Development and Demonstration of a High-Volume Manufacturing Process for a Key Intermediate of Dalcetrapib: Investigations on the Alkylation of Carboxylic Acids, Esters, and Nitriles

Dalcetrapib (1), a cholesterol ester transfer protein inhibitor, was a clinical candidate at Roche until 2012. By this time, manufacturing processes capable of efficiently delivering kilotonne annual volumes of Dalcetrapib had been developed and demonstrated at the commercial scale. This paper describes the development of synthetic routes for the manufacture of key intermediate 1-(2-ethylbutyl)-cyclohexanecarboxylic acid (2) and selection of the preferred process. The selected process involves novel methods for the α-alkylation of a nitrile using methylmagnesium chloride as a non-nucleophilic base and for the hydrolysis of a highly sterically hindered nitrile using sodium hydroxide in methanol/water at 200 °C. The performance of the process at plant scale is reported. Safety considerations and the chemistry behind the formation of side-products are discussed. Continuous-flow processes with potential operational benefits were demonstrated at laboratory scale for both the alkylation and the nitrile hydrolysis steps. A possible second-generation process for the manufacture of acid 2 is also described, which involves a novel reductive alkylation of benzoic acid.