[1] Cao Meng, Zhao Hucheng, Hu Bing, Ji Min, et al. Optimization of cross-coupling reaction for synthesisof antitumor drug vismodegib [J]. Journal of Southeast University (English Edition), 2014, 30 (1): 72-76. [doi:10.3969/j.issn.1003-7985.2014.01.014]
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Optimization of cross-coupling reaction for synthesisof antitumor drug vismodegib(
)
合成抗肿瘤药物vismodegib的交叉偶联反应工艺优化
)Journal of Southeast University (English Edition)[ISSN:1003-7985/CN:32-1325/N]
- Volumn:
- 30
- Issue:
- 2014 1
- Page:
- 72-76
- Research Field:
- Chemistry and Chemical Engineering
- Publishing date:
- 2014-03-31
Info
- Title:
- Optimization of cross-coupling reaction for synthesisof antitumor drug vismodegib
- 合成抗肿瘤药物vismodegib的交叉偶联反应工艺优化
- Author(s):
- Cao Meng, Zhao Hucheng, Hu Bing, Ji Min
- School of Biological Science and Medical Engineering, Southeast University, Nanjing 210096, China
- Keywords:
- vismodegib; synthesis; cross-coupling; optimization
- vismodegib; 合成; 交叉偶联; 优化
- PACS:
- TQ463
- DOI:
- 10.3969/j.issn.1003-7985.2014.01.014
- Abstract:
- In order to improve the yield and reduce the cost in the synthesis of antitumor drug vismodegib, the key intermediates are prepared and the Negishi reaction step is examined. The effects of different molar ratios of reactants, dosages of catalyst and time for refluxing are investigated by using single factor tests. The results demonstrate that, when the molar ratios of 2-bromopyridine, 2-chloro-N-(4-chloro-3-iodophenyl)-4-(methylsulfonyl)benzamide, zinc chloride, n-butyllithium and tetrakis(triphenyl phosphine)palladium are changed to 1.0∶0.5∶1.5∶1.1∶0.05 and the mixture is refluxed for 24 h, the production yield is improved to 72%. This reaction condition significantly enhances the synthetic efficiency, avoids consuming excessive raw materials/catalysts, and, meanwhile, prevents a prolonged reaction time. The optimization of the proportion of reactants and the heating time is proved to be important for the efficiency and economy in cross-coupling reaction to synthesize vismodegib.
- 为了提高抗肿瘤药物vismodegib合成反应的产率并控制反应成本, 制备了合成目标化合物所需的中间体, 并对Negishi偶联反应条件进行了考察. 通过单因素分析法, 研究了不同的摩尔比、催化剂用量和回流时间对反应的影响. 结果表明, 在反应混合物2-溴吡啶、2-氯-N-(4-氯-3-碘苯基)-4-(甲磺酰)苯甲酰胺、氯化锌、正丁基锂和四(三苯基膦)钯的摩尔比为1.0∶0.5∶1.5∶1.1∶0.05及回流时间为24 h的条件下, 反应收率提高到了72%. 该反应条件明显提高了合成效率, 避免了原料/催化剂的过多消耗, 同时避免了过长的反应时间.反应体系配比和反应时间的优化在合成vismodegib的过程中对提高效率和经济性有重要作用.
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Memo
- Memo:
-
Biographies: Cao Meng(1983—), male, doctor; Ji Min(corresponding author), female, doctor, professor, jimin@seu.edu.cn.
Foundation items: The National Basic Research Program of China(973 Program)(No.2011CB933503), China Postdoctoral Science Foundation(No.2013M541592).
Citation: Cao Meng, Zhao Hucheng, Hu Bing, et al. Optimization of cross-coupling reaction for synthesis of antitumor drug vismodegib[J].Journal of Southeast University(English Edition), 2014, 30(1):72-76.[doi:10.3969/j.issn.1003-7985.2014.01.014]