合成路线1

Two minor metabolites of mosapride 4-amino-5-chloro-2-ethoxy-3-hydroxy-N-(5-oxo-2-morpholinylmethyl)benzamide (A) and 4-amino-5-chloro-2-ethoxy-3-hydroxy-N-(2-morpholinylmethyl)benzamide (B) have been synthesized as follows: 1) The alkylation of 2,3-dihydroxybenzaldehyde (I) with NaH and ethyl iodide in DMSO gives 2-ethoxy-3-hydroxybenzaldehyde (II), which is nitrated with HNO3 in acetic acid yielding 2-ethoxy-3-hydroxy-4-nitrobenzaldehyde (III). The oxidation of (III) with AgNO3 in methanol/water affords the expected benzoic acid (IV), which is condensed with 2-(aminomethyl)morpholin-5-one (V) by means of carbonyldiimidazole (CDI) in THF giving the corresponding benzamide (VI). The hydrogenation of the nitro group of (VI) with H2 over Pd/C in aqueous ethanol yields 4-amino-2-ethoxy-3-hydroxy-N-(5-oxo-2-morpholinylmethyl)benzamide (VII), which is finally chlorinated to the metabolite (A) with N-chlorosuccinimide in hot DMF. 2) The reaction of the benzoic acid (IV) with SOCl2 in refluxing dichloromethane gives the corresponding acyl chloride (VIII), which is condensed with 2-(aminomethyl)-4-(4-fluorobenzyl)morpholine (IX) by means of triethylamine in dichloromethane to yield the expected amide (X). The debenzylation of (X) with 1-chloroethyl chloroformate (ACE-Cl) and reprotection with di-tert-butyl carbonate affords N-[4-(tert-butoxycarbonyl)morpholin-2-ylmethyl]-2-ethoxy-3-hydroxy-4-nitrobenzamide (XI), which is submitted to a reductive acetylation (H2 over Pd/C in acetic anhydride) giving 4-acetamido-N-[4-(tert-butoxycarbonyl)morpholin-2-ylmethyl]-2-ethoxy-3-hydroxybenzamide (XII). The chlorination of (XII) with N-chlorosuccinimide (NCS) in chloroform/DMS yields the corresponding 5-chlorobenzamide (XIII), which is finally deprotected with refluxing aqueous HCl to afford metabolite (B).