Dichloromethane → 4-Chloro-6-(trifluoromethoxy)quinazoline

Preparation D4, Step 5: A suspension of 6-(trifluoromethoxy)quinazolin-4-ol (515 mg, 2.23 mmol) in phosphorous oxychloride (1.9 mL) was treated with triethylamine (3 mL, 21.1 mmol), and the mixture was heated at reflux for 2 h. The resulting solution was cooled to room temperature, and stripped 3× from methylene chloride to remove residual phosphorous oxychloride. The residue was dissolved in 100 mL methylene chloride, 100 mL saturated sodium bicarbonate was carefully added, causing vigorous gas evolution, and the mixture was stirred for 10 min, until gas evolution had ceased. The layers were separated, and the organic phase was washed with saturated sodium bicarbonate (2×30 mL), followed by brine, dried over sodium sulfate, and concentrated in-vacuo. The residue was purified over silica gel, eluting with 40% EtOAc/heptane, to yield 377 mg of 4-chloro-6-(trifluoromethoxy)quinazoline as a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 9.10 (s, 1H), 8.16 (d, J=9.23 Hz, 1H), 8.10 (s, 1H), 7.83 (dd, J=9.23, 2.20 Hz, 1H). MS (ES+)=249 (M+H)+.

1. temperaturethe mixture was heated
2. temperatureat reflux for 2 h
3. customto remove residual phosphorous oxychloride
4. dissolutionThe residue was dissolved in 100 mL methylene chloride
5. addition100 mL saturated sodium bicarbonate was carefully added
6. customThe layers were separated
7. washthe organic phase was washed with saturated sodium bicarbonate (2×30 mL)
8. dry with materialdried over sodium sulfate
9. concentrationconcentrated in-vacuo
10. customThe residue was purified over silica gel
11. washeluting with 40% EtOAc/heptane

ORD record

ord-e68c0a1bb2c64c628ae2ecfc754754ca

Source dataset

uspto-grants-2007_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07163937B2