Synthesis Of Drug Intermediates Based On1,3,4-Thiadiazole Structure

1,3,4-thiadiazole belongs to five atoms of heterocyclic compounds containing nitrogen and sulfur,its spatial configuration is a planar structure.The modification of 1,3,4-thiadiazole at the 2-position and the 5-position can synthesize a large number of derivatized compounds.It has been reported that the compounds containing 1,3,4-thiadiazole are important drug intermediates and have good anticancer activity,for example,2-amino-1,3,4-thiadiazole can inhibit lymphosarcoma and melanoma,2-aryl-5-alkyl-1,3,4-thiadiazole is a highly effective glutamineas inhibitor,1,3,4-thiadiazole compound containing sulfonamide has a strong inhibitory effect on pancreatic cancer,1,3,4-thiadiazole compounds containing amide structure has a good inhibitory effect on lung and colon cancer.Therefore,the study of compound containing 1,3,4-thiadiazole structure has important practical value.In the paper,three new compounds were prepared by using ethyl oxalyl monochloride,diethyl malonate and succinic anhydride as the starting materials in combination with the preliminary work and relate-d literature,named 5(3-((5-(azepan-1-carboxylicacid)pyridin-2-yl)oxy)b enzamido)-1,3,4-thiadiazole-2-carboxylate,5(3-((5-(azepan-1-carboxylicacid)pyridin-2-yl)oxy)benzamido)-1,3,4-thiadiazole-2-ethyl acetate,and 5(3-((5-(azacyclopentane-1-carboxylicacid)pyridin-2-yl)oxy)benzamido)-1,3,4-thiadiazole propanoate.Now the research work of this paper is sum-marized as follows:1.(5-amino-[1,3,4]-thiadiazol-2-yl)carboxylate was synthesized by cyclization with oxalyl chloride as the starting material,yield(65.8%)increased by 41.8% comparing with the literature(24%);(5-amino-[1,3,4]-thiadiazol-2-yl)ethyl acetate was prepared by saponification,acidific-ation,chlorination and cyclization with diethyl malonate as starting materials,the yield(56.6%)increased by 19.6% comparing with the lit-erature(37%);(5-amino-[1,3,4]-thiadiazol-2-yl)ethyl propionate was pre-pared by alcoholysis,chlorination and cyclization with succ-inic anhy-dride as starting material,the yield(51.7%)increased by 14.7% comp-aring with the literature(37%).2.Three compounds were synthesized by introducing amide from2-amino-5-substituted-1,3,4-thiadiazole.2-(5-(3-hydroxybenzoylamino)-1,3,4-thiadiazole)carboxylate,the average yield was 77.5%,the overall yield was 51.0%;2-(5-(3-hydroxybenzoylamino)-1,3,4-thiadiazole)ethyl acetate,the average yield was 75.5%,the overall yield was 37.2%,a nd 2-(5-(3-hydroxybenzoylamino)-1,3,4-thiadiazole)ethyl propionate,the average yield was 70.1%,the total yield was 31.9%.3.Among the amide reactions of ethyl 2-(5-(3-hydroxybenzoylamino)-1,3,4-thiadiazolyl)ethyl acetate,the amide reaction was carried out using the L9(34)orthogonal test table optimization.The results show the optimum conditions are: n(2-amino-5-substituted-1,3,4-thiadiazole):n(m-hydroxybenzoyl chloride):n(triethylamine)=1:3:2,the temperature is 20?,the reaction time is 8h.The yield of three parallel experiments reached 74.1%?76.5% and 75.8%,the average yield can reach 75.5%.4.Three derivatives are synthesized from 2-hydroxybenzoylamino-5-substituted-1,3,4-thiadiazole and 5-chloropyrazine-2-pyrrolidonewhen the hydroxyl groups on the benzene ring were structurally modified,three novel derivatives were synthesized and characterized by 1H NM R?MS and IR.In conclusion,the synthesis route of 2-mhydroxybenzoylamino-5-s ubstituted-1,3,4-thiadiazole was developed.On this basis,three new derivatives were designed and synthesized.Three novel compounds were obtained and their structures were confirmed,which laid a materialfoundation for the study of these compounds based the compoundc ontaining 1,3,4-thiadiazole.