Development of a Scalable Process for the Insecticidal Candidate Tyclopyrazoflor. Part 2. Fit-for-Purpose Optimization of the Route to Tyclopyrazoflor Featuring [3 + 2] Cyclization of 3-Hydrazinopyridine·2HCl and Methyl Acrylate

Optimization of the route to the sap-feeding insecticidal candidate tyclopyrazoflor featuring [3 + 2] cyclization of 3-hydrazinopyridine·2HCl and methyl acrylate is described. The key impurities in the [3 + 2] cyclization were identified and successfully controlled after optimization. The hazards associated with oxidation of an intermediate pyrazolidin-3-one using the incompatible combination of potassium persulfate and N,N-dimethylformamide (DMF) were avoided by using potassium ferricyanide in the presence of potassium hydroxide in water. The two elimination impurities in the ethylation step to produce tyclopyrazoflor were successfully minimized using ethyl iodide in the presence of cesium carbonate in DMF at 0 °C. The overall yield for this seven-step synthesis of tyclopyrazoflor was improved from 10% to 41% after the optimization detailed herein.