反应详情

To thionyl chloride, obtained from Aldrich, (125 mL) at 0° C. was slowly added 2,3-Dichloro-5-nitrobenzoic acid (246) (21.7 g, 91.9 mmol). The ice bath was taken away and the resulting solution was heated to reflux for 17 hours (note: acid completely dissolves upon heating). After cooling to ambient temperature, the excess thionyl chloride was removed under vacuum and the resulting acid chloride was allowed to stand under high vacuum for 15 h and used in the next step without further purification. To a 1M solution of NaH, 60% oil dispersion obtained from Aldrich, (11.39 g, 285 mmol) in DMF at 0° C. was slowly added diethylmalonate, obtained form Aldrich, (14.65 mL, 96.5 mmol) dropwise and the resulting solution was allowed to stir for 30 minutes. The acid chloride was dissolved in DMF (184 mL) and slowly added via cannula to the reaction mixture. The resulting solution was then allowed to stir for 16 h as ambient temperature was reached followed by recooling to 0° C. and slowly quenching with excess 2M aqueous HCl (200 mL). To the crude reaction was added H2O (500 mL) and EtOAc (500 mL). The aqueous layer was extracted three times with EtOAc (500 mL), the organic layers were combined, washed four times with saturated aqueous brine (500 mL), dried over Na2SO4, and concentrated under vacuum to yield an oil which was used in the next step without further purification. The resulting product was dissolved in 111 mL of a 7.7/5/1 AcOH/H2O/conc. H2SO4, solution and heated to reflux for 22 hours. The AcOH was removed under vacuum followed by EtOAc addition (200 mL). The solution was neutralized using 2M aqueous NaOH, extracted 3 times with EtOAc (200 mL). The combined organic layers were washed twice with saturated aqueous brine (200 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude material was purified by column chromatography (30% CH2Cl2 in hexane) to yield 17.6 g (82%) of ketone 248 as a light brown solid.

1. customobtained from Aldrich, (125 mL) at 0° C.
2. temperaturethe resulting solution was heated
3. temperatureto reflux for 17 hours (note
4. dissolutionacid completely dissolves
5. temperatureupon heating)
6. customthe excess thionyl chloride was removed under vacuum
7. customused in the next step without further purification
8. customobtained from Aldrich, (11.39 g, 285 mmol) in DMF at 0° C.
9. customobtained form Aldrich, (14.65 mL, 96.5 mmol) dropwise
10. additionslowly added via cannula to the reaction mixture
11. stirringto stir for 16 h as ambient temperature
12. customby recooling to 0° C.
13. customslowly quenching with excess 2M aqueous HCl (200 mL)
14. customTo the crude reaction
15. extractionThe aqueous layer was extracted three times with EtOAc (500 mL)
16. washwashed four times with saturated aqueous brine (500 mL)
17. dry with materialdried over Na2SO4
18. concentrationconcentrated under vacuum
19. customto yield an oil which
20. customwas used in the next step without further purification
21. dissolutionThe resulting product was dissolved in 111 mL of a 7.7/5/1 AcOH/H2O/conc
22. temperatureH2SO4, solution and heated
23. temperatureto reflux for 22 hours
24. customThe AcOH was removed under vacuum
25. additionfollowed by EtOAc addition (200 mL)
26. extractionextracted 3 times with EtOAc (200 mL)
27. washThe combined organic layers were washed twice with saturated aqueous brine (200 mL)
28. dry with materialdried over Na2SO4
29. concentrationconcentrated under reduced pressure
30. customThe crude material was purified by column chromatography (30% CH2Cl2 in hexane)