Development of a Continuous Process for the Large-Scale Asymmetric Manufacture of (R)-3-Methoxy-2-(4-methylpiperazin-1-yl)propanoic Acid

Abstract

A large-scale enantioselective manufacturing route to an unusual piperazine-substituted amino acid is described. Previous synthetic routes to this amino acid relied on the resolution of racemic mixtures using L-tartaric acid that was demonstrated on a 6 kg scale, but this resulted in a reduced overall yield and efficiency. The new enantioselective route to this amino acid uses the S N 2 displacement of a chiral triflate with N-methylpiperazine that proceeds with very high levels of stereocontrol. The key chiral triflate is prepared in five synthetic steps in 38% overall yield and >99% enantiomeric purity (e.p.), starting from cheap and readily available D-serine. Subsequent reaction with N-methylpiperazine was initially demonstrated in batch, providing the benzyl-protected amino acid in 83% e.p. on a 3 kg scale. This transformation was further improved by the application of continuous manufacture to provide the benzyl-protected ester in >99% e.p. on an 80 kg scale. Simple deprotection of the benzyl ester group by hydrogenolysis, followed by isolation of the amino acid as the corresponding dihydrochloride salt, provided a scalable and efficient synthesis of (R)-3-methoxy-2-(4-methylpiperazin-1-yl)propanoic acid in good overall yield (33%) and very high optical purity (>99.5% e.p.).