WO1990008126A1

WO1990008126A1 - Resolution process

Info

Publication number: WO1990008126A1
Application number: PCT/HU1990/000005
Authority: WO
Inventors: Ferenc Faigl; Elemér Fogassy; Lajos Nagy; László CSIZ; Irén CZUDOR; Éva KOVÁCSNÉ KOZSDA
Original assignee: Chinoin Gyógyszer és Vegyészeti Termékek Gyára Rt.
Priority date: 1989-01-16
Filing date: 1990-01-16
Publication date: 1990-07-26
Also published as: HU205594B; EP0411074A1; JPH03503288A; HUT52472A

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 R2¿, independently from another, stand for halogen or a C¿1-4?alkyl group. The process of the invention comprises reacting a racemic compound of general formula (I), wherein R?1 and R2¿ are as defined above, or a salt thereof with a phenylglycine derivate of general formula (II), wherein R3 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 R3 in the compound of general formula (II) used means cyano group, or the optically active acid containing (1R) configuration, respectively, when R3 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

RESOLUTION PROCESS

This invention relates to a novel process for preparing the optical isomers of 2,2-dimethyl-3-(2,2-disubstituted vinyl)cyclopropanecarboxylic acids of the general formula (I),

where in

R ¹ and R² independently from another, stand tor halogen or a C_1-4alkyl group

by resolving the diastereoisomeric salts formed from the corresponding racemic carboxylic acids with the optically active basic 2-phenylglycine derivatives of the general formula (II),

wherein

R³ means a cyano or carboxamide group.

2,2-Dimethyl-3-(2,2-disubstituted vinyl)cyclopropanecarboxylic acids of the general formula (I) are intermediates in the synthesis of highly effective, commercially available insecticides. Due to their two asymmetry centres, the acids of general formula (I) exist in the form of four stereoisomers. It has been stated that the spectra of biological activity of esters

prepared from the separate stereoisomers are signifi-68547-77 SZO cantly different therefore, it is important to separate the enantiomers from the racemic acids as starting substances.

Several methods have been successful to separate cis- and trans-racemates from the. racemic cis,trans

acid mixtures of general formula (I) obtained in the industrial syntheses [DE-A 2,713 ,538 and 2,800,922; as well as Helv. Chim. Acta 7 , 390 (1924)]. A number of processes are known also for separating the optical isomers of the racemic cis and racemic trans acids: according e.g. to GB -PS 1,178,423 trans-chrysanthemic acid was resolved by using quinine to give the (1R) isomer after several recrystallizations and salt formations, respectively.

For separation of the isomers of acids of the general formula (I), the use of optically active

α -naphthylethylamine (DE-A 2,300,325), α-phenylethyl amine (EP-A 0,010,874) or threo-2-dimethylamino-1-(4-nitrophenyl)-propane-1,3-diol (FR-PS 79 13116) have been described. The drawback of these processes consists in that the resolving agents are used in most cases in an equivalent amount calculated for the racemic acid though these resolving agents are expensive and difficultly available compounds which can be regenerated only with a low effectivity. According to DE-A

2,826,952 ethyl (-)-2-phenylglycinate was used for separating the optical isomers of the acids of general formula (I). The diastereoisomeric salt formation was carried out in an aqueous medium and the optically active acids of general formula (I) obtained from the crystaline salt precipitated or from the mother liquor, respectively, were recrystallized from petroleum ether. However, a resolving agent of varying optical purity was used for the salt formation therefore, the optical purity of the acid enantiomers of the general formula (I) was also varying. A significant diasadvantage of this process lies therein that the diastreoisomeric salt formation is carried out in a more than 50-fold amount of water calculated for the racemic acid thus, the grade of utilization of the equipments and the productivity are low. The method of purification of the enantiomer remaining in the mother liquor of the salt formation has not benn discussed in the processes cited above, either.

In the preparation example of the above patent specification the value of the optical rotatory power given for trans-permethrinic acid (36 °) is lower by about 10% than the highest optical rotatory power known from the literature [DE-PS 2,628,4727. The resolving agent used is sensitive to hydrolytic influences and can be regenerated only with a low effectivity.

Thus, it was aimed to develop a process making possible to prepare both optical isomers of the acids of general formula (I) in an optically pure state in a simple way, by using easily available resolving agents.

It has been found that the basic (R)-2-phenylglycine derivatives of general formula (II), wherein R³ means a cyano or carboxamide group, form well-crystallizable salts with cyclopropanecarboxylic acids of general formula (I) in a polar solvent or polar solvent mixture. The resolving agents of general formula (II) can be prepared from benzaldehyde as starting compound in a simple way. (R)-2-phenylglycine nitrile can be prepared according to FR-PS 2,141,354; whereas (R)-2-phenylglycine amide may also be prepared in a very good yield by the acidic hydratation of the nitrile in a known manner.

Our recognition is unexpected and therefore novel that the configuration of the acid of general formula (I) being present in the diastereoisomeric salts crystallizing out depends in each case from the nature of the R³ group of the resolving agent of general formula (II).

Thus, the acid of gneral formula (I) bearing (1S)

configuration is in each case enriched in the crystalline salt when R³ means cyano group; whereas the acid of general formula (I) containing (1R) configuration is always obtained from the crystalline diastereoisomeric salt when R³ represents a carboxamide group.

According to this recognition, both enantiomers of cyclopropanecarboxylic acids of general formula (I) can be obtained as pure, crystalline diastereoisomeric salt by using resolving agents of general formula (II) having the same configuration.

The invention further relates to our recognition that the salt formation can be realized with a good effectivity by using the resolving agents of general formula (II) in water or in mixtures of water with C_1-4 alcohols. From the point of view of effectivity of the process our observation is important that the racemic acids of general formula (I) are reacted with a lower amount than one equivalent, suitably with a half equivalent amount of the resolving agent of general formula (II); whereas the optically active enantiomeric mixtures of general formula (I) can preferably be purified by a repeated resolution with the resolving agent of general formula (II) being equivalent to the enantiomer being present in an excess. In the course of salt formations the proportion of the acid of general formula (I) not reacting with the resolving agent is maintained in solution in the form of its alkaline metal salt.

It has been stated that it is unsuitable to use an excess of alkali in the resolutions carried out with (R)-2-phenylglycine amide since thereby, the yield and the optical purity of the acid enantiomer being present in the salt are decreased. On the use of (R)-2 -phenylglycine nitrile the yield of the diastereoisomeric salt is lowered, but its optical purity increases in the presence of an excess alkali.

Thus, the process according to the present invention comprises reacting a racemic compound of the general formula (I), wherein R ¹ and R² are as defined above, or a salt thereof with a phenylglycine derivative of the general formula (II), wherein R³ 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 R³ in the compound of general formula (II) used means cyano group, or the optically active acid containing (1R) configuration, respectively, when R³ 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.

Preferably, 1 mole of the racemic acid of general formula (I) is dissolved with 1 mole of an alkaline metal hydroxide in water, then the solution of the hydrochloride of the resolving agent of general formula (II) in water or in a mixture of water with a C_1-4 alcohol is added at a temperature between 20 °C and 60 °C. The reaction mixture is cooled to a temperature of 0 °C to 25 °C and the crystalline diastereoisomeric salt is separated by filtration. The salt obtained contains the (1R) acid enantiomer when (R)-2-phenylglycine amide is used and the (1S) acid enantiomer, respectively, when (R)-2-phenylglycicine nitrile is employed. The optically active acid isomers of general formula (I) are liberated from the diastereoisomeric salts by adding a mineral acid and separated by filtration; or they are extracted into a water-immiscible organic solvent and then recovered by evaporating the organic solution. The other acid enantiomer is recovered from the filtrate of the salt formation by acidification with a mineral acid after distilling out the alcohol content eventually being present in the solution.

Alternatively, the process according to the invention can be carried out in such a way that the racemic acids of the general formula (I) are suspended in a mixture of water with a C_{1 -4} alcohol, then the resolving agent and the required amount of alkaline metal hydroxide (this is determined so that the total amount of the resolving agent and the alkaline metal hydroxide should be equivalent to the racemic acid) are added and the mixture is heated until complete dissolution, then cooled to a temperature between 0 °C arid 25 °C and the crystalline diastereoisomeric salt is separated by

filtration.

If desired, the optical purity of the acid enantiomers of general formula (I) obtained is increased by a repeated resolution. This repeated resolution is carried out by using (R)-2-phenylglycine amide for (1R) acid isomers and (R)-2-phenylglycine nitrile for (1S) acid isomers, respectively, under the same conditions as in the first salt formation, except that the resolving agent is suitably used in an equivalent or lower amount related to the amount of the enantiomer being present in excess.

If desired, the optical purity of the acid enantiomer of the general formula (I) remaining in the mother liquor of the salt formation can be increased in such a way that the mineral acid addition salt of the resolv ing agent of general formula (II) is directly added to the mother liquor at a temperature of 20 °C to

60 °C and further on, the procedure described above is followed. Also in this case, the resolving agent is selected in such a way that (R)-2-phenylglycine amide is used for a mother liquor enriched of the (1R) acid isomer; whereas (R)-2-phenylglycine nitrile is employed for a mother liquor enriched of the (1S) acid isomer. The nearly racemic acids of the general formula (I) remaining in the course of repeated resolutions are regenerated and again used for resolution.

The process according to the invention is illustrated in detail by the following non limiting Examples.

Example 1

After dissolving 3.4 g of racemic trans-chrysanthemic acido /compound of general formula (I), wherein both R¹ and R² are methyl group] in 20 ml of methanol, 2 ml of a 5 molar sodium hydroxide solution are added. To this solution 1.52 g of (R)-2-phenylglycine amide are added under stirring, then 8 ml of water are added and the mixture is stirred at 50 to 55 °C until dissolution. After cooling the solution to 0 °C the crystalline precipitate is filtered and washed with water. The wet salt is suspended in a mixture containing 10 ml of water and 10 ml of chloroform and acidified to pH 1 by adding 5 molar hydrochlorid acid. The organic phase is

separated, the aqueous phase is extracted twice with 10 ml of chloroform each. After combining, the chloroform solution is dried over anhydrous sodium sulfate and evaporated to give a residue of 0.8 g of (1R)-trans-chrvsanthemic acid, [α]_D + 25.6° (c = 1, chloroform).

After evaporating the filtrate of salt formation the residue is suspended in 10 ml of water and worked up as described for the salt to give 2.5 g of (1S)¬

-trans-chrysanthemic acid, [α ]_D -7.8° (c = 2,

chloroform).

Example 2

After dissolving 10.2 g of racemic trans-chrysanthemic acid in a mixture of 40 ml of water and 12.4 ml of 5 molar sodium hydroxide solution, 5.1 g of (R)-2-phenylglycine nitrile hydrochloride dissolved in 30 ml of water are added at 25 °C. The mixture is cooled down to 20 °C while stirring, the precipitate is filtered and washed twice with 10 ml of water each. The wet salt is worked up as described in Example 1 to give 5.0 g of

(15) -trans-chrysanthemic acid, [α ]_D -13° (c=1,

chloroform).

The mother liquor of the salt formation is acidified to pH 1 by adding 5 molar hydrochloric acid and the precipitated oily acid is extracted 3 times with 20 ml of chloroform each. The combined organic solution is dried over sodium sulfate and evaporated to give 5.1 g of (1R)-trans-chrysanthemic acid as residue,

+12° (c=1, chloroform). The (1S)-trans-chrysanthemic acid (having an optical purity of 50%) obtained from the diastereoisomeric salt is dissolved in the mixture of 20 ml of water and 6.2 ml of 5 molar sodium hydroxide solution at 30 °C, then cooled to 20 °C and the solution αf 3.5 g of (R)-2-phenylglycine nitrile hydrochloride in 15 ml of water is added. The crystalline salt precipitated is filtered at 10 °C and decomposed as described above for the salt decomposition to obtain 3.3 g of (1S)-trans-chrysanthemic acid, [α ]_D -25,3° (c = 1, chloroform).

(1R)-trans-chrysanthemic acid recovered from the filtrate of the first salt formation is dissolved in 20 ml of methanol, 1.5 ml of 5 molar sodium hydroxide solution and then 3.4 g of (R)-2-phenylglycine amide are added. After diluting the mixture with 10 ml of water and cooling to 0 °C, the salt precipitated is filtered. The wet salt is suspended in 15 ml of water, acidified by adding 5 molar hydrochloric acid and the oily product precipitated is extracted 3 times with 15 ml of chloroform each. The chloroform solution is dried over sodium sulfate and evaporated to give a residue of 3.5 g, [α ]_D+ +25,6° (c=1, chloroform). The mother liquors arising from the salt formations of the repeated resolutions are combined and evaporated. The residue is suspended in 15 ml of water and acidified to pH 1 by adding 5 molar

hydrochloric acid. The trans-chrysanthemic acid precipitated is extracted 3 times with 15 ml of chloroform each, after combining the chloroform solution is dried over sodium sulfate and evaporated to give 3.2 g of residue which is nearly racemic trans-chrysanthemic acid,

[ α ]_D -2° (c=1, chloroform).

Example 3

10.2 g of racemic trans-chrysanthemic acid are resolved with 5.1 g of (R)-2-phenylglycine nitrile

hydrochloride as described in Example 2. After separating the crystalline diastereoisomeric salt, 2.8 g of

(R)-2-phenylglycine amide hydrochloride are added at 50 °C to the remaining aqueous solution [containing a

material enriched of (R)-trans-chrysanthemic acid], then the reaction mixture is cooled to 5 °C, the crystalline salt is filtered and washed twice with 5 ml of water each. The wet salt is suspended in 15 ml of water and acidi-fied to pH 1 by adding 5 molar hydrochloric acid. The oily precipitated (1R)-trans-chrysanthemic acid is

extracted 3 times with 10 ml of chloroform each, the chloroform phases are combined, dried over sodium sulfate and evaporated to give a residue of 2.3 g, [ α ]_D +25,2° (c=1, chloroform).

Example 4

4.18 g of racemic trans-permethrinic acid

[compound of the general formula (I), wherein both R¹ and R² are chlorine atom] are dissolved in a mixture containing 20 ml of methanol and 2 ml of 5 molar sodium hydroxide solution, and 1.52 g of (R)-2-phenylglycine amide are added at 60 ºC under stirring. Subsequently

10 ml of water are added and allowed to cool down to room temperature, then it is cooled to 0 °C by external ice¬

-cooling, the precipitate is filtered and washed with water. The wet salt is suspended in 15 ml of water and acidified to pH 1 by adding 5 molar hydrochloric acid at 10 °C while stirring. The crystalline (1R)-trans-permethrinic acid precipitate is filtered, washed with water and dried to obtain a yield of 1.75 g, [α ]_D + 38,6° (c = 1, chloroform).

After evaporating the filtrate of salt formation the residue is worked up analogously as described for the salt to obtain 2.3 g of (15) -trans-permethrinic acid, [ α ]_D -20° (c=1, chloroform).

2.3 g of (1S)-trans-permethrinic acid are

dissolved in a mixture containing 20 ml of water and 1.2 ml of 5 molar sodium hydroxide solution and 0.92 g of (R)-2-phenylglycine nitrile hydrochloride dissolved in 5 ml of water is added at 25 °C under stirring. The mixture is cooled to 10 °C, the precipitate is filtered and washed 3 times with 3 ml of water each. The wet salt is suspended in 10 ml of water and acidified to pH 1 by adding 5 molar hydrochloric acid at 10 °C. The crystalline (1S)-trans-permethrinic acid precipitate is filtered, washed with water and dried to give 1.1 g of product, [α ]_D -38,6 (c = 1, chloroform). The filtrate of the second salt formation is acidified to pH 1 by adding 5 molar hydrochloric acid at 10 °C, the nearly racemic trans-permethrinic acid precipitated is filtered and dried to give a yield of 1.15 g,

[ α ]_D -2.2° (c=2, chloroform).

Claims

1. Process for the resolution of isomers of the racemic acids of general formula (I),

wherein

R¹ and R², independently from another, stand for halogen or a C_1-4alkyl group,

which comprises reacting a racemic compound of the general formula (I), wherein R¹ and R² are as defined above, or a salt thereof with a phenylglycine derivative of the general formula (II),

wherein R³ 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 R³ in the compound of general formula (II) used means cyano group, or the optically active acid containing (1R) configuration, respectively, when R³ in the compound of the 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.

2. A process as claimed in claim 1, which comprises using (R)-2-phenylglycine nitrile as a compound of the general formula (II).

3. A process as claimed in claim 1, which comprises using (R)-2-phenylglycine amide as a compound of the general formula (II).

4. A process as claimed in claim 1, which comprises using the hydrochloride of (R)-2-phenylglycine amide or (R)-2-phenylglycine nitrile, respectively, as a compound of the general formula (II).

5. A process as claimed in claim 1, which comprises reacting an alkaline metal salt of the racemic compound of general formula (I) with a resolving agent of the general formula (II).

6. A process as claimed in claim 1, which comprises carrying out the formation of the

diastereoisomeric salt in water or in the mixture of a C_1-4 alkanol with water.

7. A process as claimed in claim 1, which comprises using the resolving agent of general formula (II) in an amount of 0.4 to 0.6 molar equivalent