盐酸缬更昔洛韦的合成工艺改进  

Improvement of synthetic technology of valganciclovir hydrochloride

作　　者：薛娜[1] 马彦 张玉辉 张恺[2] 陈兴贺 Xue Na;Ma Yan;Zhang Yuhui;Zhang Kai;Chen Xinghe(Hebei Chemical and Pharmaceutical College,Shijiazhuang 050026;Department of Medicinal Chemistry,Hebei Medical University,Shijiazhuang 050017;Renhe Yikang group New Drug Research and Development Hebei Co.,Ltd.,Shijiazhuang 050035)

机构地区：[1]河北化工医药职业技术学院,石家庄050026 [2]河北医科大学药学院,石家庄050017 [3]仁合益康集团新药研发河北有限公司,石家庄050035

出　　处：《中国抗生素杂志》2024年第7期804-808,共5页Chinese Journal of Antibiotics

基　　金：河北省教育厅科学研究项目资助(No.ZD2021313);河北省科技重大专项项目(No.22282603Z);河北省自然科学基金资助项目(No.H2021418001)。

摘　　要：目的盐酸缬更昔洛韦的合成工艺改进。方法以更昔洛韦为原料,经乙酰基保护单羟基制得O-单乙酰更昔洛韦,与Cbz-L-缬氨酸经缩合,再经盐酸脱乙酰基得更昔洛韦-Cbz-L-单缬氨酸酯,酸化后在连续流反应器中催化氢化脱苄氧羰基得盐酸缬更昔洛韦粗品,粗品在异丙醇/水(2:1,V/V)中重结晶得到盐酸缬更昔洛韦。结果工艺改进后的操作更加简便安全,可以实现长时间稳定和安全的连续流生产及后处理,目标产品1的收率和纯度得到提高,总收率48.8%,纯度99.4%。结论为盐酸缬更昔洛韦的合成提供了一种较新的方法,生产成本得以降低。Objective To improve the synthesis process of valganciclovir hydrochloride.Methods Valganciclovir hydrochloride was synthesized from ganciclovir by protection with acetyl to give O-monoacylganciclovir,which was subjected to condensation with Cbz-L-valine and deacetylated hydrochloride to obtain ganciclovir-Cbz-L-monovaline ester.After ganciclovir-Cbz-L-monovaline was acidified,hydrogenation of debenzyloxycarbonyl in a continuous flow reactor was catalyzed to obtain valganciclovir hydrochloride crude product,and the crude product was recrystallized in isopropanol/water(2:1)to obtain valganciclovir hydrochloride.Result The improved process made the operation more convenient and safe,enabling long-term stable and safe continuous production and post-treatment.The yield and purity of target product 1 had been improved,with a total yield of 48.8%and a purity of 99.4%.Conclusion This research provided a relatively new method for the synthesis of valganciclovir hydrochloride,reducing production costs.

关 键 词：盐酸缬更昔洛韦 抗病毒药 合成 工艺改进 连续流 

分 类 号：R978.7[医药卫生—药品]