Diisopropylethylamine → 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

HRID 885045Notes

Reaction equation

HRID 885045 reaction equation
[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH2:9][CH2:10][NH:11][CH2:12]2.[Br:17][C:18]1[N:19]=[CH:20][C:21]([O:32][CH3:33])=[C:22]2[C:26]([C:27](=[O:31])[C:28](O)=[O:29])=[CH:25][NH:24][C:23]=12.CCN(C(C)C)C(C)C.[B-](F)(F)(F)F.CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C>CN(C=O)C>[Br:17][C:18]1[N:19]=[CH:20][C:21]([O:32][CH3:33])=[C:22]2[C:26]([C:27](=[O:31])[C:28]([N:11]3[CH2:10][CH2:9][C:8]4[C:13](=[CH:14][CH:15]=[CH:16][C:7]=4[C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)[CH2:12]3)=[O:29])=[CH:25][NH:24][C:23]=12

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 2733207O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborateHCID 56917206HCID 56917206, compoundHCID 575904977-Bromo-4-methoxy-α-oxo-1H-pyrrolo[2,3-c]pyridine-3-acetic acid

Product 1

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-dioneYield 75.3%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a 250 mL flask was added 5-(pyridin-2-yl)-1,2,3,4-tetrahydroisoquinoline (2.250 g, 10.7 mmol) and 2-(7-bromo-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetic acid (2.75 g, 9.19 mmol). The mixture was diluted with DMF (100 mL) and Hunig's Base (16.6 mL, 95 mmol) and o-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (4 g, 12.46 mmol) was added to the mixture. The mixture was stirred at rt for 70 h, quenched with water (50 mL) and the solvent removed under reduced pressure. The residue was diluted with water (100 mL) and extracted with dichloromethane (3×100 mL). The combined organic layers were dried with Na2SO4. The drying agent was removed by filtration and the residue purified by BIOTAGE® flash chromatography using a 0-5% MeOH in dichloromethane gradient. The residue still had impurities by 1H NMR so it was dissolved in dichloromethane (150 mL) and washed with sat. NaHCO3 (100 mL) then with sat. ammonium chloride (150 mL). The organic solution was dried with Na2SO4, the drying agent was removed by filtration, and the solution was concentrated under reduced pressure to give 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 (3.40 g, 6.92 mmol, 75% yield) as a blue solid. The product still had some impurities by 1H NMR, but was used in the next step with no additional purification. LC/MS: m/z 489.14 (M+H)+, 1.169 min (method 1). 1H NMR (500 MHz, chloroform-d) δ ppm 10.89 (br. s., 1H) 8.62-8.80 (m, 1H) 7.64-7.95 (m, 3H) 6.98-7.49 (m, 5H) 4.66-4.99 (m, 2H) 3.60-3.87 (m, 5H) 2.87-3.12 (m, 2H).

Workup

  1. additionwas added to the mixture
  2. customquenched with water (50 mL)
  3. customthe solvent removed under reduced pressure
  4. additionThe residue was diluted with water (100 mL)
  5. extractionextracted with dichloromethane (3×100 mL)
  6. dry with materialThe combined organic layers were dried with Na2SO4
  7. customThe drying agent was removed by filtration
  8. customthe residue purified by BIOTAGE® flash chromatography
  9. dissolutionThe residue still had impurities by 1H NMR so it was dissolved in dichloromethane (150 mL)
  10. washwashed with sat. NaHCO3 (100 mL)
  11. dry with materialThe organic solution was dried with Na2SO4
  12. customthe drying agent was removed by filtration
  13. concentrationthe solution was concentrated under reduced pressure

Sources & evidence

ORD record
ord-7bca41c4d0774b7889fafead797e1c3c
Source dataset
uspto-grants-2012_08
Patent number
US08242124B2

Reaction notes

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