合成路线: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.
合成路线: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.
参考文献标题:RO-15-1788
文献作者:Blancafort,P.; Castar,J.; Hillier,K.; Serradell,M.N.
参考来源:Drugs Fut 1982,7(6),402
合成路线: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.
参考文献标题:The isolation and use of a benzodiazepine iminochloride for the efficient construction of flumazenil
文献作者:Rogers-Evans,M.; Spurr,P.; Hennig,M.
参考来源:Tetrahedron Lett 2003,44(11),2425
产品链接: CAS No. 78755-81-4››