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

HRID 906610Notes

Reaction equation

HRID 906610 reaction equation
CO[C:3](=[O:21])[C:4]1[CH:9]=[C:8]([C:10]2[N:11]([CH3:15])[N:12]=[CH:13][CH:14]=2)[C:7]([C:16]([F:19])([F:18])[CH3:17])=[CH:6][C:5]=1[NH2:20].CC[N:24]([CH2:27]C)CC.[CH3:29][S:30]([NH:33]N)(=[O:32])=[O:31].[OH-:35].[Na+]>C(Cl)Cl>[F:19][C:16]([C:7]1[CH:6]=[C:5]2[C:4]([C:3](=[O:21])[N:24]([NH:33][S:30]([CH3:29])(=[O:32])=[O:31])[C:27](=[O:35])[NH:20]2)=[CH:9][C:8]=1[C:10]1[N:11]([CH3:15])[N:12]=[CH:13][CH:14]=1)([F:18])[CH3:17]

Participants

6

Reactant 4

HCID 8471TriethylamineHCID 14798Sodium HydroxideHCID 269268MethanesulfonohydrazideHCID 591644402-amino-4-(1,1-difluoro-ethyl)-5-(2-methyl-2H-pyrazol-3-yl)-benzoic acid methyl ester

Product 1

HCID 50913471n-[7-(1,1-Difluoro-ethyl)-6-(2-methyl-2h-pyrazol-3-yl)-2,4-dioxo-1,4-dihydro-2h-quinazolin-3-yl]-methanesulfonamideYield 82.5%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a solution of 2-amino-4-(1,1-difluoro-ethyl)-5-(2methyl-2H-pyrazol-3-yl)-benzoic acid methyl ester (430 mg, 1.43 mmol) in DCM (33 mL) were added Et3N (0.820 mL, 5.82 mmol) and then (CCl3O)2CO (353 mg, 1.16 mmol). The resulting mixture was stirred at r.t. for 3 h. The solvent was removed in vacuo and the residue was solubilised in THF (33 mL). CH3SO2NHNH2 (213 mg, 1.90 mmol) was added and the mixture was stirred at r.t for 2 h. Aq NaOH (1N, 1.9 mL, 1.9 mmol) was then added and the mixture was stirred at r.t. for 1 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 to EtOAc/MeOH (1:1 to 8:2)) to give N-[7-(1,1-difluoro-ethyl)-6-(2-methyl-2H-pyrazol-3-yl)-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]-methanesulfonamide as a yellow solid (470 mg, 1.18 mmol, 80%) ES-MS: m/z 400.4 [M+H]+, rt 5.52 min. 1H-NMR (CDCl3, 300 MHz) 9.23 (br s, 1H); 8.06 (s, 1H); 7.90 (br s, 1H); 7.55 (d, J=2.05 Hz, 1H); 7.48 (s, 2H); 7.45 (s, 1H); 6.26 (d, J=1.8 Hz, 1H); 3.64 (s, 3H); 3.36 (s, 1H); 1.70 (t, J=18.7 Hz, 3H).

Workup

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

Sources & evidence

ORD record
ord-7f23f6b5432c49079537df30b22d0129
Source dataset
uspto-grants-2011_09
Patent number
US08012988B2

Reaction notes

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