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DOI: 10.1055/s-2006-950276
A Palladium-Catalysed Urea Arylation Route to a CRF1 Receptor Antagonist
Publication History
Publication Date:
09 October 2006 (online)
Abstract
A new synthetic approach to a potent CRF antagonist, GW808990 (NBI35583), is reported. The route hinges on the palladium-catalysed intramolecular arylation of a urea with 2-chloropyridine. Spontaneous piperazine ring closure means that a high-yielding bisannulation reaction is the final step.
Key words
CRF antagonist - palladium - catalysis - ligands - urea - arylations
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References and Notes
4-Methoxyphenyl isocyanate was purchased from Sigma-Aldrich.
17Data for 10: mp 128-129 °C (EtOAc). 1H NMR (400 MHz, CDCl3): δ = 7.22 (d, J = 9.1 Hz, 2 H), 6.80 (d, J = 9.1 Hz, 2 H), 6.70 (br s, 1 H), 6.67 (s, 1 H), 6.36 (br s, 1 H), 4.04 (t, J = 6.1 Hz, 2 H), 3.75 (s, 3 H), 3.74-3.78 (m, 1 H), 3.46 (t, J = 6.1 Hz, 2 H), 2.44 (s, 3 H), 1.89 (s, 3 H), 1.44-1.50 (m, 4 H), 1.21-1.28 (m, 4 H), 0.83 (t, J = 7.3 Hz, 6 H). 13C NMR (100 MHz, CDCl3): δ = 171.1, 157.1, 156.7, 156.4, 154.2, 152.7, 130.8, 123.2, 118.3, 114.2, 112.4, 91.4, 61.9, 61.7, 41.1, 35.7, 24.3, 20.6, 20.2, 14.2. IR (ATR mode): 1735, 1584, 1510, 1244, 1027, 986, 934, 836 cm-1. HRMS (ES): m/z [MH+] calcd for C25H36ClN4O4: 491.2425; found: 491.2406.
18The urea 10 (300 mg, 0.61 mmol) and K2CO3 (190 mg, 1.38 mmol) were suspended in dioxane (6.0 mL). Pd2(dba)3 (20 mg, 0.022 mmol, 0.036 equiv) and 2-(dicyclohexylphos-phino)-2′-methylbiphenyl (20 mg, 0.055 mmol, 0.09 equiv) were added and the reaction vessel was flushed with Ar and the reaction mixture was heated to reflux for 20 h. Solution yield of the product 1 at this point was 86%. The reaction mixture was then evaporated and partitioned between EtOAc (10 mL) and 5% aq NaHCO3 (5 mL). The EtOAc layer was then separated and dried over MgSO4 before being filtered and evaporated to give the crude product 1 which was purified by chromatography (hexane-EtOAc, 1:1) to give pure 1 in 58% yield. Data for 1: 1H NMR (400 MHz, CDCl3): δ = 7.63 (dd, J = 2.2, 6.8 Hz, 2 H), 7.00 (dd, J = 2.2, 6.8 Hz, 2 H), 6.25 (s, 1 H), 3.98 (t, J = 5.0 Hz, 2 H), 3.83 (s, 3 H), 3.74 (m, 1 H), 3.38 (t, J = 5.0 Hz, 2 H), 2.44 (s, 3 H), 1.55 (m, 4 H), 1.32 (m, 4 H), 0.92 (t, J = 7.3 Hz, 6 H). 13C NMR (100 MHz, CDCl3): δ = 158.3, 152.0, 151.2, 141.4, 138.3, 127.2, 126.8, 114.4, 106.8, 99.2, 55.7, 55.5, 39.4, 34.7, 34.7, 25.2, 20.0, 14.0. IR (ATR mode): 1712, 1654, 1515, 1246, 1036, 854, 793, 735, 691 cm-1. HRMS (ES): m/z [MH+] calcd for C23H31N4O2: 395.2447; found: 395.2441.