反应详情

Dissolve 3-{4-[2-(4-chloro-phenyl)-7-oxo-7H-thieno[2,3-c]pyridin-6-yl]-2-fluoro-phenoxy}-azetidine-1-carboxylic acid tert-butyl ester (0.491 g, 0.932 mmol) in CH2Cl2 (10 mL) and treat with TFA (3 mL), with stirring at RT for 2 h. Remove the excess reagent and solvent in vacuo. Dissolve the crude material in CH3OH (15 mL), treat with formaldehyde (0.28 mL, 3.71 mmol, 37% aqueous solution), HOAc (0.21 mL, 3.71 mmol) and NaBH3CN (0.233 g, 3.71 mmol). Stir the mixture at RT for 30 min followed by reflux for 4 h. Quench the mixture with saturated NH4Cl solution (10 mL). Dilute with water (10 mL) and saturated NaHCO3 (30 mL). Extract with EtOAc (3×50 mL). Dry the combined organic layers with Na2SO4, filter, and concentrate. Purify the crude material by chromatography, eluting with 1% Et3N, 10% CH3OH/CHCl3 to give 2-(4-chloro-phenyl)-6-[3-fluoro-4-(1-methyl-azetidin-3-yloxy)-phenyl]-6H-thieno[2,3-c]pyridin-7-one (0.3012 g, 0.683 mmol, 74%). Dissolve the free base (0.152 g, 344.7 μmoles) in CH2Cl2 (5 mL) and CH3OH (0.5 mL). Treat the mixture with 1.0 M HCl in EtOH (344.7 μmoles; 344.7 μL). Add Et2O (50 mL), filter, and wash with Et2O (2×20 mL). Dry in a vacuum oven at RT for 2 days to give 0.14 g (83%) of the title compound. LC-MS/ES m/z (35Cl) 441.0 [M+H]+.

1. customRemove the excess reagent and solvent in vacuo
2. dissolutionDissolve the crude material in CH3OH (15 mL)
3. stirringStir the mixture at RT for 30 min
4. temperatureby reflux for 4 h
5. customQuench the mixture with saturated NH4Cl solution (10 mL)
6. additionDilute with water (10 mL) and saturated NaHCO3 (30 mL)
7. extractionExtract with EtOAc (3×50 mL)
8. dry with materialDry the combined organic layers with Na2SO4
9. filtrationfilter
10. concentrationconcentrate
11. customPurify the crude material by chromatography
12. washeluting with 1% Et3N, 10% CH3OH/CHCl3