title: Hydrolysis and rearrangement of phthalamic acid derivatives and assessment of their potential as prodrug forms for amines.
abstract: Although it is well-known that N-substituted phthalamic acid derivatives are readily hydrolyzed in acidic aqueous solution due to intramolecular catalysis by the neighbouring carboxy group, sparse information is available on the degradation behaviour in neutral solutions. A recent publication [5] has claimed that N-(3-bromopropyl)phthalamic acid is very easily hydrolyzed in mildly alkaline solutions by an intramolecular catalytic effect of the ionized carboxy group. In this study, the degradation behaviour of N-(2-bromoethyl)phthalamic acid (I), N-(3-bromopropyl)phthalamic acid (II) and various other N-alkyl and N-aryl substituted phthalamic acid derivatives were examined with the primary aim of assessing their degradation rate at physiological pH. Whereas the compounds I and II were indeed found to be easily degraded in neutral aqueous solutions, the degradation was not due to hydrolysis of the amide bond as previously claimed but rather to an intramolecular displacement reaction of the bromo group by the amide moiety, as evidenced by HPLC analysis of the rection products. The other phthalamic acid derivatives studies showed a very high stability in neutral and alkaline solution. It is concluded that phthalamic acid derivatives are too stable chemically and enzymatically to be considered as prodrug forms for primary or secondary amines.
authors.affiliation: Royal Danish School of Pharmacy, Department of Pharmaceutical Chemistry, Copenhagen.
authors.forename: H
authors.initials: H
authors.lastname: Bundgaard
authors.forename: B
authors.initials: B
authors.lastname: Steffansen
mesh_terms: D000588:Amines / Q000138:chemical synthesis* / Q000737:chemistry; D001565:Benzoates / Q000138:chemical synthesis / Q000737:chemistry*; D019817:Benzoic Acid; D006868:Hydrolysis; D007700:Kinetics; D011355:Prodrugs / Q000138:chemical synthesis*
chemical_list: D000588:Amines; D001565:Benzoates; D011355:Prodrugs; D019817:Benzoic Acid