The palladium-catalyzed coupling of aryl and heteroaryl chlorides with primary amides under mild homogeneous reaction conditions is reported. Successful C−N coupling is enabled by the use of a unique "dual-base" system consisting of DBU and NaTFA, which serve as proton acceptor and halide scavenger, respectively, using low catalyst loadings (0.5 mol %) with readily available, air-stable palladium precatalysts. The DBU/NaTFA system also enables the room-temperature coupling of primary aryl amines with aryl chlorides and is tolerant of a variety of base-sensitive functional groups.

Deucravacitinib (BMS-986165) is a deuterated small-molecule TYK2 inhibitor developed for the treatment of numerous autoimmune disorders. While the first-generation discovery chemistry route to access deucravacitinib was concise and sufficient to access kilogram quantities of API, impurity control and cost-of-goods concerns necessitated the design of a new route. Once a new route was identified and demonstrated, each step was optimized for yield, purity, robustness, and sustainability. Key accomplishments include (1) the development of a novel cyclocondensation under mild conditions to afford a methylated 1,2,4triazole with excellent regiocontrol, (2) the development of safe, homogeneous conditions to quench POCl 3 following chlorination of a substrate that is sensitive to nucleophilic and basic conditions, (3) the discovery of a robust, scalable "dual-base" palladiumcatalyzed C−N coupling reaction, and (4) mechanistic understanding to inform control strategies for a number of process-related impurities in an API step amidation mediated by EDC. Ultimately, the optimized commercial route was successfully scaled up to afford more than a metric ton of deucravacitinib for clinical and commercial use.

A scalable synthesis of 2-chloro-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)aniline (1), a key intermediate in the synthesis of an immuno-oncology asset, is described. A Negishi cross-coupling between in situ generated heteroaryl zinc reagent 4 and 5-bromo-2-chloroaniline (3) catalyzed by Pd(Xantphos)Cl 2 enabled the construction of the key aryl−heteroaryl bond. A scalable first-generation process was developed that delivered 1 in multikilogram quantities. Building upon knowledge from the initial process, a more efficient workup and isolation procedure was developed that controlled levels of residual Pd and Zn to consistent levels that were acceptable for downstream processing. The high-yielding optimized process offers streamlined metals remediation, a 30% reduction in the number of unit operations, and a 34% reduction in process mass intensity (PMI) compared to the initial process.

Suspension of insoluble solids in stirred tanks is important for many operations in the pharmaceutical and specialty chemical industries. A common goal in solid suspension is to achieve the just-suspended speed, N js, where all of the particles are suspended off the tank bottom. Operating at N js results in high mass transfer between the solid and liquid phases, which is important because many solid–liquid operations rely on adequate mass transfer to achieve the goals of the operation (e.g., reaction completion in a heterogeneous reaction mixture). N js can be predicted on the basis of physical properties and tank geometry, often through the use of the Zwietering and Grenville–Mak–Brown (GMB) correlations. These correlations use impeller- and tank-geometry-specific constants (S for Zwietering and Z for GMB) that typically have been obtained in larger-scale tanks with four flat baffles. Glass-lined tanks commonly used in the pharmaceutical and specialty chemical industries often have reduced baffling. This work evaluated the effect of reduced baffling on N js and determined S and Z as functions of baffling. It was found that N js can be substantially reduced by removing baffles from a tank. Also, the values of S and Z for the N js models obtained on the lab scale are comparable to those from larger-scale studies reported in the literature.

The development of a convergent route to the NLRP3 (nucleotide-binding domain and leucine-rich repeat-containing protein 3) agonist BMS-986299 is reported. The synthesis relies on a key Miyaura borylation and a tandem Suzuki–Miyaura coupling between an iodoimidazole and an o-aminochloroarene, followed by acid-mediated cyclization to afford the aminoquinoline core. The subsequent Boc cleavage and regioselective acylation afford the target compound. Two routes to the iodoimidazole intermediate are presented, along with the synthesis of the o-aminochloroarene via Negishi coupling. The convergent six-step route leads to an 80% reduction in process mass intensity compared to the linear enabling synthesis.