Abstract
An efficient synthesis of a potent PPAR alpha (peroxisome proliferator-activated receptors) agonist is described. The key step in the synthesis is a palladium-catalyzed coupling reaction between a suitably substituted benzene and the anion of methyl isobutyrate. Amide formation with proline provided the drug substance in 62% overall yield based on 2.
Highlights
The Discovery synthesis[1] of LBS834 1, a potent and selective PPAR alpha agonist,[2] nvolved 8 chemical steps and 3 chromatographic purifications in addition to several lengthy extractions
This route proved to be suitable for the preparation of small quantities of drug substance, it was readily apparent that major changes would have to be implemented for scale up in the Pilot Plant
Coupling of oxazole 2 with phenol 3 In the Discovery procedure, oxazole 2 was prepared in two steps from benzaldehyde and 2,3butanedione monooxime in an overall yield of 40%
Summary
The Discovery synthesis[1] of LBS834 1, a potent and selective PPAR alpha agonist,[2] nvolved 8 chemical steps and 3 chromatographic purifications in addition to several lengthy extractions. The overall yield was 6% (see Scheme 1) This route proved to be suitable for the preparation of small quantities of drug substance, it was readily apparent that major changes would have to be implemented for scale up in the Pilot Plant. We felt that the best way to accomplish this was to employ a palladium-catalyzed coupling between a suitably substituted benzene and the anion of methyl isobutyrate. This would provide the basic structure of the molecule and eliminate the undesirable dialkylation step. This strategy had been used successfully in our first scale up in the laboratory (see Scheme 2).
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