Water → (S)-N-(4,4-Difluorocyclohexyl)-4-(4,5-dimethyl-6-phenylpyridazin-3-yl)-2-methylpiperazine-1-carboxamide hydrochloride

HRID 2093368Notes

Reaction equation

HRID 2093368 reaction equation
[CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[N:4][C:3]=1[N:15]1[CH2:20][CH2:19][NH:18][C@@H:17]([CH3:21])[CH2:16]1.C(N(CC)CC)C.[F:29][C:30]1([F:45])[CH2:35][CH2:34][CH:33]([NH:36][C:37](=O)[O:38]CC(Cl)(Cl)[Cl:41])[CH2:32][CH2:31]1.O>CS(C)=O>[ClH:41].[F:29][C:30]1([F:45])[CH2:31][CH2:32][CH:33]([NH:36][C:37]([N:18]2[CH2:19][CH2:20][N:15]([C:3]3[N:4]=[N:5][C:6]([C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=4)=[C:7]([CH3:8])[C:2]=3[CH3:1])[CH2:16][C@@H:17]2[CH3:21])=[O:38])[CH2:34][CH2:35]1

Participants

6

Reactant 4

HCID 962WaterHCID 8471TriethylamineHCID 583592422,2,2-Trichloroethyl 4,4-difluorocyclohexylcarbamateHCID 58359255(S)-4,5-Dimethyl-3-(3-methylpiperazin-1-yl)-6-phenylpyridazine

Product 1

HCID 46190740(S)-N-(4,4-Difluorocyclohexyl)-4-(4,5-dimethyl-6-phenylpyridazin-3-yl)-2-methylpiperazine-1-carboxamide hydrochlorideYield 76.2%

Reagents, catalysts & solvents 1

HCID 679Dimethyl SulfoxideSolvent

Procedure

Treat a mixture of (S)-4,5-dimethyl-3-(3-methylpiperazin-1-yl)-6-phenylpyridazine (199 mg, 0.70 mmol) and triethylamine (0.30 ml, 2.15 mmol) in DMSO (5 ml) with 2,2,2-trichloroethyl 4,4-difluorocyclohexylcarbamate (341 mg, 1.10 mmol). Heat the reaction at 100° C. for 4 d. Pour the reaction mixture into H2O, rinsing with EtOAc. Extract the mixture with EtOAc. Wash the organic layer twice with H2O, then brine. Dry over Na2SO4 and concentrate under reduced pressure. Purify the resulting residue by flash silica gel chromatography (gradient of 0 to 10% MeOH in CH2Cl2). Dissolve the purified free base in MeOH (1 mL) and treat with 1 M HCl in Et2O (1 mL). Concentrate the mixture to provide the title compound as a yellow foam (256 mg, 76%). ES/MS m/z 444.2 (M+1).

Workup

  1. additionTreat
  2. temperatureHeat
  3. customthe reaction at 100° C. for 4 d
  4. washrinsing with EtOAc
  5. extractionExtract the mixture with EtOAc
  6. washWash the organic layer twice with H2O
  7. dry with materialDry over Na2SO4
  8. concentrationconcentrate under reduced pressure
  9. customPurify the resulting residue by flash silica gel chromatography (gradient of 0 to 10% MeOH in CH2Cl2)
  10. dissolutionDissolve the purified free base in MeOH (1 mL)
  11. additiontreat with 1 M HCl in Et2O (1 mL)
  12. concentrationConcentrate the mixture

Sources & evidence

ORD record
ord-cbe46246751543fe816fe4ae3f05a7be
Source dataset
uspto-grants-2013_05
Patent number
US08445493B2

Reaction notes

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