Scalable Synthesis of a Cis-Substituted Cyclobutyl-Benzothiazole Pyridazinone: Process Development of an Efficient Copper Catalyzed C–N Cross-Coupling Reaction

A scalable process for the preparation of 2-(2-(cis-3-(piperidin-1-yl)cyclobutyl)benzothiazol-6-yl)pyridazin-3(2H)-one in multi-kilogram amounts and in high purity has been developed. The key features of this synthesis are the copper-catalyzed C-N cross-coupling reaction and the development of a highly diastereoselective reductive amination using NaBH(OPiv)(3) as a reducing agent. Controls were implemented to minimize both base- and acid-catalyzed isomerization of the 1,3-cis-substituted cyclobutane ring.