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

HRID 2093368ノート

反応式

HRID 2093368 の反応式
[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

参加物

6

反応物 4

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

生成物 1

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

試薬・触媒・溶媒 1

HCID 679Dimethyl Sulfoxide溶媒

実験手順

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).

後処理

  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

出典と根拠

ORDレコード
ord-cbe46246751543fe816fe4ae3f05a7be
出典データセット
uspto-grants-2013_05
特許番号
US08445493B2

反応ノート

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