Hydrochloric Acid → 6-Chloro-7-methoxyquinoline

온도

75 °C

A solution of sulfuric acid (35 mL) in water (35 mL) was treated with 3-nitrobenzenesulfonic acid (35.1 g, 159 mmol) and glycerol (80 ml, 1.1 mol) to give a thick grey suspension. The suspension was heated to 75° C. and 4-chloro-3-methoxyaniline (25.0 g, 159 mmol) was added. The mixture was stirred at 140° C. for 1 h. Additional quantities of water (35 mL), sulfuric acid (35 mL) and glycerol (40 mL) were added and the reaction was stirred an additional 2 h at 140° C. The solution was cooled to room temperature, poured onto ice, and the pH was adjusted to 13 by addition of concentrated ammonium hydroxide. The mixture was extracted with EtOAc (3×) and the extracts were washed with brine, dried over Na2SO4 and concentrated. Following the general procedure for quinoline purification described by Leir, C. M. J. Org. Chem., 1977, 42, 911, the residue was dissolved into 2 M HCl (500 mL) and zinc chloride (43.2 g, 317 mmol) was added, resulting in immediate formation of a precipitate. The mixture was stirred for 30 min. The solids were isolated by filtration, washing with cold 2 M HCl, 2-propanol, then water. The solids were added to concentrated ammonium hydroxide (400 mL) and the mixture was stirred for 10 min. EtOAc was added and the mixture was stirred for 5 min. The mixture was extracted with EtOAc (3×) and the extracts were washed with brine, dried over Na2SO4 and concentrated to a dark brown residue consisting of a mixture of the two possible cyclization regioisomers. Silica gel chromatography (15-100% gradient of EtOAc in DCM) provided 6-chloro-7-methoxyquinoline (7.03 g) as a beige solid. MS (M+1)=194.1, 1H NMR (400 MHz, Methanol-d 4) δ 8.78 (dd, J=4.5, 1.6 Hz, 1H), 8.24 (dd, J=8.4, 1.4 Hz, 1H), 8.01 (s, 1H), 7.47 (s, 1H), 7.43 (dd, J=8.3, 4.5 Hz, 1H), 4.06 (s, 3H).

1. customto give a thick grey suspension
2. stirringthe reaction was stirred an additional 2 h at 140° C
3. temperatureThe solution was cooled to room temperature
4. additionpoured onto ice
5. extractionThe mixture was extracted with EtOAc (3×)
6. washthe extracts were washed with brine
7. dry with materialdried over Na2SO4
8. concentrationconcentrated
9. customfor quinoline purification
10. additionwas added
11. customresulting in immediate formation of a precipitate
12. stirringThe mixture was stirred for 30 min
13. customThe solids were isolated by filtration
14. washwashing with cold 2 M HCl, 2-propanol
15. additionThe solids were added to concentrated ammonium hydroxide (400 mL)
16. stirringthe mixture was stirred for 10 min
17. additionEtOAc was added
18. stirringthe mixture was stirred for 5 min
19. extractionThe mixture was extracted with EtOAc (3×)
20. washthe extracts were washed with brine
21. dry with materialdried over Na2SO4
22. concentrationconcentrated to a dark brown residue
23. additionconsisting of a mixture of the two possible cyclization regioisomers

ORD 기록

ord-d765dc8adc794a7fbebbe7cd2518ab2d

출처 데이터셋

uspto-grants-2015_05

DOI

10.6084/m9.figshare.5104873.v1

특허 번호

US09040712B2