CS272528B1 - Method of optically active fluorosubstituted 2,2-dimethylcyclopropancarboxyl acids and their salts preparation - Google Patents

Abstract

Method of preparation optically active the fluoro-substituted 2,2-dimethylcyclopropanecarboxylic acid acids and their salts of formula I wherein Y is either 3,3, 3-trifluoro-2,2-dichloro-1-propyl of formula C 1-6 Clg CH 3 - or 3,3,3-trifluoro- -2-chloro-1-prop-1-enyl group of formula CF3CCl = CH- and M represents hydrogen or a cation the alkali metal and the cyclogropane ring is in lRcis or lScis configuration lRtrans or lStrans, wherein the racemate, optionally in situ prepared cyclobutanone formula II in the cis- or trans-, z-configuration the presence of water and inert organic The solvent is reacted with bisulfite an optically active base, optionally also prepared in situ, to form a mixture diaetereoisomeric salts of cyclobutane sulfonic acid acids of formula III, wherein B represents an optically active base, followed by this diastereoisomeric mixture is separated into individual diastereoisomeric sulfone salts of formula (III), as defined above, and these are either directly or after decomposition to optically active cyclobutanones of formula II optionally with hydroxides and carbonates converted to an optically active cyclopropanecarboxylic acid an acid of formula I as defined above and cyclobutanones of formula II with undesirable configuration are converted tertiary amine mineral acid or quaternary chloride back to the starting racemic ketone of formula II, which returns to the reaction cycle.

Description

The present invention relates to a novel process for the preparation of optically active fluoro-substituted-2,2-dimethylcyclopropanecarboxylic acids and their salts of general formula I, wherein Y represents either a 3,3,3-trifluoro-2,2-dichloro-1-propyl group of formula CF 3. OCl 2 CH 2 -, or a 3,3,3-trifluoro-2-chloro-1-prop-1-enyl group of the formula CF IStrans. In particular, however, the invention relates to those acids of formula I which are in the IRcis configuration. Indeed, some derivatives of the optically active acid isomers of formula I in this absolute IRcis configuration are known to have extremely high insecticidal and acaricidal activity, while the corresponding derivatives of the other optical acid isomers of formula I are substantially less effective or almost ineffective, see for example P, D, Benthley, R. Cheetham, RK Huff, R · Pascoe, J, D. Sayle: Pestic. Sci. 1980, 11, 156. There is therefore an urgent need for simple processes for the preparation of acid-derived insecticides of the formula I with an optimally effective configuration. The amount applied and the environmental problems will be significantly less than when using compositions that also contain less effective or ineffective isomers *

It is known from the prior art that an optically active isomer of an acid of formula I in the IRcis configuration can be prepared by resolution of the corresponding racemic acid of formula I in the form of a salt with an optically active base, see for example EP 0 010 874. only half of the racemic acid is used in this procedure; procedures for the use of the second half of the racemate, composed of IScis optical antipodes, are not known,.

The above drawback substantially reduces the process for the preparation of optically active fluoro-substituted-2,2-dimethylcyclopropanecarboxylic acids and their salts of formula I, wherein Y is either a 3,3,3-trifluoro-2,2-dichloro-1-propyl group of formula CP 2 CClgC N- or 3,3,3-trifluoro-2-chloro-1-prop-1-enyl of the formula CF3CCl = CHa M is hydrogen or an alkali metal cation and the cyclopropane ring is in the IRcis or IScis, IRtrans or IStrans configuration, according to the invention. Its essence consists in that the racemate, optionally prepared in situ prepared cyclobutanone of formula II in cis- or trans- configuration, in the presence of water and an inert organic solvent, preferably selected from the group of alcohols or nitriles, reacts with sulfur dioxide and optically active base or with the bisulfite of the optically active base, optionally also prepared in situ, to give a mixture of diastereoisomeric salts of the cyclobutanesulfonic acid of formula III, wherein B is an optically active base. This diastereoisomeric mixture is separated by crystallization or fractional precipitation into individual diastereoisomers of the sulfonic acid salt of the formula III, which are converted into the optically active cyclopropanecarboxylic acid of the formula I, where Y has the meanings previously or after decomposition into optically active cyclobutanone isomers of the formula II. or, if they have the undesired configuration, is isomerized back to the parent racemic ketone of formula II and reused in the next synthetic cycle.

The reaction of the cyclobutanone racemate of formula II with sulfur dioxide and an optically active base is carried out in the presence of water and an inert organic solvent, preferably selected from the group of water-miscible inert solvents, for example lower alcohols, aliphatic nitriles, amides and sulfoxides. Sulfur dioxide can be introduced into the reaction mixture as such or in the form of the bisulfite of the optically active base or, if appropriate, in the form of an alkaline bisulfite adduct derived from the racemic cyclobutanone of the formula II, in combination with a salt of the optically active base.

As optically active bases, compounds known per se can be used, preferably selected from the group of optically active amines. Examples of suitable optically active bases are, for example, / - / - ephedrine, / + / - ephedrine, S - / - / - phenylethylamine, / + / - 2-aminobutanol, I-phenylalanine tert-butyl ester. The optically active base or salts of the optically active base are used in an amount of 0.5 to 1.5 molar equivalents.

CS 272528 Bl 2

The separation of the diastereoisomeric salts of the formula III is carried out by methods known per se, preferably, for example, by fractional crystallization or fractional precipitation, usually from an inert, water-miscible organic solvent.

The resolved diastereoisomeric salt of formula III can be converted in the presence of a strong base to an optically active acid, or the salt of formula I buzzes directly or, after decomposition, into an optically active ketone of formula II. The decomposition of the salt of the formula III into the ketone of the formula II is carried out by the gentle action of an inorganic or organic acid or a base or an oxidizing agent. Preferably, the reaction is carried out in a two-phase medium, the liberated ketone of the formula II being converted into an inert organic solvent.

The actual conversion of a diastereoisomeric sulfone salt of the formula III or an optically active cyclobutanone of the formula II into an optically active cyclopropanecarboxylic acid of the formula I or its derivatives is carried out by treatment with a strong base in an inert organic solvent or water or a water-inert organic solvent mixture. Preferably, it is carried out in particular in a water-inert, water-immiscible organic solvent mixture, for example toluene, optionally in the presence of a phase transfer catalyst. The strong bases used are in particular alkali metal or alkaline earth metal hydroxides, alkoxides or carbonates, which are usually carried out with more than a molar equivalent of base, at a temperature of -20 to 100 [deg.] C. In some cases, it is advantageous to operate successively in two different temperature regimes. First, at a lower temperature, preferably in the range of -20 to +20 ° C, the four-membered ring of a compound of formula II or formula III is contractioned into a three-membered ring to give a cyclopropanecarboxylic acid salt of formula I, wherein Y is CF ₃ CCl 2 CH ₂ -. then dehydrohalogenation is carried out, if necessary, at a higher temperature, preferably in the range from 70 to 100 [deg.] C., to give an acid or an acid salt of the formula I in which Y is CP1, CC1 = CH-. The stereoselectivity of the contraction of the four-membered ring, the so-called Bavarian precinct, depends very substantially on the reaction conditions, for example temperature and solvent. At a low temperature of up to 5 ° C, in water from the optically active cis-cyclobutanone of the formula II, a predominantly optically active cis-acid of the general formula I is formed, in which Y is a 3,3,3-trifluoro-2,2-dichloro-1-propyl group. while, for example, in aqueous dioxane at a temperature of 40 to 50 ° C, an optically active mixture of cis- and trans-cyclopropanecarboxylic acids of formula I is formed, wherein Y is partly CP ₁ CCl 2 CH ₂ - and partly CF 3 CCl 2 CH-.

The main advantage of the process according to the invention is the possibility of easily converting the undesired diastereoisomer of the salt of the formula III or the undesired optical isomer of the cyclobutanone of the formula II back to the starting racemic cyclobutanone of the formula II. This conversion, which is an integral part of the invention, can be performed almost quantitatively in a two-step process. In the first step, the undesired diastereoisomer of the salt of formula III is converted to the optically active cyclobutanone of formula II with the undesired absolute configuration? in the second step, it is racemized in an inert organic solvent or without a solvent by known racemization catalysts selected from the group of tertiary amines, mineral acids and quaternary ammonium chlorides. The obtained racemate of formula II is used in the next reaction cycle.

The processes according to the invention are illustrated by the following examples, which, however, do not limit the finding in any way.

Example 1

A solution of 1.6 g (9.7 mmol) of β-ephedrine in 50 mL of 60% ethanol was saturated with sulfur dioxide at 30 ° C. To the solution was added 3.0 g (10 mmol) of racemic cyclobutanone of formula II, the mixture was saturated with SO ₂ , allowed to stand for 3 hours at room temperature and cooled to 0 ° C in the presence of a seed crystal. The precipitated crystalline salt was filtered off with suction, washed with pentane and dried. The yield was 2.4 g. Double crystallization from 60% ethanol (18 and 14 ml) at 70 ° C gave 1.8 g (67% of theory) of a salt which

CS 272528 B1 with hydrochloric acid in ethanol gave the ketone of formula -84.7 ° (c 0.5; CCl 2),

mp 143-47 ° C.

Example 2

To a solution of the potassium bisulphite adduct of the racemic ketone of formula II (4.2 g;

mmol) in 25 mL of 60% ethanol was added hot / - / - ephedrine hydrochloride (1.2 g;

5.9 mmol) in 5 ml of 60% ethanol. After seeding and slow cooling to 20 [deg.] C., the salt was filtered off with suction, washed with 1 ml of 60% ethanol and dried. The yield was 1.6 g (58% of theory). The salt was taken up in 10 ml of ethanol and 2 ml of hydrochloric acid (1: 1) with stirring at 65 DEG C. for 1 hour. water, the organic layer was separated, washed with water and dried. Evaporation gave 0.74 g (86%) of crystalline ketone J365 _CS and -90.9 ° (c 0.5, CCl ^).

Example 3

1.8 g of the resolved diastereoisomeric salt of formula III (B> / - / - ephedrine) were added to 25 ml of a 20% aqueous KOH solution at -10 ° C over 1 min with vigorous stirring. After 2 h, stirring at -10 ° C and 1 h at 0 ° C, the clear mixture was extracted with petroleum ether. The alkaline aqueous layer was acidified and the liberated acid was taken up in ether. After drying and evaporation of the solvent, 0.9 g (97% of theory) of a crystalline acid of the formula I (Y, CP2 CClgCHg-) containing 88% of the cis-isomer are obtained. Example 4 ₀

The procedure of Example 3 was followed, but the acid obtained was further heated with ml of 4% aqueous KOH with stirring for 6 hours at 100 DEG C. The reaction mixture was extracted with toluene, acidified and the product taken up in ether. Gas chromatographic analysis showed that the mixture consisted of 89% cis-acid of formula I (Y = CP 2 CCl = CH-), 4% trans-acid of formula I (Y = CF 2 CCl 2 CH 2 -) and 5% of an unknown impurity. After drying and evaporation of the ether extract, 0.74 g (90% of theory) of crude product, _D -24.7 ° (c 2.0; CHCl3), was obtained, from which the pure optically active cis-acid of formula I (Y *) was obtained. CP ^ CC1 = = CH ~) obtained by crystallization. Example 5 '

10.0 g of triturated racemic cis-cyclobutanone of formula II (0.034 mol) were poured into 80 ml of 20% aqueous potassium hydroxide at -10 DEG C. with vigorous stirring and the reaction mixture was further stirred at this temperature for 6 hours. The mixture was then washed with petroleum ether. , acidified and the product was taken up in ether. Drying and evaporation of the solvent gave 8.8 g (94% of theory) of the product of formula I (Y (CF 3 CCL 2 CH 2 -) containing 88% of the cis-isomer. Example 6

The procedure of Example 5 was followed, except that a single optical isomer was used instead of the racemate of formula II. 94% of product was obtained which, according to vpc. was practically identical to the product of Example 5, but was optically active.

Example 7

A mixture of 1.1 g of crude optically active cis-cyclobutanone of formula II and 75 mg of tetrabutylammonium chloride was heated at 125 ° C for 7 hours. The reaction mixture was partitioned between pentane and water, the organic layer was washed repeatedly with water, dried and evaporated to dryness. . The solid residue weighed 1.08 g and contained 96% of cis- and 4% of trans-racemic cyclobutanone of formula II, Example 8

The procedure of Example 1 was followed, except that 6% aqueous acetonitrile was used instead of aqueous ethanol. 50% of theory of the expected optically active salt was obtained.

Claims (2)

Process for the preparation of optically active fluoro-substituted 2,2-dimethylcyclopropanecarboxylic acids and their salts of general formula I, wherein Y represents a 3,3,3-trifluoro-2,2-dichloro-1-propyl group of formula CF 3 CClgCH 2 - or 3, 3,3-trifluoro-2-chloro-1-prop-1-enyl group of formula CP 2 CCl = CH- and M represents hydrogen or an alkali metal cation and the cyclopropane ring is in the IRcis or IScis, IRtrans or IStrans * configuration that the racemic or in situ prepared cyclobutanone of formula II in cis- or trans-configuration, in the presence of water and an inert organic solvent, preferably selected from the group of alcohols or nitriles, is reacted with a bisulfite of an optically active base, preferably from the group of amines , optionally prepared in situ, to give a mixture of diastereoisomeric salts of cyclobutanesulfonic acid of formula III, wherein B is an optically active base, after which the diastereoisomeric mixture is separated into the individual diastereo by crystallization or fractional precipitation. isomers of the sulfone salt of formula III as defined above, which are converted directly or after decomposition into optically active cyclobutanones of formula II, optionally with hydroxides and carbonates, into optically active cyclopropanecarboxylic acid of formula I as defined above, cyclobutanones of formula II with undesired configurations are converted by treatment with a tertiary amine, mineral acid or quaternary chloride back to the starting racemic ketone of formula II, which is returned to the reaction cycle. 2. Process according to claim 1, characterized in that the racemic cyclobutanone of formula I is reacted in the cis configuration.