Liarozole fumarate, R-75251(monohydrochloride), R-85246, Liazal

6-((3-氯苯基)(1H-咪唑-1-基)甲基)-1H-苯并[d]咪唑Chemical Name: (?-5-[(3-Chlorophenyl)(1H-imidazol-1-yl)methyl]-1H-benzimidazole (E)-2-butenedioate (2:3); (?-5-(3-Chloro-alpha-imidazol-1-ylbenzyl)benzimidazole fumarate (2:3)
CAS No. 145858-52-2, 145858-51-1 (free base), 115575-11-6 (free base, undefined isomer), 145858-50-0 (monoHCl)
项目整合开发状态: Phase III
项目研究机构: Barrier Therapeutics (Orphan Drug), Janssen (Originator), Barrier Therapeutics (Licensee)
合成路线:The cyclization of 3,4-diaminobenzophenone (I) with acetylimidic acid ethyl ester (II) in refluxing methanol gives 5-benzoyl-2-methylbenzimidazole (III),which is reduced with NaBH4 in methanol yielding 5-(alpha-hydroxybenzyl)-2-methylbenzimidazole (IV).Finally,this compound is condensed with imidazole (V) in refluxing acetonitrile.

合成路线:Liarozole fumarate is prepared as shown in Scheme 20970301a.Anisol is reacted with 3-chlorobenzoyl chloride (I) under Friedel-Craft conditions to give (3-chlorophenyl)(4-methoxyphenyl)methanone (II).Nitration of (II) is carried out in dichloromethane at 10 C to yield (III).The methoxy group in (III) is replaced by the amino group by means of NH3 in 2-propanol at 100 C under pressure,giving (IV).By reduction of the keto function of (IV) with sodium borohydride in 2-propanol,the corresponding alcohol (V) is obtained,which upon treatment with 1,1'-carbonyldiimidazole in refluxing dichloromethane yields the imidazolyl compound (VI).Hydrogenation of the nitro group in (VI),followed by cyclization of (VII) in a refluxing mixture of formic acid and 4N hydrochloric acid,gives the benzimidazole derivative (VIII).Finally,the treatment of (VIII) with fumaric acid in ethanol yields liarozole fumarate (IX).