【摘要】：1,3,4-噻二唑?qū)儆诤土虻奈逶与s環(huán)化合物,其空間構(gòu)型呈平面結(jié)構(gòu)。在1,3,4-噻二唑的2位和5位進(jìn)行修飾可合成大量的衍生化合物。據(jù)文獻(xiàn)報(bào)道,含有1,3,4-噻二唑結(jié)構(gòu)的化合物是重要的藥物中間體,具有良好的抗癌活性,例如,2-氨基-1,3,4-噻二唑能夠抑制淋巴肉瘤和黑色素瘤,2-芳基-5-烴基-1,3,4-噻二唑是高效的谷氨酰胺酶抑制劑,磺胺類1,3,4-噻二唑?qū)σ认侔┚哂袕?qiáng)烈的抑制作用,酰胺類1,3,4-噻二唑?qū)Ψ伟┖徒Y(jié)腸癌具有良好的抑制作用。因此,研究含有1,3,4-噻二唑結(jié)構(gòu)的化合物具有重要的實(shí)用價(jià)值。結(jié)合本課題前期工作和相關(guān)文獻(xiàn),分別以草酰氯單乙酯、丙二酸二乙酯和丁二酸酐為起始原料,可相應(yīng)制得3個(gè)新化合物,即5(3-((5-(氮雜環(huán)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-(氮雜環(huán)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-(氮雜環(huán)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�，F(xiàn)將本文的研究工作總結(jié)如下:1.以草酰氯單乙酯為起始原料,經(jīng)環(huán)合可制得(5-氨基-[1,3,4]-噻二唑-2-基)-甲酸乙酯,收率(65.8%)比文獻(xiàn)(24%)提高了41.8%;以丙二酸二乙酯為起始原料,經(jīng)選擇性皂化、酸化、氯化和環(huán)合可制得(5-氨基-[1,3,4]-噻二唑-2-基)-乙酸乙酯,收率(56.6%)比文獻(xiàn)(37%)提高了19.6%;以丁二酸酐為起始原料,經(jīng)醇解、氯化和環(huán)合可制得(5-氨基-[1,3,4]-噻二唑-2-基)-丙酸乙酯,收率(51.7%)比文獻(xiàn)(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,當(dāng)對(duì)其2位伯氨基進(jìn)行酰胺修飾引入間羥基苯甲酸時(shí),制得了3個(gè)化合物,化學(xué)名分別是2-(5-(3-羥基苯甲酰胺基)-1,3,4-噻二唑)基甲酸乙酯,平均收率達(dá)到77.5%,總收率為51.0%;2-(5-(3-羥基苯甲酰胺基)-1,3,4-噻二唑)基乙酸乙酯,平均收率達(dá)到75.5%,總收率為37.2%;2-(5-(3-羥基苯甲酰胺基)-1,3,4-噻二唑)基丙酸乙酯,平均收率達(dá)到70.1%,總收率為31.9%。3.在合成2-(5-(3-羥基苯甲酰胺基)-1,3,4-噻二唑)基乙酸乙酯的酰胺反應(yīng)中,運(yùn)用L9(34)正交試驗(yàn)表對(duì)酰胺反應(yīng)條件優(yōu)化。其結(jié)果表明最佳反應(yīng)條件為:n((5-氨基-[1,3,4]-噻二唑-2-基)-乙酸乙酯):n(間羥基苯甲酸酰氯):n(三乙胺)=1:3:2,溫度20℃,反應(yīng)時(shí)間8h。經(jīng)三批放大試驗(yàn)驗(yàn)證,收率分別是74.1%、76.5%和75.8%,平均收率可達(dá)到75.5%。4.在合成2-間羥苯甲酰胺基-5-取代-1,3,4-噻二唑中,對(duì)苯環(huán)3位羥基醚化修飾引入5-氯吡嗪-2-吡咯烷酮,合成了3個(gè)新化合物,其結(jié)構(gòu)經(jīng)1H NMR、MS和IR進(jìn)行確證。綜上所述,本文建立了2-間羥苯甲酰胺基-5-取代-1,3,4-噻二唑的合成路線,設(shè)計(jì)合成了3個(gè)新化合物,并進(jìn)行結(jié)構(gòu)確證,為研究基于1,3,4-噻二唑結(jié)構(gòu)的藥物中間體奠定了物質(zhì)基礎(chǔ)。
[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，

本文編號(hào)：2222054