反应详情

温度

100 °C

To a 50 mL flask charged with (R)-tert-butyl 2-(5-bromo-2,3-dihydro-1H-inden-1-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (4.0 g, 9.49 mmol) was added bis(triphenylphosphine)palladium(II) chloride (0.17 g, 0.24 mmol), potassium acetate (3.73 g, 37.97 mmol), bis(pinacolato)diboron (2.65 g, 10.44 mmol) followed by degassing via vacuum then backfilling with nitrogen 5 times. De-oxygenated (nitrogen stream for 30 minutes prior to addition) toluene (40 mL) was added to the mixture and the reaction was heated at 100° C. for 1.5 hours. The reaction was monitored for completion by HPLC. Upon formation of the boronic ester intermediate, the reaction was cooled to 40° C. and charged with a degassed solution of 4 M sodium hydroxide (11.87 mL, 47.46 mmol) followed by addition of 4-chloro-6-methylpyrimidine (1.53 g, 11.87 mmol). The resulting mixture was then heated to 90° C. for 5 hours under nitrogen. The reaction was cooled to room temperature and charged with water (25 mL). After stirring for 20 minutes, the mixture was filtered to remove black solids. The organic layer was extracted to an aqueous solution containing 1.5 equiv of HCl (40 mL). The organic layer was removed and the resulting solution was treated with (4 g) ISOLUTE® Ultra Pure Si-Thiol silica gel for 1.5 hours and filtered. The aqueous solution was adjusted to pH 7.8 with 4N NaOH and extracted with toluene (40 mL). The toluene layer was concentrated to approximately 15 mL under vacuum at 45° C. and heptane (75 mL) was added slowly and the mixture was stirred at 20° C. for 1 hour. The product was filtered and dried under vacuum at 45° C. for 8 hours to afford the title compound as a white solid (3.56 g, 86%). MS (ES+) 435.5 (M+H)+. 1H NMR (CDCl3) δ 1.46 (s, 9H), 1.70-1.74 (m, 4H), 1.90-2.01 (m, 1H), 2.13-2.26 (m, 1H), 2.59 (s, 3H), 2.84-2.93 (m, 1H), 3.04-3.21 (m, 5H), 3.30-3.38 (m, 4H), 3.95-4.02 (m, 1H), 7.40 (d, 1H), 7.56 (s, 1H), 7.87 (d, 1H), 7.95 (s, 1H), 9.12 (s, 1H).

1. customby degassing via vacuum
2. additionto addition) toluene (40 mL)
3. additionwas added to the mixture
4. temperatureUpon formation of the boronic ester intermediate, the reaction was cooled to 40° C.
5. temperatureThe resulting mixture was then heated to 90° C. for 5 hours under nitrogen
6. temperatureThe reaction was cooled to room temperature
7. filtrationthe mixture was filtered
8. customto remove black solids
9. extractionThe organic layer was extracted to an aqueous solution
10. customThe organic layer was removed
11. additionthe resulting solution was treated with (4 g) ISOLUTE® Ultra Pure Si-Thiol silica gel for 1.5 hours
12. filtrationfiltered
13. extractionextracted with toluene (40 mL)
14. concentrationThe toluene layer was concentrated to approximately 15 mL under vacuum at 45° C.
15. additionheptane (75 mL) was added slowly
16. stirringthe mixture was stirred at 20° C. for 1 hour
17. filtrationThe product was filtered
18. customdried under vacuum at 45° C. for 8 hours