Water → 2-(2,6-Dimethylpyridin-4-yl)-7-(2-methoxyethoxy)-5-(2-(pyrrolidin-1-yl)ethoxy)quinazolin-4(3H)-one

HRID 591845Notes

Reaction equation

HRID 591845 reaction equation
[CH3:1][O:2][CH2:3][CH2:4][OH:5].[H-].[Na+].[CH3:8][C:9]1[CH:14]=[C:13]([C:15]2[NH:24][C:23](=[O:25])[C:22]3[C:17](=[CH:18][C:19](F)=[CH:20][C:21]=3[O:26][CH2:27][CH2:28][N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)[N:16]=2)[CH:12]=[C:11]([CH3:35])[N:10]=1.O>CN(C=O)C.C(O)(=O)C>[CH3:8][C:9]1[CH:14]=[C:13]([C:15]2[NH:24][C:23](=[O:25])[C:22]3[C:17](=[CH:18][C:19]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:20][C:21]=3[O:26][CH2:27][CH2:28][N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)[N:16]=2)[CH:12]=[C:11]([CH3:35])[N:10]=1

Participants

7

Reactant 4

HCID 962WaterHCID 80192-MethoxyethanolHCID 24758Sodium hydrideHCID 1363480592-(2,6-dimethyl-pyridin-4-yl)-7-fluoro-5-(2-pyrrolidin-1-yl-ethoxy)-3H-quinazolin-4-one

Product 1

HCID 1363480182-(2,6-Dimethylpyridin-4-yl)-7-(2-methoxyethoxy)-5-(2-(pyrrolidin-1-yl)ethoxy)quinazolin-4(3H)-one

Reagents, catalysts & solvents 2

HCID 176Acetic AcidSolventHCID 6228DimethylformamideSolvent

Procedure

To a solution of 2-methoxy-ethanol (1.35 g, 17.8 mmol) in DMF (10 mL) was added sodium hydride (60% suspension in mineral oil, 0.36 g, 8.89 mmol) in small portions and the reaction mixture was stirred at room temperature for 30 minutes. To this mixture was added 2-(2,6-dimethyl-pyridin-4-yl)-7-fluoro-5-(2-pyrrolidin-1-yl-ethoxy)-3H-quinazolin-4-one (0.34 g, 0.89 mmol) and the reaction mixture was stirred at 70-80° C. for 16 h, then cooled to room temperature. Water (10 mL) was added, and the mixture was neutralized to pH approximately 6 with acetic acid. Solvent was evaporated; the residue was purified by the Simpliflash system (2-5% 7.0M ammonia in methanol and CH2Cl2 as eluent). The compound was further purified by preparative HPLC to give the title compound as a yellow solid. Yield: 72 mg (18%). MP 60.4-62.3° C. 1H NMR (400 MHz, CDCl3): δ 10.23 (br s, 1H), 8.50 (br s, 1H), 7.60 (s, 2H), 6.76 (br s, 1H), 6.43 (br s, 1H), 4.35 (m., 2H), 4.21 (m, 2H), 3.79 (s, 3H), 3.47-3.38 (m, 6H), 2.64 (s, 6H), 1.99 (m, 4H). MS (ES) m/z: 437.09 (M−1) (100%).

Workup

  1. stirringthe reaction mixture was stirred at 70-80° C. for 16 h
  2. temperaturecooled to room temperature
  3. customSolvent was evaporated
  4. customthe residue was purified by the Simpliflash system (2-5% 7.0M ammonia in methanol and CH2Cl2 as eluent)
  5. customThe compound was further purified by preparative HPLC

Sources & evidence

ORD record
ord-a3006b481081488ea8d04fc970ca46ff
Source dataset
uspto-grants-2016_01
Patent number
US09238640B2

Reaction notes

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