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129th General Meeting of Korean Chemical Society & Exposition Total Synthesis of Rucaparib

Submission Date :
2 / 28 / 2022 , 15 : 43 : 49
Abstract Number :
Presenting Type:
Poster Presentation
Presenting Area :
Organic Chemistry
Authors :
Ju-Ahn Seo, Cheol-Hong Cheon*
Department of Chemistry, Korea University, Korea
Assigned Code :
ORGN.P-628 Assigend Code Guideline
Presenting Time :
April 15 (FRI) 11:00~13:00
Rucaparib is a poly(ADP-ribose) polymerase (PARP) inhibitor used as an anti-cancer agent. It received an approval by the Food and Drug Administration (FDA) for the treatment of ovarian and prostate cancer in 2016 and 2020, respectively. Structurally, rucaparib possesses an indole subunit bearing four substituents along its periphery and an additional seven-membered lactam ring between the two substituents at C3 and C4 positions. As an indole derivative bearing the four desired substituents at appropriate positions is not readily available, most of the previous syntheses have been developed based on the protocol for the preparation of the tetra-substituted indole derivatives. Recently, our group developed a highly efficient protocol to access 2-substituted indole-3-actetic acid derivatives via the cyanide-catalyzed imino-Stetter reaction of aldimines obtained from 2-aminocinnamic acid derivatives and aldehydes. With this protocol in hand, we developed a new synthetic route for rucaparib. 2-Aminocinnamamide could be prepared from meta-fluorobenzoate, which currently used as the starting material in the process chemistry route of rucaparib, via benzylic olefination with glyoxalamide and subsequent reduction of the nitro group to amino group. The cyanide-catalyzed imino-Stetter reaction of aldimine, derived from the resulting 2-aminocinnamamide derivative and aldehyde, provided indole-3-acetamide bearing all three substituents at the right position. Final azepinone ring formation completed the total synthesis of rucaparib.