181289-39-4Relevant articles and documents
Synthetic method of environment-friendly and efficient pregabalin
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Paragraph 0071; 0086; 0087, (2019/02/04)
The invention relates to a synthetic method of environment-friendly and efficient pregabalin. The synthetic method comprises the following steps: 1) dehydrating and condensing acetate and isopentyl aldehyde to obtain 5-methyl-2-hexenoate; 2) performing cyano addition on the 5-methyl-2-hexenoate to obtain (S)-5-methyl-3-cyanohexanoate; 3) performing hydrogen reduction cyclization on the (S)-5-methyl-3-cyanohexanoate to obtain (S)-4-isobutylpyrrolidin-2-one; and 4) performing hydrolysis and ring opening on the (S)-4-isobutylpyrrolidin-2-one to obtain the pregabalin. The synthetic route has the advantages of cheap and easily available raw materials, few reaction steps, mild process conditions, simple operation, high reaction yield and less environment pollution, and is more suitable for industrial production of bulk drug pregabalin.
Chemoenzymatic asymmetric synthesis of pregabalin precursors via asymmetric bioreduction of β-cyanoacrylate esters using ene-reductases
Winkler, Christoph K.,Clay, Dorina,Davies, Simon,O'Neill, Pat,McDaid, Paul,Debarge, Sebastien,Steflik, Jeremy,Karmilowicz, Mike,Wong, John W.,Faber, Kurt
, p. 1525 - 1533 (2013/04/10)
The asymmetric bioreduction of a library of β-cyanoacrylate esters using ene-reductases was studied with the aim to provide a biocatalytic route to precursors for GABA analogues, such as pregabalin. The stereochemical outcome could be controlled by substrate-engineering through size-variation of the ester moiety and by employing stereochemically pure (E)- or (Z)-isomers, which allowed to access both enantiomers of each product in up to quantitative conversion in enantiomerically pure form. In addition, stereoselectivities and conversions could be improved by mutant variants of OPR1, and the utility of the system was demonstrated by preparative-scale applications.
Enzymatic production of (S)-3-cyano-5-methylhexanoic acid ethyl ester with high substrate loading by immobilized Pseudomonas cepacia lipase
Zheng, Ren-Chao,Li, Ai-Peng,Wu, Zhe-Ming,Zheng, Jian-Yong,Zheng, Yu-Guo
, p. 1517 - 1521 (2013/02/23)
(S)-3-Cyano-5-methylhexanoic acid ethyl ester is a valuable synthetic intermediate for pregabalin. Immobilized lipase PS from Pseudomonas cepacia was screened and shown to be the best biocatalyst for the enantioselective hydrolysis of 3-cyano-5-methylhexanoic acid ethyl ester, a racemic mixture involving a β-stereocenter. The optimum temperature and pH for the biocatalytic process were 35 °C and 6.0, respectively. Lipase PS IM exhibited a strong tolerance toward high substrate concentrations of up to 2.0 M (366 g/l). In the scaled-up biotransformation, (S)-3-cyano-5-methylhexanoic acid ethyl ester was produced in 0.89 M (162.9 g/l), 99.2% ee, and 44.5% yield. These results indicated that lipase PS IM catalyzed the preparation of (S)-3-cyano-5-methylhexanoic acid ethyl ester and could be used as an efficient route for the large-scale production of pregabalin.