JPH11279111A - Method for producing optically active chrysanthemic acid - Google Patents

Abstract

(57) [Problem] To provide a process for producing optically active chrysanthemic acid with improved trans-ratio and optical purity. SOLUTION: Trans isomer ratio is 50% or more and optical purity is 1
A process for producing optically active chrysanthemic acid, which comprises optically resolving chrysanthemic acid having an ee of 0% or more by the action of an optically active organic amine.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for producing optically active chrysanthemic acid, that is, an optically active cyclopropanecarboxylic acid derivative.

[0002]

BACKGROUND OF THE INVENTION Optically active cyclopropanecarboxylic acid derivatives are important compounds as intermediates for pharmaceuticals and agricultural chemicals. For example, (+)-2,2-dimethyl-3- (2-methyl-1-propenyl) cyclopropanecarboxylic acid, known as primary chrysanthemic acid (hereinafter simply referred to as chrysanthemic acid), is a synthetic pyrethroid. It constitutes the acid component of the insecticide (ester). Trans-esters are stronger than cis-esters in insecticidal activity, and esters composed of (+)-trans-primergic acid or (+)-trans-isomer containing (+)-cis-isomer are particularly excellent. Insecticidal effect. Therefore, it is very important to industrially produce chrysmic acid rich in (+)-trans form or (+)-trans form. Hitherto, as a method for producing an optically active chrysanthemic acid derivative by a synthetic method, for example, an optically resolving agent which is an optically active amine to primary chrysanthemic acid which is rich in (±) -trans form or trans form is used. A method for obtaining an optically active chrysanthemic acid by acting is known (JP-B-46-20382, JP-B-54-371).
No. 30, JP-A-49-109344, and JP-B-51-23497). However, such an optical resolution method has a low yield of optically active chrysanthemic acid and is not always satisfactory. As a method for asymmetrically synthesizing optically active chrysanthemic acid, a method of reacting 2,5-dimethyl-2,4-hexadiene with diazoacetic acid ester in the presence of an optically active salicylideneamino alcohol copper complex catalyst (Pure & Appl. Chem., Vol. 57, No. 12, 1839,
1985) and a method of reacting in the presence of an asymmetric copper complex using optically active bis [2- (4,5-diphenyl-1,3-oxazolinyl)] methane as a ligand (Tetrahedron Lett., 32, 737)
3 (1991)) and a method of reacting in the presence of an asymmetric copper complex using an optically active diamine (Tetrahedron Lett., 35, 7).
985 (1994) and the like are known. However, in these methods, a relatively high reaction result is obtained when an expensive ester residue such as menthyl diazoacetate is used, but a diazoacetate having a less expensive lower alkyl group is used. On the other hand, both trans / cis selectivity and optical purity were not sufficiently satisfactory.

[0003]

The inventors of the present invention have made various studies, and as a result, have found that when producing optically active chrysanthemic acid, it is optically enriched with one isomer, for example, the (+)-isomer. When purified by crystallization using a specific optical resolving agent, (+)-
I found that I could get my body. In this case, it was also found that when the trans-form ratio was 50% or more, chrysanthemic acid having a more excellent trans-form ratio was obtained, and the present invention was completed. That is, the present invention provides a trans-form ratio of 50
The present invention provides a method for producing optically active chrysanthemic acid with improved optical purity, characterized in that an optically active organic amine is allowed to act on chrysanthemic acid having an optical purity of not less than 10% ee and an optical purity of not less than 10% ee. . When chrysanthemic acid having a trans-form ratio of 50% or more and an optical purity of 10% ee or more is used in the above production method, an optically active chrysanthemic acid having an improved trans-form ratio and optical purity can be obtained.

[0006] Chrysanthemic acid having an optical purity of 10% ee or more (optically active chrysanthemic acid) may be procured by any method, but can be produced, for example, as follows. 2,5-dimethyl-2,4 in the presence of an asymmetric copper complex
-Reaction of hexadiene with a diazoacetic acid ester represented by the general formula (5) N ₂ CHCO ₂ R ₇ (5) wherein R ₇ represents an alkyl group or a cycloalkyl group having 1 to 6 carbon atoms. Then, an optically active chrysanthemic acid ester can be produced by subjecting the same to an alkali or acid decomposition (decomposition step).

Next, when the optically active chrysanthemic acid obtained above is optically resolved using an optically active organic amine, the optically active organic amine is represented by the general formula (1) (Wherein, R ₁ and R ₂ each represent a hydrogen atom, an alkyl group, an aralkyl group or an aryl group, and X and Y each represent a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group. Or an optically active organic amine represented by the general formula (2): (Wherein, R _1, R ₂ are each a hydrogen atom, an alkyl group, an aralkyl group or an aryl group, R ₃ is a carbon number 1 -
6 represents an alkyl group. * Represents an asymmetric carbon. )) Or an optically active organic amine represented by the general formula (3) (Wherein, R ₄ is naphthyl group, a cyclohexyl group; represents or halogen, nitro, lower alkyl group or an optionally substituted phenyl group by lower alkoxy, R ₅
Represents a lower alkyl group or a benzyl group optionally substituted with a lower alkyl group. R _6, when R ₅ is a lower alkyl group p- hydroxyphenyl group or a 2-hydroxy-3 represents a lower alkoxyphenyl group, R ₅ is a benzyl group which may be substituted with a lower alkyl group In the case, it represents a p-hydroxyphenyl group. * Represents an asymmetric carbon. ) Or an optically active organic amine represented by the general formula (4) (In the formula, R ₁ and R ₂ each represent a hydrogen atom, an alkyl group, an aralkyl group, or an aryl group. * Represents an asymmetric carbon atom.)

[0006]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be described below in detail.
First, in the presence of an asymmetric copper complex, 2,5-dimethyl-2,4
-Reaction of hexadiene with a diazoacetic acid ester represented by the general formula (5) N ₂ CHCO ₂ R ₇ (5) wherein R ₇ represents an alkyl group or a cycloalkyl group having 1 to 6 carbon atoms. A more efficient method for producing optically active chrysanthemic acid by producing an optically active chrysanthemic acid ester (cyclopropanation step) and subjecting it to alkali or acid decomposition (decomposition step) will be described. As the alkyl group of the diazoacetic acid ester used in the cyclopropanation step,
For example, methyl, ethyl, n-propyl, isopropyl,
Examples include n-butyl, isobutyl, t-butyl, pentyl, hexyl, and cyclohexyl groups.

The asymmetric copper complex used in the cyclopropanation step is prepared from a copper compound and an optically active organic compound (hereinafter, the optically active organic compound is referred to as an optically active ligand). As the copper compound, for example, copper naphthenate, copper trifluoromethanesulfonate, copper acetate,
Examples thereof include monovalent or divalent copper compounds such as copper bromide and copper chloride. These can be used alone or in combination of two or more.

Examples of the optically active ligand include optically active bisoxazoline compounds, optically active salicylideneamino alcohol compounds, optically active diamine compounds, optically active semicholine compounds, optically active camphor compounds and the like. However, preferred are an optically active salicylideneamino alcohol compound, an optically active bisoxazoline compound, and an optically active ethylenediamine compound.

The optically active bisoxazoline compound has the general formula (6) (Wherein, R ₈ and R ₉ are different and each represent an optionally substituted phenyl group or a hydrogen atom, and R ₁₀ and R ₁₁ represent a hydrogen atom, an alkyl group, a cycloalkyl group, and an optionally substituted phenyl group. Or an aralkyl group;
₁₀ and R ₁₁ may combine to form a cyclic alkylene group. R ₁₂ represents a hydrogen atom or an alkyl group. ).

The optically active bisoxazoline compound (6) includes, for example, 2,2'-methylenebis
[(4R) -phenyl-5,5-dimethyloxazoline], 2,2′-methylenebis [(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} (4
R) -Phenyloxazoline-5,1'-cyclohexane}], 2,2'-methylenebis [spiro} (4R)-
Phenyloxazoline-5,1′-cycloheptane}], and (4R) in each of the above compounds is (4
And the like.

The optically active salicylideneamino alcohol compound has the general formula (7) (Wherein, R ₁₃ and R ₁₄ each represent an alkyl group, an aralkyl group or an aryl group, and Z represents a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, an aralkyl group or an aryl group. It means there is.)
It is a compound shown by these.

R ₁₃ of the optically active salicylidene amino alcohol compound (7) includes, for example, methyl, ethyl, isopropyl, isobutyl, t-butyl, benzyl and phenyl groups, and R ₁₄ includes, for example, methyl , Ethyl, isopropyl, isobutyl, t-butyl,
Examples include benzyl or a phenyl group which may be substituted with an alkyl group, a halogen atom or an alkoxy group.

Specific examples of the compound represented by the general formula (7) include the following, and either (R) or (S) form thereof may be used. That is, N-salicylidene-2-amino-1,1-diphenyl-1-propanol, N-salicylidene-2-amino-1,1-di (3-methylphenyl) -1-propanol, N-salicylidene-2-propanol 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-methoxyphenyl) -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-
1,1-di (3-methylphenyl) -3-methyl-1-butanol,
N-salicylidene-2-amino-1,1-di (4-methylphenyl) -3-methyl-1-butanol, N-salicylidene-2-amino-1,1-di (2-methoxyphenyl) -3- Methyl-1-butanol, N-salicylidene-2-amino-1,1-di (2-methoxyphenyl) -3-methyl-1-butanol, N-salicylidene-2-amino-1,1-di (2- Isopropoxyphenyl) 3-methyl-1-propanol, N-salicylidene-2-amino-1,1-di (2-n-butoxy-5-t-butylphenyl)
-3-methyl-1-butanol, N-salicylidene-2-amino-
1,1-diphenyl-4-methyl-1-pentanol, N-salicylidene-2-amino-1,1-di (3-methylphenyl) -4-methyl-1-pentanol, N-salicylidene-2- Amino-1,1-
Di (4-methylphenyl) -4-methyl-1-pentanol, N-
Salicylidene-2-amino-1,1-di (2-methoxyphenyl) -4-methyl-1-pentanol, N-salicylidene-2-
Amino-1,1-di (2-methoxyphenyl) -4-methyl-1-
Pentanol, N-salicylidene-2-amino-1,1-di (2
-Isopropoxyphenyl) -4-methyl-1-pentanol, N-salicylidene-2-amino-1,1-di (2-n-butoxy-5-t-butylphenyl) -4-methyl-1-pen Tanol, N-salicylidene-2-amino-1,1-diphenyl-3-phenyl-1-propanol, N-salicylidene-2-amino-
1,1-di (3-methylphenyl) -3-phenyl-1-propanol, N-salicylidene-2-amino-1,1-di (4-methylphenyl) -3-phenyl-1-propanol, N- Salicylidene-
2-amino-1,1-di (2-methoxyphenyl) -1-propanol, N-salicylidene-2-amino-1,1-di (2-methoxyphenyl) -3-phenyl-1-propanol, N- Salicylidene-2-amino-1,1-di (2-isopropoxyphenyl) -3-phenyl-1-propanol, N-salicylidene-2
-Amino-1,1-di (2-n-butoxy-5-t-butylphenyl) -3-phenyl-1-propanol and the like.

The optically active ethylenediamine compound has the general formula (8) (Wherein, R represents a hydrogen atom or a lower alkyl group;
Represents an integer of 1 to 3. * Represents an asymmetric carbon. ).

Optically active ethylenediamine compound (8)
Specific examples of the compound include those in which R is a hydrogen atom, a methyl group, or the like, and m is an integer of 1 to 3.

Specific examples of such compounds include bis
[N- (2,4,6-trimethylphenyl) methyl- (1R), (2R) -diphenylethylenediamine, and (1R), 2 (R) are (1S), (2
And the like.

In preparing the asymmetric copper complex, it can be obtained by mixing the copper compound and an optically active ligand in a solvent. Solvents used here are toluene, aromatic hydrocarbons such as xylene, dichloromethane,
And aliphatic halides such as dichloroethane. Also, 2,5-dimethyl-2,4-hexadiene may be used as a solvent. The amount of the solvent used is usually about 10 to 500 times the weight of the copper compound.

The amount of the optically active ligand to be used is generally about 0.8 to 5 times, preferably about 1 to 2 times the molar amount of the copper compound. In the above reaction, the absence of water is preferable in terms of the reaction yield. The reaction temperature is not particularly limited, but is usually carried out in the range of about 0 to 50 ° C. In the present invention, when the complex is prepared using a divalent copper compound, the objective can be sufficiently achieved without reducing the complex to a monovalent copper compound with a reducing agent such as phenylhydrazine. When reacting an optically active bisoxazoline compound (6) with a copper compound,
It is performed under an atmosphere of an inert gas such as argon and nitrogen.

Thus, an asymmetric copper complex is obtained. The copper complex may be isolated or may be isolated without isolation from 2,5-dimethyl-2,4-hexadiene and diazoacetate (1). It can be used as it is for the reaction. 2,
The amount of the asymmetric copper complex used in the reaction between 5-dimethyl-2,4-hexadiene and diazoacetates (1) is usually 0.0001 in terms of copper compound relative to diazoacetates (1). It is about 0.01 equivalent times, preferably about 0.0005 to 0.01 equivalent times.

In the presence of an asymmetric copper complex, 2,5-dimethyl-
As a specific method of reacting 2,4-hexadiene with diazoacetic acid esters (1), for example, the asymmetric copper complex obtained as described above and 2,5-dimethyl-2,
A method of adding a diazoacetic acid ester (1) dissolved in a solvent to a mixture of 4-hexadiene is exemplified. Here, examples of the solvent include halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform and carbon tetrachloride; aliphatic hydrocarbons such as hexane, heptane and cyclohexane; and aromatic hydrocarbons such as benzene, toluene and xylene. Esters such as hydrogen, methyl acetate, and ethyl acetate are exemplified, and 2,5-dimethyl-2,4-hexadiene can be used as a solvent. These can also be used as a mixture. The amount of the solvent used is usually about 1 to 30 times the weight of the diazoacetates (1),
It is preferably about 5 to 20 times by weight.

When reacting 2,5-dimethyl-2,4-hexadiene with diazoacetic esters (1),
Usually, it is carried out under an atmosphere of an inert gas such as argon or nitrogen. 2,5-Dimethyl-2,4-hexadiene is generally used in an amount of about 1 to 50 moles, preferably about 5 to 30 moles, based on the diazoacetates. In the above reaction, the absence of water is preferable in terms of the reaction yield. The reaction temperature is not particularly limited, and when a solvent is used, the reaction can be carried out at a temperature equal to or lower than the boiling point of the solvent, but is usually about 0 to 120 ° C, preferably 5 to 100 ° C.
It is performed at about ° C. The optically active chrysanthemic acid esters obtained in the above reaction can be obtained with considerably excellent purity by distilling off the solvent.However, if necessary, they can be isolated by ordinary methods such as distillation and column chromatography. it can.

The ester residue of the optically active chrysanthemic acid ester obtained by the above reaction includes, for example, methyl, ethyl, n-propyl, i-propyl, i-butyl, t-butyl,
Pentyl, hexyl, cyclohexyl and the like can be mentioned.

The obtained optically active chrysanthemic acid esters are hydrolyzed by acid decomposition or an aqueous alkali solution (decomposition step).
This can be converted to the corresponding chrysanthemic acid. The amount of the alkali compound used in the aqueous alkali solution is usually about 1 to 20 mol times, preferably 1 to 1 mol times, relative to the chrysanthemum esters.
It is used about 0 mole times.

The thus obtained chrysanthemic acid having a trans-isomer ratio of 50% or more and an optical purity of 20% ee or more may be used as it is in the next optical resolution step. May be used as a mixture. Such trans-rich racemic chrysanthemic acid is obtained, for example, by reacting (-)-cis chrysanthemic acid or (-)-trans-rich chrysanthemic acid with t-butyl hydroperoxide and aluminum bromide in a toluene solvent. (See Japanese Patent Publication No. 5-37137). The trans-rich ratio of trans-rich racemic chrysanthemic acid used is 80% or more, preferably 85% or more.

The optically active chrysanthemic acid thus obtained is reacted with an optically active amine (resolving agent) represented by the above general formula (1), (2), (3) or (4). By performing optical resolution, the trans / cis ratio and the optical purity can be further improved. The more preferred trans-isomer ratio in the case of performing optical resolution is 60-95%, and the optical purity is 15-90% ee.

Examples of the optically active amine include, for example, 1
-Phenyl-2- (p-tolyl) ethylamine, α-
(1-naphthyl) -ethylamine, α- (2-naphthyl) -ethylamine, 1-phenylethylamine, erythro-α, β-diphenyl-β-hydroxyethylamine, N-methylephedrine, N- (2,2,2- Trichloro-1-formamidoethyl) piperidine, 2-
Benzylamino-1-butanol, ephedrine, cis-N-benzyl-2- (hydroxymethyl) cyclohexylamine, 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-phenylpropylamine N- (p-hydroxybenzyl) -2-methyl-1-phenylpropylamine, N-
(2-hydroxy-3-methoxybenzyl) -1-phenylethylamine, N- (2-hydroxy-3-methoxybenzyl) -1- (p-tolyl) ethylamine, N-
(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-cyclohexylethylamine, 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, Np-hydroxybenzyl-α-phenyl-β-paratolylethylamine, erythro-1-
p-nitrophenyl-2-N, N-dimethylaminopropane-1,3-diol, threo-1-p-nitrophenyl-2-N, N-dimethylaminopropane-1,3-diol
An optically active substance such as a diol is exemplified.

The optical resolution is usually carried out in a solvent such as aromatic hydrocarbons such as benzene, toluene and xylene, aliphatic hydrocarbons such as hexane and heptane, and the like.
Water, alcohols such as methanol and ethanol, ketones such as acetone and methyl isobutyl ketone, and ethers such as dioxane and tetrahydrofuran are used alone or as a mixed solvent of two or more kinds. The amount of such a solvent used is not particularly limited depending on the solvent used and the subsequent processing conditions and the like,
The optimum amount is selected according to each condition.

The amount of the resolving agent used for chrysanthemic acid is usually 0.2
The molar ratio is about 1.2 to 1.2 times, preferably about 0.3 to 1.1 times. The dividing operation is usually performed by mixing and dissolving chrysanthemic acid and a resolving agent in the above-mentioned solvent, and then leaving the mixture to stand or stirring. The temperature at this time is usually about -20 ° C to 150 ° C,
Preferably, it is in the range of about -10 ° C to 100 ° C. In the above treatment, if the treatment temperature is high, then cool, and if the temperature is low, as it is, or after the crystals are precipitated, raise the temperature to dissolve some or all of the precipitated crystals, and then cool the crystals. After the crystals are precipitated by an appropriate method such as precipitation, the precipitated crystals are separated by filtration or the like. The diastereomeric salt obtained by such a treatment is separated as crystals, the salt is decomposed with an acid or an alkali, and then an extraction treatment is carried out to obtain an optically active chrysanthemic acid. Collected. For example, the diastereomer salt obtained by the above method is decomposed with hydrochloric acid, sulfuric acid or the like, and after the decomposition treatment, extracted with an organic solvent, optically active chrysanthemic acid is obtained. After that, the extraction agent is subjected to the extraction treatment to collect the resolving agent.

Alternatively, the diastereomer salt obtained by the above-mentioned method is decomposed with a base such as sodium hydroxide and then subjected to an extraction treatment with an organic solvent under weak alkalinity to recover the resolving agent. By performing an extraction treatment after acidification, optically active chrysanthemic acid can be obtained. The resolving agent recovered by these treatments can be reused.

[0030]

According to the present invention, chrysanthemic acid having an improved trans / cis ratio and an improved optical purity can be industrially advantageously produced.

[0031]

EXAMPLES Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples. (Example 1) Chrysanthemic acid 2 having a trans / cis ratio of 78/22 and an optical purity of the trans form of 72% ee and an optical purity of the cis form of 52% ee
To 0.0 g, 228 g of toluene was added and dissolved by stirring. Then, 20.4 g of (S) -1-phenyl-2- (p-tolyl) ethylamine (resolving agent) was added and dissolved by heating. The crystals obtained were collected by filtration, washed with toluene, and dissolved in a 5% aqueous sodium hydroxide solution. Next, the resolving agent was extracted with toluene, the aqueous layer was acidified with 5% aqueous sulfuric acid, and then extracted with toluene. When the toluene was distilled off, the trans / cis ratio was 81%.
As a result, 14.3 g (71.5% yield) of chrysanthemic acid having an optical purity of 98% ee and an optical purity of 98% ee of the cis-form was obtained.

Example 2 Trans / cis ratio = 77/23,
The optical purity of the trans form is 40% ee, and the optical purity of the cis form is 1.
To 30.0 g of 3% ee chrysanthemic acid, 210 g of toluene was added and dissolved by stirring. Then, 24.7 g of (S) -1-phenyl-2- (p-tolyl) ethylamine (resolving agent) was added and dissolved by heating.
After cooling to room temperature, the precipitated crystals were collected by filtration, washed with toluene, and dissolved in a 5% aqueous sodium hydroxide solution. Next, the resolving agent was extracted with toluene, the aqueous layer was acidified with 5% aqueous sulfuric acid, and then extracted with toluene. When toluene was distilled off, the trans / cis ratio was 85/15, and the optical purity of the trans form was 96%. ee,
The optical purity of the cis form is 15.1 g of chrysanthemic acid with 95% ee (50.3% yield)
Obtained.

Example 3 18.05 mg (0.00.0 mg) of copper trifluoromethanesulfonate was placed in a 50 ml Schlenk tube purged with nitrogen.
5 mmol), bis [4 (R) -phenyl-2-oxazoline] methane 1
After adding 9.9 mg (0.055 mmol) and 5 ml of n-butyl chloride, the mixture was stirred at room temperature for 10 minutes. Thereafter, 30.0 g (275 mmol) of 2,5-dimethyl-2,4-hexadiene was further added, and 5.70 g (50 mmol) of ethyl diazoacetate was added dropwise at 50 ° C. over 2 hours.
After the completion of the addition of ethyl diazoacetate, the mixture was further stirred at 50 ° C. for 1 hour. The amount of produced chrysanthemic acid ethyl ester was determined by gas chromatography to be 8.43 g, the yield based on ethyl diazoacetate was 86.0%, and the trans / cis ratio was 72/28. After distilling off 2,5-dimethyl-2,4-hexadiene (boiling point: 51 ° C./30 mmHg) from the reaction mixture, 1 g of the concentrated solution was fractionated.
10 ml of 1N aqueous sodium hydroxide solution and 5 ml of ethanol were added, and the mixture was stirred at 100 ° C. for 1 hour to carry out alkali hydrolysis. The resulting chrysanthemic acid was reacted with 1-menthol and the diastereomeric ester formed was analyzed by gas chromatography. The optical purity of the trans form was 60% ee, and the optical purity of the cis form was 27% ee. When chrysanthemic acid obtained by alkali hydrolysis of this chrysanthemic acid ester and trans-rich racemic chrysanthemic acid (trans / cis ratio = 95/5) are mixed at a weight ratio of 6: 4, the trans / cis ratio = 82 / 18. The optical purity of the trans form was 27% ee, and the optical purity of the cis form was 25% ee. To 10.0 g of this mixed chrysanthemic acid, add 104.5
g, and dissolved by stirring. Then, (S) -1-phenyl-2-
7.48 g of (p-tolyl) ethylamine (resolving agent) was added and dissolved by heating. After cooling to room temperature, the precipitated crystals were collected by filtration.
After washing with toluene, it was dissolved in a 5% aqueous sodium hydroxide solution.
Then, the resolving agent was extracted with toluene, the aqueous layer was acidified with 5% sulfuric acid aqueous solution, and then extracted with toluene. When toluene was distilled off, the trans / cis ratio was 87/13, and the optical purity of the trans form was 95%. Optical purity of ee and cis isomer is 4.19 g of chrysanthemic acid of 97% ee
(41.9% yield).

Example 4 In a 50 ml Schlenk tube purged with nitrogen, 9.98 mg (0.05 mmol) of copper acetate monohydrate and (R)-
22.6 mg (0.05 mmol) of a copper complex prepared from 21.5 mg of N-salicylidene-2-amino-1,1-di (2-methoxyphenyl) propanol, 6.0 g (55 mmol) of 2,5-dimethyl-2,4-hexadiene ), And after adding 5.4 mg of phenylhydrazine, 1.14 g (10 mmol) of ethyl diazoacetate was added at 80 ° C.
It was dropped over time. After the completion of the dropwise addition of ethyl diazoacetate, the mixture was further stirred at 25 ° C for 1 hour. The amount of ethyl chrysanthemic acid produced was determined by gas chromatography to be 1.76 g.
The yield based on ethyl diazoacetate was 90.0%, and the trans / cis ratio was 58/42. After distilling off 2,5-dimethyl-2,4-hexadiene (boiling point: 51 ° C./30 mmHg) from the reaction mixture, 1 g of the concentrated solution was fractionated and 1N aqueous sodium hydroxide solution
10 ml and ethanol 5 ml were added, and the mixture was stirred at 100 ° C. for 1 hour to carry out alkali hydrolysis. The resulting chrysanthemic acid was reacted with 1-menthol and the diastereomeric ester formed was analyzed by gas chromatography. The optical purity of the trans form was 63% ee and the optical purity of the cis form was 63% ee. Chrysanthemic acid obtained by alkaline hydrolysis of this chrysanthemic acid ester and trans-rich racemic chrysanthemic acid (trans / cis ratio = 95 /
When 5) was mixed at a weight ratio of 4: 6, the trans / cis ratio was 81/19, the optical purity of the trans form was 15% ee, and the optical purity of the cis form was 53% ee. 10.0 g of this mixed chrysanthemic acid
106.2 g of toluene was added to the mixture and dissolved by stirring. Then, (S)-
7.40 g of 1-phenyl-2- (p-tolyl) ethylamine (resolving agent) was added and dissolved by heating. After cooling to room temperature, the precipitated crystals were collected by filtration, washed with toluene, and dissolved in a 5% aqueous sodium hydroxide solution. Next, the resolving agent was extracted with toluene, the aqueous layer was acidified with 5% sulfuric acid aqueous solution, and then extracted with toluene. The toluene was distilled off to obtain a trans / cis ratio of 81/19.
The optical purity of the trans form is 96% ee, and that of the cis form is 99%.
4.02 g (yield 40.2%) of chrysanthemic acid of% ee was obtained.

Example 5 In a 50 ml Schlenk tube purged with nitrogen, 9.98 mg (0.05 mmol) of copper acetate monohydrate and (R)-
19.64 mg (0.05 mM) of a copper complex prepared from 18.23 mg of N-salicylidene-2-amino-1,1-diphenylpropanol.
mol), 2,5-dimethyl-2,4-hexadiene 6.0 g (55 mmol)
And then add 5.4 mg of phenylhydrazine,
Then, 1.14 g (10 mmol) of ethyl diazoacetate was added dropwise over 2 hours. After addition of ethyl diazoacetate, 25 hours
Stirred at ° C. The amount of ethyl chrysanthemic acid produced was determined by gas chromatography to be 1.52 g, the yield based on ethyl diazoacetate was 77.7%, and the trans / cis ratio =
It was 61/39. After distilling off 2,5-dimethyl-2,4-hexadiene (boiling point 51 ° C./30 mmHg) from the reaction mixture, 1 g of the concentrated solution was fractionated, and 10 ml of 1N aqueous sodium hydroxide solution and ethanol were added.
5 ml was added, and the mixture was stirred at 100 ° C. for 1 hour to carry out alkali hydrolysis. The resulting chrysanthemic acid was reacted with 1-menthol and the diastereomeric ester formed was analyzed by gas chromatography. The optical purity of the trans form was 69% ee, and the optical purity of the cis form was 68% ee. When chrysanthemic acid obtained by alkali hydrolysis and trans-rich racemic chrysanthemic acid (trans / cis ratio = 95/5) are mixed at a weight ratio of 46:54, the trans / cis ratio = 78/22, The optical purity is 24% ee, and the optical purity of the cis form is 59% ee. To the mixed chrysanthemic acid, about 10 times by weight of toluene was added and dissolved by stirring, and then (S) -1-phenyl-2- (p-tolyl) ethylamine (resolving agent) was added about 0.69 mole times of the chrysanthemic acid. After adding and dissolving with heating and cooling to room temperature, the precipitated crystals are collected by filtration, washed with toluene, and then dissolved in a 5% aqueous sodium hydroxide solution. Next, the resolving agent was extracted with toluene, the aqueous layer was acidified with 5% sulfuric acid aqueous solution, and then extracted with toluene. The toluene was distilled off, and the trans / cis ratio was about 78/22. Chrysantic acid with 95% ee and optical purity of cis isomer of about 99% ee can be obtained in a yield of about 46%.

Example 6 In a 50 ml Schlenk tube purged with nitrogen, 9.98 mg (0.05 mmol) of copper acetate monohydrate and (R)-
N-salicylidene-2-amino-1,1-di (2-n-
(Butoxy-5-tert-butylphenyl) propanol 32.3
32 mg (0.05 mmo) of copper complex prepared from 3 mg (0.055 mmol)
l) was carried out in accordance with Example 5. The amount of ethyl chrysanthemic acid produced was determined by gas chromatography to be 1.64 g, and the yield based on ethyl diazoacetate was 83.
7%, trans / cis ratio = 57/43. From the reaction mixture
After distilling off 2,5-dimethyl-2,4-hexadiene (boiling point: 51 ° C./30 mmHg), 1 g of the concentrated solution was collected, 10 ml of 1N aqueous sodium hydroxide solution and 5 ml of ethanol were added, and the mixture was added at 100 ° C.
After stirring for an hour, alkali hydrolysis was performed. The obtained chrysanthemic acid is l-
The diastereomeric ester formed by the reaction with menthol was analyzed by gas chromatography. The optical purity of the trans form was 86% ee and that of the cis form was 84% ee. When chrysanthemic acid obtained by alkali hydrolysis and trans-rich racemic chrysanthemic acid (trans / cis ratio = 95/5) are mixed at a weight ratio of 51:49, the trans / cis ratio = 76/2
4. The optical purity of the trans form is 33% ee, and the optical purity of the cis form is 76% ee. To this mixed chrysanthemic acid, toluene was added about 10 times by weight and dissolved by stirring, and then (S) -1-
Phenyl-2- (p-tolyl) ethylamine (resolution agent)
Was added to about 0.68 mol times of chrysanthemic acid and dissolved by heating. After cooling to room temperature, the precipitated crystals were collected by filtration, washed with toluene, and dissolved in a 5% aqueous sodium hydroxide solution. Then, the resolving agent was extracted with toluene, and the aqueous layer was acidified with 5% aqueous sulfuric acid, and then extracted with toluene.
72/28, the trans-isomer has an optical purity of about 95% ee, and the cis-isomer has an optical purity of about 99% ee.

(Comparative Example 1) To 100 g of racemic chrysanthemic acid (trans / cis ratio = 75/25), 390 g of toluene was added and dissolved by stirring, and then (S) -1-phenyl-2- (p-tolyl)
47.0 g of ethylamine (resolving agent) was added and dissolved by heating. After cooling to room temperature, the precipitated crystals were collected by filtration, washed with toluene, and dissolved in a 5% aqueous sodium hydroxide solution. Next, the resolving agent was extracted with toluene, the aqueous layer was acidified with 5% sulfuric acid aqueous solution, and then extracted with toluene. When toluene was distilled off, the trans / cis ratio was 80/20, and the optical purity of the trans form was 96%. The optical purity of the ee and cis isomers was 20.8 g (yield 20.8%) of chrysanthemic acid with 98% ee.

Example 7 18.05 mg (0.00.0 mg) of copper trifluoromethanesulfonate was placed in a 50 ml Schlenk tube purged with nitrogen.
5 mmol), bis [2- [4 (R) -phenyl-5,5-dimethyl-2
[Oxazoline]] methane (19.9 mg, 0.055 mmol) and n-butyl chloride (5 ml) were added, and the mixture was stirred at room temperature for 10 minutes. After this,
After further adding 6.0 g (55 mmol) of dimethyl-2,4-hexadiene, 1.41 g (10 mm) of diazoacetic acid (t-butyl) was added at 25 ° C.
ol) was added dropwise over 2 hours. After the addition of t-butyl diazoacetate was completed, the mixture was further stirred at 25 ° C. for 1 hour. The amount of t-butyl chrysanthemic acid produced was determined by gas chromatography to be 1.86 g, the yield based on t-butyl diazoacetate was 83.1%, and the trans / cis ratio was 85/15. From the reaction mixture, 2,5-dimethyl-2,4-hexadiene (boiling point 51 ° C./30
(mmHg) was distilled off, and the optical purity of the concentrate was measured by liquid chromatography.
e. The optical purity of the cis form was 67% ee. Mixing chrysanthemic acid obtained by decomposing t-butyl chrysanthe with trifluoroacetic acid and trans-rich racemic chrysanthemic acid (trans / cis ratio = 95/5) at a weight ratio of 60:40 gives a trans / cis ratio = 89
/ 11, the optical purity of the trans form is 49% ee, and the optical purity of the cis form is 48% ee. To the mixed chrysanthemic acid, about 10 times by weight of toluene was added and dissolved by stirring, and then (S)-
α- (1-Naphthyl) -ethylamine (resolving agent) was dissolved by heating about 1.0 mol times of chrysanthemic acid and water at 8% by weight with respect to chrysanthemic acid, and after cooling to room temperature, the precipitated crystals were collected by filtration. After washing with toluene, it is dissolved in a 5% aqueous sodium hydroxide solution. Then, the resolving agent was extracted with toluene, the aqueous layer was acidified with 5% sulfuric acid aqueous solution, and then extracted with toluene. The toluene was distilled off, and the trans / cis ratio was about 98/2, and the optical purity of the trans form was about 9%.
6% ee chrysanthemic acid can be obtained with a yield of about 57%.

Example 8 In a 50 ml Schlenk tube purged with nitrogen, 9.98 mg (0.05 mmol) of copper acetate monohydrate and (R)-
19.64 mg (0.05 mM) of a copper complex prepared from 18.23 mg of N-salicylidene-2-amino-1,1-diphenylpropanol.
mol), 2,5-dimethyl-2,4-hexadiene 6.0 g (55 mmol)
And then add 5.4 mg of phenylhydrazine,
Then, 1.14 g (10 mmol) of ethyl diazoacetate was added dropwise over 2 hours. After addition of ethyl diazoacetate, 25 hours
Stirred at ° C. The amount of ethyl chrysanthemic acid produced was determined by gas chromatography to be 1.52 g, the yield based on ethyl diazoacetate was 77.7%, and the trans / cis ratio =
It was 61/39. After distilling off 2,5-dimethyl-2,4-hexadiene (boiling point 51 ° C./30 mmHg) from the reaction mixture, 1 g of the concentrated solution was fractionated, and 10 ml of 1N aqueous sodium hydroxide solution and ethanol were added.
5 ml was added, and the mixture was stirred at 100 ° C. for 1 hour to carry out alkali hydrolysis. The resulting chrysanthemic acid was reacted with 1-menthol and the diastereomeric ester formed was analyzed by gas chromatography. The optical purity of the trans form was 69% ee, and the optical purity of the cis form was 68% ee. When chrysanthemic acid obtained by alkali hydrolysis and trans-rich racemic chrysanthemic acid (trans / cis ratio = 95/5) are mixed at a weight ratio of 43:57, the trans / cis ratio = 80/20, Optical purity is 2
The optical purity of the cis form is 3% ee and 74% ee. To this mixed chrysanthemic acid, toluene was added at about 7 times the weight of chrysanthemic acid and dissolved by stirring, and then (S) -α- (1-naphthyl)-
Ethylamine (resolving agent) was dissolved by heating about 1.0 mole times the amount of chrysanthemic acid and water at 8% by weight to the chrysanthemic acid. After cooling to room temperature, the precipitated crystals were collected by filtration, washed with toluene, and washed with 5% sodium hydroxide. Dissolve in aqueous solution. Next, the resolving agent was extracted with toluene, and the aqueous layer was acidified with 5% aqueous sulfuric acid, and then extracted with toluene. When the toluene was distilled off, the trans / cis ratio was about 98%.
/ 2, Chrysantic acid with optical purity of about 96% ee of trans form
% Can be obtained.

Comparative Example 2 To 16.3 g of racemic chrysanthemic acid (trans / cis ratio = 79/21), 65.0 g of toluene was added and dissolved by stirring, and then (S) -α- (1-naphthyl) -ethylamine (Resolving agent) 16.0 g and 1.3 g of water were added and dissolved by heating. After cooling to room temperature, the precipitated crystals were collected by filtration, washed with toluene, and dissolved in a 5% aqueous sodium hydroxide solution. Next, the resolving agent was extracted with toluene, and the aqueous layer was acidified with 5% aqueous sulfuric acid, and then extracted with toluene. When toluene was distilled off, the trans / cis ratio was 98/2, and the optical purity of the trans form was 97%.
The optical purity of ee and cis isomer is 73% ee.
(25.3% yield).

────────────────────────────────────────────────── ─── Continued on the front page (51) Int.Cl. ⁶ Identification symbol FI C07C 51/487 C07C 51/487 // C07B 61/00 300 C07B 61/00 300 C07M 7:00 (72) Inventor Kunihiko Fujita Osaka 2-10-1, Tsukahara, Takatsuki City, Prefecture Sumitomo Kagaku Kogyo Co., Ltd.

Claims (7)

[Claims] (1) a trans-isomer ratio of 50% or more and an optical purity of 10
A process for producing optically active chrysanthemic acid, wherein chrysanthemic acid having an ee of not less than% ee is subjected to optical resolution by reacting with an optically active organic amine. 2. A trans-isomer ratio of 60-95% and an optical purity of 15-9.
The method for producing optically active chrysanthemic acid according to claim 1, wherein chrysanthemic acid having 0% ee is used. 3. An optical resolving agent of the general formula (1) (Wherein, R ₁ and R ₂ each represent a hydrogen atom, an alkyl group, an aralkyl group or an aryl group, and X and Y each represent a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group. Or an optically active organic amine represented by the general formula (2): (Wherein, R _1, R ₂ are each a hydrogen atom, an alkyl group, an aralkyl group or an aryl group, R ₃ is a carbon number 1 -
6 represents an alkyl group. * Represents an asymmetric carbon. )) Or an optically active organic amine represented by the general formula (3) (Wherein, R ₄ is naphthyl group, a cyclohexyl group; represents or halogen, nitro, lower alkyl group or an optionally substituted phenyl group by lower alkoxy, R ₅
Represents a lower alkyl group or a benzyl group optionally substituted with a lower alkyl group. R _6, when R ₅ is a lower alkyl group p- hydroxyphenyl group or a 2-hydroxy-3 represents a lower alkoxyphenyl group, R ₅ is a benzyl group which may be substituted with a lower alkyl group In the case, it represents a p-hydroxyphenyl group. * Represents an asymmetric carbon. ) Or an optically active organic amine represented by the general formula (4) (Wherein, R ₁ and R ₂ each represent a hydrogen atom, an alkyl group, an aralkyl group, or an aryl group. * Represents an asymmetric carbon atom). For producing an optically active chrysanthemic acid. 4. The method according to claim 1, wherein 2,5-dimethyl- is present in the presence of an asymmetric copper complex.
2,4-hexadiene and diazoacetic esters represented by the general formula (5) N ₂ CHCO ₂ R ₇ (5) (wherein R ₇ represents an alkyl group or a cycloalkyl group having 1 to 6 carbon atoms) To produce optically active chrysanthemic acid esters (cyclopropanation step), which is converted to chrysanthemic acid by alkali or acid decomposition (decomposition step), followed by the general formulas (1) and (2). ), A method for producing optically active chrysanthemic acid, comprising performing optical resolution (optical resolution step) using at least one optically active organic amine selected from general formula (3) or general formula (4). 5. A ligand of an asymmetric copper complex represented by the general formula (6): (Wherein, R ₈ and R ₉ are different and each represent an optionally substituted phenyl group or a hydrogen atom, and R ₁₀ and R ₁₁ represent a hydrogen atom, an alkyl group, a cycloalkyl group, and an optionally substituted phenyl group. Or an aralkyl group;
₁₀ and R ₁₁ may combine to form a cyclic alkylene group. R ₁₂ represents a hydrogen atom or an alkyl group. 5. The production method according to claim 4, which is an optically active bisoxazoline compound represented by the formula: 6. The ligand of the asymmetric copper complex represented by the general formula (7) (Wherein, R ₁₃ and R ₁₄ each represent an alkyl group, an aralkyl group or an aryl group, and Z represents a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, an aralkyl group or an aryl group. It means there is.)
The production method according to claim 4, which is an optically active salicylideneamino alcohol compound represented by the formula: 7. The ligand of the asymmetric copper complex represented by the general formula (8) (Wherein, R represents a hydrogen atom or a lower alkyl group;
Represents an integer of 1 to 3. * Represents an asymmetric carbon. 5. The production method according to claim 4, which is an optically active ethylenediamine compound represented by the formula: