反应详情

温度

60 °C

(3S,4S)-benzyl 3-azido-4-ethylpyrrolidine-1-carboxylate (14.0 g, 51.0 mmol) was dissolved in acetonitrile (200 mL). Added water (20 mL) and stirred at RT to a clear solution. This soln. was warmed to 60° C. for 6.5 hrs. Acetonitrile was removed in vacuo and residual aqueous portion was diluted with 1N HCl (100 mL) which was washed with ethyl acetate (5×50 mL) until all Ph3P and Ph3P oxide was removed from the aqueous portion. The aqueous portion which contains HCl salt of the amine was cooled to ˜5 deg. This acidic soln was made basic (pH 12) with 1N NaOH. Extracted this basic milky suspension with DCM (5×, 50 mL), dried (Na2SO4) and concentrated. On vacuum overnight gave (3S,4S)-benzyl 3-amino-4-ethylpyrrolidine-1-carboxylate (11.01 g, 44.3 mmol, 87% yield). LCMS:M+1=249, t=1.39 min. This material was resolved using the following chiral SFC conditions [column: Chiralpak AD-H 5×25 cm, 5 μm, Column Temp. 48° C., Flow rate: 290 mL/min, Mobile Phase: CO2/MeOH=77/23 with 0.3% triethylamine, Injection Volume: 3 mL (Conc. 68.8 mg/mL), detector wavelength: 215 nm, 100 bars]. The isolated isomers were named “Pk1” and “Pk2” in the elution order. Fractions containing Pk1 were concentrated to afford 5.1 g of the desired (3S,4S)-benzyl 3-amino-4-ethylpyrrolidine-1-carboxylate (Intermediate 9). Chiral purity: >99% ee (chiral HPLC conditions: column: Chiralpak AD-H (25×0.46 cm, 5 μm), 30% MeOH in CO2 with 0.3% triethylamine, 3 mL/min, 40° C., 200-400 nm, 100 bars). 1H NMR (400 MHz, chloroform-d) δ ppm 7.33-7.42 (5 H, m), 5.12-5.17 (2 H, m), 3.51-3.67 (3H, m), 3.32-3.40 (1 H, m), 3.14-3.21 (1 H, m), 2.0-2.15 (1 H, m), 1.44-1.55 (2 H, m), 0.97-1.02 (5 H, m). LCMS: (M+1)=249, t=1.39 min.

1. customAcetonitrile was removed in vacuo and residual aqueous portion
2. additionwas diluted with 1N HCl (100 mL) which
3. washwas washed with ethyl acetate (5×50 mL) until all Ph3P and Ph3P oxide
4. customwas removed from the aqueous portion
5. temperaturewas cooled to ˜5 deg
6. extractionExtracted this basic milky suspension with DCM (5×, 50 mL)
7. dry with materialdried (Na2SO4)
8. concentrationconcentrated