-amino N-salicylidene-2-aminO' N-salicylidene-2-amino-N-salicylidene-2-amino- ,1-di(3-methylphenyl)-3-methyl-1-butanol, J-di(4-methylphenyi)phe:i:/! B->Ti3thyl-1-butanol, ,1-di(2-methoxyphenyl) 3-inethyi-1-butanol, ,1-dip(2-ethoxthenyl)-3-methyl-1-butanol, ,1-di(2-isopropoxyphenyl)-3-methyM-propanol,' • , 1 -di(2-n-butoxy-5-t-butylphenyl-3-methyl-1 - , 1 -diphenyl-4-methyl-1 -pentanol, ,1-di(3-methylphenyl)-4-nnethyl-1-pentanol, ,1-di(4-methylphenyl)-4-nnethyl-1-pentanol, ,1-di(2-methoxtphenylphenyl)-4-methyl-1-pentanol, ,1-di(2-ethoxyphenyl)-4-methyl-1-pentanol, ,1-di(2-lsopropoxyphenyl)-4-methyl-1-pentanol, ,1-dl(2-n-butoxy-5-t-butylphenyl)-4-methyl-1- ,1-dlphenyl-3-phenyl-1-propanol, ,1-di(3-methylphenyl)-3-phenyl-1-propanol, ,1-di(4-methylphenyl)-3-phenyl-1-propanol, ,1-dl(2-methoxylphenyl)-3-phenyl-1-propanol, , 1 -di(2-ethoxylphenyl)-3-phenyl-1 -propanol, ,1-di(2-isopropoxylphenyl)-3-phenyl-1-propanol, and N-salicylidene-2-amino-1,1-di(2-n-butGxy-5-t-butylphenyl)-3-phenyl-1-propanol. The optically active ethylenediamine alcohol compound includes a compound of the formula (L-3): Rm "^ '^S-N HN-C U i) wherein R represents a hydrogen atom or a lower alkyl group, m represents an integer of 1 to 3, and * represents an asymmetR1c carbon atom. Specific compound of the optically active ethylenediamine compound (L-3) includes, for example, compounds wherein R is a hydrogen atom or a methyl group and m is an integer of 1 to 3. Specific examples thereof includes bis[N-(2,4,6-tR1methylphenyl)methyl-[1R),(2R)-diphenylethylenediamine and an antipode thereof having (1S), (2S) configuration. The asymmetR1c copper complex can be prepared by mixing the above copper compound with the optically active ligand in a solvent. The solvent used herein includes, for example, aromatic hydrocarbons such as toluene and xylene and aliphatic halogenated hydrocarbons such as dichloromethane and dichloroethane. Furthermore, 2,5-dimethyl-2,4-hexadiene may also be used as the solvent. The solvent is usually used in a 10-to 500-fold amount based on the weight of the copper compound. The amount of the optically active ligand is usually from about 0.8 to 5 moi, and preferably from about 1 to 2 mol, per mol of the copper compound. In view of the reaction yield, water is preferably excludes in the abo^e reaction. The above reaction temperature is not specifically limited The reaction is usually carR1ed out at the temperature within a range from about 0 to 50°C. In the present invention, when the complex is prepared by using a divalent cppper compound, an object can be sufficiently attained even if the divalent copper compound is not reduced to form a monovalent copper compound by using a reducing agent such as phenylhydrazine. The reaction between the copper compound and the optically active ligand is usually carR1ed out in the atmosphere of an inert gas such as argon and nitrogen. The asymmetR1c copper complex can be obtained in such a manner, but the copper complex may be isolated or can be used as it is in the reaction between 2,5-dimethyl-2,4-hexadiene and the diazoacetate (I) without being isolated. The amount of the asymmetR1c copper complex used in the reaction between 2,5-dimethyl-2,4-hexadiene and the diazoacetates (I) is usually from about 0.0001 to 0.01 mol, and preferably from about 0.0005 to 0.01 mol, per mol of the diazoacetate (I). Specific method of reacting 2,5-dimethyl-2,4-hexadiene with the diazoacetate (I) in the presence of the asymmetR1c copper complex includes, for example, a method adding the diazoacetate (I) dissolved in a solvent to a mixture .of the asymmetR1c copper complex obtained as descR1bed above and 2,5- -dimethyl-2,4-hexadiene. The solvent includes, for example, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform and carbon tetrachloR1de; aliphatic hydrocarbons such as hexane, heptane and cyclohexane; aromatic hydrocarbons such as benzene, toluene and xylene; and esters such as methyl acetate and ethyl acetate; It is also possible to use 2,5-dimethyl-2,4-hexadiene as the solvent. These solvents can also be used in combination. The solvent is usually used in a 1- to 30-fold amount, and preferably 5- to 20-fold amount, based on the weight of the diazoacetate (I). The reaction between 2,5-dimethyl-2,4-hexadiene and the diazoacetate (I) is usually carR1ed out in an atmosphere of an inert gas such as argon and nitrogen. 2,5-dimethyl-2,4-hexadine is usually used in the amount of 1 to 50 mol, and preferably 5 to 30 mol, per mol of the diazoacetate (I). In view of the reaction yield, water is preferably excluded in the above reaction. The above reaction temperature is not specifically limited. The reaction can be carR1ed out at the temperature of not more than a boiling point of the solvent when using the solvent, but is usually carR1ed out at the temperature within a range from about 0 to 120°C, and preferably from 5 to 100°C. The optically active chrysanthemic acid esters with considerably good puR1ty can be obtained in the above reaction by distilling off the solvent, but can be optionally isolated by a conventional method such as distillation and column chromatography, if necessary. The ester residue of the optically active chrysanthemic acid esters obtained by the above reaction includes, for example, methyl, ethyl, n-propyl, i-propyl, i-butyl, t-butyl, pentyl, hexyl and cydohexyl groups. The resulting optically active chrysanthemic acid esters can be converted into the corresponding chrysanthemic acid by contacting with an acid or an* aqueous alkali solution (hydrolysis step). The amount of an alkali compound of the aqueous alkali solution used is usually from 1 to 20 mol, and preferably from 1 to 10 mol, per mol of the chrysanthemic acid esters. Thechrysanthemic acid, particularly having a trans isomer ratio of not less than 50% and an optical puR1ty of not less than 10% e.e. thus obtained may be used in the optical resolution step as it is, or optionally used in combination with chrysanthemic acid enR1ched with the trans isomer. Such chrysanthemic acid enR1ched with the trans isomer can be obtained, for example, by reacting (-)-cis chrysanthemic acid or chrysanthemic acid enR1ched with a (-)-trans isomer with t-butyl hydroperoxide and aluminum bromide in the presence of a toluene solvent (see JP5-37137B/1993). The trans isomer ratio of the chrysanthemic acid enR1ched with the trans isomer used is not less than 80%, and preferably not less than 85%. According to the present invention, there can be produced chrysanthemic acid having more improved trans/cis ratio and more improved optical puR1ty in an industR1ally advantageous manner. In the above method, when using chrysanthemic acid having a trans isomer ratio of not less than 50% and an optical puR1ty of not less than 10% e.e., there cah be obtained an optically active chrysanthemic acid whose trans isomer ratio and optical puR1ty are improved. Accordingly the present invention provides a method for producing an optically active chrysanthemic acid with improved trans isomer ratio and optical puR1ty, the said method compR1ses the steps of reacting chrysairthemic acid having a trans isomer ratio of not less than 50% and an optical puR1ty of not less than 10% e.e. with an optically active amine of the formula (A-2): wherein R^ and R,, respectively represent a hydrogen atom, an aUcyl group, an iiralkyl group or an aryl group, R3 represents an alkyl group having 1 to 6 carbon atoms; and an asymmetR1c carbon atom represented by " * " is either in S-configuration or R-configuration: wherein the amount of the optically active amine is from 0,2 to 1.2 moles per mole of the chrysanthemic acid and to optically resolve said chrysanthemic acid and recoveR1ng the said optically active chrysanthemic acid in a known manner. resp6ct to trans isomer and 52% e.e. with respect to cis isomer, and a trans/cis ratio of 78/22, 228 g of toluene was added and dissolved with stirring. Then, 20.4 g ofi6)-1-phenyl-2-(p-tolyl)ethylamine (optical resolution agent) was added thereto and dissolved with heating. After cooling to room temperature, the deposited crystal was collected by filtration, washed with toluene and then dissolved in an aqueous 5% sodium hydroxide. After the optical resolution agent was extracted with toluene, the aqueous layer was acidified with aqueous 5% sulfuric acid and extracted with toluene. Then, toluene was distilled off to obtain 14.3 g of chrysanthemic acid having a trans/cis ratio of 81/19 and an optical purity of 98% e.e. with respect to (+)-trans isomer and 98% e.e. with respect to (+)-cis isomer (yield: 71.5%). Example 2 To 30 g of chrysanthemic acid having an optical purity of 40% e.e. with respect to (+)-trans isomer and 1.3 % e.e. with respect to (+)-cis isomer and a trans/cis ratio of 77/23, 210 g of toluene was added and dissolved with stirring. Then, 24.7 g of (S)-1-phenyl-2-(p-tolyl)ethylamine (optical resolution agent) was added to the solution and dissolved with heating. After cooling to room temperature, the deposited crystal was collected by filtration, washed with toluene and then dissolved in an aqueous 5% sodium hydroxide. After the optical resolution agent was extracted with toluene, the aqueous layer was acidified with aqueous 5% sulfuric-acid and extracted with'toluene. Then, the toluene was distilled off to obtain 15.1 g of chrysanthemic acid having a trans/cis ratio of 85/15 and an optical purity of 96% e.e with respect to (+)-trans isomer and 95 % e.e. with respect to (+)-cis isomer, (yield: 50.3%). Example 3 18.05 mg (0.05 mmol) of copper trifluoromethanesulfonate, 19.9 mg (0.055 mmol) of bis[2-[4(R)-phenyl-5,5-dimethyl-2-nxazoline]]methane and 5 ml of n-butyl chloride were charged in a 50 ml Schlenk' s tube wherein the atmosphere is substituted with nitrogen, followed by stirring at room temperature for 10 minutes. After 30.0 g (275 mmol) of 2,5-dimethyl-2,4-hexadiene was further added, 5.70 g (50 mmol) of ethyl diazoacetate was added dropwise at 50°C over 2 hours. After the completion of the dropwise addition of ethyl diazoacetate, the mixture was further stirred at 50°C for 1 hour. The amount of chrysanthemic acid ethyl ester formed was determined by gas chromatography. As a result, it was 8.43 g and the yield was 86.0% based on ethyl diazoacetate and, furthermore, the trans/cis ratio was 72/28. After 2,5-dimethyl-2,4-hexadiene (boiling point: 51°C/30 mmHg) was distilled off from the reaction mixture, 1 g of the concentrated solution was taken out. Then, 10 ml of an aqueous IN sodium hydroxide solution and 5 ml of ethanoi were added and alkali hydrolysis was performed by stirring at 100°C for 1 hour. The resulting chrysanthemic acid was reacted with l-menthol and the formed diastereomer ester was analyzed by gas chromatography. As a result, the optical purity of the (+)-trans isomer was 60 % e.e., whereas, the optical purity of the (+)-cis isomer was 27 % e.e. Furthermore, chrysanthemic acid obtained by hydrolyzing the ethyl chrysanthemate with 1N sodium hydroxide was mixed with racemic chrysanthemic acid enriched with trans isomer (trans/cis ratio: 95/5) in a weight • ratio of 6:4. 104.5 g of toluene was then added to 10.0 g of the mixed chrysanthemic acid, and the mixture was dissolved with stirring. Then, 7.48 g of (S)-1-phenyl-2-(p-tolyl)ethylamine (optical resolution agent) was added to the solution and dissolved with heating. After cooling to room temperature, the deposited crystal was collected by filtration, washed with toluene and then dissolved in anaqueous 5% sodium hydroxide. After the-agent for optical resolution w^^s extracted with toluene, the aqueous layer was acidified with aqueous 5% sulfuric acid and extracted with toluene to obtain 4.19 g of chrysanthemic acid.having a trans/cis ratio of 87/13 and an optical purity of 95% e.e. with respect to (+)-trans isomer and 97% e.e. with respect to (+)-cis isomer (yield: 141.9%). Example 4 22,6 mg (0.05mmol) of copper complex prepared from 9.98 mg (0.05 mmol) of copper acetate-mono hydrate and 21.5 mg of (R)-N-salicylidene-2-amino-1,1-di(2-methoxyphenyl)propanol, and 6.0 g (55 mmol) of 2,5-dimethyl-2,4-hexadiene were charged in a 50 ml Schlenk' s tube wherein the atmosphere is substituted with nitrogen, followed by the addition of 5.4 mg of phenylhydrazine, and 1.14 g (10 mmol) of ethyl diazoacetate was added dropwise at 80°C over 2 hours. After the completion of the dropwise addition ofethyl diazoacetate, the mixture was further stirred at 25°C for 1 hour. The amount of chrysanthemic acid ethyl ester formed was determined by gas chromatography. As a result, it was 1.76 g and the yield was 90.0% based on ethyl diazoacetate and, furthermore, the trans/cis ratio was 58/42. After 2,5-dimethyl-2,4-hexadiene (boiling point: 51°C/30 mmHg) was distilled off from the reaction mixture, 1 g of the concentrated solution was taken out. Then, 10 ml of an aqueous 1N sodium hydroxide solution and 5 ml of ethanol were added and alkali hydrolysis was performed by stirring at 100°C for 1 hour. The resulting chrysanthemic acid was reacted with l-menthol and the formed diastereomer was analyzed by gas chromatography. As a result, the optical purity of the (+)-trans isomer was 63 % e.e., whereas, the . . Furthermore, ehrysanthemic acid obtained by hydrolyzing the ethyl . -. chrysanthemate with 1N sodium hydroxide was mixed with racemic c - ^ ehrysanthemic acid enriched with trans isomer (trans/cis ratio: 95/5) in a weight ratio of 4:6.. 106.2g of toluene was then added to 10.0 g of ehrysanthemic add,.. and the mixture was dissolved with stirring. Then, 7.40 g of (S)-1-phenyl-2-(p-tolyl)ethylamine (optical resolution agent) was added to the solution and dissolved with heating. After cooling to room temperature, the deposited crystal was collected by filtration, washed with toluene and then dissolved in an aqueous 5% sodium hydroxide. After the optical resolution agent was extracted with toluene, the aqueous layer was acidified with aqueous 5% sulfuric acid and extracted with toluene to obtain ehrysanthemic acid having a trans/cis ratio of 81/19 and an optical purity of 99% e.e. with respect to (+)-trans isomer and 96% e.e. with respect to (+)-cis isomer(yield: 40.2%). Example 5 19.64 mg (0.05 mmol) of a copper complex prepared from 9.98 mg (0.05 mmol) of copper acetate monohydrate and 18.23 mg (0.055mmol) of (R)-N-sallcylidene-2-amino-1,1-diphenylpropanol, and 6.0 g (55 mmol) of 2,5-dimethyl-2,4-hexadiene were charged in a 50 ml Schlenk' s tube wherein the atmosphere is substituted with nitrogen. After 5.4 mg of phenylhydrazine was further added, 1.14 g (10 mmol) of ethyl diazoaeetate was added dropwise at 50°C over 2 hours. After the completion of the dropwise addition of ethyl diazoaeetate, the mixture was further stirred at 25°C for 1 hour. The amount of ehrysanthemic acid ethyl ester formed was determined by gas chromatography. As a result, it was 1.52 g and the yield was 77.7% based on ethyl diazoaeetate and, furthermore, the trans/cis ratio was 61/39. After 2,5-dimethyl-2,4-hexadiene (boiling point: 51°C/30 mmHn) was distilled off from the reaction mixture,-1 g of the concentrated solution was taken out. Then, 10 ml of an aqueous IN sodium hydroxide solution and 5 ml of ethanol were added and alkali hydrolysis was performed by stirring at 100°C for 1 hour. The resulting chrysanthemic acid was reacted with l-menthol and the formed diastereomer ester was analyzed by gas chromatography. As a result, the optical purity of the (+)-trans isomer was 69% e.e., whereas, the optical purity of the (+)-cis isomer was 68% e.e. Furthermore, chrysanthemic acid obtained by alkali hydrolysis is mixed with racemic chrysanthemic acid enriched with trans isomer (trans/cis ratio: 95/5) in a weight ratio of 46:54. Toluene is then added in an about 10-fold amount based on chrysanthemic acid, and the mixture is dissolved with stirring. Then, (S)-1-phenyl-2-(p-tolyl)ethylamine (optical resolution agent) was added in the amount of about 0.69 mol per mol of chrysanthemic acid and dissolved with heating. After cooling to room temperature, the deposited crystal is collected by filtration, washed with toluene and then dissolved in an aqueous 5% sodium hydroxide. After the agent for optical resolution is extracted with toluene, the aqueous layer is acidified with aqueous 5% sulfuric acid and extracted with toluene to obtain chrysanthemic acid having a trans/cis ratio of about 78/22 and an optical purity of about 95% e.e. with respect to (+)-trans isomer and 99%e.e. with respect to that (+)-cis isomer (yield: about 46%). Example 6 According to the same manner as that described in Example 5 except for using 32.47 mg (0.05 mmol) of a copper complex prepared from 9.98 mg (0.05 mmol) of copper acetate monohydrate and 32.33 mg (0.055 mmol) of (R)-N- salicylidene-2-amino-1,1-di(2-n-butoxy-5-t-butylphenyl)propanol in a 50 ml Schlenk' s tube wherein the atmosphere is svibstituted with nitrogen, the reaction was performed. The amount of chrysanthemic acid ethyl ester formed was determined by gas chromatography. As a result, it was 1.64 g and the yield was 8v3.Z% based on ethyl diazoacetate and, furthermore, the trans/cis ratio-was 57/43. After 2,5-dimethyl-2,4-hexadiene (boiling point: 51°C/30 mmHg) was distilled off from the reaction mixture, 1 g of the concentrated solution was taken out. Then, 10 ml of an aqueous 1N sodium hydroxide solution and 5 ml of ethanol were added and alkali hydrolysis was performed by stirring at 100°C for 1 hour. The resulting chrysanthemic acid was reacted with l-menthol and the formed diastereomer was analyzed by gas chromatography. As a result, the optical purity of the (+)-trans isomer was 86% e.e., whereas, the optical purity of the (+)-cis isomer was 84% e.e. Furthermore, chrysanthemic acid obtained by alkali hydrolysis is mixed with racemic chrysanthemic acid enriched with trans isomer (trans/cis ratio: 95/5) in a weight ratio of 51:49. Toluene is then added in an about 10-fold amount based on chrysanthemic acid, and the mixture is dissolved with stirring. Then, (S)-1-phenyl-2-(p-tolyl)ethylamine (optical resolution agent) is added in the amount of about 0.68 mol per mol of chrysanthemic acid and dissolved with heating. After cooling to room temperature, the deposited crystal is collected by filtration, washed with toluene-and then dissolved in an aqueous 5% sodium hydroxide. After the agent for optical resolution is extracted with toluene, the aqueous layer is acidified with aqueous 5% sulfuric acid and extracted with toluene to obtain chrysanthemic acid having a trans/cis ratio of about 72/28 and an optical purity of the (+)-trans isomer is about 95% e.e. and that of (+)-cis isomer is about 99^0 e.e. (yield: about 51%). Comparative Example 1 To 100 g of a racemic chrysanthemic acid (trans/cis ratio: 75/25), 390g of toluene was added, and the mixture was dissolved with stirring. Then, 47.0g of • (S)-1-phenyl-2-(p-tolyl)ethylamine (optical resolution agent) was added and dissolved with heating. After cooling to room temperature, the deposited crystal was collected by filtration, washed with toluene and then dissolved in an aqueous 5% sodium hydroxide. After the agent for optical resolution was extracted with toluene, the aqueous layer was acidified with aqueous 5% sulfuric acid and extracted with toluene to obtain 20.8 g of chrysanthemic acid having a trans/cis ratio of 80/20 and an optical purity of the (+)-trans isomer was 96% e.e. and that of (+)-cis isomer was 98% e.e.(yield: 20.8%). Example 7 18.05 mg (0.05 mmol) of trifluoromethanesulfonic acid, 19.9mg(0.055mmol), bis[2-[4-(R)-phenyl-5,5-dimethyl-2-oxazoline]]methane and 5 ml of n-butyl chloride were charged in a nitrogen charged 50 ml Schlenk's tube, and stirred for 10 min at room temperature. After 6.0 g (55 mmol) of 2,5-dimethyl-2,4-hexadiene were added thereto, 1.41 g (10 mmol) of t-butyl diazoacetate was added dropwise at 25°C over 1 hour. The amount of chrysanthemic acid t-butyl ester formed was determined by gas chromatography. As a result, it was 1.86 g and the yield was 83.1% based on t-butyl diazoacetate and, furthermore, the trans/cis ratio was 85/15. After 2,5-dimethyl-2,4-hexadiene (boiling point: 51°C/30 mmHg) was distilled off from the reaction mixture, the concentrated solution was subjected to luquid chromatography to measure the otpical activity, which revealed the optical purity of (+)-trans isomer was 86%e.e. and that of (+)-cis isomer was 67%fe".e. Then, trans-rich racemic chrysanthemic obtained by decomposing the t-butyl chrysanthemate with trifluoroacetic acid is mixed wlth-racemic chrysanthemic acid of which trans/cis ratio is 95/5 in a weight ratio of 60:40, and 10-fold amount of toluene to the chrysanthemic acid is added to the mixture, stirred ,and dissolved. Then, 1.0 mole of (S)-a-(1-naphthyl)-ethylamine, as a resolution agent, and 8% by weight of water per chrysanthemic acid are added thereto and the resulting mixture is heated to dissolved. After cooling the mixture to room temperature, deposited crystals are collected by filtration, washed with toluene, then dissolved in aqueous 5% sodium hydroxide and extracted with toluene. Separated water layer is acidified with aqueous 5% sulfuric acid and extracted with toluene to give chrysanthemic acid with a trans/cis ratio of about 98/2 and optical purity of the (+)-trans isomer is about 96%e.e. and that of (+)-cis isomer is about 57%e.e. in a yield of about 57%. Example 8 19.64 mg (O.OSmmol) of copper complex prepared from 9.98 mg (0.05 mmol) of copper acetate monohydrate, and 18.23 mg of (R)-N-salicylidene-2-amino-1,1-diphenylpropanol, and 6.0g(55mmol) of 2,5-dimethyl-2,4-hexadiene were charged in a 50 ml Schlenk' s tube wherein the atmosphere was replaced with nitrogen, and then 5.4 mg of phenylhydrazine. 1.14 g (10 mmol) of ethyl diazoacetate was added dropwise at 50°C over 2 hours and further stirred for 1 hour at 25°C. The amount of chrysanthemic acidethyl ester formed was determined by gas chromatography. As a result, it was 1.52 g and the yield was 77.7% based on t-butyl diazoacetate and, furthermore, the trans/cis ratio was 31/39. After 2,5-dimethyi-2,4-hexadiene (boiling point: 51°C/30 mmHg) was listilled off from the reaction mixture. Then, 10 ml of an aqueous IN sodium hydroxide solution and 5 ml of ethanol were added to 1 g of the concentrate and alkali hydrolysis was performed by stirring at 100°C for 1 hour. The obtained chrysanthemic acid was jDsacted with l-menthol, and the resulted diastereomer was analyzed by gas chromatography, which showed the optical purity of (+)-trans isomer was 69%e.e. and that of (t)-cis isomer was 68%e.e. Then, the chrysanthemic acid obtained by the alkali hydrolysis is mixed with trans-rich racemic chrysanthemic acid of which trans/cis ratio is 95/5 is mixed with the (+)-trans isomer in a weight ratio of 43:57, and 7-fold amount of toluene to the chrysanthemic acid is added to the mixture, stirred and dissolved. Then, 1.0 mole of (S)-α -(1-naphthyl)-ethylamine, as a resolution agent, and 8% by weight of water to chrysanthemic acid are added thereto and the resulting mixture is heated to dissolved. After cooling the mixture to room temperature, deposited crystals are collected by filtration, washed with toluene, then dissolved in aqueous 5% sodium hydroxide and extracted with toluene. Separated water layer is acidified with aqueous 5% sulfuric acid and extracted with toluene to give chrysanthemic acid with a trans/cis ratio of about 98/2 and optical purity of about 96%e.e with respect to (+)-trans isomer in a yield of about 40%. Comparative Example 2 To 16.3 g of a racemic chrysanthemic acid (trans/cis ratio: 79/21), 65.0g of oluene was added, and the mixture was dissolved with stirring. Then, 16.0 g of S)- resolution was extracted with toluene, the aqueous layer was acidified with aqueous 5% sulfuric acid and extracted with toluene to obtain 4.13 g of chrysanethemic acid having a trans/cis ratio of 98/2 and an optical purity of 97% e.e. with respect to (+)-trans isomer and 73% e.e. with respect to (+)-cis isomer (yield:25.3%). An optically active chrysanthemic acid to be resolved in additional Example below contains only (69.5/50)=L.4 times (+)-traas-isomer, which usually is a biologically effective form, as compared to a racemic compound in Comparative Example 2. Yet, a yield ratio between the two cases is (47.7/25.3)=1.9. Thus the yield increase in terms of a ratio of the yields is unexpectedly higher than is expected firom a ratio of (+)-trans-isomer content in the chrysanthemic acids to be resolved. Example 9 To 9.41 g of chrysanthemic acid (trans/cis ratio: 78/22, tratis-isomer: 39%e.e., cis-isomer: 42% e.e.), were added 85.1 g of toluene and 0.8 g of water and the resulting mixture was dissolved under stirring. Then, 11.91 g of (S) - a -(l-ninthly)ethylamine (optical resolution agent) was added thereto and dissolved with heating. After cooling to a room, temperature, the deposited crystal was collected by filtration, washed with toluene and then dissolved in an aqueous 5% sodium hydroxide. After the optical resolution agent was extracted with toluene, the aqueous layer was acidified with aqueous 5% sulfuric acid and extracted with toluene and evaporated to obtain 4.49 g of chrysanthemic acid having a trans/cis ratio of 98/2 and an optical purity of 98% e.e. with respect to (+)-trans isomer and 28% e.e. with respect to (+)-cis isomer (yield: 47.7%). This application has been divided out of Indian patent application no. 105/MAS/99 which relates to a method of producing an optically active chrysanthemic acid with improved trans-isomer ratio wherein chrysanthemic acid having less trans-isomer ratio is treated with an optically active amine of the formula given below:- WE CLAIM; 1. A method for producing an optically active chrysanthemic acid with improved trans isomer ratio and optical purity, the said method comprises the steps of reacting chrysanthemic acid having a trans isomer ratio of not less than 50% and an optical purity of not less than 10% e.e. with an optically active amine of the formula (A-2): wherein R1 and R2 respectively represent a hydrogen atom, an alkyl group, an aralkyl group or an aryl group, R3 represents an alkyl group having 1 to 6 carbon atoms; and an asymmetric carbon atom represented by " ♦ " is either in S-configuration or R-configuration: wherein the amount of the optically active amine is from 0.2 to 1.2 moles per mole of the chrysanthemic acid and to optically resolve said chrysanthemic acid and recovering the said optically active chrysanthemic acid m a known manner. 2. The method according to claim 1, wherein chrysanthemic acid has a trans isomer ratio of 60-95% and an optical purity of 30-90% e.e. 3. The method according to claim 1, wherein a chrysanthemic acid having optical purity of not less than 20% e.e is reacted with an optically active amine. 4. A method for producing an optically active chrysanthemic acid substantially as described hereinabove.

Full Text

The. present invention relates to a mutinied for producing an optically, active
chrysantliemic acid , .
DescR1ption of the Related Art
Optically active cyclopropanecarboxylic acid deR1vatives are important intermediates for drugs and pesticides. For example, (+)-2,2-dimethyl-3-(2-methyl-1-propenyi)cyclopropanecarboxylic acid known as chrysanthemum mono-carboxylic acid constitutes an acid component of synthetic parathyroid insecticide.
The insecticidal activity of a trans-pyrethroid ester is usually higher than that of a cis-isomer. Particularly, pyrethroid esters of (+)-trans-chrysanthemum mono-carboxylic acid(hereinafter referred to as "chrysanthemic acid") or chrysanthemic acid enR1ched with the (+)-trans-chrysanthemic acid have exhibited excellent insecticidal activity. Accordingly, an industR1ally advantageous method to produce (+)-trans-chrysanthemic acid or chrysanthemic acid enR1ched with the (+)-trans-chrysanthemic acid has been desired.
As a method of producing an optically active chrysanthemic acid deR1vative by using a synthetic technique, there has been known a method of reacting a (±)-trans-chrysanthemum mono-carboxylic acid or trans R1ch (±)-chrysanthemum mono-carboxylic acid with an optical resolution agent, which are an optically active amine, to obtain an optically active chrysanthemic acid (JP46-20382B/1971, JP54-37130B/1979, JP49-109344A/1974 and JP51-23497B/1976). However, these optical resolution methods were not always satisfactory, because

of low yield of the desired optically active chrysanthemic acid.
Therefore, the present inventors have intensively studied. As a result, they - .
have found that, when chrysanthemic acid optically enR1ched with one isomer, e.g. ;+)-:trans-chrysanthemic acid can be puR1fied by crystallization using an optical active amine in the production of an optically active chrysanthemic acid, whereby (+)-trans-chrysanthemic acid having excellent optical puR1ty can be obtained with surpR1singly good efficiency compared with the case of using racemes chrysanthemic acid, and trans isomer ratio of the chrysanthemic acid can also be improved efficiently when trans isomer having not less than 50% trans-isomer ratio are applied. SUMMARY OF THE INVENTION
The present invention provides:
1. a method for producing an optically active chrysanthemic acid whose
trans isomer ratio and optical puR1ty are improved, which compR1ses:
reacting chrysanthemic acid having a trans isomer ratio of not less than 50% and an optical puR1ty of not less than 10% e.e. with an optically active organic amine to optically resolve said chrysanthemic acid; and
2. a method for producing an optically active chrysanthemic acid whose
trans isomer ratio and optical puR1ty are improved, which compR1ses:
reacting 2,5-dimethyl-2,4-hexadiene with diazoacetates of the formula (I):
N2CHCO2R7 (1)
wherein R7 represents an alky! group having 1 to 6 carbon atoms or a
cycioalkyI group, in the presence of an asymmetR1c copper complex to
produce an optically active chrysanthemic acid ester (cyclopropanation
step),

contacting chrysanthemic acid esters with an acid or base to form chrysanthemic acid (hydrolysis step); and
optically resolving chrysanthemic acid using at least one optically active organic amine selected from those of the formulas (A-1), (A-2), (A^S) and (A"4i) shown below (optical resolution step).
DESCR1PTION OF THE PREFERRED EMBODIMENTS
First, a descR1ption will be made to the method for producing an optically active chrysanthemic acid of which trans isomer ratio and optical puR1ty are improved, which compR1ses:
reacting chrysanthemic acid having a trans isomer ratio of not less than
50% and an optical puR1ty of not less than 10% e.e. with an optically active
organic amine to optically resolve said chrysanthemic acid.
Chrysanthemic acid having a trans isomer ratio of not less than 50% and an optical puR1ty of not less than 10% e.e can be obtained by any method, for example, it can be produced in the following manner.
In the present invention, the "optical puR1ty" or e.e.% of (+)-trans-chrysanthemic acid in the trans isomer is calculated based on the analysis using optically active column and is defined, for example, by the following equation: 100 X {[(+)-trans-chrysanthemic acid - (-)-trans-chrysanthemic acid] / [(+)-trans-chryeanthemic acid + (-)-trans-chrysanthemic acid]}.
The optically active chrysanthemic acid can be obtained by reacting 2,5-dimethyl-2,4-hexadiene with diazoacetate of the formula (I):
N2CHCO2R7 (I)

wherein R7 represents an alkyl group having 1 to 6 carbon.atoms or a cycioalkyI group, in the presence of an asymmetR1c copper complex to produce optically active chrysanthemic acid esters (cyclopropanation step); and decomposing chrysanthemic acid esters with an alkali or acid (hydrolysis step).
In this method trans isomer ratio of not less than 50% and optical puR1ty of not less than 20% e.e is preferably employed, more preferably, chrysanthemic acid having trans isomer ratio of from 60%e.e. to 95% e.e. and optical puR1ty of from 30% e.e. to 90% e.e is employed.
The optically active organic amine for optically resolving the optically active chrysanthemic acid includes, for example, an optically active organic amine of the formula (A-1 ):

wherein R1 and R2 respectively represent a hydrogen atom, an alkyl group, an orally group or an aryl group;
R3 represents an alkyl group having 1 to 6 carbon atoms, and ^.
* represents an asymmetR1c carbon atom; or
an Spatially active organic amine of the formula (A-3):
R4—CH—R,
I NH-CK-Rg
^ ^ (A-3)
wherein R4 represents a naphthalene group, a cydohexyl group, or a phenyl group which may be substituted with halogen, nitro, lower alkyl or lower alloys;
R5 represents a lower alkyl group, or a benzyl group which may be substituted with a lower alkyl group;
Re represents a p-hydroxyphenyl group or a 2-hydroxy-3-lower alkoxyphenyl group when R5 is a lower alkyl group, and
Re represents a p-hydroxyphenyl group when R5 is a benzyl group which may be substituted with a lower alkyl group, and
* represents an asymmetR1c carbon atom, or an optically active organic
amine of the formula (A-4):
(^R,R2
CHjOH
(A-4)
wherein R1 and R2 respectively represent a hydrogen atom, an alkyl group,’ an aurally group or an aryl group, and
* represents an asymmetR1c carbon atom.
The optically active amine includes, for example, optically active compounds such as 1 -phenyl-2-(p-tolyl)ethylamine, ex -(1 -naphthyl)-ethylamine.

a-(2-naphthyl)-ethylamine, 1-phenyiethylamine, erythrism- a, α biphenyl-^ -hydroxyethylamine, N-methylephedR1ne, N-(2,2,2-tR1chloro-1-formamideethyl)pipeR1r)in£, 2-benzylamino-1-butanol, ephedR1ne, cis-N-benzyl-2-(hydroxymethyl)cyGlohexylamine, N-(p-hydroxybenzyl)-1-phenylethylamine, N-(p-hydroxybenzyl)-1-(p-tolyl)ethylamine, N-(p-hydroxybenzyl)-1-(p-isopropylphenyl)ethylamine, N-(p-hydroxybenzyl)-1-(p-nitrophenyl)ethylamine, N-(p-hydroxybenzyl)-1-(p-bromophenyl)ethylamine, N-(p-hydroxybenzyl)-1-(1-naphthyl)ethylamine, N-(p-hydroxybenzyl)-1-cyclohexylethylamine, N-(p-hydroxybenzyl)-1-(p-methoxyphenyl)ethylamine, N-(p-hydroxybenzyl)-1-phenylpropylamtne, N-(p-hydroxybenzyl)-2-methyl-1-phenylpropylamine, N-(2-hydroxy-3-methoxybenzyl)-1-phenylethylamine, N-(2-hydroxy-3-methoxybenzyl)-1-(p-tolyl)ethylamine, M-(2-hydroxy-3-methoxybenzyl)-1-(p-isopropylphenyl)ethylamine, N-(2-hydroxy-3-methoxybenzyl)-1-(p-nitrophenyl)ethylamine, N-{2-hydroxy-3-methoxybenzyl)-1-(p-bromophenyl)ethylamine, N-(2-hydroxy-3-methoxybenzyl)-1-(1-naphthyl)ethylamine, N-(2-hydroxy-3-methoxybenzyl)-1-cyciohexylethylamine, N-(2-hydroxy-3-methoxybenzyl)-1-(p-methoxyphenyl)ethylamine, N-(2-hydroxy-3-methoxybenzyl)-1-phenylpropylamine, N-(2-hydroxy-3-methoxybenzyl)-2-methyl-1-phenylpropylamine, N-p-hydroxybenzyl- a -phenyl- /S -paratolylethylamine,

erythro-1-p-nitrophenyl-2-N,N-dimethylamJnopropane-1,3-diol, and thre0-1-prnitrophenyl-2-N,N-dimethylaminopropane-1,3-diol.
Optical resolution is performed by reacting the optically active chrysanthemic acid with an optically active amine (optical resolution agent) of the formula (A-1), (A^2).- (A-3) or (A-4).
The optical resolution is usually performed in a solvent. As the solvent, there can be used aromatic hydrocarbons such as benzene, toluene and xylems; aliphatic hydrocarbons such as hexane and heptane; alcohols such as water, methanol and ethanol; ketones such as acetone and methyl isobutyl ketone; and ethers such as dioxane and tetrahydrofuran. These solvents may be used alone or in combination thereof.
The amount of the solvent vaR1es depending on the solvent and conditions of the post treatments and is not specifically limited, and an optimum amount is optionally set according to the respective conditions.
The amount of the optical resolution agent is usually from about 0.2 to 1.2 mol, and preferably from about 0.3 to 1.1 mol, per mol of chrysanthemic acid.
The optical resolution agent and chrysanthemic acid are usually dissolved in the solvent above under stirR1ng or standing. The mixture may be heated to dissolve, if necessary.
A diastereomer crystal compR1sing an optical resolution agent and optically active chrysanthemic acid is usually formed tcdeposit from the solution on standing at an ambient temperature or by cooling the solution.
The deposited crystal may be collected as it is, or alternatively, it may be totally or partially dissolved by heating and then cooled to deposit the crystal, if necessary.

The dissolution and deposition is usually conducted at a temperature ranging from -20 to 150°C, and preferably from -TO to 100°C.
The deposited diastereomer crystal is usualiy separated by filtration.
The diastereomer salt separated as a crystal is then decomposed with an acid or alkali and extracted to obtain the optically native chrysanthemic acid with higher trans ratio and optical puR1ty. The used optical resolution agent can be recovered.
For example, an optically active chrysanthemic acid is obtained by recomposing the diastereomer salt, obtained by means of the above method, with hydrochloR1c acid or sulfuR1c acid and extracting the resultant with an organic solvent. Furthermore, the agent for optical resolution is recovered by making the aqueous layer weak alkali and extracting it.
Alternatively, the optical resolution agent can be recovered by decomposing the disatereomer salt, obtained by means of the above method, with a base such as sodium hydroxide, and extracting the resultant with an organic solvent in the weak alkali condition. Thereafter, the aqueous layer is acidified and extracted, thereby making it possible to obtain an optically active chrysanthemic acid.
The optical resolution agent recovered by these methods can be reused.
Next a descR1ption will be made to the method for producing an optically active chrysanthemic acid, which compR1ses reacting 2,5-dimethyl-2,4-hexadiene with diazoacetates of the formula (I) as defined above, in the presence of an asymmetR1c copper complex to produce optically active chrysanthemic acid esters (cyclopropanation step); and contacting the chrysanthemic acid ester with an
alkali or acid (hydrolysis step).
t ■ The alkyl group of diazoacetate used in the above cyclopropanation step

includes, for example, methyl, ethyl, n-propyi, iso-propyl, n-butyl, iso-butyl, t-butyl, phenyl, hexyl and cyclohexyl groups.
The asyTifTTetR1c copper complex used in the above cyclopropanation step Is )repaired from a copper compound and an optically active organic compound hereinafter referred to as "an optically active ligand") (Pure & Appl. Chem., Vol. 57, No. 12,1839,1985, Tetrahedron Lett., 32, 7373 (1991), Tetrahedron Lett., 35, 7985(1994)).
The copper compound includes, for example, mono- or divalent copper compounds such as copper naphthenate, copper tR1fluoromethanesulfonate, copper acetate, copper bromide and copper chloR1de. These compounds may be used alone or in combination thereof.
The optically active ligand includes, for example, optically active bisoxazoline compound, optically active salicylideneamino alcohol compound, optically active diamine compound, optically active semicorR1n compound and optically active camphor compound.
Preferred examples thereof include optically active salicylideneamino alcohol compound, optically active bisoxazoline compound and optically active ethylenediamine compound.
The optically active bisoxazoline compound is of the formula (L-1):
wherein R5 and R8are different and represent an optionally substituted phenyl group or a hydrogen atom.

R1o and R11 represent a hydrogen atom, an alkyl group, a cycioalkyI group, an optionally substituted phenyl group or an aralkyi qroup,.Dr
R10 and R11 may be combined to form a Syndic alKyiene group; and
R12 represents a hydrogen atom or an alkyl group.
The optically active bisoxazoline compound (L-1) includes, for example, 2,2' -methylenebis[(4R)-phenyl-5,5-dimethyloxazoline], 2,2' -methyienebis[(4R)-phenyl-5,5-diethyloxazoline], 2,2' -methylenebis[(4R)-phenyl-5,5-di-n-propyloxazoline], 2,2' -methylenebis[(4R)-phenyl-5,5-di-i-propyloxazoline], 2,2' -methylenebis[(4R)-phenyl-5,5-dicyclohexyloxazoline], 2,2' -methylenebis[(4R)-phenyl-5,5-diphenyloxazoline], 2,2' -methylenebis[(4R)-phenyl-5,5-di-(2-methylphenyl) oxazoline], 2,2'-methylenebis[{4R)-phenyl-5,5-di-(3-methylphenyl)oxazoline], 2,2'-methylenebis[(4R)-phenyl-5,5-di-(4-methylphenyl) oxazoline],
2,2'-methylenebis[(4R)-phenyl-5,5-di-(2-methoxyphenyl)oxazoline], 2,2'-methylenebis[(4R)-phenyl-5,5-di-(3-methoxyphenyl)oxazoline], 2,2'-methylenebis[(4R)-phenyl-5,5-di-(4-methoxyphenyl)oxazoline], 2,2' -methylenebis[spiro{(4R)-phenyloxazoline-5,1' -cyclobutane}], 2,2' -methylenebis[spiro{(4R)-phenyloxazoline-5,1' -cyclopentane}], 2,2' -methylenebis[spiro{(4R)-phenyloxazoline-5,1' -cyclohexane}], 2,2' -methylenebis[spiro{(4R)-phenyloxazoline-5,1' -cycloheptane}] and compounds wherein (4R) in the-above respective compounds is replaced by (4S).
The optically active salicylideneamino alcohol compound includes a compound of the formula (L-2):

(L-2)
wherein R13 and Ru respectively represent an alkyl group, an aralkyi group or an
aryl group,
Z represents a hydrogen atom, a halogen atom, an alkyl group, an alkoxy
group, an aralkyi group or an aryl group, and * represents an asymmetR1c carbon atom. R13 of the optically active salicylideneamino alcohol compound (L-2)
includes, for example, methyl, ethyl, iso-propyl, iso-butyl, t-butyl, benzyl and
phenyl groups.
R14 includes, for example, methyl, ethyl, iso-propyl, iso-butyl, t-butyl and
benzyl groups, and phenyl group which may be substituted with an alkyl group, a
halogen atom or an alkoxy group.
Specific examples of the compound of the formula (L-2) includes (R) isomer
or (S) isomer of the following compounds:
N-salicylidene-2-amino-1,1-diphenyl-1-propanol, N-salicyiidene-2-amino-1,1-di(3-methylphenyl)-1-propanol, N-salicylidene-2-amino-1,1-di(4-methylphenyl)-1-propanol, N-salicylidene-2-amino-1,1-di(2-methoxyphenyl)-1-propanol, -N-salicylidene-2-amino-1,1-di(2-ethoxyphenyl)-1-propanol, N-salicylidene-2-amino-1,1 -di(2-isopropoxyphenyl)-1 -propanol, N-salicylidene-2-amino-1,1 -di(2-n-butoxy-5-t-butylphenyl)-1 -propanol, N-salicylidene-2-amino-1,1-diphenyl-3-methyl-1-butanol,

N-salicylidene-2-amino-N-salicylidene-2-amino-N- salicylidene-2-amino-N-salicylidene-2-amino-. N-saliGylidene-2-amino-N-salicylidene-2-amino-
butane,
N-salicylidene-2-amino-
N-salicylidene-2-amino-
N-salicylidene-2-amino-
N-salicylidene-2-amino-
N-salicylidene-2-amino
N-salicylidene-2-amino
N-salicylidene-2-amino
pentanol,
N-salicylidene-2-amino N-salicylidene-2-aminO' N-salicylidene-2-amino-N-salicylidene-2-amino-

,1-di(3-methylphenyl)-3-methyl-1-butanol, J-di(4-methylphenyi)phe:i:/! B->Ti3thyl-1-butanol, ,1-di(2-methoxyphenyl) 3-inethyi-1-butanol, ,1-dip(2-ethoxthenyl)-3-methyl-1-butanol, ,1-di(2-isopropoxyphenyl)-3-methyM-propanol,' • , 1 -di(2-n-butoxy-5-t-butylphenyl-3-methyl-1 -
, 1 -diphenyl-4-methyl-1 -pentanol, ,1-di(3-methylphenyl)-4-nnethyl-1-pentanol, ,1-di(4-methylphenyl)-4-nnethyl-1-pentanol, ,1-di(2-methoxtphenylphenyl)-4-methyl-1-pentanol, ,1-di(2-ethoxyphenyl)-4-methyl-1-pentanol, ,1-di(2-lsopropoxyphenyl)-4-methyl-1-pentanol, ,1-dl(2-n-butoxy-5-t-butylphenyl)-4-methyl-1-
,1-dlphenyl-3-phenyl-1-propanol,
,1-di(3-methylphenyl)-3-phenyl-1-propanol,
,1-di(4-methylphenyl)-3-phenyl-1-propanol,
,1-dl(2-methoxylphenyl)-3-phenyl-1-propanol,
, 1 -di(2-ethoxylphenyl)-3-phenyl-1 -propanol,
,1-di(2-isopropoxylphenyl)-3-phenyl-1-propanol,

and
N-salicylidene-2-amino-1,1-di(2-n-butGxy-5-t-butylphenyl)-3-phenyl-1-propanol.
The optically active ethylenediamine alcohol compound includes a

compound of the formula (L-3):

Rm

"^ '^S-N HN-C U i)
wherein R represents a hydrogen atom or a lower alkyl group,
m represents an integer of 1 to 3, and
* represents an asymmetR1c carbon atom.
Specific compound of the optically active ethylenediamine compound (L-3) includes, for example, compounds wherein R is a hydrogen atom or a methyl group and m is an integer of 1 to 3.
Specific examples thereof includes bis[N-(2,4,6-tR1methylphenyl)methyl-[1R),(2R)-diphenylethylenediamine and an antipode thereof having (1S), (2S) configuration.
The asymmetR1c copper complex can be prepared by mixing the above copper compound with the optically active ligand in a solvent.
The solvent used herein includes, for example, aromatic hydrocarbons such as toluene and xylene and aliphatic halogenated hydrocarbons such as dichloromethane and dichloroethane. Furthermore, 2,5-dimethyl-2,4-hexadiene may also be used as the solvent.
The solvent is usually used in a 10-to 500-fold amount based on the weight of the copper compound.
The amount of the optically active ligand is usually from about 0.8 to 5 moi, and preferably from about 1 to 2 mol, per mol of the copper compound.
In view of the reaction yield, water is preferably excludes in the abo^e

reaction.
The above reaction temperature is not specifically limited The reaction is usually carR1ed out at the temperature within a range from about 0 to 50°C.
In the present invention, when the complex is prepared by using a divalent cppper compound, an object can be sufficiently attained even if the divalent copper compound is not reduced to form a monovalent copper compound by using a reducing agent such as phenylhydrazine.
The reaction between the copper compound and the optically active ligand is usually carR1ed out in the atmosphere of an inert gas such as argon and nitrogen.
The asymmetR1c copper complex can be obtained in such a manner, but the copper complex may be isolated or can be used as it is in the reaction between 2,5-dimethyl-2,4-hexadiene and the diazoacetate (I) without being isolated.
The amount of the asymmetR1c copper complex used in the reaction between 2,5-dimethyl-2,4-hexadiene and the diazoacetates (I) is usually from about 0.0001 to 0.01 mol, and preferably from about 0.0005 to 0.01 mol, per mol of the diazoacetate (I).
Specific method of reacting 2,5-dimethyl-2,4-hexadiene with the diazoacetate (I) in the presence of the asymmetR1c copper complex includes, for example, a method adding the diazoacetate (I) dissolved in a solvent to a mixture .of the asymmetR1c copper complex obtained as descR1bed above and 2,5- -dimethyl-2,4-hexadiene.
The solvent includes, for example, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform and carbon tetrachloR1de; aliphatic hydrocarbons such as hexane, heptane and cyclohexane; aromatic

hydrocarbons such as benzene, toluene and xylene; and esters such as methyl acetate and ethyl acetate; It is also possible to use 2,5-dimethyl-2,4-hexadiene as the solvent. These solvents can also be used in combination.
The solvent is usually used in a 1- to 30-fold amount, and preferably 5- to 20-fold amount, based on the weight of the diazoacetate (I).
The reaction between 2,5-dimethyl-2,4-hexadiene and the diazoacetate (I) is usually carR1ed out in an atmosphere of an inert gas such as argon and nitrogen.
2,5-dimethyl-2,4-hexadine is usually used in the amount of 1 to 50 mol, and preferably 5 to 30 mol, per mol of the diazoacetate (I).
In view of the reaction yield, water is preferably excluded in the above reaction.
The above reaction temperature is not specifically limited. The reaction can be carR1ed out at the temperature of not more than a boiling point of the solvent when using the solvent, but is usually carR1ed out at the temperature within a range from about 0 to 120°C, and preferably from 5 to 100°C.
The optically active chrysanthemic acid esters with considerably good puR1ty can be obtained in the above reaction by distilling off the solvent, but can be optionally isolated by a conventional method such as distillation and column chromatography, if necessary.
The ester residue of the optically active chrysanthemic acid esters obtained by the above reaction includes, for example, methyl, ethyl, n-propyl, i-propyl, i-butyl, t-butyl, pentyl, hexyl and cydohexyl groups.
The resulting optically active chrysanthemic acid esters can be converted into the corresponding chrysanthemic acid by contacting with an acid or an*

aqueous alkali solution (hydrolysis step). The amount of an alkali compound of the aqueous alkali solution used is usually from 1 to 20 mol, and preferably from 1 to 10 mol, per mol of the chrysanthemic acid esters.
Thechrysanthemic acid, particularly having a trans isomer ratio of not less than 50% and an optical puR1ty of not less than 10% e.e. thus obtained may be used in the optical resolution step as it is, or optionally used in combination with chrysanthemic acid enR1ched with the trans isomer.
Such chrysanthemic acid enR1ched with the trans isomer can be obtained, for example, by reacting (-)-cis chrysanthemic acid or chrysanthemic acid enR1ched with a (-)-trans isomer with t-butyl hydroperoxide and aluminum bromide in the presence of a toluene solvent (see JP5-37137B/1993). The trans isomer ratio of the chrysanthemic acid enR1ched with the trans isomer used is not less than 80%, and preferably not less than 85%.
According to the present invention, there can be produced chrysanthemic acid having more improved trans/cis ratio and more improved optical puR1ty in an industR1ally advantageous manner. In the above method, when using chrysanthemic acid having a trans isomer ratio of not less than 50% and an optical puR1ty of not less than 10% e.e., there cah be obtained an optically active chrysanthemic acid whose trans isomer ratio and optical puR1ty are improved.

Accordingly the present invention provides a method for producing an optically active chrysanthemic acid with improved trans isomer ratio and optical puR1ty, the said method compR1ses the steps of reacting chrysairthemic acid having a trans isomer ratio of not less than 50% and an optical puR1ty of not less than 10% e.e. with an optically active amine of the formula (A-2):

wherein R^ and R,, respectively represent a hydrogen atom, an aUcyl group, an iiralkyl group or an aryl group,
R3 represents an alkyl group having 1 to 6 carbon atoms; and an asymmetR1c carbon atom represented by " * " is either in S-configuration or R-configuration: wherein the amount of the optically active amine is from 0,2 to 1.2 moles per mole of the chrysanthemic acid and to optically resolve said chrysanthemic acid and recoveR1ng the said optically active chrysanthemic acid in a known manner.

resp6ct to trans isomer and 52% e.e. with respect to cis isomer, and a trans/cis ratio of 78/22, 228 g of toluene was added and dissolved with stirring. Then, 20.4 g ofi6)-1-phenyl-2-(p-tolyl)ethylamine (optical resolution agent) was added thereto and dissolved with heating. After cooling to room temperature, the deposited crystal was collected by filtration, washed with toluene and then dissolved in an aqueous 5% sodium hydroxide. After the optical resolution agent was extracted with toluene, the aqueous layer was acidified with aqueous 5% sulfuric acid and extracted with toluene. Then, toluene was distilled off to obtain 14.3 g of chrysanthemic acid having a trans/cis ratio of 81/19 and an optical purity of 98% e.e. with respect to (+)-trans isomer and 98% e.e. with respect to (+)-cis isomer (yield: 71.5%).
Example 2
To 30 g of chrysanthemic acid having an optical purity of 40% e.e. with respect to (+)-trans isomer and 1.3 % e.e. with respect to (+)-cis isomer and a trans/cis ratio of 77/23, 210 g of toluene was added and dissolved with stirring. Then, 24.7 g of (S)-1-phenyl-2-(p-tolyl)ethylamine (optical resolution agent) was added to the solution and dissolved with heating. After cooling to room temperature, the deposited crystal was collected by filtration, washed with toluene and then dissolved in an aqueous 5% sodium hydroxide. After the optical resolution agent was extracted with toluene, the aqueous layer was acidified with aqueous 5% sulfuric-acid and extracted with'toluene. Then, the toluene was distilled off to obtain 15.1 g of chrysanthemic acid having a trans/cis ratio of 85/15 and an optical purity of 96% e.e with respect to (+)-trans isomer and 95 % e.e. with respect to (+)-cis isomer, (yield: 50.3%).
Example 3

18.05 mg (0.05 mmol) of copper trifluoromethanesulfonate, 19.9 mg (0.055 mmol) of bis[2-[4(R)-phenyl-5,5-dimethyl-2-nxazoline]]methane and 5 ml of n-butyl chloride were charged in a 50 ml Schlenk' s tube wherein the atmosphere is substituted with nitrogen, followed by stirring at room temperature for 10 minutes. After 30.0 g (275 mmol) of 2,5-dimethyl-2,4-hexadiene was further added, 5.70 g (50 mmol) of ethyl diazoacetate was added dropwise at 50°C over 2 hours. After the completion of the dropwise addition of ethyl diazoacetate, the mixture was further stirred at 50°C for 1 hour. The amount of chrysanthemic acid ethyl ester formed was determined by gas chromatography. As a result, it was 8.43 g and the yield was 86.0% based on ethyl diazoacetate and, furthermore, the trans/cis ratio was 72/28. After 2,5-dimethyl-2,4-hexadiene (boiling point: 51°C/30 mmHg) was distilled off from the reaction mixture, 1 g of the concentrated solution was taken out. Then, 10 ml of an aqueous IN sodium hydroxide solution and 5 ml of ethanoi were added and alkali hydrolysis was performed by stirring at 100°C for 1 hour. The resulting chrysanthemic acid was reacted with l-menthol and the formed diastereomer ester was analyzed by gas chromatography. As a result, the optical purity of the (+)-trans isomer was 60 % e.e., whereas, the optical purity of the (+)-cis isomer was 27 % e.e.
Furthermore, chrysanthemic acid obtained by hydrolyzing the ethyl chrysanthemate with 1N sodium hydroxide was mixed with racemic chrysanthemic acid enriched with trans isomer (trans/cis ratio: 95/5) in a weight • ratio of 6:4. 104.5 g of toluene was then added to 10.0 g of the mixed chrysanthemic acid, and the mixture was dissolved with stirring. Then, 7.48 g of (S)-1-phenyl-2-(p-tolyl)ethylamine (optical resolution agent) was added to the solution and dissolved with heating. After cooling to room temperature, the

deposited crystal was collected by filtration, washed with toluene and then dissolved in anaqueous 5% sodium hydroxide. After the-agent for optical resolution w^^s extracted with toluene, the aqueous layer was acidified with aqueous 5% sulfuric acid and extracted with toluene to obtain 4.19 g of chrysanthemic acid.having a trans/cis ratio of 87/13 and an optical purity of 95% e.e. with respect to (+)-trans isomer and 97% e.e. with respect to (+)-cis isomer (yield: 141.9%).
Example 4
22,6 mg (0.05mmol) of copper complex prepared from 9.98 mg (0.05 mmol) of copper acetate-mono hydrate and 21.5 mg of (R)-N-salicylidene-2-amino-1,1-di(2-methoxyphenyl)propanol, and 6.0 g (55 mmol) of 2,5-dimethyl-2,4-hexadiene were charged in a 50 ml Schlenk' s tube wherein the atmosphere is substituted with nitrogen, followed by the addition of 5.4 mg of phenylhydrazine, and 1.14 g (10 mmol) of ethyl diazoacetate was added dropwise at 80°C over 2 hours. After the completion of the dropwise addition ofethyl diazoacetate, the mixture was further stirred at 25°C for 1 hour. The amount of chrysanthemic acid ethyl ester formed was determined by gas chromatography. As a result, it was 1.76 g and the yield was 90.0% based on ethyl diazoacetate and, furthermore, the trans/cis ratio was 58/42. After 2,5-dimethyl-2,4-hexadiene (boiling point: 51°C/30 mmHg) was distilled off from the reaction mixture, 1 g of the concentrated solution was taken out. Then, 10 ml of an aqueous 1N sodium hydroxide solution and 5 ml of ethanol were added and alkali hydrolysis was performed by stirring at 100°C for 1 hour. The resulting chrysanthemic acid was reacted with l-menthol and the formed diastereomer was analyzed by gas chromatography. As a result, the optical purity of the (+)-trans isomer was 63 % e.e., whereas, the

.
. Furthermore, ehrysanthemic acid obtained by hydrolyzing the ethyl . -. chrysanthemate with 1N sodium hydroxide was mixed with racemic c - ^ ehrysanthemic acid enriched with trans isomer (trans/cis ratio: 95/5) in a weight ratio of 4:6.. 106.2g of toluene was then added to 10.0 g of ehrysanthemic add,.. and the mixture was dissolved with stirring. Then, 7.40 g of (S)-1-phenyl-2-(p-tolyl)ethylamine (optical resolution agent) was added to the solution and dissolved with heating. After cooling to room temperature, the deposited crystal was collected by filtration, washed with toluene and then dissolved in an aqueous 5% sodium hydroxide. After the optical resolution agent was extracted with toluene, the aqueous layer was acidified with aqueous 5% sulfuric acid and extracted with toluene to obtain ehrysanthemic acid having a trans/cis ratio of 81/19 and an optical purity of 99% e.e. with respect to (+)-trans isomer and 96% e.e. with respect to (+)-cis isomer(yield: 40.2%).
Example 5
19.64 mg (0.05 mmol) of a copper complex prepared from 9.98 mg (0.05 mmol) of copper acetate monohydrate and 18.23 mg (0.055mmol) of (R)-N-sallcylidene-2-amino-1,1-diphenylpropanol, and 6.0 g (55 mmol) of 2,5-dimethyl-2,4-hexadiene were charged in a 50 ml Schlenk' s tube wherein the atmosphere is substituted with nitrogen. After 5.4 mg of phenylhydrazine was further added, 1.14 g (10 mmol) of ethyl diazoaeetate was added dropwise at 50°C over 2 hours. After the completion of the dropwise addition of ethyl diazoaeetate, the mixture was further stirred at 25°C for 1 hour. The amount of ehrysanthemic acid ethyl ester formed was determined by gas chromatography. As a result, it was 1.52 g and the yield was 77.7% based on ethyl diazoaeetate and, furthermore, the

trans/cis ratio was 61/39. After 2,5-dimethyl-2,4-hexadiene (boiling point: 51°C/30 mmHn) was distilled off from the reaction mixture,-1 g of the concentrated solution was taken out. Then, 10 ml of an aqueous IN sodium hydroxide solution and 5 ml of ethanol were added and alkali hydrolysis was performed by stirring at 100°C for 1 hour. The resulting chrysanthemic acid was reacted with l-menthol and the formed diastereomer ester was analyzed by gas chromatography. As a result, the optical purity of the (+)-trans isomer was 69% e.e., whereas, the optical purity of the (+)-cis isomer was 68% e.e.
Furthermore, chrysanthemic acid obtained by alkali hydrolysis is mixed with racemic chrysanthemic acid enriched with trans isomer (trans/cis ratio: 95/5) in a weight ratio of 46:54. Toluene is then added in an about 10-fold amount based on chrysanthemic acid, and the mixture is dissolved with stirring. Then, (S)-1-phenyl-2-(p-tolyl)ethylamine (optical resolution agent) was added in the amount of about 0.69 mol per mol of chrysanthemic acid and dissolved with heating. After cooling to room temperature, the deposited crystal is collected by filtration, washed with toluene and then dissolved in an aqueous 5% sodium hydroxide. After the agent for optical resolution is extracted with toluene, the aqueous layer is acidified with aqueous 5% sulfuric acid and extracted with toluene to obtain chrysanthemic acid having a trans/cis ratio of about 78/22 and an optical purity of about 95% e.e. with respect to (+)-trans isomer and 99%e.e. with respect to that (+)-cis isomer (yield: about 46%).
Example 6
According to the same manner as that described in Example 5 except for using 32.47 mg (0.05 mmol) of a copper complex prepared from 9.98 mg (0.05 mmol) of copper acetate monohydrate and 32.33 mg (0.055 mmol) of (R)-N-

salicylidene-2-amino-1,1-di(2-n-butoxy-5-t-butylphenyl)propanol in a 50 ml Schlenk' s tube wherein the atmosphere is svibstituted with nitrogen, the reaction was performed. The amount of chrysanthemic acid ethyl ester formed was determined by gas chromatography. As a result, it was 1.64 g and the yield was 8v3.Z% based on ethyl diazoacetate and, furthermore, the trans/cis ratio-was 57/43. After 2,5-dimethyl-2,4-hexadiene (boiling point: 51°C/30 mmHg) was distilled off from the reaction mixture, 1 g of the concentrated solution was taken out. Then, 10 ml of an aqueous 1N sodium hydroxide solution and 5 ml of ethanol were added and alkali hydrolysis was performed by stirring at 100°C for 1 hour. The resulting chrysanthemic acid was reacted with l-menthol and the formed diastereomer was analyzed by gas chromatography. As a result, the optical purity of the (+)-trans isomer was 86% e.e., whereas, the optical purity of the (+)-cis isomer was 84% e.e.
Furthermore, chrysanthemic acid obtained by alkali hydrolysis is mixed with racemic chrysanthemic acid enriched with trans isomer (trans/cis ratio: 95/5) in a weight ratio of 51:49. Toluene is then added in an about 10-fold amount based on chrysanthemic acid, and the mixture is dissolved with stirring. Then, (S)-1-phenyl-2-(p-tolyl)ethylamine (optical resolution agent) is added in the amount of about 0.68 mol per mol of chrysanthemic acid and dissolved with heating. After cooling to room temperature, the deposited crystal is collected by filtration, washed with toluene-and then dissolved in an aqueous 5% sodium hydroxide. After the agent for optical resolution is extracted with toluene, the aqueous layer is acidified with aqueous 5% sulfuric acid and extracted with toluene to obtain chrysanthemic acid having a trans/cis ratio of about 72/28 and an optical purity of the (+)-trans isomer is about 95% e.e. and that of (+)-cis isomer is about 99*^0 e.e.

(yield: about 51%).
Comparative Example 1
To 100 g of a racemic chrysanthemic acid (trans/cis ratio: 75/25), 390g of toluene was added, and the mixture was dissolved with stirring. Then, 47.0g of • (S)-1-phenyl-2-(p-tolyl)ethylamine (optical resolution agent) was added and dissolved with heating. After cooling to room temperature, the deposited crystal was collected by filtration, washed with toluene and then dissolved in an aqueous 5% sodium hydroxide. After the agent for optical resolution was extracted with toluene, the aqueous layer was acidified with aqueous 5% sulfuric acid and extracted with toluene to obtain 20.8 g of chrysanthemic acid having a trans/cis ratio of 80/20 and an optical purity of the (+)-trans isomer was 96% e.e. and that of (+)-cis isomer was 98% e.e.(yield: 20.8%).
Example 7
18.05 mg (0.05 mmol) of trifluoromethanesulfonic acid, 19.9mg(0.055mmol), bis[2-[4-(R)-phenyl-5,5-dimethyl-2-oxazoline]]methane and 5 ml of n-butyl chloride were charged in a nitrogen charged 50 ml Schlenk's tube, and stirred for 10 min at room temperature. After 6.0 g (55 mmol) of 2,5-dimethyl-2,4-hexadiene were added thereto, 1.41 g (10 mmol) of t-butyl diazoacetate was added dropwise at 25°C over 1 hour. The amount of chrysanthemic acid t-butyl ester formed was determined by gas chromatography. As a result, it was 1.86 g and the yield was 83.1% based on t-butyl diazoacetate and, furthermore, the trans/cis ratio was 85/15. After 2,5-dimethyl-2,4-hexadiene (boiling point: 51°C/30 mmHg) was distilled off from the reaction mixture, the concentrated solution was subjected to luquid chromatography to measure the otpical activity, which revealed the optical purity of (+)-trans isomer was 86%e.e. and that of (+)-cis isomer was 67%fe".e.

Then, trans-rich racemic chrysanthemic obtained by decomposing the t-butyl chrysanthemate with trifluoroacetic acid is mixed wlth-racemic chrysanthemic acid of which trans/cis ratio is 95/5 in a weight ratio of 60:40, and 10-fold amount of toluene to the chrysanthemic acid is added to the mixture, * stirred ,and dissolved. Then, 1.0 mole of (S)-a-(1-naphthyl)-ethylamine, as a resolution agent, and 8% by weight of water per chrysanthemic acid are added thereto and the resulting mixture is heated to dissolved. After cooling the mixture to room temperature, deposited crystals are collected by filtration, washed with toluene, then dissolved in aqueous 5% sodium hydroxide and extracted with toluene. Separated water layer is acidified with aqueous 5% sulfuric acid and extracted with toluene to give chrysanthemic acid with a trans/cis ratio of about 98/2 and optical purity of the (+)-trans isomer is about 96%e.e. and that of (+)-cis isomer is about 57%e.e. in a yield of about 57%.
Example 8
19.64 mg (O.OSmmol) of copper complex prepared from 9.98 mg (0.05 mmol) of copper acetate monohydrate, and 18.23 mg of (R)-N-salicylidene-2-amino-1,1-diphenylpropanol, and 6.0g(55mmol) of 2,5-dimethyl-2,4-hexadiene were charged in a 50 ml Schlenk' s tube wherein the atmosphere was replaced with nitrogen, and then 5.4 mg of phenylhydrazine. 1.14 g (10 mmol) of ethyl diazoacetate was added dropwise at 50°C over 2 hours and further stirred for 1 hour at 25°C. The amount of chrysanthemic acidethyl ester formed was determined by gas chromatography. As a result, it was 1.52 g and the yield was 77.7% based on t-butyl diazoacetate and, furthermore, the trans/cis ratio was 31/39. After 2,5-dimethyi-2,4-hexadiene (boiling point: 51°C/30 mmHg) was listilled off from the reaction mixture. Then, 10 ml of an aqueous IN sodium

hydroxide solution and 5 ml of ethanol were added to 1 g of the concentrate and alkali hydrolysis was performed by stirring at 100°C for 1 hour. The obtained chrysanthemic acid was jDsacted with l-menthol, and the resulted diastereomer was analyzed by gas chromatography, which showed the optical purity of (+)-trans isomer was 69%e.e. and that of (t)-cis isomer was 68%e.e.
Then, the chrysanthemic acid obtained by the alkali hydrolysis is mixed with trans-rich racemic chrysanthemic acid of which trans/cis ratio is 95/5 is mixed with the (+)-trans isomer in a weight ratio of 43:57, and 7-fold amount of toluene to the chrysanthemic acid is added to the mixture, stirred and dissolved. Then, 1.0 mole of (S)-α -(1-naphthyl)-ethylamine, as a resolution agent, and 8% by weight of water to chrysanthemic acid are added thereto and the resulting mixture is heated to dissolved. After cooling the mixture to room temperature, deposited crystals are collected by filtration, washed with toluene, then dissolved in aqueous 5% sodium hydroxide and extracted with toluene. Separated water layer is acidified with aqueous 5% sulfuric acid and extracted with toluene to give chrysanthemic acid with a trans/cis ratio of about 98/2 and optical purity of about 96%e.e with respect to (+)-trans isomer in a yield of about 40%.
Comparative Example 2
To 16.3 g of a racemic chrysanthemic acid (trans/cis ratio: 79/21), 65.0g of oluene was added, and the mixture was dissolved with stirring. Then, 16.0 g of S)-
resolution was extracted with toluene, the aqueous layer was acidified with aqueous 5% sulfuric acid and extracted with toluene to obtain 4.13 g of chrysanethemic acid having a trans/cis ratio of 98/2 and an optical purity of 97% e.e. with respect to (+)-trans isomer and 73% e.e. with respect to (+)-cis isomer (yield:25.3%).
An optically active chrysanthemic acid to be resolved in additional Example below contains only (69.5/50)=L.4 times (+)-traas-isomer, which usually is a biologically effective form, as compared to a racemic compound in Comparative Example 2. Yet, a yield ratio between the two cases is (47.7/25.3)=1.9. Thus the yield increase in terms of a ratio of the yields is unexpectedly higher than is expected firom a ratio of (+)-trans-isomer content in the chrysanthemic acids to be resolved.

Example 9
To 9.41 g of chrysanthemic acid (trans/cis ratio: 78/22, tratis-isomer: 39%e.e., cis-isomer: 42% e.e.), were added 85.1 g of toluene and 0.8 g of water and the resulting mixture was dissolved under stirring. Then, 11.91 g of (S) - a -(l-ninthly)ethylamine (optical resolution agent) was added thereto and dissolved with heating. After cooling to a room, temperature, the deposited crystal was collected by filtration, washed with toluene and then dissolved in an aqueous 5% sodium hydroxide. After the optical resolution agent was extracted with toluene, the aqueous layer was acidified with aqueous 5% sulfuric acid and extracted with toluene and evaporated to obtain 4.49 g of chrysanthemic acid having a trans/cis ratio of 98/2 and an optical purity of 98% e.e. with respect to (+)-trans isomer and 28% e.e. with respect to (+)-cis isomer (yield: 47.7%).
This application has been divided out of Indian patent application no. 105/MAS/99 which relates to a method of producing an optically active chrysanthemic acid with improved trans-isomer ratio wherein chrysanthemic acid having less trans-isomer ratio is treated with an optically active amine of the formula given below:-

WE CLAIM;
1. A method for producing an optically active chrysanthemic acid with
improved trans isomer ratio and optical purity, the said method comprises the
steps of reacting chrysanthemic acid having a trans isomer ratio of not less than
50% and an optical purity of not less than 10% e.e. with an optically active amine
of the formula (A-2):

wherein R1 and R2 respectively represent a hydrogen atom, an alkyl group, an aralkyl group or an aryl group,
R3 represents an alkyl group having 1 to 6 carbon atoms; and an asymmetric carbon atom represented by " ♦ " is either in S-configuration or R-configuration: wherein the amount of the optically active amine is from 0.2 to 1.2 moles per mole of the chrysanthemic acid and to optically resolve said chrysanthemic acid and recovering the said optically active chrysanthemic acid m a known manner.
2. The method according to claim 1, wherein chrysanthemic acid has a trans
isomer ratio of 60-95% and an optical purity of 30-90% e.e.

3. The method according to claim 1, wherein a chrysanthemic acid
having optical purity of not less than 20% e.e is reacted with an optically
active amine.
4. A method for producing an optically active chrysanthemic acid
substantially as described hereinabove.

Documents:

197-mas-2001 abstract.pdf

197-mas-2001 claims.pdf

197-mas-2001 correspondence-others.pdf

197-mas-2001 correspondence-po.pdf

197-mas-2001 description(complete).pdf

197-mas-2001 form-1.pdf

197-mas-2001 form-26.pdf

197-mas-2001 form-3.pdf

197-mas-2001 form-5.pdf

197-mas-2001 others.pdf

197-mas-2001 petition.pdf

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Patent Number

191950

Indian Patent Application Number

197/MAS/2001

PG Journal Number

30/2009

Publication Date

24-Jul-2009

Grant Date

19-Aug-2004

Date of Filing

05-Mar-2001

Name of Patentee

SUMITOMO CHEMICAL COMPANY LIMITED

Applicant Address

5-33 KITAHAMA 4 CHOME CHUO-KU OSAKA 541 8550.

Inventors:

#	Inventor's Name	Inventor's Address
1	MAKOTO ITAGAKI	1-9-1-402 TAMAGAWA TAKATSUKI-SHI OSAKA.
2	GOHFU SUZUKAMO	19-10-1008 SHINASHIYAKAMI, SUITA-SHI, OSAKA
3	KAZUAKI SASAKI	4-31-861-126 HIGASHI-CHO, MISAWA-SHI, AOMORI
4	KUNIHIKO FUJITA	4-1-1-17, UMAMIMINAMI, KORYO-CHO, KITAKATSURAGI-GUN, NARA.

PCT International Classification Number

C07B 55/00

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	10-016787	1998-01-29	Japan