N,N-Dimethylaniline → 4-Chloro-2-(2-fluoro-6-methoxyphenyl)-7-methylquinazoline

HRID 2406157Notes

Reaction equation

HRID 2406157 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[C:10]1[NH:19][C:18](=O)[C:17]2[C:12](=[CH:13][C:14]([CH3:21])=[CH:15][CH:16]=2)[N:11]=1.CN(C)C1C=CC=CC=1.O=P(Cl)(Cl)[Cl:33].C([O-])(O)=O.[Na+]>C1C=CC=CC=1.C(Cl)Cl>[Cl:33][C:18]1[C:17]2[C:12](=[CH:13][C:14]([CH3:21])=[CH:15][CH:16]=2)[N:11]=[C:10]([C:3]2[C:4]([O:8][CH3:9])=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[N:19]=1

Participants

7

Reactant 4

HCID 949N,N-DimethylanilineHCID 24813Phosphorus oxychlorideHCID 516892Sodium BicarbonateHCID 1361215392-(2-fluoro-6-methoxyphenyl)-7-methylquinazolin-4(3H)-one

Product 1

HCID 586839024-Chloro-2-(2-fluoro-6-methoxyphenyl)-7-methylquinazolineYield 88.4%

Reagents, catalysts & solvents 2

HCID 241BenzeneSolventHCID 6344DichloromethaneSolvent

Procedure

Under an N2 atmosphere, 2-(2-fluoro-6-methoxyphenyl)-7-methylquinazolin-4(3H)-one (20 g, 70.35 mmol) was suspended in benzene (300 mL), followed by the addition of N,N-dimethylaniline (26.8 mL, 211.05 mmol), then POCl3 (13.11 mL, 140.7 mmol). The reaction was heated at reflux, and completion of product formation was observed after 1.5 h. After cooling to room temperature, the mixture was slowly poured over 1 liter of ice. The solution was then diluted with CH2Cl2, and the pH was adjusted to 7 using a saturated aqueous NaHCO3 solution. The layers were partitioned, separated and extracted with CH2Cl2. All organic layers were combined, dried over Na2SO4, filtered, and concentrated to a dark oil. The crude material was purified by silica gel chromatography using 75% CH2Cl2/25% hexanes to obtain 4-chloro-2-(2-fluoro-6-methoxyphenyl)-7-methylquinazoline as a yellow solid (18.82 g, 88%). LC/MS: m/z 302.9 (M+H)+ at 3.28 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). 1H NMR (400 MHz, CDCl3) δ 8.22 (d, J=8.5 Hz, 1H), 7.95 (s, 1H), 7.60 (dd, J=8.6, 1.5 Hz, 1H), 7.42-7.40 (m, 1H), 6.86-6.84 (m, 2H), 3.81 (s, 3H), 2.64 (s, 3H) ppm.

Workup

  1. temperatureThe reaction was heated
  2. temperatureat reflux
  3. customThe layers were partitioned
  4. customseparated
  5. extractionextracted with CH2Cl2
  6. dry with materialdried over Na2SO4
  7. filtrationfiltered
  8. concentrationconcentrated to a dark oil
  9. customThe crude material was purified by silica gel chromatography

Sources & evidence

ORD record
ord-8f803d071bbf482a9801d0f9dcc935ba
Source dataset
uspto-grants-2014_08
Patent number
US08809353B2

Reaction notes

Loading…