文献类型：期刊文献

英文题名：Improved synthesis of inhibitor for thymidylate synthase raltitrexed

作者：Yu, Xin-Hong; Mao, Qing-Hua; Zhang, Wei-Dong; Chen, Zhen-Jie; Sun, Le-Ying

机构：[1] School of Chemistry and Pharmaceutics, East China University of Science and Technology, Shanghai 200237, China

年份：2005

卷号：31

期号：2

起止页码：184

外文期刊名：Huadong Ligong Daxue Xuebao /Journal of East China University of Science and Technology

收录：EI(收录号：2005209110088)

语种：英文

摘要：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-dihy-dro-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 standard 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-methlation with methyl iodide in 25.4% yield. The improved process is more suitable for industrial preparation.