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Short Paper | Regular issue | Vol 94, No. 3, 2017, pp.554-559
Published online, 3rd March, 2017
DOI: 10.3987/COM-17-13662
An Improved and Economical Process for Preparation of Pregabalin, an Anticonvulsant

Fei Xiong,* Bin Yang,* Wei-Xiang Wang, Yue-Feng Zhao, Qing-Gang Tan, Shang-Wu Gu, Jia-Min Huo, Yao Xie, Jun-Zhe Yan, Xi-Lin Feng, and Ju Li

*Department of Chemistry, Fudan University, Shanghai 200043, China


An improved, practical, economical and efficient process for the preparation of highly enantiomerically pure pregabalin (1) involving chemical resolution through diastereomeric crystallization is described herein. 3-Isobutylpentanedioic acid (2) is subjected to dehydration to afford 3-isobutylglutaric anhydride (3), followed by a ring-opening esterification with cinnamyl alcohol to form the racemic hemiester rac-4, which is, in turn, salified with an inexpensive organic base (1S,2S)-2-amino-1-(p-nitrophenyl)propane-1,3-diol (CHA) to form diastereomeric salts mixture. Then subsequently chemical resolution through diastereomeric crystallization to produce the desired enantiopure hemiester 4, which is the key chiral synthetic intermediate of pregabalin (1).