摘要
对硝基苯胺经酰胺化、环化、双氯取代、消除反应得关键中间体3-(吗啉-4-基)-1-(4-硝基苯基)-5,6-二氢-1H-吡啶-2-酮(5);同时,对甲氧基苯胺经重氮化后,与2-氯乙酰乙酸乙酯通过Japp-Klingemann反应,得到中间体2-氯-2-[2-(4-甲氧基苯基)腙]乙酸乙酯(6)。中间体5与6进行[1+3]偶极环加成反应、脱吗啉、还原、酰胺化、环化、氨解反应得到Ⅹa因子直接抑制剂阿哌沙班。反应总收率为25%(以对硝基苯胺计),纯度为99%。优化后的工艺与文献报道的工艺相比,反应条件温和,操作步骤简便,更适宜工业生产。
The key intermediate 3- （4-morpholinyl） -1- （4-nitrophenyl） -5,6-dihydropyridin-2 （1H） -one （5） was obtained via amidation, cyclization, dichlorination and elimination with 4-nitroaniline as the starting material. While another intermediate ethyl 2-chloro-2-E2-（4-methoxyphenyl）hydrazono] acetate （6） was prepared from 4-anisidine by diazotization and Japp-Klingemann reaction with ethyl 2-chloro-3-oxobutanoate. Apixaban, a factor X a direct inhibitor, was synthesized from 5 and 6 by 1,3-dipolar cycloaddition, olefination, reduction, amidation, cyclization and aminolysis with an overall yield of 25 % （based on 4-nitroaniline） and an HPLC purity of 99 %. The improved process had several advantages over those reported procedures, such as mild conditions, simple operations and more suitable for industrial production.
出处
《中国医药工业杂志》
CAS
CSCD
北大核心
2014年第10期906-910,共5页
Chinese Journal of Pharmaceuticals
关键词
阿哌沙班
抗血栓
Ⅹa因子直接抑制剂
合成
apixaban
anticoagulation
factor X a direct inhibitor
synthetic process
