反应详情

3M methylmagnesium bromide in ether (99 ml, 296 mmol) was added dropwise over 1 hour to a suspension of benzyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (26 g, 119 mmol) and copper bromide-dimethyl sulfide complex (24.38 g, 119 mmol) in anhydrous THF (250 ml) at −40° C. under a nitrogen atmosphere. The reaction was allowed to stir at this temperature for an additional 1 hour before cautiously quenching of the reaction using 125 mL sat. ammonium chloride. The reaction was then allowed to warm to rt and diluted with water (125 mL), then extracted with ethyl acetate (3×150 mL). Ethyl acetate phases were combined, washed with brine, then dried with Na2SO4. After concentration, the crude material was purified by flash chromatography. (+/−)-benzyl 3-hydroxy-4-methylpyrrolidine-1-carboxylate (24.5 g, 104 mmol, 88% yield) was obtained as light yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.28-7.46 (5 H, m), 5.14 (2 H, s), 3.93-4.05 (1 H, m), 3.63-3.78 (2 H, m), 3.25-3.43 (1 H, m), 3.12 (1 H, ddd, J=13.26, 10. This material was resolved using the following chiral SFC conditions: column. Chiralpak AD-H 5×25 cm, 5 μm, Column Temp. 40° C., Flow rate: 290 mL/min, Mobile Phase: CO2/MeOH=82/18, Injection Volume: 2.5 mL (Conc. 118 mg/mL), detector wavelength: 212 nm. The isolated isomers were named “Pk1” and “Pk2” in the elution order. Fractions containing Pk2 were concentrated to afford 10 g of (3R,4S)-benzyl 3-hydroxy-4-methylpyrrolidine-1-carboxylate as a yellow oil. 84, 5.17 Hz), 2.06-2.26 (1 H, m), 1.90 (1 H, d, J=8.36 Hz), 1.03 (3 H, dd, J=6.71, 5.39 Hz); LCMS (Chromolith RP-18e 2.0×50 mm, 0.8 mL/min, Solvent A: 10% MeOH/water with 0.1% TFA, Solvent B: 90% MeOH/water with 0.1% TFA, gradient with 0-100% B over 4 minutes) retention time: 2.56 min; MS (ES+) m/z: 236.0 (M+H+); HPLC retention time: 3.028 min (analytical HPLC Method H). Chiral purity: 99.9% ee (chiral HPLC conditions: column. Chiralpak AD-H (25×0.46 cm, 5 μm), 30% MeOH in CO2, 3 mL/min, 40° C., 200-400 nm, 100 bars).

1. custombefore cautiously quenching of the reaction
2. additiondiluted with water (125 mL)
3. extractionextracted with ethyl acetate (3×150 mL)
4. washwashed with brine
5. dry with materialdried with Na2SO4
6. concentrationAfter concentration
7. customthe crude material was purified by flash chromatography