Water → HCID 21265997, compound

Temperature

-35 °C

0.38 g of lithium aluminium hydride was added portionwise to a suspension of 2.06 g of ethyl 8-bromo-6-(2-pyridyl)-4H-imidazo[1,2-a][1,4]benzodiazepine-2-carboxylate in 250 ml of tetrahydrofuran at −40° C. while stirring vigorously. A dark green solution thereby formed and this was stirred at −7 to −10° C. for 45 min. Then, the mixture was cooled to −35° C. and treated dropwise with 2 ml of water. After stirring at room temperature for 2 h. a further 6.0 ml of water were added slowly. The reaction mixture was filtered clear over Dicalite and the filtrate was evaporated in a vacuum. The residue was partitioned between 100 ml of chloroform and 50 ml of saturated aqueous sodium hydrogen carbonate solution. The chloroform phase was separated, dried over sodium sulphate and evaporated in a vacuum. The residue (1.9 g) was dissolved in 100 ml of tert-butanol and 50 ml of pyridine, treated with 1.0 g of selenium dioxide and stirred at 65° C. for 30 min. The mixture was evaporated in a vacuum, the residue was dissolved in chloroform, with a small amount of insoluble impurity being filtered off. The solution was chromatographed over 250 g of aluminium oxide (activity 1). A small amount of impurity was eluted with dichloromethane/etanol 98:2, then 0.95 g of the desired 8-bromo-6-(2-pyridyl)-4H-imidazo[1,2-a][1,4]benzodiazepine-2-methanol was eluted with dichloromethane/ethanol 95:5, 90:10 and 80:20. After recrystallization from ethyl acetate there was obtained 0.80 g of 8-bromo-6-(2-pyridyl)-4H-imidazo[1,2-a][1,4]benzodiazepine-2-methanol of m.p. 176-178° C. which was converted into the hydrochloride (m.p. above 300° C.).

1. customA dark green solution thereby formed
2. stirringthis was stirred at −7 to −10° C. for 45 min
3. additionwere added slowly
4. filtrationThe reaction mixture was filtered clear over Dicalite
5. customthe filtrate was evaporated in a vacuum
6. customThe residue was partitioned between 100 ml of chloroform and 50 ml of saturated aqueous sodium hydrogen carbonate solution
7. customThe chloroform phase was separated
8. dry with materialdried over sodium sulphate
9. customevaporated in a vacuum
10. dissolutionThe residue (1.9 g) was dissolved in 100 ml of tert-butanol
11. addition50 ml of pyridine, treated with 1.0 g of selenium dioxide
12. stirringstirred at 65° C. for 30 min
13. customThe mixture was evaporated in a vacuum
14. dissolutionthe residue was dissolved in chloroform, with a small amount of insoluble impurity
15. filtrationbeing filtered off
16. customThe solution was chromatographed over 250 g of aluminium oxide (activity 1)
17. washA small amount of impurity was eluted with dichloromethane/etanol 98:2
18. wash0.95 g of the desired 8-bromo-6-(2-pyridyl)-4H-imidazo[1,2-a][1,4]benzodiazepine-2-methanol was eluted with dichloromethane/ethanol 95:5, 90:10 and 80:20
19. customAfter recrystallization from ethyl acetate

ORD record

ord-04737e03124841bcb6e67e8ecd59e25e

Source dataset

uspto-grants-2001_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06174881B1