Tanoury Gerald J, Chen Minzhang, Dong Yong, Forslund Raymond E, Magdziak Derek
Chemical Development, Vertex Pharmaceuticals Inc., 130 Waverly Street, Cambridge, Massachusetts 02139, USA.
Org Lett. 2008 Jan 17;10(2):185-8. doi: 10.1021/ol702532h. Epub 2007 Dec 15.
A novel Pd-catalyzed coupling of Cbz-protected proline amide with 4-bromo-5-ethoxyfuran-2(5H)-one was developed for the synthesis of the P1-P2 unit (5) of VX-765. The process afforded quantitative coupling in the presence of water, providing a 1:1 mixture of 5 and its ethoxy epimer epi-5. Compound 5 was isolated as a single diastereomer via fractional crystallization, which was stereoselectively converted to 17 via hydrogenation, and subsequently transformed to VX-765. Nine examples of the Pd coupling are presented with yields ranging from 76-98%.
开发了一种新型钯催化的Cbz保护的脯氨酸酰胺与4-溴-5-乙氧基呋喃-2(5H)-酮的偶联反应，用于合成VX-765的P1-P2单元(5)。该过程在水存在下实现了定量偶联，得到了5及其乙氧基差向异构体epi-5的1:1混合物。化合物5通过分步结晶分离为单一非对映异构体，通过氢化将其立体选择性地转化为17，随后转化为VX-765。给出了9个钯偶联的实例，产率范围为76-98%。
