Scalable Synthesis of a Prostaglandin EP4 Receptor Antagonist

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.

MicroRNA-101 (miR-101) post-transcriptionally regulates the expression of EP4 receptor in colon cancers

“…Indeed, several groups have reported the discovery of potent and selective EP4 receptor antagonists. [39][40][41][42] However, the effectiveness of this new generation of EP4 antagonists against malignant lesions warrants further investigation.…”

Iron-promoted C–C bond formation in the total synthesis of natural products and drugs

“…The same iron catalyst was also successfully used in the coupling of 2,5-dimethylthiophene 102 with benzylic alcohol derivative 103 for the total synthesis of a prostaglandin EP4 receptor antagonist (Scheme 38). 65 In 2010, Li described an interesting carbonylation-peroxidation of alkenes with aldehydes and hydroperoxides under 3-component conditions. The obtained b-peroxyketones can then offer an easy access to a-keto epoxides under basic conditions.…”

Iron Catalysis in Target Synthesis

“…thesis of (-)-podophyllotoxin (Scheme 41). [106][107][108][109] Iron(III) chloride proved the most effective Lewis acid of those trialled giving the product with high diastereoselectivity and in excellent yield.…”