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Synfacts 2016; 12(3): 0223
DOI: 10.1055/s-0035-1561242
Synthesis of Natural Products and Potential Drugs
© Georg Thieme Verlag Stuttgart · New York

Synthesis of a CGRP Receptor Antagonist

Rezensent(en):
Philip Kocienski
Luo G, * Chen L, Conway CM, Kostich W, Macor JE, Dubowchik GM. Bristol-Myers Squibb Research and Development, Wallingford, USA
Asymmetric Synthesis of Heterocyclic Analogues of a CGRP Receptor Antagonist for Treating Migraine.

Org. Lett. 2015;
17: 5982-5985
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Publikationsverlauf

Publikationsdatum:
16. Februar 2016 (online)

 
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Key words

CGRP receptor antagonist - Hayashi–Miyaura reaction - asymmetric conjugate addition - intramolecular Heck reaction - Ellman–Davis amine synthesis

Significance

The target molecule M is a calcitonin gene-related peptide (CGRP) receptor anta­gonist that is of interest for the treatment of migraine. It is one of four analogues of rimegepant that were prepared by a common strategy featuring the use of a Hayashi–Miyaura asymmetric conjugate addition (A → B) and Ellman–Davis protocol (E → G) to set two of the three stereogenic centers.


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Comment

Attempts to construct the seven-membered ring from I by an intramolecular Heck reaction were thwarted by the rearrangement of the exocyclic alkene product to a trisubstituted alkene. This alkene isomerization was suppressed in part by addition of an ester group in J.


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