Sodium Hydroxide → 1-{[(1S,2S)-2-(4-bromophenyl)cyclopropyl]methyl}-(2S)-2-methylpyrrolidine

Temperature

0 °C

A solution of the product from Example 8E, (1S,2S)-2-(4-bromophenyl)cyclopropanecarbaldehyde (5.7 g, 25.3 mmol) in DCM (20 ml) and MeOH (300 mL) was treated with (S)-2-methylpyrrolidine tartrate (8.94 g, 38.0 mmol) at ambient temperature, and the mixture was stirred for 5-10 minutes. Then, the mixture was cooled to 0° C., and a solution of NaCNBH3 (2.51 g, 38.0 mmol) in MeOH (50 mL) was added dropwise. After addition, the reaction mixture was raised to room temperature and stirred overnight. The reaction mixture was treated with NaOH (1N) till basic, extracted with DCM thrice (500 mL×3), dried and concentrated under reduced pressure. The crude product was loaded onto a silica gel column and eluted with 1% to 3% methanol (containing 10% concentrated NH4OH) in dichloromethane to provide the title product. 1H NMR (300 MHz, CDCl3): δ 0.87-0.92 (m, 1H), 0.97-1.02 (m, 1H), 1.16 (d, J=6 Hz, 2H), 1.22 (m, 1H), 1.39-1.49 (m, 1H), 1.73-1.81 (m, 3H), 2.0 (m, 2H), 2.36 (q, J=6 Hz, 1H), 2.45 (m, 1H), 3.13 (dd, J=12 Hz, J=6 Hz, 1H), 3.25 (m, 1H), 7.00 (d, J=6 Hz, 2H), 7.37 (d, J=6 Hz, 2H). MS (DCI—NH3) m/z 294 (M+H)+.

1. additionAfter addition
2. temperaturethe reaction mixture was raised to room temperature
3. stirringstirred overnight
4. extractionextracted with DCM thrice (500 mL×3)
5. customdried
6. concentrationconcentrated under reduced pressure
7. washeluted with 1% to 3% methanol (containing 10% concentrated NH4OH) in dichloromethane

ORD record

ord-5918241426e34593adad257e7430c2ac

Source dataset

uspto-grants-2015_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09186353B2