合成路线1

Treatment of 1-bromo-3,3-dimethyl-2-butanone (I) with hexamethylenetetraamine affords the quaternary salt (II), which is then hydrolyzed to amino ketone (III) under acidic conditions (1-3). Alternatively, reaction of butanone (I) with sodium azide in acetone gives the azido derivative (IV), which is reduced with H2 over Pd/C in methanol to yield 1-amino-3,3-dimethyl-2-butanone (III). Acylation of amine (III) with 2-chloroacetyl chloride by means of triethylamine in dichloromethane yields the chloroacetamide (V), which is cyclized in POCl3 at 105 ºC to provide 5-tert-butyl-2-(chloromethyl)oxazole (VI) (1-4). Condensation of chloride (VI) with thiourea gives the S-alkylated thiouronium salt (VII), which is then submitted to alkaline hydrolysis followed by condensation with 2-amino-5-bromothiazole (VIII) under phase-transfer conditions in the presence of tetrabutylammonium sulfate, leading to thioether (IX) (1-3). Acylation of aminothiazole (IX) with 1-Boc-piperidine-4-carboxylic acid (X) —obtained by reaction of piperidine-4-carboxylic acid (XI) with Boc2O and NaOH in dioxane/acetonitrile— by means of EDAC and DMAP in DMF/dichloromethane yields the carboxamide (XII), which is finally deprotected upon treatment with trifluoroacetic acid (1-3) or by means of HCl in hot dioxane/CHCl (4). Scheme 1.