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) Utilizing Potassium Fluoride-Alumina Catalyzed N-Alkylation

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N-Isopropylation of methyl 2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylate (2a) with various reagents was examined in order to prepare 3a, the key intermediate in the synthesis of N-(4-isopropyl-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl)guanidine methanesulfonate (1,KB-R9032), a novel, potent Na/H exchange inhibitor. When a base such as sodium hydride, potassium carbonate or potassium tert-butoxide was used, the undesired O-isopropyl derivative 4a was produced as the main product. Among the hydrogen bond assisted mild bases examined, potassium fluoride (KF)-alumina afforded the best N-/O-selectivity with a ratio of about four. The undersired O-isopropyl derivative 4a could be easily converted to the starting 2a under non-aqueous acidic conditions. Combination of the above two processes increased the N-/O-ratio (to about 42). Consequently, the N-isopropyl derivative 3a was isolated without column chromatography in more than 70% yield. This KF-alumina catalyzed repeated isopropylation was applicable to N-selective alkylation of other hindered cyclic amides to afford N-alkyl derivatives in high yields.
公益社団法人日本薬学会の論文
1998-08-15