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

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.

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(R)-3-Aminopyrrolidine: (S)-methoxy-2-phenylacetic acid, 1:2C22H30N2O6[α]D20=+91.8 (c 0.5, H2O)De 99.5%Source of chirality: resolutionAbsolute configuration: (R,S)