Dissertation
Dissertation > Industrial Technology > Chemical Industry > Pharmaceutical chemical industry > General issues > Basic theory

Asymmetric Reduction of Tert-butyl (S)-6-chloro-5-hydroxy-3-oxo-hexanoate with Yeast

Author WangSheng
Tutor YangLiRong
School Zhejiang University
Course Biochemical Engineering
Keywords Yeast Asymmetric reduction (S) -4 - chloro-3 - hydroxy- ethyl (S) -6 - chloro-5 - hydroxy-3 - oxo-hexanoate tert-Butyl Biocatalysis Candida pseudotropicakis Rhodotorula gracilis AS2.499
CLC TQ460.1
Type Master's thesis
Year 2006
Downloads 227
Quotes 5
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The optically active β, δ-dihydroxy ester of natural products has been in the polyhydroxy compound, and the synthesis of chiral drugs has been widely used. (3R, 5S) -6 - chloro -3,5 - dihydroxy-hexanoic acid tert-butyl ester is an important pharmaceutical intermediate for synthesis of HMG-CoA reductase inhibitors (statins), such drugs can effectively prevent atherosclerosis and coronary heart disease. First, since in the latter experiments needed in step a substrate (S) -6 - chloro-5 - hydroxy-3 - oxo-hexanoate require the use of tert-butyl (S) -4 - chloro -3 - hydroxybutyrate prepared from the line, so from the laboratory preserved seven yeast strains were screened for the COBE with high selectivity and chiral reducing ability of the strains - Candida pseudotropicalis. COBE initial concentration of 22g / L, 100g / L of Candida pseudotropicalis at 30 ℃, with 10g / L glucose for the auxiliary substrate buffer (pH6.0, 180rpm) oscillating reaction 8h, 94.1% yield of product at this time , eep value gt; 99%. The reaction process there was a significant substrate inhibition. In particular, the substrate concentration exceeds a critical value (approximately 22g / L) after the initial reaction rate appeared sharp decline. Therefore, from economic considerations, as the substrate concentration 22g / L more appropriate. Secondly, from the laboratory yeast strain deposited seven screened for (S) -6 - chloro-5 - hydroxy-3 - oxo-hexanoic acid t-butyl group has a high reducing ability of the strains - Rhodotorula gracilis AS 2.499. The method of using a thermal pretreatment of the Rhodotorula gracilis AS 2.499 improved asymmetric catalytic reduction (S) -6 - chloro-5 - hydroxy-3 - oxo-hexanoate t-butyl generate (3R, SS) -6 - chloro-3.5-bis hydroxy acid tert-butyl stereoselectivity. 100g / L of yeast Rhodotorula gracilis AS 2.499 to 10g / L of glucose as co - substrate buffer solution (pH6.0, 180rpm) after activation, the thermal pre-treatment at 50 ℃ 30min, then add 1g / L of initial substrate material (S) -6 - chloro-5 - hydroxy-3 - oxo-hexanoate, tert-butyl at 30 ℃, oscillating reaction 48h, the product obtained at this time was 68.3%, de is 95.1%. The reaction process there was a significant substrate inhibition. In particular, the substrate concentration exceeds a critical value (approximately 2.5g / L), the reaction yield and decreased de value occurs. When the substrate concentration of 1g / L, the yield is 65.7%, and de, 95.0%, while the substrate concentration was 2.5g / L, the yield is 52.9%, and de and 80.7%. Therefore, from economic considerations, as the substrate concentration 1g / L more appropriate. Finally, through the single factor experiment from carbon, organic nitrogen, inorganic nitrogen and other aspects affecting Rhodotorula gracilis AS 2.499 investigated reducing ability factors that determine the glucose as carbon source, nitrogen source and ammonium dihydrogen phosphate as -5:5 nitrogen, phosphate ratio of 1:2 (K 2 HPO 4 : KH 2 PO 4 ) . Culture medium by orthogonal experiments are optimized to determine the optimal medium composition: glucose 50g / L, protein

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