【摘要】 目的改进抗癌药物雷替曲塞的制备工艺.方法以5-硝基-2-噻吩甲酸为原料,经酯化、硝基还原、乙酰化、N-甲基化、酸性水解、酯化得到5-(N-甲基)-氨基噻吩-2-甲酸甲酯;5-(N-甲基)-氨基噻吩-2-甲酸甲酯与6-溴甲基-3,4-二氢-2-甲基-4-氧代喹唑啉缩合,经碱性水解、酰化后与L-谷氨酸二甲酯发生亲核取代反应制得N-[[5-[[(3,4-二氢-2-甲基-4-氧代-6-喹唑啉基)甲基]甲氨基]-2-噻酚基]羰基]-L-谷氨酸二甲酯,最后经水解、酸化制得雷替曲塞.结果与讨论总收率20.4%,反应条件温和,试剂价格便宜、毒性低,环境污染小.目标产物结构经红外、质谱、核磁共振氢谱确证.更多还原

【Abstract】 OBJECTIVE To improve the process of the preparation of anti-cancer drug raltitrexed.METHODS 5-(N-Methyl)-amino-thiophene-2-methyl formate was prepared by esterification,nitroreduction,acetylation,N-methylation,acidic hydrolysis and esterification from 5-nitro-2-thiophene carboxylic acid used as a starting material.And then the condensation reaction of 5-(N-methyl)-amino-thiophene-2-methyl formate with 6-(bromomethyl)-2-methylquinazolin-4(3H)-one followed by alkaline hydrolysis,acylation and nucleophilic substitution reaction with dimethyl L-glutamate gave (S)-dimethyl 2-(5-(methyl((2-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)methyl)amino)thiophene-2-carboxamido)pentanedioate.At last the desired product raltitrexed was obtained by hydrolysis and acidification.RESULTS and CONCLUSION The overall yield of this method was 20.4%,and the synthetic route is environmentally friendly with these advantages of mild reaction conditions,regents of low prices and less toxicity.The product structure was confirmed by IR,MS,and 1H NMR.更多还原