Toward the Development of a Manufacturing Process for the Insecticide Tyclopyrazoflor. Part I. Evaluation of Strategies using Ullmann Coupling of Pyrazole Derivatives

Synthetic strategies based on Ullmann coupling of functionalized pyrazoles and 3-halopyridine to access the insecticide tyclopyrazoflor (1) were evaluated. A five-step route featuring a middle-stage Ullmann coupling approach was selected as the lead route for optimization and was scaled up in a pilot plant at more than 50 kg scale of each step. This route started from reductive chlorination of 4-nitropyrazole followed by acetylation to provide N-(3-chloro-1H-pyrazol-4-yl)acetamide as the key coupling nucleophile, which readily coupled with 3-bromopyridine in the presence of copper(I) chloride as catalyst and 1,2-dimethylethylenediamine (DMEDA) as ligand. Subsequent NaBH4 reduction afforded the corresponding ethyl amine, which was coupled with 3-((3,3,3-trifluoropropyl)thio)propanoyl chloride to furnish tyclopyrazoflor (1). This highly concise route offered a critical foundation for development of a scalable manufacturing process.