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

HRID 1801949Notes

Reaction equation

HRID 1801949 reaction equation
[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

Participants

5

Reactant 3

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

Product 1

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

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Procedure

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, 3 H) 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, 1 H); LC-MS (ESI) m/z 392 (M+H)+.

Workup

  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)

Sources & evidence

ORD record
ord-d04281b79d1949bd968b699b67daf508
Source dataset
uspto-grants-2013_01
Patent number
US08349851B2

Reaction notes

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