Synthesis of BI 201420

Key words

BI 201420 - HCV NS3/4a protease inhibitor - 4-methylsulfonyl quinolines - quinoline ring formation - S_NAr reaction

Significance

A new method for the synthesis of 4-quinolinyl ethers has been applied to BI 201420, an HCV NS3/4a protease inhibitor. In the key step, methylsulfone C underwent an S_NAr reaction with alcohol D in the presence of potassium 3,7-di­methyloctan-3-oxide (KDMO, 4.0 equiv) to give 4-quinolyl ether E in 75% yield. Scoping studies revealed that 1°, 2°, 3°, allylic, and propargylic alcohols participate (20 examples).

Comment

The corresponding S_NAr reaction of 4-chloroquinolines with alcohols is sluggish, even with excess base (>5.0 equiv), and significant decomposition of starting material and product are observed during the long reaction times (12–24 h). Extensive optimization of solvent and reaction conditions failed to produce the desired 4-quinolinyl ethers in reasonable yield and quality.

Publication History

Article published online:
18 August 2020