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

HRID 13183

Reaction equation

HRID 13183 reaction equation
[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]

Participants

8

Reactant 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

Product 1

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

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 57417360Sodium chloride; waterSolvent

Conditions

Temperature
0 °C

Procedure

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%).

Workup

  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

Sources & evidence

ORD record
ord-7f516627afab46d8ad26f89cc7c5f42b
Source dataset
uspto-grants-2010_06
Patent number
US07728030B2

Linked notes

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