Method for the production of 4-hydroxyphenylacetic acid

DETAILED DESCRIPTION We claim: 1.
A method for producing 4-hydroxyphenylacetic acid, which consists essentially of sequentially (a) reacting o-chlorophenol with glyoxylic acid in an alkaline solution at a temperature of from -5.
degree.
to 100.
degree.
C.
to form 3-chloro-4-hydroxymandelic acid after acidification, (b) reducing the 3-chloro-4-hydroxymandelic acid by conventional means to 3-chloro-4-hydroxyphenylacetic acid, and (c) cleaving the chloro group from the 3-chloro-4-hydroxyphenylacetic acid in alkaline solution at between room temperature and the boiling point of the reaction mixture.
2.
The method according to claim 1 wherein the reduction of step (b) is carried out with red phosphorus and iodine.
3.
The method according to claim 2 or 1 wherein the chloro group cleavage in step (c) is carried out catalytically with hydrogen and a palladium catalyst.




Description:
4-Hydroxyphenylacetic acid is an important intermediate product in the synthesis of pharmaceutical preparations.
There is, therefore, a general interest in achieving the most efficient synthesis possible.
Known methods are based, for example, on anisole which is converted into 4-methoxyphenylacetonitrile by chloromethylation and cyanidation (see Organikum, Berlin, 9th Edition, page 363).
Saponification of the nitrile into acid, and subsequent cleavage of the ether with phosphorus/hydriodic acid (R.
J.
Meltzer et al.
, J.
Org.
Chem.
22 (1957) 1577) produces 4-hydroxyphenylacetic acid.
The 4-stage synthesis however, has very unsatisfactory yields.
The total yield, in relation to anisole, is generally below 21%.
Another known method, based upon phenol, through the Friedel-Crafts reaction leads to 4-hydroxyacetophenone which is converted into the desired compound by means of the Willgerodt-Kindler reaction (C.
D.
Joshi et al.
, J.
Sci.
Ind.
Res.
(New Delhi) Sect.
B 21 (1962) 284).
Here again, the total yield, in relation to phenol, of about 30% is extremely unsatisfactory.
In addition, sulfides which are by-products of the reaction create a waste-water problem and the cost of overcoming it is disproportionately high