Acetic Acid → HCID 56848628, compound

HRID 473152Notes

Reaction equation

HRID 473152 reaction equation
Cl[C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[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.C(O)(=O)C>CC(N(C)C)=O>[F:21][C:13]([F:22])([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=1)[C:4]1[N:3]=[C:2]([NH:36][C:32]2[CH:33]=[C:34]([CH3:35])[NH:30][N:31]=2)[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=1

Participants

5

Reactant 3

HCID 176Acetic AcidHCID 113215371H-Pyrazole-1-carboxylicacid,3-amino-5-methyl-,1,1-dimethylethylesterHCID 86662696HCID 86662696, compound

Product 1

HCID 56848628HCID 56848628, compoundYield 13%

Reagents, catalysts & solvents 1

HCID 31374DimethylacetamideSolvent

Conditions

Temperature
100 °C

Procedure

To 4-chloro-2-[difluoro-(5-fluoro-pyridin-2-yl)-methyl]-8-methylquinazoline (0.255 g, 0.79 mmol) in DMA (2 mL) were added 3-amino-5-methyl-pyrazole-1-carboxylic acid tert-butyl ester prepared according to US2007/219195 (0.31 g, 1.58 mmol) and acetic acid (0.15 mL) and the mixture was heated at 100° C. for 6.5 h. The mixture was allowed to cool to rt and then was purified by reverse phase HPLC using an ammonium acetate modifier. Fraction 1 containing pure product were combined, treated with saturated aq NaHCO3 and concentrated under reduced pressure. The aqueous residue was extracted with DCM and the combined extracts were washed with saturated aq NaHCO3 and brine, dried over MgSO4, filtered, and concentrated under reduced pressure to afford 2-(difluoro(5-fluoropyridin-2-yl)methyl)-8-methyl-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine (28 mg, 13%). 1H NMR (300 MHz, DMSO-d6) δ 12.15 (br s, 1H), 10.57 (s, 1H), 8.67 (s, 1H), 8.50 (d, J=8.3 Hz, 1H), 7.92-8.11 (m, 2H), 7.75 (d, J=7.0 Hz, 1H), 7.52 (t, J=7.6 Hz, 1H), 5.96 (s, 1H), 2.59 (s, 3H), 2.17 (s, 3H); LC-MS (ESI) m/z 385 (M+H)+.

Workup

  1. customprepared
  2. temperatureto cool to rt
  3. customwas purified by reverse phase HPLC
  4. additiontreated with saturated aq NaHCO3
  5. concentrationconcentrated under reduced pressure
  6. extractionThe aqueous residue was extracted with DCM
  7. washthe combined extracts were washed with saturated aq NaHCO3 and brine
  8. dry with materialdried over MgSO4
  9. filtrationfiltered
  10. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-08361b5f852a408ba5fa1e20baf4c10b
Source dataset
uspto-grants-2014_01
Patent number
US08633207B2

Reaction notes

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