沙格列汀合成路线的改进

Improvement of synthetic route of saxagliptin

目的:改进沙格列汀的合成路线。方法:以(S)-N-叔丁氧羰基-(3-羟基金刚烷-1-基)甘氨酸和2,2'-二硫化二苯并噻唑为原料,在亚磷酸三乙酯的还原作用下生成(S)-N-叔丁氧羰基-(3-羟基金刚烷-1-基)甘氨酸苯并[d]噻唑-2-硫酯;该硫醇活性酯与(1S,3S,5S)-2-氮杂双环[3.1.0]己烷-3-甲腈对甲苯磺酸盐发生缩合反应,再经盐酸脱氨基保护基等步骤得到抗糖尿病药物沙格列汀。结果:所得目标产物总收率35.6%,产品纯度在99.9%以上。结论:改进后的工艺操作简单,产率较高,产品纯度高,适合工业化生产。

Objective： To improve the synthetic route of saxagliptin. Methods： Starting from （S）-N- （t-butoxycarbonyl） -3-hydroxyadamantylglycine and 2,2 ＇-dithiobis （ benzothiazole ） , （ S ） -N-（ t-butoxycarbonyl ） -3- hydroxyadamantylglycine 2-benzol d] thiazolyl thioester was obtained under the reduction of triethyl phosphite. The active thioester was reacted with （ 1 S, 3S, 5S） -2-azabicyclo [ 3. 1.0 ] hexane-3-carbonitrile methanesulfonate, and then it was subjected to hydrochloride to deprotect the amino protecting group to give the antidiabetic agent saxagliptin. Results： Saxagliptin was synthesized with a total yield of 35.6% , and the product purity was more than 99.9% as determined by HPLC. Conclusion： The improved synthetic process, with simplified operation, good yield and high purity, is applicable for industrial production.