反应详情

温度

80 °C

Treat methyl 1-(5-methyl-2-nitrobenzyl)-4-(methylsulfanyl)-1H-pyrrole-2-carboxylate (3.49 mmoles; 1.12 g) with acetic acid (15 mL) then treat with iron, powder (10.5 mmoles; 585 mg) then slowly heat in an oil bath at 80° C. After a few hours increase the oil bath temperature to 90° C. Then leave the reaction at 60° C. for 2 days. Then concentrate to dryness to remove acetic acid then treat with EtOAc and wash through a pad of silica with more EtOAc until the orange colour stops coming off. Concentrate the red eluant to dryness then treat with methanol then re-concentrate and dissolve in DCM (20 mL) and treat with phosphoryl chloride (1.0 mL). Heat the reaction in an oil bath at 50° C. overnight. Then cool the reaction to RT and treat with ice then wash with water twice and then NaHCO3 (aq). Dry the organic layer over MgSO4, filter and concentrate to a tar. Meanwhile dissolve methyl 2,2-dimethyl-3-(piperazin-1-yl)-propanoate dihydrochloride (1.60 g, 5.86 mmoles) in water then load on to a SCX-2 cartridge (2×10 g) and wash with methanol and then elute with ammonia in methanol. Concentrate the basic solution to dryness to an oil. Then dissolve this oil in acetonitrile (50 mL) and add to a mixture of the tar and potassium carbonate (1.0 g) then heat to reflux. After 2 hours, microwave the reaction to 140° C. for 2 hours. Then filter the reaction and extract with acetonitrile and acetone. Combine and concentrate the mother liquors to dryness onto silica then purify by flash chromatography silica (40 g) (10-50% EtOAc in hexane). Take the fractions which contain clean product, combine and concentrate to yield methyl 2,2-dimethyl-3-[4-(7-methyl-2-(methylsulfanyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepin-11-yl)piperazin-1-yl]-propanoate (418 mg; 27% yield). MS (m/z): 441.18 (M+1).

1. temperatureAfter a few hours increase the oil bath temperature to 90° C
2. customThen leave
3. customthe reaction at 60° C. for 2 days
4. concentrationThen concentrate to dryness
5. customto remove acetic acid
6. additionthen treat with EtOAc
7. washwash through a pad of silica with more EtOAc until the orange colour
8. concentrationConcentrate the red eluant to dryness
9. additionthen treat with methanol
10. concentrationthen re-concentrate
11. dissolutiondissolve in DCM (20 mL)
12. additiontreat with phosphoryl chloride (1.0 mL)
13. temperatureHeat
14. customthe reaction in an oil bath at 50° C. overnight
15. temperatureThen cool
16. customthe reaction to RT
17. additiontreat with ice
18. washthen wash with water twice
19. dry with materialDry the organic layer over MgSO4
20. filtrationfilter
21. concentrationconcentrate to a tar
22. washwash with methanol
23. washelute with ammonia in methanol
24. concentrationConcentrate the basic solution to dryness to an oil
25. dissolutionThen dissolve this oil in acetonitrile (50 mL)
26. additionadd to a mixture of the tar and potassium carbonate (1.0 g)
27. temperaturethen heat to reflux
28. customthe reaction to 140° C. for 2 hours
29. filtrationThen filter
30. customthe reaction
31. extractionextract with acetonitrile and acetone
32. concentrationCombine and concentrate the mother liquors to dryness onto silica
33. customthen purify by flash chromatography silica (40 g) (10-50% EtOAc in hexane)
34. concentrationconcentrate