反应详情

温度

88 °C

To a solution of 4-(2-chloro-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)thieno[3,2-d]pyrimidin-4-yl)morpholine 9 (96.5 g, 223 mmol, 1.0 equiv.) in 1,4-dioxane (1.75 L) was added water (772 ml), sodium carbonate (47.4 g, 447 mmol, 2.0 equiv.) and 2-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole 10 (73 w/w %, 150.7 g, 325 mmol, 1.5 equiv.). The mixture was degassed for three times. Bis(triphenylphosphine)palladium (II) chloride (6.28 g, 9.94 mmol, 0.04 equiv.) was added and the resulting slurry was degassed for 4 times. The mixture was heated to 88° C. and stirred for 14 hours. The reaction mixture was cooled to 50° C., concentrated under vacuum to half of the total volume and then cooled to 15° C., and acetonitrile (900 ml) was added. After 2 hours of agitation, the resulting slurry was cooled to −5° C., filtered and rinsed with acetonitrile (40 ml), water (90 ml), and acetonitrile (40 ml). The cake was dried in a vacuum oven at 50° C. for 24 hours to afford a brown-yellow solid (140 g, the Pd content: 2000 ppm). The cake was dissolved in methylene chloride (1930 ml) and FLORISIL® (60-100 mesh, 193 g, purchased from Aldrich Chemical Company, Inc) was then added. The slurry was stirred at the ambient temperature for a minimum of 5 hours and SILIABOUND®Thiol (28 g) was added. The mixture was stirred at ambient temperature for a minimum of 12 hours, filtered and rinsed with methylene chloride (2 L), followed by a mixture of methylene chloride (2 L) and ethyl acetate (2 L). All the filtrate and the rinse were combined and concentrated to give 4-(6-((4-(methylsulfonyl)piperazin-1-yl)methyl)-2-(2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-4-yl)thieno[3,2-d]pyrimidin-4-yl)morpholine 14 as an off-white solid (93 g) with Pd content of less than 20 ppm, and containing a minor amount of THP regioisomer 14A. 1H NMR (300 MHz, CDCl3) 1.20-4.30 (br, 8H), 2.61-2.64 (m, 4H), 2.74 (s, 3H), 3.23-3.26 (m, 4H), 3.83-3.86 (m, 6H), 3.99-4.02 (m, J=4.15 Hz, 4H), 5.66-5.70 (m, 1H), 7.32 (s, 1H), 7.32-7.37 (dd, 8.6 Hz, 7.1 Hz, 1H), 7.77-7.80 (d, 8.6 Hz, 1H), 8.22-8.25 (d, 6.99 Hz, 1H), 9.04 (s, 1H). LCMS (ESI pos) m/e 598 (M+1).

1. customThe mixture was degassed for three times
2. customthe resulting slurry was degassed for 4 times
3. temperatureThe reaction mixture was cooled to 50° C.
4. concentrationconcentrated under vacuum to half of the total volume
5. temperaturecooled to 15° C.
6. additionacetonitrile (900 ml) was added
7. waitAfter 2 hours of agitation
8. temperaturethe resulting slurry was cooled to −5° C.
9. filtrationfiltered
10. washrinsed with acetonitrile (40 ml), water (90 ml), and acetonitrile (40 ml)
11. customThe cake was dried in a vacuum oven at 50° C. for 24 hours
12. customto afford a brown-yellow solid (140 g
13. additionwas added
14. stirringThe mixture was stirred at ambient temperature for a minimum of 12 hours
15. filtrationfiltered
16. washrinsed with methylene chloride (2 L)
17. additionfollowed by a mixture of methylene chloride (2 L) and ethyl acetate (2 L)
18. concentrationconcentrated