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Synthesis of 3-Palmityloxy Shikimic Acid Catalyzed by Lipase in Non-Aqueous Media

Author: XiangHong
Tutor: TangLuHong
School: Jiangnan University
Course: Microbial and Biochemical Pharmacy
Keywords: 3 - palmitoyl shikimate Shikimate Novozym 435 Non-aqueous phase Biocatalysis
CLC: R284
Type: Master's thesis
Year: 2008
Downloads: 75
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Abstract


3 - palmitoyl shikimic acid (3-Palmityloxy Shikimic acid, 3-PSA) is a chemical monomer (Chemical New Entity), is a fat-soluble shikimic acid derivatives. The shikimate (Shikimic acid, SA) with the physiological activity of the natural product extracted from a Chinese medicine Magnoliaceae plant star anise, is anti-H5N1 avian influenza miracle drug \and to reduce the role of focal cerebral ischemic injury. The 3 - bit selective esterification protection SA in the synthesis of chiral drugs have important role of anti-H5N1 avian influenza drugs target the neuraminidase and its natural substrate sialic acid (2 - deoxy-N-acetyl neuraminidase) configuration with 3 - position chiral unchanged, 4 - and 5 - positions configuration flipped coincide the turn Ammoniating SA. Of 3 - palmitoyl the shikimate or other fatty acid acylated shikimate synthesis intermediates, can be synthesized in a series of \The shikimate continue intermediates synthesis of other drugs to provide a simple way. Compared with SA ,3-PSA in the structure intact to maintain the SA has three chiral centers, and the selective esterification of protection of the 3 - hydroxy, and thus in the body may have a similar anti-and SA blood clots and reduce the physiological activity of focal cerebral ischemic injury; mono-acylated lipid water distribution characteristics modification will make 3-PSA compared with SA improved lipid solubility and ability to penetrate the blood-brain barrier is enhanced. In summary, the 3 - bit selective protection of SA is important in two aspects of the synthesis of chiral drugs and improve the physiological activity of the SA itself. This article first, with LC-MS to establish a thin analysis the shikimate monoacylated product, including expand the system and the color choice of methods. Enzymatic Synthesis of the fat-soluble derivatives of shikimic acid in the synthesis, the first preliminary study confirmed Novozym 435 shikimate the hydroxy selective catalytic acylation of shikimic acid carboxyl catalytic activity. Concentrated sulfuric acid relative to the chemical catalyst, thionyl chloride, enzyme catalysis does not occur racemization, polymerization and other side reactions. Compare the two kinds of the acylating agent, acetic anhydride and vinyl acetate, which acylation activity is too strong and is not conducive to enzyme catalyzed reflect its advantages. The study shows that activity of the enzyme-catalyzed shikimate palmitoylation can be obtained when a single one-acylate, this reaction does not proceed without enzyme catalysis. Synthesis product was purified by silica gel column for further structural identification and Novozym 435 may be selectively catalytic shikimate 3 hydroxyl groups. Since this synthesis method the reaction of water can not be timely removed, resulting in the synthetic conversion rate is not high, to increase the burden on the separation and purification of. In order to solve the problems in addition to water, the use of the solvent tert-amyl alcohol may be a minimum azeotropic mixture with water to form this nature, using the method of vacuum distillation and the stream plus t-amyl alcohol, in addition to water in the reaction process. The new method for the synthesis of shikimic acid and palmitic acid ratio of 1:1.24 when the the shikimate conversion rate increased to 95%. Designed according to the composition of the reaction mixture after the separation and purification methods, to avoid this restriction amount of separation using silica gel column chromatography, and contamination and serious separation method, the final form Preparation and Purification of up to 10g stage process. Finally, the range of extension of the application of the non-aqueous phase enzymatic acylation method, proved to be saturated fatty acids - lauric acid, myristic acid, stearic acid, arachidic acid; unsaturated fatty acids - oleic, linoleic, palmitoleic acid can be applied Such catalytic methods, palmitic acid methyl ester also can be replaced by palmitic acid acylation.

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