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 82445노트

반응식

HRID 82445 반응식
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

참가 물질

8

반응물 2

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

생성물 1

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

시약·촉매·용매 5

HCID 23994Zinc촉매HCID 178418851HCID 178418851, 화합물촉매HCID 962Water용매HCID 6344Dichloromethane용매HCID 8028Tetrahydrofuran용매2회

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온도
0 °C

실험 절차

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).

후처리

  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

출처 및 근거

ORD 기록
ord-cb44d478f1ca41229956b073ab777d78
출처 데이터셋
uspto-grants-2014_09
특허 번호
US08846702B2

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