Reaction Steps
A 2-5 mL microwave vial equipped with a stirring bar was charged with 92 (94 mg, 0.3506 mmol, 1.1 equiv), (3S,4R)-1-benzyl-4-(4-methoxyphenyl)pyrrolidin-3-amine (90 mg, 0.3187 mmol, 1.0 mmol, CASRN 114616-86-5), DMF (2.0 mL) and HATU (187.4 mg, 0.4780 mmol, 1.5 equiv). The reaction mixture was stirred 20 min at RT and treated with TEA (0.1347 mL, 0.956 mmol, 3.0 equiv). The microwave vial was capped, and the reaction was stirred for 2 h at RT. The DMF solution was partitioned between EtOAc and water (120 mL/40 mL). The EtOAc layer was washed twice with brine, dried, filtered, and concentrated to give a crude oil. A portion of the crude (20%) was purified by RP HPLC to give 3.5 mg of N-((3S,4R)-1-benzyl-4-(4-methoxyphenyl)pyrrolidin-3-yl)-3-((1-methyl-1H-pyrazol-5-yl)amino)isoquinoline-6-carboxamide (purity=100%, 254 nM). The remainder of the crude (80%) was purified on a SiO2 column (ISCO) eluting with a MeOH/DCM gradient (2 to 8% MeOH) to afford an additional 48 mg (total 51.5 mg, 30%). 1H NMR (400 MHz, DMSO-d6) δ 9.05 (s, 1H), 8.87 (s, 1H), 8.80 (d, J=7.5 Hz, 1H), 8.16 (s, 1H), 7.96 (d, J=8.6 Hz, 1H), 7.64 (d, J=8.4 Hz, 1H), 7.42 (s, 1H), 7.34 (q, J=7.7 Hz, 4H), 7.26 (d, J=8.1 Hz, 3H), 6.92 (s, 1H), 6.86 (d, J=8.4, 2H), 6.23 (s, 1H), 4.49-4.43 (m, 1H), 3.76 (s, 3H), 3.70 (s, 3H), 3.62 (d, J=10.4 Hz, 1H), 3.43 (q, J=7.5 Hz, 1H), 3.04 (m, 2H), 2.60 (m, 2H). LCMS M+H+=534.
