药物Pexidartinib（培西达替尼、吡昔替尼）合成检
索总结报告
一、Pexidartinib（培西达替尼、吡昔替尼）简介
Pexidartinib（培西达替尼、吡昔替尼）于2019年8月在美国上市，主要用于症状严重、功能受限且不适合手术改善的症状性腱鞘巨细胞瘤成人患者。
Pexidartinib（培西达替尼、吡昔替尼）分子结构式如下:
CAS:2040295-03-0
英文名称：Pexidartinib hydrochloride
中文名称：培西达替尼、吡昔替尼盐酸盐
二、Pexidartinib（培西达替尼、吡昔替尼）合成路线
三、Pexidartinib（培西达替尼、吡昔替尼）合成检索总结报告
(一)Pexidartinib（培西达替尼、吡昔替尼）中间体2的合成
合成方法
实验步骤参考文献操作方法
一To a mixture
of compound 1(10g,81.88mmol,1eq)and TEA (33.14g,327.53mmol,45.59mL,4eq)in THE (150mL)was added Boc 2O (53.61g,245.65mmol,56.43mL,3eq)and DMAP (1.60g,13.10mmol,0.16eq)in one portion at 25°C under N 2.The mixture was stirred at 25°C for 10hours.The reaction mixture was quenched by addition of Na 2SO 4·10H 2O (30g),then filtered.The filtrate was diluted with H 2O (200mL)and extracted with EtOAc (200ML×3).The combined organic layers were washed with brine (500mL),dried
reactor then
over Na 2SO 4,filtered and concentrated under reduced pressure to give a residue.The residue was purified by column chromatography (SiO 2,Petroleum ether/Ethyl acetate=2:1)to give compound 2(11g,34.12mmol,42%yield)as a yellow solid.WO2018/209132;(2018);(A1)English
(二)Pexidartinib （培西达替尼、吡昔替尼）中间体4的合成合成方法
实验步骤参考文献操作方法
一The reactor was charged with Compound 2(1000gm,1.0eq.),Compound 3(497gm,1.05eq.),tetrabutylammonium hydrogen sulfate (31.6gm,0.03eq.)and isopropanol (12L,11.8vol).The reaction mixture was stirred for at least about an hour to obtain a near clear,yellow solution.Then potassium tert -pentoxide (73mL,0.04eq.)was added over 30seconds.The reaction mixtu
re was stirred at about 15-25°C for about 20-24hours.The reaction was monitored by HPLC.When the content of compound 4was more than 80%,the reaction was deemed complete.The reaction mixture was cooled to about 0-10°C and then stirred for at least about 2hours.The precipitate was filtered,washed with 3L isopropanol that had been cooled to 0°C and dried to
WO2016/179412;(2016);(A1)English