Optimization of the Preparation of (R)-3,5-Bis(trifluoromethyl)-伪-methyl-N-methylbenzylamine l-(鈭?-Malic Acid Salt through Classical Resolution

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• 作者：Cl茅ment M. Brandel ; Jason W. B. Cooke ; Richard A. J. Horan ; Franck P. Mallet ; David R. Stevens
• 刊名：Organic Process Research & Development
• 出版年：2015
• 出版时间：December 18, 2015
• 年：2015
• 卷：19
• 期：12
• 页码：1954-1965
• 全文大小：636K
• ISSN：1520-586X

文摘

An improved process for the manufacture of (R)-3,5-bis(trifluoromethyl)-伪-methyl-N-methylbenzylamine l-(鈭?-malic acid salt (1), a key starting material for many pharmaceutical targets, is described. Rapid process understanding for the synthesis of the racemic benzylamine was achieved by the use of time coursing studies and design of experiments (DoE). Preferred conditions for resolution of the pure diastereomer with l-(鈭?-malic acid were readily determined through the consideration of ternary phase diagrams. These were simply constructed from a series of single solubility experiments that allowed the rapid screening and evaluation of the resolution conditions. Optimized conditions, practical operating ranges, and their robustness for use in manufacturing were confirmed by the use of DoE resulting in product with diastereomeric purity of >99%. For this resolution, it was shown that a further recrystallization was necessary to achieve a chiral purity of >99.9%. The new process offers significant advantages in terms of operational simplicity, robustness, and freedom to operate and has been successfully carried out at the intended commercial scale.