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

HRID 1894114Notes

Reaction equation

HRID 1894114 reaction equation
CO[C:3](=[O:23])[C:4]1[CH:9]=[C:8]([C:10]2[N:11]([CH:15]([CH3:17])[CH3:16])[N:12]=[CH:13][CH:14]=2)[C:7]([C:18]([F:21])([F:20])[CH3:19])=[CH:6][C:5]=1[NH2:22].CC[N:26]([CH2:29]C)CC.[CH3:31][S:32]([NH:35]N)(=[O:34])=[O:33].[OH-:37].[Na+]>C(Cl)Cl>[F:20][C:18]([C:7]1[CH:6]=[C:5]2[C:4]([C:3](=[O:23])[N:26]([NH:35][S:32]([CH3:31])(=[O:34])=[O:33])[C:29](=[O:37])[NH:22]2)=[CH:9][C:8]=1[C:10]1[N:11]([CH:15]([CH3:16])[CH3:17])[N:12]=[CH:13][CH:14]=1)([F:21])[CH3:19]

Participants

6

Reactant 4

HCID 8471TriethylamineHCID 14798Sodium Hydroxide2×HCID 269268MethanesulfonohydrazideHCID 591645302-amino-4-(1,1-difluoro-ethyl)-5-(2-isopropyl-2H-pyrazol-3-yl)-benzoic acid methyl ester

Product 1

HCID 50913472n-[7-(1,1-Difluoro-ethyl)-6-(2-isopropyl-2h-pyrazol-3-yl)-2,4-dioxo-1,4-dihydro-2h-quinazolin-3-yl]-methanesulfonamideYield 39%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a solution of 2-amino-4-(1,1-difluoro-ethyl)-5-(2-isopropyl-2H-pyrazol-3-yl)-benzoic acid methyl ester (141 mg, 0.436 mmol) in DCM (10 mL) were added Et3N (0.244 mL, 1.74 mmol) and then (CCl3O)2CO (106 mg, 0.349 mmol). The resulting mixture was stirred at r.t. for 3 h. The solvent was removed in vacuo and the crude solubilised in THF (5 mL). CH3SO2NHNH2 (44.8 mg, 0.399 mmol) was added and the mixture was stirred at r.t. for 2 h. Aq NaOH (1N, 0.4 mL, 0.4 mmol) was then added. After stirring the mixture at r.t. for 1 h, another portion of aq NaOH (1N, 0.4 mL, 0.4 mmol) was added and stirring was continued for 12 h. The solvent was removed in vacuo and water was added. The pH was adjusted to 3-4 by addition of 2N 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 residue was purified by flash chromatography (silica gel, EtOAc/hexanes (1:1 to 10:0)) to give N-[7-(1,1-difluoro-ethyl)-6-(2-isopropyl-2H-pyrazol-3-yl)-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]-methanesulfonamide as a yellow solid (52 mg, 0.122 mmol, 39%). ES-MS: m/z 428.4 [M+H]+, rt 5.94 min. 1H-NMR (CDCl3, 300 MHz) 10.15 (s, 1H); 7.99 (s, 1H); 7.90 (br s, 1H); 7.58 (d, J=1.7 Hz, 1H); 7.54 (s, 2H); 6.17 (d, J=1.8 Hz, 1H); 4.02 (m, 1H); 3.33 (s, 1H); 1.71 (t, J=18.7 Hz, 3H), 1.41 (br d, 6H).

Workup

  1. customThe solvent was removed in vacuo
  2. stirringthe mixture was stirred at r.t. for 2 h
  3. stirringAfter stirring the mixture at r.t. for 1 h
  4. stirringstirring
  5. waitwas continued for 12 h
  6. customThe solvent was removed in vacuo and water
  7. additionwas added
  8. additionThe pH was adjusted to 3-4 by addition of 2N HCl
  9. extractionThe aqueous phase was extracted with EtOAc (2×)
  10. washwashed with brine
  11. dry with materialdried (Na2SO4)
  12. concentrationconcentrated in vacuo
  13. customto afford a crude solid
  14. customThe residue was purified by flash chromatography (silica gel, EtOAc/hexanes (1:1 to 10:0))

Sources & evidence

ORD record
ord-cbb2225ac1954039908054617e910527
Source dataset
uspto-grants-2013_08
Patent number
US08513268B2

Reaction notes

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