HU205594B - Process for producing optical isomeres of cyclopropane-carboxylic acids5 - Google Patents

Abstract

The invention relates to a novel process for preparing the optical isomers of 2,2-dimethyl-3-(2,2-disubstituted vinyl)cyclopropanecarboxylic acids of general formula (I), wherein R<1> and R<2>, independently from another, stand for halogen or a C1-4alkyl group. The process of the invention comprises reacting a racemic compound of general formula (I), wherein R<1> and R<2> are as defined above, or a salt thereof with a phenylglycine derivate of general formula (II), wherein R<3> means a cyano or carboxamide group, or an acid addition salt thereof, separating the member of the diastereoisomeric salt pair, which precipitates in crystalline form, in a manner known per se and liberating by an acid therefrom the optically active acid of general formula (I) containing (1S) configuration when R<3> in the compound of general formula (II) used means cyano group, or the optically active acid containing (1R) configuration, respectively, when R<3> in the compound of general formula (II) used means carboxamide group, repeating, if desired, this operation 1 to 5 times, recovering the diastereoisomeric salt remaining in the mother liquor in a manner known per se and obtaining therefrom the optically active antipode acid of general formula (I) in a manner known per se.

Description

The present invention relates to a process for the preparation of a compound of formula I wherein R ¹ and R ² are independently halogen or C 1-4 alkyl-3- (2,2-disubstituted-vinyl) -2,2-dimethylcyclopropanecarbonate. for the preparation of blind optical isomers, starting from the corresponding racemic carboxylic acids, by resolution of diastereomeric salts with optically active basic 2-phenylglycine derivatives of the formula (() wherein R ³ is cyano or an acid amide group.

3- (2,2-Disubstituted-vinyl) -2,2-dimethyl-cyclopropanecarboxylic acids of formula I are intermediates of high potency commercial insecticides. Because the acids of Formula © contain two asymmetric centers, they have four stereoisomers. It has been found that the biological activity spectrum of esters made from stereoisomers differs significantly and it is therefore important to isolate the optical antipodes from the racemic acids. The separation of cis and trans racemates from the racemic cis, trans acidic mixtures of the general formula (©) in industrial syntheses has been solved in several ways. Disclosures in the Federal Republic of Germany, Helv. Chim. Acta 7, 390 (1924)]. Several methods are known for separating optical isomers of racemic cis-trans acids. For example, according to British Patent No. 1,178,423, trans-chrysanthemic acid was resolved with quinine and, after repeated recrystallization or salt formation, gave the 1R-isomer.

For example, optically active alpha-naphthylethylamine (U. S. Patent Publication No. 2,300,325), alpha-phenylethylamine (European Patent Application No. 10,874), threo-2-dimethylamino- have been described for the separation of isomers of acids of formula © 1- (4-nitrophenyl) propanediol-1,3 (French Patent No. 7,913,116). The disadvantage of these processes is that the resolving agents are most often used in equivalent amounts with respect to the racemic acids, and the resolving agents are expensive, difficult to access and poorly recoverable compounds. U.S. Patent No. 2,826,952 discloses the use of (-) - 2-phenylglycine ethyl ester to separate optical isomers of acids of Formula ©. The diastereomeric salt formation is carried out in an aqueous medium and the optically active acids of formula (I) obtained from crystalline salt or mother liquor are recrystallized from petroleum ether. However, a salt of alternating optical purity is used for salt formation and therefore the optical purity of the acid enantiomers of formula (I) obtained from diastereomeric salts is also variable. A significant disadvantage of the process is that the diastereomeric salt formation is carried out in more than fifty times the amount of water calculated as racemic acid, thus the utilization of the devices and the productivity are low. Neither of these methods describes the purification of the enantiomer remaining in the mother liquor of the salt formation. In the embodiment of the above description, the specific rotation value of trans-permetric acid (36 ° is about 10% less than the maximum specific rotation capacity known in the literature (U.S. Patent No. 2,628,477). The revolving agent used is sensitive to hydrolysis, regeneration can be done with poor efficiency.

It is therefore an object of the present invention to provide a method by which both optical isomers of the acids of formula © can be prepared in a simple manner using optically pure, readily available resolving agents.

It has been found that the basic (R) -2-phenylglycine derivatives of formula (Π), wherein R ³ is cyano or an acid amide group, form a well crystallizing salt with the cyclopropanecarboxylic acids of formula (©) in a polar solvent or solvent mixture. The resolution agents of formula (I) can be prepared from benzaldehyde in a simple manner. (R) -2-Phenylglycine nitrile can be prepared according to French Patent No. 2,141,354 and (R) -2-phenylglycine amide can also be obtained in a well known manner by acid hydration of the nitrile in very good yields. It was unexpected and therefore novel to observe that the configuration of the acid of Formula © in the crystallizing diastereomeric salts is always dependent on the quality of the R ₃ substituent of the compound of Formula ©.

When R ³ is a cyano group, it will always be (1 S) configuration of the formula © acid enriched in the salt crystals, and when R ³ is an amide function, it is always the (R) -configuration on the acid of formula © give crystalline diastereomeric ethoxycarbonylethyl.

It has been found that both enantiomers of cyclopropanecarboxylic acids © can be obtained purely as crystalline diastereomeric salts with the same configuration as the resolution agents H. It is also an object of the present invention to realize that salt formation can be carried out with water or in a mixture of water and a C 1 -C 4 alcohol with high efficiency in the formation of salts with the formula (H). It is important for the efficiency of the process that the racemic acids of formula (I) are reacted with less than one equivalent, preferably a semi-equivalent resolving agent (Π), while the optically active enantiomeric mixtures of formula (I) are preferably equivalent to the can be purified by reconstitution with a resolving agent of the formula. During the salt formation, a portion of the acid of formula I which does not react with the resolving agent is kept in solution as an alkali metal salt. It has been found that the use of an excess of alkali is not advisable in the resolution with (R) -2-phenylglycine amide because it causes a decrease in the production and in the optical purity of the acid enantiomer in the salt. The use of (R) -2-phenylglycine nitrile in the presence of excess alkali also reduces the diastereomeric salt production, but the optical purity increases.

Accordingly, the present invention provides a phenylglycine of a racene compound of formula (I) wherein R ¹ and R ² are as defined above or a salt thereof of formula (II) wherein R ³ is cyano or an acid amide group. reaction with a derivative or an acid addition salt, the crystalline excellent member of the resulting diastereomeric salt pair alone

EN 205 594 Β in a known manner and is optically active with an acid - when R ³ is cyano in the compound of formula (II) then it is in the S configuration when R ^{3 in the} compound of the formula (II) used an acid amide group, liberating an acid of formula (I) - l) and, if desired,

Repeatedly, 1 to 5 times, the diastereomeric salt remaining in the mother liquor is recovered in a manner known per se, and the optically active acidantipod of formula (I) is recovered therefrom in a known manner.

Preferably, one mole of the racemic acid of formula (I) is dissolved in one mole of alkali hydroxide in water, and a solution of the hydrochloride of the resolving agent (II) in water or water and a C 1 -C 4 alcohol is added at 20-60 ° C. .

The reaction mixture was cooled to 0-25 ° C and the crystalline diastereomeric salt was isolated by filtration. The salt contains the 1R-acid enantiomer when using R-2-phenylglycine amide, and the R-2-phenylglycinonitrile when using the R-2-phenylglycine nitrile. The optically active acid isomers of formula (I) are liberated from the diester stereoisomeric salts by the addition of mineral acid and, for example, by filtration or extraction with a water-immiscible organic solvent and evaporation of the organic solvent solution. The other acid enantiomer is also recovered from the salt filtration filtrate after distillation of the possible alcoholic strength of the solution by mineral acidification. Alternatively, the racemic acids of formula (I) may be suspended in a mixture of water and a C 1 -C 4 alcohol to which is added the resolving agent and the required amount of alkaline hydroxide, determined by the resolution of the resolving agent and the alkali hydroxide. the total amount is equivalent to the racemic acid and the reaction mixture is heated to dissolution, cooled to 0-25 ° C and the crystalline diastereomeric salt is isolated by filtration. If desired, the optical purity of the acid enantiomers of formula (I) thus obtained is increased by re-resolution. The re-resolution is carried out with (R) 2-phenylglycine amide for the 1R-acid isomers and (R) 2-phenylglycine-nitrile for the 1S-acid isomers under the same conditions as the first salt formation, except that the resolving agent is preferably in an amount equivalent to or less than the amount of enantiomer present. If desired, the optical purity of the acid enantiomer of formula (I) remaining in the mother liquor of the salt formation may be further increased by adding the mineral acid salt of the resolving agent (II) directly to the mother liquor at a temperature of 20-60 ° C. Even so, the resolving agent. if the mother liquor is rich in the 1R acid isomer, then (R) -2-phenylglycine amide is used, otherwise (R) -phenylglycine nitrile is used. The near-racemic acids of formula (I) which remain in the resolvations are regenerated and reused for resolution.

However, the invention is illustrated by the following non-limiting examples.

Example 1

3.4 g of racemic trans-chrysanthemic acid (R ¹ and R ^{2 in} formula I are methyl) are dissolved in 20 ml of methanol and 2 ml of 5 M sodium hydroxide are added. 1.52 g of (R) -2-phenylglycine amide are then added with stirring, another 8 ml of water is added and the mixture is dissolved at 50-55 ° C. The solution was cooled to 0 ° C and the precipitated crystals were filtered and washed with water. The wet salt was suspended in a mixture of 10 mL of water and 10 mL of chloroform and acidified to pH 1 with 5 M salt. The organic layer was separated and the aqueous layer was extracted with chloroform (2 x 10 mL). The combined chloroform solutions were dried over sodium sulfate and evaporated. The residue was 0.8 g of 1R-trans-chrysanthemic acid, [α] _D + 25.6 ° (c: 1 chloroform). The salt filtrate was evaporated and the residue was suspended in 10 ml of water and worked up in the same manner as the salt. The mass of the obtained 1S-trans-chrysanthemic acid was 2.5 g [α] _D : -7.8 ° (c: 2, chloroform).

Example 2

10.2 g of racemic trans-chrysanthemic acid was dissolved in 40 ml of water and 12.4 ml of 5M sodium hydroxide and a mixture of 25 ^Q C in 5.1 g of (R) -2-phenylglycine nitrile hydrochloride with 30 ml of water solution. The mixture was cooled to 10 ° C with stirring and the precipitate was filtered and washed with water (2 x 10 mL). The wet salt was processed in an analogous manner to Example 1. The resultant 1S-trans-chrysanthemic acid was 5.0 g, [α] _D : -13 ° (c: 1, chloroform). The mother liquor of the salt formation was acidified to pH = 1 with 5M hydrochloric acid and the oily residue was extracted with chloroform (3 x 20 mL). The chloroform solution was dried over sodium sulfate and evaporated. The residue was 5.1 g of 1R-trans-chrysanthemic acid [α] _D : + 12 ° (c: 1, chloroform). The 1S-trans-chrysanthemic acid obtained from the diastereomeric salt having an optical purity of 50% was dissolved in a mixture of 20 ml of water and 6.2 ml of 5 M sodium hydroxide at 30 ° C, then cooled to 20 ° C and 3.5 g (R ) A solution of -2-phenylglycine nitrile hydrochloride in 15 ml of water was added. The precipitated crystalline salt was filtered at 10 ° C and decomposed analogously to the previous salt decomposition. The resultant 1S-trans-chrysanthemic acid was 3.3 g [α] _D : -25.3 ° (c: 1, chloroform). The 1R-trans-chrysanthemic acid recovered from the first salt filtrate was dissolved in methanol (20 mL) and 5M sodium hydroxide (1.5 mL) was added followed by (R) -2-phenylglycine amide (3.4 g). The reaction mixture was diluted with water (10 mL) and cooled to 0 ° C, and the precipitated salt was filtered. The wet salt was suspended in water (15 mL) and acidified with 5 M hydrochloric acid, and the oily product was extracted with chloroform (3 x 15 mL). The chloroform solution was dried over sodium sulfate and evaporated. The residue was 3.5 g, [α] _D : + 25.6 ° (c: 1, chloroform). The mother liquors of the salt formation of the re-resolutions were combined and evaporated. The residue is suspended in 15 ml of water and acidified to pH 1 with 5M hydrochloric acid. The precipitated trans-chrysanthemic acid is extracted with 3 x 15 ml of chloroform3

The combined chloroform solutions were dried over sodium sulfate and evaporated. The remaining 3.2 g is nearly racemic. trans-chrysanthemic acid [α] _D : -2 ° (c: 1, chloroform).

Example 3

10 (2 g of ore trans-chrysanthemic acid) is resolved as described in Example 2 with 5.1 g of (R) -2-phenylglycine nitrile hydrochloride. To an aqueous solution (containing R-trans-chrysanthemic acid test substance) containing 2.8 g of (R) -2-phenylglycine amide hydrochloride at 50 ° C, the reaction mixture is cooled to + 5 ° C and the crystalline salt is filtered off, washed with water (2 x 5 ml). and suspended in 5 M hydrochloric acid to pH = 1 mL of water to precipitate an oil form R-trans-chrysanthemic acid was extracted with 3x10 ml of chloroform and the combined chloroform layers were dried over sodium sulfate and evaporated and the residual 2.3 g [a] _D..: + 25.2 ° (c: 1, chloroform).

Example 4

Dissolve 4.18 g of racemic trans-permetric acid (R ₁ and R _{2 in the} formula (I) are chlorine) in 20 ml of methanol and 2 ml of 5 M sodium hydroxide and 1.52 g of (R) -2-phenyl at 60 ° C. glycine amide is added with stirring. Water (10 mL) was added and allowed to cool to room temperature, cooled to 0 ° C with external ice cooling, and the precipitate was filtered and washed with water. The wet salt was suspended in 15 ml of water and acidified to pH = 1 with 5M hydrochloric acid with stirring at + 10 ° C. The precipitated crystalline 1R-trans-permethric acid was filtered, washed with water, dried, and weighed 1.75 g [α] _D : + 38.6 ° (c: 1, chloroform). The salt filtrate was evaporated and the residue was worked up analogously to the salt. The mass of the obtained 1S-trans-permethric acid was 2.3 g [α] _D : -20 ° (c: 1, chloroform). Dissolve 2.3 g of 1S-trans-permetric acid in 20 ml of water and 1.2 ml of 5 M sodium hydroxide and add 0.92 g of (R) -2-phenylglycine nitrile hydrochloride in 5 ml of water. while stirring 25 'Con. The mixture was cooled to + 10 ° C, and the desired precipitate was washed with narrow, 3 x 3 mL water. The wet salt was suspended in 10 ml of water and acidified to pH = 1 with 5 M hydrochloric acid at + 10 ° C. The crystalline precipitated IS-trans-permethric acid was filtered off, washed with water, dried, and weighed 1.1 g [α] _D : -38.6 ° (c: 1, chloroform). The second salt-forming filtrate was acidified with 5 M hydrochloric acid at +10 ° C to pH = 1 and the nearly racemic trans-permethric acid precipitated was filtered, dried, weighing 1.15 g [α] _D : -2.2 ° (c: 2, chloroform).

Claims (7)

A process for the resolution of isomers of a compound of formula I wherein R 1 s R ² represents a halogen atom or a C 1-4 alkyl group racemic acid, wherein R ¹ and R ² represent a above - racemic compound or a salt thereof with one which formula: wherein formula (H) ^R3 is a cyano or amide csoportfenil-glycyl-derivative or an acid addition salt of the resultant diastereomeric salt pair; crystals of high member itself, is separated in known manner, and it with an acid optically active - when R ^{3 in the} compound of formula (Π) has the cyano group in the 1S-trans or IR-cis configuration; if R ^{3 in the} compound of the formula (H) it is in the 1R-trans or 1S-cis configuration in the formula liberating the acid of formula (I) and, if desired, repeating the process 1 to 5 times; the diastereomeric salt remaining in the leachate is recovered in a manner known per se, and the optically active acidant of formula (I) is recovered therefrom in a manner known per se. 2. A process according to claim 1 wherein the compound of formula (Π) is (R) -2-phenylglycine nitrile. 3. The process of claim 1 wherein the compound of formula (H) is (R) -2-phenylglycine amide. 4. The process of claim 1 wherein the compound of formula (II) is (R) -2-phenylglycine amide or (R) -2-phenylglycine nitrile hydrochloride. The process of claim 1, wherein the alkali metal salt of the racemic compounds of formula (I) is reacted with the resolving agent of formula (Π). 6. A process according to claim 1, wherein the diastereomeric salt is formed in a mixture of water or a C 1 -C 4 alkanol and water. The process of claim 1, wherein the resolving agent of formula (II) is used in an amount of 0.4-0-6 molar equivalents.