m-Tolylacetic acid → HCID 66823859, compound

To a stirred dark greenish solution of 5-(2,3-dihydro-1H-indol-5-yl)furo[2,3-d]pyrimidin-4-amine (500 mg, 1.98 mmol) and HATU (829 mg, 2.18 mmol, 1.1 equiv) in 5 mL of DMF was added DIEA (381 uL, 2.18 mmol, 1.1 equiv). To this mixture was added (3-methylphenyl)acetic acid portionwise (298 mg total, 1.98 mmol, 1 equiv), about 100 mg at 30 min intervals. After a total of 2.5 hours, the mixture was poured into 50 mL of ice cold water to give a suspension, which was filtered. The cake was washed with water (2×10 mL) and dried under house vacuum for 18 h to afford crude product (1.0 g), which was dissolved in 10% MeOH in DCM and absorbed onto a dryload cartridge. First pass purification was done on an SF25-60 g silica gel cartridge using gradient elution of 1% A in DCM to 55% A in DCM (A was a mixture of 3200/800/80 DCM/MeOH/NH4OH). The desired product eluted impure from 24-30% A. The fractions were combined and concentrated in vacuo, and reabsorbed onto a dryload cartridge. Second pass purification was done on an SF25-80 g silica gel cartridge using gradient elution of 1% B to 100% B in EtOAc. (B was a 2.5% MeOH in EtOAc). The desired pure product fractions combined, and concentrated in vacuo. The residue was taken up in CHCl3 (1 mL) and MTBE (7 mL) to give a suspension, which was filtered. The cake was washed with MTBE (2×3 mL) and hexane (3×3 mL) and dried under vacuum at 65° C. to afford 5-{1-[(3-methylphenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}furo[2,3-d]pyrimidin-4-amine (431 mg) as beige-colored solids. LC-MS (ES) m/z=385 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.31 (s, 3H), 3.22 (t, J=8.5 Hz, 2H), 3.84 (s, 2H), 4.22 (t, J=8.6 Hz, 2H), 7.04-7.15 (m, 3H), 7.19-7.26 (m, 1H), 7.30 (d, J=8.3 Hz, 1H), 7.37 (s, 1H), 7.92 (s, 1H), 8.18 (d, J=8.3 Hz, 1H), 8.25 (s, 1H), NH2 protons not visible.

1. customto give a suspension, which
2. filtrationwas filtered
3. washThe cake was washed with water (2×10 mL)
4. customdried under house vacuum for 18 h
5. customto afford crude product (1.0 g), which
6. customabsorbed onto a dryload cartridge
7. customFirst pass purification
8. washelution of 1% A in DCM to 55% A in DCM (
9. additiona mixture of 3200/800/80 DCM/MeOH/NH4OH)
10. washThe desired product eluted impure from 24-30% A
11. concentrationconcentrated in vacuo
12. customreabsorbed onto a dryload cartridge
13. customSecond pass purification
14. washelution of 1% B to 100% B in EtOAc
15. concentrationconcentrated in vacuo
16. customMTBE (7 mL) to give a suspension, which
17. filtrationwas filtered
18. washThe cake was washed with MTBE (2×3 mL) and hexane (3×3 mL)
19. customdried under vacuum at 65° C.

ORD record

ord-564043f807764f47a3a6e515bb0d79d7

Source dataset

uspto-grants-2013_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08598156B2