Acetic Acid → HCID 56848629, compound

HRID 473156Notes

Reaction equation

HRID 473156 reaction equation
Cl[C:2]1[C:11]2[C:6](=[C:7]([Br:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]([F:22])([F:21])[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=2)[N:3]=1.C(OC([N:30]1[C:34]([CH3:35])=[CH:33][C:32]([NH2:36])=[N:31]1)=O)(C)(C)C.CC(O)=O>CC(N(C)C)=O>[Br:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[C:4]([C:13]([F:22])([F:21])[C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=1)[N:3]=[C:2]2[NH:36][C:32]1[CH:33]=[C:34]([CH3:35])[NH:30][N:31]=1

Participants

5

Reactant 3

HCID 176Acetic AcidHCID 113215371H-Pyrazole-1-carboxylicacid,3-amino-5-methyl-,1,1-dimethylethylesterHCID 86662697HCID 86662697, compound

Product 1

HCID 56848629HCID 56848629, compoundYield 21.8%

Reagents, catalysts & solvents 1

HCID 31374DimethylacetamideSolvent

Conditions

Temperature
100 °C

Procedure

To 4-chloro-2-[difluoro-(5-fluoro-pyridin-2-yl)-methyl]-8-bromo-quinazoline (0.19 g, 0.49 mmol) in DMA (1.0 mL) were added 3-amino-5-methyl-pyrazole-1-carboxylic acid tert-butyl ester (0.30 g, 1.53 mmol) and HOAc (0.065 mL, 1.1 mmol) and the mixture was heated to 100° C. for 5 h. The mixture was allowed to cool to rt and purified by reverse phase HPLC (ammonium acetate modifier). Fraction 1 containing pure product was treated with saturated aq NaHCO3 (2-4 mL) and concentrated under reduced pressure. The aqueous residue was extracted with DCM (3×30 mL) and the combined extracts were washed with sat aqueous NaHCO3 (10 mL) and brine (10 mL), dried over MgSO4, filtered, and concentrated to dryness under reduced pressure to afford 8-bromo-2-(difluoro(5-fluoropyridin-2-yl)methyl)-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine (48 mg, 20%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 12.22 (br s, 1H), 10.87 (br s, 1H), 8.57-8.81 (m, 2H), 8.24 (d, J=7.5 Hz, 1H), 8.02 (d, J=5.3 Hz, 2H), 7.54 (t, J=7.9 Hz, 1H), 5.95 (s, 1H), 2.17 (s, 3H); LC-MS (ESI) m/z 449/451 (M+H+).

Workup

  1. temperatureto cool to rt
  2. custompurified by reverse phase HPLC (ammonium acetate modifier)
  3. additionFraction 1 containing pure product was treated with saturated aq NaHCO3 (2-4 mL)
  4. concentrationconcentrated under reduced pressure
  5. extractionThe aqueous residue was extracted with DCM (3×30 mL)
  6. washthe combined extracts were washed with sat aqueous NaHCO3 (10 mL) and brine (10 mL)
  7. dry with materialdried over MgSO4
  8. filtrationfiltered
  9. concentrationconcentrated to dryness under reduced pressure

Sources & evidence

ORD record
ord-aaba5fb91e7b44c29318f3f896fd3e20
Source dataset
uspto-grants-2014_01
Patent number
US08633207B2

Reaction notes

Loading…