枸橼酸托法替布的合成工艺优化

Improved synthetic process of tofacitib citrate

目的在现有专利和文献的基础上对枸橼酸托法替布合成工艺进行优化。方法以(3R,4R)-1-苄基-N,4-二甲基哌啶-3-胺二盐酸盐和2,4-二氯-7H-吡咯并[2,3-d]嘧啶为起始原料,经过缩合、氢化、中和、酰化、成盐等反应得到枸橼酸托法替布,并对各步合成工艺进行优化。结果目标物的结构经MS、^(1)H-NMR确证,总收率为55.7%(以原料(3R,4R)-1-苄基-N,4-二甲基哌啶-3-胺二盐酸盐计),纯度为99.86%。结论优化后的合成路线具有收率较高、操作简便、节能环保、适合工业化生产等优势。

On the basis of existing patents and literatures,the synthesis process of tofacitib citrate was optimized.With(3R,4R)-1-benzyl-N,4-dimethylpiperidine-3-amine dihydrochloride and 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine as the starting materials,the target compound was obtained by a series of reactions such as condensation,hydrogenation,neutralization,acy lation and salification,the synthesis process of each step was optimized.The structure of the target compound was confirmed by MS and^(1)H-NMR.The total yield was 55.7%with the purity of 99.86%(HPLC).The optimized synthetic route has the advantages of high yield,simple operation,energy saving and environmental protection,and is suitable for industrial production.