Design and process study of chiral separation of (2S,4S)-1-(tert-butoxy carbonyl)-4-(methoxymethyl) pyrrolidine-2-carboxylic acid for green manufacturing

Abstract

An effective approach to separate chiral (2S,4S)-1-(tert-butoxy carbonyl)-4-(methoxymethyl) pyrrolidine-2-carboxylic acid ((2S,4S)-TBMP)) from mixed (2S,4S)-TBMP and (2S,4R)-1-(tert-butoxy carbonyl)-4-(methoxymethyl) pyrrolidine-2-carboxylic acid ((2S,4R)-TBMP), an important intermediate for the anti-HCV drug Velpatasvir, was developed for the first time, eliminating the need for salinization and dissociation processes and several organic solvents with water. Conceivable binding modes were set up by Gaussian calculation, and the separation process was designed and studied based on the calculation. The results showed that only the monohydrate of (2S,4S)-TBMP could be crystallized since three hydrogen bonds were formed between (2S,4S)-TBMP and water, which resulted in more stability and isomer separation. Compared to the original approach, our new approach exhibits a remarkable 17.4% increase in yield, a 43.3% rise in atom economy (AE), a 43.3% improvement in reaction mass efficiency (RME), and a substantial 32.0 g g⁻¹ reduction in process mass intensity (PMI). An industrial-scale implementation was set up successfully according to the new approach, achieving a batch capacity of 100 kg.