反应详情

A mixture of 2,5-dichloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine (Method 10 of WO 03/048133) (158 mg, 0.648 mmol), 2-[3-(pyrid-2-yl)isoxazol-5-yl]pyrrolidine (Method 12) (212 mg, 0.972 mmol) and di-isopropylethylamine (282 μL, 1.62 mmol) was stirred and heated at 140° C. in n-hexanol (7.0 ml) under nitrogen for 9 hours. The bulk of the hexanol was then removed by evaporation and the residue partitioned between ethyl acetate and water. The ethyl acetate layer was separated, washed with 1.0 molar phosphate buffer pH 4 (×2), then water and finally brine. The organic layer was dried (Na2SO4), filtered and evaporated and the crude product was absorbed onto a 10 g isolute SCX2 ion exchange column. The column was eluted with DCM/methanol (4:1) to remove neutrals and then with dichloromethane/2M methanolic ammonia (4:1) to elute the product. The purified product was dissolved in the minimum volume of DCM and to the stirred solution a slight excess of 1.0 M ethereal hydrogen chloride was added. Further diethyl ether was added and the solid product collected by filtration, washed with diethyl ether and dried to give the hydrochloride salt of the title compound (300 mg, 100%).

1. customThe bulk of the hexanol was then removed by evaporation
2. customthe residue partitioned between ethyl acetate and water
3. customThe ethyl acetate layer was separated
4. washwashed with 1.0 molar phosphate buffer pH 4 (×2)
5. dry with materialThe organic layer was dried (Na2SO4)
6. filtrationfiltered
7. customevaporated
8. customthe crude product was absorbed onto a 10 g isolute SCX2 ion exchange column
9. washThe column was eluted with DCM/methanol (4:1)
10. customto remove neutrals
11. washwith dichloromethane/2M methanolic ammonia (4:1) to elute the product
12. dissolutionThe purified product was dissolved in the minimum volume of DCM and to the stirred solution a slight excess of 1.0 M ethereal hydrogen chloride
13. additionwas added
14. additionFurther diethyl ether was added
15. filtrationthe solid product collected by filtration
16. washwashed with diethyl ether
17. customdried