Remote electronic control in the regioselective reduction of succinimides: a practical, scalable synthesis of Ep4 antagonist MF-310.
A practical large-scale chromatography-free synthesis of EP4 antagonist MF-310, a potential new treatment for chronic inflammation, is presented. The synthetic route provided MF-310 as its sodium salt in 10 steps and 17% overall yield from commercially available pyridine dicarboxylate 7. The key features of this sequence include a unique regioselective reduction of succinimide 2 controlled by the electronic properties of a remote pyridine ring, preparation of cyclopropane carboxylic acid 3 via a Corey-Chaykovsky cyclopropanation, and a short synthesis of sulfonamide 5.
Molinaro
Carmela
C
Department of Process Research, Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Highway, Kirkland, Quebec, Canada, H9H 3L1. carmela_molinaro@merck.com
Gauvreau
Danny
D
Hughes
Gregory
G
Lau
Stephen
S
Lauzon
Sophie
S
Angelaud
Rémy
R
O'Shea
Paul D
PD
Janey
Jacob
J
Palucki
Michael
M
Hoerrner
Scott R
SR
Raab
Conrad E
CE
Sidler
Rick R
RR
Belley
Michel
M
Han
Yongxin
Y
D002264:Carboxylic Acids / Q000737:chemistry; D002625:Chemistry, Organic / Q000295:instrumentation / Q000379:methods*; D002626:Chemistry, Pharmaceutical / Q000295:instrumentation / Q000379:methods*; D003460:Crystallization; D003521:Cyclopropanes / Q000138:chemical synthesis* / Q000737:chemistry; D015195:Drug Design; D004581:Electronics; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis* / Q000737:chemistry; D008956:Models, Chemical; D015394:Molecular Structure; D018078:Receptors, Prostaglandin E / Q000037:antagonists & inhibitors*; D058309:Receptors, Prostaglandin E, EP4 Subtype; D013237:Stereoisomerism; D013388:Succinimides / Q000737:chemistry*; D013449:Sulfonamides / Q000737:chemistry; D013678:Technology, Pharmaceutical
D002264:Carboxylic Acids; D003521:Cyclopropanes; D006575:Heterocyclic Compounds, 3-Ring; C545573:MF-310; D018078:Receptors, Prostaglandin E; D058309:Receptors, Prostaglandin E, EP4 Subtype; D013388:Succinimides; D013449:Sulfonamides