1-Methylpiperazine → HCID 68877543, compound

Participants

Reaction Steps

A solution of the more polar (lower Rf on silica gel TLC plate) diastereomeric 1-(2-bromobutanoyl)-3-(2,5-difluorophenyl)-5-methyl-5-phenyl-4,5-dihydro-1H-pyrazole (1-1, 370 mg, 0.878 mmol, 1 equiv) and 1-methylpiperazine (0.500 mL, 0.536 mmol, 6.11 equiv) in n-BuOH (3 mL) was heated at 100° C. for 20 h. The reaction mixture was cooled and purified by reverse-phase LC (H2O/CH3CN gradient w/0.1% TFA present). The desired fractions were partitioned between a 1:1 saturated aqueous sodium bicarbonate solution and brine and ethyl acetate (2×100 mL). The combined organic layers were dried over sodium sulfate and concentrated to give 1-(1-{[3-(2,5-difluorophenyl)-5-methyl-5-phenyl-4,5-dihydro-1H-pyrazol-1-yl]carbonyl}propyl)-4-methylpiperazine as a diastereomerically pure racemic mixture. The racemic mixture was separated by normal-phase chiral chromatography (ChiralPak AD column: 95% Hex and 5% i-PrOH with 0.1% diethylamine as a modifier) to provide 1-((1S)-1-{[(5S)-3-(2,5-difluorophenyl)-5-methyl-5-phenyl-4,5-dihydro-1H-pyrazol-1-yl]carbonyl}propyl)-4-methylpiperazine (1-2, more polar enantiomer) as a white foam. 1H NMR (300MHz, CDCl3) δ 7.63 (m, 1H), 7.35-7.19 (m, 5H), 7.07 (m, 2H), 4.37 (dd, 1H, J=9.2, 5.5 Hz), 3.54 (dd, 1H, J=18.6, 3.0 Hz), 3.46 (dd, 1H, J=18.6, 3.0 Hz), 2.73 (m, 4H), 2.41 (m, 4H), 2.26 (s, 3H), 2.07 (s, 3H), 1.80 (m, 1H), 1.58 (m, 1H), 0.86 (t, 3H, J=7.3 Hz). LRMS m/z (M+H) 441.5 found, 441.2 required.

Provenance & Evidence