Chemical and Synthetic Development, Bristol-Myers Squibb , One Squibb Drive, New Brunswick, New Jersey 08903, United States.
J Org Chem. 2017 Apr 21;82(8):4044-4049. doi: 10.1021/acs.joc.7b00450. Epub 2017 Apr 12.
The direct conversion of a hydroxamic acid to an amine has been accomplished in a single step in the synthesis of HIV drug candidate BMS-955176. This process utilizes catalytic base and proceeds under mild conditions (CHCN, cat. DBU, 60 °C), without the need for strong electrophiles required for typical Lossen rearrangements, and can be applied to aliphatic and aromatic hydroxamic acids. Through investigation of the kinetics of this transformation, a mechanism was revealed involving a novel initiation pathway and a self-propagation cycle. The initiation pathway involves activation of hydroxamic acid by nitriles and subsequent Lossen rearrangement to generate the corresponding isocyanate. The isocyanate functions as a "pseudo-catalyst" for this system, leading to generation of product through a second Lossen rearrangement and regeneration of a new isocyanate molecule. Thorough mechanistic understanding allowed for this highly efficient process to be implemented on a 55 kg scale in 95.5% isolated yield.
在 HIV 药物候选物 BMS-955176 的合成中，已在单步反应中将羟肟酸直接转化为胺。该过程利用催化碱，在温和条件下（CHCN、cat. DBU、60°C）进行，无需典型的 Lossen 重排所需的强亲电试剂，并且可适用于脂肪族和芳香族羟肟酸。通过对该转化动力学的研究，揭示了一种涉及新型引发途径和自传播循环的机理。引发途径涉及通过腈激活羟肟酸，随后进行 Lossen 重排，生成相应的异氰酸酯。异氰酸酯在该体系中充当“假催化剂”，通过第二次 Lossen 重排生成产物，并再生新的异氰酸酯分子。深入的机理理解使得该高效工艺能够在 55 公斤规模上以 95.5%的分离收率实施。
