Dichloromethane → 3-[(3R,4S)-3-Hydroxytetrahydro-2H-pyran-4-yl]-6-[(6-methylpyridin-3-yl)methyl]benzo[h]quinazolin-4(3H)-one

HRID 82441

反応式

HRID 82441 の反応式
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.[Cl-].C[Zn+].[CH2:34](Cl)Cl>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[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]([CH3:34])=[CH:3][CH:4]=4)[CH:10]=3)[N:15]=[CH:14]2)[CH2:28][CH2:27][O:26][CH2:25]1

参加物

6

反応物 3

HCID 6344DichloromethaneHCID 510006176-[(6-chloropyridin-3-yl)methyl]-3-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]benzo[h]quinazolin-4(3H)-oneHCID 178477797HCID 178477797、化合物

生成物 1

HCID 510006183-[(3R,4S)-3-Hydroxytetrahydro-2H-pyran-4-yl]-6-[(6-methylpyridin-3-yl)methyl]benzo[h]quinazolin-4(3H)-one

試薬・触媒・溶媒 2

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)触媒HCID 8028Tetrahydrofuran溶媒

反応条件

温度
50 °C

実験手順

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 methyl zinc chloride (0.095 mL, 2 M in THF, 1.90 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), 1:1 complex with DCM (3 mol %). The reaction was heated at 50° C. for 18 h, cooled to rt, and quenched with water (2 mL). The mixture was filtered through celite and the aqueous layer was extracted 2× with 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 10-60% ethyl acetate in hexanes, to provide the title compound that gave proton NMR spectra consistent with theory and a mass ion (ES+) of 401.46 for [M+H]+: 1H NMR (400 MHz, CDCl3) δ 8.92 (d, J=7.5 Hz, 1H), 8.38 (s, 1H), 8.29 (s, 1H), 7.83 (d, J=7.3 Hz, 1H), 7.79 (s, 1H), 7.66-7.59 (m, 2H), 7.15 (d, J=8.1 Hz, 1H), 6.90 (d, J=7.9 Hz, 1H), 4.87-4.78 (m, 1H), 4.26-4.19 (m, 4H), 4.12-4.08 (m, 1H), 3.81 (br s, 1H), 3.61-3.54 (m, 1H), 3.44-3.37 (m, 1H), 2.43 (s, 3H), 2.33-2.23 (m, 1H), 2.03-1.99 (m, 1H).

後処理

  1. temperaturecooled to rt
  2. customquenched with water (2 mL)
  3. filtrationThe mixture was filtered through celite
  4. extractionthe aqueous layer was extracted 2× with 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 10-60% ethyl acetate in hexanes

出典と根拠

ORDレコード
ord-6e922bd8d561444a811506cacae4afba
出典データセット
uspto-grants-2014_09
特許番号
US08846702B2

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