Diisopropylethylamine → N-((6-Amino-4-(cyclohexyloxy)-2-methylpyridin-3-yl)methyl)-1-benzyl-1H-pyrazole-4-carboxamide

Participants

Reaction Steps

To a mixture of 6-Amino-4-(cyclohexyloxy)-2-methylnicotinonitrile (30.0 mg, 0.130 mmol) in EtOH (5 ml) were added about 10 cm3 of a Raney-Ni suspension in MeOH under Ar. The flask was sealed, and the suspension was vigorously stirred at it for 3 d under an atmosphere of hydrogen. The reaction mixture was filtered over a plug of cellite and eluted with DCM-MeOH (9:1, 100 ml), DCM (50 ml), MeOH (50 ml) and NH3 in MeOH (7N, 50 ml). The combined filtrates were concentrated. Dry THF (5 ml), 1-benzyl-1H-pyrazole-4-carboxylic acid (26.3 mg, 0.130 mmol, prepared in analogy to example 13), DIPEA (0.091 ml, 0.520 mmol), DMAP (0.80 mg, 0.0065 mmol) and HATU (49.4 mg, 0.130 mmol) were added, and the reaction mixture was stirred at it for 10 h, before it was concentrated to dryness. The crude product was purified by column chromatography (CombiFlash Companion, 4 g SiO2, DCM to DCM:MeOH 9:1), followed by preparative HPLC (Waters Sunfire Prep C18 OBD 5 um, 100×19 mm, A: H2O+0.1% TFA, B: MeCN+0.1% TFA, 15-45% B in 10 min, 30 ml/min, rt) affording the title compound. 1H-NMR (DMSO-d6, 400 MHz): 1.15-1.27 (m, 1H), 1.27-1.38 (m, 2 H), 1.40-1.50 (m, 1H), 1.51-1.62 (m, 2H), 1.62-1.72 (m, 2H), 1.77-1.88 (m, 2 H), 2.44 (s, 3H), 4.24 (d, 2H), 4.47 (mc, 1H), 5.34 (s, 2H), 6.29 (s, 1H), 7.19-7.25 (m, 2H), 7.27-7.41 (m, 5H), 7.84 (s, 1H), 7.92 (t, 1H), 8.21 (s, 1H), 12.81 (s, 1H); LCMS RtK=1.11 min, [M+H]+=420.4.

Provenance & Evidence