Sodium hydride → HCID 46183671, compound

HRID 1467403Notes

Reaction equation

HRID 1467403 reaction equation
[F:1][C:2]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:3]=1[C:4]([NH:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([O:23][CH3:24])[CH:17]=1)=[N:5][CH:6]=[N:7]2.[H-].[Na+].F[C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][N:29]=1>CN(C=O)C.FC1C=CC(C(F)(F)F)=CN=1>[F:1][C:2]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:3]=1[C:4]([NH:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][N:29]=3)=[C:18]([O:23][CH3:24])[CH:17]=1)=[N:5][CH:6]=[N:7]2

Participants

6

Reactant 3

HCID 24758Sodium hydride2×HCID 54637542-Fluoro-5-(trifluoromethyl)pyridineHCID 59222945HCID 59222945, compound

Product 1

HCID 46183671HCID 46183671, compoundYield 98.1%

Reagents, catalysts & solvents 2

HCID 54637542-Fluoro-5-(trifluoromethyl)pyridineCatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
25 °C

Procedure

To a solution of 4-[2-(5,8-difluoroquinazolin-4-ylamino)-ethyl]-2-methoxyphenol (3.73 g, 11.25 mmol) in DMF (25 mL) in a dry 250 mL round bottom flask equipped with a dry nitrogen line and a magnetic stir bar was added sodium hydride (324 mg, 13.5 mmol). After gas evolution had subsided, 2-fluoro-5-trifluoromethyl-pyridine (2.05 g, 12.3 mmol) was added, and the reaction mixture was stirred at 25° C. After 20 h, additional sodium hydride (50 mg, 2.1 mmol) and 2-fluoro-5-trifluoromethyl-pyridine (100 mg, 0.6 mmol) were added. After 20 min, the reaction mixture was quenched by addition of sat. aq. NH4Cl (30 mL) and concentrated in vacuo. The residue was suspended in water (50 mL) and stirred vigorously to break up chunks. The solid product was collected by suction filtration and washed on the filter with water. The filter cake again was suspended in water (50 mL) and stirred vigorously to break up chunks. The solid product was collected by suction filtration and washed with water. The filter cake was dried with suction on the filter overnight to provide 5.26 g (98% yield) of (5,8-difluoroquinazolin-4-yl)-{2-[3-methoxy-4-(5-trifluoromethylpyridin-2-yloxy)-phenyl]-ethyl}-amine as an off-white powder, M.P. 119-121° C. LC-MS: 477 (M++1); 1H NMR (CDCl3): δ 8.69 (s, 1H), 8.4 (m, 1H), 7.89 (dd, 1H), 7.36 (m, 1H), 7.12 (m, 1H), 7.01 (m, 2H), 6.93 (m, 2H), 6.78 (bd, 1H), 3.97 (m, 2H), 3.75 (s, 3H), 3.06 (m, 2H).

Workup

  1. waitAfter 20 min
  2. customthe reaction mixture was quenched by addition of sat. aq. NH4Cl (30 mL)
  3. concentrationconcentrated in vacuo
  4. stirringstirred vigorously
  5. filtrationThe solid product was collected by suction filtration
  6. washwashed on the
  7. filtrationfilter with water
  8. stirringstirred vigorously
  9. filtrationThe solid product was collected by suction filtration
  10. washwashed with water
  11. customThe filter cake was dried with suction on the filter overnight

Sources & evidence

ORD record
ord-aa65f573de4f463ab8c8dec68783745c
Source dataset
uspto-grants-2015_04
Patent number
US09000162B2

Reaction notes

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