Practical Synthesis of MDM2 Antagonist RG7388. Part 2: Development of the Cu(I) Catalyzed [3+2] Asymmetric Cycloaddition Process for the Manufacture of Idasanutlin

被引：17

作者：

Rimmler, Gosta ^{[1
]}

Alker, Andre ^{[2
]}

Bosco, Marcello ^{[1
]}

Diodone, Ralph ^{[1
]}

Fishlock, Dan ^{[1
]}

Hildbrand, Stefan ^{[1
]}

Kuhn, Bernd ^{[2
]}

Moessner, Christian ^{[1
]}

Peters, Carsten ^{[1
]}

Rege, Pankaj D. ^{[1
]}

Schantz, Markus ^{[1
]}

机构：

[1] F Hoffmann La Roche Ltd, Small Mol Tech Dev, Grenzacherstr 124,Bldg 86,Room 602, CH-4070 Basel, Switzerland

[2] F Hoffmann La Roche Ltd, Roche Innovat Ctr Basel, Roche Pharma Res & Early Dev, Therapeut Modal, CH-4070 Basel, Switzerland

来源：

ORGANIC PROCESS RESEARCH & DEVELOPMENT | 2016年 / 20卷 / 12期

关键词：

3+2] cycloaddition; asymmetric; idasanutlin; copper-catalyzed; silver-catalyzed; AZOMETHINE; RG7112;

D O I：

10.1021/acs.oprd.6b00319

中图分类号：

O69 [应用化学];

学科分类号：

081704 ;

摘要：

A concise catalytic asymmetric synthesis of idasanutlin (1) was developed in which the key pyrrolidine core, containing four contiguous stereocenters, was constructed via a Ag/MeOBIPHEP promoted [3 + 2] cycloaddition reaction. Further development of the [3 + 2] cycloaddition reaction resulted in an improvement in diastereoselectivity and enantioselectivity by changing the catalyst system to Cu(I)/BINAP. While producing equivalent high quality API, the copper(I) catalyzed process not only increased the overall yield but also demonstrated benefit with respect to cycle times, waste streams, and processability. The optimized copper(I) catalyzed process has been used to prepare more than 1500 kg of idasanutlin (1).

引用

页码：2057 / 2066

页数：10