Enantio- and regioselective opening of 2-alkyl nosylaziridines by indoles mediated by boron trifluoride. Application to a practical synthesis of a GnRH antagonist

ORGN 74

Roger N. Farr1, Ramon J. Alabaster2, John Y. L. Chung1, Bridgette Craig1, John S. Edwards2, Andrew W. Gibson2, Guo-Jie Ho1, Guy R. Humphrey1, Simon A. Johnson2, and Edward J. J. Grabowski1. (1) Department of Process Research, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065-0900, (2) Department of Process Research, Merck Research Laboratories, Hertford Road, Hoddesdon, Hertfordshire, EN11 9BU, UK, United Kingdom

An efficient, high yield process for the synthesis of a GnRH antagonist has been developed. We have demonstrated that under boron trifluoride catalysis, nosyl aziridines will react with 2-arylindole derivatives to afford b-substituted tryptamines with remarkably high regio- and enantioselectivity. The scope of the reaction was explored with several 2-substituted nosyl aziridines. The key reaction was developed expressly for the GnRH antagonist program and has been demonstrated on 40 kilogram scale.

Process R&D 1:00 PM-5:00 PM, Sunday, September 7, 2003 Sheraton New York -- Royal Ballroom B, Oral Division of Organic Chemistry The 226th ACS National Meeting, New York, NY, September 7-11, 2003