摘要
洛拉曲克是一种新型的胸苷酸合成酶抑制剂。本研究以4-硝基甲苯为起始原料,经溴代、硝基还原、再与水合氯醛和盐酸羟胺反应,浓硫酸作用下环合得4-溴-5-甲基靛红;再在双氧水作用下氧化开环得2-氨基-6-溴-5-甲基苯甲酸,经与双氰胺得关键中间产物2-胍基-5-溴-6-甲基-3H-喹唑啉-4-酮,强碱条件下以4-巯基吡啶作为保护剂脱脒基成2-氨基-5-溴-6-甲基-3H-喹唑啉-4-酮,最后与4-巯基吡啶经Ullmann反应制得标题化合物。总收率9.3%。改进后的方法简化了操作、降低了成本、适合工业生产。
Nolatrexed was known as a novel inhibitor of thymidylate synthase（TS）.It was synthesizedby using 4-nitortoluene as starting material viabromination,reduction,reacting with chloral hydrate and hydroxylamine hydrochloride,cyclization to give 4-bromo-5-methylisation,which was then oxidizied by H2O2 to produce 2-amino-6-bromo-5-methyl-benzoic acid.2-amino-6-bromo-5-methyl-benzoic acid reacting with chloroformamidine hydrochloride to form 2-guanidino-5-bromo-6-methyl-3H-quinazolin-4-one as the key intermediate,then treatment of compound 4-nitortoluene as starting material via 2-guanidino-5-bromo-6-methyl-3H-quinazolin-4-one with 4-mercaptopyridine and KOH to provide 2-amino-5-bromo-6-methyl-3H-quinazolin-4-one.Finally the title compound was obtained by reacting with 4-mercaptopyridine via the Ullmann reaction.The overall yield was 9.3%.The simplified synthetic process is feasible for further industrialization production.
出处
《化学试剂》
CAS
CSCD
北大核心
2011年第12期1131-1134,共4页
Chemical Reagents
基金
广东省自然科学基金资助项目(915106320-1000053)
