Abstract:

A new synthetic strategy of heterocyclic ring system 4-chlorothieno[3,2-d]pyrimidine is described. The dropwise addition of 2-chloroacrylonitrile to a solution of ethyl mercaptoacetate and sodium ethoxide in ethanol at room temperature is applied to obtain 3-aminothiophene-2-barboxylate through a ring-closure reaction. The amine is stabilized and separated as a HCl salt when it is treated with HCl in ethyl acetate. The HCl salt is heated directly in excess formamide at 140 ℃ to give thieno[3,2-d]pyrimidin-4（3H）-one through a second ring-closure reaction. Chlorination of thieno[3,2-d]pyrimidin-4（3H）-one with POCl₃ in toluene in the presence of Et₃N at 100 ℃ gives 4-chlorothieno[3,2-d]pyrimidine. Compared with traditional method，the synthetic strategy can avoid the use of excess toxic POCl₃，makes its aftertreatment simple and safe.

摘要：

报道了一条合成杂环4-氯噻吩并[3,2-d]嘧啶的新工艺。室温下2-氯丙烯腈缓慢滴加到巯基乙酸乙酯和乙醇钠的乙醇溶液中，经环合反应制得3-氨基噻吩-2-甲酸乙酯，其溶于乙酸乙酯后通入氯化氢成盐进行稳定和分离。3-氨基噻吩-2-甲酸乙酯的盐酸盐直接在过量的甲酰胺中，于140 ℃下第二次关环生成噻吩并[3,2-d]嘧啶-4(3H)- 酮。噻吩并[3,2-d]嘧啶-4(3H)-酮在甲苯为溶剂，三乙胺为碱，100 ℃条件下与三氯氧磷进行氯代制备了4-氯噻吩并[3,2-d]嘧啶。本工艺与传统氯代方法进行比较后的优点是避免了使用过量有毒的三氯氧磷，后处理简单安全。