1-(7-bromo-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(5-(pyridin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)ethane-1,2-dione → HCID 58026069, compound

HRID 885046Notes

Reaction equation

HRID 885046 reaction equation
Br[C:2]1[N:3]=[CH:4][C:5]([O:31][CH3:32])=[C:6]2[C:10]([C:11](=[O:30])[C:12]([N:14]3[CH2:23][CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][C:20]=4[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)[CH2:15]3)=[O:13])=[CH:9][NH:8][C:7]=12.C([Sn](CCCC)(CCCC)[C:38]1[CH:42]=[C:41]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[NH:40][N:39]=1)CCC>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:32][O:31][C:5]1[CH:4]=[N:3][C:2]([C:38]2[CH:42]=[C:41]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[NH:40][N:39]=2)=[C:7]2[NH:8][CH:9]=[C:10]([C:11](=[O:30])[C:12](=[O:13])[N:14]3[CH2:23][CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][C:20]=4[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)[CH2:15]3)[C:6]=12

Participants

5

Reactant 2

HCID 580260391-(7-bromo-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(5-(pyridin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)ethane-1,2-dioneHCID 178448219HCID 178448219, compound

Product 1

HCID 58026069HCID 58026069, compoundYield 30.4%

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
110 °C

Procedure

To a sealable rb flask containing 1-(7-bromo-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(5-(pyridin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)ethane-1,2-dione (0.5 g, 1.018 mmol) and ethyl 3-(tributylstannyl)-1H-pyrazole-5-carboxylate (0.480 g, 1.119 mmol) in 1,4-dioxane (2 mL) was added tetrakis(triphenylphosphine)palladium(0) (0.235 g, 0.204 mmol). The flask was flushed with N2, sealed, and heated to 110° C. After heating the mixture for 17 h, the mixture was cooled to rt. The crude LC/MS showed no starting material remained and the mass for the expected product was present. The crude mixture was diluted with MeOH and was passed through a plug of CELITE® to remove solids. The CELITE® was washed with MeOH, and the organic solution was concentrated under reduced pressure. The residue was diluted with MeOH and ether was added slowly to the mixture. The product that formed was collected by filtration and washed with MeOH. The mother liquor was concentrated under reduced pressure. A second recrystallization was performed using hot MeOH and Et2O. The expected product, ethyl 3-(4-methoxy-3-(2-oxo-2-(5-(pyridin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-1H-pyrazole-5-carboxylate (0.17 g, 0.309 mmol, 30.3% yield), was isolated as a light-brown solid and was used in the next step although impurities were still apparent by 1H NMR. LC/MS: m/z 551.18 (M+H)+, 1.778 min (method 1). 1H NMR (500 MHz, DMSO-d6) δ ppm 14.04-14.50 (m, 1H) 11.90-12.88 (m, 1H) 8.58-8.76 (m, 1H) 7.81-8.28 (m, 3H) 7.14-7.67 (m, 6H) 4.29-4.96 (m, 4H) 3.53-3.89 (m, 5H) 2.79-3.06 (m, 2H) 1.36 (t, J=7.02 Hz, 3H).

Workup

  1. customThe flask was flushed with N2
  2. customsealed
  3. temperatureAfter heating the mixture for 17 h
  4. temperaturethe mixture was cooled to rt
  5. additionThe crude mixture was diluted with MeOH
  6. customto remove solids
  7. washThe CELITE® was washed with MeOH
  8. concentrationthe organic solution was concentrated under reduced pressure
  9. additionThe residue was diluted with MeOH and ether
  10. additionwas added slowly to the mixture
  11. customThe product that formed
  12. filtrationwas collected by filtration
  13. washwashed with MeOH
  14. concentrationThe mother liquor was concentrated under reduced pressure
  15. customA second recrystallization

Sources & evidence

ORD record
ord-b9afaf0232ad430297ae2071213972aa
Source dataset
uspto-grants-2012_08
Patent number
US08242124B2

Reaction notes

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