CA2044570A1 - Process for resolution of racemates of 2,2-dimethylcyclopropanecarboxylic acid - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

A process is disclosed for preparing optically pure 2,2-dimethylcyclopropanecarboxylic acid, in which the enantiomers are separated from the racemate by esterification with the hydroxy group of optically active mandelic acid methyl ester, crystallization of the diastereomeric esters and subsequent hydrolysis of the diastereomeric esters.

Description

20~7~

This invention relates to the production of optically-pure 2,2-dimethylcyclopropanecarboxylic acid by resolution of its racemates.

2,2-Dimethylcyclopropanecarboxylic acid is an important intermediate product for the synthesis of the enzyme inhibitor cilastatin (European Patent No. 0,048,301) and of insecticides of the pyrethrin type ~British Patent No. 1,260,847).
In particular for the production of pharmaceutically active ingredients, it is desirable to have available 2,2-dimethylcyclopropanecarboxylic acid in optically pure form, i.e., in the form of the pure (S)-(+)- or pure (R)-t-~-enantiomer. Since the chemical synthesis of 2,2-dimethylcyclopropanecarboxylic acid provides the compound in the form of its racemate, it is necessary to perform a resolution of this racemate. Such resolutions of racemates are usually brought about by first converting the enantiomer mixture to be separated first into a mixture of diastereomeric derivatives by means of an optically active auxiliary substance, which can be separated because of the different physical properties of the diastereomers by fractionating crystalli2ation or chromatography. From the diastereomers thus separated, a pure enantiomer of the compound to be separated and the optically active auxiliary substance is then ideally set free in each case.
In reality, with a given auxiliary substance, even though suah substance is optically completely pure, in most cases only an incomplete separation of one pure enantiomer is possible, so that a mixture remains which mainly consists of the other enantiomer. In less advantageous cases, neither of the two enantiomers can be isolated in pure form. As derivatives of carboxylic acids for the purpose of the resolution of racemates, their salts with optically active bases, in particular amines, are often used. These salts have the advantage that they are .

20~4~

formed very easily and quickly and can also be cleaved again by adding a strong acid. For resolution of racemates of 2,2-dimethylcyclopropanecarboxylic acid, (S)-(-)-l-phenylethylamine (British Patent No. 1,260,847), (-)-N-methylephredrin (Japanese Published Patent Application Nos.
60-56936 and 60-56942), quinine (European Published Patent Application No. 0,161,546) and various 1,2-diphenylethylamines (European Published Patent Application No. 0,039,511) have already been used.
However, when using l-phenylethylamine, neither a satisfactory yield nor a sufficient optical purity was achievable. Quinine yielded an enantiomer with good optical purity, but in poor yield, no yield was indicated for N-methylephedrine. In the case of 1,2-diphenylethylamine, the yield is satisfactory and the optical purity is very good, but the reagent is very expensive, as also is N-methylephedrine.
Further, it is known that 2,2-dimethylcyclopropanecarboxylic acid can be separated into the enantiomers via the diastereomeric menthyl esters, which are obtainable from the acid chloride with (+)- or (-)-menthol (U.S. Patent No. 4,487,956). This process does provide usable yields and optical purities, but is relatively complicated in the working-up and requires the use of the relatively expensive menthol.
The main object of the invention is to provide a process for the resolution of the racemate of 2,2-dimethylcyclopropanecarboxylic acid, which is simple to perform and requires only reasonably priced optically-active auxiliary substances which are as nontoxic aspossible.
According to the invention, there is provided a process which involves resolution of the racemate of 2,2-dimethylcyclopropanecarboxylic acid by esterification with an optically active hydroxy compound, followed by fractionating crystallization of the formed diastereomeric .
.:

', 204~570 esters and subsequent hydrolysis of the crystallized diastereomeric esters. Mandelic acid methyl ester is used as the optically active hydroxy compound.
The fractionating crystallization of the 5 diastereomeric esters is preferably performed with an alkane as a solvent. Preferably n-hexane is used as the alkane. Preferably the esterification of 2,2-dimethylcyclopropanecarboxylic acid by the corresponding racemic acid chloride takes place in the presence of an 10 auxiliary base. The racemic acid chloride is preferably produced by the reaction of 2, 2-dimethylcyclopropanecarboxylic acid with thionyl chloride, Also preferably, the racemic acid chloride is produced by using the enantiomer mixture (recovered by hydrolysis from 15 the mother liquor of the crystallization) of 2,2-dimethylcyclopropanecarboxylic acid and is racemized by heating to 100 to 200 C. The hydrolysis of the esters of 2,2-dimethylcyclopropanecarboxylic acid is preferably performed with an aqueous alkali hydroxide. Preferably the 20 2,2-dimethylcyclopropanecarboxylic acid is isolated by acidification and extraction with n-hexane from the hydrolysis mixture.
Another aspect of the invention comprises alpha-(2,2-dimethylcyclopropanecarbonyloxy)-phenylacetic 25 acid methyl ester.
Thus, it has been found surprisingly that optically active mandelic acid methyl ester reacts not only with (RSj-2,2-dimethylcyclopropanecarboxylic acid chloride at the OH group smoothly to form the corresponding 30 diastereomeric esters, but that surprisingly the latter are also separable by fractioning crystallization and, after their hydrolysis, the released 2, 2-dimethylcyclopropanecarboxylic acid can be separated very easily from the likewise resultant mandelic acid. Nandelic 35 acid, in contrast to 2,2-dimethylcyclopropanecarboxylic acid, is practically insoluble in alkanes and remains in `

2 ~ 7 0 the aqueous phase during the extraction with these alkane solvents.
The process according to the invention is advantageously performed in such a way that the racemic 2,2-dimethylcyclopropanecarboxylic acid is first converted to the corresponding acid chloride. This step is known in the art and can be performed, for example, with thionyl chloride in the presence of a catalytic amount of N,N-dimethylformamide. The acid chloride thus obtained is purified advantageously by distillation. Then, the racemic acid chloride is reacted with optically active mandelic acid methyl ester while adding an auxiliary base to bond the resulting hydrochloric acid. As the auxiliary base, for example, pyridine may be used. The esterification is advantageously performed in an inert solvent, such as dichloromethane.
Of course, it is also within the scope of the invention to perform the esterification by the direct reaction of 2,2-dimethylcyclopropanecarboxylic acid with mandelic acid methyl ester in the presence of a catalyst, such as dicyclohexylcarbodiimide or 1,1'-carbonyldiimidazole. Such esterification methods are known to those skilled in the art and are described, for example, in "Methoden der organischen Chemie", [Methods of Organic Chemistry], (Houben-Weyl), 4th Edition, Vol. E5, p. 659 ff, and Vol. VIII, p. 516 ff.
The diastereomeric esters present after the esterification are fractionatingly crystallized: an alkane being preferably used as the solvent. n-Hexane is especially preferred as the solvent. The diastereomer with the same absolute configuration on both asymmetric centers crystallizes first from n-hexane.
T o o b t a i n ( S ) - ( + ) - 2 , 2 -dimethylcyclopropanecarboxylic acid in optically pure form, (S)-(+)-mandelic acid methyl ester is therefore used advantageously, the (R)-ester being correspondingly used :

2 ~ 7 ~

for the (R)-acid. An advantage of the process according to the invention lies in the fact that both enantiomers of mandelic acid and, thus, also their esters are easily accessible.
After the isolation of the desired diastereomeric ester, the latter is hydrolyzed. The hydrolysis is preferably performed according to a conventional method with aqueous alkali hydroxide solution, and both ester groups are hydrolyzed in the molecule. Then, by adding a strong acid, for example hydrochloric acid, 2,2-dimethylcyclopropanecarboxylic acid and mandelic acid (which are present as anions after the hydrolysis) are released. The separation of the optically-pure 2,2-dimethylcyclopropanecarboxylic acid takes place preferably by extraction with a nonpolar solvent. Especially preferred as extracting agents are the straight-chain, branched or cyclic alkanes having 5 to 10 C atoms. Most especially preferred is n-hexane, in which mandelic acid is practically insoluble.
T h e o p t i c a l l y - p u r e 2 , 2 -dimethylcyclopropanecarboxylic acid thus obtained can be further processed in known manner, for example by conversion to the acid chloride and further to the amide.
In order to make use of the mother liquor of the crystallization (in which the more easily soluble diastereomer is concentrated) the latter is advantageously also subjected to a hydrolysis.
The enantiomer mixture thus obtained is suitably converted again to the mixture of the acid chlorides, which can be racemized in a manner known in the art by heating to 100 to 200 C. The thus obtainable racemic acid chloride can again be added to the initial material of the process according to the invention, so that neither the undesirable enantiomer has to be removed nor do significant losses ~5 occur.

: ,:
' ,; , :

.

2 ~ 7 0 The following examples illustrate the performance of the process according to the invention.
Example 1 (RS)-2 2-dimethylcyclopropanecarboxylic acid chloride 52.8 g of (RS)-2,2-dimethylcyclopropanecarboxylic acid and 0.25 g of N,N-dimethylformamide were dissolved in 50 ml of n-hexane and mixed under reflux by instillation with 104.0 g of thionyl chloride in 100 ml of n-hexane.
After a further 2 hours of stirring under reflux, the solvent was distilled off and the residue was quickly distilled at 200 mbars and 100 C (bath temperature). The yield of the product was 55.0 g.
Example 2 (S.S)-alpha-(2.2-dimethylcyclopropanecarbonyloxy)phenyl-acetic acid methyl ester 14.0 g of (S)-2,2-dimethyIcyclopropanecarboxylic acid chloride was dissolved in 70 ml of dichloromethane, cooled to 0 C and mixed as quickly as possible with 8.1 g of pyridine. Then a solution of 17.0 g of (S)-(+)-mandelic acid methyl ester {[a]D2=+146.5 (c = 1, MeOH)3 in 35 ml of dichloromethane was instilled in this mixture at 0 to 5 C
over 10 minutes. The reaction mixture was stirred for a further 2 ho~rs at room temperature and then washed successively with water, dilute hydrochloric acid and again with water. The organic phase was dried on sodium sulfate and concentrated by evaporation. The crude product thus obtained (26.0 g) was suspended in 7.0 ml of n-hexane at room temperature. The crystalline residue was filtered off, dried and recrystallized three times hot from 40 ml of n-hexane, each time. The yield of (S,S)-alpha-2,2-dimethylcyclopropanecarbonyloxy)phenylacetic acid methyl ester was 7.6 g. Other data for the product were:
Melting point: 80 to 82 C, colorless crystals ~a]D20: +158.0 (c = 1, CHCl3) 1H-NMR (300 MHz, C6D6):

.
.
.

2 ~ 7 0 ~7.43 to 7.52 (m, 2H), 6.97 to 7.12 (m, 3H), 6.11 (s, lH), 3.19 (s, 3H), 1.55 to 1.60 (m, lH), 1.39 (s, 3H), 1.19 to 1.23 (m, lH), 0.86 (s, 3H), 0.55 to 0.60 (m, lH) Example 3 (S~-(+)-2~2-Dimethylcyclopropanecarboxylic acid 1 8 . 4 g o f ( S , S ) - a 1 p h a - ( 2 , 2 -dimethylcyclopropanecarbonyloxy)phenylacetic acid methyl ester (produced according to Example 2) was mixed with a solution of 20.6 g of potassium hydroxide (85 percent) in 235 ml of water and stirred for 6 hours at 80C, and a clear solution was formed. Then the reaction mixture was cooled to room temperature and acidified to pH 1 with dilute hydrochloric acid. The aqueous solution was extracted four times with 100 ml of n-hexane, each time.
The combined organic phases were dried on sodium sulfate and filtered. After distilling off the solvent, (S)-(+)-2,2-dimethylcyclopropanecarboxylic acid was obtained in a purity (GC) of 99.0 percent. The yield of the product was 7.7 g. Other data for the product were: [~] D20: +14 6 (neat), corresponding to an optical purity (ee value) greater than or equal to 98 percent.
Example 4 2S Racemization of 2.2-dimethylcyclopropan _arboxylic acid From the mother liquors resulting during the c ry 5 t a 1 1 iz at i on o f (S, S) -a 1 p h a - (2 , 2 -dimethylcyclopropanecarbonyloxy)phenylacetic acid methyl ester according to Example 2, the solvent was distilled off and the residue, analogously to Example 3, was hydrolyzed alkaline and worked up. 11.4 g of 2,2-dimethylcyclopropanecarboxylic acid (~D20 = -51.8 (c = 1, CHCl3)), consisting of 69 percent of the (R)-(-)- form and 31 percent of the (S)-(+)- form, was obtained. The enantiomer mixture was diluted with 12.0 g of hexane, heated to 75 C and was mixed over 30 minutes by . : ,-. , , -. , , . :
., . ..: .
.
- . .

.. . ~
--2 ~ 7 ~ -instillation with a mixture of 17.9 g of thionyl chloride and 5.0 g of hexane and refluxed for a further 2.5 hours.
The solvent and the excess thionyl chloride were distilled off and the residue was heated to 135 C with stirring for 2 hours. After cooling to room temperature, the acid chloride mixture was hydrolyzed with dilute sodium hydroxide solution, and the resultant aqueous solution was extracted twice with 10 g of toluene, each time. The organic phase was discarded; and the aqueous phase was acidified with concentrated hydrochloric acid and extracted five times with 40 g of hexane, each time. 11.4 g of crude 2,2-dimethylcyclopropanecarboxylic acid, which was distilled in the water jet vacuum, was obtained from the hexane phases by distilling off the solvent. The yield was 9.4 g (83 percent) of colorless, fetid liquid consisting of 48.5 percent of the (S)-(+)- form and 51.5 percent of the (R)-(-)- form.

, .

Claims (9)

1. Process for resolution of racemic 2,2-dimethylcyclopropanecarboxylic acid comprising esterifying the racemate of 2,2-dimethylcyclopropanecarboxylic acid with an optically active hydroxy compound, which is mandelic acid methyl ester, fractionating crystallizing the formed diastereomeric esters and subsequently hydrolyzing the crystallized diastereomeric esters.

2. A process according to claim 1, wherein the fractionating crystallization of the diastereomeric esters is performed with an alkane as a solvent.

3. A process according to claim 2, wherein the alkane is n-hexane.

4. A process according to claim 1, wherein the esterification of 2,2-dimethylcyclopropanecarboxylic acid by the corresponding racemic acid chloride takes place int he presence of an auxiliary base.

5. A process according to claim 4, wherein the racemic acid chloride is produced by the reaction of 2,2-dimethylcyclopropanecarboxylic acid with thionyl chloride.

6. A process according to claim 4 or 5, wherein the racemic acid chloride is produced by using the enantiomer mixture of 2,2-dimethylcyclopropanecarboxylic acid recovered by hydrolysis from the mother liquor of the crystallization step, and is racemized by heating to 100 to 200 C.

7. A process according to claim 1, 2, 3, 4 or 5, wherein the hydrolysis of the esters of 2,2-dimethylcyclopropanecarboxylic acid is performed with an aqueous alkali hydroxide.

8. A process according to claim 1, 2, 3, 4, or 5, wherein 2,2-dimethylcyclopropanecarboxylic acid is isolated by acidification and extraction with n-hexane from the hydrolysis mixture.

9. Alpha-(2,2-dimethylcyclopropanecarbonyloxy)-phenylacetic acid methyl ester.