CRF Ligands via suzuki and negishi couplings of 3-pyridyl boronic acids or halides with 2-benzyloxy-4-chloro-3-nitropyridine

Bioorganic and Medicinal Chemistry Letters

Volumn 13, Issue 2, 2003, Pages 289-291

  Arvanitis, Argyrios G ^a   Arnold, Charles R ^a   Fitzgerald, Lawrence W ^a   Frietze, William E ^a   Olson, Richard E ^a   Gilligan, Paul J ^a   Robertson, David W ^a  

^a BRISTOL MYERS SQUIBB   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

2 BENZYLOXY 4 CHLORO 3 NITROPYRIDINE; BORONIC ACID DERIVATIVE; CORTICOTROPIN RELEASING FACTOR; HALIDE; LIGAND; PALLADIUM; PYRIDINE DERIVATIVE; UNCLASSIFIED DRUG; ZINC DERIVATIVE; 2-BENZYLOXY-4-CHLORO-3-NITROPYRIDINE; CORTICOTROPIN RELEASING FACTOR RECEPTOR; DYES, REAGENTS, INDICATORS, MARKERS AND BUFFERS; IMIDAZOLE DERIVATIVE;

ARTICLE; CATALYSIS; CATALYST; DRUG STRUCTURE; DRUG SYNTHESIS; ANIMAL; BRAIN CORTEX; CHEMISTRY; DRUG EFFECT; IN VITRO STUDY; METABOLISM; PHYSICAL CHEMISTRY; RAT; SYNTHESIS;

ANIMALS; BORONIC ACIDS; CATALYSIS; CEREBRAL CORTEX; CHEMISTRY, PHYSICAL; IMIDAZOLES; INDICATORS AND REAGENTS; LIGANDS; PALLADIUM; PYRIDINES; RATS; RECEPTORS, CORTICOTROPIN-RELEASING HORMONE;

EID: 0037212688     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(02)00835-1     Document Type: Article

References (11)

1. Arvantis A.G., Rescinito J.T., Arnold C.R., Wilde R.G., Cain G.A., Sun J.-H., Yan J.-S., Teleha C.A., Fitzgerald L.W., McElroy J., Zaczek R., Hartig P.R., Grossman S., Arneric S.P., Giligan P.J., Olson R.E., Robertson D.W. Bioorg. Med. Chem. Lett. 2002;12. Update BMCL 6255.
2. Wilde, R. G.; Klaczkiewicz, J. D.; Carter, K. L.; Gilligan, P. J.; Olson, R. E.; Frietze, W. E.; Buckner, W. H.; Beck, J. P.; Curry, M. A.; Robertson, D. W.; Sun, J. H.; Arneric, S. P.; Hartig, P. R.; Fitzgerald, L. W.; Marshall, W. J. Abstracts of Papers, 219th National Meeting of the American Chemical Society: San Francisco, CA, 26-30 March, 2000.
3. 2 (0.5 M/THF, 59.4 mL, 29.7 mmol) was added dropwise, via addition funnel. The reaction was warmed to 0 °C, and tetrakis(triphenylphosphine)palladium(0) (172 mg, 0.149 mmol) and 2-beznyloxy-4-chloro-3-nitropyridine (3.93 g, 14.85 mmol) were added. The reaction was then heated at reflux for 5 h, after which time it was concentrated in vacuo. The crude product was partitioned between ethyl acetate and 1 M EDTA disodium (aq). The ethyl acetate was washed with brine, dried and concentrated. The residue was chromatographed on silica gel using ethyl acetate/hexane (1:4) as eluent. 4.28 g, 12.1 mmol, 82% yield.
4. The 3-iodo-6-methoxy-2-trifluoromethylpyridine was synthesized by the following scheme.
5. 4 (202 mg, 0.176 mmol) and 12 (858 mg, 3.36 mmol) and heated to reflux for 24 h. The mixture was filtered through Celite, extracted with EtOAc and the organic solution was dried and stripped in vacuo. The product was purified by silica gel chromatography (15% EtOAc/hexanes eluent), and crystallized from hexanes, 1.15 g, 56% yield. For other zinc-mediated couplings of 3-iodopyridines, see: Sakamoto T., Kondo Y., Murata N., Yamanaka H. Tetrahedron Lett. 33:1992;5373 Sakamoto T., Kondo Y., Murata N., Yamanaka H. Tetrahedron. 49:1993;7913.
6. 4 (202 mg, 0.176 mmol) and 12 (858 mg, 3.36 mmol) and heated to reflux for 24 h. The mixture was filtered through Celite, extracted with EtOAc and the organic solution was dried and stripped in vacuo. The product was purified by silica gel chromatography (15% EtOAc/hexanes eluent), and crystallized from hexanes, 1.15 g, 56% yield. For other zinc-mediated couplings of 3-iodopyridines, see: Sakamoto T., Kondo Y., Murata N., Yamanaka H. Tetrahedron Lett. 33:1992;5373 Sakamoto T., Kondo Y., Murata N., Yamanaka H. Tetrahedron. 49:1993;7913.
7. Gray M.A., Konopski L., Langlois Y. Synth. Commun. 24:1994;1367.
8. To 5-bromo-2-methoxy-4-methylpyridine (3.5 g, 17.3 mmol) and tri-isopropylborate (5.0 mL, 21.7 mmol) in 50 mL dry THF (-100 °C) was added n-BuLi (1.6 M/hexanes, 11.9 mL, 19.0 mmol) dropwise. The reaction was stirred at -100 °C for 1.5 h, warmed slowly to room temperature (1 h), and stirred 18 h. To the reaction was then added 1 N HCl and the reaction stirred for 1 h. The pH was adjusted to 9 with NaOH, and the mixture was extracted with ethyl acetate and ether. The pH of the aqueous layer was then adjusted to 7, and again extracted with ethyl acetate. All the extracts when concentrated contained the desired product. 2.7 g, 93% yield.
9. 2-Benzyloxy-4-chloro-3-nitropyridine (198 mg, 0.749 mmol), the pyridyl boronic acid (150 mg, 0.898 mmol), bis(triphenylphosphine)palladium(II) chloride (26 mg, 0.037 mmol), ethylene glycol dimethyl ether (2.5 mL), water (2.5 mL), and barium hydroxide octahydrate (282 mg, 0.898 mmol) were combined, degassed under vacuum, and heated at reflux 18 h. To the cooled reaction was added water, which was extracted with ethyl acetate. The ethyl acetate was washed with brine, dried and concentrated. the residue was chromatographed on silica gel using ethyl acetate/hexane (1:4) as eluent, yielding 105 mg, 40% yield.
10. Synthesized from 7a by treatment with 48% HBr at 110 °C for 16 h.
11. 6. The regiochemistry of the 7g was established by NOE experiments.