A Palladium-Catalysed Urea Arylation Route to a CRF1 Receptor Antagonist

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.

CRF antagonist - palladium - catalysis - ligands - urea - arylations

References and Notes

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9

4-Methoxyphenyl isocyanate was purchased from Sigma-Aldrich.

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17

Data 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.

18

The 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.