Hydrochloric Acid → (3S,4S)-benzyl 3-amino-4-methylpyrrolidine-1-carboxylate

Temperature

60 °C

Triphenylphosphine (11.96 g, 45.6 mmol) was added to a stirred acetonitrile (164 ml) and water (16.44 ml) solution of benzyl 3-azido-4-methylpyrrolidine-1-carboxylate (11.3 g, 43.4 mmol). The reaction mixture was heated up to 60° C. overnight. The reaction mixture was concentrated. The resulting residue was diluted with 50 mL ice water, treated with 1N HCl (47.8 ml, 47.8 mmol). The aqueous acidic solution (pH 1) was extracted with EtOAc (4×100 mL) to remove Ph3P and Ph3PO by-products/impurities. The acidic aqueous portion containing the product was cooled in an ice bath, neutralized with 1N NaOH (52.1 ml, 52.1 mmol). The resulting cloudy mixture was then extracted with DCM (3×150 mL). The combined DCM phases were washed with brine, dried over anhydrous sodium sulfate. After concentration, (3S,4S)-benzyl 3-amino-4-methylpyrrolidine-1-carboxylate (9.8 g, 96% yield) was obtained as a light yellow oil. 1H NMR (400 MHz, chloroform-d) δ ppm 7.31-7.47 (5H, m), 5.09-5.23 (2H, m), 3.42-3.69 (3H, m), 3.12-3.38 (2H, m), 2.17-2.36 (1H, m), 1.31 (2H, br), 1.06 (3H, dd, J=6.82, 3.30 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: 1.97 min; MS(ES+) m/z: 235.1 (M+H+).

1. concentrationThe reaction mixture was concentrated
2. additionThe resulting residue was diluted with 50 mL ice water
3. extractionThe aqueous acidic solution (pH 1) was extracted with EtOAc (4×100 mL)
4. customto remove Ph3P and Ph3PO by-products/impurities
5. additionThe acidic aqueous portion containing the product
6. temperaturewas cooled in an ice bath
7. extractionThe resulting cloudy mixture was then extracted with DCM (3×150 mL)
8. washThe combined DCM phases were washed with brine
9. dry with materialdried over anhydrous sodium sulfate
10. concentrationAfter concentration

ORD record

ord-6fd1e0df174d4ddcbab1f2cdd4ba66db

Source dataset

uspto-grants-2016_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09428511B2