反应详情

To a suspension of 5-(4-fluoro-2,3-dihydro-1H-indol-5-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine dihydrochloride (200 mg, 0.56 mmol, 1 equiv) and HATU (235 mg, 0.62 mmol, 1.1 equiv) in DMF (2 mL) at room temperature was added DIEA (412 uL, 2.36 mmol, 4.2 equiv) in one portion. To this mixture was added [6-(trifluoromethyl)-2-pyridinyl]acetic acid (179 mg) portionwise over a 1 hour period. After an additional 30 minutes, LCMS showed conversion complete. The mixture was poured into 20 mL of ice cold water, which gave a suspension that was filtered. The cake was washed with water and dried under house vacuum to give crude product, which was dissolved in 10% MeOH in DCM and absorbed onto a dryload cartridge. Purification was done on an Analogix SF25-40 g silica gel cartridge using gradient elution of 1% A in CHCl3 to 65% A in CHCl3 (A was a mixture of 3200/800/80 CHCl3/MeOH/NH4OH, gradient: 0-5 min: 1% A, 5-35 min 5-60% A). The product eluted from 26-31% A. The combined fractions with product were concentrated in vacuo. The residue was dissolved in 10% MeOH in DCM and absorbed onto a dryload cartridge. Purification was done on an Analogix SF25-60 g silica gel cartridge using gradient elution of 1% A in EtOAc 75% A (A was a mixture of 20% MeOH in EtOAc). The desired product eluted from 51-70% A. The combined fractions were conc in vacuo. The residue was dissolved in 12 mL of 10% MeOH in DCM and concentrated in vacuo to a suspension (about 1 mL). This mixture was diluted with 12 mL of MTBE. The resulting suspension was concentrated in vacuo to reduce to half volume. The mixture was diluted with another 10 mL of MTBE. The suspension was filtered. The cake was washed with MTBE (2×4 mL) and hexane (3×4 mL), and dried under vacuum at 65° C. for 18 h to afford 5-(4-fluoro-1-{[6-(trifluoromethyl)-2-pyridinyl]acetyl}-2,3-dihydro-1H-indol-5-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (205 mg) as white solids. LC-MS (ES) m/z=471 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.28 (t, J=8.5 Hz, 2H), 3.74 (s, 3H), 4.22 (s, 2H), 4.38 (t, J=8.6 Hz, 2H), 5.90-6.19 (br s, 1.5H), 7.20 (t, J=8.1 Hz, 1H), 7.28 (s, 1H), 7.71 (d, J=7.8 Hz, 1H), 7.83 (d, J=7.6 Hz, 1H), 7.89 (d, J=8.1 Hz, 1H), 8.10 (t, J=7.8 Hz, 1H), 8.14 (s, 1H).

1. customgave a suspension that
2. filtrationwas filtered
3. washThe cake was washed with water
4. customdried under house vacuum
5. customto give crude product, which
6. customabsorbed onto a dryload cartridge
7. customPurification
8. washelution of 1% A in CHCl3 to 65% A in CHCl3 (
9. additiona mixture of 3200/800/80 CHCl3/MeOH/NH4OH, gradient
10. custom0-5 min
11. custom1% A, 5-35 min 5-60% A
12. washThe product eluted from 26-31% A
13. concentrationThe combined fractions with product were concentrated in vacuo
14. dissolutionThe residue was dissolved in 10% MeOH in DCM
15. customabsorbed onto a dryload cartridge
16. customPurification
17. washelution of 1% A in EtOAc 75% A (A
18. additiona mixture of 20% MeOH in EtOAc)
19. washThe desired product eluted from 51-70% A
20. dissolutionThe residue was dissolved in 12 mL of 10% MeOH in DCM
21. concentrationconcentrated in vacuo to a suspension (about 1 mL)
22. additionThis mixture was diluted with 12 mL of MTBE
23. concentrationThe resulting suspension was concentrated in vacuo
24. additionThe mixture was diluted with another 10 mL of MTBE
25. filtrationThe suspension was filtered
26. washThe cake was washed with MTBE (2×4 mL) and hexane (3×4 mL)
27. customdried under vacuum at 65° C. for 18 h