反应详情

D-Alanine (5 g, 0.056 mole) was dissolved in dimethylformamide (100 ml) and treated with chlorotrimethylsilane (6.7 g, 0.063 mole). The reaction mixture was stirred at room temperature until homogeneous (approx. 1 hour). Meanwhile, Nα -9-fluorenylmethyloxycarbonyl-β-benzyl-L-aspartic acid (22.3 g, 0.050 mole) was dissolved in dimethylformamide/tetrahydrofuran (1:1, v/v, 200 ml), cooled to -15° C. and treated with N-methylmorpholine (5.5 ml, 0.050 mole) and isobutyl chloroformate (6.5 ml, 0.050 mole). After 10 minutes' activation at -15° C., the precooled solution of D-alanine silyl ester from above was added, followed by a second equivalent of N-methylmorpholine (5.5 ml, 0.050 mole). The reaction mixture was allowed to warm to room temperature, stirred for 3 hours and then acidified (pH 1-2) using aqueous hydrochloric acid. The reaction mixture was stirred for 30 minutes and ethyl acetate added and the phases separated. The aqueous phase was re-extracted with ethyl acetate and the combined organic extracts washed with 1N hydrochloric acid (3×) and dried (MgSO4). After evaporation of the solvent under reduced pressure the residue was crystallized from ethyl acetate/hexanes to give Nα -9-fluorenylmethyloxycarbonyl-β-benzyl-L-aspartyl-D-alanine (22.5 g), m.p. 114°-116° C., which was homogeneous by TLC. The nmr spectrum of the product was consistent with the assigned structure.

1. temperaturecooled to -15° C.
2. waitAfter 10 minutes' activation at -15° C.
3. temperatureto warm to room temperature
4. stirringstirred for 3 hours
5. stirringThe reaction mixture was stirred for 30 minutes
6. customthe phases separated
7. extractionThe aqueous phase was re-extracted with ethyl acetate
8. washthe combined organic extracts washed with 1N hydrochloric acid (3×)
9. dry with materialdried (MgSO4)
10. customAfter evaporation of the solvent under reduced pressure the residue
11. customwas crystallized from ethyl acetate/hexanes