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

Participants

Reaction Conditions

Reaction Steps

A mixture of 6-amino-4-methoxy-2-methylnicotinonitrile (100 mg, 0.613 mmol) in THF (4 ml) was cooled to −78° C., and treated with DIBAL-H (1M in THF, 3.68 ml, 3.68 mmol). The mixture was slowly warmed to rt. Stirring was continued for 24 h at rt, before the reaction mixture was carefully transferred to an ice-cold mixture of MeOH (50 ml) and water (0.2 ml, 11.0 mmol). The resulting suspension was adsorbed on celite (ca. 30 cm3) and dried in vacuo. Elution with DCM-MeOH (9:1, 200 ml) and removal of all volatiles afforded a yellow oil. Dry THF (5 ml), 1-benzyl-1H-pyrazole-4-carboxylic acid (79.0 mg, 0.389 mmol, prepared in analogy to example 13), DIPEA (0.209 ml, 1.20 mmol), DMAP (1.8 mg, 0.015 mmol) and HATU (148 mg, 0.389 mmol) were added, and the reaction mixture was stirred at it for 14 h, before it was concentrated to dryness. The crude product was purified by column chromatography (CombiFlash Rf, 13 g RediSep Rf C18, MeCN:water 5:95+0.1% TFA to MeCN), followed by preparative HPLC (Waters Sunfire Prep C18 OBD 5 um, 100×30 mm, A: H2O+0.1% TFA, B: MeCN+0.1% TFA, 5-35% B in 15 min, 30 ml/min, rt) to afford the title compound. 1H-NMR (DMSO-d6, 400 MHz): 2.47 (s, 3H), 3.91 (s, 3 H), 4.22 (d, 2H), 5.33 (s, 2H), 6.26 (s, 1H), 7.22-7.27 (m, 2H), 7.28-7.38 (m, 3H), 7.53 (br, s, 2H), 7.86 (s, 1H), 8.09 (t, 1H), 8.23 (s, 1H), 12.95 (s, 1H); LCMS RtK=0.82 min, [M+H]+=352.4.

Provenance & Evidence