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有机化学 ›› 2008, Vol. 28 ›› Issue (08): 1398-1403. 上一篇    下一篇

研究论文

酶催化拆分制备手性2-氯-1-(2,4-二氟苯基)乙醇及 光学活性抗真菌药物的合成

王明慧a,b ; 杨 光a ; 杨立荣*,a   

  1. (a浙江大学化学工程与生物工程学系 杭州 310027)
    (b青岛科技大学化学与分子工程学院 青岛 266042)
  • 收稿日期:2007-08-09 修回日期:2008-01-18 发布日期:2008-08-18
  • 通讯作者: 杨立荣

Preparation of Chiral 2-Chloro-1-(2,4-difluorophenyl)ethanol by Lipase-Catalyzed Resolution and Synthesis of Optically Active Antifungal Drug

WANG, Ming-Hui a,b; YANG, Gang a ; YANG, Li-Rong*,a   

  1. (a Department of Chemical and Biochemical Engineering, Zhejiang University, Hangzhou 310027)
    (b College of Chemistry and Molecular Engineering, Qingdao University of Science & Technology, Qingdao 266042)
  • Received:2007-08-09 Revised:2008-01-18 Published:2008-08-18
  • Contact: YANG, Li-Rong

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被引次数

19 | 2

用Pseudomonas stutzeri脂肪酶催化转酯化反应动力学拆分外消旋体法制备高对映体纯的手性2-氯-1-(2,4-二氟苯基)乙醇, 得到95.8% ee值的(R)-异构体和94.5% ee值的(S)-异构体, 以此手性醇为关键中间体合成了4种具有抗真菌活性的光学活性化合物α-氯代苄氧基-β-(1-咪唑基)-2,4-二氟乙苯硝酸盐. 纸片扩散法测试体外抗真菌活性结果表明, 对各种念珠菌(Candida species) (R)-5a和(R)-5b具有与氟康唑相当的抗菌活性, 特别是对氟康唑耐药的烟曲霉菌(Aspergillus fumigatus), 5a, 5b及其两种光学活性异构体均有优异的抗菌活性, 而且(R)-异构体的活性明显高于(S)-异构体和外消旋体.

关键词: 酶催化拆分, 2-氯-1-(2,4-二氟苯基)乙醇, 抗真菌药, 手性

Key chiral intermediates (R)- and (S)-2-chloro-1-(2,4-difluorophenyl)ethanols were prepared by kinetic resolution of the racemic mixture with Pseudomonas stutzeri lipase-catalyzed irreversible transesterification yielding (R)-alcohol and (S)-acetate, the (R)-alcohol with 95.8% ee and (S)-alcohol with 94.5% ee were obtained. And four optically active 2,4-difluoro-1-[1-(p-chlorobenzyloxy)-2-(1-imidazolyl)]ethyl- benzene nitric acid compounds possessing antifungal activity were synthesized. The results of antifungal tests in vitro by a method of filter paper disk diffusion showed that (R)-5a and (R)-5b had excellent antifungal activity against various candida species, and equal to fluconazole. Especially, 5a, 5b and their two optically active isomers have excellent antifungal efficacy against Aspergillus fumigatus that is resistant to fluconazole, moreover their (R)-isomers are more potent than their (S)-isomers and the racemate.

Key words: lipase-catalyzed resolution, chirality, antifungal drug, 2-chloro-1-(2,4-difluorophenyl)ethanol