Citric Acid → ethyl (3S)-3-hydroxy-3-{6-[(methylamino)carbonyl]-2-naphthyl}-3-(1-tosyl-1H-imidazol-4-yl)propanoate

Participants

Reaction Conditions

Reaction Steps

The Reformatsky reagent was obtained according to the method described in Example 14. The obtained Reformatsky reagent (27.1 mL, corresponding to 2.5 eq.) was cooled to 0° C., cinchonine (2.1 g, 7.2 mmol) and pyridine (1.9 mL, 23.0 mmol) was added thereto, and the mixture was stirred at the same temperature for 30 min. The reaction mixture was cooled to −25° C., N-methyl-6-[(1-tosyl-1H-imidazol-4-yl)carbonyl]-2-naphthamide (2.5 g, 5.76 mmol) was added thereto, and the mixture was stirred at the same temperature for 1 hr. To the obtained reaction mixture was added the Reformatsky reagent (10.9 mL, corresponding to 1.0 eq.) at −25° C., and the mixture was stirred for 1 hr. The Reformatsky reagent (5.4 mL, corresponding to 0.5 eq.) was added again −25° C., and the mixture was stirred for 1 hr. To the obtained reaction mixture were added ethyl acetate (35 mL) and 20 w/v % aqueous citric acid solution (35 mL) at 10° C. or below. The separated organic layer was washed with 10% sodium chloride-containing 20 w/v % aqueous citric acid solution (35 mL) at 5° C. (twice), 5 w/v % aqueous sodium bicarbonate (35 mL) (three times), and water (35 mL). The separated organic layer was concentrated under reduced pressure to give ethyl (3S)-3-hydroxy-3-{6-[(methylamino)carbonyl]-2-naphthyl}-3-(1-tosyl-1H-imidazol-4-yl)propanoate (2.92 g, 5.6 mmol). yield: 97%.

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