Note: Descriptions are shown in the official language in which they were submitted.
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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
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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
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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
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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
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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.
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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):
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~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
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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.
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