Process for resolution of racemates of 2,2-dimethylcyclopropanecarboxylic acid

The enantiomers of 2,2-dimethylcyclopropanecarboxylic acid are separated 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.

BACKGROUND OF THE INVENTION 
1. Field Of The Invention 
The invention relates to the production of optically-pure 
2,2-dimethylcyclopropane-carboxylic acid by resolution of its racemates. 
2. Background Art 
2,2-Dimethylcyclopropanecarboxylic acid is an important intermediate 
product for the synthesis of enzyme inhibitor cilastatin (European Patent 
No. 0,048,301) and of insecticides of the pyrethrin type (British Patent 
No. 1,260,847), respectively. 
In particular for the production of pharmaceutical active ingredients, it 
is desirable to have available 2,2-dimethylcyclopropanecarboxylic acid in 
optically pure form, i.e., in the form of pure (S)-(+)- or pure 
(R)-(-)-enantiomers. 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 in that the 
enantiomer mixture to be separated first is converted to a mixture of 
diastereomeric derivatives by an optically active auxiliary substance, 
which can be separated because of the different physical properties of the 
diastereomers by fractionating crystallization 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 such substance is 
optically completely pure, in most cases only the 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 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)-(-)-1-phenylethylamine (British Patent No. 1,260,847), 
(-)-N-methylephredrine (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. 0,093,511) have already been used. 
With 1-phenylethylamine, neither a satisfactory yield nor a sufficient 
optical purity was able to be achieved. Quinine yielded an enantiomer in 
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, as also 
is N-methylephedrine, is very expensive. 
Further, it is known that 2,2-dimethylcyclopropanecarboxylic acid can be 
separated in the enantiomers via the diastereomeric menthyl esters, which 
are obtainable from the acid chloride with (+)- or (-)-menthol (U.S. Pat. 
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. 
BROAD DESCRIPTION OF THE INVENTION 
The main object of the invention is to provide a process for the resolution 
of the racemates of 2,2-dimethylcyclopropanecarboxylic acid, which is 
simple to perform and requires only reasonably priced optically active 
auxiliary substances which are as nontoxic as possible. Other objects and 
advantages of the invention are set out herein or are obvious herefrom to 
one skilled in the art. 
According to the invention, the main object of the invention is achieved by 
the process according to the invention. The invention process involves 
resolution of the racemates of 2,2-dimethylcyclopropanecarboxylic acid by 
esterification with an optically active hydroxy compound, followed by the 
fractionating crystallization of the formed diastereomeric esters and the 
subsequent hydrolysis of the formed diastereomeric esters. Mandelic acid 
methyl ester is used as the optically active hydroxy compound. 
The fractionating crystallization of the 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-dimethylcyclopropane-carboxylic acid by the corresponding racemic acid 
chloride takes place in the presence of an auxiliary base. Preferably the 
racemic acid chloride is 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 the mother liquor of the 
crystallization, of 2,2-dimethylcyclopropanecarboxylic acid and is 
racemized by heating to 100.degree. to 200.degree. C. The hydrolysis of 
the esters of 2,2-dimethylcyclopropanecarboxylic acid is preferably 
performed with an aqueous alkali hydroxide. Preferably the 
2,2dimethylcyclopropanecarboxylic acid is isolated by acidification and 
extraction with n-hexane from the hydrolysis mixture. 
The invention also includes 
alpha-(2,2-dimethylcyclopropanecarbonyloxy)-phenylacetic acid methyl 
ester.

DETAILED DESCRIPTION OF THE INVENTION 
It was found surprisingly that optically active mandelic acid methyl ester 
reacts not only with (RS)-2,2-dimethylcyclopropanecarboxylic acid chloride 
on the OH group smoothly to the corresponding 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. Mandelic acid, in contrast to 
2,2-dimethylcyclopropanecarboxylic acid, is practically insoluble in 
alkanes and remains in 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 catalytic amounts 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 is 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 2,2dimethylcyclopropanecarboxylic 
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 one 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 is 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. 
To obtain (S)-(+)-2,2-dimethylcyclopropanecarboxylic acid in optically pure 
form, (S)-(+)-mandelic acid methyl ester therefore is used advantageously, 
(R)-ester is correspondingly used for the (R)-acid. An advantage of the 
process according to the invention lies in the fact that both enantiomers 
of the 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 usual 
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 first 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 an extracting agent are the straight-chain, 
branched or cyclic alkanes having 5 to 10 C atoms. Quite especially 
preferred is n-hexane, in which mandelic acid is practically insoluble. 
The optically-pure 2,2-dimethylcyclopropanecarboxylic acid thus obtained 
can be further processed in a known way, for example, conversion to the 
acid chloride and further to th amide. 
To use 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 way known in 
the art by heating to 100.degree. to 200.degree. 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 no significant losses occur. 
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 another 2 hours of stirring under reflux, the solvent was 
distilled off and the residue was quickly distilled at 200 mbars and 
100.degree. C. (bath temperature). The yield of the product was 55.0 g. 
EXAMPLE 2 
(S,S)-alpha-(2,2-dimethylcyclopropanecarbonnloxy)phenylacetic acid methyl 
ester 
14.0 g of (S)-2,2-dimethylcyclopropanecarboxylic acid chloride was 
dissolved in 70 ml of dichloromethane, cooled to 0.degree. 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 {[.alpha.].sub.D.sup.20 =+146.5.degree. 
(c=1, MeOH)}in 35 ml of dichloromethane was instilled in this mixture at 
0.degree. to 5.degree. C. within 10 minutes. The reaction mixture was 
stirred for another 2 hours at room temperature and then washed in 
succession 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 hot three times 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 was: 
Melting point: 80.degree. to 82.degree. C., colorless crystals. 
[.alpha.].sub.D.sup.20 :+158.0.degree. (c=1, CHCl.sub.3). 
.sup.1 H-NMR (300 MHz, C.sub.6 D.sub.6): .delta.7.43 to 7.52 (m, 2H), 6.97 
to 7.12 (m,3H), 6.11 (s, 1H), 3.19 (s,3H), 1.55 to 1.60 (m, 1H), 1.39 
(s,3H), 1.19 to 1.23 (m, 1H), 0.86 (s,3H), 0.55 to 0.60 (m, 1H). 
EXAMPLE 3 
(S)-(+)-2,2-Dimethylcyclopropanecarboxylic acid 
18.4 g of (S,S)-alpha-(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 80.degree. C., and a clear solution was formed. 
Then the reaction mixture was cooled to room temperature and acidified 
with dilute hydrochloric acid to pH 1. 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 was: [.alpha.].sub.D.sup.20 : +146.degree. (neat), 
corresponding to an optical purity (ee value) greater than or equal to 98 
percent. 
EXAMPLE 4 
Racemization of 2,2-dimethylcyclopropanecarboxylic acid 
From the mother liquors resulting during the crystallization of 
(S,S)-alpha-(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 {[.alpha.].sub.D.sup.20 
=-51.8.degree. (c=1, CHCl.sub.3)}, 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.degree. 
C. and, within 30 minutes, was mixed by instillation with a mixture of 
17.9 g of thionyl chloride and 5.0 g of hexane and refluxed for another 
2.5 hours. The solvent and the excess thionyl chloride were distilled off 
and the residue was heated to 135.degree. 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.