Phenyl Methylcarbamate → 5-((2-Aminopyridin-4-yl)oxy)-6-isopropoxy-N-methyl-1H-indole-1-carboxamide

HRID 1427022Notes

Reaction equation

HRID 1427022 reaction equation
[CH:1]([O:4][C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][NH:11]2)=[CH:7][C:6]=1[O:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]([NH2:21])[CH:16]=1)([CH3:3])[CH3:2].[H-].[Na+].[CH3:24][NH:25][C:26](=O)[O:27]C1C=CC=CC=1.[Cl-].[NH4+]>CN(C)C=O.C(OCC)(=O)C.O>[NH2:21][C:17]1[CH:16]=[C:15]([O:14][C:6]2[CH:7]=[C:8]3[C:12](=[CH:13][C:5]=2[O:4][CH:1]([CH3:3])[CH3:2])[N:11]([C:26]([NH:25][CH3:24])=[O:27])[CH:10]=[CH:9]3)[CH:20]=[CH:19][N:18]=1

Participants

8

Reactant 4

HCID 16034Phenyl MethylcarbamateHCID 24758Sodium hydrideHCID 25517Ammonium ChlorideHCID 867303244-((6-Isopropoxy-1H-indol-5-yl)oxy)pyridin-2-amine

Product 1

HCID 867303255-((2-Aminopyridin-4-yl)oxy)-6-isopropoxy-N-methyl-1H-indole-1-carboxamideYield 98%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

4-((6-Isopropoxy-1H-indol-5-yl)oxy)pyridin-2-amine described in Production Example 17-6 (65.6 mg, 0.232 mmol) was dissolved in N,N-dimethylformamide (1.5 mL), 50-72% oily sodium hydride (16.7 mg) was added under nitrogen atmosphere at 0° C., and the mixture was stirred at room temperature for 50 minutes. The mixture was cooled to 0° C. again, phenyl methylcarbamate described in Production Example 1-7 (69.2 mg, 0.458 mmol) was added, and the mixture was stirred at room temperature for 3 hours. A saturated aqueous ammonium chloride solution, water, and ethyl acetate were added to the reaction mixture for partition. The aqueous layer was extracted with ethyl acetate and the combined organic layer was washed with water and then with a saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate and then filtered, then the filtrate was concentrated under vacuum. The residue was dissolved in dichloromethane and the resultant was purified with NH silica gel column chromatography (n-heptane:ethyl acetate=3:7-0:1-ethyl acetate:methanol=99:1-19:1), then the target fraction was concentrated under vacuum to obtain the title compound (77.0 mg, 98%).

Workup

  1. temperatureThe mixture was cooled to 0° C. again
  2. additionwas added
  3. stirringthe mixture was stirred at room temperature for 3 hours
  4. customfor partition
  5. extractionThe aqueous layer was extracted with ethyl acetate
  6. washthe combined organic layer was washed with water
  7. dry with materialThe organic layer was dried over anhydrous magnesium sulfate
  8. filtrationfiltered
  9. concentrationthe filtrate was concentrated under vacuum
  10. dissolutionThe residue was dissolved in dichloromethane
  11. customthe resultant was purified with NH silica gel column chromatography (n-heptane:ethyl acetate=3:7-0:1-ethyl acetate:methanol=99:1-19:1)
  12. concentrationthe target fraction was concentrated under vacuum

Sources & evidence

ORD record
ord-20ba3153d221442c947c50a07c19f12b
Source dataset
uspto-grants-2015_01
Patent number
US08933099B2

Reaction notes

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