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
posted on 2023-11-13, 09:03authored byGerard
J. Harnett, Ulrike Hauck, John J. Hayes, Ursula Hoffmann, Bruno Lohri, Michael Meade, Falk Morawitz, Mateusz P. Plesniak, Helmut Stahr, Joachim Veits, Andrew Walsh, Andreas Zogg, Reinhard Reents, Dennis A. Smith, Rainer E. Martin
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.