CS257291B2 - Process for preparing a mixture of permethrin acid a-cyano-3-phenoxy-4-fluorobenzyl ester pairs - Google Patents

Abstract

A method for producing a mixture of pairs of enantiomers of permethrin acid alpha-cyano-3-phenoxy-4-fluorobenzyl ester (b) lR-3R-alpha-S + lS-3S-alpha-R and (d) lR-3S-alpha-S· + lS-3R-alpha-R, characterized in that a mixture of all 8 stereoisomers of permethrin acid alpha-cyano-3-phenoxy-4-fluorobenzyl ester is dissolved in an alcohol with 2 to 4 carbon atoms, a secondary or tertiary amine with 2 to 6 carbon atoms in each of the alkyl moieties is added as a base, and a mixture of pairs of enantiomers b and d is crystallized from the solution obtained.

Description

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

It is known that enantiomers of compounds with an acidic hydrogen atom on the asymmetric carbon atom can epimerize under the action of bases. The carbanions formed by reaction with bases undergo a permanent rapid conversion to their respective enantiomeric forms. In doing so, they briefly assume a planar state (P. Sykes: Reaktionsaufklarung - Methoden und Kriterien der organischen Reaktionsmechanistik; Verlag Chemie 1973, p. 133 and D. J. Cram: Fundamentals in Carbanion Chemistry, p. 85-105, Academie Press New York (1965).

This case is also observed, for example, in the epimerization of the optically active mandelic acid nitrile of the formula

CN

and the corresponding methyl ester of the formula

CN

H which readily proceeds under base catalysis, forming 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 in the labile diastereomer, the equilibrium can be shifted very significantly or completely to one side if part of it crystallizes. This case is referred to as a second order asymmetric transformation (K. Mislow, Introduction to Stereochemistry, W. C. Benjamin lne. New York, Amsterdam 1966, p. 122 above).

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

Such a reaction was already known, for example, in the case of the optically active alpha-cyano-(alpha-RS)-3-phenoxybenzyl ester of 2,2-dimethyl-3R-(2,2-dichlorovinyl)cyclopropane-1R-carboxylic acid (cf. DE-OS 2 718 039). Ammonia and amines are used as epimerization-active bases. Acetonitrile and lower alkanols are used as solvents. However, the ester of a certain enantiomer of the carboxylic acid (1R3R) is used as the starting material.

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

Furthermore, it is known from DE-OS 2 903 057 that also 4 stereoisomeric alpha-cyano-(alpha-RS)-3-phenoxybenzyl esters of racemic carboxylic acid can be epimerized by the action of bases on the carbon atom in the alpha position next to the cyano group and the individual enantiomeric pair can be crystallized from suitable solvents. Lower alcohols, in particular methanol, are also mentioned as suitable solvents. Aqueous ammonia is used as the base.

In a similar manner, according to EP-OS 22 382, a method 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 is carried out by crystallization of the more difficultly soluble pair of enantiomers in a suitable solvent, followed by epimerization of another pair of enantiomers remaining in solution by the action of a base and recrystallization of the more difficultly soluble pair of enantiomers. Crystallization and epimerization are carried out in separate stages. Suitable solvents include hydrocarbons, especially hexane. Amines, especially triethylamine, are used as bases.

Another method for converting a mixture of stereoisomers of all 4 cis-isomers of alpha-cyano-3-phenoxybenzyl ester of 3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylic acid into an individual pair of enantiomers is known from DE-OS 3 115 881. An organic amine is used as solvent and at the same time as base. Triethylamine and diisopropylamine are described as being very suitable. Tri-n-propylamine and n-butylmethylamine are listed as unsuitable. However, in this process, a sterically uniform portion of the racemic acid (cis-isomers) is also used. There is also no mention here of whether it is also possible to separate the individual stereoisomers from a mixture of all 8 possible stereoisomers.

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

It is therefore necessary to develop a suitable division 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 fundamentally similar cases can only be transferred occasionally and then not in a completely predictable way.

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

Alpha-cyano-3'-phenoxy-4'-fluorobenzyl ester of 2,2-dimethyl-3-dichlorovinylcyclopropanecarboxylic acid (permethrinic acid) corresponds to the structural formula I

(AND)

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

(3) and alpha. This compound therefore occurs b

c d

lR-3R-alpha-R lR-3R-alpha-S lR-3S-alpha~R lR-3S-alpha-S + lS-3S-alpha-S + lS-3S-alpha-R + lS-3R-alpha-S + lS-3R-alpha-R

1,3 cis

1.3 trans

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

In the industrial production of a compound of formula I, the ratios of the enantiomer pairs a to d vary only within a narrow range. In the case of a typically industrially produced compound of formula I, the enantiomer pairs 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 way to change the ratio of enantiomer pairs a to d in a mixture of all enantiomers in favor of enantiomer pairs b and d.

It has been found that a mixture of all 8 stereoisomers of alpha-cyano-3-phenoxy-4-fluorobenzyl ester of permethrin acid can be converted into pairs of enantiomers b lR-3R-alpha-S + lS-3S-alpha-R and d lR-3S-alpha-S + lS-3R-alpha-S by dissolving this mixture of all stereoisomers in an alkanol with 2 to 4 carbon atoms, adding a secondary or tertiary amine with 2 to 6 carbon atoms in each of the alkyl moieties as a base, and crystallizing a mixture of pairs of enantiomers b and d from the resulting solution, the ratio of the co-crystallized pairs of enantiomers b/d corresponding to the cis/trans ratio of the pairs of enantiomers (a + b)/(c + d) used.

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

The process according to the invention is carried out in an alkanol with 2 to 4 carbon atoms as solvent. Isopropyl alcohol is preferably used.

Secondary or tertiary alkylamines with 2 to 6 carbon atoms in each alkyl moiety are used as bases. Diisobutylamine and tri-n-butylamine are preferably used.

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

The mutual ratio of the technical compound of structural formula I used and the alkanol used (in parts by weight) can vary in the range I/alkanol = 10/1 to 1/10. The range 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 as base at a temperature of 40 to 80 °C, preferably at a temperature of between 50 and 70 °C. The solution is then cooled to a temperature of -25 to +30 °C. Crystallization can be accelerated by adding a few small crystals of the enantiomer pair b + d. However, crystallization also occurs spontaneously. Isolation of the enantiomer pairs b + d is carried out in the usual manner, for example by filtration or centrifugation.

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

In the examples, a technical product with the following composition was used:

Isomer composition (based on 100%):

Ia = 25.2%

Ib = 19.2%

Ic = 32.2%

Id = 23.3%.

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

Example 1

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

82.2 g (87.8% of theory) of a colorless crystalline product with a melting point of 82-89°C and the following isomer composition (based on 100%) was obtained, which was determined by high-performance liquid chromatography.

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

Example 2

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

Table I

Alkanol + Amine Quantity in g Mixing time in days Yield of crystalline product in % of theory Composition of isomers Ia Ib Xc Id methanol 100 9 0 diisobutylamine 4 decomposition occurs n-propanol 100 9 64 0.5 31.8 1.9 65.8 diisobutylamine 4 n-butanol 100 9 51.3 0.4 16.1 2.2 81.0 diisobutylamine 4 sec.butanol 100 9 49 - - - - diisobutylamine : 4 tert.butanol 100 9 40 - - - -- diisobutylamine 4 ethanol 100 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;