Diisopropylethylamine → (S)-4-Amino-6-((1-(6-fluoro-1-(5-fluoropyridin-3-yl)-1H-benzo[d]imidazol-2-yl)ethyl)amino)pyrimidine-5-carbonitrile

Participants

Reaction Steps

A mixture of {(S)-1-[6-fluoro-1-(5-fluoropyridin-3-yl)-1H-benzoimidazol-2-yl]ethyl}carbamic acid tert-butyl ester (165 mg, 0.44 mmol) in DCM (3 mL) and TFA (1 mL) was stirred at RT for 2 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge and washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined and concentrated in vacuo to afford a yellow oil. A mixture of this residue, 4-amino-6-chloropyrimidine-5-carbonitrile (68 mg, 0.44 mmol) and DIPEA (230 mL, 1.32 mmol) in IPA (1 mL) was heated at 90° C. in a sealed vial for 16 h. After cooling to RT, the crude mixture was diluted with MeOH and loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-100% EtOAc in cyclohexane) followed by trituration from EtOAc/cyclohexane/Et2O to afford 277 as an off white solid (73 mg, 42% over 2 steps). 1H NMR (DMSO-d6, 400 MHz): δ 8.66 (1H, d, J=2.64 Hz), 8.62 (1H, s), 8.11-8.03 (1H, m), 7.83 (1H, s), 7.78-7.73 (2H, m), 7.26-7.04 (4H, m), 5.64-5.54 (1H, m), 1.58 (3H, d, J=6.77 Hz). LCMS (Method K): RT 3.40 min [M+H]+ 393

Provenance & Evidence