Synthesis of 4-[1-alkyl-5-oxo-1H-1,2,4-triazol-4(5H)-yl] benzoic acids
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摘要: 目的 制备用于全合成卡泊芬净类环六脂肽抗真菌剂的关键脂肪酸侧链4-[1-烷基-5-氧代-1H-1,2,4-三唑-4(5H)-基]-苯甲酸(5)。 方法 以对氨基苯甲酸(1)为起始原料,经氨基苯氧羰酰化、肼解、甲脒环合及N-烃化4步反应制备目标化合物。 结果 以42.9%~46.2% 的总收率成功合成了目标化合物5a~5n,其结构经电喷雾质谱(ESI-MS)和氢谱(1H NMR)确证;所有目标化合物均为首次报道。 结论 该合成路线具有操作简便及收率高等优点,适合工业化生产。
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关键词:
- 4-[1-烷基-5-氧代-1H-1,2,4-三唑-4(5H)-基]-苯甲酸 /
- 合成 /
- 环六脂肽 /
- 卡泊芬净 /
- 抗真菌
Abstract: Objective To prepare 4-[1-alkyl-5-oxo-1H-1,2,4-triazol-4 (5H)-yl] benzoic acids (5), which was the key fatty acid chain pharmaceutical intermediates for the total synthesis of novel caspofungin-like cyclohexa lipopeptide antifungal agents. Methods Starting from 4-aminobenzoic acid (1), the target compounds 5a~5n were prepared via amino phenoxy-carbonyl acylation, hydrazinolysis, formamidine cyclization, and the N-alkylation reaction, respectively. Results Target compounds 5a~5n had been successfully synthesized with the overall yield ranged from 42.9% to 46.2%. Their structures were confirmed by ESI-MS and 1H-NMR spectra. All target compounds were reported for the first time. Conclusion The process developed had several advantages such as convenient workup and high yield, which was suitable to industrial production. -
[1] Georgopapakou NH.Update on antifungals targeted to the cellwall focus on beta-1, 3-glucan synthase inhibitors[J].Expert Opin Invest Drugs, 2001,10 (2):269. [2] Petrikkos G,Skiada A.Recent advances in antifungal chemotherapy[J].Intl J Antimicrob Agents,2007,30:108. [3] Kathiravan MK,Salake AB,Chothe AS,et al.The biology and chemistry of antifungal agents:a review[J].Bioorg Med Chem,2012,20:5678. [4] Sheng CQ,Che XY,Wang WY,et al.Design and synthesis of novel triazole antifungal derivatives by structure-based bioisosterism[J].Eur J Med Chem,2011,46,5276.
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