Stereoselective synthesis of new conformationally restricted analogues of a potent CGRP receptor antagonist

Dmitry Zuev; Jodi A Michne; Hong Huang; Brett R Beno; Dedong Wu; Qi Gao; John R Torrente; Cen Xu; Charles M Conway; John E Macor; Gene M Dubowchik

doi:10.1021/ol0510062

Stereoselective synthesis of new conformationally restricted analogues of a potent CGRP receptor antagonist

Org Lett. 2005 Jun 9;7(12):2465-8. doi: 10.1021/ol0510062.

Authors

Dmitry Zuev¹, Jodi A Michne, Hong Huang, Brett R Beno, Dedong Wu, Qi Gao, John R Torrente, Cen Xu, Charles M Conway, John E Macor, Gene M Dubowchik

Affiliation

¹ Bristol-Myers Squibb Pharmaceutical Research Institute, P.O. Box 5100, Wallingford, Connecticut 06492, USA. [email protected]

PMID: 15932224
DOI: 10.1021/ol0510062

Abstract

[structures: see text] A stereocontrolled racemic synthesis of conformationally restricted analogues 2a and 2b of a potent CGRP receptor antagonist 1 by novel functionalization of 2-substituted octahydropyrido[1,2-a]pyrazin-6-ones is described. The new diastereoselective LDA-promoted alpha-nitration of intermediate lactams established the required trans-configuration in the desired products.

MeSH terms

Benzimidazoles / chemical synthesis*
Benzimidazoles / chemistry
Calcitonin Gene-Related Peptide Receptor Antagonists*
Crystallography, X-Ray
Lactams / chemistry
Molecular Conformation
Molecular Structure
Piperazines / chemical synthesis*
Piperazines / chemistry
Piperidines / chemical synthesis*
Piperidines / chemistry
Pyrazines / chemistry*
Stereoisomerism

Substances

4-(2-oxo-2,3-dihydrobenzimidazol-1-yl)piperidine-1-carboxylic acid (1-(3,5-dibromo-4-hydroxybenzyl)-2-oxo-2-(4-phenylpiperazin-1-yl)ethyl)amide
Benzimidazoles
Calcitonin Gene-Related Peptide Receptor Antagonists
Lactams
Piperazines
Piperidines
Pyrazines