Diisopropylethylamine → HCID 66823760, compound

Participants

Reaction Steps

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-fluoro-5-(trifluoromethyl)phenyl]acetic acid portionwise (440 mg total, 1.98 mmol, 1 equiv), about 110 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 (2×15 mL) and dried under house vacuum at rt for 18 h to afford crude product (1.10 g), which 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 50% A in DCM (A was a mixture of 3200/800/80 DCM/MeOH/NHeOH). The desired product eluted impure from 25-30% A. These fractions were combined and concentrated in vacuo. the residue was re-dissolved in 10% MeOH in DCM and absorbed to dryload cartridge. A second 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 mixture of 2.5% MeOH in EtOAc). Note: the product was not very soluble in EtOAc. Two fractions were collected. The first fraction eluted from 8-12% B. The second fraction eluted from 33-100% B. Both were pure by TLC. They were combined and conc in vacuo. The residue was taken up in CHCl3 (3 mL) and MTBE (7 mL) as a suspension, which was filtered. The solids were washed with MTBE (2×3 mL) and hexane (3×4 mL), and dried under vacuum at 65° C. for 18 h to afford 5-(1-{[3-fluoro-5-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indol-5-yl)furo[2,3-d]pyrimidin-4-amine (445 mg) as beige solids. LC-MS (ES) m/z=457 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.28 (t, J=8.5 Hz, 2H), 4.08 (s, 2H), 4.28 (t, J=8.5 Hz, 2H), 7.31 (d, J=8.3 Hz, 1H), 7.40 (s, 1H), 7.51 (d, J=9.9 Hz, 1H), 7.57 (s, 1H), 7.60 (d, J=8.1 Hz), 7.93 (s, 1H), 8.14 (d, J=8.1 Hz, 1H), 8.25 (s, 1H), NH2 protons not visible.

Provenance & Evidence