Diisopropylethylamine → 1-(4-(2-Carbamoylpyridin-4-yloxy)-2,5-difluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea

HRID 2237290Notes

Reaction equation

HRID 2237290 reaction equation
[NH2:1][C:2]1[C:17]([F:18])=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([C:13]([NH2:15])=[O:14])[CH:8]=2)=[C:4]([F:19])[CH:3]=1.C(N(C(C)C)CC)(C)C.COC1C=CC(CNC2N=CN=C(OC3C=CC(N[C:51]([NH:53][C:54](=[O:63])[CH2:55][C:56]4[CH:61]=[CH:60][C:59]([F:62])=[CH:58][CH:57]=4)=[O:52])=CC=3F)C=2)=CC=1.FC1C=CC(CC(N=C=O)=O)=CC=1>C1COCC1>[C:13]([C:9]1[CH:8]=[C:7]([O:6][C:5]2[C:4]([F:19])=[CH:3][C:2]([NH:1][C:51]([NH:53][C:54](=[O:63])[CH2:55][C:56]3[CH:61]=[CH:60][C:59]([F:62])=[CH:58][CH:57]=3)=[O:52])=[C:17]([F:18])[CH:16]=2)[CH:12]=[CH:11][N:10]=1)(=[O:14])[NH2:15]

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 115698931-(4-(6-(4-Methoxybenzylamino)pyrimidin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea2×HCID 231530882-(4-Fluorophenyl)acetyl isocyanate2×HCID 247886284-(4-Amino-2,5-difluorophenoxy)pyridine-2-carboxamide

Product 1

HCID 598528981-(4-(2-Carbamoylpyridin-4-yloxy)-2,5-difluorophenyl)-3-(2-(4-fluorophenyl)acetyl)ureaYield 91%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a homogeneous mixture of 4-(4-amino-2,5-difluorophenoxy)picolinamide (0.15 g, 0.57 mmol) in THF (5 mL) was added diisopropylethylamine (0.10 mL, 0.57 mmol). The mixture was stirred for two minutes at ambient temperature before 2-(4-fluorophenyl)acetyl isocyanate (Compound D of Example 11, 0.36 M in toluene, 2.0 mL, 0.72 mmol) was added. After 3.5 hours, 2-(4-fluorophenyl)acetyl isocyanate (0.36 M in toluene, 2.0 mL, 0.72 mmol) was added to the reaction mixture. After an additional two hours, 2-(4-fluorophenyl)acetyl isocyanate (0.36 M in toluene, 2.0 mL, 0.72 mmol) was added to the reaction mixture. The mixture was then stirred for 16 hours before being concentrated in vacuo. The residue was treated with Et2O and sonication and the resultant white solid was removed by filtration. The solid was treated with Et2O and sonication two more times before vacuum filtration afforded a white solid (0.23 g, 91%). 1H NMR (DMSO-d6) δ 11.29 (s, 1H), 10.92 (s, 1H), 8.56 (d, 1H, J=5.6 Hz), 8.21-8.26 (m, 1H), 8.16 (br s, 1H), 7.76 (br s, 1H), 7.66-7.71 (m, 1H), 7.12-7.44 (m, 6H), 3.77 (s, 2H); MS(ESI+) m/z 445 (M+H)+.

Workup

  1. additionwas added
  2. waitAfter an additional two hours
  3. concentrationbefore being concentrated in vacuo
  4. additionThe residue was treated with Et2O and sonication
  5. customthe resultant white solid was removed by filtration
  6. additionThe solid was treated with Et2O and sonication two more times before vacuum filtration

Sources & evidence

ORD record
ord-2282bce7a8dd44d0bece8dfc5433c9af
Source dataset
uspto-grants-2010_05
Patent number
US07714138B2

Reaction notes

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