【作者】 张明道；

【导师】 方志杰；

【作者基本信息】 南京理工大学 ， 应用化学， 2010， 硕士

【摘要】 布林佐胺是一种局部碳酸酐酶抑制剂,具有高效低毒、副作用小的优点,已经成为治疗开角型青光眼的一线药物。本论文在简述布林佐胺合成进展的基础上,拟定布林佐胺的合成路线,同时分析比较了各步单元反应的方法。从3-溴代乙酰基-5-氯-2-噻吩磺酰胺出发,经过不对称还原、关环、N-烃基化、亚硫酸化、磺胺化、胺基保护、胺化等七步反应制得布林佐胺。优化了工艺条件,路线总产率达到29%。通过分析实验现象和实验数据,推测了各步反应的可能历程。用类似方法合成了(S)-布林佐胺,七步反应总产率23%；将其与布林佐胺按1∶1混合并进行HPLC分析,筛选出分离效果较佳的液相色谱柱(Chiralpak AD-H),并优化了测试条件,结果表明：布林佐胺的纯度为99.86%,e.e.值接近100%。HPLC验证了(+)-二异松蒎基氯硼烷在不对称还原关环反应中具有较优的手性选择性：中间产物5的纯度为98.91%,e.e.值为97.81%。针对布林佐胺存在的作用时间短、水溶性差、有眼部刺激等不足,在结构修饰成功案例的基础上,依据药物设计相关原理提出结构修饰方案,合成了5个具有潜在药物活性的布林佐胺类似物。更多还原

【Abstract】 Brinzolamide is a topical carbonic anhydrase inhibitor. The well curative effects, tiny toxicity and small side effects of Brinzolamide make it an important medicine for curing open angle glaucoma.In this thesis, the preparative methods of Brinzolamide were briefly reviewed, and then the synthetic route of Brinzolamide was designed. The methods of each step in the synthetic route were summarized and compared. Brinzolamide was synthesized from 3-(2-bromoacetyl)-5-chloro-2-thiophenesulfonamide through seven-step reactions, including asymmetric reduction, cyclization, N-alkylation, sulfitation, sulfamation, amino protection and amination. The reactive conditions were optimized in overall yield of 29%. According to the phenomenon and data,the reasonable mechanism of the reactions was presumed respectively.Brinzolamide (S)-isomer was synthesized in similar methods through seven-step reactions in overall yield of 23%.The mixture of brinzolamide and its (S)-isomer, on the ratio 1/1,was analyzed by HPLC, so that the column with ideal resolution factor was screened out, and the test conditions were optimized. The results showed that the purity and e.e. value of synthesized Brinzolamide were 99.86% and 100% respectively. The purity and e.e.value of product compound 5 were 98.91% and 97.81% through HPLC analysis respectively, which showed the excellent chiral selectivity of (+)-Ipc2BCl in related reaction.Considering the disadvantages of Brinzolamide, such as short effective time, poor water-solubility, and eye irritating reaction, the plan of structural modification was proposed on the basis of successful cases and the theoretics of drug design. Five analogs of Brinzolamide with potential biological activity were synthesized.更多还原