第 48 卷第 2 期 Vol. 48 No. 2 2018 年 4 月 Apr 2018

所属栏目：医药及中间体 达格列净的合成研究

吕久安1，范龙涛2，张克军1，徐少婕2，彭效明2，居瑞军2，晁建平2* （1. 北京红惠新医药科技有限公司 北京 102600；2. 北京石油化工学院 北京 102600）

摘　要：以5-溴-2-氯-4'-乙氧基二苯甲烷为原料，经过缩合反应得到2-氯-5-（1-甲氧基-D-吡喃葡萄糖-1-基）-4'-乙氧基二苯甲烷，除去甲氧基得达格列净粗品，然后通过上乙酰基、重结晶除去异构体，后再脱乙酰基得纯度较高的达格列净，最后再与S-丙二醇成溶剂化合物，得到目标晶型产物。达格列净产品单杂小于0.1%，纯度大于99.5%。产物经过ESI-MS、1H NMR、热分析、X-粉末衍射确证。

关键词：达格列净；5-溴-2-氯苯甲酸；D-葡萄糖酸内酯

中图分类号：R914　　文献标识码：A　　文章编号：1009-9212（2018）02-0033-03

Synthetic of Dapagliflozin

L?譈 Jiu-an1, FAN Long-tao2, ZHANG Ke-jun1, XU Shao-jie2, PENG Xiao-ming2, JU Rui-jun2, CHAO Jian-ping2* (1. Beijing Honghui Meditech Co., Ltd., Beijing 102600, China; 2. Beijing Institute of Petrochemical Technology, Beijing 102600, China)

Abstract：2-Chloro-5-(1-methoxy-D-glucopyranosyl-1)-4'-ethoxydiphenylmethane was obtained from a condensation reaction using 5-bromo-2-chloro-4'-ethoxy diphenyl methane as the starting material. The crude Dagliflozin was obtained by removing methoxyl group. Acetyl groups were introduced to the Dagliflozin and isomers were separated by recrystallization. Higher purity dapagliflozin was achieved by removing acetyl groups, followed by mixing with S-propanediol as a solvent compound to obtain the desired crystalline product. The target product was confirmed by ESI-MS, 1H NMR, thermal analysis and X-ray powder diffraction. Dapaglifloxzin was obtained with a single impurity of less than 0.1% and a purity of greater than 99.5%.

Key words：dapagliflozin; 5-bromo-2-chlorobenzoic acid; D-gluconolactone

基金项目：国家自然科学基金项目（21406015）。

作者简介：吕久安（1983-），男，辽宁海城人，工程师，研究方向：药物合成与质量控制（E-mail：jiuan.lv@mail.honghui-meditech.com）。

联 系 人：晁建平，副教授，研究方向：药物合成工艺研究（E-mail：chaojp@bipt.edu.cn）。

收稿日期：2018-04-20