1202757-89-8

Bruton’s tyrosine kinase (BTK) is a non-receptor tyrosine kinase involved in signal transduction pathways regulating the proliferation, activation, and differentiation of B cells. AVL-292 is an orally available, selective, and irreversible inhibitor of BTK (IC50 = 0.5 nM in vitro in B cell lymphoma cell lines) that targets and covalently binds to BTK at cysteine-481, thereby preventing its activity. AVL-292 has been shown to inhibit osteoclast function and to reduce osteoclast-stimulated proliferation of multiple myeloma cells in animal models of rheumatoid arthritis and multiple sclerosis, both of which are diseases where B cells play an important role. In clinical trials, AVL-292 has demonstrated therapeutic significance in the treatment of both B cell-related cancers (e.g., non-Hodgkin’s lymphoma and B cell chronic lymphocytic leukemia) and autoimmune diseases (e.g., rheumatoid arthritis).[Cayman Chemical]

N-(3-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino) was synthesized using N4-(3-aminophenyl)-5-fluoro-N2-(4-(2-methoxyethoxy)phenyl)pyrimidin-1,4-diamide (309 mg, 0.84 mmol) and acryloyl chloride (71 μL, 0.88 mmol) as the raw materials. The general procedure for phenyl)acrylamide was as follows: a THF (10 mL) solution of N4-(3-aminophenyl)-5-fluoro-N2-(4-(2-methoxyethoxy)phenyl)pyrimidine-1,4-diamine was cooled in a water/ice-MeOH bath (-10°C). Acryloyl chloride (71 μL, 0.88 mmol) was slowly added to the cooled solution and the reaction was stirred for 10 min. Hunig base (145 μL, 0.88 mmol) was then added and stirring was continued for 10 min. Upon completion of the reaction, the reaction mixture was partitioned between water/brine (10 mL) and the organic layer was separated after thorough stirring. The organic phase was dried with anhydrous sodium sulfate and the solvent was subsequently removed by rotary evaporation. The residue was ground with ether and filtered to give 285 mg of off-white solid product in 80% yield. The product was analyzed by LC/MS with retention time (RT) = 2.79 min and molecular ion peak (M+H)+ m/z = 424.2.

Btk

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[1] Patent: WO2009/158571, 2009, A1. Location in patent: Page/Page column 190; 192
[2] Patent: US2014/179720, 2014, A1. Location in patent: Paragraph 0380; 0383
[3] Patent: US2015/174128, 2015, A1. Location in patent: Paragraph 0629