反应详情

温度

0 °C

To a stirred solution of N-(5-amino-2-chloropyridin-3-yl)morpholine-4-sulfonamide (0.0819 g, 0.280 mmol) and 4-(2-fluoro-5-methoxypyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (Example 330 step 5, 0.0621 g, 0.264 mmol) in DMF (1 mL) in 5 mL microwave vial, NaHMDS (Aldrich, 1 M in THF, 1.06 mL, 1.06 mmol) was added dropwise at 0° C. The mixture was stirred at 0° C. for 45 min. The reaction mixture was partitioned between saturated aqueous ammonium chloride (30 mL) and 25% isopropanol in chloroform (20 mL). The aqueous phase was acidified to pH 3 to 4 then extracted with 25% isopropanol in chloroform (2×30 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by preparative HPLC using a Phenomenex, Gemni 5 micron C18 100×30 mm column (1% to 90% CH3CN w/0.1% TFA/H2O w/0.1% TFA in 10 min). The fraction was collected and the solvent was evaporated to give a red solid. The solid was partitioned between tris-HCl buffer (1 M, pH 7.0) and 25% IPA in CHCl3. The aqueous phase was acidified to pH about 3 then extracted with 25% IPA in CHCl3. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. This material was dissolved in about 1 mL DMSO and about 2 mL of water was added. The resulting solid was collected via filtration and washed with copious amount of water and dried to afford N-(5-(3-(4-amino-6-methyl-1,3,5-triazin-2-yl)-5-methoxypyridin-2-ylamino)-2-chloropyridin-3-yl)morpholine-4-sulfonamide (0.015 g, 11% yield) as a dark yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.01 (br. s., 1H) 9.73 (br. s., 1H) 8.79 (br. s., 1H) 8.52 (br. s., 1H) 8.38-8.47 (m, 1H) 8.18 (br. s., 1H) 7.76-7.99 (m, 2H) 3.86 (br. s., 3H) 3.57-3.66 (m, 4H) 3.09-3.21 (m, 4H) 2.45 (br. s., 3H). m/z (ESI, positive ion): 508.0 (M+H)+.

1. customThe reaction mixture was partitioned between saturated aqueous ammonium chloride (30 mL) and 25% isopropanol in chloroform (20 mL)
2. extractionthen extracted with 25% isopropanol in chloroform (2×30 mL)
3. dry with materialThe combined organic phases were dried over sodium sulfate
4. filtrationfiltered
5. concentrationconcentrated in vacuo
6. customThe crude product was purified by preparative HPLC
7. customC18 100×30 mm column (1% to 90% CH3CN w/0.1% TFA/H2O w/0.1% TFA in 10 min)
8. customThe fraction was collected
9. customthe solvent was evaporated
10. customto give a red solid
11. customThe solid was partitioned between tris-HCl buffer (1 M, pH 7.0) and 25% IPA in CHCl3
12. extractionthen extracted with 25% IPA in CHCl3
13. dry with materialThe combined organic phases were dried over sodium sulfate
14. filtrationfiltered
15. concentrationconcentrated in vacuo
16. dissolutionThis material was dissolved in about 1 mL DMSO
17. additionabout 2 mL of water was added
18. filtrationThe resulting solid was collected via filtration
19. washwashed with copious amount of water
20. customdried