雷替曲塞的制备工艺研究

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.

Research of the preparation of raltitrexed

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 -- methy- lation,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 -- methylquin- azolin--4（3H）- one followed by alkaline hydrolysis, acylation and nucleophilic substitution reaction with dimethyl L--gluta- mate gave （S） -- dimethy] 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 ad- vantages of mild reaction conditions, regents of low prices and less toxicity. The product structure was confirmed by IR, MS, and 1H NMR.