An Acid-Catalyzed O, N-Acyl Migration and Application to the Synthesis of N-(4-Isopropyl-2, 2-dimethyl-3-oxo-3, 4-dihydro-2H-benzo[1, 4]oxazine-6-carbonyl) guanidine Methanesulfonate (KB-R9032), a Novel Na/H Exchange Inhibitor

Abstract

In the search for a practical synthesis of N-(4-isopropyl-2, 2-dimethyl-3-oxo-3, 4-dihydro-2H-benzo[1, 4]oxazine-6-carbonyl)guanidine methanesulfonate (KB-R9032), a potent Na/H exchange inhibitor, the acylation of methyl 4-hydroxy-3-isopropylaminobenzoate 6a with 2-bromoisobutyryl bromide was carried out in order to prepare an N-acyl derivative, 8a. However, an O-acyl derivative 7a was obtained selectively. Acylations of derivatives of 6a were examined. The results revealed that the O-acylation occurred because of the steric repulsion between the N-isopropyl moiety and the bulky acyl bromide. Then, we investigated the O, N-acyl migration of 7a. We found that the migration was catalyzed by carboxylic acid and that 8a was precipitated from a diisopropyl ether solution in good yield. Treatment of 8a with potassium carbonate and subsequent guanidine gave the synthetic intermediate for KB-R9032 in high yield.