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 (314 uL, 1.80 mmol, 3.2 equiv) in one portion. To this mixture was added [3-(trifluoromethyl)phenyl]acetic acid (115 mg, 0.56 mmol, 1 equiv) portionwise over a 1 h period. After a total of 1.5 hours, 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. The solid residue was dissolved in 10% MeOH in DCM and absorbed onto a dryload cartridge. Purification was done on an 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 27-32% A. The combined fractions were conc in vacuo to give the product, which LCMS showed was only 89% pure. The sample was dissolved in 10% MeOH in DCM and absorbed onto a dryload cartridge. Purification was done on an SF25-60 g silica gel cartridge using gradient elution of 1% A in EtOAc 100% A (A was a mixture of 10% MeOH in EtOAc). The desired product eluted from 67-87% A. The combined fractions were conc in vacuo. The residue was dissolved in 10 mL of 10% MeOH in DCM and concentrated in vacuo to a suspension (about 2 mL). This mixture was diluted with 12 mL of MTBE. The resulting suspension was filtered. The cake was washed with MTBE (3×4 mL) and hexane (3×4 mL), and dried under vacuum at 65° C. for 18 h to afford 5-(4-fluoro-1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indol-5-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (182 mg) as white solids. LC-MS (ES) m/z=470 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.28 (t, J=8.1 Hz, 2H), 3.74 (s, 3H), 4.04 (s, 2H), 4.34 (t, J=8.3 Hz, 2H), 5.88-6.16 (br s, 1.6H), 7.20 (t, J=8.0 Hz, 1H), 7.27 (s, 1H), 7.54-7.73 (m, 4H), 7.92 (d, J=8.3 Hz, 1H), 8.14 (s, 1H).

1. customAfter a total of 1.5 hours, LCMS
2. customto give a suspension, which
3. filtrationwas filtered
4. washThe cake was washed with water
5. customdried under house vacuum
6. dissolutionThe solid residue was dissolved in 10% MeOH in DCM
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 27-32% A
14. customto give the product, which LCMS
15. customabsorbed onto a dryload cartridge
16. customPurification
17. washelution of 1% A in EtOAc 100% A (A
18. additiona mixture of 10% MeOH in EtOAc)
19. washThe desired product eluted from 67-87% A
20. dissolutionThe residue was dissolved in 10 mL of 10% MeOH in DCM
21. concentrationconcentrated in vacuo to a suspension (about 2 mL)
22. additionThis mixture was diluted with 12 mL of MTBE
23. filtrationThe resulting suspension was filtered
24. washThe cake was washed with MTBE (3×4 mL) and hexane (3×4 mL)
25. customdried under vacuum at 65° C. for 18 h