5-(Chloromethyl)-2-methoxypyridine → 3-[(3R,4S)-3-Hydroxytetrahydro-2H-pyran-4-yl]-6-[(6-methoxypyridin-3-yl)methyl]benzo[h]quinazolin-4(3H)-one

HRID 1774899Notes

Reaction equation

HRID 1774899 reaction equation
Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:9][CH3:10])=[N:7][CH:8]=1.Br[C:12]1[CH:13]=[C:14]2[C:19](=[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=13)[N:18]=[CH:17][N:16]([C@H:26]1[CH2:31][CH2:30][O:29][CH2:28][C@@H:27]1[OH:32])[C:15]2=[O:33]>C1COCC1.ClCCl.O.[Zn].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:32][C@@H:27]1[C@@H:26]([N:16]2[C:15](=[O:33])[C:14]3[C:19](=[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]4=[C:12]([CH2:2][C:3]4[CH:8]=[N:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=4)[CH:13]=3)[N:18]=[CH:17]2)[CH2:31][CH2:30][O:29][CH2:28]1

Participants

8

Reactant 2

HCID 137528915-(Chloromethyl)-2-methoxypyridineHCID 699279036-bromo-3-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]benzo[h]quinazolin-4(3H)-one

Product 1

HCID 510007023-[(3R,4S)-3-Hydroxytetrahydro-2H-pyran-4-yl]-6-[(6-methoxypyridin-3-yl)methyl]benzo[h]quinazolin-4(3H)-one

Reagents, catalysts & solvents 5

HCID 23994ZincCatalystHCID 178418851HCID 178418851, compoundCatalystHCID 962WaterSolventHCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
0 °C

Procedure

To a solution of 5-(chloromethyl)-2-methoxy pyridine (0.158 g, 0.999 mmol) in 0.5 mL of THF under an atmosphere of nitrogen was added Rieke Zn (1.3 mL, 1.0 mmol, 0.76 M in THF). The mixture was heated to reflux for 18 h, then cooled to 0° C. A solution of 6-bromo-3-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]benzo[h]quinazolin-4(3H)-one (see Example 1, 0.125 g, 0.333 mmol) in 0.5 mL of THF was added, followed by bis(tri-tert-butylphosphine)palladium(0) (5.1 mg, 0.010 mmol). The mixture was warmed to rt. After 2 h, the reaction was diluted with dichloromethane and water, and the aqueous layer was extracted with additional dichloromethane. The combined organic fractions were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 0-3% methanol in dichloromethane to provide the title compound that gave proton NMR spectra consistent with theory and a mass ion (ES+) of 418.0 for [M+H]+: 1H NMR (400 MHz, CDCl3) δ 8.94-8.92 (m, 1H), 8.27 (s, 1H), 8.03 (s, 1H), 7.91-7.87 (m, 2H), 7.65-7.61 (m, 2H), 7.29 (dd, J=2.4 Hz, 8.5 Hz, 1H), 6.58 (d, J=8.5 Hz, 1H), 4.86-4.79 (m, 1H), 4.28 (s, 2H), 4.23-4.06 (m, 3H), 3.85 (s, 3H), 3.58-3.53 (m, 1H), 3.31 (t, J=10.3 Hz, 1H), 2.96 (d, J=6.7 Hz, 1H), 2.30-2.20 (m, 1H), 2.01-1.97 (m, 1H).

Workup

  1. temperatureThe mixture was heated
  2. temperatureto reflux for 18 h
  3. temperatureThe mixture was warmed to rt
  4. extractionthe aqueous layer was extracted with additional dichloromethane
  5. dry with materialThe combined organic fractions were dried over sodium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customThe residue was purified via silica gel chromatography
  9. washeluting with 0-3% methanol in dichloromethane

Sources & evidence

ORD record
ord-7c269bc20b7f4618b03aabf19a16084a
Source dataset
uspto-grants-2016_02
Patent number
US09260418B2

Reaction notes

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