반응 #69783

반응 방정식

1,1-dimethyl-2-propyn-1-ol

2-amino-5-bromo-3-iodopyridine

triethylamine

→

5-bromo-7-azaindole

수율 62.3%

용매

dichloromethane

toluene

water

dichloromethane

dichloromethane

반응 조건

후처리

1. 1
   세척washed with water (2×25 mL)
2. 2
   workup.ADDITIONThe organic phase was then treated with 1 M HCl (40 mL)
3. 3
   기타The layers were separated
4. 4
   추출the organic layer was extracted with 1 M HCl (15 mL)
5. 5
   workup.ADDITIONThe combined product containing aqueous layers
6. 6
   세척were washed with dichloromethane (2×8 mL)
7. 7
   workup.ADDITIONThe pH of the aqueous layer was adjusted to pH 7-9 by the drop wise addition of sodium hydroxide solution (28% in water)
8. 8
   workup.STIRRINGThe resulting suspension was stirred at 20° C. over night
9. 9
   여과the crystals were then filtered off
10. 10
    세척washed with water (2×5 mL)
11. 11
    workup.DISSOLUTIONThe wet crystals were dissolved in N-methylpyrrolidone (50 mL)
12. 12
    workup.ADDITIONtreated within 2 hours at 60° C.
13. 13
    온도The resulting mixture was heated to 75° C.
14. 14
    workup.STIRRINGstirred at this temperature and under reduced pressure (50-100 mbar) for 15-20 hours
15. 15
    workup.ADDITIONToluene (20 mL) and water (20 mL) were then added
16. 16
    기타the layers were separated
17. 17
    추출The aqueous layer was extracted with toluene (3×25 mL)
18. 18
    세척The combined organic layers were washed with water (3×10 mL)
19. 19
    농축concentrated to dryness
20. 20
    workup.DISSOLUTIONThe residue was dissolved in N-methylpyrrolidone (50 mL)
21. 21
    workup.STIRRINGAfter stirring for 3 hours at 60° C.
22. 22
    온도the mixture was cooled to ambient temperature
23. 23
    기타The aqueous layer was separated
24. 24
    추출back extracted with toluene (3×50 mL)
25. 25
    세척The combined toluene layers were washed with water (3×10 mL)
26. 26
    농축concentrated to dryness
27. 27
    workup.DISSOLUTIONThe residue was dissolved in a hot mixture of toluene and n-heptane (20 mL)
28. 28
    온도The clear solution was cooled to −5° C. within 4 to 6 hours whereupon crystals
29. 29
    기타precipitated
30. 30
    workup.STIRRINGThe suspension was stirred at −5° C. for 2-4 hours
31. 31
    여과The crystals were filtered off
32. 32
    세척washed with heptane
33. 33
    기타dried at 45° C./<30 mbars over night

실험 절차

A suspension of 2-amino-5-bromo-3-iodopyridine (5.0 g, 16.7 mmol), bis-(triphenyl-phosphine)-palladium(II)-dichloride (43 mg, 0.061 mmol), copper(I)iodide (29.4 mg, 0.15 mmol) and triethylamine (2.21 g, 21.8 mmol) in dichloromethane (20 mL) was treated at 23 to 30° C. within 1 to 2 hours with a solution of 1,1-dimethyl-2-propyn-1-ol (1.85 g, 21.7 mmol) in dichloromethane (10 mL) and the resulting mixture was stirred at 25° C. for 4 hours. The mixture was diluted with dichloromethane (10 mL) and washed with water (2×25 mL). The organic phase was then treated with 1 M HCl (40 mL). The layers were separated and the organic layer was extracted with 1 M HCl (15 mL). The combined product containing aqueous layers were washed with dichloromethane (2×8 mL). The pH of the aqueous layer was adjusted to pH 7-9 by the drop wise addition of sodium hydroxide solution (28% in water). The resulting suspension was stirred at 20° C. over night and the crystals were then filtered off and washed with water (2×5 mL). The wet crystals were dissolved in N-methylpyrrolidone (50 mL) and treated within 2 hours at 60° C. and 50-100 mbar with an aqueous solution of lithium hydroxide (2.4 M, 32 mL). The resulting mixture was heated to 75° C. and stirred at this temperature and under reduced pressure (50-100 mbar) for 15-20 hours. Toluene (20 mL) and water (20 mL) were then added and the layers were separated. The aqueous layer was extracted with toluene (3×25 mL). The combined organic layers were washed with water (3×10 mL) and then concentrated to dryness. The residue was dissolved in N-methylpyrrolidone (50 mL) and treated at 60° C. with potassium tert.-butylate (3.52 g, 30.7 mmol). After stirring for 3 hours at 60° C., the mixture was cooled to ambient temperature and diluted with toluene (40 mL) and water (40 mL). The aqueous layer was separated and back extracted with toluene (3×50 mL). The combined toluene layers were washed with water (3×10 mL) and then concentrated to dryness. The residue was dissolved in a hot mixture of toluene and n-heptane (20 mL). The clear solution was cooled to −5° C. within 4 to 6 hours whereupon crystals precipitated. The suspension was stirred at −5° C. for 2-4 hours. The crystals were filtered off, washed with heptane and dried at 45° C./<30 mbars over night to afford 5-bromo-7-azaindole (2.05 g, 62% yield) as slightly yellow crystals with a purity of 99.6% (HPLC, area%).

출처