Methyl iodide → 3-Methoxy-2,2-dimethylpropanoic acid

Temperature

0 °C

Sodium hydride (1.16 g, 48.4 mmol) was dissolved in THF (48 mL) and cooled to 0° C. 3-Hydroxy-2,2-dimethylpropanoate (6.4 g, 48.4 mmol) was added dropwise and the mixture was stirred at 0° C. for 30 min, allowed to warm to RT, and stirred an additional 1 h. The mixture was cooled back to 0° C. and iodomethane (3.0 mL), 48.4 mmol) was added. The reaction mixture was allowed to warm to RT and stirred for 16 h. The reaction mixture was filtered through a pad of diatomaceous earth and the filter cake was washed with THF (2×35 mL). The filtrates were combined and diluted with water (150 mL). Lithium hydroxide hydrate (8.13 g, 194 mmol) was added and the reaction mixture was stirred at RT for 16 h. The aqueous phase was collected and the organic phase was extracted with 0.5 N NaOH (aq) (3×50 mL). The combined aqueous phases were washed with Et2O (20 mL) and hexanes (2×100 mL), saturated with solid NaCl, and the pH of the solution was adjusted to ˜2 by the careful addition of conc. HCl (aq). The acidic solution was extracted with EtOAc (4×100 mL) and the combined organics were dried (Na2SO4) and concentrated in vacuo to afford 3-methoxy-2,2-dimethylpropanoic acid (5.8 g, 91%) as a red oil. 1H NMR (400 MHz, DMSO-d6): δ 12.02 (s, 1H), 3.29 (s, 2H), 3.23 (s, 3H), 1.06 (s, 6H).

1. temperatureto warm to RT
2. stirringstirred an additional 1 h
3. temperatureThe mixture was cooled back to 0° C.
4. temperatureto warm to RT
5. stirringstirred for 16 h
6. filtrationThe reaction mixture was filtered through a pad of diatomaceous earth
7. washthe filter cake was washed with THF (2×35 mL)
8. additiondiluted with water (150 mL)
9. stirringthe reaction mixture was stirred at RT for 16 h
10. customThe aqueous phase was collected
11. extractionthe organic phase was extracted with 0.5 N NaOH (aq) (3×50 mL)
12. washThe combined aqueous phases were washed with Et2O (20 mL) and hexanes (2×100 mL), saturated with solid NaCl
13. additionthe pH of the solution was adjusted to ˜2 by the careful addition of conc. HCl (aq)
14. extractionThe acidic solution was extracted with EtOAc (4×100 mL)
15. dry with materialthe combined organics were dried (Na2SO4)
16. concentrationconcentrated in vacuo

ORD record

ord-4365756a09c646fcb221cd1fac5166d9

Source dataset

uspto-grants-2015_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09193719B2