An Enantioselective Synthesis of (S)-(+)-3-Aminomethyl-5-methylhexanoic Acid via Asymmetric Hydrogenation
The Journal of Organic Chemistry2003Vol. 68(14), pp. 5731–5734
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Mark J. Burk, Pieter D. de Koning, Todd M. Grote, Marvin S. Hoekstra, Garrett Hoge, Rex A. Jennings, William S. Kissel, Tung Le, Ian C. Lennon, Thomas A. Mulhern, James A. Ramsden, Robert A. Wade
Abstract
A concise enantioselective synthesis of (S)-(+)-3-aminomethyl-5-methylhexanoic acid (1, Pregabalin) has been developed. The key step is the asymmetric hydrogenation of a 3-cyano-5-methylhex-3-enoic acid salt 2 with a rhodium Me-DuPHOS catalyst, providing the desired (S)-3-cyano-5-methylhexanoate 3 in very high ee. Subsequent hydrogenation of the nitrile 3 with a heterogeneous nickel catalyst provides Pregabalin 1 in excellent overall yield and purity.
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