Development of a Chemoenzymatic Manufacturing Process for Pregabalin Export

@article{citeulike:4610040, abstract = {A new manufacturing process for (S)-3-(aminomethyl)-5-methylhexanoic acid (Pregabalin), the active ingredient in Lyrica, has been developed. Using Lipolase, a commercially available lipase, rac-2-carboxyethyl-3-cyano-5-methylhexanoic acid ethyl ester (1) can be resolved to form 2-carboxyethyl-3-cyano-5-methylhexanoic acid (2). A heat-promoted decarboxylation of 2 efficiently generates (S)-3-cyano-5-methylhexanoic acid ethyl ester (3), a known precursor of Pregabalin. This new route dramatically improved process efficiency compared to the first-generation process by setting the stereocenter early in the synthesis and enabling the facile racemization and reuse of (R)-1. The chemoenzymatic process also reduced organic solvent usage resulting in a mostly aqueous process. Compared to the first-generation manufacturing process, the new process resulted in higher yields of pregabalin (40–45\% after one recycle of (R)-1), and substantial reductions of waste streams corresponding to a 5-fold decrease in the E factor from 86 to 17.}, author = {Martinez, Carlos A. and Hu, Shanghui and Dumond, Yves and Tao, Junhua and Kelleher, Patrick and Tully, Liam}, citeulike-article-id = {4610040}, citeulike-linkout-0 = {http://dx.doi.org/10.1021/op7002248}, citeulike-linkout-1 = {http://pubs.acs.org/doi/abs/10.1021/op7002248}, day = {1}, doi = {10.1021/op7002248}, journal = {Organic Process Research \& Development}, keywords = {industrial, pregabalin}, month = {May}, number = {3}, pages = {392--398}, posted-at = {2009-05-23 13:39:41}, priority = {2}, title = {Development of a Chemoenzymatic Manufacturing Process for Pregabalin}, url = {http://dx.doi.org/10.1021/op7002248}, volume = {12}, year = {2008} }

TY - JOUR ID - citeulike:4610040 L3 - citeulike-article-id:4610040 N2 - A new manufacturing process for (S)-3-(aminomethyl)-5-methylhexanoic acid (Pregabalin), the active ingredient in Lyrica, has been developed. Using Lipolase, a commercially available lipase, rac-2-carboxyethyl-3-cyano-5-methylhexanoic acid ethyl ester (1) can be resolved to form 2-carboxyethyl-3-cyano-5-methylhexanoic acid (2). A heat-promoted decarboxylation of 2 efficiently generates (S)-3-cyano-5-methylhexanoic acid ethyl ester (3), a known precursor of Pregabalin. This new route dramatically improved process efficiency compared to the first-generation process by setting the stereocenter early in the synthesis and enabling the facile racemization and reuse of (R)-1. The chemoenzymatic process also reduced organic solvent usage resulting in a mostly aqueous process. Compared to the first-generation manufacturing process, the new process resulted in higher yields of pregabalin (40–45% after one recycle of (R)-1), and substantial reductions of waste streams corresponding to a 5-fold decrease in the E factor from 86 to 17. IS - 3 JF - Organic Process Research & Development EP - 398 TI - Development of a Chemoenzymatic Manufacturing Process for Pregabalin VL - 12 SP - 392 KW - industrial KW - pregabalin AU - Martinez, Carlos AU - Hu, Shanghui AU - Dumond, Yves AU - Tao, Junhua AU - Kelleher, Patrick AU - Tully, Liam PY - 2008/05/01/ UR - http://dx.doi.org/10.1021/op7002248 ER -