Bromide ion → (2-methoxyphenyl)(4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)methanone

HRID 1424467Notes

Reaction equation

HRID 1424467 reaction equation
Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([O:14]CC)=O)[N:3]=1.[Br-].Cl.[Na+].[Cl-].[CH3:21][C:22]1[NH:26][N:25]=[C:24]([NH2:27])[CH:23]=1.[I-].[K+].CCN(C(C)C)[CH:33]([CH3:35])[CH3:34].[CH2:39]1[CH2:43][O:42][CH2:41][CH2:40]1>CN(C=O)C.O>[CH3:41][O:42][C:43]1[CH:39]=[CH:40][CH:35]=[CH:33][C:34]=1[C:12]([C:4]1[N:3]=[C:2]([NH:27][C:24]2[CH:23]=[C:22]([CH3:21])[NH:26][N:25]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)=[O:14]

Participants

11

Reactant 8

HCID 259Bromide ionHCID 313Hydrochloric AcidHCID 4875Potassium IodideHCID 5234Sodium ChlorideHCID 8028TetrahydrofuranHCID 81531DiisopropylethylamineHCID 931461H-Pyrazol-3-amine, 5-methyl-HCID 3477840Ethyl 4-chloroquinazoline-2-carboxylate

Product 1

HCID 46893386(2-methoxyphenyl)(4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)methanone

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
-40 °C

Procedure

To a solution of ethyl 4-chloroquinazoline-2-carboxylate (500 mg, 2.11 mmol) in THF (20 mL) at −40° C. was added dropwise 1M 2-methoxyphenylmagnesum bromide (2.6 mL, 2.5 mmol) and the mixture was stirred at −40° C. for 4 h. To the mixture were added 1N HCl to pH <2 and saturated aq NaCl (50 mL), and the mixture was extracted with EtOAc (3×80 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. To the residue (673 mg) were added a solution of 5-methyl-1H-pyrazol-3-amine (247 mg, 2.84 mmol) in DMF (8 mL), potassium iodide (387 mg, 2.33 mmol), and DIEA (822 mg, 6.36 mmol), and the mixture was stirred at rt overnight and then at 50° C. for 5 h and then at 80° C. for 2 h. The mixture was allowed to cool to rt and then H2O (30 mL) was added. The mixture was stirred and cooled to 0° C., and the precipitated solid was collected by filtration and washed with MeOH. A portion of the solid was purified by preparative reverse phase HPLC to afford (2-methoxyphenyl)(4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)methanone. 1H NMR (300 MHz, DMSO-d6) δ 2.11 (s, 3H), 3.48 (s, 3H), 6.15 (s, 1H), 7.11-7.18 (m, 2H), 7.56-7.64 (m, 3H), 7.56 (bs, 2H), 8.70 (d, 1H), 10.58 (s, 1H), 12.11 (s, 1H); LC-MS (ESI) m/z 360 (M+H)+.

Workup

  1. extractionthe mixture was extracted with EtOAc (3×80 mL)
  2. washThe combined organic layers were washed with brine (50 mL)
  3. dry with materialdried over Na2SO4
  4. filtrationfiltered
  5. concentrationconcentrated under reduced pressure
  6. stirringthe mixture was stirred at rt overnight
  7. waitat 50° C. for 5 h
  8. waitat 80° C. for 2 h
  9. temperatureto cool to rt
  10. stirringThe mixture was stirred
  11. temperaturecooled to 0° C.
  12. filtrationthe precipitated solid was collected by filtration
  13. washwashed with MeOH
  14. customA portion of the solid was purified by preparative reverse phase HPLC

Sources & evidence

ORD record
ord-26ac77508f23482dbede46e4dcb3d667
Source dataset
uspto-grants-2015_01
Patent number
US08927711B2

Reaction notes

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