Water → HCID 118286585, compound

HRID 513257Notes

Reaction equation

HRID 513257 reaction equation
[CH2:1]([NH:8][C:9]1[C:14]([C:15]#[N:16])=[CH:13][N:12]=[C:11](Cl)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[CH:20]=1.CC1C=CC(S(O)(=O)=O)=CC=1.O>CN1C(=O)CCC1>[CH2:1]([NH:8][C:9]1[C:14]([C:15]#[N:16])=[CH:13][N:12]=[C:11]([NH:18][C:19]2[CH:20]=[C:21]([CH3:25])[CH:22]=[CH:23][CH:24]=2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1

Participants

6

Reactant 4

HCID 962Water2×HCID 6101p-Toluenesulfonic acidHCID 7934m-ToluidineHCID 118286586HCID 118286586, compound

Product 1

HCID 118286585HCID 118286585, compound

Reagents, catalysts & solvents 1

HCID 13387N-methyl-2-pyrrolidoneSolvent

Conditions

Temperature
120 °C

Procedure

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.

Workup

  1. customReaction
  2. customDue to inadequate conversion to product, the reaction mixture was transferred to a microwave tube
  3. temperaturesubsequently heated via microwave irradiation at 220° C. for 20 minutes
  4. customreaction mixture

Sources & evidence

ORD record
ord-6301263933df4f759de154e4f26d6488
Source dataset
uspto-grants-2015_08
Patent number
US09102625B2

Reaction notes

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