| Structure Identification: |
| Organic Process Research & Development, 2002, 6(4):357-366. | | Process Research on the Synthesis of Silthiofam: A Novel Fungicide for Wheat.[Reference: WebLink] | The development of an efficient, low-cost synthesis of the novel wheat fungicide silthiofam (1) is described. Improvements to the original Discovery route allowed 300 kg of material to be prepared in two, overlapping pilot-plant campaigns. Thereafter, efforts were focused on further optimizing the pilot-plant route, and on devising alternate, lower cost routes to silthiofam.
METHODS AND RESULTS:
One potential new route involved a cycloaddition reaction between 3-mercapto-2-butanone and N-(2-propenyl)-3-trimethylsilylpropynamide. The cyclic product could be directly dehydrated to silthiofam, however the overall yield was modest, raw material costs were high, and there were purification problems. The route ultimately selected for development proceeds in 6 chemical steps and about 60% yield from the inexpensive precursors 3-chloro-2-butanone and Methyl 3-methoxyacrylate. Key features of the route are a novel thiophene-3-carboxylate synthesis involving cycloaddition of 3-mercapto-2-butanone with the acrylate followed by acid catalyzed aromatization, the room temperature formation and silylation of a thiophene-3-carboxylate dianion, and conversion of the resulting carboxylic acid into silthiofam with negligible loss of the silyl group.
CONCLUSIONS:
The process involves isolation of just two intermediates, only one of which is purified, and uses only three organic solvents, all of which are recycled. It can be run safely on large scale to give high-purity silthiofam. |
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