p-Toluenesulfonic acid monohydrate → 2-(6-fluoropyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one

HRID 922359Notes

Reaction equation

HRID 922359 reaction equation
[NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[F:15][C:16]1[N:21]=[C:20]([CH:22]=O)[CH:19]=[CH:18][CH:17]=1.OS([O-])=O.[Na+].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[F:15][C:16]1[N:21]=[C:20]([C:22]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][C:9]([O:11][CH3:12])=[CH:8][C:7]=3[O:13][CH3:14])[N:1]=2)[CH:19]=[CH:18][CH:17]=1

Participants

6

Reactant 4

HCID 521998p-Toluenesulfonic acid monohydrateHCID 106067416-Fluoropyridine-2-carboxaldehydeHCID 203490162-Amino-4,6-dimethoxybenzamideHCID 23665763Sodium Bisulfite

Product 1

HCID 1364081482-(6-fluoropyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-oneYield 49%

Reagents, catalysts & solvents 1

HCID 31374DimethylacetamideSolvent

Conditions

Temperature
120 °C

Procedure

To a solution of 2-amino-4,6-dimethoxybenzamide (0.737 g, 3.76 mmol) and 6-fluoropicolinaldehyde (0.470 g, 3.76 mmol) in N,N-dimethylacetamide (20 mL), NaHSO3 (58.5% SO2 content, 1.0 g, 5.63 mmol) and p-toluenesulfonic acid monohydrate (0.143 g, 0.75 mmol) were added. The reaction was heated at 120° C. for 20 h. After that time the reaction was cooled to rt, concentrated under reduced pressure, diluted with water (50 mL) and saturated NaHCO3 solution was added to adjust the pH to 8. The precipitated solids were collected by filtration, washed with water and dried. The product was purified by flash column chromatography (silica gel, 99:1 dichloromethane/methanol to 97:3 dichloromethane/methanol) to give 2-(6-fluoropyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.550 g, 49%) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ 11.34 (s, 1H), 8.28-8.33 (m, 1H), 8.19-8.27 (m, 1H), 7.47 (dd, J=8.01, 1.76 Hz, 1H), 6.82 (d, J=2.34 Hz, 1H), 6.62 (d, J=2.34 Hz, 1H), 3.91 (s, 3H), 3.86 (s, 3H); 19F NMR (376 MHz, DMSO-d6) δ −68.08 (d, J=8.03 Hz); ESI MS m/z 302 [M+H]+.

Workup

  1. temperatureAfter that time the reaction was cooled to rt
  2. concentrationconcentrated under reduced pressure
  3. additiondiluted with water (50 mL) and saturated NaHCO3 solution
  4. additionwas added
  5. filtrationThe precipitated solids were collected by filtration
  6. washwashed with water
  7. customdried
  8. customThe product was purified by flash column chromatography (silica gel, 99:1 dichloromethane/methanol to 97:3 dichloromethane/methanol)

Sources & evidence

ORD record
ord-9dbf94ea01ef4f5dbdb55341c899ff4d
Source dataset
uspto-grants-2016_03
Patent number
US09278940B2

Reaction notes

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