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The development of an improved kilogram-scale synthesis of the JAK1 inhibitor GDC-4379 for the treatment of asthma is described. The new process is highlighted by a step-economical construction of ...

The development of a redesigned and improved second-generation synthesis of the Nav1.7 inhibitor GDC-0276 based on experience gained from a fit-for-purpose first-generation synthesis will be described. The first-generation synthesis proceeded via a regioselective SNAr reaction on the advanced starting material t-butyl 5-chloro-2,4-difluorobenzoate with 1-adamantanemethanol. In the newly developed second-generation synthesis, the much improved regioselective SNAr reaction was performed on the readily available starting material 1-chloro-2,4-difluorobenzene, followed by installation of the carboxylate group by electrophilic aromatic bromination and a palladium-catalyzed alkoxycarbonylation. A subsequent Suzuki–Miyaura cross-coupling reaction was then telescoped directly into a phase-transfer-catalyzed ester hydrolysis. Amidation of the resulting acid intermediate with 1-azetidine sulfamide in turn provided GDC-0276 in high overall yield and purity on a 100 kg scale.

Boronic acids and boronate esters are commonly used reagents in Suzuki–Miyaura coupling chemistry which are known to be weakly mutagenic in microbial assays. In this paper, we describe an inductively coupled plasma mass spectrometer method (ICP-MS) for the analysis of boron at low parts per million levels. Boronic acid and ester levels are then calculated stoichiometrically in a drug substance based on the determination of boron with good sensitivity (LOQ of 0.8 ppm). The paper outlines some of the important aspects of the method and instrument features such as use of organic diluent, spray chamber configuration, and its optimization which are critical for analysis of trace inorganic species in drug substances.

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.

A process leading to the multikilogram GMP synthesis of Chk1 inhibitor GDC-0425 (1) 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.

The optically active, facial complex Cr(CO)3(PP′P″) (1) with the tridentade ligand PP′P″ = (R)-(+)-1,2,4-tris (diphenylphosphino)butane has been synthesized and characterized. The complex Cr(CO)3(PP′)P″ (PP′ = (R)-(+)-prophos, P″ = PMe2Ph) forms two pairs of diastereomers, facial (3, 4) and meridional (5, 6), respectively, that can be separated by preparative column chromatography. Surprisingly, the CD spectra of Cr(CO)3(PP′P″) (1) and the facial diastereomer of Cr(CO)3(PP′P″ (3), which have the same configuration at the Cr atom, are dissimilar. The meridional configuration of the two isomers 5 and 6 of Cr(CO)3 (PP′)PMe2Ph is supported by the 31P and 1H NMR spectra of the optically inactive complex Cr(CO)3(PP′)P″ (PP′ = 1-[di (4-methoxyphenyl)phosphinol-2-(diphenylphosphino)ethane P″ = PMePh2) which forms the meridional isomers 9 and 10.