反应详情

温度

25 °C

Under argon atmosphere, 10 liters of THF and 253 mL (2 mol) of chlorotrimethylsilane were added to 2616 g (40 mol) of zinc powders. The mixture was stirred at 25° C. for 30 minutes. A solution of 2212 mL (20 mol) of ethyl bromoacetate in 25 L of THF was added dropwise at 25˜35° C. 21.2 g (72 mmol, 1.25 eq) of (+)-cinchonine was added to 431 mL (0.23 mol) of the above Reformatsky reagent at 0˜5° C. 18.6 mL (230 mmol, 4 eq) of pyridine was added dropwise at 0˜5° C. over 7 minutes. The mixture was stirred at 0˜5° C. for 20 minutes. A solution of 30 g (57.5 mmol) of N-methyl-6-[(1-trityl-1H-imidazol-4-yl)carbonyl]-2-naphthamide in 300 mL of THF was added dropwise at −42˜−40° C. over 30 minutes. The mixture was stirred at −45˜−40° C. for 1 hour. 430 mL of 1N hydrochloric acid was added dropwise, diluted with 430 mL of ethyl acetate, and stirred at 20˜25° C. for 30 minutes. After the layers were separated, the organic layer was washed successively with 290 mL of 1N hydrochloric acid, 290 mL of water and 290 mL of an aqueous saturated sodium bicarbonate solution two times, and 290 mL of an aqueous saturated sodium chloride solution. After concentrated under reduced pressure, 90 mL of ethyl acetate was added to the concentration residue, and the mixture was warmed to 50° C. to dissolve it. The solution was stirred at 20˜25° C. for 1 hour. 90 mL of IPE was added, followed by stirring at 0˜5° C. for 2 hours. Crystals were filtered, and washed with 30 mL of IPE. Vacuum drying (50° C.) to a constant weight afforded 29.2 g of ethyl (3S)-3-hydroxy-3-{6-[(methylamino)carbonyl]-2-naphthyl}-3-(1-trityl-1H-imidazol-4-yl)propanoate (yield 83%, enantiomer excess 93.5% ee).

1. stirringThe mixture was stirred at 0˜5° C. for 20 minutes
2. stirringThe mixture was stirred at −45˜−40° C. for 1 hour
3. stirringstirred at 20˜25° C. for 30 minutes
4. customAfter the layers were separated
5. washthe organic layer was washed successively with 290 mL of 1N hydrochloric acid, 290 mL of water and 290 mL of an aqueous saturated sodium bicarbonate solution two times, and 290 mL of an aqueous saturated sodium chloride solution
6. concentrationAfter concentrated under reduced pressure, 90 mL of ethyl acetate
7. additionwas added to the concentration residue
8. temperaturethe mixture was warmed to 50° C.
9. dissolutionto dissolve it
10. stirringThe solution was stirred at 20˜25° C. for 1 hour
11. addition90 mL of IPE was added
12. stirringby stirring at 0˜5° C. for 2 hours
13. filtrationCrystals were filtered
14. washwashed with 30 mL of IPE
15. customVacuum drying (50° C.) to a constant weight