JPH0586191B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a method for producing an optically active ester, and more specifically, the present invention relates to a method for producing an optically active ester, and more specifically, the present invention relates to a method for producing an optically active ester, and more specifically, the present invention relates to a method for producing an optically active ester, and more specifically,

[ka] [In the formula, *represents an asymmetric carbon, R is a general formula

[expression] or

[Formula] (Here, R ₁ represents a hydrogen atom or a methyl group, and when R ₁ represents a hydrogen atom, R ₂ represents 2,2
-represents a dihalobinyl group, 2-methyl-1-propenyl group, 1,2,2,2-tetrahaloethyl group or 2,3,3,3-tetrahalo-1-propenyl group, and R ₁ represents a methyl group Time,
R ₂ also represents a methyl group. X represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower haloalkyl group, a lower alkoxyl group, or a lower haloalkoxyl group, and n represents 1 or 2.
R ₃ is a lower alkyl group, a lower haloalkyl group,
represents a lower cycloalkyl group or a lower halocycloalkyl group, and R ₄ represents a hydrogen atom,
Alternatively, R ₃ and R ₄ are bonded at the terminals and represent an alkylene group which may be substituted with a halogen atom. ) represents a group represented by ] It is related with the manufacturing method of the optically active ester shown by these. α-Cyano-3-phenoxybenzyl alcohol, which is the alcohol component of the ester represented by the above general formula, is represented by fuenvalerate, cypermethrin, deltamethrin, etc.
It is known as an alcohol component of a group of ester compounds with insecticidal activity called synthetic pyrethroids. Since this alcohol has an asymmetric carbon at the α-position, two types of optical isomers exist, and the insecticidal efficacy of the S-form alcohol as an ester is higher than that of the corresponding R-form alcohol. It is known to be far superior (Kosuke Yoshioka, Synthetic Organic Chemistry, Vol. 38, No. 12, pp. 1152-1162 (1980)). Therefore, it has been desired to develop a technique for producing (S)-α-cyano-3-phenoxybenzyl alcohol ester by an industrially advantageous method. By the way, as a method for obtaining (S)-α-cyano-3-phenoxybenzyl alcohol ester, which is the intermediate raw material, (i) racemic α-cyano-3-phenyl alcohol ester is prepared in the presence of an acidic reagent. Cis-enoxybenzyl alcohol
2,2-Dimethyl-3S-(dihydroxymethyl)cyclopropane-1R-carboxylic acid lactone is reacted to form an ether compound, and the resulting two isomer mixtures are separated by physical means to form (S) A method of hydrolyzing an ether compound containing an alcohol component in an acidic medium to obtain (S)-α-cyano-3-phenoxybenzyl alcohol (Japanese Patent Application Laid-open No. 109944/1983) and (ii) chiral cyclopropane. (S)-α of carboxylic acid
- A method for obtaining (S)-α-cyano-3-phenoxybenzyl alcohol by reacting boron halide with cyano-3-phenoxybenzyl alcohol ester and further reacting with water (JP-A-56-
No. 12355). However, method (i) requires an expensive optically active reagent and the recovery of this optically active reagent, requiring multiple steps; Pre-optically active α-cyano-3
- It cannot be said that this method is necessarily sufficient for industrial implementation because it requires an ester of phenoxybenzyl alcohol. Under these circumstances, the present inventors investigated various methods for producing the optically active ester represented by the above general formula [] with high optical purity and industrially advantageously, and found that α-cyano - Asymmetrically hydrolyzing the ester of 3-phenoxybenzyl alcohol by allowing an esterase produced by a microorganism of the genus Arthrobacter that has the ability to asymmetrically hydrolyze the ester to act on the ester, resulting in an optical After subjecting a mixture of active α-cyano-3-phenoxybenzyl alcohol and an unreacted ester, which is an ester of its enantiomer, to an acylation reaction in the presence of a deoxidizing agent, The present invention was completed based on the discovery that the optically active ester represented by the general formula [] can be separated and obtained, and that the desired ester can be obtained efficiently by such a method without impairing the optical purity. I came to the conclusion. That is, the general formula of the present invention []

[In the formula, A represents a hydrogen atom, a lower alkyl group which may be substituted with a halogen atom, a lower alkenyl group which may be substituted with a halogen atom, or a lower alkenyl group which may be substituted with a halogen atom. Represents a lower alkenyl group, lower alkoxyl group, lower alkenyloxy group or lower alkynyloxy group. ] An esterase produced by a microorganism of the genus Arthrobacter that has the ability to asymmetrically hydrolyze the ester is reacted with the ester represented by the formula [].

[In the formula, * represents an asymmetric carbon. ] After introducing a mixture of the optically active alcohol represented by the formula and the optically active ester represented by the general formula [ ], which is an ester of its enantiomer, the mixture is added to the mixture in the presence of a deoxidizing agent, General formula []

[In the formula, R represents the same meaning as above. ] An acid halide or acid anhydride of a carboxylic acid represented by is reacted to form an optically active ester represented by the general formula [] and an optically active ester represented by the general formula [].
General formula [] by obtaining a mixture of esters represented by, and then separating and obtaining an optically active ester represented by the above general formula [] from the mixture.
The present invention provides a method for producing an optically active ester shown in the following. The method of the present invention will be explained in detail below. In the method of the present invention, esters of α-cyano-3-phenoxybenzyl alcohol and various carboxylic acids can be used as the raw ester represented by the general formula [], but from an industrial standpoint, Typical examples of group A include methyl group, ethyl group, chloromethyl group, methoxy group, and ethoxy group in view of their availability, price, and ease of handling. The ester can also be produced by conventional methods for producing esters, such as by reacting racemic α-cyano-3-phenoxybenzyl alcohol with a carboxylic acid halide or carboxylic acid anhydride;
It can be easily produced by the reaction of phenoxybenzaldehyde with hydrogen cyanide and carboxylic acid halide. In order to asymmetrically hydrolyze the ester represented by the general formula [], a culture solution in which the microorganisms are cultured,
This is carried out by mixing the ester represented by the general formula [] with an aqueous solution containing an esterase-containing material such as a culture solution, an esterase extract or a concentrate, a crude esterase, or a purified esterase, and stirring or shaking the mixture. A non-ester surfactant may be added if necessary. Furthermore, it is also possible to use the enzyme by immobilizing it.
The reaction temperature is 10-65°C, preferably 20-50°C, and the reaction time is usually 1-48 hours. during reaction
It is important that the pH is 7 or less, and it is preferable to keep it within the range of 3.5 to 6.5. General formula that is a group []
The amount of ester used is 1 for the reaction solution.
-80% by weight, preferably 5-35% by weight. After performing the asymmetric hydrolysis reaction in this way,
The reaction solution is subjected to operations such as static separation and extraction with a solvent to separate the optically active alcohol represented by the formula [] and the general formula [], which is an ester of its enantiomer that remains without undergoing hydrolysis. A mixture of optically active esters is obtained. Next, the mixture thus obtained is reacted with an acid halide or an acid anhydride of a carboxylic acid represented by the general formula [] as an acylating agent in the presence of a deoxidizing agent to obtain the above formula [].
The optically active alcohol represented by is acylated to form a mixture of the optically active ester represented by the general formula [] and the optically active ester represented by the general formula []. Although a reaction solvent is not essential in the acylation reaction, it is preferable to use an inert solvent in order to allow the reaction to proceed smoothly. Such solvents include aromatic hydrocarbons such as benzene, toluene, xylene, methylene chloride, dichloroethane,
Halogenated hydrocarbons such as chloroform, carbon tetrachloride, and monochlorobenzene, aliphatic or alicyclic hydrocarbons such as heptane, hexane, and cyclohexane, ethers such as ethyl ether, dioxane, and tetrahydrofuran, dimethylformamide, dimethyl oxide, etc. Examples include organic solvents such as aprotic polar solvents, and mixed solvents of two or more thereof. Examples of deoxidizing agents include aromatic amines such as pyridine, collidine, dimethylaminopyridine, and N,N-diethylaniline, and aliphatic tertiary amines such as triethylamine and trimethylamine. The equivalent mole of optically active alcohol represented by the formula []
A range of 1.5 times the mole can sufficiently achieve the purpose. The reaction temperature is arbitrary within the range of -78℃ to the boiling point of the solvent used, but it is recommended to use a temperature range of -15 to 30℃ because racemization of asymmetric sites tends to occur at high temperatures and the reaction progresses slowly at low temperatures. A range is preferred. In addition, as for the acylation reaction, (i) an optically active alcohol represented by the formula [] and an optically active ester represented by the general formula [] are added in a solution of a deoxidizing agent and an acylating agent in an organic solvent. (ii) Adding the above acylating agent and deoxidizing agent to a solution of the above mixture dissolved in a solvent, either as such or as a solution of the organic solvent. (vi) A method in which the deoxidizing agent is added dropwise as it is or as a solution in an organic solvent into a solution of the above mixture and the acylating agent in an organic solvent; (iv) A method in which the above mixture and the deoxidizing agent are added dropwise into a solution of the above mixture and the above acylating agent in an organic solvent. Examples include a method in which the above-mentioned acylating agent is dropped as it is or as a solution of an organic solvent into a solution of an organic solvent. The above method (i), (ii) or (iii) is preferable in terms of suppressing the racemization of the optically active ester represented by the general formula [] and the production of by-products. Specifically, the acid halide or acid anhydride of a carboxylic acid represented by the general formula [] used as an acylating agent in the acylation reaction includes:
2,2-dimethyl-3-(2-methyl-1-propenyl)cyclopropane-1-carboxylic acid chloride, 2,2-dimethyl-3-(2,2-dichlorovinyl)cyclopropane-1-carboxylic acid chloride, 2,2-dimethyl-3-(2,2-dibromvinyl)cyclopropane-1-carboxylic acid chloride, 2,2-dimethyl-3-(1,2,2,
2-tetrabromoethyl)cyclopropane-1-
Carboxylic acid chloride, 2,2-dimethyl-3-
(2,3,3,3-tetrafluoro-1-propenyl)cyclopropane-1-carboxylic acid chloride, 2,2,3,3-tetramethylcyclopropane-1-carboxylic acid chloride, 2-(4-chlorophenyl) )-3-methyl-butyric acid chloride, 2
-(4-difluoromethoxyphenyl)-3-methyl-butyric acid chloride, 2,2-dichloro-1-
(4-ethoxyphenyl)cyclopropane-1-
Examples include carboxylic acid chlorides and their chirotropic and/or optical isomers. The amount of such an acylating agent to be used is usually in the range of equivalent mole to 1.2 times the mole, more preferably equivalent mole to 1.1 times the mole of the optically active alcohol represented by the formula [] in the mixture. After carrying out the acylation reaction as described above, the desired general formula [] is obtained from the mixture of the optically active ester represented by the general formula [] and the optically active ester represented by the general formula []. In order to separate and obtain the optically active ester represented by the formula, the deoxidizing agent used and its salt are removed by washing with an aqueous mineral acid solution, and then fractional distillation is performed under reduced pressure, or the general formula [] When the ester of the ester represented by is crystalline, a method of crystallization separation can be used. In this way, the general formula obtained separately []
The optically active ester represented by is highly pure as it is, but if necessary, it can be further purified by means such as recrystallization or chromatography. Incidentally, the optically active ester represented by the general formula [] separated and removed here can be racemized by separately treating with a base such as ammonia, pyridine, or triethylamine, and can be used again as a raw material in the method of the present invention. can. Next, the present invention will be explained in more detail with reference to examples, but the present invention is of course not limited to these. Example 1 80 g of (R,S)-α-cyano-3-phenoxybenzyl acetate and 3.2 g of Arthrobacter esterase (Lipase Godo BSL manufactured by Godo Shusei Co., Ltd.)
was added to 20 ml of 0.1M acetate buffer (PH4.0) and reacted at 40°C with stirring. During the reaction, as the reaction progresses, an aqueous solution of 1 molar sodium hydroxide is made into minute water droplets using a drop controller, and the pH is adjusted using a PH controller while carefully adding the solution.
was controlled at a constant level. Stirring was continued at the same temperature for 24 hours, then 40g of water was added and extracted with ethyl acetate, and the ethyl acetate layer was reduced to 5%
After washing with an aqueous hydrochloric acid solution, the solvent was distilled off to obtain (S)-α-cyano-3-phenoxybenzyl alcohol (content: 41.1% (S)/(R) = 98/2) and (R )−α
71 g of a mixture of -cyano-3-phenoxybenzyl acetate (content: 57.2% (R)/(S) = 99.1/0.9) was obtained. Then, (S)-2-(4-chlorophenyl)-3-
Methyl-butyric acid chloride ((S)/(R)=97.6/2.4)
Dissolve 6.65g and 2.8g of pyridine in 25ml of toluene,
To this, (S)-α-cyano-3-phenoxybenzyl alcohol obtained above and (R)-α-cyano-3
- 15.05g mixture of phenoxybenzyl acetate
A toluene (25 ml) solution of was added dropwise to the mixture over 2 hours while stirring at 150 mL, and stirring was continued for an additional 2 hours at the same temperature. 30 g of 5% hydrochloric acid was added to the reaction solution and stirred, and the organic layer was mixed with 5% hydrochloric acid, water, 5% sodium carbonate aqueous solution,
After sequentially washing with 30 g each of water, the solvent was distilled off under reduced pressure, and 21.2 g of (S)-α-cyano-3-phenoxybenzyl (S)-2(4-chlorophenyl)-3-
A mixture of methyl-butyric acid ester and (R)-α-cyano-3-phenoxybenzyl acetate was obtained. 10g of the above mixture was subjected to vacuum distillation and 0.1
Fractions up to a bottom liquid temperature of 180°C were distilled off at mmHg. From the distillate, 3.9 g of (R)-α-cyano-3-phenoxybenzyl acetate ((R)/(S) = 98.7/1.3) was obtained.
In addition, 5.2 g of (S)-α-cyano-3-phenoxybenzyl (S)-2-(4-chlorophenyl)-3-methyl-butyric acid ester ((S), (S)-isomer content:
95.5%). Separately, add 10g of the above mixture to 40mg of acetic acid.
After dissolving in 13.5 g of methanol containing 3.7 g of (S)-
α-Cyano-3-phenoxybenzyl alcohol
(S)-2-(4-chlorophenyl)-3-methyl-
Butyric acid ester ((S), (S)-isomer content: 99.1%) was obtained. After concentrating the mother liquor, it was distilled under reduced pressure to obtain 3.7 g of (R)-α.
-Cyano-3-phenoxybenzyl acetate ((R)/(S)=98.6/1.4) was obtained. Example 2 In Example 1, (1R)-cis-2,2-dimethyl-3-(2-methyl-1-propenyl) was used instead of (S)-2-(4-chlorophenyl)-3-methyl-butyric acid chloride. )-Cyclopropanecarbonyl chloride (5.46 g) was used. After acylation was carried out in the same manner as in Example 1, the crystallization separation operation was carried out in accordance with Example 1 to obtain (S)-α-cyano-3-phenoxy. Benzyl (1R)-cis-2,2-dimethyl-3-
5.9 g of (2-methyl-1-propenyl)cyclopropanecarboxylic acid ester was obtained. Examples 3 to 6 In Example 1, instead of (S)-2-(4-chlorophenyl)-3-methyl-butyric acid chloride,
Acylation was carried out in the same manner as in Example 1, except that various carboxylic acid chlorides shown in the table below were used,
Thereafter, the following separation operations were performed according to Example 1 to obtain the corresponding (S)-α-cyano-3-phenoxybenzyl esters.

[Table] Values for benzyl alcohol content.

Claims (1)

[Claims] 1 General formula [] [Chemical formula] [In the formula, A represents a hydrogen atom or a lower alkyl group optionally substituted with a halogen atom,
Represents a lower alkenyl group which may be substituted with a halogen atom, a lower alkynyl group which may be substituted with a halogen atom, a lower alkoxyl group, a lower alkenyloxy group or a lower alkynyloxy group. ] An esterase produced by a microorganism of the genus Arthrobacter that has the ability to asymmetrically hydrolyze the ester is reacted with the ester represented by the formula [ ] [where * represents an asymmetric carbon]. ] After introducing a mixture of the optically active alcohol represented by the formula and the optically active ester represented by the general formula [ ], which is the ester of its enantiomer,
To the mixture, in the presence of a deoxidizing agent, a compound of the general formula [] [formula] [wherein R ₁ represents a hydrogen atom or a methyl _group , represents a hydrogen atom, R ₂ is a 2,2-dihalovinyl group, 2-methyl-1-propenyl group, 1,2,2,2-tetrahaloethyl group or 2,3,3,3-tetrahalo-1 -represents a propenyl group, and when R ₁ represents a methyl group, R ₂ also represents a methyl group.
X represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower haloalkyl group, a lower alkoxyl group, or a lower haloalcosyl group, and n is 1
or 2. R ₃ represents a lower alkyl group, lower haloalkyl group, lower cycloalkyl group, or lower halocycloalkyl group, and R ₄ represents a hydrogen atom, or R ₃ is bonded to R ₄ at the terminal and substituted with a halogen atom. represents an optionally substituted alkylene group. ). ] An acid halide or acid anhydride of a carboxylic acid represented by the following is reacted to form a compound of the general formula [ ] [where R and * have the same meanings as above. ] A mixture of the optically active ester represented by the above general formula [] and the optically active ester represented by the above general formula [] is obtained, and then from the mixture, the above general formula []
A method for producing an optically active ester represented by the general formula [ ], which comprises separating and obtaining an optically active ester represented by the formula [ ]. 2. The manufacturing method according to claim 1, wherein in the carboxylic acid represented by the above general formula [], the group A is a methyl group, an ethyl group, or a monochloromethyl group. 3 The absolute configuration of the optically active alcohol represented by the above formula [] is the (S)-configuration, and the absolute configuration of the alcohol component of the optically active ester represented by the resulting general formula [] is the (S)-configuration. A manufacturing method according to claim 1 or 2. 4 The carboxylic acid represented by the above general formula [] is cis/trans, cis or trans 2,2
-dimethyl-3-(2-methyl-1-propenyl)cyclopropane-1-carboxylic acid, 2,2
-dimethyl-3-(2,2-dichlorovinyl)
cyclopropane-1-carboxylic acid or 2,2
-dimethyl-3-(2,2-dibromvinyl)
The method for producing cyclopropane-1-carboxylic acid according to claim 1, 2, or 3. 5 The carboxylic acid represented by the above general formula [] is 2-(4-chlorophenyl)-3-methyl-
The manufacturing method according to claim 1, 2 or 3, which is butyric acid or 2-(4-difluoromethoxyphenyl)-3-methyl-butyric acid. 6 Claims 1 and 2 in which the carboxylic acid represented by the above general formula [] is an optically active substance.
3. The manufacturing method according to item 3, item 4, or item 5. 7 The carboxylic acid represented by the above general formula [] is
(S)-2-(4-chlorophenyl)-3-methyl-
The manufacturing method according to claim 1, 2, 3, 5, or 6, wherein the manufacturing method is butyric acid. 8 A patent claim in which the carboxylic acid represented by the above general formula [] is (1R)-cis/trans-2,2-dimethyl-3-(2-methyl-1-propenyl)cyclopropane-1-carboxylic acid. The manufacturing method according to scope 1, 2, 3, 4 or 6. 9 The carboxylic acid represented by the above general formula [] is 2,2,3,3-tetramethylcyclopropane-1-carboxylic acid, according to claim 1, 2 or 3. Manufacturing method.