1-Methylpiperazine → HCID 68877543, compound

HRID 1987746Notes

Reaction equation

HRID 1987746 reaction equation
Br[CH:2]([CH2:25][CH3:26])[C:3]([N:5]1[C:9]([CH3:16])([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][C:7]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])=[N:6]1)=[O:4].[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>CCCCO>[F:24][C:18]1[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:17]=1[C:7]1[CH2:8][C:9]([CH3:16])([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:5]([C:3]([CH:2]([N:31]2[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]2)[CH2:25][CH3:26])=[O:4])[N:6]=1

Participants

4

Reactant 2

HCID 531671-MethylpiperazineHCID 57725046HCID 57725046, compound

Product 1

HCID 68877543HCID 68877543, compound

Reagents, catalysts & solvents 1

HCID 2631-ButanolSolvent

Procedure

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.

Workup

  1. temperatureThe reaction mixture was cooled
  2. custompurified by reverse-phase LC (H2O/CH3CN gradient w/0.1% TFA present)
  3. customThe desired fractions were partitioned between a 1:1 saturated aqueous sodium bicarbonate solution and brine and ethyl acetate (2×100 mL)
  4. dry with materialThe combined organic layers were dried over sodium sulfate
  5. concentrationconcentrated

Sources & evidence

ORD record
ord-08379eba84614f72968a8affbacbb096
Source dataset
uspto-grants-2009_06
Patent number
US07553838B2

Reaction notes

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