Nitromethane → Gabapentin

Temperature

-60 °C

n-Butyllithium (5.1 mL of a 2.5 M solution in hexanes, 12.75 mmol) was added dropwise to a stirring mixture of nitromethane (0.34 mL, 6.3 mmol) in THF (20 mL) and HMPA (2 mL) at −78° C. under argon. The mixture was allowed to warm to −60° C. and stirred for 1 hour. The mixture was cooled to −78° C. and 3 (0.79 g, 5.73 mmol) was added. The mixture was allowed to warm to −60° C. and stirred for a further 2 hours. The mixture was quenched by addition of saturated ammonium chloride solution (5 mL). After warming to room temperature, dilute hydrochloric acid (10 mL) and ether (30 mL) were added. The organic layer was separated, and the aqueous layer was further extracted with ether (2×25 mL). The combined organic fractions were washed with brine, dried (MgSO4), and the solvent was evaporated under reduced pressure. The residue was chromatographed (SiO2, heptane/ethyl acetate, 95:5) to give the nitro-alcohol 1 (0.50 g, 43%) as a white solid; Rf (heptane/ethyl acetate, 9:1) 0.14; νmax(CH2Cl2)/cm−1 3424 (OH), 1548 (NO2), 1379 (NO2); δH (400 MHz; CDCl3): 4.45 (2H, s, CH2NO2), 3.26 (1H, s, OH), 2.04-1.95 (2H, m), 1.85-1.80 (4H, m), 1.64-1.24 (8H, m).

1. temperatureThe mixture was cooled to −78° C.
2. temperatureto warm to −60° C.
3. stirringstirred for a further 2 hours
4. customThe mixture was quenched by addition of saturated ammonium chloride solution (5 mL)
5. temperatureAfter warming to room temperature
6. additiondilute hydrochloric acid (10 mL) and ether (30 mL) were added
7. customThe organic layer was separated
8. extractionthe aqueous layer was further extracted with ether (2×25 mL)
9. washThe combined organic fractions were washed with brine
10. dry with materialdried (MgSO4)
11. customthe solvent was evaporated under reduced pressure
12. customThe residue was chromatographed (SiO2, heptane/ethyl acetate, 95:5)

ORD record

ord-f1a74755a8a24d6984042258dd237034

Source dataset

uspto-grants-2003_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06620829B2