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 1774899ノート

反応式

HRID 1774899 の反応式
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

参加物

8

反応物 2

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

生成物 1

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

試薬・触媒・溶媒 5

HCID 23994Zinc触媒HCID 178418851HCID 178418851、化合物触媒HCID 962Water溶媒HCID 6344Dichloromethane溶媒HCID 8028Tetrahydrofuran溶媒2 回

反応条件

温度
0 °C

実験手順

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).

後処理

  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

出典と根拠

ORDレコード
ord-7c269bc20b7f4618b03aabf19a16084a
出典データセット
uspto-grants-2016_02
特許番号
US09260418B2

反応ノート

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