Water → 2-(4-((3R,5S)-4-Acetyl-3,5-dimethylpiperazin-1-yl)phenyl)-5-methoxy-7-(2-methoxyethoxy)quinazolin-4(3H)-one

HRID 591600Notes

Reaction equation

HRID 591600 reaction equation
[CH3:1][O:2][CH2:3][CH2:4][OH:5].[H-].[Na+].[C:8]([N:11]1[CH:16]([CH3:17])[CH2:15][N:14]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[NH:33][C:32](=[O:34])[C:31]4[C:26](=[CH:27][C:28](F)=[CH:29][C:30]=4[O:35][CH3:36])[N:25]=3)=[CH:20][CH:19]=2)[CH2:13][CH:12]1[CH3:38])(=[O:10])[CH3:9].O>CS(C)=O.C(O)(=O)C>[C:8]([N:11]1[C@@H:16]([CH3:17])[CH2:15][N:14]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[NH:33][C:32](=[O:34])[C:31]4[C:26](=[CH:27][C:28]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:29][C:30]=4[O:35][CH3:36])[N:25]=3)=[CH:20][CH:19]=2)[CH2:13][C@H:12]1[CH3:38])(=[O:10])[CH3:9]

Participants

7

Reactant 4

HCID 962WaterHCID 80192-MethoxyethanolHCID 24758Sodium hydrideHCID 1363480522-[4-(4-acetyl-3,5-dimethyl-piperazin-1-yl)-phenyl]-7-fluoro-5-methoxy-3H-quinazolin-4-one

Product 1

HCID 1359390872-(4-((3R,5S)-4-Acetyl-3,5-dimethylpiperazin-1-yl)phenyl)-5-methoxy-7-(2-methoxyethoxy)quinazolin-4(3H)-one

Reagents, catalysts & solvents 2

HCID 176Acetic AcidSolventHCID 679Dimethyl SulfoxideSolvent

Procedure

To a solution of 2-methoxy-ethanol (1.00 g, 13.4 mmol) in dimethyl sulfoxide (4 mL), sodium hydride (60% suspension in mineral oil, 0.50 g, 12.5 mmol) was added in portions, and the reaction mixture was stirred at room temperature for 20 minutes. To this reaction mixture was added 2-[4-(4-acetyl-3,5-dimethyl-piperazin-1-yl)-phenyl]-7-fluoro-5-methoxy-3H-quinazolin-4-one (0.57 g, 1.34 mmol) and the reaction mixture was stirred at 85° C. for 24 hours. Water was added. The mixture was acidified to pH approximately 4-5 with acetic acid, and the precipitated solid was filtered to give crude product, which was purified by column chromatography (silica gel 230-400 mesh; eluting with 2% methanol in dichloromethane). The resulting mixture was purified by preparative HPLC to obtain the title compound as a white solid. Yield: 0.140 g (23.2%). MP 225-227° C. 1H NMR (400 MHz, CDCl3): δ 8.10 (d, J=8.8 Hz, 2H), 7.08 (d, J=8.8 Hz, 1H), 6.70 (d, J=2.4 Hz, 1H), 6.49 (d, J=2.4 Hz, 1H), 4.50 (bs, 1H), 4.23 (m, 2H), 4.14 (bs, 1H), 3.84 (s, 3H), 3.81 (m, 2H), 3.69 (m, 2H), 3.32 (s, 3H), 2.99 (bs, 2H), 2.07 (s, 3H), 1.25 (bs, 6H). MS (ES) m/z: 481.11 (M++1).

Workup

  1. stirringthe reaction mixture was stirred at 85° C. for 24 hours
  2. filtrationthe precipitated solid was filtered
  3. customto give crude product, which
  4. customwas purified by column chromatography (silica gel 230-400 mesh; eluting with 2% methanol in dichloromethane)
  5. customThe resulting mixture was purified by preparative HPLC

Sources & evidence

ORD record
ord-301c042aa9e149b18618b5dae2b21c2d
Source dataset
uspto-grants-2016_01
Patent number
US09238640B2

Reaction notes

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