تفاعل #461435

معادلة التفاعل

bromine

N-bromosuccinimide

1,3-dibromo-5,5-dimethylhydantoin

carbon tetrachloride

nitric acid

4-Acetylamino-2-methylbenzoic acid

→

benzoyl peroxide

1,1,1-trichloroethane

المذيبات

acetonitrile

chloroform

ظروف التفاعل

المعالجة

1. 1
   workup.ADDITIONThe reaction mix
2. 2
   workup.ADDITIONwas poured
3. 3
   أخرىinto crushed ice
4. 4
   ترشيحthe solid product collected by filtration
5. 5
   أخرىpurified by recrystallization from DMF/water or by silica chromatography
6. 6
   أخرىThe acetamide is removed by alkaline hydrolysis with 1-10% NaOH solution in 90% ethanol
7. 7
   workup.ADDITIONThe reaction mixture was added to excess dilute HCl
8. 8
   أخرىthe solvent evaporated
9. 9
   workup.WAITmethanolic HCl at room temperature for several days
10. 10
    أخرىAfter removal of solvent the product
11. 11
    أخرىis partitioned between ethyl acetate
12. 12
    غسيلAfter washing with water the organic phase
13. 13
    أخرىis evaporated
14. 14
    أخرىthe residue purified by silica chromatography
15. 15
    ترشيحAfter filtration
16. 16
    أخرىthrough celite and evaporation
17. 17
    درجة الحرارةat reflux
18. 18
    درجة الحرارةThe mixture is cooled
19. 19
    workup.ADDITIONpoured into satd
20. 20
    ترشيحaq. sodium bicarbonate and the solid product filtered
21. 21
    أخرىpurified by recrystallization
22. 22
    درجة الحرارةby refluxing with phthaloyl dichloride in pyridine
23. 23
    أخرىfollowed by reaction of the diazepine with pyrazole

الإجراء التجريبي

4-Acetylamino-2-methylbenzoic acid (Peltier) is converted into the 5-nitro compound by treatment with cold fuming nitric acid. The reaction mix was poured into crushed ice and the solid product collected by filtration and purified by recrystallization from DMF/water or by silica chromatography. The acetamide is removed by alkaline hydrolysis with 1-10% NaOH solution in 90% ethanol. The reaction mixture was added to excess dilute HCl and the solvent evaporated. The crude acid is esterified with satd. methanolic HCl at room temperature for several days. After removal of solvent the product is partitioned between ethyl acetate and satd. sodium bicarbonate. After washing with water the organic phase is evaporated and the residue purified by silica chromatography. The nitro group is reduced to the amino using hydrogen and palladium on carbon in ethanol or DMF. After filtration through celite and evaporation, the crude diamine is converted to the methyl 2-amino-6-methylbenzimidazole-5-carboxylate using cyanogen bromide in methanol at reflux. The mixture is cooled and poured into satd. aq. sodium bicarbonate and the solid product filtered and purified by recrystallization. The exocyclic amino group is acylated by refluxing with phthaloyl dichloride in pyridine followed by reaction of the diazepine with pyrazole in refluxing acetonitrile according to the method of Katritzky. The compound is reacted with either bromine or N-bromosuccinimide or 1,3-dibromo-5,5-dimethylhydantoin either neat or in carbon tetrachloride or chloroform or 1,1,1-trichloroethane with the aid of a high intensity sun lamp and/or benzoyl peroxide, to provide the benzylic bromide. It is possible to acylate the diazepine further with isobutryl chloride in pyridine to produce a triply acylated benzimidazole species. This is normally done prior to the bromination.

المصدر