Development of a Chemoenzymatic Manufacturing Process for Pregabalin
| Autor: | Dumond Yves Rene, Junhua Tao, Liam Tully, Carlos A. Martinez, Shanghui Hu, Kelleher Patrick Gerard Thomas |
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| Rok vydání: | 2008 |
| Předmět: | |
| Zdroj: | Organic Process Research & Development. 12:392-398 |
| ISSN: | 1520-586X 1083-6160 |
| DOI: | 10.1021/op7002248 |
| Popis: | 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 facto... |
| Databáze: | OpenAIRE |
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