CS257291B2 - Production method of pairs of enantiomeres alfa-kyan-3-phenoxy-4-fluorbenzylester permethrin acid - Google Patents

Abstract

Process for preparing a mixture of enantiomeric pairs .alpha.-cyano-3-phenoxy-4-fluorobenzyl ester permethrin acids (b) 1R-3R-alpha-S + 1S-3S-alpha-R a (d) 1R-3S-alpha-S · + 1S-3R-alpha-R, characterized in that all 8 stereoisomers are mixed .alpha.-cyano-3-phenoxy-4-fluorobenzyl ester permethrin acids dissolve in an alcohol having from 2 to 4 carbon atoms the secondary or tertiary amine is always present From 2 to 6 carbon atoms in each of the alkyl the base and the solution obtained a mixture of pairs of enantiomers b and d crystallizes.

Description

The present invention relates to a process for preparing certain pairs of permethrinic acid alpha-cyano-3-phenoxy-4-fluorobenzyl ester enantiomers using a mixture of all steric and optical isomers as starting material.

It is known that enantiomers of compounds with an acidic hydrogen atom on an asymmetric carbon atom can be epimerized by treatment with bases. The carbanions formed by the reaction with bases are rapidly converted to their possible enantiomeric forms. In the short term, they occupy a planar state (P. Sykes: Reaktionsaufklarung - Methoden und Kriterien der Organischen Reaktionsmechanistik; Verlag Chemie 1973, pp. 133 and D. J. Cram: Fundamentals in Carbanion Chemistry, pp. 85-105, Academic Press New York (1965).

This case is also observed, for example, in the epimerization of optically active mandelonitrile of formula

CN

and the corresponding methyl ester of formula

CN

H which readily proceeds with base catalysis to form racemic compounds (Smith: J. Chem. Soc. 1935, p. 194 and Smith: Ber. 64 (1931) p. 427).

Depending on the solubility of the equilibrium components of the epimerization equilibrium state in the labile diastereomer, the equilibrium can be shifted to a great extent or completely if the part crystallizes. This case is referred to as second order asymmetric transformation (K. Mislow, Introduction to Stereochemistry, W. C. Benjamin Inc., New York, Amsterdam 1966, p. 122 above).

However, this effect can be practiced only if a solvent is found in which the stereoisomer and / or its mirror image is more soluble and the second stereoisomer and / or its mirror image is more difficult to dissolve.

Such a reaction has already been known, for example, in the case of optically active 2,2-dimethyl-3R- (2,2-dichlorvinyl) -cyclopropane-1R-carboxylic acid alpha-cyano- (alpha-RS) -3-phenoxybenzyl ester (cf. DE-OS) 2,718,039). Ammonia and amines are used as epimerizing bases. Acetonitrile as well as lower alkanols are used as solvents. However, this is based on an ester of a certain carboxylic acid enantiomer (1R3R).

However, no mention is made that this process can also be used to achieve separation of certain stereoisomers from the racemic mixture of all 8 stereoisomers of the above compound by epimerization of others.

Furthermore, it is known from DE-OS 2 903 057 that the 4 stereoisomeric alpha-cyano- (alpha-RS) -3-phenoxybenzyl esters of racemic carboxylic acid can also be epimerized by treatment with bases on the alpha carbon atom next to the cyano group and crystallize from suitable solvents a single enantiomeric pair. Also here, lower alcohols, especially methanol, are mentioned as suitable solvents. Aqueous ammonia is used as the base.

According to EP-OS 22 382, a process for converting a mixture of stereoisomers of 4 cis-isomers of alpha-cyano-3-phenoxybenzyl ester of permethrin acid into a pure pair of enantiomers proceeds by crystallizing the more difficultly soluble pair of enantiomers in a suitable solvent. and recrystallizing the more difficultly soluble pair of enantiomers. The crystallization and epimerization are carried out in separate stages. A suitable solvent is hydrocarbons, in particular hexane. The bases used are amines, in particular triethylamine.

DE-OS 3 115 881 discloses another method for converting a mixture of stereoisomers of all 4 cis-isomers of 3- (2,2-dichloro-vinyl) -2,2-dimethylcyclopropanecarboxylic acid alpha-cyano-3-phenoxybenzyl ester into a single pair of enantiomers. An organic amine is used as the solvent and at the same time as the base. Triethylamine and diisopropylamine are described as well suited. Tri-n-propylamine and n-butylmethylamine are not suitable. However, this procedure also uses a sterically uniform portion of the racemic acid (cis-isomers). There is also no mention of whether it is possible to separate the individual stereoisomers also from the mixture of all 8 possible stereoisomers.

It was not possible to predict which solvents were suitable for resolution of enantiomers or diastereomers of pairs of enantiomers.

It is therefore necessary to provide a suitable resolution system for each individual compound and, in the case of cis-trans isomers, also for each individual cis- and / or trans-pair of stereoisomers. Experience from principally similar cases can only be transmitted occasionally and not in a completely predictable way.

In particular, it is not clear from the above literature whether and with which solvents the desired cis and trans diastereomers can be separated simultaneously.

2,2-Dimethyl-3-dichloro-vinyl-cyclopropanecarboxylic acid alpha-cyano-3'-phenoxy-4'-fluorobenzyl ester (permethrinic acid) corresponds to structural formula I

(AND)

This compound has 3 asymmetric centers (T), melts in the following pairs of enantiomers:

(3) and alpha. This compound is therefore b

c d

1R-3R-alpha-R 1R-3R-alpha-S 1R-3S-alpha-R 1R-3S-alpha-S + 1S-3S-alpha-S + 1S-3S-alpha-R + 1S-3R-alpha -S + 1S-3R-alpha-R

1,3 cis

1,3 trans

The pairs of enantiomers b and d are particularly effective against numerous economically interesting pests.

In the technical preparation of the compound of formula I, the ratios of the enantiomeric pairs a to d vary only within a certain narrow range. In the case of a typically engineered compound of formula I, pairs of enantiomers a to d occur, for example, in the following ratio (based on 100%):

a = 24.5% b = 17.5% c = 34.5% d = 23.5%.

It was necessary to find a method by which the ratio of pairs of enantiomers a to d in the mixture of all enantiomers was changed in favor of pairs of enantiomers b and d.

It has been found that a mixture of all 8 permethrinic acid alpha-cyano-3-phenoxy-4-fluorobenzyl ester stereoisomers can be converted to pairs of enantiomers b of 1R-3R-alpha-S + 1S-3S-alpha-R and 1R-3S-alpha- S + 1S-3R-alpha-S, by dissolving this mixture of all stereoisomers in a (C 2 -C 4) alkanol, a secondary or tertiary amine (C 2 -C 6) is added in each of the alkyl moieties as the base and from the obtained of the solution, a mixture of pairs of bad enantiomers crystallizes, the ratio of co-crystallized pairs of enantiomers b / d corresponding to the cis / trans ratio of the used pairs of enantiomers (a + b) / (c + d).

It is surprising that for this process it is not necessary to start from an ester which is sterically uniform in part of the acid, but that the conversion of a technically formed mixture of all 8 cis- and trans-series stereoisomers results in a mixture consisting essentially only of 4 cis and trans-stereoisomers.

The process of the invention is carried out in a C 2 -C 4 alkanol solvent. Isopropyl alcohol is preferably used.

The base used is a secondary or tertiary alkylamine having from 2 to 6 carbon atoms in each of the alkyl moieties. Preferably, diisobutylaithine and tri-n-butylamine are used.

The ratio between alkanol and amine (in parts by weight) may vary between alkanol / amine = 1000/1 to 1/10. Preferably an alkanol / amine ratio of 100 / 0.5 to 100/20 is used.

. The ratio of the technical compound of structural formula I used and the alkanol used (in parts by weight) can vary in the range of I / alkanol = 10/1 to 1/10. A range of 3/1 to 1/3 is preferred.

The alkanols and amines are used in a substantially anhydrous state. The technical cis / trans starting material is dissolved in a mixture of alkanol and amine base at a temperature of 40 to 80 ° C, preferably at a temperature between 50 and 70 ° C. The solution is then cooled to -25 to +30 ° C. Crystallization may be accelerated by the addition of a few small crystals of the pair of enantiomers b + d. However, crystallization also occurs spontaneously. Isolation of pairs of b + d enantiomers is carried out in a conventional manner, for example by filtration or centrifugation.

The following examples illustrate the invention in more detail without limiting its scope.

The technical composition of the following composition was used in the examples:

isomer composition (based on 100%):

Ia = 25.2%

Ib = 19.2%

Ic = 32.2%

Id = 23.3%.

Active substance content = 92% (Ia + b + c + d)

Example 1

100 g of the cis / trans technical mixture of all-8 stereoisomers of 3- (2,2-dichloro-vinyl) -2,2-dimethyl-cyclopropanecarboxylic acid alpha-cyano-3-phenoxy-4-fluorobenzyl ester was dissolved in 100 g with heating at 50 ° C isopropyl alcohol. After cooling to 20 ° C, 4 g of diisobutylamine are added to this mixture. The reaction mixture was then stirred at 20-23 ° C. This usually results in spontaneous crystallization, which can be accelerated by the addition of several seed crystals Ib and Id. After stirring at 20-23 ° C for nine days, the reaction mixture was cooled to 5 ° C and the resulting crystals were filtered off. The crystals were washed twice with 50 ml of ice-cold isopropyl alcohol, filtered off with suction and air-dried.

82.2 g (87.8% of theory) of a colorless crystalline product, m.p. 82 DEG-89 DEG C., are obtained, followed by an isomer composition (based on 100%) which is determined by high performance liquid chromatography.

Ia = 0.8%, Ib = 38.8%, Ic = 1.9%, Id = 58.5%.

Example 2

100 g of a cis / trans technical mixture of all 8 3- (2,2-dichloro-vinyl) -2,2-dimethyl-cyclopropanecarboxylic acid alpha-cyano-3-phenoxy-4-fluorobenzyl ester stereoisomers were reacted as described in Example 1 with the alkanols and amines mentioned above. The results are shown in Table I.

Table I

Alkanol + Amin Amount in g Time stirring in days Yield of crystalline product in% of theory Isomer composition Ia [0057] Ib Xc Id methanol 100 ALIGN! 9 0 diisobutylamine 4 decomposition occurs n-propanol 100 ALIGN! 9 64 0.5 31.8 1.9 65.8 diisobutylamine 4 n-butanol 100 ALIGN! 9 51.3 0.4 16.1 2.2 81.0 di i sobutylamine 4 sec.butanol 100 ALIGN! 9 49 - - - - diisobutylamine : 4 tert.butanol 100 ALIGN! 9 40 - - - - diisobutylamine 4 ethanol 100 ALIGN! 7 55 0.24 15.8 1.4 82.6 diisobutylamine 4

Claims (5)

A process for the preparation of a mixture of pairs of enantiomers of permethric acid alpha-cyano-3-phenoxy-4-fluorobenzyl ester bR-3R-alpha-S + 1S-3S-alpha-R and 1R-3S-alpha-S + 1S-3R- alpha-R, characterized in that the mixture of all 8 perethrinic acid alpha-cyano-3-phenoxy-4-fluorobenzyl ester stereoisomers is dissolved in a C 2 -C 4 alcohol, a C 2 -C 6 secondary or tertiary amine is added in each case of each of the alkyl moieties as a base and a mixture of pairs of enantiomers crystallized from the solution obtained: 2. A process according to claim 1, and / or tri-n-butylamine. 3. The process of claim 1, wherein isopropyl alcohol is used. 4. Method according to claims 1 to 3, characterized in that the load-bearing parts are 1000/1 to 1/10. Method according to one of Claims 1 to 4, characterized in that the load-bearing parts are 100 / 0.5 to 100/20. i and d. according to claim 1, characterized in that diisobutylamine is used as the base;