Pyridine → 2-(5-methoxy-2-methyl-1H-indol-3-yl)-N-[6-(1H-pyrazol-4-yl)isoquinolin-3-yl]acetamide

HRID 1672437Notes

Reaction equation

HRID 1672437 reaction equation
[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:12])=[C:6]2[CH2:13][C:14]([OH:16])=O.C(Cl)(=O)C(Cl)=O.[NH:23]1[CH:27]=[C:26]([C:28]2[CH:29]=[C:30]3[C:35](=[CH:36][CH:37]=2)[CH:34]=[N:33][C:32]([NH2:38])=[CH:31]3)[CH:25]=[N:24]1.N1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.O.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:12])=[C:6]2[CH2:13][C:14]([NH:38][C:32]1[N:33]=[CH:34][C:35]2[C:30]([CH:31]=1)=[CH:29][C:28]([C:26]1[CH:25]=[N:24][NH:23][CH:27]=1)=[CH:37][CH:36]=2)=[O:16]

Participants

9

Reactant 5

HCID 1049PyridineHCID 11430Potassium CarbonateHCID 65578Oxalyl chlorideHCID 761515-Methoxy-2-methylindole-3-acetic acidHCID 580822936-(1H-Pyrazol-4-yl)-isoquinolin-3-ylamine

Product 1

HCID 580823152-(5-methoxy-2-methyl-1H-indol-3-yl)-N-[6-(1H-pyrazol-4-yl)isoquinolin-3-yl]acetamide

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolvent

Procedure

To a solution of 2-(5-methoxy-2-methyl-1H-indol-3-yl)acetic acid (219.2 mg, 0.5 mmol) in 5 mL of anhydrous THF was added oxalyl chloride (119.6 mg, 0.95 mmol), and 100 μL of DMF also was added. A effervescence occurred. Within 1-4 minutes the effervescence stopped. The mixture was stirred for 30 minute at room temperature, followed by addition of 6-(1H-Pyrazol-4-yl)-isoquinolin-3-ylamine in 5 mL of pyridine (100.0 mg, 0.5 mmol). The reaction was stirred at the ambient temperature over 16 hours as it was monitored by LC/MS. To the reaction mixture was added K2CO3 (196.7 mg, 1.4 mmol) and water (2 mL). The solution was heated to 70° C. for 5 hours. Removal of the solvents provided a crude mixture that was purified by HPLC using H2O/CH3CN/0.1% acetic acid as a mobile phase to give the title compound as a crystalline solid product (9.9 mg, 5.1%). 1H NMR (DMSO-d6, 400 MHz): δ 3.68 (2H, s), 3.73 (3H, s), 6.90 (2H, d, J=8.8 Hz), 7.31 (2H, d, J=8.6 Hz), 7.31 (1H, d, J=8.6 Hz), 7.81 (1H, dd, J=8.6, 1.5 Hz), 8.00 (1H, d, J=8.8 Hz), 8.08 (1H s), 8.10-8.22 (1H, m), 8.40 (2H, s), 9.03 (1H, s), 10.69 (1H, s), 13.09 (1H, s). 13CNMR (DMSO-d6, 100 MHz): δ 40.13, 55.00, 106.29, 113.75, 120.55, 124.10, 124.38, 127.87, 128.04, 130.12, 135.25, 137.87, 147.50, 150.75, 158.04, 170.13. HRMS: m/z 359.14959, calc 359.15025. MS m/z, (APCI); 359.1 [(M+1)+100].

Workup

  1. additionalso was added
  2. stirringThe reaction was stirred at the ambient temperature over 16 hours as it
  3. temperatureThe solution was heated to 70° C. for 5 hours
  4. customRemoval of the solvents
  5. customprovided a crude mixture that
  6. customwas purified by HPLC

Sources & evidence

ORD record
ord-7e26297dd277469d9e52b056ccfe18e7
Source dataset
uspto-grants-2011_08
Patent number
US07998978B2

Reaction notes

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