合成路线1

Synthesis of the intermediate 5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one (IV) is accomplished by condensation of 3-amino-2-chloropyridine (I) and the anthranilic ester (II) using potassium tert-butoxide as a catalyst. The resulting anthranilic amide (III) is cyclized under the influence of catalytic amounts of sulfuric acid. Treatment of (IV) with chloroacetylchloride in toluene furnishes the corresponding chloroacetamide (V). The diamine part of AF-DX 116 is prepared starting from 2-(hydroxymethyl)piperidine (VI). Reaction with thionylchloride in dichloromethane affords the pipecolylchloride hydrochloride (VII), which is converted with diethylamine to the required 2-[(diethylamino)methyl]piperidine (IX) via nucleophilic ring opening of the intermediate aziridine (VIII). Minor amounts of 3-(diethylamino)hexahydroazepine (X), formed by a side reaction, are separated by thorough fractional distillation of the diamine (IX) and/or recrystallization of its hydrochloride (XI). Coupling of (V) and (XI) in the presence of sodium carbonate yields AF-DX 116 as its free base.