合成路线1

Trovafloxacin can be obtained by two related ways: 1) The cyclization of ethyl diazoacetate (I) with N-benzylmaleimide (II) in ethyl ether gives 5-benzyl-4,6-dioxo-1,3a,4,5,6,6a-hexahydropyrrolo[3,4-c]pyrazole-3-carboxylic acid ethyl ester (III), which by thermolysis at 185 C is converted into (1alpha,5alpha,6alpha)-3-benzyl-2,4-dioxo-3-azabicyclo[3.1.0]hexane-6-carboxylic acid ethyl ester (IV). The reduction of (IV) with LiAlH4 in refluxing THF affords (1alpha,5alpha,6alpha)-3-benzyl-6-(hydroxymethyl)-3-azabicyclo[3.1.0] hexane (V), which is debenzylated by hydrogenolysis with H2 over Pd/C in methanol to the free azabicyclo compound (VI) (1, 2). The reaction of (VI) with benzyl chloroformate and NaHCO3 in doxane/water yields the corresponding N-benzyloxycarbonyl compound (VII), which is oxidized with the Jones reagent to (1alpha,5alpha,6alpha)-3-(benzyloxycarbonyl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid (VIII). The reaction of (VIII) with diphenylphosphoryl azide (DPA) and triethylamine in refluxing tert-butanol gives (1alpha,5alpha,6alpha)-3-(benzyloxycarbonyl)-6-(tert-butoxycarbonylamino)-3-azabicyclo[3.1.0]hexane (IX), which is submitted to hydrogenolysis with ammonium formate over Pd/C to afford (1alpha,5alpha,6alpha)-6-(tert-butoxycarbonylamino)-3-azabicyclo[3.1.0] hexane (X). The condensation of (X) with 7-chloro-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid ethyl ester (XI) by means of triethylamine in hot acetonitrile gives (1alpha,5alpha,6alpha)-7-[6-(tert-butoxycarbonylamino)-3-azabicyclo [3.1.0]hex-3-yl]-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid ethyl ester (XII) (1-3), which is finally deprotected with refluxing 6N HCl (1) or methanesulfonic acid in dioxane/water. The cyclization of 1-(benzyloxycarbonyl)-2,5-dihydro-1H-pyrrole (XIII) with ethyl diazoacetate (I) gives 5-(benzyloxycarbonyl)-1,3a,4,5,6,6a-hexahydropyrrolo[3,4-c]pyrazole-3-carboxylic acid ethyl ester (XIV), which by thermolysis is converted into (1alpha,5alpha,6alpha)-3-(benzyloxycarbonyl)-2,4-dioxo-3-azabicyclo [3.1.0]hexane-6-carboxylic acid ethyl ester (XV). Finally, this compound is hydrolyzed to the desired carboxylic acid (VIII). 2) The carboxylic acid (VIII) can also be obtained as follows: