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-methyl-2-pyridinyl)acetic acid TFA salt (148 mg) portionwise over a 1 h period. After a total of 2 h, LCMS showed conversion complete. The mixture was poured into 20 mL of ice cold water to give a suspension, which was filtered. The cake was washed with water and dried under house vacuum to afford 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 60% 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 desired product eluted from 27-34% A. The combined fractions 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 100% A (A was a mixture of 20% MeOH in EtOAc). The desired product eluted from 83-100% A. The combined fractions were concentrated in vacuo. The residue was dissolved in 12 mL of 10% MeOH in DCM and conc in vacuo to a suspension (about 2 mL). This mixture was diluted with 12 mL of MTBE. The resulting suspension was conc 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-methyl-2-pyridinyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (123 mg) as white solids. LC-MS (ES) m/z=417 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.45 (s, 3H), 3.25 (t, J=8.5 Hz, 2H), 3.74 (s, 3H), 4.00 (s, 2H), 4.35 (t, J=8.5 Hz, 2H), 5.90-6.17 (br. s., 1.6H), 7.12-7.23 (m, 3H), 7.27 (s, 1H), 7.66 (t, J=7.7 Hz, 1H), 7.92 (d, J=8.1 Hz, 1H), 8.14 (s, 1H). (ES) m/z=417 [M+H]+.

1. customAfter a total of 2 h, LCMS
2. customto give a suspension, which
3. filtrationwas filtered
4. washThe cake was washed with water
5. customdried under house vacuum
6. customto afford crude product, which
7. customabsorbed onto a dryload cartridge
8. customPurification
9. washelution of 1% A in CHCl3 to 60% A in CHCl3 (
10. additiona mixture of 3200/800/80 CHCl3/MeOH/NH4OH, gradient
11. custom0-5 min
12. custom1% A, 5-35 min 5-60% A
13. washThe desired product eluted from 27-34% A
14. concentrationThe combined fractions were concentrated in vacuo
15. dissolutionThe residue was dissolved in 10% MeOH in DCM
16. customabsorbed onto a dryload cartridge
17. customPurification
18. washelution of 1% A in EtOAc 100% A (A
19. additiona mixture of 20% MeOH in EtOAc)
20. washThe desired product eluted from 83-100% A
21. concentrationThe combined fractions were concentrated in vacuo
22. dissolutionThe residue was dissolved in 12 mL of 10% MeOH in DCM and conc in vacuo to a suspension (about 2 mL)
23. additionThis mixture was diluted with 12 mL of MTBE
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