Sodium hydride → 5-(2-Aminopyridin-4-yloxy)-2,3-dihydro-1H-indole-1-carboxylic acid methylamide

HRID 2376823Notes

Reaction equation

HRID 2376823 reaction equation
[H-].[Na+].[CH3:3][NH:4][C:5]([N:7]1[C:15]2[C:10](=[CH:11][C:12]([OH:16])=[CH:13][CH:14]=2)[CH2:9][CH2:8]1)=[O:6].[NH2:17][C:18]1[CH:23]=[C:22](Cl)[CH:21]=[CH:20][N:19]=1>CS(C)=O>[CH3:3][NH:4][C:5]([N:7]1[C:15]2[C:10](=[CH:11][C:12]([O:16][C:22]3[CH:21]=[CH:20][N:19]=[C:18]([NH2:17])[CH:23]=3)=[CH:13][CH:14]=2)[CH2:9][CH2:8]1)=[O:6]

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 5818662-Amino-4-chloropyridineHCID 210548535-hydroxy-2,3-dihydro-1H-indole-1-carboxylic acid methylamide

Product 1

HCID 210548125-(2-Aminopyridin-4-yloxy)-2,3-dihydro-1H-indole-1-carboxylic acid methylamideYield 4.6%

Reagents, catalysts & solvents 1

HCID 679Dimethyl SulfoxideSolvent

Conditions

Temperature
160 °C

Procedure

Sodium hydride (202 mg, 3.89 mmol, 60% in oil) was suspended in dimethyl sulfoxide (5.0 ml), then 5-hydroxy-2,3-dihydro-1H-indole-1-carboxylic acid methylamide (971 mg, 5.06 mmol) and 2-amino-4-chloropyridine (500 mg, 3.89 mmol) were added at room temperature under nitrogen atmosphere, and the reaction mixture was heated and stirred at 160° C. for 12 hours under nitrogen atmosphere. After naturally cooled down to room temperature, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, was dried over anhydrous magnesium sulfate, and was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Fuji Silysia BW-300; eluent: ethyl acetate, ethyl acetate:methanol=85:10 in this order). The fractions containing the desired compound were concentrated, and the residue was further purified by silica gel column chromatography (Fuji Silysia NH, eluent; from ethyl acetate to ethyl acetate:methanol=90:10). The obtained crystals were suspended in diethyl ether:acetone=3:1, filtered off, washed with diethyl ether, and dried under aeration to yield the title compound (51 mg, 0.18 mmol, 4.6%) as pale green crystals.

Workup

  1. temperaturethe reaction mixture was heated
  2. temperatureAfter naturally cooled down to room temperature
  3. customthe reaction mixture was partitioned between ethyl acetate and water
  4. washThe organic layer was washed with brine
  5. dry with materialwas dried over anhydrous magnesium sulfate
  6. concentrationwas concentrated under reduced pressure
  7. customThe residue was purified by silica gel column chromatography (Fuji Silysia BW-300
  8. additionThe fractions containing the desired compound
  9. concentrationwere concentrated
  10. customthe residue was further purified by silica gel column chromatography (Fuji Silysia NH, eluent; from ethyl acetate to ethyl acetate:methanol=90:10)
  11. filtrationacetone=3:1, filtered off
  12. washwashed with diethyl ether
  13. customdried under aeration

Sources & evidence

ORD record
ord-8a74aa1227ef424b9aeda05dcd6c01e8
Source dataset
uspto-grants-2008_12
Patent number
US07468380B2

Reaction notes

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