Citric Acid → 3-{[(alpha-Isobutanoyloxyethoxy)carbonyl]aminomethyl]-5-Methylhexanoic Acid

Temperature

0 °C

To a stirred suspension of pregabalin (2) (150 mg, 0.94 mmol) in anhydrous dichloromethane (10 mL) at 0° C. was added triethylamine (0.26 mL, 1.88 mmol) and trimethylchlorosilane (0.24 mL, 1.88 mmol). After stirring for 15 min at 0° C., a solution of α-isobutanoyloxyethyl-p-nitrophenyl carbonate (111) (267 mg, 0.94 mmol) in dichloromethane (3 mL) was added. The resulting mixture was stirred at room temperature for 1.5 h. The reaction mixture was acidified with citric acid and extracted with dichloromethane. The combined organic extracts were washed with brine and dried over Na2SO4. After filtration and evaporation, the crude product was purified by silica gel chromatography, eluting first with dichloromethane to remove nitrophenol, then with 30% ethyl acetate in dichloromethane to afford 130 mg (48%) of the title compound as a mixture of two diastereomers. 1H-NMR (CDCl3, 400 MHz): δ 0.90 (m, 6H), 1.70 (m, 8H), 1.46 (d, J=5.6 Hz, 3H), 1.66 (1H, m), 2.15 (m, 1H), 2.33 (m, 2H), 2.53 (m, 1H), 3.12 (m, 1H), 3.29 (m, 1H), 5.08 (t, J=6.0 Hz, 1H), 6.79 (m, 1H).

1. stirringThe resulting mixture was stirred at room temperature for 1.5 h
2. extractionextracted with dichloromethane
3. washThe combined organic extracts were washed with brine
4. dry with materialdried over Na2SO4
5. filtrationAfter filtration and evaporation
6. customthe crude product was purified by silica gel chromatography
7. washeluting first with dichloromethane
8. customto remove nitrophenol

ORD record

ord-931df604c5f742dbbdfba4a60fcbf5c5

Source dataset

uspto-grants-2007_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07186855B2