Development of a Chemoenzymatic Manufacturing Process for Pregabalin

Abstract

A new manufacturing process for ( S )-3-(aminomethyl)-5-methylhexanoic acid (Pregabalin), the active ingredient in Lyrica, has been developed. Using Lipolase, a commercially available lipase, rac -2-carboxyethyl-3-cyano-5-methylhexanoic acid ethyl ester ( 1 ) can be resolved to form 2-carboxyethyl-3-cyano-5-methylhexanoic acid ( 2 ). A heat-promoted decarboxylation of 2 efficiently generates ( S )-3-cyano-5-methylhexanoic acid ethyl ester ( 3 ), a known precursor of Pregabalin. This new route dramatically improved process efficiency compared to the first-generation process by setting the stereocenter early in the synthesis and enabling the facile racemization and reuse of ( R )- 1 . The chemoenzymatic process also reduced organic solvent usage resulting in a mostly aqueous process. Compared to the first-generation manufacturing process, the new process resulted in higher yields of pregabalin (40–45% after one recycle of ( R )- 1 ), and substantial reductions of waste streams corresponding to a 5-fold decrease in the E factor from 86 to 17.