3-Bromopyridine → tert-Butyl 4-nicotinoylpiperidine-1-carboxylate

Temperatur

85 °C

A solution of n-butyllithium (14.2 mL of a 2.51M solution in hexanes, 35.54 mmol) in tetrahydrofuran (50 mL) was cooled to ←85° C. and treated dropwise with a solution of 3-bromopyridine (5.90 g, 37.31 mmol) in tetrahydrofuran (50 mL). The resulting pale yellow-green solution was stirred at ←85° C. for 15 min, then was treated with a solution of N-methoxy-N-methyl 1-(1,1-dimethylethyloxycarbonyl)-4-piperidine carboxamide (8.80 g, 32.31 mmol) in tetrahydrofuran (50 mL). The reaction mixture was allowed to warm to -20° C. over 1 h, then was cooled to -60° C. and quenched by addition of water (20 mL). The mixture was vaned to 0° C., acidified to pH~ 2 by addition of 3M hydrochloric acid and stirred at 0° C. for 10 min. The mixture was then poured into 10% aqueous sodium hydroxide (50 mL) and extracted with ethyl acetate (3×150 mL). The organic extracts were washed sequentially with 1N aqueous sodium hydroxide (100 mL) and brine (100 mL), combined, dried over Na2SO4, filtered and concentrated to leave a yellow semi solid mass. This mass was triturated with hexane (50 mL) and the solid which formed was removed by filtration. The solid was rinsed with hexane (25 mL) and dried to afford the title ketone (6.62 g, 22.8 mmol, 71%) as off-white needles. From the filtrate, an additional 300 mg (1.03 mmol, 3%) of the ketone was obtained. 1H NMR CDCL3 : δ9.16 (d, J=2.2 Hz, 1H, H--C(2')), 8.79 (dd, J=1.7 Hz, 4.8 Hz, 1H, H--C(6')), 8.23 (ddd, J=1.7, 2.2, 8.0 Hz, 1H, H--C(4')), 7.45 (dd, J=4.8, 8.0 Hz, 1H, H--C(5')), 4.17 (brd, J=11 Hz, 2H, eq-H--C(2)), 3.39 (m, 1H, H--C(4)), 2.92 (dd, J=11.6, 11.6 Hz, 2H, ax-H--C(2)), 1.87 (m, 2H, eq-H--C(3)), 1.71 (m, 2H, ax-H--C(3)), 1.47 (s, 9H, (CH3)3C).

1. customto ←85° C.
2. temperatureto warm to -20° C. over 1 h
3. temperaturewas cooled to -60° C.
4. customquenched by addition of water (20 mL)
5. customwas vaned to 0° C.
6. additionacidified to pH~ 2 by addition of 3M hydrochloric acid
7. stirringstirred at 0° C. for 10 min
8. additionThe mixture was then poured into 10% aqueous sodium hydroxide (50 mL)
9. extractionextracted with ethyl acetate (3×150 mL)
10. washThe organic extracts were washed sequentially with 1N aqueous sodium hydroxide (100 mL) and brine (100 mL)
11. dry with materialdried over Na2SO4
12. filtrationfiltered
13. concentrationconcentrated
14. customto leave a yellow semi solid mass
15. customThis mass was triturated with hexane (50 mL)
16. customthe solid which formed
17. customwas removed by filtration
18. washThe solid was rinsed with hexane (25 mL)
19. customdried

ORD-Eintrag

ord-281eabb0b11a4a009a8fb5509c8f782b

Quelldatensatz

uspto-grants-1998_02

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US05719166