The Fit For Purpose Development of S1P1 Receptor Agonist GSK2263167 Using a Robinson Annulation and Saegusa Oxidation to Access an Advanced Phenol Intermediate

• Robert M. Harris
• Benjamin I. Andrews
• Stacy Clark
• Jason W. B. Cooke
• John C. S. Gray
• Stephanie Q. Q. Ng

• Chemical Development, GlaxoSmithKline Research and Development Ltd., UK

A fit for purpose approach has been adopted in order to develop a robust, scalable route to the S1P₁ receptor agonist, GSK2263167. The key steps include a Robinson ring annulation followed by a Saegusa oxidation, providing rapid access to an advanced phenol intermediate. Despite the use of stoichiometric palladium acetate for the Saegusa oxidation, near complete recovery of the palladium has been demonstrated. The remaining steps have been optimised including the removal of all chromatography. An alternative to the Saegusa oxidation is described as well as the development of a flow process to facilitate further scale-up of the amidoxime preparation using hydroxylamine at elevated temperature.

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