Hydrochloric Acid → Tert-butyl 4-((2-(5-cyanopyrazin-2-ylamino)-5-(phenylcarbamoyl)pyridin-4-ylamino)methyl)piperidine-1-carboxylate

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Reaction Steps

Lithium hydroxide (3 mg, 0.12 mmol) was added to a solution of methyl 6-(5-cyanopyrazin-2-ylamino)-4-(piperidin-4-ylmethylamino)nicotinate (30 mg, 0.06 mmol) in a mixture of tert-butanol and water (2:1, 0.3 mL). The reaction mixture was stirred for 4 days at room temperature then acidified to pH 3-4 with 1M HCl and extracted with ethyl acetate. The organic extract was dried (Na2SO4) and solvent was evaporated. The crude acid was used in the next step without further purification. Triethylamine (10.0 μL, 0.07 mmol) was added to a solution of the acid (29 mg, 0.06 mmol), aniline (4.8 μL, 0.05 mmol) and TBTU (24 mg, 0.06 mmol) in DMF (0.3 mL). The reaction mixture was stirred overnight at room temperature. The mixture was purified by ion exchange chromatography on SCX-II acidic resin (500 mg) eluting with methanol, then 2M ammonia-methanol. The basic fractions were combined and solvent was evaporated. Preparative TLC, eluting with ethyl acetate-hexane (1:1) gave tert-butyl 4-((2-(5-cyanopyrazin-2-ylamino)-5-(phenylcarbamoyl)pyridin-4-ylamino)methyl)piperidine-1-carboxylate as a yellow solid (12 mg, 42%).

Provenance & Evidence