An enantioselective synthesis of (S)-(+)-3-aminomethyl-5-methylhexanoic acid via asymmetric hydrogenation |
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| Authors: | Burk Mark J De Koning Pieter D Grote Todd M Hoekstra Marvin S Hoge Garrett Jennings Rex A Kissel William S Le Tung V Lennon Ian C Mulhern Thomas A Ramsden James A Wade Robert A |
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| Affiliation: | Dowpharma, Chirotech Technology Limited, A Subsidiary of The Dow Chemical Company, Cambridge Science Park, Milton Road, Cambridge CB4 0WG, United Kingdom. |
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| 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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