胸苷酸合成酶抑制剂雷替曲塞的合成

An Improved Synthesis of Inhibitor for Thymidylate Synthase Raltitrexed

以L-谷氨酸二乙酯为手性元,采用汇聚合成法分别以2-氨基-5-甲基-苯甲酸为原料经环合、溴化制得2-甲基-6-溴甲基-3-氢-喹唑啉-4-酮(4),收率为69.1%;以2-噻吩甲醛为原料经硝化、氧化、酰氯化、缩合、还原及N-甲基化制得N-[5-(N-甲氨基)-2-噻吩甲酰基]-L-谷氨酸二乙酯(3),收率为25.4%;2-噻吩甲醛以硝酸-乙酸酐硝化后再经过氧化氢氧化制备5-硝基噻吩-2-甲酸,收率为62.2%;N-(5-氨基-噻吩-2-甲酰基)-L-谷氨酸二乙酯(10)的N-甲烷化反应中采用胺与碘甲烷摩尔比1∶1.1,一次性加入碘甲烷,收率为79.9%。化合物3与化合物4缩合生成N-[5-[N-[(3,4-二氢-2-甲基-4-氧-6-喹唑啉基)-甲基]-N-甲氨基]-2-噻吩甲酰基]-L-谷氨酸二乙酯(2),继而水解即得目标化合物雷替曲塞(1),总收率为22.5%。其结构经红外光谱、核磁共振谱、高分辨质谱及元素分析确证。

In this paper, a practical process for convergent synthesis of the title compound raltitrexed, a specific inhibitor for thymidylate synthase, was developed. Condensation of 6-(bromomethyl)-3,4-dihydro-2-methyl-4-oxo-quinazoline with diethyl N-[5-(N-methylamino)-2-thenoyl]-L-glutamate, followed by hydrolysis under basic condition gave the title compound raltitrexed, which was confirmed by IR, ()~1H-NMR, MS as well as element analysis and qualified for the standrand for clinic study. 6-(Bromomethyl)-3,4-dihydro-2-methy 4-oxoquinazoline, one of the key intermediates for preparing raltitrexed, was prepared from 2-amino-5-methylbenzoic acid by N-acetylation with acetic anhydride, cyclization with ammonium (acetate) as well as bromination with N-bromosuccini mide (NBS) in 69.1% yield. Diethyl N-(5-(N-methylamino)-2-thenoyl)-L-glutamate, another key intermediate for preparing raltirexed, was prepared from (2-thenoylcarboxaldehyde) via direct nitration by the mixture of nitric acid and acetic anhydride, oxidation with hydroperoxide in room temperature, chlorination with thionyl chloride, condensation with the chiral synthon diethyl L-glutamate, reduction with iron in acetic acid, and N-methylation with methyl iodide in 25.4% yield. The improved process is more suitable for indrustrial preparation.