Acetic Acid → HCID 56848630, compound

HRID 473160Notes

Reaction equation

HRID 473160 reaction equation
Cl[C:2]1[C:11]2[C:6](=[C:7]([F: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.[NH2:23][C:24]1[CH:28]=[C:27]([CH3:29])[N:26](C(OC(C)(C)C)=O)[N:25]=1.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:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)[C:11]2[C:6](=[C:7]([F: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 866626984-Chloro-2-(difluoro(5-fluoropyridin-2-yl)methyl)-8-fluoroquinazoline

Product 1

HCID 56848630HCID 56848630, compoundYield 4%

Reagents, catalysts & solvents 1

HCID 31374DimethylacetamideSolvent

Conditions

Temperature
100 °C

Procedure

To 4-chloro-2-(difluoro(5-fluoropyridin-2-yl)methyl)-8-fluoroquinazoline (295 mg, 0.90 mmol) in DMA (2.2 mL) were added tert-butyl 3-amino-5-methyl-1H-pyrazole-1-carboxylate and acetic acid (0.12 mL), and the mixture was heated at 100° C. for 6.5 h. The mixture was allowed to cool to rt and was purified by preparative reverse-phase HPLC using an ammonium acetate modifier. A later eluting fraction was treated with saturated aq NaHCO3 and concentrated under reduced pressure. The aqueous residue was extracted with DCM (3×30 mL) and the combined extracts were washed with saturated aq NaHCO3 (10 mL) and brine (10 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was treated with DCM, whereupon a precipitate formed, which was collected by filtration to afford 2-(difluoro(5-fluoropyridin-2-yl)methyl)-8-fluoro-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine as a colorless solid (13 mg, 4%). 1H NMR (300 MHz, DMSO-d6) δ 12.23 (br s, 1H), 10.86 (br s, 1H), 8.67 (s, 1H), 8.52 (d, J=9 Hz, 1H), 8.00-8.02 (m, 2H), 7.77 (m, 1H), 7.63 (m, 1H), 5.97 (s, 1H), 2.17 (s, 3H). LCMS (ESI) m/z 389 (M+H)+.

Workup

  1. temperatureto cool to rt
  2. customwas purified by preparative reverse-phase
  3. washA later eluting fraction
  4. additionwas treated with saturated aq NaHCO3
  5. concentrationconcentrated under reduced pressure
  6. extractionThe aqueous residue was extracted with DCM (3×30 mL)
  7. washthe combined extracts were washed with saturated aq NaHCO3 (10 mL) and brine (10 mL)
  8. dry with materialdried over MgSO4
  9. filtrationfiltered
  10. concentrationconcentrated under reduced pressure
  11. additionThe residue was treated with DCM, whereupon a precipitate
  12. customformed
  13. filtrationwhich was collected by filtration

Sources & evidence

ORD record
ord-f10e4c068c0c4c72a8d47831a285babf
Source dataset
uspto-grants-2014_01
Patent number
US08633207B2

Reaction notes

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