合成路线1

A new synthesis for T-3761 has been described: The esterification of 2,3,4,5-tetrafluorobenzoic acid (I) with SOCl2 and ethanol gives ethyl 2,3,4,5-tetrafluorobenzoate (II), which is condensed with di-tert-butyl malonate (III) by means of NaH in DMF and decarboxylated with HCl/trifluoroacetic acid to 4-(carboxymethyl)-2,3,5-trifluorobenzoic acid ethyl ester (IV). Esterification of (IV) with diphenyldiazomethane in ether affords the corresponding ester (V), which is methylenated with bis(dimethylamino)methane (VI) and acetic anhydride in DMSO to give 4-[1-(diphenylmethoxycarbonyl)vinyl]-2,3,5-trifluorobenzoic acid ethyl ester (VII). The cyclopropanation of (VII) with trimethylsulfoxonium iodide and potassium tert-butoxide [(CH3)2SO=CH2] yields the cyclopropane compound (VIII), which is selectively hydrolyzed with trifluoroacetic acid to 4-(1-carboxycyclopropyl)-2,3,5-trifluorobenzoic acid ethyl ester (IX). The decarboxylative amination of (IX) with ethyl chloroformate, sodium azide and benzyl alcohol gives 4-[1-(benzyloxycarbonylamino)cyclopropyl]-2,3,5-trifluorobenzoic acid ethyl ester (X), which is saponified with NaOH in dioxane/ethanol to the corresponding acid (XI). The condensation of (XI) with the magnesium salt of malonic acid mono-tert-butyl ester (XII) by means of carbonyldiimidazole (Im2CO) in THF affords the benzoylacetic ester (XIII), which is treated first with dimethylformamide dimethylacetal (XIV) in refluxing benzene and then with 2-amino-1-propanol (XV) to yield 2-[4-[1-(benzyloxycarbonylamino)cyclopropyl]-2,3,5-trifluorobenzoyl]-3-(2-hydroxy-1-methylethylamino)-2-propenoic acid ethyl ester (XVI). The cyclization of (XVI) by means of K2CO3 in hot DMF gives the pyridobenzoxazine (XVII), which is saponified with NaOH in ethanol/dioxane to the corresponding free acid (XVIII). Finally, the amino group of (XVIII) is deprotected by hydrogenation with H2 over Pd/C