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Synthesis and Optimization of Canagliflozin by Employing Quality by Design (QbD) Principles
Organic Process Research & Development ( IF 3.4 ) Pub Date : 2017-12-20 00:00:00 , DOI: 10.1021/acs.oprd.7b00281
Dattatray S. Metil 1, 2 , Swapnil P. Sonawane 1 , Sharad S. Pachore 1 , Aaseef Mohammad 1 , Vilas H. Dahanukar 1 , Peter J. McCormack 3 , Ch. Venkatramana Reddy 2 , Rakeshwar Bandichhor 1
Affiliation  

Efforts toward a synthesis and process optimization of canagliflozin 1 are described. Canagliflozin synthesis was accomplished via purified open ring intermediate 12. The process was optimized by employing quality by design (QbD) methodologies, and a telescopic strategy was executed for the first three and last two steps in a total six-step sequence. Optimization of the Friedel–Craft acylation reaction followed by Lewis acid mediated reductive elimination, n-BuLi mediated C-arylation, and reductive demethoxylation was performed to develop a robust process. These steps were found to be critical; therefore, critical process parameters (CPPs) were identified by employing design of experiment (DoE) methodology. In addition, control strategies for dealing with impurities are described.

中文翻译:

通过设计(QbD)原理质量来合成和优化Canagliflozin

描述了对卡格列净1的合成和工艺优化的努力。Canagliflozin的合成是通过纯化的开环中间体12完成的。该过程通过采用设计质量(QbD)方法进行了优化,并在总共六步的顺序中针对前三步和后两步执行了伸缩策略。优化Friedel-Craft酰化反应,然后进行路易斯酸介导的还原消除,n -BuLi介导的C进行芳基化和还原性脱甲氧基化以开发出可靠的方法。这些步骤被认为是至关重要的。因此,通过采用实验设计(DoE)方法来确定关键过程参数(CPP)。另外,描述了用于处理杂质的控制策略。
更新日期:2017-12-20
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