1 research outputs found
Practical Synthesis of MDM2 Antagonist RG7388. Part 2: Development of the Cu(I) Catalyzed [3 + 2] Asymmetric Cycloaddition Process for the Manufacture of Idasanutlin
A concise catalytic
asymmetric synthesis of idasanutlin (<b>1</b>) 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 CuĀ(I)/BINAP.
While producing equivalent high quality API, the copperĀ(I) catalyzed
process not only increased the overall yield but also demonstrated
benefit with respect to cycle times, waste streams, and processability.
The optimized copperĀ(I) catalyzed process has been used to prepare
more than 1500 kg of idasanutlin (<b>1</b>)