Acetic Acid → 6-Methoxy-3-nitroquinoline

Temperature

4 °C

p-Anisidine hydrochloride (35.0 g, 219.4 mmol) was weighed into a dry 300 mL three-necked round-bottomed flask, equipped with a magnetic stirring bar, a pressure-equalizing addition funnel, a solid addition funnel and a thermometer. Glacial acetic acid (150 mL) was added to the solid, with vigorous stirring to maintain a homogeneous suspension. To this suspension was added sodium nitromalonaldehyde monohydrate (12.0 g, 76.4 mmol) and the mixture stirred for 1.0 h at 25° C. A short-path distillation head was placed on the flask and approximately 120 mL of acetic acid/water removed under reduced pressure at 40° C. To the residue (imine 13) was added glacial acetic acid (40 mL) and sulfolane (75 mL). The resulting solution was flushed with argon to :remove air and the flask immersed in an oil bath preheated to 195° C. The mixture was vigorously stirred while acetic acid was removed by distillation. When the temperature reached 184°-185° C. the mixture was stirred for a further 15 min at 185° C. and then poured (while still at ca. 180° C.) onto crushed ice (750 g). The resulting solution was allowed to stand in a refrigerator (overnight) until precipitation was complete. The dark brown solid precipitate was filtered and transferred to a round-bottomed flask (500 mL) containing 2M hydrochloric acid (250 mL). The mixture was heated at reflux for 50-60 min and the boiling; solution filtered through a preheated Buchner funnel to remove an insoluble brown gum. The hot filtrate was cooled to ca. 4° C. and extracted with chloroform (4×50 mL). The combined extracts were dried (MgSO4) and the chloroform removed on a rotatory evaporator to give the crude 3-nitro-6-methoxyquinoline 14 (9.3 g, brown solid).

1. customequipped with a magnetic stirring bar, a pressure-equalizing addition funnel, a solid addition funnel
2. temperatureto maintain a homogeneous suspension
3. stirringthe mixture stirred for 1.0 h at 25° C
4. customremoved under reduced pressure at 40° C
5. additionTo the residue (imine 13) was added glacial acetic acid (40 mL) and sulfolane (75 mL)
6. customThe resulting solution was flushed with argon to :
7. customremove air
8. customthe flask immersed in an oil bath
9. custompreheated to 195° C
10. stirringThe mixture was vigorously stirred while acetic acid
11. customwas removed by distillation
12. customreached 184°-185° C.
13. stirringwas stirred for a further 15 min at 185° C.
14. additionpoured (while still at ca. 180° C.)
15. customonto crushed ice (750 g)
16. customto stand in a refrigerator (overnight) until precipitation
17. filtrationThe dark brown solid precipitate was filtered
18. customtransferred to a round-bottomed flask
19. addition(500 mL) containing 2M hydrochloric acid (250 mL)
20. temperatureThe mixture was heated
21. temperatureat reflux for 50-60 min
22. filtrationsolution filtered through a preheated Buchner funnel
23. customto remove an insoluble brown gum
24. extractionextracted with chloroform (4×50 mL)
25. dry with materialThe combined extracts were dried (MgSO4)
26. customthe chloroform removed on a rotatory evaporator

ORD record

ord-e4ebe02743a54a9e8971a25f86474748

Source dataset

uspto-grants-1995_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US05442065