- Synthetic method of environment-friendly and efficient pregabalin
-
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.
- -
-
Paragraph 0071; 0086; 0087
(2019/02/04)
-
- Evaluation of several routes to advanced pregabalin intermediates: Synthesis and enantioselective enzymatic reduction using ene-reductases
-
This publication describes the evaluation of four synthetic routes to the advanced pregabalin (Lyrica) intermediate 7. Asymmetric reduction of (E)-7 with an ene-reductase (OPR1 from Lycopersicon esculentum) gave a saturated cyanoester intermediate 5 with the desired S stereocenter in ≥99% ee. OPR1 also catalyzed the reduction of (Z)-7 to (S)-5, but with lower conversion and selectivity.
- Debarge, Sebastien,McDaid, Paul,O'Neill, Pat,Frahill, James,Wong, John W.,Carr, Donncha,Burrell, Adam,Davies, Simon,Karmilowicz, Mike,Steflik, Jeremy
-
p. 109 - 121
(2014/05/20)
-
- Chemoenzymatic asymmetric synthesis of pregabalin precursors via asymmetric bioreduction of β-cyanoacrylate esters using ene-reductases
-
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.
- 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)
-
- Enzymatic production of (S)-3-cyano-5-methylhexanoic acid ethyl ester with high substrate loading by immobilized Pseudomonas cepacia lipase
-
(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.
- Zheng, Ren-Chao,Li, Ai-Peng,Wu, Zhe-Ming,Zheng, Jian-Yong,Zheng, Yu-Guo
-
p. 1517 - 1521
(2013/02/23)
-
- PROCESS FOR THE PREPARATION OF ( S ) - 3 - CYANO - 5 - METHYLHEXANOIC ACID DERIVATIVES ADN OF PREGABALIN
-
The invention provides a process for the manufacture of a compound of formula (I) using an enzyme catalysed reduction of a compound of formula (lla) or llb). Compounds of formula (I) are useful for preparing pregabalin.
- -
-
-
- IMPROVED SYNTHESIS OF OPTICALLY PURE (S) - 3-CYANO-5-METHYL-HEXANOIC ACID ALKYL ESTER, AN INTERMEDIATE OF (S)- PREGABALIN
-
The present invention is directed towards synthesis of (S) - 3-cyano-5-methyl-hexanoic acid ethyl ester. A cost effective, eco-friendly process for preparation of enantiomerically pure (S)-3-cyano-5-methyl-hexanoic acid alkyl ester, intermediate of γ-amino acids, particularly (S)-pregabalin.
- -
-
-
- Development of a chemoenzymatic manufacturing process for Pregabalin
-
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-earboxyethyl-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-rnethylhexanoic 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)-l. 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)-l), and substantial reductions of waste streams corresponding to a 5-fold decrease in the E factor from 86 to 17.
- Martinez, Carlos A.,Hu, Shanghui,Dumond, Yves,Tao, Junhua,Kelleher, Patrick,Tully, Liam
-
p. 392 - 398
(2013/01/03)
-
- Preparation of pregabalin and related compounds
-
Materials and methods for preparing (S)-(+)-3-aminomethyl-5-methyl-hexanoic acid and structurally related compounds via enzymatic kinetic resolution are disclosed.
- -
-
Page/Page column 19
(2008/06/13)
-
- An enantioselective synthesis of (S)-(+)-3-aminomethyl-5-methylhexanoic acid via asymmetric hydrogenation
-
A concise enantioselective synthesis of (S)-(+)-3-aminomethyl-5-methylhexanoic acid (1, Pregabalin) has been developed. The key step is the asymmetric hydrogenation of a 3-cyano-5-methylhex-3-enoic acid salt 2 with a rhodium Me-DuPHOS catalyst, providing the desired (S)-3-cyano-5-methylhexanoate 3 in very high ee. Subsequent hydrogenation of the nitrile 3 with a heterogeneous nickel catalyst provides Pregabalin I in excellent overall yield and purity.
- Burk, Mark J.,De Koning, Pieter D.,Grote, Todd M.,Hoekstra, Marvin S.,Hoge, Garrett,Jennings, Rex A.,Kissel, William S.,Le, Tung V.,Lennon, Ian C.,Mulhern, Thomas A.,Ramsden, James A.,Wade, Robert A.
-
p. 5731 - 5734
(2007/10/03)
-