Diisopropylethylamine → HCID 66561010, compound

To a stirred dark brownish solution of 5-(2,3-dihydro-1H-indol-5-yl)furo[2,3-d]pyrimidin-4-amine (360 mg, 1.43 mmol) and HATU (597 mg, 1.57 mmol, 1.1 equiv) in 3 mL of DMF was added DIEA (274 uL, 1.57 mmol, 1.1 equiv). To this mixture was added (2,5-difluorophenyl)acetic acid portionwise (246 mg total, 1.43 mmol, 1 equiv) over a 1 h period. The mixture was stirred for another 2 h and then added to 50 mL of ice water. The resulting suspension was filtered. The brownish cake was washed with water (2×10 mL) and then sucked under house vacuum for 20 h to give crude product (760 mg). This material 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 to 55% A (A was a mixture of 3200 mL DCM, 800 mL of MeOH and 80 mL of conc NH4OH). The desired product eluted from 29-32%. Each fraction was checked by LCMS and the 2 pure fractions were combined with impure product from a previous run and concentrated in vacuo. The residue was dissolved in 10% MeOH in CHCl3, and filtered The filtrate was concentrated in vacuo. The residue was taken up in 1.5 mL of CHCl3, and MTBE (1 mL) and hexane (7 mL) were added to give a suspension. Which was filtered. The cake was washed with hexane (2×4 mL) and then dried under vacuum at 65° C. for 18 h to afford 5-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}furo[2, 3-d]pyrimidin-4-amine (295 mg) as an off-white solid. NMR, LCMS and HPLC showed this sample was pure. LC-MS (ES) m/z=407 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.28 (t, J=8.6 Hz, 2H), 3.96 (s, 3H), 4.30 (t, J=8.5 Hz, 2H), 7.13-7.28 (m, 3H), 7.30 (d, J=9.1 Hz, 1H), 7.40 (s, 1H), 7.93 (s, 1H), 8.12 (d, J=8.3 Hz, 1H), 8.25 (s, 1H), NH2 protons are not visible.

1. filtrationThe resulting suspension was filtered
2. washThe brownish cake was washed with water (2×10 mL)
3. waitsucked under house vacuum for 20 h
4. customto give crude product (760 mg)
5. customabsorbed onto a dryload cartridge
6. customPurification
7. washelution of 1% A to 55% A (A
8. additiona mixture of 3200 mL DCM, 800 mL of MeOH and 80 mL of conc NH4OH)
9. washThe desired product eluted from 29-32%
10. concentrationconcentrated in vacuo
11. dissolutionThe residue was dissolved in 10% MeOH in CHCl3
12. filtrationfiltered The filtrate
13. concentrationwas concentrated in vacuo
14. additionMTBE (1 mL) and hexane (7 mL) were added
15. customto give a suspension
16. filtrationWhich was filtered
17. washThe cake was washed with hexane (2×4 mL)
18. customdried under vacuum at 65° C. for 18 h

ORD record

ord-ee442cfec6924539b67fdfa603691a8c

Source dataset

uspto-grants-2013_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08598156B2