Department of Process Research and Development, Merck & Co., Inc., Rahway, New Jersey 07065, United States.
Department of Computational and Structural Chemistry, Merck & Co., Inc. Rahway, New Jersey 07065, United States.
J Am Chem Soc. 2021 Mar 31;143(12):4817-4823. doi: 10.1021/jacs.1c01454. Epub 2021 Mar 16.
A facile one-pot strategy for CN and CN exchange with aryl, heteroaryl, and alkenyl nitriles using a Ni phosphine catalyst and BPh is described. This late-stage carbon isotope exchange (CIE) strategy employs labeled Zn(CN) to facilitate enrichment using the nonlabeled parent compound as the starting material, eliminating synthesis for precursor development. A broad substrate scope encompassing multiple pharmaceuticals is disclosed, including the preparation of [C] belzutifan to illustrate the exceptional functional group tolerance and utility of this labeling approach. Preliminary experimental and computational studies suggest the Lewis acid BPh is not critical for the oxidative addition step and instead plays a role in facilitating CN exchange on Ni. This CIE method dramatically reduces the synthetic steps and radioactive waste involved in preparation of C labeled tracers for clinical development.
本文描述了一种使用 Ni 膦配体催化剂和 BPh 的简便一锅法策略，用于芳基、杂芳基和烯基腈的 CN 和 CN 交换。这种晚期碳同位素交换（CIE）策略使用标记的 Zn(CN) 来促进富集，使用非标记的母体化合物作为起始原料，从而避免了前体开发的合成。本文公开了一个广泛的底物范围，包括多种药物的制备，包括 [C]belzutifan 的制备，以说明这种标记方法的出色的官能团耐受性和实用性。初步的实验和计算研究表明，Lewis 酸 BPh 对于氧化加成步骤并不是关键的，而是在促进 Ni 上的 CN 交换中起作用。这种 CIE 方法大大减少了用于临床开发的 C 标记示踪剂制备中涉及的合成步骤和放射性废物。
