Potassium Carbonate → 1-(4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(5-phenyl-3,4-dihydroisoquinolin-2(1H)-yl)ethane-1,2-dione

HRID 885043Notes

Reaction equation

HRID 885043 reaction equation
Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([C:12](=[O:32])[C:13]([C:15]1[C:23]3[C:18](=[C:19]([N:26]4[CH:30]=[N:29][C:28]([CH3:31])=[N:27]4)[N:20]=[CH:21][C:22]=3[O:24][CH3:25])[NH:17][CH:16]=1)=[O:14])[CH2:7]2.[C:33]1(B(O)O)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.O>[CH3:25][O:24][C:22]1[CH:21]=[N:20][C:19]([N:26]2[CH:30]=[N:29][C:28]([CH3:31])=[N:27]2)=[C:18]2[NH:17][CH:16]=[C:15]([C:13](=[O:14])[C:12]([N:6]3[CH2:5][CH2:4][C:3]4[C:8](=[CH:9][CH:10]=[CH:11][C:2]=4[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH2:7]3)=[O:32])[C:23]=12

Participants

7

Reactant 4

HCID 11430Potassium CarbonateHCID 312751,4-DioxaneHCID 66827Phenylboronic AcidHCID 580260681-(5-bromo-3,4-dihydroisoquinolin-2(1H)-yl)-2-(4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)ethane-1,2-dione

Product 1

HCID 445400131-(4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(5-phenyl-3,4-dihydroisoquinolin-2(1H)-yl)ethane-1,2-dioneYield 48.5%

Reagents, catalysts & solvents 2

HCID 178418807HCID 178418807, compoundCatalystHCID 962WaterSolvent

Conditions

Temperature
85 °C

Procedure

To a sealable vial containing 1-(5-bromo-3,4-dihydroisoquinolin-2(1H)-yl)-2-(4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)ethane-1,2-dione (0.05 g, 0.101 mmol) was added phenylboronic acid (0.018 g, 0.151 mmol), PdCl2(dppf)-CH2Cl2 adduct (0.016 g, 0.020 mmol), K2CO3 (0.06 g, 0.434 mmol), 1,4-dioxane (2 mL), and water (0.5 mL). The vessel was flushed with N2, then the vial was sealed and heated to 85° C. After 2 h the mixture was cooled to rt, and concentrated under reduced pressure. The residue was diluted with water (30 mL) and extracted with dichloromethane (3×30 mL). The organic solution was dried with Na2SO4, the drying agent was removed by filtration, and the organic solution was concentrated under reduced pressure. The residue was purified by prep HPLC. Some impurities were still present by LC/MS, so the mixture was further purified by flash chromatography using a 0-5% MeOH in dichloromethane gradient. The expected product, 1-(4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(5-phenyl-3,4-dihydroisoquinolin-2(1H)-yl)ethane-1,2-dione (0.024 g, 0.049 mmol, 48.3% yield), was isolated as an off-white solid. LC/MS: m/z 493.25 (M+H)+, 2.12 min (method 1). 1H NMR (500 MHz, chloroform-d) δ ppm 11.01 (br. s., 1H) 9.14 (s, 1H) 8.19-8.27 (m, 1H) 7.67-7.72 (m, 1H) 7.01-7.50 (m, 8H) 4.74-5.00 (m, 2H) 3.67-3.87 (m, 5H) 2.79-2.98 (m, 2H) 2.55-2.61 (m, 3H).

Workup

  1. customThe vessel was flushed with N2
  2. customthe vial was sealed
  3. temperatureAfter 2 h the mixture was cooled to rt
  4. concentrationconcentrated under reduced pressure
  5. additionThe residue was diluted with water (30 mL)
  6. extractionextracted with dichloromethane (3×30 mL)
  7. dry with materialThe organic solution was dried with Na2SO4
  8. customthe drying agent was removed by filtration
  9. concentrationthe organic solution was concentrated under reduced pressure
  10. customThe residue was purified by prep HPLC
  11. customwas further purified by flash chromatography

Sources & evidence

ORD record
ord-133dd38acd564dc5940f4b517a939993
Source dataset
uspto-grants-2012_08
Patent number
US08242124B2

Reaction notes

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