Showing posts with label ring-closing metathesis. Show all posts
Showing posts with label ring-closing metathesis. Show all posts

Saturday 16 November 2013

BI 201302 a 15-membered macrocyclic hepatitis C virus (HCV) protease inhibitor

Abstract Image

A highly convergent large scale synthesis of a 15-membered macrocyclic hepatitis C virus (HCV) protease inhibitor BI 201302 was achieved, in which the key features are the practical macrocyclization by Ru-catalyzed ring-closing metathesis (0.1 mol % Grela catalyst, 0.1–0.2 M concentration) and the efficient sulfone-mediated SNAr reaction.


Wei X * et al. Boehringer-Ingelheim Pharmaceuticals, Ridgeway, USA
A Highly Convergent and Efficient Synthesis of a Macrocyclic Hepatitis C Virus Protease Inhibitor BI 201302.

Org. Lett. 2013; 15: 1016-1019
Chemical Development, Boehringer-Ingelheim Pharmaceuticals, 900 Ridgebury Road, Ridgefield, Connecticut 06877, United States
Org. Lett.201315 (5), pp 1016–1019
DOI: 10.1021/ol303498m




Significance

The synthesis of the HCV protease inhibitor BI 201302 features an efficient ruthenium-catalyzed ring-closing metathesis reaction (0.1–0.2 M) requiring only 0.1 mol% of the Grela catalyst E to generate the 15-membered macrocycle F. This enhanced efficiency was achieved by installing a Boc substituent on the nitrogen of fragment D.


Comment

The SNAr reaction using a phenylsulfonyl leaving group in quinoline derivative H was more efficient than the reaction with the corresponding chloride (92% vs 40% yield). Potassium 3,7-dimethyl-3-octanoxide (KDMO) was used as a base instead of t-BuOK because transcarbamoylation byproducts (1–2%) were easily removed by crystallization.