Process for the resolution of enantiomeric aryloxyphenoxy propionates

A process for the effective analytical or preparative resolution of the enantiomers of 2-(4-aryloxyphenoxy)propionic acids or the C.sub.1 -C.sub.4 alkyl esters thereof which comprises converting a racemic or partially resolved mixture of said 2-(4-aryloxyphenoxy)propionic acids or the C.sub.1 -C.sub.4 alkyl esters thereof to a pair of diastereomeric terpene esters by reaction with an optically active terpene alcohol and separating the diastereomers of the terpene ester by liquid chromatography with a silica column.

BACKGROUND OF THE INVENTION 
The herbicidal activity of aryloxyphenoxy propionic acids and derivatives 
thereof is well known in the art. Furthermore, optical isomers are often 
known to exhibit enhanced herbicidal activity over the corresponding 
racemates. For example, U.S. Pat. No. 4,531,969 has disclosed that the 
R-enantiomers of certain 2-(4-aryloxyphenoxy)propionic acids and certain 
derivatives thereof are distinguished by a considerably enhanced 
herbicidal action compared to the racemic modifications. Since reduced 
quantities of herbicide are required to achieve comparable levels of 
control, the application of mixtures enriched in the more efficacious 
R-enantiomer offers both economical and environmental advantages. 
To exploit the agrinomic benefits of these advantages, it is necessary to 
efficiently resolve the racemic mixtures of the herbicides that are 
normally produced industrially and to accurately determine the ratio of 
the R- and S-enantiomers in the resulting composition. 
Various methods for obtaining high concentrations of individual enantiomers 
are known. The most common method of resolution of a racemic modification 
involves its conversion by an optically active reagent into a mixture of 
diastereomers which can then be separated on the basis of their different 
physical properties. Diastereomers are generally separated by fractional 
crystallization, though occasionally by fractional distillation or 
chromatography. Once the diastereomers have been separated, they can be 
reconverted to the individual enantiomers and the optically active 
resolving agent can be recovered. 
Unfortunately, the differences in physical properties of the diastereomers 
are rarely if ever great enough to effect a total separation with one 
crystallization. Usually repeated crystallizations must be used and the 
process is long and tedious. The same situation generally applies to 
differential boiling points and differential absorption with respect to 
distillation and chromatographic separations. 
SUMMARY OF THE INVENTION 
The present invention provides a process for the effective analytical or 
preparative resolution of the enantiomers of 2-(4-aryloxyphenoxy)propionic 
acids of formula (I) 
##STR1## 
wherein Ar is 
##STR2## 
and X is CF.sub.3, F, Cl, Br or I and Y is H, F, Cl, Br or I 
or the C.sub.1 -C.sub.4 alkyl esters thereof which comprises converting a 
racemic or partially resolved mixture of said 
2-(4-aryloxyphenoxy)propionic acid or C.sub.1 -C.sub.4 alkyl ester thereof 
to a pair of diastereomeric terpene esters by reaction with an optically 
active terpene alcohol and separating the diastereomers of the terpene 
ester by liquid chromatography with a silica column. After separation the 
individual enantiomers of (I) can be recovered by hydrolysis of the 
separated terpene ester diastereomers. 
This procedure allows the efficient separation of the enantiomers of 
2-(4-aryloxyphenoxy)propionic acids to produce high optical purity 
materials of greater herbicidal activity than the unresolved racemates. 
Additionally, the method is useful for the accurate determination of the 
enantiomeric content of commercial compositions. 
Any naturally occurring, optically active terpene alcohol is contemplated 
as the resolving agent. Relatively inexpensive d-menthol and l-menthol are 
the preferred embodiments. 
The diastereomeric terpene esters to be separated can be prepared by a 
variety of methods, either with or without a solvent. However, it is 
important that the chosen methods do not cause racemization of the chiral 
center. For example, the racemic or partially resolved 
2-(4-aryloxyphenoxy)propionic acid (I) can be treated with excess thionyl 
chloride to form the acid chloride. Removal of excess thionyl chloride 
followed by reaction of the acid chloride at elevated temperatures with a 
terpene alcohol, for example, d-menthol or l-menthol, provides a product 
consisting of a pair of diastereomeric esters. Alternatively, the 
2-(4-aryloxyphenoxy)propionic acid (I) can be directly esterified with the 
terpene alcohol by standard procedures, preferably in the presence of a 
dehydrating agent such as 2,2-dimethoxypropane. 
Similarly, the C.sub.1 -C.sub.4 alkyl esters of 
2-(4-aryloxyphenoxy)propionic acids (I) can be transesterified with the 
terpene alcohol by conventional techniques. Alternatively, the esters can 
be initially hydrolyzed to the acid which can be further converted to the 
diastereomeric terpene esters as described hereinabove. 
The pair of diastereomeric terpene esters can be separated on a silica 
liquid chromatographic column. Silica is advantageously employed because 
it is relatively inexpensive and stable. The silica particle size may vary 
from 1 to 500.mu.. Particle sizes of from 5 to 150.mu. are preferred. Best 
resolutions are obtained by using particles of a narrow range, for 
example, less than .+-.10.mu.. 
The column size is limited only by mechanical considerations. Those skilled 
in the art will appreciate the limitations on column size imposed by the 
scale of the operation. In general, the diastereomer weight load into the 
chromatographic system is limited by the capacity of the silica packing. 
More loading results in less resolution. 
The eluents employed are simple and non-optically active. As is well known 
to those skilled in the art, the choice of eluents greatly affects the 
separation. Various components and concentrations of these components can 
be used. The optimal choice of eluent is dictated by the compounds to be 
separated and the column characteristics. Mixtures of hydrocarbons and 
halogenated hydrocarbons are preferred to achieve the desired separation. 
Various eluent flow rates can be used limited by the pressure limitations 
of the chromatographic system. Optimum flow rates can be readily 
determined by procedures well known to those skilled in the art. 
After the diastereomeric terpene esters have been separated, hydrolysis of 
the individual esters provides both the R- and S-enantiomers of 
exceedingly high optical purity. The more herbicidally active 
R-2-(4-aryloxyphenoxy)propionic acid may be esterified using conventional 
ester formation procedures to produce agriculturally acceptable esters 
which include the following: methyl, ethyl, propyl, butyl, octyl, 
ethoxyethyl, butoxyethyl and methoxypropyl. 
The less herbicidally active S-enantiomer is preferably racemized by 
heating in the presence of a strong base and recycling the resulting 
racemate to the separation process.