Eco-friendly, industrial process for synthesis of ( S )-3-(aminomethyl)-5-methylhexanoic acid [pregabalin]
Bhairab Nath Roy, Girij Pal Singh, Piyush S. Lathi, Manoj K. Agrawal, Rangan Mitra, Vijay Sadashiv Pise, Nande Village · 2012
In the present work pregabalin has been synthesized by four novel routes, which have been broadly categorized into two approaches. In the first strategy, it has been synthesized through a hemiaminal intermediate. In the second approach, (RS)-ethyl-3-cyano-5-methylhexanoate, a key intermediate, has been synthesized through novel and cost effective routes, followed by either lipase catalyzed kinetic resolution to optically pure (S)-ethyl-3-cyano-5-methylhexanoate (>99% ee, 85% yield) or resolution via diastereomeric salt formation with cinchonidine to obtain optically pure (S)-3-cyano-5-methylhexanoic acid (>99% ee, 85% yield), which has been subsequently converted to pregabalin (>99% ee). In addition, for improvement of atom economy as well as cost effectiveness, an efficient process for complete racemization of (R)-3-cyano5-methyl-hexanoic acid has been developed.