Diisopropylethylamine → 4-(2-(2-(1,1-difluoroethyl)-1H-benzo[d]imidazol-1-yl)-9-methyl-8-((4-(oxetan-3-yl)piperidin-1-yl)methyl)-9H-purin-6-yl)morpholine

Participants

Reaction Steps

To a mixture of N-[9-methyl-6-morpholin-4-yl-8-(4-oxetan-3-ylpiperidin-1-ylmethyl)-9H-purin-2-yl]benzene-1,2-diamine (0.115 g, 0.24 mmol) and 2,2-difluoropropionic acid (0.028 g, 0.25 mmol) and DIPEA (0.091 mL, 0.53 mL) in DMF (7 mL) was added HATU (0.11 g, 0.29 mmol). The reaction mixture was stirred at room temperature for 24 h, then at 90° C. for 24 h. The reaction mixture was concentrated in vacuo and the residue was loaded in MeOH onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the desired product was eluted with 2 M NH3 in MeOH. The solution was concentrated in vacuo, the residue was diluted in acetic acid (15 mL) and the reaction mixture was stirred at 90° C. for 7 h. The reaction mixture was concentrated in vacuo and the resultant residue was purified by flash chromatography (Si—PPC, MeOH:DCM, 0:100 to 10:90) followed by reverse phase HPLC (Phenomenex Gemini 5u C18, 20 mM triethylamine in water on a gradient of acetonitrile 95:5 to 2:98) to give 459 as a white solid (0.032 g, 27%). LCMS (Method I): RT=3.30 min, [M+H]+ 553.3. 1H NMR (400 MHz, DMSO-d6): δ 7.84-7.81 (m, 1 H); 7.74-7.71 (m, 1 H); 7.43-7.35 (m, 2 H); 4.40-4.15 (m, 4 H); 3.84 (s, 2 H); 3.81 (d, J=4.3 Hz, 2 H); 3.78-3.71 (m, 7 H); 3.37 (t, J=6.9 Hz, 2 H); 3.30-3.18 (m, 2 H); 2.96 (t, J=6.9 Hz, 2 H); 2.34-2.21 (t, J=19.5 Hz, 3 H); 2.20-2.08 (m, 1 H); 1.64 (d, J=12.1 Hz, 1 H); 1.50 (d, J=13.0 Hz, 2 H); 1.06 (td, J=12.1, 4.3 Hz, 2 H)

Provenance & Evidence