The oxidation of 2-nitro-5-fluorotoluene (I) with KMnO4 in water gives 2-nitro-5-fluorobenzoic acid (II), which by reduction with H2 over Pd/C in methanol - aqueous HCl yields 2-amino-5-fluorobenzoic acid (III). The reaction of (III) with phosgene in THF aqueous HCl affords 5-fluoroisatoic acid anhydride (IV), which by cyclization with N-methylglycine (V) in OMS at 100 C affords 7-fluoro-4-methyl-3,4-dihydro-2H-1,4-benzodiazepin-2,5(1H)-dione (VI). Finally, this compound is cyclized again with ethyl isocyanacetate (VII) by means of potassium tert-butylate and diethyl chlorophosphate in DMF.
The cyclization of anhydride (IV) with N-(2,4-dimethoxybenzyl)glycine (VIII) as before gives 7-fluoro-4-(2,4dimethoxybenzyl)-3,4-dihydro-2H-1,4-benzodiazepin-2,5(1H)-dione (IX), which by a new cyclization with (VII) as before is converted into ethyl-8-fluoro-5-(2,4dimethoxybenzyl)-5,6-dihydro-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate (X). The deprotection of (X) with trifluoroacetic acid yields ethyl-8-fluoro-5,6-dihydro-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate (XI), which is finally methylated with methyl iodide and NaH in DMF.
The reaction of 7-fluoro-4-methyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2,5-dione (I) with POCl3 and N,N-dimethyl-p-toluidine in hot toluene gives 2-chloro-7-fluoro-4-methyl-4,5-dihydro-3H-1,4-benzodiazepin-5 one (II), which is condensed with N-(dimethylaminomethylene)glycine ethyl ester (III) (obtained by condensation of glycine ethyl ester (IV) with dimethylformamide (V) and TEA in dichloromethane) to yield a mixture of intermediates (VI) and (VII). Finally, these compounds are cyclized in refluxing AcOH to provide the target flumazenil.