Journal of Organic Chemistry 2010-06-18

Scalable synthesis of a prostaglandin EP4 receptor antagonist.

Danny Gauvreau, Sarah J Dolman, Greg Hughes, Paul D O'Shea, Ian W Davies

Index: J. Org. Chem. 75(12) , 4078-85, (2010)

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Abstract

The evolution of scalable, economically viable synthetic approaches to the potent and selective prostaglandin EP4 antagonist 1 is presented. The chromatography-free synthesis of multikilogram quantities of 1 using a seven-step sequence (six in the longest linear sequence) is described. This approach has been further modified in an effort to identify a long-term manufacturing route. Our final synthesis involves no step requiring cryogenic (< -25 degrees C) conditions; comprises a total of four steps, only three of which are in the longest linear synthesis; and features the use of two consecutive iron-catalyzed Friedel-Crafts substitutions.