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

Article abstract of DOI:10.1248/cpb.47.22

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.

Full text of DOI:10.1248/cpb.47.22

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