Synthesis of 4‐chloro‐7‐ethoxy‐2(3H)‐benzoxazolone‐6‐carboxylic acid

As a part of metabolic studies of mosapride ( 1 ), a potential gastroprokinetic agent, the synthesis of 4‐chloro‐7‐ethoxy‐2(3 H )‐benzoxazolone‐6‐carboxylic acid ( 7 ) as a derivative of 4‐amino‐5‐chloro‐2‐ethoxy‐3‐hydroxybenzoic acid ( 6 ), which has served a benzoic acid part of the metabolites 4 and 5 , is described. Treatment of methyl 3‐amino‐4‐substituted amino‐5‐chloro‐2‐ethoxybenzoate derivatives 11a‐c with sodium nitrate in acidic medium gave the benzotriazole derivatives 13x,y instead of the objective 3‐hydroxy counterpart. The synthesis of 7 started from o ‐vanillin acetate ( 15 ) and proceeded through the intermediates 2‐hydroxy‐3‐methoxy‐4‐nitrobenzaldehyde ( 18 ), methyl 4‐amino‐2,3‐dihydroxybenzoate ( 23 ), and methyl 7‐hydroxy‐2(3 H )‐benzoxazolone‐6‐carboxylate ( 30 ). Compound 30 was alternatively prepared from 23 via methyl 4‐ethoxycarbonylamino‐2‐ethoxycarbonyloxy‐3‐hydroxybenzoate ( 29 ), which is the product resulting from the migration of the ethoxycarbonyl group of methyl 4‐amino‐2,3‐diethoxycar‐bonyloxybenzoate ( 27 ).