Chemical Development on the Chiral Auxiliary (S)-4-(Phenylmethyl)-2-oxazolidinone Utilizing Automated Synthesis and DoE

Abstract

Enantiopure 4-substituted oxazolidinones are well-known chiral auxiliaries for asymmetric synthesis of carboxylic acid derivatives. The 4-(phenylmethyl)-substituted oxazolidinones derived from d- or l-phenylalanine are known to be particularly useful. We have conducted chemical development studies toward an efficient and scaleable “one-pot” process for production of (S)-4-(phenylmethyl)-2-oxazolidinone 2. The first step in the process employed a sodium borohydride reduction of phenylalanine mediated by an additive. The second step utilized triphosgene as a phosgene source to effect cyclization of the intermediate amino alcohol. Both chemical steps and workup procedures were screened and optimized utilizing statistical design of experiments (DoE) and parallel synthesis. The procedure was further characterized in an automated reactor system that provided heat flow measurements and modeled production at the plant scale. The efficiency of this process was compared to those of others previously reported on the basis of raw material cost, time requirements, safety, and hazardous waste generation.