反应详情

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).

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))