反应详情

温度

15 °C

Carbon tetrachloride (550 mL), acetonitrile (550 mL), and water (550 mL) were dissolved in (3S)-3-(3-hydroxy-1-propyl)-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester (38.2 g, 0.110 mol), and ruthenium (III) chloride hydrate (456 mg, 2.20 mmol) and sodium periodide (94.1 g, 0.440 mol) were sequentially added. The mixture was stirred in a water bath with a thermostatic circulator at 15° C. for 2.5 hours while maintaining the internal temperature at 20 to 25° C. The reaction solution was cooled in an ice bath and a 1N hydrochloric acid solution (2.2 L) was added at an internal temperature of 10° C. or less, followed by extraction with 2 L of chloroform. The aqueous layer was extracted with chloroform (1 L×3). Then, the organic layers were combined, washed with brine (2 L×2), and dried over anhydrous sodium sulfate. After filtration, the solvent was concentrated under reduced pressure. The resulting crude was dissolved in N,N-dimethylformamide (370 mL). Sodium bicarbonate (37.9 g, 0.451 mol) and methyl iodide (70.7 g, 0.498 mol) were added with stirring at room temperature, and the mixture was stirred for three days. The reaction solution was poured into ice water (1.8 L), followed by extraction with ethyl acetate (1.8 L, 0.5 L). The organic layers were combined, washed with brine, and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography (hexane:ethyl acetate=1:1), and the fraction containing the target substance was concentrated under reduced pressure. The resulting solid was dissolved in ethyl acetate, washed with a 10% sodium thiosulfate solution, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting solid was dried to give 35.0 g of the title compound as a pale yellow brown solid.

1. temperaturewhile maintaining the internal temperature at 20 to 25° C
2. temperatureThe reaction solution was cooled in an ice bath
3. extractionfollowed by extraction with 2 L of chloroform
4. extractionThe aqueous layer was extracted with chloroform (1 L×3)
5. washwashed with brine (2 L×2)
6. dry with materialdried over anhydrous sodium sulfate
7. filtrationAfter filtration
8. concentrationthe solvent was concentrated under reduced pressure
9. dissolutionThe resulting crude was dissolved in N,N-dimethylformamide (370 mL)
10. stirringwith stirring at room temperature
11. stirringthe mixture was stirred for three days
12. extractionfollowed by extraction with ethyl acetate (1.8 L, 0.5 L)
13. washwashed with brine
14. dry with materialdried over anhydrous sodium sulfate
15. filtrationAfter filtration
16. concentrationthe filtrate was concentrated under reduced pressure
17. additionthe fraction containing the target substance
18. concentrationwas concentrated under reduced pressure
19. dissolutionThe resulting solid was dissolved in ethyl acetate
20. washwashed with a 10% sodium thiosulfate solution
21. dry with materialdried over anhydrous sodium sulfate
22. filtrationAfter filtration
23. concentrationthe filtrate was concentrated under reduced pressure
24. customthe resulting solid was dried