Reaktionsschritte
To a solution of (S)-methyl 2-(2-(3-bromophenyl)-7-chloro-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (50 mg, 0.107 mmol, 1 equiv) in DMF (0.54 mL) was added 8-azabicyclo[3.2.1]octane hydrochloride (31 mg, 0.214 mmol, 2 equiv) and DIPEA (0.075 mL, 0.428 mmol, 4 equiv). The resulting solution was stirred at 85° C. for 18 h. Complete conversion to pyrimidyl amine was observed. To this solution was then added phenyl boronic acid (30 mg, 0.250 mmol, 2.5 equiv), potassium phosphate, tribasic (0.25 mL of a 2 M aqueous solution, 0.500 mmol, 4.7 equiv), and PdCl2(dppf).CH2Cl2 adduct (8 mg, 0.010 mmol, 0.09 equiv). The mixture was heated at 85° C. for 2 h. Upon completion of the Suzuki reaction, the reaction temperature was lowered to 60° C. Methanol (1 mL), water (0.3 mL), and LiOH.H2O (24 mg, 1.00 mmol, 9 equiv) added and heating was continued for 2 h. Upon completion of hydrolysis, reaction was removed from heat and filtered through a syringe filter. The crude reaction mixture was purified via preparative LC/MS with the following conditions: Column. Waters XBridge C18, 19×200 mm, 5-μμm particles Mobile Phase A: water with 20-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 20-mM ammonium acetate; Gradient: 40-80% B over 20 minutes, then a 5-minute hold at 100% B, to provide (S)-2-(2-([1,1′-biphenyl]-3-yl)-7-((1R,5 S)-8-azabicyclo[3.2.1]octan-8-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetic acid (8.9 mg, 17% yield). 1H NMR (500 MHz, DMSO-d6) δ 8.23 (s, 1H), 7.97 (d, J=8.2 Hz, 1H), 7.74 (d, J=7.3 Hz, 2H), 7.69 (d, J=7.6 Hz, 1H), 7.61-7.55 (m, 1H), 7.51 (t, J=7.2 Hz, 2H), 7.44-7.38 (m, 1H), 7.00 (s, 1H), 5.45 (br. s., 1H), 5.15 (br. s., 1H), 4.37 (br. s., 1H), 2.86 (br. s., 1H), 2.46 (s, 3H), 2.29 (br. s., 1H), 1.92 (d, J=13.7 Hz, 3H), 1.78 (d, J=12.8 Hz, 2H), 1.69 (d, J=14.0 Hz, 3H), 1.14 (s, 9H). LCMS (ESI, M+1): 525.4.
