反应详情

温度

55 °C

tert-Butyl 5-(3-fluoroisoquinolin-6-yl)-1,3,4-thiadiazol-2-ylcarbamate (0.30 g, 0.860 mmol) and cesium carbonate (0.56 g, 1.72 mmol) in DMF (5.0 mL) were stirred under nitrogen at 55° C. for 10 minutes. tert-Butyl (4S)-4-(4-(trifluoromethyl)benzyl)-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (0.362 g, 0.946 mmol) as prepared in Schemes 1a and 1b for Example 1 was added as a solid. The resulting reaction mixture was stirred at 55° C. for 1.5 hours. The solvent was removed and the residue was partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc (3×140 mL), the combined organic extracts were washed with brine, dried over sodium sulfate and evaporated. The residue was partially purified by chromatography on silica gel (0-35% EtOAc:hexane) to provide the product contaminated with tert-butyl ((2Z)-3-((2S)-2-((tert-butoxycarbonyl)amino)-3-(6-(trifluoromethyl)-3-pyridinyl)propyl)-5-(3-fluoro-6-isoquinolinyl)-1,3,4-thiadiazol-2(3H)-ylidene)carbamate. The mixture was taken up in DMSO (6 mL) and water (0.019 mL). Lithium chloride (0.15 g, 3.5 mmol) was added and the mixture was heated at 100° C. with stirring 16 hours. Saturated NH4Cl was added, and the mixture was extracted with EtOAc (120 mL×3). The organic extracts were washed with water (3×100 mL), brine, dried over sodium sulfate and evaporated. The residue was purified by chromatography on silica gel (0-3% MeOH-DCM) to provide the product as an off-white solid (57 mg, 30%). LCMS (API-ES) m/z: 548 (M+H+).

1. additionwas added as a solid
2. customThe resulting reaction mixture
3. customThe solvent was removed
4. customthe residue was partitioned between water and EtOAc
5. extractionThe aqueous layer was extracted with EtOAc (3×140 mL)
6. washthe combined organic extracts were washed with brine
7. dry with materialdried over sodium sulfate
8. customevaporated
9. customThe residue was partially purified by chromatography on silica gel (0-35% EtOAc:hexane)
10. customto provide the product
11. temperaturethe mixture was heated at 100° C.
12. stirringwith stirring 16 hours
13. extractionthe mixture was extracted with EtOAc (120 mL×3)
14. washThe organic extracts were washed with water (3×100 mL), brine
15. dry with materialdried over sodium sulfate
16. customevaporated
17. customThe residue was purified by chromatography on silica gel (0-3% MeOH-DCM)