Separation of stereoisomeric cyclic carboxylic acids

A process for the separation of the stereoisomers of a stereoisomer mixture of a cyclic carboxylic acid of the formula ##STR1## in which R.sup.1 and R.sup.2 each independently is hydrogen, halogen, C.sub.1 -C.sub.6 -alkyl or C.sub.2 -C.sub.6 -alkenyl, PA1 R.sup.3 is alkyl, alkenyl or alkynyl having up to 6 carbon atoms and optionally substituted by halogen, or alkoxycarbonyl having up to 5 carbon atoms, or is aralkyl or aryl, or PA1 R.sup.1 plus R.sup.2, or R.sup.1 plus R.sup.3, together with the adjacent C atom, form a carbocyclic ring, PA1 R.sup.3 and COOH are cis or trans to one another and the COOH group is in the exo or endo position if R.sup.1 and R.sup.3 together form a ring, and PA1 n is 0, 1 or 2, which comprises contacting a weakly alkaline, aqueous solution of the stereoisomeric mixture with a non-polar organic solvent, whereby the cis or endo isomeric free acid enters the organic solvent while the trans or exo isomer remains in the aqueous solution as a salt, and separating the aqueous solution from the organic solvent, thereby to separate the isomers. Preferred acids are cyclopropanecarboxylic acid derivatives, the aqueous solution is preferably buffered to a pH of about 7 to 9 and the organic solvent is preferably a hydrocarbon, halogenated hydrocarbon, aromatic hydrocarbon or ether.

The present invention relates to a novel process for the separation of 
known substituted cycloaliphatic carboxylic acids into their 
stereoisomers. 
It has already been disclosed that mixtures of stereoisomeric 
cis-substituted and trans-substituted cyclopropanecarboxylic acids can be 
separated by fractional crystallization. (Coll. Czech. Chem. Commun. 24; 
2230 (1959); Pestic. Sci. 1971, 245 and Pestic. Sci. 1974, 791). However, 
this process is troublesome and wasteful. This process is not suitable for 
the preparation of relatively large amounts of pure cis and trans isomers. 
The present invention now provides a process for the separation of the 
stereoisomers of a carboxylic acid of the general formula 
##STR2## 
in which R.sup.1 and R.sup.2 each represents hydrogen, halogen, C.sub.1 
-C.sub.6 -alkyl or C.sub.2 -C.sub.6 -alkenyl, 
R.sup.3 represents alkyl, alkenyl or alkynyl, which are optionally 
substituted by halogen and have, in each case, up to 6 C atoms, or 
represents aralkyl or aryl and 
n represents 0, 1 or 2, 
R.sup.1 and R.sup.2, as well as R.sup.1 and R.sup.3, together with the 
adjacent C atom, can also form a carbocyclic ring, 
R.sup.3 and COOH are cis or trans to one another and the COOH group is in 
the exo or endo position if R.sup.1 and R.sup.3 together form a ring, 
(which compounds (I), as chiral molecules, also exist in the optically 
active forms), in which the cis or endo isomeric free acid is removed from 
a weakly alkaline, aqueous solution of the trans or exo isomer, which 
remains in the aqueous solution as a salt, by extraction with a non-polar 
organic solvent. 
It is surprising that the cis or endo isomer can be separated off, as the 
free acid, from a weakly alkaline solution by the process according to the 
invention. 
The process according to the invention has a number of advantages. Thus, 
the cis or endo isomers, which are frequently present in a cis/trans or 
exo/endo mixture only in minor amounts, can be separated off from the 
large amount of the other isomers, and this can be used both for 
purification and for concentration purposes. Furthermore, the process 
according to the invention is also suitable for isolating relatively large 
amounts of the particular isomers and can be carried out continuously. 
If, for example, 2,2-dichlorovinyl-3,3-dimethyl-cyclopropanecarboxylic acid 
is used as the cis/trans mixture, the process according to the invention 
can be represented by the following equation: 
##STR3## 
The compounds of the general formula (I) which are especially suitable are 
presented by the general formula 
##STR4## 
in which R.sup.4 represents alkyl or alkenyl with up to 4 carbon atoms, 
alkoxycarbonyl, F, Cl or Br. 
Examples of the compounds which can be separated into stereoisomers by the 
process according to the invention are: 
2-(2,2-difluorovinyl)-3,3-dimethyl-cyclopropanecarboxylic acid, 
2-(2,2-dichlorovinyl)-3,3-dimethyl-cyclopropanecarboxylic acid, 
2-(2,2-dibromovinyl)-3,3-dimethyl-cyclopropanecarboxylic acid and 
2-(2-methylbuten-1-yl)-3,3-dimethylcyclopropanecarboxylic acid. 
The isomer mixtures, used as the starting material, of the compounds of the 
general formula (I) are known (Coll. Czech. Chem. Commun. 24, 2230 (1959); 
DOS (German Published Specification) 2,615,159; J. Agr. Food Chem. 21, 767 
(1973); British Pat. No. 1,446,304; Pestic. Sci. 1971, 245; Pestic. Sci. 
1974, 537; British Patent 1,413,491; J. Chem. Soc. 1945, 285; DOS (German 
Published Specification) 2,432,951; J. Org. Chem. 17, 381 (1952); DOS 
(German Published Specification) 2,439,177; British Pat. No. 1,415,491 and 
Pestic. Sci. 1975, 537). 
Extraction agents which can be used are non-polar solvents which are not 
water-miscible, such as, for example, aliphatic, optionally halogenated 
hydrocarbons, aromatic hydrocarbons and aliphatic ethers. Preferably, 
aliphatic hydrocarbons, such as petroleum ether and cyclohexane, ethers, 
such as diethyl ether or diisopropyl ether, or halogenated hydrocarbons, 
such as carbon tetrachloride, chloroform or methylene chloride, are used. 
The process according to the invention can be carried out in the presence 
of buffer substances which maintain a constant, weakly alkaline medium. 
Inorganic salts of polybasic acids (including dibasic acids), such as, for 
example, phosphoric acid, boric acid or carbonic acid, are suitable for 
this. Sodium bicarbonate is preferably used. The pH range is generally 
between about 7 and 9, preferably between about 8 and 8.5. The separation 
is carried out generally at temperatures between about 0.degree. and 
100.degree. C., preferably between about 10.degree. and 30.degree. C. 
In general, it is not necessary to apply pressures, unless very highly 
volatile extraction agents, such as butane or propane or the fluorinated 
lower alkanes, are used. 
In carrying out the process according to the invention, appropriately more 
that one mole of a weak inorganic base, such as sodium bicarbonate, but at 
least the amount of base corresponding to the proportion of trans or exo 
isomers previously determined analytically (for example spectroscopically 
or by gas chromatography), is used per mole of isomer mixture. 
The subsequent procedure is to carry out the extraction, according to 
general laboratory practice, by shaking several times with the extraction 
agent, or to carry out the separation continuously with the aid of an 
extraction apparatus. The organic phase can then be concentrated, and the 
cis or endo acids can be either distilled or recrystallized for a final 
purification. The trans or exo isomers are obtained from the aqueous phase 
after acidification, filtration, separation or extraction and can be 
finally purified in the same manner. It is, of course, also possible to 
add fresh isomer mixture, as a weakly alkaline aqueous salt solution, 
continuously to the extraction operation, and it is also possible to carry 
out the operation by a counter-current distribution, in a manner such that 
a solution of the isomer mixture in one of the above-mentioned solvents is 
passed against a stream of the weakly alkaline buffer solution or of a 
saturated sodium bicarbonate solution, only the trans isomer being drawn 
off from the solution as a salt. 
The stereoisomeric cyclopropanecarboxylic acids of the formula (I) obtained 
by the process according to the invention may be used for the preparation 
of highly active insecticides.

The examples which follow illustrate the process according to the 
invention, without indicating a limitation with regard to the range of its 
applicability. 
EXAMPLE 1 
The potassium salt of an isomer mixture of 
2-(2,2-dichlorovinyl)-3,3-dimethylcyclopropanecarboxylic acid (cis/trans 
ratio=40/60) was dissolved in water and the resulting solution was 
extracted by shaking with ether. The NMR spectrum of the crystals obtained 
after concentrating showed that almost pure 
cis-(2-(2,2'-dichlorovinyl)-3,3-dimethylcyclopropanecarboxylic acid had 
been extracted. The substance was pure after recrystallizing once from 
petroleum ether at 0.degree. C. 
EXAMPLE 2 
1 mole of an isomer mixture of 
2-(2,2-dichlorovinyl)-3,3-dimethylcyclopropanecarboxylic acid (cis/trans 
ratio=40/60) was dissolved in 2.5 liters of water with the aid of 5 moles 
of sodium bicarbonate. A continuous, vigorous stream of fine, small 
bubbles of ether was allowed to bubble through this solution in an 
extraction apparatus. After some time, about 0.4 mole of the cis isomer 
was obtained by concentration of the ether layer and, after 
recrystallizing once from petroleum ether, was spectroscopically pure. 
It will be appreciated that the instant specification and examples are set 
forth by way of illustration and not limitation, and that various 
modifications and changes may be made without departing from the spirit 
and scope of the present invention.