1234779-91-9Relevant academic research and scientific papers
Asymmetric synthesis of a glucagon receptor antagonist via friedel-crafts alkylation of indole with chiral α-phenyl benzyl cation
Chung, John Y. L.,Steinhuebel, Dietrich,Krska, Shane W.,Hartner, Fred W.,Cai, Chaoxian,Rosen, Jonathan,Mancheno, Danny E.,Pei, Tao,Dimichele, Lisa,Ball, Richard G.,Chen, Cheng-Yi,Tan, Lushi,Alorati, Antony D.,Brewer, Sarah E.,Scott, Jeremy P.
, p. 1832 - 1845 (2013/01/15)
Development of a practical asymmetric synthesis of a glucagon receptor antagonist drug candidate for the treatment of type 2 diabetes is described. The antagonist consists of a 1,1,2,2-tetrasubstituted ethane core substituted with a propyl and three aryl groups including a fluoro-indole. The key steps to construct the ethane core and the two stereogenic centers involved a ketone arylation, an asymmetric hydrogenation via dynamic kinetic resolution, and an anti-selective Friedel-Crafts alkylation of a fluoro-indole with a chiral α-phenyl benzyl cation. We also developed two new efficient syntheses of the fluoro-indole, including an unusual Larock-type indole synthesis and a Sugasawa-heteroannulation route. The described convergent synthesis was used to prepare drug substance in 52% overall yield and 99% ee on multikilogram scales.
