Studies in Ranitidine Chemistry: An Unusual O→N Methyl Migration

Ranitidine (IV), an H₂-receptor antagonist, has been recently introduced in ulcer therapy as a powerful inhibitor of gastric acid secretion.¹Its synthesis is described in serveral patents.^2-5Some of the published procedures^2-3 involve the intermediacy of III, prepared by the reaction of I with II (Scheme I). Compound III has been reported to be isolated either as an oil⁶ or as its oxalate salt.⁷ We have recently been able to synthesize III as the free base and isolate it as a crystalline solid. In the course of this work we became aware of the instability of III in methanolic solutions where it is completely transformed to another product upon standing at room temperature. This product, a very polar compound, was isolated and fully characterized. Spectral and analytical results confirmed its structure to be that of 1-oxo-1-[(2-(((((5-trimethylammonio)methyl)-2-furanyl)- methyl)thio)ethyl)amino]-2-nitroethene (V), indicating.