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Hydrochloric Acid → N-(5-(7-methoxyquinolin-4-yloxy)pyridin-2-yl)-1-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide

HRID 2359673
Notes
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Reaction equation

HRID 2359673 reaction equation
[CH3:1][N:2]1[CH:6]=[C:5]([C:7]([O:9]CC)=O)[C:4](=[O:12])[N:3]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+].Cl.[CH3:22][O:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28]([O:34][C:35]3[CH:36]=[CH:37][C:38]([NH2:41])=[N:39][CH:40]=3)=[CH:29][CH:30]=[N:31]2)=[CH:26][CH:25]=1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CO.O.CN(C=O)C.CCOC(C)=O.ClCCl>[CH3:22][O:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28]([O:34][C:35]3[CH:36]=[CH:37][C:38]([NH:41][C:7]([C:5]4[C:4](=[O:12])[N:3]([C:13]5[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=5)[N:2]([CH3:1])[CH:6]=4)=[O:9])=[N:39][CH:40]=3)=[CH:29][CH:30]=[N:31]2)=[CH:26][CH:25]=1
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

12

Reactant 6

HCID 313Hydrochloric AcidHCID 8471TriethylamineHCID 14798Sodium HydroxideHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 15192740ethyl 2,3-dihydro-1-methyl-3-oxo-2-phenyl-1H-pyrazole-4-carboxylate
HCID 59598394
5-(7-Methoxyquinolin-4-yloxy)pyridin-2-amine

Product 1

HCID 44516532N-(5-(7-methoxyquinolin-4-yloxy)pyridin-2-yl)-1-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamideYield 20.3%

Reagents, catalysts & solvents 5

HCID 887MethanolSolventHCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
60 °C

Procedure

A solution of ethyl 1-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylate (260 mg, 1056 μmol) in MeOH was treated with NaOH (1000 μl, 5000 μmol) in H2O (3 mL). The mixture was heated to 60° C. for 30 min and then cooled to room temperature. Then, the mixture was neutralized with aq. HCl (5 N, 1.1 mL) and concentrated to dryness. The residue was further dried with (azeotrope distillation with toluene, 3×5 mL). The resulting carboxylic acid was mixed with 5-(7-methoxyquinolin-4-yloxy)pyridin-2-amine (282 mg, 1054 μmol), Et3N (500 μl, 3587 μmol), and HATU (401 mg, 1054 μmol) in DMF (4 mL)-dichloromethane (5 mL) and was stirred at 60° C. for 2 h. Upon cooling to room temperature, the mixture was diluted with EtOAc containing 10% MeOH (30 mL) and washed with H2O. The organic layer was dried over Na2SO4, concentrated, and eluded on silica (1-10% 2N NH3-MeOH in CHCl3). The product was further purified on preparative HPLC to afford a white powder (100 mg, 20%).

Workup

  1. temperaturecooled to room temperature
  2. concentrationconcentrated to dryness
  3. dry with materialThe residue was further dried with (azeotrope distillation with toluene, 3×5 mL)
  4. temperatureUpon cooling to room temperature
  5. washwashed with H2O
  6. dry with materialThe organic layer was dried over Na2SO4
  7. concentrationconcentrated
  8. customThe product was further purified on preparative HPLC

Sources & evidence

ORD record
ord-940cb03090f14bdf8bf18777fa28f56c
Source dataset
uspto-grants-2014_04
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08685983B2

Reaction notes

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On this pageParticipantsConditionsProcedureWorkupSources & evidenceReaction notes