Derek M. Dalton*, Juno Castillo Siu, Marcelino Varona-Ortiz, C. Gregory Sowell and Francis Gosselin,
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Development of a Robust Pd-Catalyzed C–S Coupling for the Synthesis of Janus Kinase Inhibitor GDC-9918
The development of an in situ formed (Xantphos)Pd oxidative addition complex made possible a robust, scalable C–S coupling of a functionalized aryl bromide with 2-mercaptoethanol that ultimately enabled the synthesis of Janus Kinase inhibitor GDC-9918 on a kilogram scale. An insoluble, catalytically inactive, [12]metallacrown-6 palladium(II) complex, [Pd6(μ2-SCH2CH2OH)12], was found to form quickly under most reaction conditions in the presence of 2-mercaptoethanol and a Pd catalyst and required up to 12 mol % Pd for full conversion in our generation route. A second-generation process was developed to minimize the formation of the [12]metallacrown-6 palladium(II) complex and enabled the decrease in catalyst loading to 2 mol % Pd. A soluble Pd scavenger, PIX, effectively removed Pd to <5 ppm. Catalytic sodium tungstate oxidation of the resulting thioether smoothly provided crude GDC-9918 that was recrystallized to the desired polymorph and micronized to a particle size distribution suitable for development as an inhalable treatment for asthma.
期刊介绍：
The journal Organic Process Research & Development serves as a communication tool between industrial chemists and chemists working in universities and research institutes. As such, it reports original work from the broad field of industrial process chemistry but also presents academic results that are relevant, or potentially relevant, to industrial applications. Process chemistry is the science that enables the safe, environmentally benign and ultimately economical manufacturing of organic compounds that are required in larger amounts to help address the needs of society. Consequently, the Journal encompasses every aspect of organic chemistry, including all aspects of catalysis, synthetic methodology development and synthetic strategy exploration, but also includes aspects from analytical and solid-state chemistry and chemical engineering, such as work-up tools，process safety, or flow-chemistry. The goal of development and optimization of chemical reactions and processes is their transfer to a larger scale; original work describing such studies and the actual implementation on scale is highly relevant to the journal. However, studies on new developments from either industry, research institutes or academia that have not yet been demonstrated on scale, but where an industrial utility can be expected and where the study has addressed important prerequisites for a scale-up and has given confidence into the reliability and practicality of the chemistry, also serve the mission of OPR&D as a communication tool between the different contributors to the field.
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