Diisopropylethylamine → 5-{1-[(3-chloro-5-fluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

To a suspension of 5-(2,3-dihydro-1H-indol-5-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine 2HCl salt (200 mg, 0.59 mmol, 1 equiv) and HATU (247 mg, 0.65 mmol, 1.1 equiv) in 2 mL of DMF was added DIEA (0.36 mL, 2.07 mmol, 3.5 equiv) in one portion. The mixture turned into a clear but pitch dark solution, to which was added (3-Chloro-5-fluorophenyl)acetic acid (60 mg, 0.59 mmol,) as solids. After 1.5 h, added another 30 mg of the acid. After 30 min, the resulting suspension was diluted with 15 mL of water. The aq suspension was filtered, and the cake was washed with water, and dried under house vacuum. This solid was dissolved in 10% MeOH in DCM (not totally dissolved, some was loaded as suspension), and absorbed onto a dryload cartridge. Purification was done on an 24 g silica gel cartridge using gradient elution of 1% A in EtOAc to 100% A (A was a mixture of 9% MeOH in EtOAc, gradient: 0-5 min, 1% A, 5-15 min, 5-100% A, 15-60 min, 100% A). The desired fractions were combined and concentrated in vacuo to give a solid residue, which upon standing for 10 min developed a light tan color. The residue was taken up in CHCl3 (1 mL) and MTBE (6 mL) to give a suspension, which was filtered. The light tan colored cake was washed with MTBE (3 mL) and hexane (2×3 mL), and dried under vacuum at 65° C. for 20 h to give (93 mg) as light tan colored solids. LC-MS (ES) m/z=436 [M+H]+. 1H NMR (400 MHz, DMSO-d6+2 drops TFA) δ ppm 3.25 (t, J=8.2 Hz, 2H), 3.84 (s, 3H), 3.96 (s, 2H), 4.25 (t, J=8.5 Hz, 2H), 7.17 (d, J=9.6 Hz, 1H), 7.23-7.29 (m, 2H), 7.30-7.37 (m, 2H), 7.61 (s, 1H), 8.15 (d, J=8.3 Hz, 1H), 8.47 (s, 1H).

1. waitAfter 30 min
2. filtrationThe aq suspension was filtered
3. washthe cake was washed with water
4. customdried under house vacuum
5. dissolutionThis solid was dissolved in 10% MeOH in DCM (not
6. dissolutiontotally dissolved
7. customabsorbed onto a dryload cartridge
8. customPurification
9. washelution of 1% A in EtOAc to 100% A (A
10. additiona mixture of 9% MeOH in EtOAc, gradient
11. custom0-5 min, 1% A, 5-15 min, 5-100% A, 15-60 min, 100% A
12. concentrationconcentrated in vacuo
13. customto give a solid residue, which
14. waitupon standing for 10 min
15. filtrationwas filtered
16. washThe light tan colored cake was washed with MTBE (3 mL) and hexane (2×3 mL)
17. customdried under vacuum at 65° C. for 20 h
18. customto give (93 mg) as light tan colored solids

ORD record

ord-bd170f75b31441219eed0eb1a0b21b52

Source dataset

uspto-grants-2013_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08598156B2