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Chiral Resolution of Naproxen by Lipase in Water-miscible Organic-solvents

Author: ZhouQingQuan
Tutor: QianJunQing
School: Zhejiang University of Technology
Course: Pharmaceutical Engineering
Keywords: Naproxen Candida rugosa lipase Chiral separation Enantioselectivity
CLC: TQ463
Type: Master's thesis
Year: 2011
Downloads: 98
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Abstract


Naproxen is the major drug of anti-inflammatory, anti-inflammatory and anti-rheumatic.The physiological activity of the S-form is 28-fold greater that of the R-form.It is necessary to products optically pure naproxen to avoid side effects caused by R-(-) form. This article explored the resolution of naproxen by Candida rugosa lipase catalyzed stereoselective hydrolysis of Naproxen methyl ester In the micro water organic solvent system. Experiments had obtained the optimal process parameters of reaction. And also attempted to Improve enzyme enantioselectivity initially.First of all, Naproxen were methylated by rufluxeing in methanol under the catalyst of concentrated sulfuric acid. The high purity Naproxen methyl ester was prepared with some purification treatments including using the hot alkaline washing mixed products of the reaction. the esterification yield was up to 96.51% after optimizing reaction parameters. Second, n-hexane and isooctane were selected after inspection of organic solvents, and the two solvents Combined into dual-component mixtures system with the volume ratio (20:80). Experiments took it as reaction medium in lipase catalyzed stereoselective hydrolysis of Naproxen methyl ester. The optimum conditions were:mixed solvent 20mL, 0.2mol/L phosphate-citric acid buffer 5%, pH 5.5, naproxen methyl ester 300mg, Candida lipase 125mg, reaction temperature 45℃, reaction time 72h. Reaction obtained Naproxen 30mg and its ee value was 32%.Finally, methods to improve the stereoselectivity of enzymes was studied by adding additives and enzyme pretreatment, and this result is that Adding 10% DMSO and enzyme pretreated by acetone can improve weakly enzyme selectivity, buffer solution containing Ba2+can increase the value of ee of the product to 40.35%.To some extent,Fe3+also increased the yield of Naproxen.

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