Methyl iodide → (5S)-5-(Hydroxymethyl)-1-methyl-2-pyrrolidinone

To a solution of (S)-methyl 5-oxo-pyrrolidine-2-carboxylate (Aldrich, 2.86 g, 20 mmol) in tetrahydrofuran (50 mL) at 0° C. was added in portions 60% oil dispersion NaH (720 mg, 30 mmol). Methyl iodide (1.88 mL, 30 mmol) was added and the mixture was allowed to warm to ambient temperature and stirred for 16 h. The mixture was concentrated under reduced pressure and residue was partitioned between water and ethyl acetate. The organic layer was washed with water, brine, dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was redissolved in anhydrous tetrahydrofuran (50 mL), sodium borohydride (946 mg, 25 mmol) was added followed by dropwise addition (˜20 min) of methanol (20 mL) at 50° C. The reaction mixture was stirred for an additional 1 h at a range from 45° C. to 50° C., then cooled to room temperature and concentrated under reduced pressure. Citric acid (10%) was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water, brine, dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by chromatography (SiO2, ethyl acetate-ethanol 4:1) to afford 1.3 g of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 1.77 (m 1H), 1.95 (m, 1H), 2.18 (m, 2H), 2.69 (s, 3H), 3.43 (m, 2H), 3.55 (m, 1H), 4.77 (t, J=6 Hz, 1H); MS (DCI/NH3) m/z 130 (M+H)+, 147 (M+NH4)+.

1. concentrationThe mixture was concentrated under reduced pressure and residue
2. customwas partitioned between water and ethyl acetate
3. washThe organic layer was washed with water, brine
4. dry with materialdried with anhydrous MgSO4
5. filtrationfiltered
6. concentrationconcentrated under reduced pressure
7. dissolutionThe residue was redissolved in anhydrous tetrahydrofuran (50 mL)
8. stirringThe reaction mixture was stirred for an additional 1 h at a range from 45° C. to 50° C.
9. temperaturecooled to room temperature
10. concentrationconcentrated under reduced pressure
11. additionCitric acid (10%) was added
12. extractionthe mixture was extracted with ethyl acetate
13. washThe organic layer was washed with water, brine
14. dry with materialdried with anhydrous MgSO4
15. filtrationfiltered
16. concentrationconcentrated under reduced pressure
17. customThe residue was purified by chromatography (SiO2, ethyl acetate-ethanol 4:1)

ORD record

ord-96610fbc8898489ba5075ea28564126e

Source dataset

uspto-grants-2012_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08338467B2