Cbz的脱除：巯基乙醇法，怎么样？
文摘
科技
2024-10-20 08:02
天津
经典的方法往往是通用的方法
特定的方法，反应条件突破的结果，往往是大量失败数据中的结晶，其产生根本离不开最基本的化学反应原理。巯基乙醇可以去除Ns，原理是一物降一物，比拼谁的亲核能力更强。- 巯基乙醇/DMAc/磷酸钾，很顺利的实现了Cbz的去除，产品直接在水体系中析出
N,N-dimethylacetamide (DMAc) (717 kg,2.81 X) and intermediate 24 Tosylate (255 kg, 1.00 X) are charged to a suitable inert reaction vessel. The vessel is then charged with anhydrous K3PO4 (258 kg, 4.00 equiv) which is rinsed into the mixture with additional DMAc (240 kg, 0.94X). The reactor is degassed with nitrogen and to the vessel is then added 2-mercaptoethanol (48.5 kg, 0.19 X, 2.00 equiv). The reaction mass is heated to a critical temperature range of 73−76 °C and monitored by HPLC analysis. The conversion is considered to be complete when the level of residual 24 is not more than 0.4 A% relative to product 25. Upon achieving a passing IPC result, the reaction stream is cooled to 25−30 °C and the vessel is charged with purified water (638 kg, 2.50 X). The solution is warmed to approximately 35−45 °C and held with agitation. The organic phase is separated and it is then added purified water (179 kg, 0.70 X) while maintaining an internal temperature of 15−25 °C. The mixture is seeded with intermediate 25, aged, and treated with additional purified water (459 kg 1.8 X) to complete crystallization. The solids are collected by filtration, washed with a mixture of purified water/ DMAc (306 and 191 kg, respectively; 1.2 X:0.75 X respectively), and the resulting wet solid is then slurried in a mixture of acetonitrile (58.7 kg, 0.23 X) and purified water (765 kg, 3.00 X). The product is then collected by filtration, washed twice with purified water (74 kg, 0.29 X), and subsequently, dried under vacuum at not more than 40 °C until the moisture content is NMT 10% by KF analysis. 157 kg of white solid was collected with a potency of 93.5 wt % and 98.7 A% purity (89% yield).https://doi.org/10.1021/acs.oprd.2c00386
