Methyl iodide → 1-tert-butyl 2-methyl (2S)-4-methylidenepyrrolidine-1,2-dicarboxylate

To a mixture of (S)-1-(tert-butoxycarbonyl)-4-methylenepyrrolidine-2-carboxylic acid (35 g, 154 mol) in DMF (155 mL) was added potassium carbonate (32 g, 1.5 eq) at room temperature. The mixture was stirred at room temperature for 1 hr before being cooled with a water bath. Methyl iodide (19.2 mL, 2 eq) was added dropwised. The mixture was stirred at room temperature for 6 hr. The reaction mixture was filtered through a pad of celite, diluted with ethyl acetate (300 mL), washed with water (200 mL). The aqueous layer was extracted with ethyl acetate (300 and 200 mL). The combined organic layers were washed with 10% Na2S2O3 solution (100 mL), water (3×200 mL) and brine, dried (Na2SO4), filtered and evaporated to dryness. The residue was passed through a silica gel (2 wt. volumes) pad with 0-15% ethyl acetate in hexanes to afford the title compound (37.06 g, quantitative yield) as a colorless oil. 1H NMR (500 MHz, CDCl3): 5.03 and 4.99 (2 br s, 2H), 4.51 (dd, J=9.5, 2.7 Hz) and 4.40 (dd, J=9.5, 3.3 Hz, 1H), 4.09 and 4.06 (2 br s, 2H), 3.73 (s, 3H), 3.01-2.92 (m, 1H), 2.65-2.60 (m, 1H), 1.47 and 1.42 (2 s, 9H).

1. temperaturebefore being cooled with a water bath
2. stirringThe mixture was stirred at room temperature for 6 hr
3. filtrationThe reaction mixture was filtered through a pad of celite
4. additiondiluted with ethyl acetate (300 mL)
5. washwashed with water (200 mL)
6. extractionThe aqueous layer was extracted with ethyl acetate (300 and 200 mL)
7. washThe combined organic layers were washed with 10% Na2S2O3 solution (100 mL), water (3×200 mL) and brine
8. dry with materialdried (Na2SO4)
9. filtrationfiltered
10. customevaporated to dryness

ORD record

ord-f545a4a50e104654a6bc8d4c0c5f6148

Source dataset

uspto-grants-2015_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08927739B2