O-Toluidine → HCID 66926955, compound

HRID 81046Notes

Reaction equation

HRID 81046 reaction equation
Cl[C:2]1[C:3]([Cl:18])=[C:4]([C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)=[CH:8][N:9]=1)[C:5]#[N:6].[NH2:19][C:20]1[C:21]([CH3:26])=[CH:22][CH:23]=[CH:24][CH:25]=1>CS(C)=O.C(OCC)(=O)C>[Cl:18][C:3]1[C:2]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])=[N:9][CH:8]=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)[C:4]=1[C:5]#[N:6]

Participants

5

Reactant 2

HCID 7242O-ToluidineHCID 86665690HCID 86665690, compound

Product 1

HCID 66926955HCID 66926955, compound

Reagents, catalysts & solvents 2

HCID 679Dimethyl SulfoxideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
180 °C

Procedure

A mixture of 2,3-dichloro-5-(3-methoxyphenyl)isonicotinonitrile (50 mg, 0.179 mmol, from Step 3 of Example 128) and o-toluidine (384 mg, 3.58 mmol) in DMSO (1 mL) was heated to 180° C. under microwave for 1 h. LCMS and HPLC analysis indicated that the reaction was ˜25% complete. The mixture was cooled to room temperature, diluted with ethyl acetate (60 mL), washed with 1 N HCl (5 mL), water (5 mL), brine (5 mL), dried (MgSO4) and concentrated. Purification by reverse phase HPLC (Sunfire S10 30×250 mm column), eluting with 80-100% solvent B (10% methanol-90% water-0.1% TFA) in solvent A (90% methanol-10% water-0.1% TFA), gave 3-chloro-5-(3-methoxyphenyl)-2-(o-tolylamino)isonicotinonitrile as yellow solid, assumed as TFA salt (7 mg, 8% yield). 1H NMR (400 MHz, methanol-d4) δ ppm 8.13 (1H, s), 7.38-7.54 (2H, m), 7.28-735 (1H, m), 7.15-7.27 (2H, m), 7.07-7.14 (2H, m), 6.97-7.05 (1H, m), 3.87 (3H, s), 2.27 (3H, s); MS (ES+) m/z: 350 (M+H); LC retention time: 3.848 min (analytical HPLC Method A).

Workup

  1. temperatureThe mixture was cooled to room temperature
  2. washwashed with 1 N HCl (5 mL), water (5 mL), brine (5 mL)
  3. dry with materialdried (MgSO4)
  4. concentrationconcentrated
  5. customPurification by reverse phase HPLC (Sunfire S10 30×250 mm column)
  6. washeluting with 80-100% solvent B (10% methanol-90% water-0.1% TFA) in solvent A (90% methanol-10% water-0.1% TFA)

Sources & evidence

ORD record
ord-48bfcaba05884187917efcf2c644291a
Source dataset
uspto-grants-2014_09
Patent number
US08846673B2

Reaction notes

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