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

Participants

Reaction Steps

To a suspension of 5-(4-fluoro-2,3-dihydro-1H-indol-5-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine dihydrochloride (200 mg, 0.56 mmol, 1 equiv) and HATU (235 mg, 0.62 mmol, 1.1 equiv) in DMF (2 mL) at room temperature was added DIEA (314 uL, 1.80 mmol, 3.2 equiv) in one portion. To this mixture was added [4-fluoro-3-(trifluoromethyl)phenyl]acetic acid (125 mg, 0.56 mmol, 1 equiv) portionwise over a 1 h period. After an additional 1 hour, the mixture was poured into ice cold water to give a suspension, which was filtered. The cake was washed with water and dried under house vacuum to afford crude product, which was dissolved in 10% MeOH in DCM and absorbed onto a dryload cartridge. Purification was done on an Analogix SF25-40 g silica gel cartridge using gradient elution of 1% A in CHCl3 to 65% A in CHCl3 (A was a mixture of 3200/800/80 CHCl3/MeOH/NH4OH, gradient: 0-5 min: 1% A, 5-35 min 5-60% A). The desired product eluted from 30-36% A. The combined fractions were concentrated in vacuo. The residue was dissolved in 10% MeOH in DCM and absorbed onto a dryload cartridge. Purification was done on an Analogix SF25-60 g silica gel cartridge using gradient elution of 1% A in EtOAc 75% A (A was a mixture of 20% MeOH in EtOAc). The desired product eluted from 34-64% A. The combined fractions were concentrated in vacuo. The residue was dissolved in 20 mL of 10% MeOH in DCM and concentrated in vacuo. The volume was reduced down to about 4 mL, and the mixture was diluted with 10 mL of MTBE. The resulting suspension was concentrated in vacuo to a wet paste, which was diluted with another 10 mL of MTBE. The suspension was filtered. The cake was washed with MTBE (3×4 mL) and dried under vacuum at 65° C. for 18 h to afford 5-(4-fluoro-1-{[4-fluoro-3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indol-5-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (181 mg) as white solids. LC-MS (ES) m/z=488 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.28 (s, J=8.3 Hz, 2H), 3.74 (s, 3H), 4.03 (s, 2H), 4.34 (t, J=8.3 Hz, 2H), 5.87-6.19 (br s, 1.6H), 7.20 (t, J=8.0 Hz, 1H), 7.27 (s, 1H), 7.45-7.55 (m, 1H), 7.63-7.70 (m, 1H), 7.73 (d, J=7.1 Hz, 1H), 7.91 (d, J=8.1 Hz, 1H), 8.14 (s, 1H).

Provenance & Evidence