摘要
氨基吡啶类化合物是一类重要的医药中间体,在众多药物中有广泛的应用。为了支持公司新药研发,本文开发了关键中间体C(2-氯-4-异丙基氨基-5-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)吡啶)的高效合成路线。以5-溴-2,4-二氯吡啶作为起始原料,分别经过亲核芳香取代和钯催化硼酸酯化反应获得目标产品。第一步反应优化了投料比,温度,时间,可以有效避免二取代杂质。在优化Miyaura硼酸酯化反应过程中,使用公司高通量催化平台,筛选出醋酸钯/三苯基膦的催化体系组合,可以高效合成目标产物。通过简单的工艺参数优化,两步收率达到80.9%。本合成工艺具有反应干净,后处理简单,产品纯度好等优点。
Aminopyridine compounds are a class of important pharmaceutical intermediates, which are widely used in many drugs. In order to support the company’s new drug development, an efficient synthesis route of the key intermediate C(2-chloro-4-isopropyl amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboron heterocyclopentane-2-yl) pyridine) was developed. Using 5-bromo-2,4-dichloropyridine as starting material, the target products were obtained by nucleophilic aromatic substitution and palladium catalyzed boric acid esterification, respectively. In the first step, the feeding ratio, temperature and time are optimized, which can effectively avoid dissubstituted impurities. In the optimization of the Miyaura borate esterification process, palladium acetate/triphenylphosphine catalytic system combination was selected using the company’s high-throughput catalytic platform for efficient synthesis of the target product. By simple optimization of process parameters, the two-step yield reached 80.9 %. The synthesis process has the advantages of clean reaction, simple post treatment and good product purity.
作者
董吉喆
段雨琳
万里晶
胡锦阳
Dong Jizhe;Duan Yulin;Wan Lijing;Hu Jinyang(Hengbang Research Institute,Changzhou Hengbang Pharmaceutical Co.,Ltd.,Changzhou 213000,China)
出处
《广东化工》
CAS
2023年第4期1-4,共4页
Guangdong Chemical Industry
关键词
氨基吡啶
亲核芳香取代
Miyaura硼酸酯化反应
钯催化
高通量
aminopyridine
nucleophilic aromatic substitution
miyaura borylation reaction
palladium catalyst
high throughput
作者简介
董吉喆(1985-),男,江苏南京人,博士研究生,主要研究方向为创新药合成及工艺开发。;通讯作者:胡锦阳(1991-),男,江苏常州人,博士研究生,主要研究方向为药物生产工艺研发。
