4-Aminophenol → Methyl 7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)-phenoxy]thieno[3,2-b]pyridine-2-carboxylate

HRID 525789Notes

Reaction equation

HRID 525789 reaction equation
Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[S:10][C:3]=12.CCOC(C1C(=O)CCCC1)=O.C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:33][C:34]1[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=1.[F:41][C:42]1[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][C:43]=1[N:49]=[C:50]=[O:51]>CS(C)=O.C1COCC1.O>[F:41][C:42]1[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][C:43]=1[NH:49][C:50]([NH:33][C:34]1[CH:39]=[CH:38][C:37]([O:40][C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[S:10][C:3]=23)=[CH:36][CH:35]=1)=[O:51]

Participants

9

Reactant 5

HCID 4034-AminophenolHCID 10796Cesium carbonateHCID 95543Ethyl 2-oxocyclohexanecarboxylateHCID 27333772-Fluoro-5-methylphenyl isocyanateHCID 67042765Methyl 7-bromothieno[3,2-b]pyridine-2-carboxylate

Product 1

HCID 51041147Methyl 7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)-phenoxy]thieno[3,2-b]pyridine-2-carboxylate

Reagents, catalysts & solvents 3

HCID 679Dimethyl SulfoxideSolventHCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
70 °C

Procedure

To a stirred solution of methyl 7-bromothieno[3,2-b]pyridine-2-carboxylate (200 mg, 0.74 mmol) in 8 ml of DMSO, were added CuBr (10 mg, 0.074 mmol), ethyl 2-cyclohexanonecarboxylate (26 mg, 0.15 mmol), cesium carbonate (500 mg, 1.54 mmol) and 4-aminophenol (96 mg, 0.88 mmol). The mixture was purged with nitrogen for 10 minutes, and then heated at 70° C. under N2 for 3 hours. The reaction was cooled to room temperature and poured into 100 ml of water. The precipitates were filtered, washed with water and dried to give the crude aniline intermediate as a pale green solid (˜140 mg). This crude material was dissolved in 10 ml of THF, and 2-fluoro-5-methylphenyl isocyanate (70 mg, 0.46 mmol) was added. The mixture was stirred at room temperature for 5 hours, and poured into 100 ml of water. The brown precipitates were filtered, washed with water and dried to give the crude product, which was purified by silica gel chromatography, eluting with 2-3% MeOH/CHCl3 to give methyl 7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxylate as light brown solid. Yield: 90 mg, 27%.

Workup

  1. customThe mixture was purged with nitrogen for 10 minutes
  2. temperatureThe reaction was cooled to room temperature
  3. additionpoured into 100 ml of water
  4. filtrationThe precipitates were filtered
  5. washwashed with water
  6. customdried
  7. customto give the crude aniline intermediate as a pale green solid (˜140 mg)
  8. customThe brown precipitates
  9. filtrationwere filtered
  10. washwashed with water
  11. customdried
  12. customto give the crude product, which
  13. customwas purified by silica gel chromatography
  14. washeluting with 2-3% MeOH/CHCl3

Sources & evidence

ORD record
ord-5a59d5b0626646c18126fd14b79e86af
Source dataset
uspto-grants-2016_05
Patent number
US09340555B2

Reaction notes

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