Hydrochloric Acid → Ethyl (3S)-3-hydroxy-3-(6-((methylamino)carbonyl))-2-naphthyl)-3-(1-trityl-1H-imidazil-4-yl) propanoate

Participants

Reaction Conditions

Reaction Steps

Under argon atmosphere, 21.2 g (72 mmol, 1.25 equivalent) of (+)-cinchonine was added to 431 mL (0.23 mol) of the solution of ethyl bromozincacetate in tetrahydrofuran obtained in Example 43 at 0˜5° C. 18.6 mL (230 mmol, 4 equivalent) 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 the mixture was 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, 290 mL (×2) of an aqueous saturated sodium bicarbonate solution, and 290 mL of an aqueous saturated sodium chloride solution. After washing and concentration under reduced pressure, to the concentration residue was added 90 mL of ethyl acetate, and this 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, and the mixture was stirred at, 0˜5° C. for 2 hours. Crystals were filtered, and washed with 30 mL of IPE. After washing, 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).

Provenance & Evidence