Morpholine → 2,2,2-trifluoro-N-((1R,2S)-1-(1-(3-(morpholinomethyl)phenyl)-1H-indazol-5-yloxy)-1-phenylpropan-2-yl)acetamide

HRID 13183

반응식

HRID 13183 반응식
[F:1][C:2]([F:34])([F:33])[C:3]([NH:5][C@@H:6]([CH3:32])[C@H:7]([O:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30]O)[CH:25]=1)[N:19]=[CH:18]2)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].C(N(CC)CC)C.CS(Cl)(=O)=O.OS([O-])(=O)=O.[K+].[NH:53]1[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1>[Cl-].[Na+].O.ClCCl>[F:33][C:2]([F:1])([F:34])[C:3]([NH:5][C@@H:6]([CH3:32])[C@H:7]([O:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][N:53]3[CH2:58][CH2:57][O:56][CH2:55][CH2:54]3)[CH:25]=1)[N:19]=[CH:18]2)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4]

참가 물질

8

반응물 5

HCID 8083MorpholineHCID 8471TriethylamineHCID 31297Methanesulfonyl chlorideHCID 516920Potassium bisulfateHCID 593398812,2,2-trifluoro-N-((1R,2S)-1-(1-(3-(hydroxymethyl)phenyl)-1H-indazol-5-yloxy)-1-phenylpropan-2-yl)acetamide

생성물 1

HCID 593396442,2,2-trifluoro-N-((1R,2S)-1-(1-(3-(morpholinomethyl)phenyl)-1H-indazol-5-yloxy)-1-phenylpropan-2-yl)acetamide

시약·촉매·용매 2

HCID 6344Dichloromethane용매HCID 57417360Sodium chloride; water용매

반응 조건

온도
0 °C

실험 절차

To a stirred, ice-cooled solution of 2,2,2-trifluoro-N-((1R,2S)-1-(1-(3-(hydroxymethyl)phenyl)-1H-indazol-5-yloxy)-1-phenylpropan-2-yl)acetamide (144, 119 mg, 0.35 mmol) and triethylamine (0.35 mL, 2.5 mmol) was added methanesulfonyl chloride (140 μL, 1.8 mmol). The mixture was stirred for 55 min at 0° C. and brine was then added followed by dichloromethane (10 mL) and aqueous KHSO4 (1M). The phases were separated and the organic phase washed with sat aqueous NaHCO3. To the organic phase was the added morpholine (1 mL, 11.5 mmol). The mixture was stirred at ambient temperature for 16 h and was then evaporated. The residue was subjected to preparative HPLC (Kromasil C-18, 2.5×20 cm) using a gradient (holding 0.1% TfA) of 30-90% acetonitrile in water/60 min. Fractions containing the title compound were combined and evaporated. The residue, comprising the TfA-salt of the title compound was dissolved in MeOH and absorbed on a plug of acidic ion exchange resin (SCX, 5 g, pre-washed with MeOH). Eluting with MeOH and methanolic ammonia (2M) subsequently afforded after evaporation, re-dissolving in water and lyophilization 2,2,2-trifluoro-N-((1R,2S)-1-(1-(3-(morpholinomethyl)phenyl)-1H-indazol-5-yloxy)-1-phenylpropan-2-yl)acetamide (105 mg, 77%).

후처리

  1. customThe phases were separated
  2. washthe organic phase washed
  3. stirringThe mixture was stirred at ambient temperature for 16 h
  4. customwas then evaporated
  5. customa gradient (holding 0.1% TfA) of 30-90% acetonitrile in water/60 min
  6. additionFractions containing the title compound
  7. customevaporated
  8. dissolutionwas dissolved in MeOH
  9. customabsorbed on a plug of acidic ion exchange resin (SCX, 5 g, pre-washed with MeOH)
  10. washEluting with MeOH and methanolic ammonia (2M)
  11. customsubsequently afforded
  12. customafter evaporation
  13. dissolutionre-dissolving in water

출처 및 근거

ORD 기록
ord-7f516627afab46d8ad26f89cc7c5f42b
출처 데이터셋
uspto-grants-2010_06
특허 번호
US07728030B2

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