| 79% |
With SiO2 |
Intermediate 7: tert-Butyl 6-(((trifluoromethyl)sulfonyl)oxy)-2-azaspiro[3.4]oct-6-ene-2-carboxylate
Intermediate 7: tert-Butyl 6-(((trifluoromethyl)sulfonyl)oxy)-2-azaspiro[3.4]oct-6-ene-2-carboxylate To a solution of tert-butyl 6-oxo-2-azaspiro[3.4]octane-2-carboxylate (1.5 g, 6.66 mmol) in THF (16.6 mL) at -78° C. was added LiHMDS (1.06 M in THF, 9.12 mL, 9.12 mmol) dropwise via syringe and the reaction stirred at -78° C. for 1 h. A solution of 2-[N,N-bis(trifluoromethanesulfonyl)amino]-5-chloropyridine (3.07 g, 7.82 mmol) in THF (1.7 mL) was then added dropwise, and the reaction stirred at -78° C. for an additional 1 h before removing the cold bath and allowing the mixture to warm to rt for 30 min. The reaction was quenched with H2O and the aqueous layer extracted with EtOAc. The combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified via FCC (SiO2, 0-50% EtOAc in hexanes) to afford the title compound as a white solid (1.89 g, 79% yield). MS (ESI): mass calcd. for C13H18F3NO5S, 357.1; m/z found, 302.0 [M-tBu+2H]+. 1H NMR (500 MHz, Chloroform-d) δ 5.79 (t, J=1.9 Hz, 1H), 3.96 (d, J=8.7 Hz, 2H), 3.86 (d, J=8.7 Hz, 2H), 2.65-2.61 (m, 2H), 2.31-2.26 (m, 2H), 1.44 (s, 9H). |
| 79% |
Stage #1: tert-butyl 6-oxo-2-azaspiro[3.4]octane-2-carboxylate With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 1h; Inert atmosphere;
Stage #2: N-(5-chloropyridin-2-yl)-1,1,1-trifluoro-N-((trifluoromethyl)sulfonyl)methanesulfonamide In tetrahydrofuran at -78℃; for 1h; Inert atmosphere; |
Intermediate 7: tert-Butyl 6-(((trifluoromethyl)sulfonyl)oxy)-2-azaspiro[3.4]oct-6-ene-2-carboxylate
To a solution of tert-butyl 6-oxo-2-azaspiro[3.4]octane-2-carboxylate (1.5 g, 6.66 mmol) in THF (16.6 mL) at -78° C. was added LiHMDS (1.06 M in THF, 9.12 mL, 9.12 mmol) dropwise via syringe and the reaction stirred at -78° C. for 1 h. A solution of 2-[N,N-bis(trifluoromethanesulfonyl)amino]-5-chloropyridine (3.07 g, 7.82 mmol) in THF (1.7 mL) was then added dropwise, and the reaction stirred at -78° C. for an additional 1 h before removing the cold bath and allowing the mixture to warm to rt for 30 min. The reaction was quenched with H2O and the aqueous layer extracted with EtOAc. The combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified via FCC (SiO2, 0-50% EtOAc in hexanes) to afford the title compound as a white solid (1.89 g, 79% yield). MS (ESI): mass calcd. for C13H18F3NO5S, 357.1; m/z found, 302.0 [M-tBu+2H]+. 1H NMR (500 MHz, Chloroform-d) δ 5.79 (t, J=1.9 Hz, 1H), 3.96 (d, J=8.7 Hz, 2H), 3.86 (d, J=8.7 Hz, 2H), 2.65-2.61 (m, 2H), 2.31-2.26 (m, 2H), 1.44 (s, 9H). |
| 79% |
Stage #1: tert-butyl 6-oxo-2-azaspiro[3.4]octane-2-carboxylate With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 1h; Inert atmosphere;
Stage #2: N-(5-chloropyridin-2-yl)-1,1,1-trifluoro-N-((trifluoromethyl)sulfonyl)methanesulfonamide In tetrahydrofuran at -78℃; for 1h; Inert atmosphere; |
Intermediate 7: tert-Butyl 6-(((trifluoromethyl)sulfonyl)oxy)-2-azaspiro[3.4]oct-6-ene-2-carboxylate
To a solution of tert-butyl 6-oxo-2-azaspiro[3.4]octane-2-carboxylate (1.5 g, 6.66 mmol) in THF (16.6 mL) at -78° C. was added LiHMDS (1.06 M in THF, 9.12 mL, 9.12 mmol) dropwise via syringe and the reaction stirred at -78° C. for 1 h. A solution of 2-[N,N-bis(trifluoromethanesulfonyl)amino]-5-chloropyridine (3.07 g, 7.82 mmol) in THF (1.7 mL) was then added dropwise, and the reaction stirred at -78° C. for an additional 1 h before removing the cold bath and allowing the mixture to warm to rt for 30 min. The reaction was quenched with H2O and the aqueous layer extracted with EtOAc. The combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified via FCC (SiO2, 0-50% EtOAc in hexanes) to afford the title compound as a white solid (1.89 g, 79% yield). MS (ESI): mass calcd. for C13H18F3NO5S, 357.1; m/z found, 302.0 [M-tBu+2H]+. 1H NMR (500 MHz, Chloroform-d) δ 5.79 (t, J=1.9 Hz, 1H), 3.96 (d, J=8.7 Hz, 2H), 3.86 (d, J=8.7 Hz, 2H), 2.65-2.61 (m, 2H), 2.31-2.26 (m, 2H), 1.44 (s, 9H). |
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