反应详情

A solution of crude Suzuki coupling product (15) in THF (22 mL) was treated with water (108 mL) and a solution of 10% aqueous HCl prepared by mixing 19.6 mL of concentrated HCl with 64 mL of H2O at room temperature. The resulting reaction mixture was stirred at room temperature for 4-6 h. When TLC and HPLC showed the de-protection reaction was deemed complete, a 30% aqueous sodium hydroxide (NaOH) solution prepared by dissolving 10.4 g of NaOH in 21.0 mL of H2O was added slowly to the reaction mixture while maintaining the temperature below 25° C. The solid gradually dissolved and re-precipitated after 10 min. The mixture was stirred at room temperature for 1-2 h before the solids were collected by filtration and washed with H2O (50 mL). The wet cake was transferred to a 250 mL three-necked flask and treated with acetonitrile (MeCN, 112 mL) at room temperature. The mixture was heated to reflux for 2 h before being cooled gradually to room temperature and stirred at room temperature for 1 h. The solids were collected by filtration, washed with MeCN (36 mL) and dried at 40-45° C. in a vacuum oven to afford 4-(1H-pyrazol-4-yl)-7-(2-trimethylsilanyl-ethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine (5, 15.3 g, 20.7 g theoretical, 73.9% yield) as white crystalline solids (99.4 area % by HPLC), which was found to be identical in every comparable aspect to the material made from Method A, B, and C.

1. customThe resulting reaction mixture
2. customthe de-protection reaction
3. additionwas added slowly to the reaction mixture
4. temperaturewhile maintaining the temperature below 25° C
5. dissolutionThe solid gradually dissolved
6. customre-precipitated after 10 min
7. stirringThe mixture was stirred at room temperature for 1-2 h before the solids
8. filtrationwere collected by filtration
9. washwashed with H2O (50 mL)
10. customThe wet cake was transferred to a 250 mL three-necked flask
11. additiontreated with acetonitrile (MeCN, 112 mL) at room temperature
12. temperatureThe mixture was heated
13. temperatureto reflux for 2 h
14. temperaturebefore being cooled gradually to room temperature
15. stirringstirred at room temperature for 1 h
16. filtrationThe solids were collected by filtration
17. washwashed with MeCN (36 mL)
18. customdried at 40-45° C. in a vacuum oven