p-Toluenesulfonic acid monohydrate → Dimethyl (2S)-5-methoxypyrrolidine-1,2-dicarboxylate

Temperature

-78 °C

To a cold solution (−78° C.) of dimethyl (2S)-5-oxopyrrolidine-1,2-dicarboxylate (5.80 g, 28.8 mmol) in tetrahydrofuran (100 mL) was added a solution of lithium triethylborohydride (1 M in THF, 35 mL, 35 mmol) dropwise via syringe over 10 minutes. The resulting solution was stirred at −78° C. for 30 minutes and then quenched by the careful addition of saturated sodium bicarbonate solution (50 mL). After warming to 0° C., 30% hydrogen peroxide (6 mL) was carefully added dropwise. The mixture was stirred for 30 minutes at room temperature, concentrated under reduced pressure, and diluted with ethyl acetate (300 mL) and brine (200 mL). The milky aqueous layer was separated and further extracted with ethyl acetate (2×300 mL). The combined organic layers were dried (sodium sulfate), filtered, and concentrated to a light yellow oil. The yellow oil was taken up in methanol (50 mL) containing para-toluenesulfonic acid hydrate (487 mg, 2.6 mmol) and stirred at room temperature for 16 hours. The reaction was diluted with aqueous sodium bicarbonate solution (40 mL), the volatile solvents were removed under reduced pressure and the residue partitioned between ethyl acetate (200 mL) and brine (200 mL). The aqueous layer was further extracted with ethyl acetate (200 mL). The combined organic layers were dried (sodium sulfate), filtered, and concentrated to an oil which was purified by flash chromatography using 60% hexane/40% ethyl acetate as eluent to provide the titled compound (3.80 g, 61% yield) as a mixture of diastereomers. (mixture of amide bond rotomers) 1H NMR (300 MHz, CDCl3): δ ppm 5.37 (d, 1H), 5.33 (dd, 1H), 5.24 (d, 1H), 5.18 (dd, 1H), 4.44–4.31 (m, 2H), 3.76 (s, 3H), 3.73 (s, 3H), 3.72 (s, 3H), 3.42 (s, 3H), 3.34 (s, 3H).

1. customquenched by the careful addition of saturated sodium bicarbonate solution (50 mL)
2. temperatureAfter warming to 0° C.
3. addition30% hydrogen peroxide (6 mL) was carefully added dropwise
4. stirringThe mixture was stirred for 30 minutes at room temperature
5. concentrationconcentrated under reduced pressure
6. additiondiluted with ethyl acetate (300 mL) and brine (200 mL)
7. customThe milky aqueous layer was separated
8. extractionfurther extracted with ethyl acetate (2×300 mL)
9. dry with materialThe combined organic layers were dried (sodium sulfate)
10. filtrationfiltered
11. concentrationconcentrated to a light yellow oil
12. stirringstirred at room temperature for 16 hours
13. customthe volatile solvents were removed under reduced pressure
14. customthe residue partitioned between ethyl acetate (200 mL) and brine (200 mL)
15. extractionThe aqueous layer was further extracted with ethyl acetate (200 mL)
16. dry with materialThe combined organic layers were dried (sodium sulfate)
17. filtrationfiltered
18. concentrationconcentrated to an oil which
19. customwas purified by flash chromatography

ORD record

ord-90bbd384969347798a3ff9f323158f59

Source dataset

uspto-grants-2007_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07205409B2