基于1,3,4-噻二唑结构的药物中间体合成研究
发布时间：2018-09-04 12:07
【摘要】：1,3,4-噻二唑属于含氮和硫的五原子杂环化合物,其空间构型呈平面结构。在1,3,4-噻二唑的2位和5位进行修饰可合成大量的衍生化合物。据文献报道,含有1,3,4-噻二唑结构的化合物是重要的药物中间体,具有良好的抗癌活性,例如,2-氨基-1,3,4-噻二唑能够抑制淋巴肉瘤和黑色素瘤,2-芳基-5-烃基-1,3,4-噻二唑是高效的谷氨酰胺酶抑制剂,磺胺类1,3,4-噻二唑对胰腺癌具有强烈的抑制作用,酰胺类1,3,4-噻二唑对肺癌和结肠癌具有良好的抑制作用。因此,研究含有1,3,4-噻二唑结构的化合物具有重要的实用价值。结合本课题前期工作和相关文献,分别以草酰氯单乙酯、丙二酸二乙酯和丁二酸酐为起始原料,可相应制得3个新化合物,即5(3-((5-(氮杂环戊烷-1-羧酸)吡啶-2-基)氧基)苯甲酰胺基)-1,3,4-噻二唑-2-甲酸乙酯、5(3-((5-(氮杂环戊烷-1-羧酸)吡啶-2-基)氧基)苯甲酰胺基)-1,3,4-噻二唑-2-乙酸乙酯和5(3-((5-(氮杂环戊烷-1-羧酸)吡啶-2-基)氧基)苯甲酰胺基)-1,3,4-噻二唑-2-丙酸乙酯。现将本文的研究工作总结如下:1.以草酰氯单乙酯为起始原料,经环合可制得(5-氨基-[1,3,4]-噻二唑-2-基)-甲酸乙酯,收率(65.8%)比文献(24%)提高了41.8%;以丙二酸二乙酯为起始原料,经选择性皂化、酸化、氯化和环合可制得(5-氨基-[1,3,4]-噻二唑-2-基)-乙酸乙酯,收率(56.6%)比文献(37%)提高了19.6%;以丁二酸酐为起始原料,经醇解、氯化和环合可制得(5-氨基-[1,3,4]-噻二唑-2-基)-丙酸乙酯,收率(51.7%)比文献(37%)提高了14.7%。2.在合成2-氨基-5-取代-1,3,4-噻二唑化合物中,当对其2位伯氨基进行酰胺修饰引入间羟基苯甲酸时,制得了3个化合物,化学名分别是2-(5-(3-羟基苯甲酰胺基)-1,3,4-噻二唑)基甲酸乙酯,平均收率达到77.5%,总收率为51.0%;2-(5-(3-羟基苯甲酰胺基)-1,3,4-噻二唑)基乙酸乙酯,平均收率达到75.5%,总收率为37.2%;2-(5-(3-羟基苯甲酰胺基)-1,3,4-噻二唑)基丙酸乙酯,平均收率达到70.1%,总收率为31.9%。3.在合成2-(5-(3-羟基苯甲酰胺基)-1,3,4-噻二唑)基乙酸乙酯的酰胺反应中,运用L9(34)正交试验表对酰胺反应条件优化。其结果表明最佳反应条件为:n((5-氨基-[1,3,4]-噻二唑-2-基)-乙酸乙酯):n(间羟基苯甲酸酰氯):n(三乙胺)=1:3:2,温度20℃,反应时间8h。经三批放大试验验证,收率分别是74.1%、76.5%和75.8%,平均收率可达到75.5%。4.在合成2-间羟苯甲酰胺基-5-取代-1,3,4-噻二唑中,对苯环3位羟基醚化修饰引入5-氯吡嗪-2-吡咯烷酮,合成了3个新化合物,其结构经1H NMR、MS和IR进行确证。综上所述,本文建立了2-间羟苯甲酰胺基-5-取代-1,3,4-噻二唑的合成路线,设计合成了3个新化合物,并进行结构确证,为研究基于1,3,4-噻二唑结构的药物中间体奠定了物质基础。
[Abstract]:The space configuration of the 5-atom heterocyclic compounds containing nitrogen and sulfur is plane structure. A large number of derivatives can be synthesized by modification at the 2 and 5 sites of 1, 3 and 4-thiadiazole. According to the literature, the compounds containing the structure of 1C 3N 4 thiadiazole are important drug intermediates, and have good anticancer activity. For example, 2-amino-1-tiadiazole can inhibit lymphosarcoma and melanoma, 2-aryl-5-alkyl-4-thiadiazole is an effective inhibitor of glutaminase, and sulfamethanediazole has a strong inhibitory effect on pancreatic cancer. Amides have good inhibitory effect on lung cancer and colon cancer. Therefore, it is of great practical value to study the compounds containing 1 C 3 O 4-thiadiazole. Three new compounds were prepared by using oxaloyl chloride monoethyl ester, diethyl malonate and succinic anhydride as starting materials. That is, 5 (3- (5- (5- (azacyclic pentane -1-carboxylic acid) pyridyl) -2-yl) benzoyl amine) -1- (3- (5- (azacyclic pentane 1-carboxylic acid) pyridyl) benzoyl) -1- (5- (5- (azacyclic pentane -1-carboxylic acid) pyridyl) -benzoyl) -1- (5- (5- (aza-heterocyclic) pyridyl) -2- ethyl acetate and 5 (3- (5- (aza-heterocyclic) pyridine) -2- ethyl acetate and 5 (3- (5- (aza-heterocyclic) -1-carboxylic acid) pyridine-2-oxy) Pentane -1-carboxylic acid) pyridine -2-yl) oxy) benzoyl) -1C _ 3N _ 4-thiadiazole-2-propionate ethyl ester. The research work of this paper is summarized as follows: 1. Using oxaloyl chloride monoethyl ester as the starting material, (5-amino- [1o 3N 4] -thiadiazole-2-yl) -ethyl formate was synthesized by cyclization. The yield of ethyl formate (65.8%) was increased by 41.8% compared with that in the literature (24%), and diethyl malonate was used as the starting material for selective saponification and acidification. Ethyl (5-amino- [1o 3n 4] -thiadiazole-2-yl) -ethyl acetate was synthesized by chlorination and cyclization in a yield of 56.6% higher than that in the literature (37%). Ethyl (5- amino-[ 13t4] -thiadiazole-2-yl) -propionate was synthesized from succinic anhydride by alcoholysis, chlorination and cyclization. The yield (51.7%) was higher than that in literature (37%). In the synthesis of 2-amino-5- substituted -1-thiadiazole compounds, three compounds were synthesized by amide-modifying and introducing m-hydroxybenzoic acid into 2-amino groups. The chemical names of these compounds were 2- (5- (3- (3-hydroxybenzoylamino) -1) -1- (3) -thiadiazolyl) ethyl formate. The average yield was 77.5%, the total yield was 51.0% (5- (3- (3-hydroxybenzoylamino) -1Hbbamino) -1HbAZ) ethyl acetate, the average yield was 75.5% and the total yield was 37.2% (5- (3-hydroxybenzoylamino) -1334-thiadiazole) ethyl propionate, the average yield was 70.1% and the total yield was 31.99.0.3.The average yield was 5- (3- (3-hydroxybenzoylamino) -133-thiadiazole) ethyl propionate, and the average yield was 70.1%, and the total yield was 31.99.93%. In the synthesis of 2- (5- (3-hydroxybenzoamido) -1- (3-thiadiazolyl) -4-thiadiazole) ethyl acetate, the reaction conditions were optimized by L _ 9 (34) orthogonal test. The results show that the optimum reaction conditions are as follows: 1: 3: 2, temperature 20 鈩，
本文编号：2222054
[Abstract]:The space configuration of the 5-atom heterocyclic compounds containing nitrogen and sulfur is plane structure. A large number of derivatives can be synthesized by modification at the 2 and 5 sites of 1, 3 and 4-thiadiazole. According to the literature, the compounds containing the structure of 1C 3N 4 thiadiazole are important drug intermediates, and have good anticancer activity. For example, 2-amino-1-tiadiazole can inhibit lymphosarcoma and melanoma, 2-aryl-5-alkyl-4-thiadiazole is an effective inhibitor of glutaminase, and sulfamethanediazole has a strong inhibitory effect on pancreatic cancer. Amides have good inhibitory effect on lung cancer and colon cancer. Therefore, it is of great practical value to study the compounds containing 1 C 3 O 4-thiadiazole. Three new compounds were prepared by using oxaloyl chloride monoethyl ester, diethyl malonate and succinic anhydride as starting materials. That is, 5 (3- (5- (5- (azacyclic pentane -1-carboxylic acid) pyridyl) -2-yl) benzoyl amine) -1- (3- (5- (azacyclic pentane 1-carboxylic acid) pyridyl) benzoyl) -1- (5- (5- (azacyclic pentane -1-carboxylic acid) pyridyl) -benzoyl) -1- (5- (5- (aza-heterocyclic) pyridyl) -2- ethyl acetate and 5 (3- (5- (aza-heterocyclic) pyridine) -2- ethyl acetate and 5 (3- (5- (aza-heterocyclic) -1-carboxylic acid) pyridine-2-oxy) Pentane -1-carboxylic acid) pyridine -2-yl) oxy) benzoyl) -1C _ 3N _ 4-thiadiazole-2-propionate ethyl ester. The research work of this paper is summarized as follows: 1. Using oxaloyl chloride monoethyl ester as the starting material, (5-amino- [1o 3N 4] -thiadiazole-2-yl) -ethyl formate was synthesized by cyclization. The yield of ethyl formate (65.8%) was increased by 41.8% compared with that in the literature (24%), and diethyl malonate was used as the starting material for selective saponification and acidification. Ethyl (5-amino- [1o 3n 4] -thiadiazole-2-yl) -ethyl acetate was synthesized by chlorination and cyclization in a yield of 56.6% higher than that in the literature (37%). Ethyl (5- amino-[ 13t4] -thiadiazole-2-yl) -propionate was synthesized from succinic anhydride by alcoholysis, chlorination and cyclization. The yield (51.7%) was higher than that in literature (37%). In the synthesis of 2-amino-5- substituted -1-thiadiazole compounds, three compounds were synthesized by amide-modifying and introducing m-hydroxybenzoic acid into 2-amino groups. The chemical names of these compounds were 2- (5- (3- (3-hydroxybenzoylamino) -1) -1- (3) -thiadiazolyl) ethyl formate. The average yield was 77.5%, the total yield was 51.0% (5- (3- (3-hydroxybenzoylamino) -1Hbbamino) -1HbAZ) ethyl acetate, the average yield was 75.5% and the total yield was 37.2% (5- (3-hydroxybenzoylamino) -1334-thiadiazole) ethyl propionate, the average yield was 70.1% and the total yield was 31.99.0.3.The average yield was 5- (3- (3-hydroxybenzoylamino) -133-thiadiazole) ethyl propionate, and the average yield was 70.1%, and the total yield was 31.99.93%. In the synthesis of 2- (5- (3-hydroxybenzoamido) -1- (3-thiadiazolyl) -4-thiadiazole) ethyl acetate, the reaction conditions were optimized by L _ 9 (34) orthogonal test. The results show that the optimum reaction conditions are as follows: 1: 3: 2, temperature 20 鈩，
本文编号：2222054
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