(±)‐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.
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Ishitani et al. (2017) studied this question.