【药物名称】GT-2203, VUF-5296
化学结构式(Chemical Structure):
参考文献No.537437
标题:Characterization of the binding site of the histamine H3 receptor. 1. Various approaches to the synthesis of 2-(1H-imidazol-4-yl)cyclopropylamine and histaminergic activity of (1R,2R)- and (1S,2S)-2-(1H-imidazol-4-yl)-cyclopropylamine
作者:De Esch, I.J.; Vollinga, R.C.; Goubitz, K.; Schenk, H.; Appelberg, U.; Hacksell, U.; Lemstra, S.; Zuiderveld, O.P.; Hoffmann, M.; Leurs, R.; Menge, W.M.; Timmerman, H.
来源:J Med Chem 1999,42(7),1115
合成路线图解说明:

Reaction of racemic ethyl trans-2-formyl-1-cyclopropane carboxylate (I) with tosylmethyl isocyanide in the presence of NaCN produced oxazoline (II) which, upon treatment with ethanolic ammonia at 120 C in a pressurized reactor afforded imidazole (III). Subsequent protection of the imidazole nucleus with dimethylsulfamoyl chloride gave (IV). Then, basic hydrolysis of ethyl ester of (IV) provided carboxylic acid (V). After activation of (V) as the mixed anhydride with ethyl chloroformate, treatment with NaN3 produced acyl azide (VI). Curtius rearrangement of (VI) in boiling toluene gave isocyanate (VII), which was converted to a mixture of diastereomeric carbamates (VIII) and (IX) using (R)-1-(2-naphthyl)ethanol. Finally, chromatographic separation of the required isomer, followed by hydrolysis in refluxing 30% HBr furnished the target compound.

合成路线图解说明:

Reaction of racemic ethyl trans-2-formyl-1-cyclopropane carboxylate (I) with tosylmethyl isocyanide in the presence of NaCN produced oxazoline (II) which, upon treatment with ethanolic ammonia at 120 C in a pressurized reactor afforded imidazole (III). Subsequent protection of the imidazole nucleus with dimethylsulfamoyl chloride gave (IV). Then, basic hydrolysis of ethyl ester of (IV) provided carboxylic acid (V). After activation of (V) as the mixed anhydride with ethyl chloroformate, treatment with NaN3 produced acyl azide (VI). Curtius rearrangement of (VI) in boiling toluene gave isocyanate (VII), which was converted to a mixture of diastereomeric carbamates (VIII) and (IX) using (R)-1-(2-naphthyl)ethanol. Finally, chromatographic separation of the required isomer, followed by hydrolysis in refluxing 30% HBr furnished the target compound.

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