Triethylamine → N-(1-(4-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)piperidin-4-yl)methanesulfonamide

HRID 591612Notes

Reaction equation

HRID 591612 reaction equation
[NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[NH:23][C:22](=[O:24])[C:21]4[C:16](=[CH:17][C:18]([O:27][CH3:28])=[CH:19][C:20]=4[O:25][CH3:26])[N:15]=3)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH3:29][S:30](Cl)(=[O:32])=[O:31].CCN(CC)CC>C(Cl)Cl>[CH3:26][O:25][C:20]1[CH:19]=[C:18]([O:27][CH3:28])[CH:17]=[C:16]2[C:21]=1[C:22](=[O:24])[NH:23][C:14]([C:11]1[CH:12]=[CH:13][C:8]([N:5]3[CH2:4][CH2:3][CH:2]([NH:1][S:30]([CH3:29])(=[O:32])=[O:31])[CH2:7][CH2:6]3)=[CH:9][CH:10]=1)=[N:15]2

Participants

5

Reactant 3

HCID 8471TriethylamineHCID 31297Methanesulfonyl chlorideHCID 1363480492-(4-(4-aminopiperidin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one

Product 1

HCID 135939091N-(1-(4-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)piperidin-4-yl)methanesulfonamideYield 58.4%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

A mixture of 2-(4-(4-aminopiperidin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.105 g, 0.28 mmol), methanesulfonylchloride (0.035 g, 0.30 mmol), and Et3N (0.057 g. 0.56 mmol) in CH2Cl2 (10 mL) was stirred at room temperature under nitrogen for 2 hours. The mixture was concentrated, redissolved in THF (5 mL), 2 M NaOH (5 mL) added and stirred for 20 minutes. The pH was adjusted to 8 with 1 M HCl and the mixture extracted with CH2Cl2 (3×150 mL). The organic phase was dried over anhydrous MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography, eluting with 1:1 CH2Cl2/(92:7:1 CHCl3/MeOH/concentrated NH4OH) to 100% 92:7:1 CHCl3/MeOH/concentrated NH4OH. Further purification by reverse-phase HPLC. eluting with 10% to 90% CH3CN in H2O with 0.1% TFA. afforded the title compound as a yellow solid (0.075 g, 58%). 1H NMR (300 MHz, DMSO-d6): δ11.75 (s, 1H), 8.08 (d, J=9.0 Hz, 2H), 7.13 (d, J=7.3 Hz, 1H), 7.00 (d, J=9.0 Hz, 2H), 6.66 (d, J=2.3 Hz, 1H), 6.46 (d, J=2.3 Hz, 1H), 3.81-3.94 (m, 8H), 3.34-3.47 (m, 1H), 2.90 (m, 6H), 1.87-1.95 (m, 2H), 1.42-1.54 (m, 2H); ESI MS m/z 459 [M+H]+.

Workup

  1. concentrationThe mixture was concentrated
  2. dissolutionredissolved in THF (5 mL)
  3. addition2 M NaOH (5 mL) added
  4. stirringstirred for 20 minutes
  5. extractionthe mixture extracted with CH2Cl2 (3×150 mL)
  6. dry with materialThe organic phase was dried over anhydrous MgSO4
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customThe residue was purified by silica gel chromatography
  10. washeluting with 1:1 CH2Cl2/(92:7:1 CHCl3/MeOH/concentrated NH4OH) to 100% 92:7:1 CHCl3/MeOH/concentrated NH4OH
  11. customFurther purification by reverse-phase HPLC
  12. washeluting with 10% to 90% CH3CN in H2O with 0.1% TFA

Sources & evidence

ORD record
ord-bfa341e88d3e4d249a3f377756c432a4
Source dataset
uspto-grants-2016_01
Patent number
US09238640B2

Reaction notes

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