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Practical Asymmetric Synthesis of a Calcitonin Gene-Related Peptide (CGRP) Receptor Antagonist Ubrogepant

2017; American Chemical Society; Volume: 21; Issue: 11 Linguagem: Inglês

10.1021/acs.oprd.7b00293

1520-586X

Nobuyoshi Yasuda, Ed Cleator, Birgit Kosjek, Jianguo Yin, Bangping Xiang, Frank Chen, Shen‐Chun Kuo, Kevin M. Belyk, Peter R. Mullens, Adrian Goodyear, John S. Edwards, Brian Bishop, Scott S. Ceglia, Justin K. Belardi, Lushi Tan, Zhiguo J. Song, Lisa DiMichele, Robert A. Reamer, Fabien L. Cabirol, Weng Lin Tang, Guiquan Liu,

Pharmacological Receptor Mechanisms and Effects

The development of a scalable asymmetric route to a new calcitonin gene-related peptide (CGRP) receptor antagonist is described. The synthesis of the two key fragments was redefined, and the intermediates were accessed through novel chemistry. Chiral lactam 2 was prepared by an enzyme mediated dynamic kinetic transamination which simultaneously set two stereocenters. Enzyme evolution resulted in an optimized transaminase providing the desired configuration in >60:1 syn/anti. The final chiral center was set via a crystallization induced diastereomeric transformation. The asymmetric spirocyclization to form the second fragment, chiral spiro acid intermediate 3, was catalyzed by a novel doubly quaternized phase transfer catalyst and provided optically pure material on isolation. With the two fragments in hand, development of their final union by amide bond formation and subsequent direct isolation is described. The described chemistry has been used to deliver over 100 kg of our desired target, ubrogepant.