Acetyl chloride → 1-acetyl-3-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide

HRID 1524406노트

반응식

HRID 1524406 반응식
COC1C=C(OC)C=CC=1C[N:6]([C:35]1[S:39][N:38]=[CH:37][N:36]=1)[S:7]([C:10]1[CH:18]=[C:17]2[C:13]([C:14]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=3[C:29]3[N:33]([CH3:34])[N:32]=[CH:31][CH:30]=3)=[CH:15][NH:16]2)=[CH:12][CH:11]=1)(=[O:9])=[O:8].[H-].[Na+].[C:48](OC(=O)C)(=[O:50])[CH3:49].C(Cl)(=O)C>O.CCOC(C)=O.[Cl-].[Na+].O.CN(C=O)C>[C:48]([N:16]1[C:17]2[C:13](=[CH:12][CH:11]=[C:10]([S:7]([NH:6][C:35]3[S:39][N:38]=[CH:37][N:36]=3)(=[O:9])=[O:8])[CH:18]=2)[C:14]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=2[C:29]2[N:33]([CH3:34])[N:32]=[CH:31][CH:30]=2)=[CH:15]1)(=[O:50])[CH3:49]

참가 물질

9

반응물 4

HCID 6367Acetyl chlorideHCID 7918Acetic AnhydrideHCID 24758Sodium hydrideHCID 71259342N-(2,4-dimethoxybenzyl)-3-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide2회

생성물 1

HCID 712598761-acetyl-3-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide수율 68%

시약·촉매·용매 4

HCID 962Water용매HCID 6228Dimethylformamide용매HCID 8857Ethyl Acetate용매HCID 57417360Sodium chloride; water용매

실험 절차

A 10-mL round-bottom flask was charged with N-(2,4-dimethoxybenzyl)-3-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide (Intermediate B) (85.95 mg, 0.131 mmol) and DMF (1.3 mL) to give a clear, light-yellow solution. Sodium hydride (60% in mineral oil) (7.88 mg, 0.197 mmol) was added, and the resulting mixture was stirred for 15 min. Acetic anhydride (24.77 μl, 0.263 mmol) was added dropwise to give a thick slurry. After 15 min of stirring, the mixture was diluted with water, EtOAc, and a small amount of brine. The layers were separated, and the aq. layer was extracted with EtOAc. The organic extracts were combined, dried over sodium sulfate, and concentrated. The residue was dissolved in MeOH (1 mL) and treated dropwise with acetyl chloride (46.7 μl, 0.656 mmol) for 1.5 h. The reaction mixture was concentrated in vacuo, and the residue was suspended in DCM (2 mL) and triethylamine (0.5 mL). The resulting solution was again concentrated, and the crude product was purified by chromatography on silica gel (0 to 10% MeOH/DCM) to give 1-acetyl-3-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide (48.77 mg, 0.089 mmol, 68.0% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ=8.82 (dd, J=0.5, 1.7 Hz, 1 H), 8.42 (s, 1 H), 8.06-7.97 (m, 1 H), 7.93-7.85 (m, 3 H), 7.60 (dd, J=1.8, 8.4 Hz, 1 H), 7.41 (d, J=8.4 Hz, 1 H), 7.33 (s, 1 H), 6.31 (d, J=1.9 Hz, 1 H), 3.43 (s, 3 H), 2.59 (s, 3 H). m/z (ESI) 547.2 (M+H)+.

후처리

  1. customto give a clear, light-yellow solution
  2. customto give a thick slurry
  3. stirringAfter 15 min of stirring
  4. customThe layers were separated
  5. extractionthe aq. layer was extracted with EtOAc
  6. dry with materialdried over sodium sulfate
  7. concentrationconcentrated
  8. dissolutionThe residue was dissolved in MeOH (1 mL)
  9. concentrationThe reaction mixture was concentrated in vacuo
  10. concentrationThe resulting solution was again concentrated
  11. customthe crude product was purified by chromatography on silica gel (0 to 10% MeOH/DCM)

출처 및 근거

ORD 기록
ord-0f270e66de3c4bebb4812ee73b04ec0c
출처 데이터셋
uspto-grants-2015_07
특허 번호
US09079902B2

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