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

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.

• Publication year

  2020

• Venue

  Journal of Organic Chemistry

• Publication date

  2020-07-23

• Fields of study

  Medicine, Chemistry

• Identifiers
  DOI 10.1021/acs.joc.0c01311PMID 32701287PMCID 7445745
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Pharmacological effects of TAK-828F: an orally available RORγt inverse agonist, in mouse colitis model and human blood cells of inflammatory bowel disease

  2019cited by this paper
• Design, Synthesis, and Biological Evaluation of Retinoic Acid-Related Orphan Receptor γt (RORγt) Agonist Structure-Based Functionality Switching Approach from In House RORγt Inverse Agonist to RORγt Agonist.

  2019cited by this paper
• 5,6,7,8-Tetrahydro-1,6-naphthyridine Derivatives as Potent HIV-1-Integrase-Allosteric-Site Inhibitors.

  2019cited by this paper
• Pharmacological evaluation of TAK-828F, a novel orally available RORγt inverse agonist, on murine chronic experimental autoimmune encephalomyelitis model.

  2019cited by this paper
• Biochemical Properties of TAK-828F, a Potent and Selective Retinoid-Related Orphan Receptor Gamma t Inverse Agonist

  2018cited by this paper
• Pharmacological inhibitory profile of TAK‐828F, a potent and selective orally available ROR&ggr;t inverse agonist

  2018cited by this paper
• Discovery of [ cis-3-({(5 R)-5-[(7-Fluoro-1,1-dimethyl-2,3-dihydro-1 H-inden-5-yl)carbamoyl]-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5 H)-yl}carbonyl)cyclobutyl]acetic Acid (TAK-828F) as a Potent, Selective, and Orally Available Novel Retinoic Acid Receptor-Related Orphan Receptor γt Inverse Agonis

  2018cited by this paper
• Model Guided Development of a Simple Catalytic Method for the Synthesis of Unsymmetrical Stilbenes by Sequential Heck Reactions of Aryl Bromides with Ethylene

  2018cited by this paper
• Pharmacological Evaluation of TAK-828F, a Novel Orally Available RORγt Inverse Agonist, on Murine Colitis Model

  2018cited by this paper
• Lewis Acid‐Catalyzed C(sp3)–C(sp3) Bond Forming Cyclization Reactions for the Synthesis of Tetrahydroprotoberberine Derivatives

  2017cited by this paper
• Catalytic Enantioselective Synthesis of Tetrahydocarbazoles and Exocyclic Pictet-Spengler-Type Reactions.

  2016cited by this paper
• Organocatalytic enantioselective Pictet-Spengler approach to biologically relevant 1-benzyl-1,2,3,4-tetrahydroisoquinoline alkaloids.

  2015cited by this paper
• Asymmetric Transfer Hydrogenation of Imines in Water by Varying the Ratio of Formic Acid to Triethylamine.

  2015cited by this paper
• α,β-Unsaturated acyl cyanides as new bis-electrophiles for enantioselective organocatalyzed formal [3+3]spiroannulation.

  2014cited by this paper
• Optimization of potency and pharmacokinetic properties of tetrahydroisoquinoline transient receptor potential melastatin 8 (TRPM8) antagonists.

  2014cited by this paper
• Tetrahydronaphthyridine and Dihydronaphthyridinone Ethers As Positive Allosteric Modulators of the Metabotropic Glutamate Receptor 5 (mGlu5)

  2014cited by this paper
• Conjugate-base-stabilized Brønsted acids: catalytic enantioselective Pictet-Spengler reactions with unmodified tryptamine.

  2014cited by this paper
• Scaling Up of Continuous Flow Processes with Gases Using a Tube-in-Tube Reactor: Inline Titrations and Fanetizole Synthesis with Ammonia

  2013cited by this paper
• Total Syntheses of AF-2785 and Gamendazole—Experimental Male Oral Contraceptives

  2013cited by this paper
• Asymmetric Hydrogenation of Cyclic Imines Catalyzed by Chiral Spiro Iridium Phosphoramidite Complexes for Enantioselective Synthesis of Tetrahydroisoquinolines

  2012cited by this paper
• Highly enantioselective Pictet-Spengler reaction catalyzed by SPINOL-phosphoric acids.

  2012cited by this paper
• The Development of an Asymmetric Hydrogenation Process for the Preparation of Solifenacin

  2012cited by this paper
• Enantioselective synthesis of 1-aryl-tetrahydroisoquinolines through iridium catalyzed asymmetric hydrogenation.

  2012cited by this paper
• Faculty Opinions recommendation of Digoxin and its derivatives suppress TH17 cell differentiation by antagonizing RORγt activity.

  2011cited by this paper
• Digoxin and its derivatives suppress TH17 cell differentiation by antagonizing RORγt activity

  2011cited by this paper
• Suppression of TH17 Differentiation and Autoimmunity by a Synthetic ROR Ligand

  2011cited by this paper
• Direct synthesis of chiral 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazines via a catalytic asymmetric intramolecular aza-Friedel-Crafts reaction.

  2011cited by this paper
• A highly efficient and enantioselective access to tetrahydroisoquinoline alkaloids: asymmetric hydrogenation with an iridium catalyst.

  2011cited by this paper
• Asymmetric organocatalytic cyclization and cycloaddition reactions.

  2011cited by this paper
• The Continuous-Flow Synthesisof Styrenes Using Ethylene in a Palladium-Catalysed Heck Cross-CouplingReaction

  2011cited by this paper
• Organic Synthesis Toward Small-Molecule Probes and Drugs Special Feature: Diversity through phosphine catalysis identifies octahydro-1,6-naphthyridin-4-ones as activators of endothelium-driven immunity

  2011cited by this paper
• Applications of N′-alkylated derivatives of TsDPEN in the asymmetric transfer hydrogenation of CO and CN bonds

  2010cited by this paper
• Dialkylbiaryl Phosphines in Pd-Catalyzed Amination: A User's Guide.

  2010cited by this paper
• Enantioselective synthesis of (R)-(+)- and (S)-(-)-higenamine and their analogues with effects on platelet aggregation and experimental animal model of disseminated intravascular coagulation.

  2008cited by this paper
• Discovery and understanding of transition-metal-catalyzed aromatic substitution reactions

  2006cited by this paper
• The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells.

  2006cited by this paper
• Heck Cross-Coupling for Synthesizing Metal-Complexing Monomers.

  2006cited by this paper
• Heck cross-coupling for synthesizing metal-complexing monomers

  2006cited by this paper
• The intermolecular Pictet-Spengler condensation with chiral carbonyl derivatives in the stereoselective syntheses of optically-active isoquinoline and indole alkaloids

  2005cited by this paper
• Iridium-catalyzed asymmetric hydrogenation

  2004cited by this paper
• Synthesis of 5-phenyl-5,6,7,8-tetrahydro-1,6-naphthyridines and 5-phenyl-6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepines as potential D1 receptor ligands

  2004cited by this paper
• Modern synthetic methods for copper-mediated C(aryl)[bond]O, C(aryl)[bond]N, and C(aryl)[bond]S bond formation.

  2003cited by this paper
• Modern Synthetic Methods for Copper‐Mediated C(aryl) ? O, C(aryl) ? N, and C(aryl) ? S Bond Formation

  2003cited by this paper
• Suppression of Immune Induction of Collagen-Induced Arthritis in IL-17-Deficient Mice 1

  2003cited by this paper
• First Application of Secondary Phosphines as Supporting Ligands for the Palladium‐Catalyzed Heck Reaction: Efficient Activation of Aryl Chlorides

  2002cited by this paper
• A Reliable Multikilogram-Scale Synthesis of 2-Acetamido-5-Vinylpyridine Using Catalytic BINAP in a Modified Heck Reaction

  2002cited by this paper
• Copper-catalyzed halogen exchange in aryl halides: an aromatic Finkelstein reaction.

  2002cited by this paper
• A chiral rhodium complex for rapid asymmetric transfer hydrogenation of imines with high enantioselectivity.

  1999cited by this paper
• Synthesis of Substituted 1,4‐Divinylbenzenes by Heck Reactions with Compressed Ethene.

  1999cited by this paper
• Asymmetric Transfer Hydrogenation of Imines

  1996cited by this paper
• ANTIVERTIGO AGENTS. IV. SYNTHESIS AND ANTIVERTIGO ACTIVITY OF 6-(Ω-(4-ARYL-1-PIPERAZINYL)ALKYL)-5,6,7,8-TETRAHYDRO-1,6-NAPHTHYRIDINES

  1985cited by this paper
• Antivertigo agents. IV. Synthesis and antivertigo activity of 6-[omega-(4-aryl-1-piperazinyl)alkyl]-5,6,7,8-tetrahydro-1,6-naphth yridines.

  1984cited by this paper
• Halide-directed nitrile hydrolysis

  1981cited by this paper
• The Pyridylethylation of Active Hydrogen Compounds. V. The Reaction of Ammonia, Certain Amines, Amides and Nitriles with 2- and 4-Vinylpyridine and 2-Methyl-5-vinylpyridine1

  1956cited by this paper
• The Orphan Nuclear Receptor ROR g t Directs the Differentiation Program of Proinflammatory IL-17 + T Helper Cells

  year unknowncited by this paper
• EncephalomyelitisDevelopment of Experimental Autoimmune IL-17 Plays an Important Role in the

  year unknowncited by this paper

• Switchable and Ring-Selective Hydrogenation of Naphthyridine Isomers.

  2025cites this paper
• Lewis Acid-Catalyzed Ring-Opening Reaction of Bicyclobutanes (BCBs) for the Highly Selective Synthesis of 1,1,3-Trisubstituted Cyclobutanes.

  2025cites this paper
• 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

  2023cites this paper
• Sequential Ag(I) Salt and Chiral N-Heterocyclic Carbene Catalysis Enables Enantioselective and Diastereoselective Construction of Complex Heterocyclic Molecules and the Switch of Stereoselectivity.

  2022cites this paper
• High-Throughput Experimentation in Organometallic Chemistry and Catalysis

  2021cites this paper
• Synthesis of TAK-828F

  2020cites this paper