Tubulozole hydrochloride, R-46846

盐酸九布洛唑-C Chemical Name: Ethyl (?-cis-[4-[[[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methyl]thio]phenyl]carbamate monohydrochloride; Ethyl (?-cis-p-[[[2-(2,4-dichlorophenyl)-2-(imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methyl]thio]carbanilate monohydrochloride
CAS No. 83529-08-2, 84697-22-3 (free base)
项目整合开发状态: Preclinical
项目研究机构: Janssen (Originator)
合成路线:The acylation of 4-aminothiophenol (I) with ethyl chloroformate (II) is performed in a nitrogen atmosphere in the presence of NaHCO3 in CH2Cl2 / water medium giving ethyl (4-mercaptophenyl)carbamate (III).This compound is condensed with cis-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dixolan-4-yl]methyl methanesulfonate (IV) in the presence of K2CO3 in refluxing acetone under nitrogen,affording the title compound,which is converted to the monohydrochloride with i-PrOH / HCl in 4-methyl-2-pentanone.

合成路线:Coupling of (IV) in a nitrogen atmosphere with 4-acetamidothiophenol (V) in refluxing acetone in the presence of K2CO3 affords cis-N-[4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethylthio]phenyl]acetamide,which is deacylated with NaOH in refluxing i-PrOH to give cis-4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl-methyl)-1,3-dioxolan-4-ylmethylthio]benzenamine (VII).This compound is converted with ethylchloroformate (II) into the title compound which is isolated as the monohydrochloride on treatment with i-PrOH / HCl.

合成路线:The synthesis of erbulozole,starting from 1-(4-methoxyphenyl)-2-(1H-imidazol-1-yl)ethanone (I) is outlined.Ketalization of (I) with glycerin (II) was performed in n-heptane with p-toluenesulfonic acid as the catalyst and under azeotropic removal of H2O.The resulting dioxolane derivative (III),arising as a cis-trans mixture,was benzoylated to the ester (IV).Cis-trans isomers were separated by column chromatography over silica gel (Merck,Silica gel 60),using a mixture of trichloromethane and methanol (98:2 by volume) as the eluent.Saponification of the cis-benzoate (V) with sodium hydroxide in dioxane-water medium at room temperature afforded the alcohol (VI),which was converted to the methanesulfonate (VII) with methanesulfonylchloride in dry pyridine and methylenechloride (1:1 by volume).Under a nitrogen atmosphere,compound (VII) was coupled with (VIII) in acetone using K2CO3 as an acid acceptor to the target compound,erbulozole.