Pyrrolidine → (R)-tert-butyl 3-(pyrrolidine-1-carbonyl)piperidine-1-carboxylate

To a solution of (R)-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (50.64 g, 220.9 mmol) in anhydrous tetrahydrofuran (552 mL) at 2° C. was added 1,1′-carbonyldiimidazole (77.59 g, 460 mmol). The mixture was stirred at room temperature for 2 h, cooled to 10° C. and then pyrrolidine (74 mL, 890 mmol) was added slowly. The reaction mixture was stirred at room temperature for 18 h. The solvent was removed under reduced pressure and water (200 mL) was added to the residue. The mixture was extracted with ethyl acetate (2×). The combined organics were washed with aqueous hydrochloric acid (200 mL×4, 1N) and with a saturated aqueous solution of sodium bicarbonate (200 mL×2). The organics were dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford (R)-tert-butyl 3-(pyrrolidine-1-carbonyl)piperidine-1-carboxylate as a white solid (58.82 g). The compound was used for the next step without further purification. 1H NMR (400 MHz, CD3OD) δ 1.39-1.54 (m, 10H) 1.59-1.65 (m, 1H) 1.67 (d, 1H) 1.69-1.77 (m, 1H) 1.80-2.05 (m, 5H) 2.58 (tt, 1H) 2.77 (br s, 1H) 3.33-3.46 (m, 2H) 3.51-3.66 (m, 2H) 3.98-4.12 (m, 2H); MS (AP+) (M+H) 283.3.

1. temperaturecooled to 10° C.
2. stirringThe reaction mixture was stirred at room temperature for 18 h
3. customThe solvent was removed under reduced pressure and water (200 mL)
4. additionwas added to the residue
5. extractionThe mixture was extracted with ethyl acetate (2×)
6. washThe combined organics were washed with aqueous hydrochloric acid (200 mL×4, 1N) and with a saturated aqueous solution of sodium bicarbonate (200 mL×2)
7. dry with materialThe organics were dried over magnesium sulfate
8. filtrationfiltered
9. concentrationconcentrated under reduced pressure

ORDレコード

ord-f04b421cdf4f4935a6cb3249f830ba1f

出典データセット

uspto-grants-2016_03

DOI

10.6084/m9.figshare.5104873.v1

特許番号

US09296745B2