Capture of Reactive Monophosphine-Ligated Palladium(0) Intermediates by Mass Spectrometry

A long-sought-after reactive monophosphine-ligated palladium(0) intermediate, Pd⁰L (L = phosphine ligand), was detected for the first time from the activation of the Buchwald precatalyst with base. The detection was enabled using desorption electrospray ionization mass spectrometry (DESI-MS) in combination with online reaction monitoring. The subsequent oxidative addition of Pd⁰L with aryl halide and C–N coupling with amine via reductive elimination was also probed using DESI-MS

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 Robust Kilo-Scale Synthesis of Doravirine

Doravirine is non-nucleoside reverse transcriptase inhibitor (NNRTI) currently in phase III clinical trials for the treatment of HIV infection. Herein we describe a robust kilo-scale synthesis for its manufacture. The structure and origin of major impurities were determined and their downstream fate-and-purge studied. This resulted in a redesign of the route to introduce the key nitrile functionality via a copper mediated cyanation which allowed all impurities to be controlled to an acceptable level. The improved synthesis was scaled to prepare ∼100 kg batches of doravirine to supply all preclinical and clinical studies up to phase III. The synthesis affords high-quality material in a longest linear sequence of six steps and 37% overall yield

Enantioselective Synthesis of Hemiaminals via Pd-Catalyzed C–N Coupling with Chiral Bisphosphine Mono-oxides

A novel approach to hemiaminal synthesis via palladium-catalyzed C–N coupling with chiral bisphosphine mono-oxides is described. This efficient new method exhibits a broad scope, provides a highly efficient synthesis of HCV drug candidate elbasvir, and has been applied to the synthesis of chiral <i>N,N</i>-acetals

Convergent, Kilogram Scale Synthesis of an Akt Kinase Inhibitor

The development of a convergent, chromatography-free synthesis of an allosteric Akt kinase inhibitor is described. The route comprised 17 total steps and was used to produce kilogram quantities of the target molecule. A key early transformation, for which both batch and flow protocols were developed, was formylation of a dianion derived by deprotonation and subsequent lithium-halogen exchange from a 2-bromo-3-aminopyridine precursor. Improved reaction yield and practicality were achieved in the continuous processing mode. Further significant process developments included the safe execution of a high temperature and pressure hydrazine displacement, separation of substituted cyclobutane diastereomers by means of chemoselective ester hydrolysis, and a late-stage Suzuki fragment coupling under mild conditions