3-Fluorophenol → Methyl 4-[(1S)-1-({[5-chloro-2-(3-fluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoate

HRID 1293190Notes

Reaction equation

HRID 1293190 reaction equation
Cl[C:2]1[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[CH:6][C:5]([Cl:23])=[CH:4][N:3]=1.[F:24][C:25]1[CH:26]=[C:27]([OH:31])[CH:28]=[CH:29][CH:30]=1.C(=O)(O)[O-].[Na+]>CN1CCCC1=O>[Cl:23][C:5]1[CH:6]=[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])[C:2]([O:31][C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([F:24])[CH:26]=2)=[N:3][CH:4]=1

Participants

5

Reactant 3

HCID 97433-FluorophenolHCID 516892Sodium BicarbonateHCID 86601543Methyl 4-((1S)-1-{[(2,5-dichloropyridin-3-yl)carbonyl]amino}ethyl)benzoate

Product 1

HCID 69415945Methyl 4-[(1S)-1-({[5-chloro-2-(3-fluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoateYield 84%

Reagents, catalysts & solvents 1

HCID 13387N-methyl-2-pyrrolidoneSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of methyl 4-((1S)-1-{[(2,5-dichloropyridin-3-yl)carbonyl]amino}ethyl)benzoate (step 1, 177 mg, 0.50 mmol), 3-fluorophenol (224 mg, 2.0 mmol) and sodium bicarbonate (105 mg, 1.25 mmol) in 1-methylpyrrolidin-2-one (2 mL) was stirred at 100° C. for 24 h. After cooling, the reaction mixture was partitioned between water (50 mL) and dichloromethane (50 mL) and the organic phase was separated. The aqueous phase was extracted with dichloromethane (50 mL). The combined organic layer was washed with brine (100 mL), dried (sodium sulfate), and concentrated. The residue was purified by flash column chromatography on silica gel (10 g) eluting with hexane/ethyl acetate (4/1) to afford 180 mg (84%) of the title compound as white solids: 1H-NMR (CDCl3) δ 8.55 (1H, d, J=2.7 Hz), 8.15 (1H, d, J=2.7 Hz), 8.07–7.98 (3H, m), 7.47–7.37 (3H, m), 7.07–6.99 (1H, m), 6.98–6.88 (2H, m), 5.42–5.31 (1H, m), 3.90 (3H, s), 1.60 (3H, d, J=7.0 Hz); MS (ESI) m/z 429 (M+H)+, 427 (M−H)−.

Workup

  1. temperatureAfter cooling
  2. customthe reaction mixture was partitioned between water (50 mL) and dichloromethane (50 mL)
  3. customthe organic phase was separated
  4. extractionThe aqueous phase was extracted with dichloromethane (50 mL)
  5. washThe combined organic layer was washed with brine (100 mL)
  6. dry with materialdried (sodium sulfate)
  7. concentrationconcentrated
  8. customThe residue was purified by flash column chromatography on silica gel (10 g)
  9. washeluting with hexane/ethyl acetate (4/1)

Sources & evidence

ORD record
ord-9a58d41cf70d43e28578c1fa67b1fc58
Source dataset
uspto-grants-2007_07
Patent number
US07238714B2

Reaction notes

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