A new, scalable, rapid, high yielding, and practical synthesis of 4-(difluoromethyl)pyridin-2-amine provides a key intermediate for the preparation of numerous protein kinase inhibitors and clinical candidates targeting phosphoinositide 3-kinase (PI3K) and the mechanistic target of rapamycin (mTOR) kinase. Starting from 2,2-difluoroacetic anhydride, an efficient five-step and two-pot procedure to prepare 4-(difluoromethyl)pyridin-2-amine (1) has been developed. Noteworthy aspects of this strategy include the avoidance of an amination process using a sealed vessel. Each step of the synthetic route has been optimized, and key intermediates have been isolated and characterized prior to the final two-pot procedure, which has been successfully applied for large-scale production.

中文翻译：

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可扩展，经济，实用的合成4-（二氟甲基）吡啶-2-胺，脂质激酶抑制剂的关键中间体

一种新的，可扩展的，快速的，高产且实用的4-（二氟甲基）吡啶-2-胺合成方法，为制备众多针对磷酸肌醇3-激酶（PI3K）的蛋白激酶抑制剂和临床候选药物以及该机制提供了关键的中间体雷帕霉素（mTOR）激酶的靶标。从2，2-二氟乙酸酐开始，已经开发了制备4-（二氟甲基）吡啶-2-胺（1）的有效的五步法和两锅法。该策略的值得注意的方面包括避免使用密封容器的胺化过程。在最后的两锅法之前，已经优化了合成路线的每个步骤，并且对关键中间体进行了分离和表征，该方法已成功应用于大规模生产。