Pd-Catalyzed Cyanation of a Bromoaryl Carboxylate En Route to Etrumadenant: Robust Process with Low Catalyst Loading Enabled by Preactivation

Palladium-catalyzed cyanation of aryl bromides is a powerful approach to install a functional group commonly found in active pharmaceutical ingredients starting from readily available precursors. The development of a robust cyanation of a bromo benzoic acid to generate an intermediate en route to etrumadenant is described. Full conversion with catalyst loading as low as 0.13 mol % was enabled by study of the catalyst preactivation step, which was affected by trace water levels. Details of the scale-up of this process to the hundred-kilogram batch size are included

Asymmetric Synthesis of Letermovir Using a Novel Phase-Transfer-Catalyzed Aza-Michael Reaction

The development of a concise asymmetric synthesis of the antiviral development candidate letermovir is reported, proceeding in >60% yield over a total of seven steps from commercially available materials. Key to the effectiveness of this process is a novel cinchonidine-based PTC-catalyzed aza-Michael reaction to configure the single stereocenter

Synthesis of Bis-Macrocyclic HCV Protease Inhibitor MK-6325 via Intramolecular <i>sp</i>²–<i>sp</i>³ Suzuki–Miyaura Coupling and Ring Closing Metathesis

A practical asymmetric synthesis of the complex fused bis-macrocyclic HCV protease inhibitor MK-6325 (<b>1</b>) is described. Through the combination of a high yielding and low catalyst loading ring-closing metathesis (RCM) to forge the 15-membered macrocycle with an intramolecular <i>sp</i>²–<i>sp</i>³ Suzuki–Miyaura cross-coupling to append the 18-membered macrocycle, multikilogram access to the unique and challenging architecture of MK-6325 (<b>1</b>) has been achieved

Development of an Efficient Route to 2-Ethynylglycerol for the Synthesis of Islatravir

The unnatural, alkyne-containing nucleoside analog islatravir (MK-8591) is synthetically accessed through a biocatalytic cascade starting from 2-ethynylglycerol as a building block. Herein, we describe the development of an efficient synthesis of this building block including the initial route, route scouting and final process development. Key challenges that have been overcome are the development of an efficient and safe acetylenic nucleophile addition to an appropriate ketone, and the identification of a 2-ethynylpropane-1,2,3-triol derivative with favorable physical properties. An acid-catalyzed cracking of commercially available 1,3-dihydroxyacetone dimer and subsequent 1,2-addition of an acetylenic nucleophile has been discovered and optimized into the manufacturing proces