Phosphorus oxychloride → 2-Chloro-8-iodo-3-methyl-quinazolin-4-one

温度

105 °C

At RT, to the off-white solid of 2-hydroxy-8-iodo-3-methylquinazolin-4(3H)-one (700c; 12.79 g, 42.3 mmol) was added POCl3 (46.5 mL, 508 mmol). The resulting white suspension was treated with DIPEA (14.73 mL, 85 mmol) dropwise. The heterogeneous mixture was heated in an oil bath at 105° C. for 26 h. LCMS indicated the reaction was about 60% conversion. It was cooled to RT, and treated with additional POCl3 (12 mL) and DIPEA (14.73 mL, 85 mmol). The resulting dark homogeneous solution was heated at 110° C. in an oil bath for 24 h. LCMS indicated the reaction was about >95% conversion. It was concentrated under reduced pressure. The brown sticky solution was treated with 50 mL of toluene and concentrated under reduced pressure again. The brown residue was cooled with an ice bath, ice was added to the flask, followed by 5 N NaOH solution till pH >9. It was extracted with 3×250 mL of EtOAc. The combined organic solution was washed with 2×25 mL of brine, dried over Na2SO4, filtered and concentrated. The brown residue was purified via silica gel chromatography (25-50% EtOAc in hexanes) to afford 2-chloro-8-iodo-3-methylquinazolin-4(3H)-one (700; 10.51 g, 32.8 mmol, 77% yield) as an off-white crystalline solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.21-8.32 (m, 2H), 7.22 (t, J=7.82 Hz, 1H), 3.77 (s, 3H). m/z (ES, +ve) 328.8 (M+H)+.

1. temperatureIt was cooled to RT
2. temperatureThe resulting dark homogeneous solution was heated at 110° C. in an oil bath for 24 h
3. concentrationIt was concentrated under reduced pressure
4. additionThe brown sticky solution was treated with 50 mL of toluene
5. concentrationconcentrated under reduced pressure again
6. temperatureThe brown residue was cooled with an ice bath
7. additionice was added to the flask
8. extractionIt was extracted with 3×250 mL of EtOAc
9. washThe combined organic solution was washed with 2×25 mL of brine
10. dry with materialdried over Na2SO4
11. filtrationfiltered
12. concentrationconcentrated
13. customThe brown residue was purified via silica gel chromatography (25-50% EtOAc in hexanes)

ORDレコード

ord-be46f5f0c5104f449b42d4a74802cfd8

出典データセット

uspto-grants-2016_07

DOI

10.6084/m9.figshare.5104873.v1

特許番号

US09394297B2