Acrylic Acid → (S)-N-(1-(9-isopropyl-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-9H-purin-2-yl)pyrrolidin-3-yl)acrylamide

Participants

Reaction Steps

(S)-2-(3-Aminopyrrolidin-1-yl)-9-isopropyl-N-(4-(4-methylpiperazin-1-yl)phenyl) -9H-purin-6-amine (436 mg, 1 mmol) was suspended in DMF (3.3 mL). DIPEA (0.53 mL, 3 mmol, 3 mol eq) and acrylic acid (73 μL, 1.05 mmol, 1.05 mol eq) were added to give a suspension. Propylphosphonic anhydride (CAS 68957-94-8, 50% in DMF, 0.7 mL, 1.2 mmol, 1.2 mol eq) was added in one portion. The reaction mixture warmed up slightly to afford a solution. After 15 min, aqueous Na2CO3 (1 M, 2 mL, 2 mmol) was added and stirred for 30 min. Water (10 mL) and ethyl acetate (50 mL) were added. The organic layer was separated, washed with water (3×10 mL), dried over Na2SO4 and evaporated to give a light yellow foamy solid, which was purified by SFC (Column ZymorSpher HADP 150×21.2 mm I.D., 5 μm particles. Modifier: ethanol. Gradient 21% (hold 2 min) to 24% (hold 1 min) at 1.5% per min. Flow rate (58 mL/min) to give the title product (167 mg, 34% yield, >95% purity). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.17 (s, 1 H) 8.36 (d, J=6.85 Hz, 1 H) 7.91 (s, 1 H) 7.85 (d, J=9.05 Hz, 2 H) 6.87 (d, J=9.05 Hz, 2 H) 6.19-6.32 (m, 1 H) 6.05-6.16 (m, 1 H) 5.59 (dd, J=10.09, 2.38 Hz, 1 H) 4.62 (quin, J=6.72 Hz, 1 H) 4.34-4.48 (m, 1 H) 3.76 (dd, J=11.31, 6.30 Hz, 1 H) 3.54-3.70 (m, 2 H) 3.43 (dd, J=11.19, 3.85 Hz, 1 H) 2.93-3.14 (m, 4 H) 2.39-2.47 (m, 4 H) 2.22 (s, 3 H) 2.12-2.20 (m, 1 H) 1.83-1.95 (m, 1 H) 1.51 (d, J=6.72 Hz, 6 H). m/z (APCI+) for C26H35N9O 490.4 (M+H)+.

Provenance & Evidence