Patent Watch

August 25, 2014

Clean up fungicide intermediate before making the final product. Inventors G. McDougald, J. P. Muxworthy, and B. A. Wilde discuss compounds that are intermediates in the production of several pyrazole herbicides. Two patents on the synthesis of these pyrazoles have been reviewed previously (Turner, K. Org. Process Res. Dev. DOI: 10.1021/op500039p).

As shown in the figure, ester 2 is synthesized by the reaction of ethoxy ester 1 with methylhydrazine. The reaction is carried out in xylene with aqueous methylhydrazine because it is less hazardous than the neat compound.

Synthesis of acid chloride 4 from ethoxy ether 1

Ester 2 is recovered as a solution in xylene and can be used to prepare acid 3. The acid is then converted to acid chloride 4, the direct precursor of several fungicides.

In this patent, the inventors tackle the problem of impurities in acid 3 that form tar products when acid chloride 4 is prepared. They solved the problem by washing ester 2 with a base before they synthesized the acid.

In the inventors’ procedure, the xylene solution of 2 is washed with a water-soluble base (NaOH or Na2CO3) because the ester is not miscible with water. The purified ester is easily recovered by phase separation. After the washing step, the purified ester is hydrolyzed with hydrochloric acid to give the acid.

The inventors identified the oligomeric impurities in 3 by using gel permeation chromatography. The patent provides copies of the chromatograms of the acid before and after washing to show the absence of oligomer peaks. When the sodium salt of the acid was washed with xylene, the oligomeric impurities were not removed.

The inventors’ claims include the use of acid chloride 4 to prepare fungicides such as isopyrazam, sedaxane, bixafen, penthiopyrad, fluxapyroxad, and some unnamed structurally similar compounds. (Syngenta [Guildford, UK]. US Patent 8,735,600, May 27, 2014; Keith Turner)