Pharmaceutical Development, AstraZeneca R&D, S41/18 PR&D Building, Silk Road Business Park, Charter Way, Macclesfield, Cheshire, SK10 2NA, United Kingdom.
J Org Chem. 2010 Dec 3;75(23):8117-25. doi: 10.1021/jo101767h. Epub 2010 Nov 10.
The kinetics of the HCl-catalyzed deprotection of the Boc-protected amine, thioester 2 to liberate AZD3409 1 have been studied in a mixture of toluene and propan-2-ol. The reaction rate was found to exhibit a second-order dependence upon the HCl concentration. This behavior was found to have a degree of generality as the deprotection of a second Boc-protected amine, tosylate 3 to yield amine 4 using HCl, sulfuric acid, and methane sulfonic acid showed the same kinetic dependence. In contrast the deprotection of tosylate 3 with trifluoroacetic acid required a large excess of acid to obtain a reasonable rate of reaction and showed an inverse kinetic dependence upon the trifluoroacetate concentration. These observations are rationalized mechanistically in terms of a general acid-catalyzed separation of a reversibly formed ion-molecule pair arising from the fragmentation of the protonated tert-butyl carbamate.
已在甲苯和异丙醇的混合物中研究了 Boc 保护的胺、硫代酯 2 的 HCl 催化脱保护以释放 AZD3409 1 的动力学。发现反应速率对 HCl 浓度表现出二级依赖性。这种行为具有一定的普遍性，因为使用 HCl、硫酸和甲烷磺酸对第二个 Boc 保护的胺、对甲苯磺酸盐 3 进行脱保护以生成胺 4 也表现出相同的动力学依赖性。相比之下，用三氟乙酸对对甲苯磺酸盐 3 进行脱保护需要大量的酸才能获得合理的反应速率，并且反应速率对三氟乙酸根的浓度呈逆动力学依赖性。这些观察结果从质子化叔丁基氨基甲酸酯的片段化中形成的可逆形成的离子-分子对的一般酸催化分离的角度在机理上得到了合理化。
