反应详情

温度

70 °C

A mixture of tert-butyl N-[[4-[5-[3-[bis(tert-butoxycarbonyl)amino]-6-bromo-pyrazin-2-yl]isoxazol-3-yl]phenyl]methyl]-N-tetrahydropyran-4-yl-carbamate (110.0 g, 151 mmol), K2CO3 (41.6 g, 301 mmol), and 2-methyl-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]propanenitrile (41.0 g, 151 mmol) in toluene (770 mL) and water (220 mL) is stirred and degassed with N2 for 30 min. at 20° C. The catalyst Pd(dtbpf)Cl2 (1.96 g, 3.01 mmol) is added and the mixture is degassed for an additional 10 min. The mixture is heated at 70° C. until the reaction is complete. The mixture is cooled to ambient temperature, diluted with water (220 mL), and filtered through a bed of Celite. The organic phase is concentrated to remove most of the solvent. The concentrate is diluted with i-PrOH (550 mL). The resultant suspension is stirred for at least 1 h and then the solid is collected by filtration to afford a tan powder. The solid is dissolved in toluene (990 mL) and stirred with Biotage MP-TMT resin (18.6 g) for 2 h at ambient temperature. The resin is removed by filtration. The filtrate is concentrated then diluted with i-PrOH (550 mL) and then re-concentrated. Add i-PrOH (550 mL) and stir for 1 h at ambient temperature. Cool the suspension to 5° C. and collect the solid by filtration then dry to afford tert-butyl N-[[4-[5-[3-[bis(tert-butoxycarbonyl)amino]-6-[2-(1-cyano-1-methyl-ethyl)-4-pyridyl]pyrazin-2-yl]isoxazol-3-yl]phenyl]methyl]-N-tetrahydropyran-4-yl-carbamate (Compound I-1) (81.9 g; 68%, yield, 98.7 area % purity by HPLC) as a cream-colored powder.

1. customdegassed with N2 for 30 min. at 20° C
2. customthe mixture is degassed for an additional 10 min
3. temperatureThe mixture is cooled to ambient temperature
4. additiondiluted with water (220 mL)
5. filtrationfiltered through a bed of Celite
6. concentrationThe organic phase is concentrated
7. customto remove most of the solvent
8. additionThe concentrate is diluted with i-PrOH (550 mL)
9. stirringThe resultant suspension is stirred for at least 1 h
10. filtrationthe solid is collected by filtration
11. customto afford a tan powder
12. customThe resin is removed by filtration
13. concentrationThe filtrate is concentrated
14. additionthen diluted with i-PrOH (550 mL)
15. concentrationre-concentrated
16. stirringAdd i-PrOH (550 mL) and stir for 1 h at ambient temperature
17. temperatureCool the suspension to 5° C.
18. customcollect the solid
19. filtrationby filtration
20. customthen dry