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Chemo-enzymatic Synthesis of Chiral Intermediates of Pregabalin

Author: WangZuo
Tutor: WuJianPing；YangLiRong
School: Zhejiang University
Course: Biochemical Engineering
Keywords: Pregabalin chiral intermediates (3S) -2 - carboxyethyl -3 - cyano-5 - methyl- hexanoic acid Biological split Process Improvement
CLC: TQ463.2
Type: Master's thesis
Year: 2010
Downloads: 203
Quote: 0
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Abstract


Pregabalin is a gamma-aminobutyric acid (GABA), three isobutyl substitution. Pregabalin in neuropathic pain, epilepsy, pain secondary treatment showed a strong advantage, and have a therapeutic effect on patients with neuropathic pain associated with sleep disorders. (3S) -2 - carboxyethyl -3 - cyano-5 - methyl-hexanoic acid is the key chiral intermediates for the synthesis of pregabalin. Isovaleraldehyde and malonate, as raw materials, through the Knoevenagel condensation, synthesis of 2 - carboxyethyl -5 - methyl - 2 - hexenoic acid ethyl ester, and then by the addition reaction with sodium cyanide , synthesized pregabalin Intermediate 2 - carboxyethyl -3 - cyano-5 - methyl-hexanoic acid ethyl ester; respectively the lipase and microbial catalyzed asymmetric hydrolysis reaction is carried out on the racemic 2 - carboxyethyl ethyl-3 - cyano-5 - methyl-hexanoic acid ethyl ester of the split, the development of chemical - enzymatic preparation (3S) -2 - carboxyethyl -3 - cyano-5 - methyl-hexanoic acid new route. First, through the existing synthetic methods, determine the synthesis of racemic 2 - carboxyethyl -3 - cyano-5 - methyl-hexanoic acid ethyl ester as a starting material of isovaleraldehyde, and improve and optimize the synthesis process, so that the yield was increased from 78% to 88.5%, the yield of the second reaction stage is from 90% to 99% of the first reaction; Meanwhile, in order to establish (3S) -2 - carboxymethyl ethyl -3 - Cyanide -5-yl - methyl-hexanoic acid gas analysis method, we synthesized a racemic 3 - cyano-5 - methyl-hexanoic acid ethyl ester. Secondly, the use of lipase-catalyzed asymmetric hydrolysis reaction is carried out on the racemic 2 - carboxyethyl -3 - cyano-5 - methyl-hexanoic acid ethyl ester of the split. As a substrate, 2 - carboxyethyl -3 - cyano-5 - ethyl methylhexyl lipases were screened to determine the 23 # (Lipoprime 50T) enzyme as a catalyst, and the catalytic conditions were optimized. When 2 - carboxyethyl -3 - cyano-5 - methyl-hexanoic acid ethyl ester concentration is 150mmol / L, and control the reaction time within at 48h, and the product ee% is 99%, the conversion was 40%. Finally, in order, the establishment of high-throughput screening by thin layer chromatography, petroleum ether - ethanol (90:10) as eluent to a good separation of product and substrate hydrolysis ability of the strains from the soil mass screening method, and determined by GC analysis ee_p screening the strains of high activity and selectivity. From the soil, we screened 16 strains selective hydrolysis, the ultimate choice of these 16 bacteria, including 14 # strain Select rate the best diester ee% to 87.9%, the conversion rate of 39.9%.

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CLC: > Industrial Technology > Chemical Industry > Pharmaceutical chemical industry > Production of organic compounds in drug > Aliphatic compounds, drugs
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