反应详情

A mixture of methyl 3-hydroxy-5-[(3S)-1-methyl-2-oxo-pyrrolidin-3-yl]oxy-benzoate (Intermediate 8) (265 mg, 1 mmol), azetidin-1-yl-(3-chloro-4-fluoro-phenyl)methanone (CAS no. 863454-79-9) (320 mg, 1.5 mmol) and potassium carbonate (276 mg, 2.0 mmol) in DMA (10 mL) was stirred at 120° C. for 16 hours. The solution was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (50 mL), washed with water (3×20 mL), dried (MgSO4), filtered and the solvent removed under reduced pressure. The combined aqueous extracts were acidified with 2N hydrochloric acid, extracted with a mixture of ethyl acetate and DCM (1:1, 3×20 mL), washed with brine, dried (MgSO4), filtered and the solvent removed under reduced pressure. The residue from this was dissolved in THF (2 mL) and methanol (1 mL) and treated with 2M (trimethylsilyl)diazomethane (0.240 mL, 0.48 mmol) and stirred for 30 minutes. The solution was treated with acetic acid (1 drop), evaporated under reduced pressure. This residue was combined with that from the initial ethyl acetate extraction and purified by flash chromatography on silica eluting with 20-100% ethyl acetate in isohexane to afford the product (380 mg, 83%). m/z 459 (M+H)+

1. customThe solution was evaporated under reduced pressure
2. dissolutionThe residue was dissolved in ethyl acetate (50 mL)
3. washwashed with water (3×20 mL)
4. dry with materialdried (MgSO4)
5. filtrationfiltered
6. customthe solvent removed under reduced pressure
7. extractionextracted with a mixture of ethyl acetate and DCM (1:1, 3×20 mL)
8. washwashed with brine
9. dry with materialdried (MgSO4)
10. filtrationfiltered
11. customthe solvent removed under reduced pressure
12. dissolutionThe residue from this was dissolved in THF (2 mL)
13. customevaporated under reduced pressure
14. extractionfrom the initial ethyl acetate extraction
15. custompurified by flash chromatography on silica eluting with 20-100% ethyl acetate in isohexane