3-(Trifluoromethyl)benzeneacetic acid → HCID 66823694, compound

To a stirred dark greenish solution of 5-(2,3-dihydro-1H-indol-5-yl)furo[2,3-d]pyrimidin-4-amine (400 mg, 1.59 mmol) and HATU (663 mg, 1.74 mmol, 1.1 equiv) in 4 mL of DMF was added DIEA (305 uL, 1.74 mmol, 1.1 equiv). To this mixture was added [3-(trifluoromethyl)phenyl]acetic acid portionwise (324 mg total, 1.59 mmol, 1 equiv), about 80 mg at 30 min intervals. After a total of 3 h, LCMS showed there was still 16% starting material left by UV. The mixture was diluted with ice cold water (40 mL) to give a dark greenish suspension, which was filtered. The cake was washed with water (2×8 mL), and sucked under house vacuum for 18 h to afford crude product (900 mg), which was dissolved in 10% DCM in MeOH and absorbed onto a dryload cartridge. Purification was done on an SF25-60 g silica gel cartridge using gradient elution of 1% A to 50% A in DCM (A was a mixture of 3200 mL DCM, 800 mL of MeOH and 80 mL of conc NH4OH). The product eluted around 25-30% A. The fractions with product were combined and concentrated in vacuo. This material contained an impurity, and the residue underwent another silica gel purification on an SF25-80 g silica gel cartridge using gradient elution of 1% B in EtOAc to 50% B (B was a mixture of 10% MeOH in EtOAc). The desired product eluted from 10-13% B. Pure fractions were combined and evaporated. The residue (200 mg) was taken up in CHCl3 (0.45 mL), MTBE (3 mL) and hexane (3 mL) to give a suspension, which was filtered. The solids were washed with hexane (2×3 mL) and dried under vacuum at 65° C. for 18 h to afford 5-(1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indol-5-yl)furo[2,3-d]pyrimidin-4-amine (170 mg) as light cream-colored solids. LC-MS (ES) m/z=439 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.27 (t, J=8.3 Hz, 2H), 4.05 (s, 2H), 4.28 (t, J=8.6 Hz, 2H), 7.30 (d, J=8.1 Hz, 1H), 7.39 (s, 1H), 7.56-7.66 (m, 3H), 7.68 (s, 1H), 7.93 (s, 1H), 8.15 (d, J=8.3 Hz, 1H), 8.25 (s, 1H), NH2 protons not visible or existed as broad hump.

1. customAfter a total of 3 h, LCMS
2. waitleft by UV
3. customto give a dark greenish suspension, which
4. filtrationwas filtered
5. washThe cake was washed with water (2×8 mL)
6. customto afford crude product (900 mg), which
7. customabsorbed onto a dryload cartridge
8. customPurification
9. washelution of 1% A to 50% A in DCM (
10. additiona mixture of 3200 mL DCM, 800 mL of MeOH and 80 mL of conc NH4OH)
11. washThe product eluted around 25-30% A
12. concentrationconcentrated in vacuo
13. customthe residue underwent another silica gel purification on an SF25-80 g silica gel cartridge
14. washelution of 1% B in EtOAc to 50% B (B
15. additiona mixture of 10% MeOH in EtOAc)
16. washThe desired product eluted from 10-13% B
17. customevaporated
18. customMTBE (3 mL) and hexane (3 mL) to give a suspension, which
19. filtrationwas filtered
20. washThe solids were washed with hexane (2×3 mL)
21. customdried under vacuum at 65° C. for 18 h

ORD record

ord-21134c3eecbc49a08b51d779de9ba1c4

Source dataset

uspto-grants-2013_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08598156B2