Diethyl Ether → Methyl 4-[1-({[5-fluoro-2-(4-fluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoate

HRID 1293164Notes

Reaction equation

HRID 1293164 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:10][C:11](=[O:27])[C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[N:14][C:13]=2[O:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH3:9])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.CN(C)[CH:66]=[O:67].C[CH2:70][O:71]CC>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CO>[F:18][C:16]1[CH:17]=[C:12]([C:11]([NH:10][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([C:70]([O:67][CH3:66])=[O:71])=[CH:3][CH:4]=2)[CH3:9])=[O:27])[C:13]([O:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[N:14][CH:15]=1

Participants

8

Reactant 5

HCID 3283Diethyl EtherHCID 6228DimethylformamideHCID 8471TriethylamineHCID 812191,3-Bis(diphenylphosphino)propaneHCID 57572321N-[1-(4-Bromophenyl)ethyl]-5-fluoro-2-(4-fluorophenoxy)nicotinamide

Product 1

HCID 57572284Methyl 4-[1-({[5-fluoro-2-(4-fluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoateYield 78%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 887MethanolSolvent

Conditions

Temperature
80 °C

Procedure

A mixture of N-[1-(4-bromophenyl)ethyl]-5-fluoro-2-(4-fluorophenoxy)nicotinamide (step 1, 398 mg, 0.92 mmol), 1,3-bis(diphenylphosphino)-propane (38 mg, 0.09 mmol), palladium (II) acetate (21 mg, 0.09 mmol), triethylamine (0.38 mL, 2.76 mmol), N,N-dimethylforamide (6 mL) and methanol (4 mL) was stirred at 80° C. for 16 h under carbon monoxide atmosphere. After cooling to room temperature, the mixture was diluted with ether (100 mL) and washed with water (60 mL×3). The organic layer was dried over magnesium sulfate and evaporated. The residue was purified by flush column chromatography on silica gel eluting with hexane/ethyl acetate (2:1) to afford 296 mg (78%) of the title compounds as white solids: 1H-NMR (CDCl3) δ 8.32 (1H, dd, J=8.1, 3.1 Hz), 8.21 (1H, d, J=7.3 Hz), 8.04–7.99 (3H, m), 7.43 (2H, d, J=8.2 Hz), 7.27–7.13 (4H, m), 5.38 (1H, dq, J=7.3, 6.9 Hz), 3.90 (3H, s), 1.60 (3H, d, J=6.9 Hz); MS (ESI) m/z 413 (M+H)+, 411 (M−H)−.

Workup

  1. temperatureAfter cooling to room temperature
  2. washwashed with water (60 mL×3)
  3. dry with materialThe organic layer was dried over magnesium sulfate
  4. customevaporated
  5. customThe residue was purified
  6. customby flush column chromatography on silica gel eluting with hexane/ethyl acetate (2:1)

Sources & evidence

ORD record
ord-ef3d75c097494ab6b283ba05f751d1d3
Source dataset
uspto-grants-2007_07
Patent number
US07238714B2

Reaction notes

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