Process Research, Development, and Pilot-Plant Preparation of Clofencet, a Novel Wheat Hybridizing Agent: Lewis Acid-Catalyzed Reaction of Ethyl Diazoacetate with 4-Chlorophenyl Hydrazonoacetaldehyde

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Abstract

Described are studies directed toward the chemical research and development of an alternative synthesis to 9, the penultimate intermediate of clofencet (1), a novel wheat-hybridizing agent. Retrosynthetic analyses as well as the results obtained from feasibility studies are detailed, leading to the successful development of an alternative process. The key features of the novel route are a method for preparing on-scale ethyl diazoacetate (28) in a safe and effective manner, and the Lewis acid-catalyzed reaction of 28 with hydrazonoacetaldehyde 29, affording β-ketoester 30. The synthesis is completed via propionylation of 30, acid-catalyzed cyclization of 31 to pyridazinecarboxylic acid ester 32, followed by saponification and isolation of carboxylic acid 9. The results and challenges of eight pilot-plant runs are reported. The baseline process developed produced over 45 kg of 9 in 43−45% yield.

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