Asymmetric Synthesis of a 5,6,7,8-Tetrahydro-1,6-naphthyridine Scaffold Leading to Potent Retinoid-Related Orphan Receptor γt Inverse Agonist TAK-828F

Overview

Journal J Org Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2020 Jul 24

PMID 32701287

Citations 1

Authors

Ryoji Tsuruoka

Naoki Yoshikawa

Takahiro Konishi

Mitsuhisa Yamano

Affiliations

Soon will be listed here.

Abstract

An asymmetric synthesis of the tetrahydronaphthyridine scaffold of TAK-828F as a RORγt inverse agonist has been developed. The synthesis features a newly discovered atom-economical protocol for Heck-type vinylation of chloropyridine using ethylene gas, an unprecedented formation of dihydronaphthyridine directly from 2-vinyl-3-acylpyridine mediated by ammonia, and a ruthenium-catalyzed enantioselective transfer hydrogenation as key steps. This represents the first example of the enantioselective synthesis of a 5,6,7,8-tetrahydro-1,6-naphthyridine compound. The new synthesis is also free of chromatography or distillation purification processes and therefore qualifies for extension to large-scale manufacture.

Citing Articles

Discovery, Synthesis, and In Vitro Characterization of 2,3 Derivatives of 4,5,6,7-Tetrahydro-Benzothiophene as Potent Modulators of Retinoic Acid Receptor-Related Orphan Receptor γt.

Fouda A, Negi S, Zaremba O, Gaidar R, Moroz Y, Rusanov E J Med Chem. 2023; 66(11):7355-7373.

PMID: 37172324 PMC: 10259452. DOI: 10.1021/acs.jmedchem.3c00021.

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