Synthesis of the Biaryl Core of Anacetrapib

Key words

anacetrapib - ruthenium-catalyzed direct arylation - regioselective S_NAr reaction - reductive dehydration

Significance

Anacetrapib inhibits cholesteryl ester transfer protein (CETP), a plasma glycoprotein that transfers cholesteryl ester from high density ­lipoprotein to low density lipoprotein and very low density lipoprotein, consequently lowering the risk of atherosclerosis. Key steps in the synthesis depicted are (1) a highly regioselective S_NAr reaction of 1-bromo-2,4-fluorobenzene (A) with potassium methoxide (rr =17:1) and (2) a multi-kilogram scale ruthenium-catalyzed direct arylation of oxazoline F to construct the biaryl G.

Comment

The Merck workers noted a significant difference in the reaction efficiency and robustness of the ruthenium-catalyzed direct arylation reactions, which was a consequence of low levels of γ-butyrolactone contamination of the NMP. This fortuitous discovery led to the use of potassium acetate as an additive that allowed the reduction of catalyst loading while maintaining reproducibly high yields.