Practical Synthesis of a 6‑Triazolylazabicyclo[3.1.0]hexane

We describe a practical, scalable synthesis of an advanced heterocyclic intermediate, (1<i>R</i>,5<i>S</i>,6<i>s</i>)-6-(4<i>H</i>-1,2,4-triazol-4-yl)-3-azabicyclo­[3.1.0]­hexane. A robust synthetic sequence based on a Kulinkovich–de Meijere pyrroline cyclopropanation followed by transamination of <i>N</i>,<i>N</i>′-dimethylformamide azine with the resultant amine was developed to supply >18 kg of the target triazolyl azabicycle with 98 wt % purity in its free base form. Reaction conditions and isolation methods for the key 1,2,4-triazole formation step were explored to minimize undesired reaction pathways and to increase the purity of the product. Additionally, at several stages different freebasing methods were implemented that addressed the high water solubility of the associated nitrogen-rich compounds

Development of an Efficient, Safe, and Environmentally Friendly Process for the Manufacture of GDC-0084

An improved, efficient process with a significantly reduced process mass intensity (PMI) led to the multikilogram synthesis of a brain penetrant PI3K inhibitor GDC-0084. Highlights of the synthesis include a phase transfer catalyzed annulation in water, an efficient Suzuki-Miyaura cross-coupling of a chloropyrimidine with an arylboronic acid using a low palladium catalyst loading, and the development of a controlled crystallization to provide the API. The process delivered GDC-0084 with low levels of both impurities and residual metals

Magnesium Ethoxide Promoted Conversion of Nitriles to Amidines and Its Application in 5,6-Dihydroimidazobenzoxazepine Synthesis

Magnesium ethoxide has been shown to be a mild, safe, and scalable alternative to trimethylaluminum for the direct addition of amines to aryl nitriles to access cyclic amidines. A variety of electronically diverse oxa-, thia-, and diazepine products were successfully synthesized in moderate to high yields. Further elaboration of these compounds to 5,6-dihydroimidazobenzoxazepines, a privileged class of pharmacologically active heterocycles, highlights the utility of this method

Development of an Expedient Process for the Multi-Kilogram Synthesis of Chk1 Inhibitor GDC-0425

A process leading to the multikilogram GMP synthesis of Chk1 inhibitor GDC-0425 (<b>1</b>) was developed. Highlights of the synthesis include protection of the pyrrole ring of a 1,7-diazacarbazole as propyl ethyl ether, an efficient Pd catalyzed cyanation of an aryl chloride, aryl ether formation by SNAr fluoride displacement, and development of a controlled crystallization providing the API with the required polymorphic form. The process delivered high-quality GDC-0425 with low levels of impurities and residual metals in five steps and 31% overall yield

Manufacturing Development and Genotoxic Impurity Control Strategy of the Hedgehog Pathway Inhibitor Vismodegib

The development work toward the robust and efficient manufacturing process to vismodegib, the active pharmaceutical ingredient (API) in Erivedge, is described. The optimization of the four-stage manufacturing process was designed to produce the API with the required critical quality attributes: (1) the selective catalytic hydrogenation reduction of the nitro compound <b>3</b> to the corresponding aniline <b>4</b> while minimizing the formation of potential genotoxic (mutagenic) impurities; (2) the control of the polymorphic phase and multipoint specification for particle size distribution

Development of an Efficient Manufacturing Process for Reversible Bruton’s Tyrosine Kinase Inhibitor GDC-0853

Efforts toward the process development of reversible Bruton’s tyrosine kinase (BTK) inhibitor GDC-0853 (<b>1</b>) are described. A practical synthesis of GDC-0853 was accomplished via a key highly regioselective Pd-catalyzed C–N coupling of tricyclic lactam <b>5</b> with 2,4-dichloronicotinaldehyde (<b>6</b>) to afford the C–N coupling product <b>3</b>, a Suzuki–Miyaura cross-coupling of intermediate <b>3</b> with boronic ester <b>4</b> derived from a Pd-catalyzed borylation of tetracyclic bromide <b>7</b>, to generate penultimate aldehyde intermediate <b>2</b> and subsequent aldehyde reduction and recrystallization. Process development of starting materials <b>5</b>, <b>6</b>, and <b>7</b> is also discussed