Facile synthesis of arylmaleic acids and anhydrides

A process for making acrylmaleic acid and arylmaleic anhydride derivative useful as intermediates for the preparation of arylmaleimides in the synthesis of compounds having activity in the central nervous system. The process involves reacting arylacetonitriles with glyoxylic acid to provide novel intermediate 3-aryl-3-cyanopropeneoates which may be converted to the arylmaleic acid and arylmaleic anhydride derivatives.

BACKGROUND OF THE INVENTION 
1. Field of the Invention 
The invention relates to a novel and facile process for making arylmaleic 
acid and arylmaleic anhydride derivatives, which are used as intermediates 
in the preparation of aryl-maleimides. The arylmaleimides are subsequently 
used to synthesize compounds which possess activity as antidepressants and 
as antistress agents in mammals. 
2. Description of the Related Art 
The Meerwein arylation of maleimides (Rondestvedt, C. S. Jr.; Vogl, O. J. 
Amer. Chem. Soc., 1955, 77, 2313) or dialkylmaleates (Taylor, G. C., 
Strojny, E. J., J. Amer. Chem. Soc., 1954, 76, 1872) is the most general 
method of making arylmaleic acid derivatives. Several factors preclude 
scaleup of the above reactions. In particular, the maleimides used are 
expensive and the arylations are always accompanied by a substantial 
quantity of aryl coupling to form biphenyls. 
Another method explored involves a Wittig reaction of aroyl cyanides with 
carbalkoxymethylenetriphenylphosphoranes (Kalvode, L. Coll. Czech. Chem. 
Comm., 1976, 41 2034). In our hands, the reaction of commercially 
available benzoyl cyanide with carboethyoxymethylenetriphenylphosphorane 
gives ethyl 3-cyano-3 -phenylpropenoate as a 2.5:1 mixture of Z:E isomers. 
This ratio can be improved to about 10:1 Z:E by treatment of the mixture 
with thiophenol in refluxing toluene. The desired Z-cyanoester is then 
crystallized in hot formic acid to phenylmaleimide. Despite the overall 
efficiency, this method is impractical due to the lack of availability of 
the desired aroyl cyanides. 
The prior art references are directed to laboratory scale synthesis. 
Attempts to produce the arylmaleic acid derivatives in a large scale 
according to the prior art procedures have proven to be unsatisfactory as 
detailed above. 
This novel and facile process gives the arylmaleic acid derivatives in high 
yield. In addition, a highly pure product, a single geometric isomer, is 
obtained without the need for further purification, such as chromatography 
of the Z:E isomeric mixture. 
SUMMARY OF THE INVENTION 
The invention relates to a novel and facile process for making arylmaleic 
acid derivatives represented by formula I: 
##STR1## 
and aryl maleic anhydrides of the formula II: 
##STR2## 
wherein Ar-- is phenyl or substituted phenyl having one or more 
substituents selected from the group consisting of straight or branched 
chain (C.sub.1 -C.sub.4)alkyl, (C.sub.1 -C.sub.3)alkoxy, or halo selected 
from bromine, chlorine, fluorine or iodine; which comprises: 
1) reacting a compound of the formula Ar--CH.sub.2 CN, wherein Ar-- is 
hereinbefore defined; with glyoxylic acid hydrate in the presence of a 
sodium, potassium or cesium containing base, to yield an intermediate of 
formula III, wherein B is a salt selected from sodium, potassium or 
cesium; and 
##STR3## 
2) reacting a compound of formula III with a weak mineral acid at room 
temperature to yield arylmaleic acid derivative of Formula I or a strong 
mineral acid at reflux temperature to yield arylmaleic anhydrides of 
formula II.