Process Development and Pilot-Plant Synthesis of (2-Chlorophenyl)[2-(phenylsulfonyl)pyridin-3-yl]methanone

Abstract

Routes to (2-chlorophenyl)[2-(phenylsulfonyl)pyridin-3-yl]metha-none, 1, an intermediate in the manufacture of NK1-II inhibitor LY686017 are described which produce 1 in >75% yield and 95% purity. A highly selective telescoped ortho lithation/condensation/ oxidation process was developed and successfully scaled to the clinical pilot plant to produce 25 kg of 1. For the pilot-plant campaign, the lithiation step was developed to operate at -50 °C using commercial lithium diisopropylamide (LDA), and the oxidation step employed catalytic TEMPO as the primary and NaOCl as the terminal oxidant. After completion of the pilot-plant campaign second-generation approaches to 1 were developed to improve process greenness where the lithiation and condensation step were operated as warm as -10 °C, the highly efficient AZADO catalyst was used as a substitute for TEMPO in the Anelli-Montanari oxidation, and process mass intensity was reduced 25%.

Regioselective Lithium Diisopropylamide-Mediated Ortholithiation of 1-Chloro-3-(trifluoromethyl)benzene: Role of Autocatalysis, Lithium Chloride Catalysis, and Reversibility

“…It is now obvious that commercial LDA offers little advantage because the slight bias toward formation of 3 is eroded by the equilibration of 3 to 2 during protracted reaction times. You could have enjoyed the convenience and greater safety of commercial LDA with the activity of LDA prepared in situ by adding a few mole percent LiCl generated using Et 3 NHCl …”

Leveraging an Industrial–Academic Partnership To Optimize Small Molecule Process Development within the Pharmaceutical Industry

“…Process Development and Pilot-Plant Synthesis of (2-Chlorophenyl)[2-(phenylsulfonyl)pyridin-3-yl]methanone (4). 8 The synthetic route for the preparation of 4, an important intermediate in the synthesis of a potent NK1-II inhibitor which has been studied clinically for the treatment of depression at Lilly, has been optimized at UCC. A highly selective telescoped ortho lithiation/condensation/ oxidation process was developed and successfully scaled to clinical pilot plant (Scheme 4).…”

Genotoxic Impurities in Pharmaceutical Manufacturing: Sources, Regulations, and Mitigation

“…147,148 In its pilotplant synthesis, TEMPO is used as an oxidation agent with NaOCl, where a secondary alcohol is efficiently oxidized using the Anelli−Montanari protocol (Scheme 42). 149 BYK405879 is a potassium-competitive acid blocker, a promising candidate for the treatment of gastroesophagealreflux-related diseases. The oxidation step of the alcoholic intermediate of BYK308944 was found to be crucial during the synthetic route, and a recently published article by Webel et al describes in exhaustive detail the development and conditions of the TEMPO-mediated oxidation leading to the desired aldehyde (Scheme 43).…”