[Synthesis]
To a dry 500 mL round-bottomed flask were added a stirrer, 8-methyl-8-azabicyclo[3.2.1]octan-3-one (10.0 g, 0.072 mol) and potassium carbonate (0.050 g). Anhydrous toluene (90 mL) was added, followed by slow dropwise addition of ethyl chloroformate (21 mL, 0.22 mol) via syringe. A condenser tube and nitrogen bubbler were installed and the reaction was heated to reflux with stirring overnight. Upon completion of the reaction, the mixture was concentrated under reduced pressure and the resulting brown oil was dissolved in dichloromethane (100 mL) and washed with water (100 mL). The organic and aqueous layers were separated in a partition funnel and the aqueous layer was extracted with dichloromethane (3 x 50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane, 1:3) to afford ethyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (13.1 g, 92% yield) as a light yellow oil.1H NMR (δ): 4.51 (br s, 2H), 4.16 (q, J = 7.2 Hz, 2H), 2.63 (br s , 2H), 2.31 (dd, J = 17.4, 1.6 Hz, 2H), 2.07-2.03 (m, 2H), 1.65 (d, J = 7.6 Hz, 2H), 1.25 (t, J = 7.2 Hz, 3H).13C NMR (δ): 208.3, 154.1, 61.6, 53.2, 49.1, 29.5 (2), 28.8 (2), 14.8 (2), 28.8 (2), 29.5 (2), 29.5 (2), 28.8 (2), 28.8 (2), 28.8 (2), 29.5 (2) 28.8 (2), 14.9. |
[References]
[1] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 4, p. 629 - 632
[2] Journal of Heterocyclic Chemistry, 2004, vol. 41, # 4, p. 569 - 574
[3] Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 24, p. 7551 - 7558
[4] Patent: CN105294674, 2016, A. Location in patent: Paragraph 0147; 0148; 0149
[5] Patent: WO2018/140876, 2018, A1. Location in patent: Page/Page column 216 |