反应详情

温度

87 °C

A 1L flask was equipped with magnetic stirring bar, cooling bath (liquid nitrogen), stopcock connected to an ammonia cylinder and a vacuum system. The flask was charged with FeCl3 (0.1 g) and evacuated. Ammonium gas was condensed to give liquid ammonium (600 ml). Potassium (19.50 g 0.50 mole) was added in small pieces (each about 0.5 g) under an argon atmosphere. The solution initially became blue but became a grey suspension after heating at reflux for 30 min. Into the potassium amide/liquid ammonia suspension was added in small portions isoquinoline-7-carboxylic acid {ref F. T. Tyson, JACS, 1939,61,183} (17.0 g 0.10 mole). The free acid initially dissolved but the formed potassium salt soon precipitated as fine particles to give a suspension which was heated at reflux for 6 h. After careful addition of tetraethylethylene diamine (TEEDA) (86 g 0.50 mole), toluene (170 ml) and 18-crown-6 (1 g) the ammonia was allowed to evaporate slowly over 40 h to give a new suspension of the isoquinoline-7-carboxylic acid potassium salt. The reaction mixture was heated to 87° C. for 48 h. A sample was removed and analysed by nmr which indicated that there was still some unreacted starting material present. Ammonia was bubbled through the reaction mixture for 2 h and nmr analysis then revealed that no starting material remained. The reaction was then cooled to −16° C., ice (200 g) was added to destroy excess potassium amide and all solvents evaporated at 76° C. and 7 mmHg and then at 65° C. and 0.7 mmHg to give a powder which was dissolved in water (1.2L) and filtered through Celite to give a clear solution. This was acidified to pH 7 by addition of acetic acid (34 g) and allowed to stand overnight. The precipitate was collected by filtration, washed with water (50 ml×2) and dried by azeotroping with ethanol (50 ml×2) at 50° C. and 7 mmHg then at 50° C. and 0.7 mmHg to give the crude product (17.6 g 94%) as an off-white powder. The crude product (17.6 g) was dissolved in water (4L), and concentrated HCl was added to give a pH of 1.30. The solution was stirred for 1 h, and filtered through Celite to give a clear solution to which was added concentration ammonia solution to give a pH of 5.07. After stirring for 2 h and standing overnight the precipitate was filtered, washed with water (50 ml×2) and dried by azeotroping with ethanol (50 ml×2) at 50° C. and 7 mmHg, and then at 50° C. and 0.7 mmHg to give title compound (15.5 g 88%) as a pale brown solid.

1. temperatureafter heating
2. temperatureat reflux for 30 min
3. dissolutionThe free acid initially dissolved
4. customthe formed potassium salt soon precipitated as fine particles
5. customto give a suspension which
6. temperaturewas heated
7. temperatureat reflux for 6 h
8. customto evaporate slowly over 40 h
9. customto give
10. customA sample was removed
11. customAmmonia was bubbled through the reaction mixture for 2 h
12. temperatureThe reaction was then cooled to −16° C.
13. additionice (200 g) was added
14. customto destroy excess potassium amide
15. customall solvents evaporated at 76° C.
16. custom7 mmHg and then at 65° C. and 0.7 mmHg to give a powder which
17. filtrationfiltered through Celite
18. customto give a clear solution
19. filtrationThe precipitate was collected by filtration
20. washwashed with water (50 ml×2)
21. customdried
22. customby azeotroping with ethanol (50 ml×2) at 50° C.
23. custom7 mmHg then at 50° C. and 0.7 mmHg to give the crude product (17.6 g 94%) as an off-white powder
24. customto give a pH of 1.30
25. filtrationfiltered through Celite
26. customto give a clear solution to which
27. additionwas added
28. concentrationconcentration ammonia solution
29. customto give a pH of 5.07
30. stirringAfter stirring for 2 h
31. waitstanding overnight
32. filtrationthe precipitate was filtered
33. washwashed with water (50 ml×2)
34. customdried
35. customby azeotroping with ethanol (50 ml×2) at 50° C.