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.