噻唑乙酸及其酯衍生物的合成及生物活性研究
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摘要
以乙酰丙酸乙酯为原料,经氯代、缩合得2-氨基-4-甲基噻唑-5-乙酸乙酯3,再经酰氯的氨解、酯的水解等反应分别合成了新型2-芳基甲酰胺-4-甲基噻唑-5-乙酸及其酯衍生物4 (收率为51%～63%)和5 (收率为40%～50%),其结构均经1 H NMR,13 C NMR,HRMS表征.并对3的合成工艺进行优化和目标化合物4与5清除DPPH自由基和黄嘌呤氧化酶抑制活性进行检测.3的最佳合成工艺条件是:乙酰丙酸乙酯、磺酰氯和硫脲的物质的量比1∶1.2∶1,氯化反应以二氯甲烷作溶剂回流反应1h,缩合反应以无水乙醇作溶剂回流反应3h,浓盐酸5mL,总收率达到82.5%.该合成工艺过程简单、生产安全、反应条件温和、环境友好、产品收率高.活性检测结果显示:酯类化合物4和乙酸类化合物5均具有一定的清除DPPH自由基的能力,且5的活性优于4;但对黄嘌呤氧化酶均无抑制作用.
2-amino-4-methylthiazole-5-ethyl 3 acetate was synthesized from ethyl levulinate by chlorination and condensation reaction,and then novel 2-primary aryl amides-4-methylthiazole-5-acetic acid and its ester derivatives 4(the yield of 51%-63%)and 5(the yield of 40%-50%)were synthesized via ammonolysis of acyl chloride and hydrolysis of ester reaction.The target compounds were confirmed by 1 HNMR,13 C NMR and HRMS.The synthesis process of 3 was optimized and the DPPH free radical scavenging activity and xanthine oxidase inhibitory activity of target compounds 4 and 5 were detected.The optimum synthetic conditions of 3 were as follows:molar ratio of ethyl levulinate,sulfonyl chloride and thiourea was 1∶1.2∶1.Dichloromethane was used as the solvent in the reaction of chlorination and refluxed of 1 h and absolute ethyl alcohol was used as the solvent in the reaction of concentration and refluxed of 3 h.5.0 mL hydrochloric acid was needed,and the total yield was 82.5%.The synthetic process are simple,safe,mild reaction conditions,environmentally friendly and high yield.The test of biological activity shows that:Esters 4 and Acetic acids 5 have certain ability to scavenge DPPH free radicals,and the activity of 5 is better than 4;but it has no inhibitory effect on xanthine oxidase.
2-amino-4-methylthiazole-5-ethyl 3 acetate was synthesized from ethyl levulinate by chlorination and condensation reaction,and then novel 2-primary aryl amides-4-methylthiazole-5-acetic acid and its ester derivatives 4(the yield of 51%-63%)and 5(the yield of 40%-50%)were synthesized via ammonolysis of acyl chloride and hydrolysis of ester reaction.The target compounds were confirmed by 1 HNMR,13 C NMR and HRMS.The synthesis process of 3 was optimized and the DPPH free radical scavenging activity and xanthine oxidase inhibitory activity of target compounds 4 and 5 were detected.The optimum synthetic conditions of 3 were as follows:molar ratio of ethyl levulinate,sulfonyl chloride and thiourea was 1∶1.2∶1.Dichloromethane was used as the solvent in the reaction of chlorination and refluxed of 1 h and absolute ethyl alcohol was used as the solvent in the reaction of concentration and refluxed of 3 h.5.0 mL hydrochloric acid was needed,and the total yield was 82.5%.The synthetic process are simple,safe,mild reaction conditions,environmentally friendly and high yield.The test of biological activity shows that:Esters 4 and Acetic acids 5 have certain ability to scavenge DPPH free radicals,and the activity of 5 is better than 4;but it has no inhibitory effect on xanthine oxidase.
引文
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[2]AI W,ZHOU W,DU Z,et al.Benzoxazole and benzimidazole heterocycle-grafted graphene for high-performance supercapacitor electrodes[J].Journal of Materials Chemistry,2012,22(44):23439-23446.
[3]SASHIDHARA K V,RAO K B,KUSHWAHA V,et al.Synthesis and antifilarial activity of chalcone-thiazole derivatives against a human lymphatic filarial parasite,Brugiamalayi.[J].European Journal of Medicinal Chemistry,2014,81(81C):473-480.
[4]RAMIREZ,J,SVETAZ L,QUIROGA J,et al.Synthesis of novel thiazole-based 8,9-dihydro-7H-pyrimido[4,5-b][1,4]diazepines as potential antitumor and antifungal agents[J].European Journal of Medicinal Chemistry,2015,92(6):866-875.
[5]SANTOS,THIAGO A R D SILVA A C D,et al.Antitumor and immunomodulatory activities of thiosemicarbazones and1,3-Thiazoles in Jurkat and HT-29cells[J].Biomedicine&Pharmacotherapy,2016,82:555-560.
[6]MOHAREB R M,ZAKI M Y,ABBAS N S.Synthesis,anti-inflammatory and anti-ulcer evaluations of thiazole,thiophene,pyridine and pyran derivatives derived from androstenedione[J].Steroids,2015,98:80-91.
[7]RAHUL D K,ROHAN J M,SHRIKANT V H,et al.Synthesis and In Silico Investigation of Thiazoles Bearing Pyrazoles Derivatives As Anti-Inflammatory Agents[J].Computational Biology and Chemistry,2016,61:86-96.
[8]SIVAKUMAR A,ROGELIO M,CANNEY D J,et al.Design and synthesis of 2-aminothiazole based antimicrobials targeting MRSA[J].Bioorganic&Medicinal Chemistry Letters,2012,22(24):7719-7725.
[9]MOHAMMAD H,MAYHOUB A S,CUSHMAN M,et al.Anti-biofilm activity and synergism of novel thiazole compounds with glycopeptide antibiotics against multidrug-resistant staphylococci[J].Journal of Antibiotics,2014,68(4):259-66.
[10]KYOUNG R P,JAESEONG O,SUNG V Y,et al.Population pharmacokinetic analysis of cefdinir in healthy adults[J].Drug Metabolism and Pharmacokinetics,2017,1(32):S96.
[11]KAUR K,KUMAR V,BENIWAL V,et al.Synthesis of some novel oxazolidinone-thiazole hybrids as potential antimicrobial,antioxidant and UV mediated DNA damage protecting agents[J].Medicinal Chemistry Research,2016:25(10),2237-2249.
[12]YAPATI H,DEVINENI S R,CHIRUMAMILLA S,et al.Synthesis,characterization and studies on antioxidant and molecular docking of metal complexes of 1-(benzo[d]thiazol-2-yl)thiourea[J].Journal of Chemical Sciences,2016,128(1):1-9.
[13]徐泽民,赖苗军,朱华强,等.芳香杂环甲酰胺类化合物的合成研究[J].化学世界,2018,59(1):49-53.XU Z M,LAI M J,ZHU H Q,et al.Synthesis of aromatic heterocyclic formamide compounds[J].Chemical World,2018,59(1):49-53.
[14]刘娜,谷雨,杜源,等.噻唑酰胺生物碱及其衍生物的合成与杀藻活性[J].中国科学:化学,2016,46(11):1219-1225.LIU N,GU Y,DU Y,et al.Synthesis and algicidal activity of thiazole alkaloid and its derivatives[J].Scientia Sinica Chimica,2016,46(11):1219-1225.
[15]LV P,LI C,NIU Y,et al.Design,synthesis,and in vitro activity of methylisoxazole/isothiazole amides as BACE1inhibitors[J].Journal of Chinese Pharmaceutical Sciences,2018,27(03):143-158.
[16]LIU X W,ZHANG H,LI J Y,et al.Synthesis and antibacterial activities of nitazoxanide derivatives[C]//全国青年药学工作者最新科研成果交流会.2012.
[17]ALI M R,KUMAR S,AFZAL O,et al.2-Benzamido-4-methylthiazole-5-carboxylic acid derivatives as potential xanthine oxidase inhibitors and free radical scavengers[J].Archiv der Pharmazie,2017,350(2):e1600313-e1600313.
[18]黄振华,宋运涛.含有甲酰胺杂环基巯基吡咯烷的培南衍生物.中国专利:中国,200810017056.2[P].2009-12-30.HUANG Z H,SONG Y T.Preparation of mercaptopyrrolidine containing penem derivatives as antiinfective agents:CN,200810017056.2[P].2009-12-30.
[19]毛红晶,王可人,龚祝南.苄醇类化合物氯代反应的研究[J].安徽农业科学,2009,37(3):926-927.MAO H J,WANG K R,GONG Z N.Study on chlorination of benzyl alcohol[J].Journal of Anhui Agricultural Sciences,2009,37(3):926-927.
[20]关润伶,朱红.2-氨基-4-甲基-5-甲酰乙氧基噻唑氢溴酸盐的合成[J].北京交通大学学报,2006,30(3):40-42.GUAN R L,ZHU H.Synthesis of ethyl 2-amino-4-methylthiazole-5-carboxylate[J].Journal of Beijing Jiaotong University,2006,30(3):40-42.
[21]王华.2-氨基-4-氯苯并噻唑的合成工艺研究[D].合肥:合肥工业大学,2010.WANG H.The synthesis of 2-amino-4-chloro-benzothiazole abstract[D].Hefei:Hefei University of Technology,2010.
[22]WANG S,YAN J,WANG J,et al.Synthesis of some 5-phenylisoxazole-3-carboxylic acid derivatives as potent xanthine oxidase inhibitors[J].European Journal of Medicinal Chemistry,2010,45(6):2663-2670.
[23]MAURIN C,BAILLY F,COTELLE P.Improved preparation and structural investigation of 4-aryl-4-oxo-2-hydroxy-2-butenoic acids and methyl esters[J].Tetrahedron,2004,35(47):6479-6486.
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