Water → HCID 118286585, compound

Participants

Reaction Conditions

Reaction Steps

To ˜10 ml of NMP was added 15.1 (150 mg) and DIEA (˜0.1 mL). To this stirring solution was added benzylamine (1.1 eq in ˜5 mL NMP) dropwise. After stirring for 1 hour, H2O was added to the reaction mixture, followed by EtOAc. HPLC analysis indicated substantial amounts of product in each layer. Both layers were concentrated and the resulting oil was dissolved in a H2O/TFA/ACN mixture. This solution was purified via preparative rpHPLC utilizing a mobile phase with 0.1% TFA in water as solvent A and 0.1% TFA in acetonitrile as solvent B and eluting with a 20% to 60% B mixture over 10 minutes to give 205 mg of 4-(benzylamino)-6-chloronicotinonitrile (11). To 100 mg of 4-(benzylamino)-6-chloronicotinonitrile (11) in ˜3 mL NMP was added 1 ml of 60 mg/ml m-toluidine and 45 mg pTSA.H2O. Reaction heated at 120° C. for 72 hours. Due to inadequate conversion to product, the reaction mixture was transferred to a microwave tube and subsequently heated via microwave irradiation at 220° C. for 20 minutes. Water was added to the crude reaction mixture and a preparative rpHPLC was run in order to isolate pure 4-(benzylamino)-6-(m-tolylamino)nicotinonitrile (12). To 12 in ˜3 mL DMSO was added K2CO3 (˜100 mg) and 1.5 mL H2O2 (50% by wt.). The reaction was heated to 70° C. at which point the reaction mixture bubbled rigorously. Heat was removed until bubbling ceased and then the reaction mixture was again heated at 70° C. for an additional hour. The reaction mixture was cooled and a H2O/TFA mixture was added. The resulting solution was purified via preparative rpHPLC utilizing a mobile phase with 0.1% TFA in water as solvent A and 0.1% TFA in acetonitrile as solvent B and eluting with a 15% to 55% B mixture over 10 minutes. UV: 257 nm. M+H found for C20H20N4O: 333.3. NMR (CD3OD): 8.12 (1H, s), 7.37-7.24 (6H, m), 7.14-7.09 (1H, m), 6.99 (1H, br), 6.92-6.87 (1H, m), 5.88 (1H, s), 4.45 (2H, s), 2.38 (3H, s) ppm.

Provenance & Evidence