反应详情

温度

85 °C

To a 1 liter round bottom flask was added 15.00 g (40.76 mmol) of isopropyl 4-(3-bromopyrazolo[1,5-a]pyrimidin-5-yl)piperazine-1-carboxylate, 8.85 g (52.99 mmol) of (2-ethoxypyridin-3-yl)boronic acid, 14.06 g (101.90 mmol) of K2CO3, 1.41 g (1.22 mmol) of P(PPh3)4, and a stirring rod. After adding all the solids, 200 ml of MeCN was added, followed by the addition of 100 mL of water. The reaction flask was plunged into an oil bath pre-heated to 85° C., and stirred vigorously. This reaction was setup to reflux. After stirring at 85° C. for about 16 hr, it was allowed to cool to RT and diluted with 200 mL of EtOAc. The organic layer was separated, and the aqueous layer was extracted twice with 80 mL portions of EtOAc. The combined organic layers was washed with brine, dried over MgSO4, and concentrated. A small volume of DCM was used to dissolve the crude mixture, and then loaded directly onto a 750 g silica gel column for separation on the ISCO-XL. A gradient of 50% EtOAc/hex to 100% EtOAc was run for the first 35 minutes. The desired product did not elute, only some impurities eluted. However, about 10 minutes into running with 100% EtOAc, the desbromo side product starts eluting together with the desired product. Even though the desbromo compound is spread through all the fractions containing the desired product, the percentage of the desbromo compound seem to decrease with time. Therefore, the initial fractions containing the highest percentages of the desbromo were discarded, and the remaining fractions were concentrated to obtain 13.46 g of about 86% purity at 254 nm. (with about 14% desbromo compound). This material was recrystallized twice, using IPAC and heptanes, to obtain 11.4 g (68%) of the desired product. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.30 (d, J=6.32 Hz, 6 H) 1.53 (t, J=7.07 Hz, 3 H) 3.59-3.70 (m, 4H) 3.70-3.81 (m, 4 H) 4.53 (q, J=7.07 Hz, 2 H) 5.00 (dt, J=12.44, 6.28 Hz, 1 H) 6.38 (d, J=7.83 Hz, 1 H) 6.98 (dd, J=7.45, 4.93 Hz, 1 H) 8.01 (dd, J=4.93, 1.89 Hz, 1H) 8.37 (d, J=7.83 Hz, 1 H) 8.70 (s, 1 H) 8.76 (dd, J=7.45, 1.89 Hz, 1 H). LRMS (ESI) m/e 411 [(M+H)+, calcd for C21H26N6O3 410].

1. additionwas added
2. customThe reaction flask was plunged into an oil bath
3. temperatureto reflux
4. stirringAfter stirring at 85° C. for about 16 hr
5. temperatureto cool to RT
6. customThe organic layer was separated
7. extractionthe aqueous layer was extracted twice with 80 mL portions of EtOAc
8. washThe combined organic layers was washed with brine
9. dry with materialdried over MgSO4
10. concentrationconcentrated
11. dissolutionto dissolve the crude mixture
12. customloaded directly onto a 750 g silica gel column for separation on the ISCO-XL
13. customwas run for the first 35 minutes
14. washThe desired product did not elute
15. washonly some impurities eluted
16. customabout 10 minutes
17. washthe desbromo side product starts eluting together with the desired product
18. additioncontaining the desired product
19. additionTherefore, the initial fractions containing the highest percentages of the desbromo
20. concentrationthe remaining fractions were concentrated
21. customto obtain 13.46 g of about 86% purity at 254 nm
22. customThis material was recrystallized twice