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

Participants

Reaction Steps

Under a nitrogen atmosphere, zinc powder (15.0 g, 229.4 mmol) was suspended in tetrahydrofuran (57 mL), trimethylsilyl chloride (1.5 mL, 11.5 mmol) was added thereto at room temperature, and the mixture was stirred for 30 min. The reaction mixture was heated to 40° C., a solution of ethyl bromoacetate (12.7 mL, 114.5 mmol) in tetrahydrofuran (144 mL) was added dropwise thereto, and the mixture was stirred at the same temperature for 30 min. The reaction mixture was kept stand at room temperature, the excess amount of zinc was filtered off to give a reaction mixture containing (bromo(2-ethoxy-2-oxoethyl)zinc (hereinafter to be abbreviated as Reformatsky reagent). The prepared Reformatsky reagent (89.6 mL, corresponding to 2.5 eq.) was cooled to 0° C., cinchonine (7.1 g, 24.0 mmol), pyridine (6.2 mL, 76.8 mmol) and tetrahydrofuran (80 mL) were 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-trityl-1H-imidazol-4-yl)carbonyl]-2-naphthamide (10.0 g, 19.2 mmol) and tetrahydrofuran (20 mL) were added thereto, and the mixture was stirred at the same temperature for 1 hr and 45 min. The Reformatsky reagent (35.7 mL, corresponding to 1.0 eq.) was added thereto at the same temperature, and the mixture was stirred for 1 hr. To the reaction mixture were added ethyl acetate (140 mL) and 20 w/v % aqueous citric acid solution (140 mL) at 10° C. or below. The organic layer was separated, and washed with 10% sodium chloride-containing 20 w/v % aqueous citric acid solution (100 mL) at 5° C. (twice), 5 w/v % aqueous sodium bicarbonate (100 mL) (three times), and water (100 mL). The organic layer was concentrated to the volume of 60 mL under reduced pressure. To the residue was added methanol (100 mL), and the mixture was concentrated to the volume of 60 mL under reduced pressure. To the residue was added methanol to adjust the volume to 200 mL. Water (20 mL) was added thereto at room temperature, and the mixture was stirred for 1 hr. Then water (140 mL) was added dropwise thereto at the same temperature, and the mixture was stirred. The obtained crystals were collected by filtration, and washed with a mixed solvent (60 mL) of methanol/water (1:3, volume ratio). The obtained wet crystals were dried under reduced pressure to give ethyl (3S)-3-hydroxy-3-{6-[(methylamino)carbonyl]-2-naphthyl}-3-(1-trityl-1H-imidazol-4-yl)propanoate (11.3 g, 18.5 mmol). yield: 97%. enantiomeric excess: 96% ee.

Provenance & Evidence