Scalable synthesis of a prostaglandin EP4 receptor antagonist.
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.
Gauvreau
Danny
D
Department of Process Research, Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Hwy, Kirkland, Québec, Canada H9H 3L1. danny_gauvreau@merck.com
Dolman
Sarah J
SJ
Hughes
Greg
G
O'Shea
Paul D
PD
Davies
Ian W
IW
D000215:Acylation; D018674:Adrenergic Antagonists; D002626:Chemistry, Pharmaceutical / Q000191:economics*; D003080:Cold Temperature; D003521:Cyclopropanes / Q000737:chemistry / Q000494:pharmacology; D007659:Ketones / Q000737:chemistry / Q000494:pharmacology; D018078:Receptors, Prostaglandin E / Q000037:antagonists & inhibitors*; D058309:Receptors, Prostaglandin E, EP4 Subtype; D013237:Stereoisomerism; D013696:Temperature; D013876:Thiophenes / Q000737:chemistry / Q000494:pharmacology
D018674:Adrenergic Antagonists; D003521:Cyclopropanes; D007659:Ketones; D018078:Receptors, Prostaglandin E; D058309:Receptors, Prostaglandin E, EP4 Subtype; D013876:Thiophenes; C067351:cyclopropylamine