Efficient Synthesis and Practical Resolution of 1-(Naphthalen-1-yl)ethanamine, a Key Intermediate for Cinacalcet

Abstract

An efficient synthesis of 1-(naphthalen-1-yl)ethanamine ( RS -2) and its practical resolution to optically pure (1R)-(naphthalen-1-yl)ethanamine ( R -(+)-2), a key intermediate in the synthesis of cinacalcet hydrochloride (1), is described. The resolution of RS -2 using R-(−)-mandelic acid as a resolving agent in ethanol was established on an industrial scale to give pure R -(+)-2 with >99.8% ee after liberation of the amine from its mandelate salt. An efficient process for the racemization of undesired isomer S -(−)-2 is also provided to maximize the yield of desired enantiomer.

Keywords:

• Cinacalcet
• industrially feasible
• 1-(naphthalen-1-yl)ethanamine
• R-(−)-mandelic acid
• resolution

ACKNOWLEDGMENTS

The authors thank the management of Megafine Pharma (P) Ltd. for the permission to publish this work. The authors also thank the colleagues of the Analytical Research and Development team for their valuable contribution to this work.