Triethylamine → n-[7-(1-Fluoro-ethyl)-6-(2-methyl-2h-pyrazol-3-yl)-2,4-dioxo-1,4-dihydro-2h-quinazolin-3-yl]-methanesulfonamide

HRID 906616Notes

Reaction equation

HRID 906616 reaction equation
CO[C:3](=[O:20])[C:4]1[CH:9]=[C:8]([C:10]2[N:11]([CH3:15])[N:12]=[CH:13][CH:14]=2)[C:7]([CH:16]([F:18])[CH3:17])=[CH:6][C:5]=1[NH2:19].CC[N:23]([CH2:26]C)CC.[CH3:28][S:29]([NH:32]N)(=[O:31])=[O:30].[OH-:34].[Na+]>C(Cl)Cl>[F:18][CH:16]([C:7]1[CH:6]=[C:5]2[C:4]([C:3](=[O:20])[N:23]([NH:32][S:29]([CH3:28])(=[O:31])=[O:30])[C:26](=[O:34])[NH:19]2)=[CH:9][C:8]=1[C:10]1[N:11]([CH3:15])[N:12]=[CH:13][CH:14]=1)[CH3:17]

Participants

6

Reactant 4

HCID 8471TriethylamineHCID 14798Sodium HydroxideHCID 269268Methanesulfonohydrazide2×HCID 591644892-amino-4-(1-fluoro-ethyl)-5-(2-methyl-2H-pyrazol-3-yl)-benzoic acid methyl ester

Product 1

HCID 50913470n-[7-(1-Fluoro-ethyl)-6-(2-methyl-2h-pyrazol-3-yl)-2,4-dioxo-1,4-dihydro-2h-quinazolin-3-yl]-methanesulfonamideYield 37.9%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a solution of 2-amino-4-(1-fluoro-ethyl)-5-(2-methyl-2H-pyrazol-3-yl)-benzoic acid methyl ester (280 mg, 1.01 mmol) in DCM (20 mL) were added Et3N (0.565 mL, 4.04 mmol) and then (CCl3O)2CO (245 mg, 0.808 mmol). The resulting mixture was stirred at r.t. for 3 h. The solvent was removed in vacuo and the residue solubilised in THF (20 mL). CH3SO2NHNH2 (152 mg, 1.35 mmol) was added and, after stirring at r.t for 3 h, a second portion of CH3SO2NHNH2 was added (117 mg) and the reaction was allowed to proceed for 1 h. Aq NaOH (1N, 1.4 mL, 1.4 mmol) was then added and the mixture was stirred for 19 h. The solvent was removed in vacuo and water was added. The pH was adjusted to 3-4 by addition of 2N aq HCl. The aqueous phase was extracted with EtOAc (2×). The organic phases were combined, washed with brine, dried (Na2SO4) and concentrated in vacuo to afford a crude solid. The crude product was purified by flash chromatography (silica gel, EtOAc/hexanes (3:7 to 10:)) to give N-[7-(1-fluoro-ethyl)-6-(2-methyl-2H-pyrazol-3-yl)-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]-methanesulfonamide (150 mg, 0.383 mmol, 36%) as a light yellow solid. ES-MS: m/z 382 [M+H]+. 1H-NMR (CDCl3, 400 MHz) 10.5 (s, 1H); 8.02 (s, 1H); 7.61 (d, J=1.6 Hz, 1H); 7.53 (s, 1H); 6.27 (d, J=1.95 Hz, 1H); 5.44-5.45 (qd, J=6.3, 46.9 Hz, 1H); 3.72 (s, 3H); 3.33 (s, 1H); 1.40-1.48 (dd, J=6.3, 24.2 Hz, 3H).

Workup

  1. customThe solvent was removed in vacuo
  2. stirringafter stirring at r.t for 3 h
  3. waitto proceed for 1 h
  4. stirringthe mixture was stirred for 19 h
  5. customThe solvent was removed in vacuo and water
  6. additionwas added
  7. additionThe pH was adjusted to 3-4 by addition of 2N aq HCl
  8. extractionThe aqueous phase was extracted with EtOAc (2×)
  9. washwashed with brine
  10. dry with materialdried (Na2SO4)
  11. concentrationconcentrated in vacuo
  12. customto afford a crude solid
  13. customThe crude product was purified by flash chromatography (silica gel, EtOAc/hexanes (3:7 to 10:))

Sources & evidence

ORD record
ord-df5df5bd19b14345af029d324d8fad82
Source dataset
uspto-grants-2011_09
Patent number
US08012988B2

Reaction notes

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