Reaction Steps
A microwave vial was charged with pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [3-(5-chloro-2-difluoromethoxy-phenyl)-1H-pyrazol-4-yl]-amide (100 mg, 0.25 mmol), (4-dimethylamino-piperidin-1-yl)-(4-iodo-phenyl)-methanone (107 mg, 0.30 mmol), copper (I) iodide (15 mg, 0.08 mmol), potassium carbonate (73 mg, 0.53 mmol), trans-N,N′-dimethyl-1,2-cyclohexane diamine (24 μL, 0.15 mmol). The vessel was sealed and purged with argon before the addition of toluene (1.0 mL). The reaction mixture was stirred at 110° C. for 18 hours. The reaction was cooled to room temperature, diluted with water and the resultant precipitate was collected by filtration, washed with ethyl acetate and dried under reduced pressure. The resultant solid was purified by MDAP (Method 1), the solid was taken up into a mixture of MeOH/DCM and loaded onto an Isolute® SCX-2 cartridge which had been conditioned with MeOH. The cartridge was washed with MeOH then eluted with 2M NH3/MeOH. The basic fractions were combined, evaporated and the resultant solid suspended in MeOH before being treated with 1.25M HCl in MeOH. The suspension was allowed to evaporate and the solid was triturated with ethyl acetate, dried under reduced pressure giving the title compound as a yellow solid (67 mg, 40%). LCMS (Method 5) [M+H]+=635.2, RT=3.27 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.88 (s, 1H), 9.38 (dd, 1H, J=7.1, 1.8 Hz), 9.04 (s, 1H), 8.71 (s, 1H), 8.70 (dd, 1H, J=4.3, 1.7 Hz), 8.04-7.99 (m, 2H), 7.79 (d, 1H, J=2.7 Hz), 7.72 (dd, 1H, J=8.8, 2.6 Hz), 7.63-7.57 (m, 2H), 7.53 (d, 1H, J=8.8 Hz), 7.33 (dd, 1H, J=7.0, 4.3 Hz), 7.31 (t, 1H, J=73.1 Hz), 4.65 (brs, 1H), 2.98 (s, 2H), 2.67 (s, 6H), 2.14-1.82 (m, 2H), 1.69-1.54 (m, 2H).
