299411-67-9Relevant articles and documents
IMIDAZO[1,2-B]PYRIDAZIN-6-AMINE DERIVATIVES AS KINASE JAK-2 INHIBITORS
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Page/Page column 16, (2014/02/16)
A compound represented by the general formula (I) wherein R1represents H or C1-C4 alkyl; R2 represents phenyl substituted with one or two substituents selected from the group consisting of halogen atom and OCsu
Development and a practical synthesis of the JAK2 inhibitor LY2784544
Mitchell, David,Cole, Kevin P.,Pollock, Patrick M.,Coppert, David M.,Burkholder, Timothy P.,Clayton, Joshua R.
experimental part, p. 70 - 81 (2012/05/31)
The route selection and process research and development of a practical synthesis for JAK2 inhibitor LY2784544 is described. The first-generation synthesis route, similar to that used in discovery for derivatization of a benzylic amine moiety, was 14 overall steps and possessed several steps that required extensive development for large-scale production. Route selection considerations led to a modified synthesis that utilized a novel vanadium-catalyzed carbon-carbon bond-forming arylation reaction for incorporation of the key benzylic morpholine moiety. A protecting group used to mask an amino pyrazole unit was modified from PMB to tert-butyl, resulting in a dramatic reduction in the overall length of the route. These two major changes resulted in an eight-step synthesis, which was six steps shorter than the first-generation synthesis. In the pilot plant, the new synthesis was scaled to produce >100 kg of LY2784544 in high yield and purity under GMP conditions. The overall development including the vanadium-catalyzed C-C bond-forming methodology, a ketone reductive deoxygenation, and a palladium-catalyzed amination is described.