JPH0679557B2 - Process for producing optically active cis-cyclopropanecarboxylic acid - Google Patents

Description

TECHNICAL FIELD The present invention relates to a method for producing an optically active cis-cyclopropanecarboxylic acid.

More specifically, the invention has the general formula: (In the formula, X represents chlorine, bromine or a methyl group, and R '
Represents a C1-C4 alkyl group. This formula does not represent a steric relationship. ) Represented by (±) -cis-cyclopropanecarboxylic acid ester, or a mixture of (±) -cis-cyclopropanecarboxylic acid ester and (±) -trans-cyclopropanecarboxylic acid ester, Preferentially act a microorganism having the ability to asymmetrically hydrolyze the cis-cyclopropanecarboxylic acid esters or an esterase produced by the microorganism, (In the formula, X represents chlorine, bromine or a methyl group, and R
Represents hydrogen or a metal ion. This formula does not represent a steric relationship. ) Resolving the optically active cis-cyclopropanecarboxylic acids of formula (II) after resolution into optically active cis-cyclopropanecarboxylic acids of the formula and their enantiomers or diastereomeric esters. And a method for producing an optically active cis-cyclopropanecarboxylic acid represented by the formula (II).

PRIOR ART AND PROBLEMS The cyclopropanecarboxylic acid represented by the formula (II) is a compound constituting the acid component of a low toxicity fast-acting insecticidal ester generally called so-called pyrethroid such as allethrin, permethrin, and decamethrin.

The cyclopropanecarboxylic acids of formula (II) above have C1
There are asymmetric carbons at positions C3 and C4, and there are four types of diastereomers. Those with an absolute configuration of "1R3S" in the "RS nomenclature" have optical rotation (in a specific solvent). ) (+)
And the substituents are in the cis relationship, the "(+)-cis" form, and the one of "1R3R" is (+) in the optical rotation and the substituents are in the trans relationship. Trance"
The body, "1S3S" and "1S3R", have optical rotation (-)
And the substituents are in a cis and trans relationship, respectively, so that the “(−)-cis” form and the “(−)” form, respectively.
-Referred to as the "trans" form.

The insecticidal efficacy of these pyrethroid esters is
Only the (+)-form is valid and the (-)-form is almost invalid.

The efficacy correlation between the cis and trans isomers depends on the target pest and the nature of the efficacy, and the (+)-trans pyrethroid and the (+)-cis pyrethroid can be used for different purposes. Industrially advantageous (+)
-It is important to produce cis cyclopropanecarboxylic acids.

Currently known methods for producing (+)-cis isomers are mainly organic synthetic chemical resolution methods, but require relatively expensive optically active reagents, or require complicated steps, etc. In view of the above, it is the current situation that the development of a more economically advantageous optical resolution method is desired.

On the other hand, as a method for asymmetrically hydrolyzing the cyclopropanecarboxylic acid ester of the general formula (1) with an enzyme or a microorganism to obtain optically active trans-cyclopropanecarboxylic acid, a method using a microorganism-derived esterase (special Kaisho 60-244295) is known. In this known method, it is disclosed that the trans-form of the cyclopropanecarboxylic acid ester represented by the formula (I) is preferentially asymmetrically hydrolyzed.

Description of the Invention Under the circumstances, the present inventors have conducted research to develop an industrially advantageous method for producing (+)-cis cyclopropanecarboxylic acid (II). Or the esterase produced by the microorganism specifically and preferentially asymmetrically hydrolyzes the cis-cyclopropanecarboxylic acid ester of the formula (I) to produce the cis-cyclopropanecarboxylic acid of the formula (II). The present invention has been completed based on the finding.

That is, the present invention, Rhodotorula, Rhodosporidium, Ploirotas, Rhizomucor, Framulina,
Geotricum, Aspergillus, Candida,
Saccharomyces, Hansenula, Tolulopsis,
Rhodococcus, Penicillium, Dipoduscus,
Apsidia spp, Streptomyces spp, Nocardia spp, Arthrobacter spp, Pseudomonas spp, Escherichia spp, Bacillus spp, Bear Uberia spp, Metinicobia spp, Chromobacterium spp, Brevibacterium spp, Acinetobacter spp, Achromobacter spp, Kluyveromyces, Frateuria, Corynebacterium, Alcaligenes, Flavobacterium, Klebziella, (In the formula, X represents chlorine, bromine or a methyl group, and R '
Represents a C1-C4 alkyl group. This formula does not represent a steric relationship. ) Represented by (±) -cis-cyclopropanecarboxylic acid ester or a mixture of (±) -cis-cyclopropanecarboxylic acid ester and (±) -trans-cyclopropanecarboxylic acid ester When this occurs, the microorganism having the ability to preferentially asymmetrically hydrolyze the cis-form or the esterase produced by the microorganism is treated with the (±) -cis-cyclopropanecarboxylic acid esters or (±) -cis-cyclo Acting on a mixture of propanecarboxylic acid esters and (±) -trans-cyclopropanecarboxylic acid esters, (In the formula, X represents chlorine, bromine or a methyl group, and R
Represents hydrogen or a metal ion. This formula does not represent a steric relationship. ) Is produced, and the optically active cis-cyclopropanecarboxylic acid represented by the formula (II) is produced.
The present invention provides a method for producing cyclopropanecarboxylic acid. In the present invention, as the microorganism used,
The microorganisms belonging to the above genus may be any microorganisms having the above-mentioned ability, and preferable examples thereof include the following microorganisms.

Rhodosporidium toruloides IFO−0559 Rhodosporidium toruloides IFO−0871 Rhodosporidium toruloides IFO−8766 Rhodotorula glutinis (Rhodotorula)
−1501 Pleurotus ostreat
us) IFO−7051 Candida tropicalis I
FO-0618 Hansenula anomala var.ciferii IFO-0994 Torulopsis candida I
FO-0768 Arthrobacter citreu
s) IFO-12957 Pseudomonas putida IFO-
12996 Escherichia coli IFO-1316
8 Bacillus Iicheniformi
s) IFO-12195 Flavobacterium capsulatum IFO-12533 Chromobacterium chocolatum IFO-3758 Achromobacter lyticus ATCC-21456 Rhizomucor pusillus IFO
−9856 Flammulina velutipes I
FO-7046 Geotricum. Geotrichum candidu
m) IFO-4597 Dipodascus uninucleatus ATCC-14626 Beauveria bassiana ATCC
−26037 Metschinikowia pulcherr
ima) IFO-0561 Kluyveromyces lacti
s) IFO-1090 Frateuria auranti
a) IFO-3247 Klebsiella pneumoniae
IFO-12059 Pediococcus acidilactici IFO-3076 All of these bacteria are ATCC (Amercan Type Culture).
Collection) or Fermentation Research Institute (IFO) and is easily available.

The ester represented by the general formula (1) used as a raw material of the present invention can be easily produced by a method known per se.

For example, 1,1-dibromo-4-methyl-1,3-pentadiene, 1,1-dichloro-4-methyl-1,3-pentadiene or 2,5-dimethyl-hexa-2,4-diene and diazoacetic acid. Examples thereof include a method by reaction with an ester.

The ester used as a raw material is C1 such as methyl ester, ethyl ester, propyl ester and butyl ester.
Although ~ C4 alkyl ester is conveniently used, methyl ester and ethyl ester are particularly preferable because of easy availability and easy handling.

As for the steric relationship of the ester of the general formula (1) used as a raw material, various combinations are possible as long as it includes a (+)-cis isomer, but a mixture of (±) -cis or a (±)
-A mixture of cis and trans forms is convenient because of its easy availability.

Cultivation of the above-mentioned microorganisms is carried out by liquid culture according to a conventional method, for example, a sterilized liquid medium is inoculated with the microorganisms, and usually 1 to 8 at 20-40 ° C.
Reciprocal shaking culture can be carried out for a day, and if necessary, solid culture can be carried out.

The composition of the medium is used for culturing ordinary microorganisms, and is not particularly limited as long as it can be utilized by the above microorganisms. For example, as carbon and nitrogen sources, glucose, starch, dextrin, molasses, oils and fats , Soybean powder, defatted soybean powder, fatty soybean meal, corn steep liquor and the like can be used. As the inorganic salts, ammonium sulfate, potassium phosphate, magnesium sulfate, urea and the like can be used. In addition, depending on the case, it is possible to add cyclopropanecarboxylic acid esters or fatty acid esters represented by the general formula (I) to the medium.

In carrying out the method of the present invention, the asymmetric hydrolysis reaction of cyclopropanecarboxylic acid esters of general formula (I) is
A culture solution obtained by culturing the microorganism, a culture filtrate, a bacterial cell suspension,
An esterase-containing material such as an esterase extract or a concentrated solution, or a treated product thereof, for example, an aqueous solution containing a crude esterase or a purified esterase, and the general formula (I).
The cyclopropanecarboxylic acid represented by is mixed and stirred or shaken. If necessary, a non-ester type surfactant may be added, or the enzyme may be immobilized and used.

At this time, a reaction temperature of 10 to 65 ° C is suitable,
The temperature is preferably 20 to 50 ° C. because the stability of esterase tends to decrease at high temperature and the reaction rate is slow at too low temperature.

The pH during the reaction is preferably pH 3 to 11, preferably pH 5 to 9.

Next, after carrying out the asymmetric hydrolysis reaction in this manner, the released carboxylic acid or its salt and unreacted esters are separated and recovered. In this separation and recovery, operations such as solvent extraction, column chromatography, and fractional distillation can be appropriately adopted. For example, the reaction solution is extracted with an organic solvent such as methyl isobutyl ketone, chloroform, ether, benzene or toluene, and the extract is fractionally distilled under reduced pressure to separate free carboxylic acid or its salt and unreacted ester.

When the free carboxylic acid or its salt is the (+)-cis isomer, the unreacted ester is introduced into the raw material of the present invention by a method such as racemization.

When the free carboxylic acid or its salt is the (−)-cis isomer, the unreacted ester can be chemically hydrolyzed to obtain the (+)-cis isomer.

EXAMPLES Next, the present invention will be described in detail with reference to examples, but the present invention is not limited to these examples and includes ordinary changes and improvements.

Examples 1 to 23 Liquid medium in 500 ml shoulder flask [(for yeasts and molds (Examples 1 to 7 and 15 to 21) include malt extract, yeast extract medium (peptone 5.0 g in water 1 and glucose 10.0). g,
Dissolve 3.0 g of malt extract and 3.0 g of yeast extract, pH 6.
Set to 5. ), For bacteria, and for actinomycetes (Examples 8 to 14 and 22-23), sweetened broth medium (water 1 to glucose).
Dissolve 10.0 g, peptone 5.0 g, meat extract 5.0 g and salt 3.0 g to adjust the pH to 7.2. )] After sterilizing by adding 100 ml,
Each of the microorganisms listed in Table 1 was inoculated with 1 platinum loop from a slope culture.
Culture was carried out at 30 ° C. for 20 hours with reciprocal shaking.

Then, 1.0 g of ethyl- (±) -cis-permethylate (in the general formula (I), X = chlorine and R ′ = ethyl)
Was added and reacted at 30 ° C. for 40 hours while shaking. After the reaction, the reaction product was adjusted to pH 2 or less with concentrated hydrochloric acid, and then extracted with methyl isobutyl ketone. An internal standard substance (dimethyl phthalate) was added to the extract, and the mixture was analyzed by gas chromatography (column: 3% Thermon 3000 1.1 m, 140 ° C), and permethrate and permethrin acid (in the general formula (II),
(X = chlorine and R = hydrogen), and from the peak area ratio of dimethyl phthalate, the yield of permethric acid and the recovery rate of starting material permetholate were calculated. Of the added permethrate, all but the one converted into permethrin acid were recovered. Further, a 1N sodium hydroxide solution was added to the extract to extract only permethrinic acid as a sodium salt into an aqueous layer, and the aqueous layer was adjusted to pH 2 or less with hydrochloric acid, and the liberated permethrinic acid was extracted with methyl isobutyl ketone. The extract was concentrated and dried to obtain chemically almost pure permethrin acid.

10 mg of the obtained permethrin acid was dissolved in 1 ml of toluene, and equimolar thionyl chloride, pyridine and (+)-
2-Octanol was added and reacted to obtain the (+)-2-octanol diastereomer of permethrin acid and gas chromatography (column: 10% DCQF-1, 5.1m, 180
Optical isomer analysis was performed at (° C.). The results are shown in Table 1. In Table 1, the yield of permethrin acid is ethyl-
(±) -Ethyl contained in cis-permetholate-
It represents the molar yield corresponding to (+)-cis-permetholate.

Example 24 Pleulotus ostreatus (Pleulos) as a microorganism
tus ostreatus) IFO-7051 and reacted for 96 hours in the same manner as in Examples 1 to 23.

After the reaction, the reaction product was adjusted to pH 2 or less with concentrated hydrochloric acid, and then extracted with methyl isobutyl ketone. The permethyric acid produced from this was extracted with 1N sodium hydroxide and separated into an aqueous layer and an organic layer. Unreacted ethyl permetholate obtained by concentrating the organic layer was mixed with 10 cc of ethanol and 1 N sodium hydroxide
cc was added and the mixture was refluxed at 110 ° C. for 1 hour to hydrolyze the recovered ethyl permetholate. The reaction mixture was concentrated and dried to dryness, water was added to dissolve the residue, and permetrinic acid liberated by adjusting the pH to 2 or less with hydrochloric acid was extracted with methyl isobutyl ketone.

The extract was concentrated and evaporated to dryness to obtain 0.23 g of chemically almost pure permethyric acid. When the optical isomer analysis was performed in the same manner as in Examples 1 to 23, the (+) / (-) ratio was 96.2 / 3.8.

Examples 25 to 31 Reactions and analyzes were performed in the same manner as in Examples 1 to 23 except that 2.0 g of ethyl- (±) -cis, trans-permetholate (cis / trans ratio = 45/5) was used as a substrate. It was No trans-permethrinic acid was formed, and only cis-permethrinic acid was obtained. The results are shown in Table 2.

Examples 32 to 36 In the same manner as in Examples 1 to 23 except that 1.0 g of ethyl- (±) -cis-chrysancemate (in the general formula (I), X = methyl, R ′ = ethyl) was used as a substrate. Reaction and analysis were carried out to obtain cis-chrysanthenic acid (in the general formula (I), X = methyl, R = hydrogen).

The results are shown in Table 3.

Examples 37 to 41 Methyl- (±) -cis-dibromovinyl-dimethylcyclopropanecarboxylate as a substrate (general formula (I)
Then, the reaction and analysis were conducted in the same manner as in Examples 1 to 23 except that 1.0 g of X = bromine and R ′ = methyl) was used, and cis-dibromovinyl-dimethylcyclopropanecarboxylic acid (in the general formula (II), X = bromine, R = hydrogen) was obtained.

The results are shown in Table 4.

Continuation of the front page (51) Int.Cl. ⁵ Identification number Office reference number FI technical display location (C12P 41/00 C12R 1:06) (C12P 41/00 C12R 1:10) (C12P 41/00 C12R 1: 19) (C12P 41/00 C12R 1:20) (C12P 41/00 C12R 1:22) (C12P 41/00 C12R 1:40) (C12P 41/00 C12R 1: 645) (C12P 41/00 C12R 1: 74) (C12P 41/00 C12R 1:78) (C12P 41/00 C12R 1:88)

Claims (5)

[Claims] 1. A general formula (In the formula, X represents chlorine, bromine or a methyl group, and R '
Represents a C1-C4 alkyl group. This formula does not represent a steric relationship. ) Represented by (±) -cis-cyclopropanecarboxylic acid ester, or (±) -cis-cyclopropanecarboxylic acid ester and (±) -trans-
The mixture with cyclopropanecarboxylic acid esters is preferentially treated with a microorganism having the ability to asymmetrically hydrolyze cis-cyclopropanecarboxylic acid esters of the esters of general formula (1) or an esterase produced by the microorganism. Let (In the formula, X represents chlorine, bromine or a methyl group, and R
Represents hydrogen or a metal ion. This formula does not represent a steric relationship. ), And then recovering the optically active cis-cyclopropanecarboxylic acid of the formula (II) after resolution into the optically active cis-cyclopropanecarboxylic acid and its enantiomer or diastereomeric ester. Process for producing optically active cis-cyclopropanecarboxylic acid represented by formula (II) 2. A microorganism used or an esterase produced by the microorganism is Rhodotorula, Rhodosporidium, Ploirotas, Rhizomucor, Framulina,
Geotricum, Aspergillus, Candida,
Saccharomyces, Hansenula, Tolulopsis,
Rhodococcus, Penicillium, Dipoduscus,
Apsidia spp, Streptomyces spp, Nocardia spp, Arthrobacter spp, Pseudomonas spp, Escherichia spp, Bacillus spp, Bear Uberia spp, Metinicobia spp, Chromobacterium spp, Brevibacterium spp, Acinetobacter spp, Achromobacter spp, The microorganism according to claim 1, which is a microorganism belonging to the genus Kluyveromyces, the genus Frateuria, the genus Corynebacterium, the genus Alcaligenes, the genus Flavobacterium, the genus Klebziella, or the esterase produced by the microorganism. Method 3. The method according to claim 1 or 2, wherein X is chlorine and R'is methyl or ethyl. 4. The method according to claim 1 or 2, wherein X is bromine and R'is methyl or ethyl. 5. The method according to claim 1 or 2, wherein X is methyl and R'is methyl or ethyl.