反应详情

75.0 mL (75.0 mmol) of the solution of ethyl bromozincacetate in cyclopentyl methyl ether obtained in Example 65 was added dropwise to 100 mL of THF at −15˜−5° C. 11.0 g (37.5 mmol) of cinchonine was added at −15˜−5° C., 9.7 mL (120 mmol) of pyridine was added dropwise, and the mixture was stirred for 20 minutes. 15.6 g (30.0 mmol) of N-methyl-6-[(1-trityl-1H-imidazol-4-yl)carbonyl]-2-naphthamide was added at once by assisting by 25 mL of flowing THF at −15˜−5° C., and the mixture was stirred at the same temperature for 1 hour. 30.0 mL (30.0 mmol) of the solution of ethyl bromozincacetate in cyclopentyl methyl ether obtained in Example 65 was added dropwise at −15˜−5° C. over 40 minutes, and the mixture was stirred at the same temperature for 1 hour. 420 mL of ethyl acetate and 210 mL of 1N hydrochloric acid were added in this order at −15˜10° C., and the mixture was stirred at 15˜25° C. for 30 minutes. The organic layer was washed with 210 mL of 1N hydrochloric acid, and further 210 mL (×3) of water, 210 mL (×2) of an aqueous saturated sodium bicarbonate solution, and 210 mL of water. After washing, the organic layer was concentrated to about 50 mL under heating and reduced pressure (inner temperature 20˜40° C.). 50 mL of ethyl acetate was added, followed by re-concentration procedure two times. 50 mL of ethyl acetate was added to the residue, the mixture was stirred at room temperature for 1 hour, 50 mL of IPE was added, and the mixture was stirred at room temperature. After stirred at 0˜10° C. for 1 hour, crystals were filtered, washed with 16 mL (×2) of IPE, and dried to obtain 17.0 g of ethyl (3S)-3-hydroxy-3-{6-[(methylamino)carbonyl]-2-naphthyl}-3-(1-trityl-1H-imidazol-4-yl)propanoate (yield 93%, enantiomer excess 94.3% ee).

1. stirringthe mixture was stirred at the same temperature for 1 hour
2. stirringthe mixture was stirred at the same temperature for 1 hour
3. stirringthe mixture was stirred at 15˜25° C. for 30 minutes
4. washThe organic layer was washed with 210 mL of 1N hydrochloric acid, and further 210 mL (×3) of water, 210 mL (×2) of an aqueous saturated sodium bicarbonate solution, and 210 mL of water
5. washAfter washing
6. concentrationthe organic layer was concentrated to about 50 mL
7. temperatureunder heating
8. customreduced pressure (inner temperature 20˜40° C.)
9. addition50 mL of ethyl acetate was added
10. concentrationfollowed by re-concentration procedure two times
11. addition50 mL of ethyl acetate was added to the residue
12. stirringthe mixture was stirred at room temperature for 1 hour
13. addition50 mL of IPE was added
14. stirringthe mixture was stirred at room temperature
15. stirringAfter stirred at 0˜10° C. for 1 hour
16. filtrationcrystals were filtered
17. washwashed with 16 mL (×2) of IPE
18. customdried