反应详情

温度

110 °C

To an oven-dried round-bottomed flask was added (R)-tert-butyl-2-(5-bromo-2,3-dihydro-1H-inden-1-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (3-1a, 600 mg, 1.42 mmol), bispinacolatodiboron (398 mg, 1.71 mmol), 559 mg potassium acetate (559 mg, 5.70 mmol) and anhydrous dioxane (20 mL). The resulting mixture was purged with nitrogen (3×). Pd(dppf)Cl2 (58.0 mg, 0.07 mmol) was added and the reaction mixture was purged with nitrogen (3×). The reaction was heated under nitrogen at 110° C. for 4 hours at which time LCMS showed conversion to the desired boronate intermediate. Pd(dppf)Cl2 catalyst (58.0 mg, 0.07 mmol), 2-chloro-5-ethylpyrimidine (224 mg, 1.57 mmol) and aqueous K2CO3 solution (de-oxygenated with nitrogen for 15 minutes prior to addition, 2M, 5.0 mL) were added to the reaction mixture. The reaction was purged with nitrogen (3×) and heated for 6 hours at 110° C. The reaction was cooled to room temperature and the dioxane solvent was removed under reduced pressure. The residue was partitioned between 100 mL of ethyl acetate and 100 mL of 1N NaOH solution. The organic layer was washed with 100 mL of brine, dried (Na2SO4) and concentrated to afford thecrude product as a dark brown oil. The crude product was purified on an Analogix (Analogix Inc., Burlington, Wis.) 8 g silica column, eluted with 0-10% MeOH in CH2Cl2 over 20 minutes to afford 583 mg (92%) of the desired product (3-1b) as a brown foam. MS (ES+) 449.5 (M+H)+. 1H NMR (CDCl3) δ 1.23 (t, 3H), 1.40 (s, 9H), 1.56-1.67 (m, 4H), 1.83-1.91 (m, 1H), 2.07-2.16 (m, 1H), 2.59 (q, 2H), 2.76-2.85 (m, 1H), 2.99-3.13 (m, 5H), 3.24-3.31 (m, 4H), 3.91 (dd, 1H), 7.27-7.34 (m, 1H), 8.17-8.23 (m, 2H), 8.56 (s, 2H).

1. customThe resulting mixture was purged with nitrogen (3×)
2. customthe reaction mixture was purged with nitrogen (3×)
3. additionto addition, 2M, 5.0 mL)
4. additionwere added to the reaction mixture
5. customThe reaction was purged with nitrogen (3×)
6. temperatureheated for 6 hours at 110° C
7. temperatureThe reaction was cooled to room temperature
8. customthe dioxane solvent was removed under reduced pressure
9. customThe residue was partitioned between 100 mL of ethyl acetate and 100 mL of 1N NaOH solution
10. washThe organic layer was washed with 100 mL of brine
11. dry with materialdried (Na2SO4)
12. concentrationconcentrated
13. customto afford thecrude product as a dark brown oil
14. customThe crude product was purified on an Analogix (Analogix Inc., Burlington, Wis.) 8 g silica column
15. washeluted with 0-10% MeOH in CH2Cl2 over 20 minutes