Development and a Practical Synthesis of Nepafenac Intermediate via Modified Gassman Reaction

Modification of nepafenac intermediate synthesis (5A) via Gassman specific ortho-substitution is reported. According to the process, 2-aminobenzophenone (1A) and 2-(methylthio)acetamide (2) were reacted in the convenient temperature conditions, in the presence of N-chlorophthalimide (3) or 1,3-dichloro-5,5-dimethylhydantoin (4), to activate the formation of azasulfonium salt and rearrangement thereof to pure 2-amino-3-benzoyl-α-(methylthio)phenylacetamide (5A). The procedure appears to be suitable for a reaction carried out in a large scale. Keywords: Gasmann reaction, Nepafenac, N-chlorophthalimide, Sommelet-Hauser-type rearrangement, N-chloroaniline, 2-(methylthio)acetamide, chlorosulfonium, salt, sulfoxide, oxalyl