反应详情

温度

110 °C

To a solution of tert-butyl 2-[(1R)-5-bromo-2,3-dihydro-1H-inden-1-yl]-2,7-diazaspiro[3.5]nonane-7-carboxylate (3-1a, 700 mg, 1.66 mmol) in anhydrous dioxane (10 mL) was added bis(pinacolato)diboron (473 mg, 1.86 mmol) and potassium acetate (659 mg, 6.71 mmol). The mixture was purged with nitrogen for 15 minutes. Pd(dppf)Cl2 (62 mg, 0.07 mmol) was added and the reaction mixture was purged with nitrogen for an additional 15 minutes. The reaction was heated to 110° C. under nitrogen for 5 hours. TLC indicated the complete consumption of the starting material (3-1a). The reaction was cooled to room temperature and 5-chloropyrazine-2-carbonitrile (278 mg, 1.99 mmol), Pd(dppf)Cl2 (62 mg, 0.07 mmol) and 5.81 mL of 2M aqueous K2CO3 solution (de-oxygenated with a stream of nitrogen for 15 minutes prior to addition) were added. The reaction was purged with nitrogen (3×) and was heated for 20 hours at 110° C. The reaction was cooled and concentrated in vacuo. The residue was partitioned between 50 mL of ethyl acetate and 50 mL of 1N NaOH solution. The organics layer was washed with 50 mL of brine, dried (Na2SO4) and concentrated to give crude product as black semi-solid. The crude product was purified via silca gel chromatography using a Combiflash ISCO purification system (Teledyne Corp., Lincoln, Nebr.) system, eluting with 0-100% EtOAc:heptanes to give the title compound as a brown solid (440 mg, 59%). MS (ES+) 446.3 (M+H)+. 1H NMR (DMSO-d6) δ 1.39 (s, 9H), 1.56-1.64 (m, 4H), 1.81-1.92 (m, 1H), 2.06 (dd, 1H), 2.77-2.87 (m, 1H), 2.92-3.04 (m, 3H), 3.12 (d, 2H), 3.24-3.28 (m, 4H), 3.86 (dd, 1H), 7.41 (d, 1H), 7.55 (d, 1H), 7.62-7.68 (m, 1H), 8.09 (s, 1H), 8.90 (s, 1H).

1. customThe mixture was purged with nitrogen for 15 minutes
2. customthe reaction mixture was purged with nitrogen for an additional 15 minutes
3. customthe complete consumption of the starting material (3-1a)
4. temperatureThe reaction was cooled to room temperature
5. additionto addition)
6. additionwere added
7. customThe reaction was purged with nitrogen (3×)
8. temperaturewas heated for 20 hours at 110° C
9. temperatureThe reaction was cooled
10. concentrationconcentrated in vacuo
11. customThe residue was partitioned between 50 mL of ethyl acetate and 50 mL of 1N NaOH solution
12. washThe organics layer was washed with 50 mL of brine
13. dry with materialdried (Na2SO4)
14. concentrationconcentrated
15. customto give crude product as black semi-solid
16. customThe crude product was purified via silca gel chromatography
17. customa Combiflash ISCO purification system (Teledyne Corp., Lincoln, Nebr.) system
18. washeluting with 0-100% EtOAc