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(3H)-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(3H)-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-diethoxycarbonyloxybenzoate (27).