(2S)-1-(tert-butoxycarbonyl)-4-oxopyrrolidine-2-carboxylic acid → (2S)-1-((tert-butoxy)carbonyl)-4-methylidenepyrrolidine-2-carboxylic acid

Temperature

0 °C

To a mixture of methyltriphenylphosphonium bromide (236.4 g, 2.7 eq) in THF (1 L) was rapidly added potassium tert-butoxide (75.6 g, 2.75 eq) while maintaining the temperature around 0° C. The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 2 hours, and re-cooled to 0° C. (S)-1-(tert-butoxycarbonyl)-4-oxopyrrolidine-2-carboxylic acid (56.2 g, 0.245 mol) was added portionwise to the reaction mixture while maintaining the temperature below 5° C. Then, the reaction was allowed to warm to room temperature and stirred at room temperature overnight before being re-cooled to 0° C. and quenched by addition of saturated NaHCO3 solution (500 mL) and water (200 mL). The mixture was evaporated. The aqueous layer was extracted with tert-butyl methyl ether (2×400 mL). The aqueous layer was filtered through a pad of celite and the filtrate was acidified with 6N HCl (200 mL) and extracted with ethyl acetate (2×1 L). The combined organic layers were washed with brine, dried (Na2SO4), filtered and evaporated to dryness. The residue was dissolved in ethyl acetate (0.7 L), extracted with 0.5 N NaOH (0.7 and 0.3 L). The aqueous layer was acidified with 6N HCl (100 mL), extracted with ethyl acetate (1 L and 0.8 L). The combined organic layers were washed with brine, dried (Na2SO4), filtered and evaporated to dryness. The residue was dissolved in 50% ethyl acetate in cyclohexane (150 mL), slowly evaporated to give a yellowish solid. It was filtered and dried to give the title compound (26 g). The filtrate was evaporated to give a yellowish solid, filtered and dried to provide the title compound (10 g). Total 36 g (65%) as a white solid. Also, the residue contained 18 g of the product as 80% purity. 1H NMR (500 MHz, CDCl3): 5.04-5.02 (m, 2H), 4.53 (dd, J=8.4, 3.2 Hz, 0.5H), 4.42 (d, J=9.3 Hz, 0.5H), 4.09-3.98 (m, 2H), 3.05-2.69 (m, 2H), 1.49 and 1.43 (2 s, 9H).

1. temperatureto warm to room temperature
2. additionwas added portionwise to the reaction mixture
3. temperaturewhile maintaining the temperature below 5° C
4. temperatureto warm to room temperature
5. stirringstirred at room temperature overnight
6. temperaturebefore being re-cooled to 0° C.
7. customquenched by addition of saturated NaHCO3 solution (500 mL) and water (200 mL)
8. customThe mixture was evaporated
9. extractionThe aqueous layer was extracted with tert-butyl methyl ether (2×400 mL)
10. filtrationThe aqueous layer was filtered through a pad of celite
11. extractionextracted with ethyl acetate (2×1 L)
12. washThe combined organic layers were washed with brine
13. dry with materialdried (Na2SO4)
14. filtrationfiltered
15. customevaporated to dryness
16. dissolutionThe residue was dissolved in ethyl acetate (0.7 L)
17. extractionextracted with 0.5 N NaOH (0.7 and 0.3 L)
18. extractionextracted with ethyl acetate (1 L and 0.8 L)
19. washThe combined organic layers were washed with brine
20. dry with materialdried (Na2SO4)
21. filtrationfiltered
22. customevaporated to dryness
23. dissolutionThe residue was dissolved in 50% ethyl acetate in cyclohexane (150 mL)
24. customslowly evaporated
25. customto give a yellowish solid
26. filtrationIt was filtered
27. customdried

ORD record

ord-59d0192eb9e542d7854ff9fdf9d64666

Source dataset

uspto-grants-2015_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08927739B2