Pyridine → N1-(3-Fluoro-4-(pyridin-4-yloxy)phenyl)-N3-(4-fluorophenyl)malonamide

HRID 1670216Notes

Reaction equation

HRID 1670216 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:22])[CH2:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[O:13])[CH:5]=[CH:6][C:7]=1[OH:8].[N:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:22])[CH2:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[O:13])[CH:5]=[CH:6][C:7]=1[O:8][C:26]1[CH:27]=[CH:28][N:23]=[CH:24][CH:25]=1

Participants

6

Reactant 3

HCID 1049PyridineHCID 2734379(Pyridin-4-yl)boronic acidHCID 44203043N1-(3-Fluoro-4-hydroxyphenyl)-N3-(4-fluorophenyl)malonamide

Product 1

HCID 59852940N1-(3-Fluoro-4-(pyridin-4-yloxy)phenyl)-N3-(4-fluorophenyl)malonamideYield 21%

Reagents, catalysts & solvents 2

HCID 8895Cupric acetateCatalystHCID 6344DichloromethaneSolvent

Conditions

Temperature
120 °C

Procedure

N1-(3-Fluoro-4-hydroxyphenyl)-N3-(4-fluorophenyl)malonamide (31 mg, 0.10 mmol), copper(II) acetate (27 mg, 0.15 mmol), pyridin-4-ylboronic acid (25 mg, 0.20 mmol), and pyridine (16 μL, 0.20 mmol) were placed in a pressure tube in that order. The tube was charged with methylene chloride (0.5 mL) and sealed. The reaction was stirred at 120° C. for 5 h. The reaction mixture was filtered through silica gel using 5% methanol/ethyl acetate. After concentration, the crude product was purified by prep HPLC. The appropriate fraction was concentrated to remove methanol and the resulting aqueous solution was made basic with saturated NaHCO3 solution (5 mL). The aqueous solution was extracted with EtOAc (3×10 mL) and the combined organic extracts were dried over anhydrous Na2SO4 and concentrated in vacuo. The product was treated with 4N HCl in dioxane and concentrated. Lyophilization with water gave the title compound (8 mg, 21%) as a yellow solid. 1H NMR (CD3OD) δ 8.31 (d, 2H, J=6.1 Hz), 7.72 (dd, 1H, J=12.7, 2.4 Hz), 7.49-7.46 (m, 2H), 7.27-7.25 (m, 1H), 7.15 (t, 1H, J=8.8 Hz), 6.97 (t, 2H, J=8.7 Hz), 6.85 (dd, 2H, J=5.1, 1.2 Hz), 3.46 (s, 2H); MS (ESI+) m/z 384.21 (M+H)+.

Workup

  1. customsealed
  2. filtrationThe reaction mixture was filtered through silica gel using 5% methanol/ethyl acetate
  3. concentrationAfter concentration
  4. customthe crude product was purified by prep HPLC
  5. concentrationThe appropriate fraction was concentrated
  6. customto remove methanol
  7. extractionThe aqueous solution was extracted with EtOAc (3×10 mL)
  8. dry with materialthe combined organic extracts were dried over anhydrous Na2SO4
  9. concentrationconcentrated in vacuo
  10. additionThe product was treated with 4N HCl in dioxane
  11. concentrationconcentrated

Sources & evidence

ORD record
ord-ac2ec174af2c4741927c3cfb49c7046d
Source dataset
uspto-grants-2011_08
Patent number
US07989477B2

Reaction notes

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