An enantioselective synthesis of (S)-(+)-3-aminomethyl-5-methylhexanoic acid via asymmetric hydrogenation.
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.
Burk
Mark J
MJ
Dowpharma, Chirotech Technology Limited, A Subsidiary of The Dow Chemical Company, Cambridge Science Park, Milton Road, Cambridge CB4 0WG, United Kingdom.
De Koning
Pieter D
PD
Grote
Todd M
TM
Hoekstra
Marvin S
MS
Hoge
Garrett
G
Jennings
Rex A
RA
Kissel
William S
WS
Le
Tung V
TV
Lennon
Ian C
IC
Mulhern
Thomas A
TA
Ramsden
James A
JA
Wade
Robert A
RA
D000927:Anticonvulsants / Q000138:chemical synthesis*; D001426:Bacterial Proteins; D006865:Hydrogenation; D000069583:Pregabalin; D013237:Stereoisomerism; D014157:Transcription Factors; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis*
D000927:Anticonvulsants; D001426:Bacterial Proteins; C442131:ScoC protein, Bacillus subtilis; D014157:Transcription Factors; D000069583:Pregabalin; D005680:gamma-Aminobutyric Acid