反应详情

A solution of the crude (3R,4S)-3-amino-1-[N-(tert-butoxycarbonyl)-4-(trifluoromethyl)phenylalanyl]-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl]pyrrolidine-3-carboxylic acid (Step 2, 242 mg) in anhydrous THF (6 mL) under nitrogen was treated with 4 N HCl in 1,4-dioxane (6 mL). After stirring for 2 h at room temperature, 1M aqueous HCl (6 mL) was added and stirring was continued for an additional 1.5 h. The reaction mixture was diluted with water (15 mL) and washed successively with ethyl acetate (25 mL) and methylene chloride (25 mL). The aqueous phase was concentrated and the residue was purified by reverse phase HPLC. Product fractions (mixture of diastereomers) were pooled and concentrated. The residue was reconstituted in 1 M HCl and re-concentrated. The resulting residue was diluted with deionized water and lyophilized to give give (3R,4S)-3-amino-4-[3-(dihydroxyboryl)propyl]-1-[4-(trifluoromethyl)phenylalanyl]-pyrrolidine-3-carboxylic acid dihydrochloride (mixture of two diastereomers, each a racemate) (43 mg, 12% overall for 3 steps) as a pale yellow amorphous solid. MS (ESI+) m/z 414 (M−H2O+H+), 396 (M−2 H2O+H+); MS (ESI−) m/z 412 (M−H2O−H+).

1. stirringstirring
2. waitwas continued for an additional 1.5 h
3. washwashed successively with ethyl acetate (25 mL) and methylene chloride (25 mL)
4. concentrationThe aqueous phase was concentrated
5. customthe residue was purified by reverse phase HPLC
6. additionProduct fractions (mixture of diastereomers)
7. concentrationconcentrated
8. concentrationre-concentrated
9. additionThe resulting residue was diluted with deionized water
10. customto give