反应详情

1-Oxa-2-aza-spiro[4.5]dec-2-ene-3-carboxylic acid (4.02 g, 21.9 mmol, as prepared in Example 1, step B) was placed in a round-bottom flask equipped with a magnetic stir bar. DCM (40 mL) and DMF (50 μL) were added. Oxalyl chloride (2.5 mL, 28.5 mmol) was added dropwise via syringe, and the mixture was stirred at RT for 1 h. The solvent was removed under reduced pressure. 3-Chloro-5-nitro-2′-trifluoromethyl-biphenyl-4-ylamine (6.96 g. 21.9 mmol) was placed in a round-bottom flask equipped with a magnetic stir bar. The flask was evacuated and backflushed with argon, and dry THF (50 mL) was added. The mixture was cooled to 0° C. in an ice bath, then NaH (2.64 g, 65.8 mmol, 60% dispersion in oil) was added in small portions. The above-prepared acid chloride was taken up in dry THF (20 mL) and added dropwise to the 3-chloro-5-nitro-2′-trifluoromethyl-biphenyl-4-ylamine solution at 0° C. over 10 min. After the addition was complete, the mixture was allowed to stir an additional 30 min at 0° C. then warm to RT and stir at that temperature for 16 h. The mixture was quenched with water, diluted with brine, and extracted three times with EtOAc. The combined organic extracts were dried over MgSO4, filtered, and the solvent was removed under reduced pressure. The residue was dissolved in AcOH and placed in a round-bottom flask equipped with a magnetic stir bar. Fe powder (6.14 g, 110 mmol) was added. The flask was tightly capped, and the mixture was heated to 80° C. for 1 h. The mixture was cooled to RT and poured into ice. The resulting precipitate was filtered and washed with water. The filtrate was extracted with EtOAc. The combined organic extracts were dried over MgSO4, filtered, and the solvent was removed under reduced pressure. The crude material was chromatographed on an 80-g SiO2 pre-packed column eluting with EtOAc/hexanes, 0:1 to 3:7, v/v over 30 min. The resulting material was recrystallized from MeOH and isolated by filtration, yielding 5.12 g (54%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ: 13.52 (br. s., 1H), 7.86 (d, J=7.6 Hz, 1H), 7.75 (t, J=7.5 Hz, 1H), 7.65 (t, J=7.6 Hz, 1H), 7.51 (d, J=7.6 Hz, 1H), 7.35 (s, 1H), 7.25 (s, 1H), 1.63-1.82 (m, 6H), 1.34-1.60 (m, 4H).

1. customequipped with a magnetic stir bar
2. customThe solvent was removed under reduced pressure
3. customequipped with a magnetic stir bar
4. customThe flask was evacuated
5. additionwas added
6. temperatureThe mixture was cooled to 0° C. in an ice bath
7. additionAfter the addition
8. stirringto stir an additional 30 min at 0° C.
9. temperaturethen warm to RT
10. stirringstir at that temperature for 16 h
11. customThe mixture was quenched with water
12. additiondiluted with brine
13. extractionextracted three times with EtOAc
14. dry with materialThe combined organic extracts were dried over MgSO4
15. filtrationfiltered
16. customthe solvent was removed under reduced pressure
17. dissolutionThe residue was dissolved in AcOH
18. customplaced in a round-bottom flask
19. customequipped with a magnetic stir bar
20. customThe flask was tightly capped
21. temperaturethe mixture was heated to 80° C. for 1 h
22. temperatureThe mixture was cooled to RT
23. additionpoured into ice
24. filtrationThe resulting precipitate was filtered
25. washwashed with water
26. extractionThe filtrate was extracted with EtOAc
27. dry with materialThe combined organic extracts were dried over MgSO4
28. filtrationfiltered
29. customthe solvent was removed under reduced pressure
30. customThe crude material was chromatographed on an 80-g SiO2 pre-packed column
31. washeluting with EtOAc/hexanes, 0:1 to 3:7, v/v over 30 min
32. customThe resulting material was recrystallized from MeOH
33. customisolated by filtration