1-(4-(6-(4-Methoxybenzylamino)pyrimidin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea → 1-(4-(2-Carbamoylpyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea

HRID 1670229Notes

Reaction equation

HRID 1670229 reaction equation
COC1C=CC(C[NH:8][C:9]2N=CN=[C:11]([O:15][C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26](=[O:35])[CH2:27][C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)=[O:24])=[CH:18][C:17]=3[F:36])[CH:10]=2)=CC=1.NC1C=CC(OC2C=CN=[C:47]([C:51]([NH2:53])=[O:52])[CH:46]=2)=C(F)C=1>C(Cl)Cl.CN(C=O)C>[C:51]([C:47]1[CH:46]=[C:11]([O:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26](=[O:35])[CH2:27][C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)=[O:24])=[CH:18][C:17]=2[F:36])[CH:10]=[CH:9][N:8]=1)(=[O:52])[NH2:53]

Participants

4

Reactant 2

HCID 115698931-(4-(6-(4-Methoxybenzylamino)pyrimidin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea2×HCID 231532054-(4-Amino-2-fluorophenoxy)picolinamide

Product 1

HCID 231531111-(4-(2-Carbamoylpyridin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)ureaYield 69%

Reagents, catalysts & solvents 1

HCID 22350042dichloromethane N,N-dimethylformamideSolvent

Procedure

A solution of 2-(4-fluorophenyl)acetyl isocyanate (Compound D of Example 11, 0.29 M in toluene, 54.9 mL, 15.9 mmol, 2.1 eq) was added to 4-(4-amino-2-fluorophenoxy)picolinamide (1.86 g, 7.53 mmol, 1.0 eq) in 10/3 DCM/DMF (65 mL) at room temperature and the reaction mixture was stirred for 17 h. The reaction mixture was concentrated in vacuo and the residue redissolved in CHCl3. The organic layer was washed with saturated aqueous NaCl, the organic fraction separated, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (eluting 1/3 hexane/EtOAc, then to elute product 5% MeOH in CHCl3), and the appropriate fractions concentrated in vacuo to afford the product (2.2 g, 69%) as a solid. 1H NMR (DMSO-d6) δ 11.07 (s, 1H), 10.62 (s, 1H), 8.54 (d, 1H, J=5.60 Hz), 8.16-8.19 (m, 1H), 7.76-7.84 (m, 2H), 7.35-7.49 (m, 5H), 7.16-7.23 (m, 3H), 3.76 (s, 2H); MS (ESI+) m/z 427 (M+H)+. HRMS (ESI+) calcd.: 427.1218. found: 427.1214.

Workup

  1. concentrationThe reaction mixture was concentrated in vacuo
  2. dissolutionthe residue redissolved in CHCl3
  3. washThe organic layer was washed with saturated aqueous NaCl
  4. customthe organic fraction separated
  5. dry with materialdried (Na2SO4)
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customThe residue was purified by silica gel chromatography (
  9. washeluting 1/3 hexane/EtOAc
  10. washto elute product 5% MeOH in CHCl3), and the appropriate fractions
  11. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-1109a332d38b465cb7265bbd1a8dcb1c
Source dataset
uspto-grants-2011_08
Patent number
US07989477B2

Reaction notes

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