The condensation of 2-chloro-1-(4-fluorobenzyl)-1H-benzimidazole (I) with methoxymethyl bromide (II) in toluene gives the benzimidazolium bromide (III), which is condensed with 4-aminopiperidine-1-carboxylic acid ethyl ester (IV) in hot toluene to yield the adduct (V). Finally, this compound is treated first with BBr3 in dichloromethane and then with HBr or HCl at 110 C to provide the target Norastemizole.
The condensation of 2-chloro-1-(4-fluorobenzyl)-1H-benzimidazole (I) with 2-methoxyethoxymethyl bromide (II) in toluene gives the benzimidazolium bromide (III), which is condensed with 1-acetyl-4-aminopiperidine (IV) in hot toluene to yield the adduct (V). Finally, this compound is treated first with BBr3 in dichloromethane and then with HBr or HCl at 110 C to provide the target Norastemizole.
Norastemizole can be obtained in the following way as shown in scheme: The synthesis is carried out by mild and selective palladium coupling of readily available 1-(4-fluorobenzyl)- 2-chlorobenzimidazole (I) with 4-aminopiperidine dihydrochloride (II) to obtain norastemizole in 84% isolated yield. The synthesis is highly selective and involves a one-step process.