Practical resolution of 3-aminopyrrolidine via diastereomeric salt formation with ( S)-2-methoxy-2-phenylacetic acid

Abstract

The resolution of 3-aminopyrrolidine 1, a versatile key intermediate for chiral pharmaceuticals, via diastereomeric salt formation was investigated. The resolution conditions were optimized focusing on an industrial-scale production to afford enantiopure ( R)- 1, while ( S)-methoxy-2-phenylacetic acid 5 was found to be a suitable resolving agent. The less-soluble diastereomeric salt, 1:2 ( R)- 1:( S)- 5, was obtained with high resolution efficiency ( E) (yield 44%, 98% de, E 86%) under the best resolution conditions; ( RS)- 1/( S)- 5/HCl molar ratio = 1.0/1.0/1.0 in water solvent in the presence of sodium chloride. The optimized resolution process was scaled up to a pilot-scale production using 50 kg of ( RS)- 1 dihydrochloride as a starting racemate, and the resolution efficiency successfully reproduced the laboratory results.