Aniline → 3-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-5-phenylamino-pyridine-2-carbonitrile

HRID 535904Notes

Reaction equation

HRID 535904 reaction equation
[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:61]1[CH:62]=[C:63]([NH:69][C:70]2[CH:75]=[CH:74][C:73]([N:76]3[CH2:81][CH2:80][N:79]([CH3:82])[CH2:78][CH2:77]3)=[CH:72][CH:71]=2)[C:64]([C:67]#[N:68])=[N:65][CH:66]=1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:82][N:79]1[CH2:80][CH2:81][N:76]([C:73]2[CH:74]=[CH:75][C:70]([NH:69][C:63]3[C:64]([C:67]#[N:68])=[N:65][CH:66]=[C:61]([NH:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:62]=3)=[CH:71][CH:72]=2)[CH2:77][CH2:78]1

Participants

7

Reactant 4

HCID 6115AnilineHCID 10796Cesium carbonateHCID 634876Binap, (A+-)-HCID 704984275-Bromo-3-(4-(4-methylpiperazin-1-yl)phenylamino)picolinonitrile

Product 1

HCID 704979853-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-5-phenylamino-pyridine-2-carbonitrile

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 1140TolueneSolvent

Conditions

Temperature
110 °C

Procedure

Aniline (22.4 mg, 0.24 mmol), cesium carbonate (91 mg, 0.28 mmol), palladium (II) acetate (2.25 mg, 0.01 mmol) and (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (9.34 mg, 0.015 mmol) were added to a dry microwave vial. The vial was capped and purged with nitrogen. A degassed solution of EXAMPLE 70A (74.5 mg, 0.2 mmol) in toluene (1 mL) was added to the microwave vial and the reaction was stirred at 110° C. for 3 hours. The reaction mixture was concentrated and purified on silica gel with 2-25% methanol in dichloromethane to afford 3-[4-(4-methyl-piperazin-1-yl)-phenylamino]-5-phenylamino-pyridine-2-carbonitrile. A solution of this (20 mg, 0.052 mmol) in dimethylsulfoxide was treated with potassium carbonate (36 mg, 0.26 mmol) and 30% hydrogen peroxide (1 mL) while keeping temperature below 0° C. The reaction mixture was stirred at 0° C. for 1 hour and then at room temperature for 18 hours. The reaction was quenched by the addition water, filtered, washed with water and dried to provide the title compound. 1H NMR (DMSO-d6) δ ppm 10.15 (s, 1H), 8.64 (s, 1H), 7.83-7.78 (m, 1H), 7.65 (d, J=2.3, 1H), 7.26 (t, J=7.7, 2H), 7.21 (d, J=3.4, 1H), 7.11-7.04 (m, 4H), 6.96-6.88 (m, 4H), 3.12-3.04 (m, 4H), 2.42-2.32 (m, 4H), 2.20 (s, 3H); MS (ESI) m/z 402 (M+H)+.

Workup

  1. customThe vial was capped
  2. custompurged with nitrogen
  3. concentrationThe reaction mixture was concentrated
  4. custompurified on silica gel with 2-25% methanol in dichloromethane

Sources & evidence

ORD record
ord-c0b55be2ea144155b01a96eb67e5cc2d
Source dataset
uspto-grants-2014_10
Patent number
US08859546B2

Reaction notes

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