磷酸西格列汀的酶法合成工艺改进

Enzymatic Synthesis Modification of Sieglitine Phosphate

磷酸西格列汀的酶法合成工艺是美国Merck公司与Codexis公司合作开发的一条绿色高效合成途径。主要在酶法合成工艺基础上进行改进,具体通过可表达转氨酶的重组大肠杆菌BL21(ED3)培养获得菌泥,经破碎后投入催化反应,底物转化率达95.83%。调酸性分离使有机杂质含量低于1.0%,调碱性分离西格列汀,与磷酸成盐后精制得到磷酸西格列汀一水合物,收率84.6%,ee>99.99%,综合回收并使用二甲基亚砜与异丙醇。改进后相比文献方法提高约3%的转化率,明显降低了生产成本,适用于大量生产,为同类型酶催化工艺设计提供了一个新的思路。

The enzymatic synthesis of sitagliptin phosphate is a green and efficient way developed by Merck and Codexis.In this study,the enzymatic synthesis process was improved.The sludge was obtained by culturing recombinant Escherichia coli BL21(ed3)which can express transaminase,After being broken,the substrate conversion rate was 95.83%.The content of organic impurity was lower than 1.0% by acidic separation,and the purity of sigliptin was 99.3 by alkaline separation.The crude product was obtained by salt reaction.The yield was 84.6%,and enantiomeric excess was more than 99.99%,Dimethyl sulfoxide and isopropanol were recovered and used.Compared with the literature method,the improved method improves the conversion rate by about 3%,obviously reduces the production cost,is suitable for mass production,and provides a good idea for the same type of enzyme catalytic process design.