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Synthesis of (±)‐Pregabalin by Utilizing a Three‐Step Sequential‐Flow System with Heterogeneous Catalysts
Author(s) -
Ishitani Haruro,
Kanai Kan,
Saito Yuki,
Tsubogo Tetsu,
Kobayashi Shū
Publication year - 2017
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/ejoc.201700998
Subject(s) - chemistry , pregabalin , catalysis , yield (engineering) , knoevenagel condensation , hydrolysis , malonate , flow chemistry , organic chemistry , combinatorial chemistry , derivative (finance) , psychology , materials science , economics , financial economics , metallurgy , psychotherapist
(±)‐Pregabalin, a γ‐amino acid derivative, has been synthesized by utilizing flow methods. A three‐step sequential‐flow reaction starting from commercial isovaleraldehyde and methyl malonate proceeded smoothly with heterogeneous catalysts to afford the precursor of pregabalin in yields of 75–100 %, and a space‐time yield of 52.2 g/L d was reached. In addition, a heterogeneous catalyst for the Knoevenagel reactions of aldehydes with malonates, which is the first step of the synthesis, has been developed. Pregabalin was finally obtained by acid‐catalyzed hydrolysis of the precursor followed by neutralization.