合成路线1

A new synthesis for medetomidine has been reported: The silylation of N,N-dimethylimidazole-1-sulfonamide (I) with tert-butyldimethylsilyl chloride and butyllithium in THF gives the 2-silyl derivative (II), which is acylated with 2,3-dimethylbenzoyl chloride (III) by means of butyllithium in THF, yielding 2-(tert-butyldimethylsilyl)-5-(2,3-dimethylbenzoyl)-N,N-dimethylimidazo le-1-sulfonamide (IV). Hydrolysis of (IV) with refluxing aqueous HCl affords 5-(2,3-dimethylbenzoyl)imidazole (V), which is finally methylated with methyllithium in THF and reduced with Li in liquid NH3.

合成路线2

Lithiation of 1-(N-N-dimethylsulfamoyl)imidazole (I) followed by reaction with tert-butyldimethylsilyl chloride produced the 2-silyl protected imidazole (II). Further lithiation of (II) allowed the introduction of a bromohexyl group at position 5 upon treatment with 1,6-dibromohexane yielding (III). Bromide (III) was subsequently converted into primary amine (VI) through a Gabriel synthesis involving condensation with potassium phthalimide (IV) with concomitant desilylation, and then hydrazinolysis of the resulting alkylated phthalimide (V). Condensation of amine (VI) with naphthalene-2-sulfonyl chloride (VII) furnished sulfonamide (VIII). The sulfamoyl protecting group of (VIII) was finally removed by hydrolysis with HCl.

合成路线3