A New Class of Non‑<i>C</i>₂‑Symmetric Ligands for Oxidative and Redox-Neutral Palladium-Catalyzed Asymmetric Allylic Alkylations of 1,3-Diketones

We report the discovery, synthesis, and application of a new class of non-<i>C</i>₂-symmetric phosphoramidite ligands derived from pyroglutamic acid for use in both oxidative and redox-neutral palladium-catalyzed asymmetric allylic alkylations of 1,3-diketones. The resulting chiral products are typically obtained in high yield with good to excellent levels of enantioselectivity

Characterization of a Unique Co-crystal of the BACE1 Inhibitor Verubecestat and a Reaction Intermediate: Implications for the Development of a Commercial Manufacturing Process

Verubecestat is an inhibitor of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) that is currently under clinical evaluation for the treatment of prodromal Alzheimer’s disease. This article describes the characterization of a co-crystal composed of a HBr salt of verubecestat and a HBr salt of a reaction intermediate as the components. This unique co-crystal was formed during production of a multikilogram batch of verubecestat. The impact of this observation is discussed, followed by the description of a modified procedure that served to prevent the formation of this highly unusual crystalline material

Synthesis of Verubecestat, a BACE1 Inhibitor for the Treatment of Alzheimer’s Disease

Verubecestat is an inhibitor of β-secretase being evaluated for the treatment of Alzheimer’s disease. The first-generation route relies on an amide coupling with a functionalized aniline, the preparation of which introduces synthetic inefficiencies. The second-generation route replaces this with a copper-catalyzed C–N coupling, allowing for more direct access to the target. Other features of the new route include a diastereoselective Mannich-type addition into an Ellman sulfinyl ketimine and a late-stage guanidinylation

A Next Generation Synthesis of BACE1 Inhibitor Verubecestat (MK‑8931)

The development of a commercial manufacturing route to verubecestat (MK-8931) is described, highlights of which include the application of a continuous processing step to outcompete fast proton transfer in a Mannich-type ketimine addition, a copper-catalyzed amidation reaction, and an optimized guanidinylation procedure to form the key iminothiadiazine dioxide core