4-Methoxyphenylacetic Acid → 2-(4-methoxyphenyl)-N-[6-(1H-pyrazol-4-yl)isoquinolin-3-yl]acetamide

HRID 1672435Notes

Reaction equation

HRID 1672435 reaction equation
[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[NH:44]1[CH:48]=[C:47]([C:49]2[CH:50]=[C:51]3[C:56](=[CH:57][CH:58]=2)[CH:55]=[N:54][C:53]([NH2:59])=[CH:52]3)[CH:46]=[N:45]1.C([O-])([O-])=O.[K+].[K+]>CC(N(C)C)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([NH:59][C:53]2[N:54]=[CH:55][C:56]3[C:51]([CH:52]=2)=[CH:50][C:49]([C:47]2[CH:46]=[N:45][NH:44][CH:48]=2)=[CH:58][CH:57]=3)=[O:12])=[CH:7][CH:8]=1

Participants

7

Reactant 5

HCID 76904-Methoxyphenylacetic AcidHCID 8471TriethylamineHCID 11430Potassium CarbonateHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 580822936-(1H-Pyrazol-4-yl)-isoquinolin-3-ylamine

Product 1

HCID 580826052-(4-methoxyphenyl)-N-[6-(1H-pyrazol-4-yl)isoquinolin-3-yl]acetamide

Reagents, catalysts & solvents 1

HCID 31374DimethylacetamideSolvent

Conditions

Temperature
75 °C

Procedure

Activation of (4-Methoxy-phenyl)-acetic acid (315.6 mg, 1.9 mmol) is accomplished by treatment of the carboxylic acid in DMA (5 mL) with HATU (802.6 mg, 2.1 mmol) and triethylamine (388.2 mg, 3.8 mmol) at room temperature for 1 hour. The 6-(1H-Pyrazol-4-yl)-isoquinolin-3-ylamine (200.0 mg, 0.9 mmol) was added and the mixture was stirred at 75° C. for 24 hours. The reaction was monitored by LC/MS. Evaporation of DMA gave a residue that was washed with NaHCO3 to remove the by-products from HATU. The crude residue then was dissolved in MeOH (10 mL) and was treated with K2CO3 (26.0 mg, 0.5 mmol) at 75° C. for 18 hrs. The solvent was evaporated and the product extracted with CH2Cl2 (20 mL). The extracts were washed with water (3×10 mL) and evaporated. The crude product was purified by ISCO (with petroleum ether:ethyl acetate 50:50) to give the title compound as a light yellow crystalline solid product (143.3 mg, 41.4%). 1H NMR (DMSO-d6, 400 MHz): δ 3.68 (2H, s), 3.73 (3H, s), 6.79-6.98 (2H, m), 7.31 (2H, d, J=8.8 Hz,), 7.81 (1H, dd, J=8.6, 1.5 Hz,), 8.00 (1H, d, J=8.6 Hz), 8.08 (1H, s), 8.14 (1H, s), 8.41 (2H, d, J=8.3 Hz), 9.03 (1H, s), 10.69 (1H, s), 13.09 (1H, s). 13CNMR (DMSO-d6, 100 MHz): δ 42.18, 55.01, 106.30, 113.76, 120.44, 120.56, 124.11, 124.39, 126.71, 127.87, 128.06, 130.13, 135.26, 136.96, 137.87, 147.51, 150.75, 158.14, 170.14. HRMS: m/z 359.1489, calc. 359.1503. MS m/z, (APCI); 359.2 [(M+1)+100].

Workup

  1. customEvaporation of DMA
  2. customgave a residue that
  3. washwas washed with NaHCO3
  4. customto remove the by-products from HATU
  5. dissolutionThe crude residue then was dissolved in MeOH (10 mL)
  6. customThe solvent was evaporated
  7. extractionthe product extracted with CH2Cl2 (20 mL)
  8. washThe extracts were washed with water (3×10 mL)
  9. customevaporated
  10. customThe crude product was purified by ISCO (with petroleum ether:ethyl acetate 50:50)

Sources & evidence

ORD record
ord-6af93740a200492f9a434ac205c50cd2
Source dataset
uspto-grants-2011_08
Patent number
US07998978B2

Reaction notes

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