Ethylene Glycol → 2-(2-(4-fluorophenyl)-1,3-dioxolan-2-yl)-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine

HRID 625803Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 625803
[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[N:19]=[C:18]([NH:20][C:21]3[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=3)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)=[O:9])=[CH:4][CH:3]=1.[CH2:27](O)[CH2:28][OH:29].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:10]3[N:19]=[C:18]([NH:20][C:21]4[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=4)[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[N:11]=3)[O:29][CH2:28][CH2:27][O:9]2)=[CH:4][CH:3]=1

Komponenten

5

Edukt 3

HCID 174Ethylene GlycolHCID 521998p-Toluenesulfonic acid monohydrateHCID 46892243(4-fluorophenyl)(4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)methanone

Produkt 1

HCID 468932582-(2-(4-fluorophenyl)-1,3-dioxolan-2-yl)-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amineAusbeute 1 %

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 1140TolueneLösungsmittel

Versuchsvorschrift

To (4-fluorophenyl)(4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)methanone from Example 3 (0.20 g, 0.58 mmol) in toluene (20 mL) were added ethylene glycol (0.2 mL) and p-toluenesulfonic acid monohydrate (catalytic quantity). The mixture was heated under reflux overnight while collecting water in a Dean-Stark trap. Additional ethylene glycol (1.5 mL) and p-toluenesulfonic acid monohydrate (50 mg) were added and mixture was heated at reflux overnight with collection of water. After cooling, the mixture was evaporated to dryness, and then dissolved in DMSO (8 mL). A 5 mL aliquot of this solution was purified by preparative reverse-phase HPLC (Varian diphenyl reverse phase column eluting with gradient of solvent B=0.05% HOAC/ACN and solvent A=0.05% HOAc/H2O) followed by additional purification by preparative reverse-phase HPLC (Phenomenex C-18 reverse phase column, eluted with gradient of solvent B=0.05% HOAC/ACN and solvent A=0.05% HOAc/H2O) to afford 2-(2-(4-fluorophenyl)-1,3-dioxolan-2-yl)-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine (2 mg, 1%). 1H NMR (300 MHz, DMSO-d6) δ 2.20 (s, 3H) 4.05-4.22 (m, 4H) 6.2 (s, 1H) 7.19 (t, 2H) 7.5-7.65 (m, 3H) 7.81 (m, 2H) 8.59 (d, 1H) 10.38 (s, 1H) 12.08 (s, 1H); LC-MS (ESI) m/z 392 (M+H)+.

Aufarbeitung

  1. temperatureThe mixture was heated
  2. temperatureunder reflux overnight
  3. customwhile collecting water in a Dean-Stark trap
  4. additionAdditional ethylene glycol (1.5 mL) and p-toluenesulfonic acid monohydrate (50 mg) were added
  5. temperaturemixture was heated
  6. temperatureat reflux overnight with collection of water
  7. temperatureAfter cooling
  8. customthe mixture was evaporated to dryness
  9. dissolutiondissolved in DMSO (8 mL)
  10. customA 5 mL aliquot of this solution was purified by preparative reverse-phase HPLC (Varian diphenyl reverse phase column
  11. washeluting with gradient of solvent B=0.05% HOAC/ACN and solvent A=0.05% HOAc/H2O)
  12. customfollowed by additional purification by preparative reverse-phase HPLC (Phenomenex C-18 reverse phase column
  13. washeluted with gradient of solvent B=0.05% HOAC/ACN and solvent A=0.05% HOAc/H2O)

Quellen und Nachweise

ORD-Eintrag
ord-cc66687068254ce982ff845e3a6b930b
Quelldatensatz
uspto-grants-2016_04
Patentnummer
US09308207B2

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