Synthesis of Ethyl 2-[5-(3-Hydroxybenzamido)-1,3,4-thiadiazol-2-yl]acetateZHU Fei, LI Xin, CHEN Yu-hang, CHEN Huan, WANG Wu, WAN Chun-mei, GAN Zong-jie, YU Yu*College of Pharmaceutical Sciences, Chongqing Medical University, Chongqing 400016, ChinaEthyl 2-[5-(3-hydroxybenzamido)-1,3,4-thiadiazol-2-yl]acetate(1), with total yield of 37.2%, was synthesized by the reactions of saponification, acidification, chlorination, cyclization and amidation from diethyl malonate.The structure was confirmed by 1H NMR, 13C NMR, IR and LC-MS(ESI).The amidation conditions were optimized by orthogonal experiment[L9(34)].The results showed that under the optimum conditions{n[ethyl-(5-amino-1,3,4-thiadiazol-2-yl)acetate] ∶n(NEt3) ∶n(3-hydroxybenzoyl chloride)=1 ∶2 ∶3, reaction at 20 ℃ for 8 h}, the yield of 1 was 75.5%.

Succinic acid monoethyl ester chloride (3) was prepared by alcoholysis , acetylation reaction from succinic anhydride.The important intermediate, (5-amino-[1,3,4] thiadiazol-2-yl)-propionic acid ethyl ester , was synthesized by cyclization of 3 with thiosemicarbazide catalyzed by methane sulfo-nic acid.The structure was confirmed by 1 H NMR, IR and MS.The reaction conditions for cyclizating reaction was investigated by the orthogonal design .The results showed that the optimal reaction condi-tions were as followed:3 132 mmol, n(thiosemicarbazide) ∶n(3) ∶n(methane sulfonic acid)=1∶3∶3, reaction at 110 ℃for 3 h, the total yield was 51.3%.