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Dimethylformamide → 4-{3-[(4-{[5-Chloro-7-(4-methoxypent-1-yn-1-yl)-1,3-benzodioxol-4-yl]amino}-6-methoxyquinazolin-7-yl)oxy]propyl}-1-methylpiperazin-2-one

HRID 1785148
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Druckvorschau

Reaktionsgleichung

Reaktionsgleichung von HRID 1785148
[Cl:1][C:2]1[CH:10]=[C:9](I)[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH2:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[C:31](=[O:36])[CH2:30]3)=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1.[CH3:37][O:38][CH:39]([CH3:43])[CH2:40][C:41]#[CH:42].C(NC(C)C)(C)C.CN(C=O)C>C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[CH:10]=[C:9]([C:42]#[C:41][CH2:40][CH:39]([O:38][CH3:37])[CH3:43])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH2:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[C:31](=[O:36])[CH2:30]3)=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1
KomponentenVersuchsvorschriftAufarbeitungQuellen und NachweiseNotizen zur Reaktion

Komponenten

8

Edukt 4

HCID 6228DimethylformamideHCID 7912DiisopropylamineHCID 688822194-[3-({4-[(5-Chloro-7-iodo-1,3-benzodioxol-4-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]-1-methylpiperazin-2-oneHCID 866015644-Methoxypent-1-yne2×

Produkt 1

HCID 688829434-{3-[(4-{[5-Chloro-7-(4-methoxypent-1-yn-1-yl)-1,3-benzodioxol-4-yl]amino}-6-methoxyquinazolin-7-yl)oxy]propyl}-1-methylpiperazin-2-one
Ausbeute 73 %

Reagenzien, Katalysatoren, Lösungsmittel 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)KatalysatorHCID 178418476HCID 178418476, VerbindungKatalysatorHCID 8857Ethyl AcetateLösungsmittel

Versuchsvorschrift

4-[3-({4-[(5-Chloro-7-iodo-1,3-benzodioxol-4-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]-1-methylpiperazin-2-one (250 mg, 0.40 mmol) and 4-methoxypent-1-yne (120 mg, 1.2 mmol) in ethyl acetate (8 ml) stirred at room temperature, under an atmosphere of nitrogen, and treated with bis(triphenylphosphine)palladium(II) dichloride (28 mg, 10 mol %) followed by copper(I) iodide (8 mg, 10 mol %) and diisopropylamine (82 mg, 0.81 mmol). The reaction was stirred 2 hr then DMF (3 ml) added followed by a further 120 mg 4-methoxypent-1-yne. The mixture was stirred for 1 hr then evaporated and the residue partitioned between water and dichloromethane. The organic layer was separated, washed with brine, dried over magnesium sulphate and evaporated to an orange oil. Purified by column chromatography on silica using increasing concentrations of methanol in dichloromethane as eluent to give the title compound (174 mg, 73%) as a pale yellow solid; NMR Spectrum:(DMSOd6) 1.23 (d, 3H), 1.98 (quintet, 2H), 2.54 (t, 2H), 2.61 (dd, 1H), 2.65-2.75 (m, 3H), 2.82 (s, 3H), 3.01 (s, 2H), 3.27 (t, 2H), 3.30 (s, 3H), 3.53 (m, 1H), 3.92 (s, 3H), 4.18 (t, 2H), 6.13 (s, 2H), 7.06 (s, 1H), 7.22 (s(broad), 1H), 7.84 (s, 1H), 8.38 (s(broad), 1H), 9.49 (s, 1H); Mass Spectrum: M+H+ 596/598.

Aufarbeitung

  1. stirringThe mixture was stirred for 1 hr
  2. customthen evaporated
  3. customthe residue partitioned between water and dichloromethane
  4. customThe organic layer was separated
  5. washwashed with brine
  6. dry with materialdried over magnesium sulphate
  7. customevaporated to an orange oil
  8. customPurified by column chromatography on silica using
  9. temperatureincreasing concentrations of methanol in dichloromethane as eluent

Quellen und Nachweise

ORD-Eintrag
ord-0a3ac54f66474a0b88147a0694c6ec41
Quelldatensatz
uspto-grants-2009_03
DOI
10.6084/m9.figshare.5104873.v1
Patentnummer
US07504408B2

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