Cesium carbonate → 3-[(3R,4S)-3-Hydroxytetrahydro-2H-pyran-4-yl]-6-{[6-(1-methyl-1H-pyrazol-4-yl)pyridine-3-yl]methyl}benzo[h]quinazolin-4(3H)-one

HRID 1774897Notes

Reaction equation

HRID 1774897 reaction equation
Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:10]=[C:11]3[C:16](=[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=24)[N:15]=[CH:14][N:13]([C@H:23]2[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]2[OH:29])[C:12]3=[O:30])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:37][N:38]1[CH:42]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH:40]=[N:39]1>C1COCC1.C(OCC)(=O)C.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[OH:29][C@@H:24]1[C@@H:23]([N:13]2[C:12](=[O:30])[C:11]3[C:16](=[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]4=[C:9]([CH2:8][C:5]4[CH:6]=[N:7][C:2]([C:41]5[CH:40]=[N:39][N:38]([CH3:37])[CH:42]=5)=[CH:3][CH:4]=4)[CH:10]=3)[N:15]=[CH:14]2)[CH2:28][CH2:27][O:26][CH2:25]1

Participants

7

Reactant 3

HCID 10796Cesium carbonateHCID 27739871-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole2×HCID 510006176-[(6-chloropyridin-3-yl)methyl]-3-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]benzo[h]quinazolin-4(3H)-one

Product 1

HCID 509151303-[(3R,4S)-3-Hydroxytetrahydro-2H-pyran-4-yl]-6-{[6-(1-methyl-1H-pyrazol-4-yl)pyridine-3-yl]methyl}benzo[h]quinazolin-4(3H)-one

Reagents, catalysts & solvents 3

HCID 178418851HCID 178418851, compoundCatalyst2×HCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
85 °C

Procedure

To a solution of 6-[(6-chloropyridin-3-yl)methyl]-3-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]benzo[h]quinazolin-4(3H)-one (Example 1, 0.040 g, 0.095 mmol) in 1 mL of THF under an atmosphere of nitrogen was added cesium carbonate (0.19 mL, 1 N aqueous, 0.19 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.040 g, 0.19 mmol), and bis(tri-tert-butylphosphine)palladium(0) (10 mol %). The reaction was heated at 85° C. for 20 h, and additional 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.040 g, 0.19 mmol), and bis(tri-tert-butylphosphine)palladium(0) (10 mol %) were added. After 24 h, the reaction was cooled to rt, diluted with ethyl acetate, and washed with saturated aqueous sodium bicarbonate and brine. The solution was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 0-5% methanol in dichloromethane, to provide the title compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 467.53 for [M+H]+: 1H NMR (400 MHz, CD3OD) δ 8.87 (d, J=7.9 Hz, 1H), 8.35 (s, 1H), 8.23 (s, 1H), 7.80-7.78 (m, 2H), 7.72 (s, 2H), 7.66-7.55 (m, 2H), 7.22-7.19 (m, 1H), 7.08 (d, J=8.2 Hz, 1H), 4.80-4.73 (m, 1H), 4.28-4.15 (m, 1H), 4.08-4.04 (m, 1H), 3.85 (s, 3H), 3.61-3.51 (m, 1H), 3.34-3.29 (m, 1H), 2.28-2.18 (m, 1H), 1.99-1.95 (m, 1H).

Workup

  1. temperaturethe reaction was cooled to rt
  2. washwashed with saturated aqueous sodium bicarbonate and brine
  3. dry with materialThe solution was dried over sodium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated in vacuo
  6. customThe residue was purified via silica gel chromatography
  7. washeluting with 0-5% methanol in dichloromethane

Sources & evidence

ORD record
ord-3236c5d5218a4bf0ae752b69a5316983
Source dataset
uspto-grants-2016_02
Patent number
US09260418B2

Reaction notes

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