The development of a robust process for a Pd-catalyzed Buchwald–Hartwig C–N coupling reaction to manufacture PF-06842874, a clinical candidate for the treatment of pulmonary arterial hypertension, on kilogram scale is reported. The variability in reaction kinetics initially encountered was resolved via the use of sodium tert-butoxide as a homogeneous base and a careful selection of precatalyst by examination of the catalyst activation mechanism. Extraction with aqueous acid followed by careful pH adjustment allowed us to isolate the product with excellent purge of impurities. The process was successfully implemented in up to 18 kg demonstration.

据报道，开发了一种用于 Pd 催化 Buchwald-Hartwig C-N 偶联反应的稳健工艺来生产 PF-06842874，这是一种用于治疗肺动脉高压的临床候选药物，其规模达到公斤级。通过使用叔丁醇钠作为均相碱并通过检查催化剂活化机制仔细选择预催化剂，解决了最初遇到的反应动力学的可变性。用酸水溶液萃取，然后仔细调节 pH 值，使我们能够分离出具有出色杂质清除效果的产品。该工艺已在重达 18 公斤的演示中成功实施。