Abstract
An improved process for the manufacture of (R)-3,5-bis(trifluoromethyl)-α-methyl-N-methylbenzylamine l-(−)-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-(−)-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 ...
Published Version
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