Potassium Phosphate, Tribasic → Acetic Acid 2-bromo-6-(6-tert-butyl-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-benzyl Ester

HRID 2069795

Reaction equation

HRID 2069795 reaction equation
[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[NH:10][CH2:9][CH2:8]2)([CH3:4])([CH3:3])[CH3:2].[Br:16][C:17]1[CH:27]=[CH:26][CH:25]=[C:24](Br)[C:18]=1[CH2:19][O:20][C:21](=[O:23])[CH3:22].[O-]P([O-])([O-])=O.[K+].[K+].[K+].CNC1CCCCC1NC>O1CCOCC1.[Cu](I)I>[Br:16][C:17]1[CH:27]=[CH:26][CH:25]=[C:24]([N:10]2[CH2:9][CH2:8][C:7]3[C:12](=[CH:13][CH:14]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=3)[C:11]2=[O:15])[C:18]=1[CH2:19][O:20][C:21](=[O:23])[CH3:22]

Participants

7

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 5510741-N,2-N-dimethylcyclohexane-1,2-diamine2×HCID 592164132,6-Dibromobenzyl acetateHCID 598366606-(tert-Butyl)-3,4-dihydroisoquinolin-1(2H)-one

Product 1

HCID 59216426Acetic Acid 2-bromo-6-(6-tert-butyl-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-benzyl EsterYield 6.1%

Reagents, catalysts & solvents 2

HCID 83717Copper iodideCatalyst3×HCID 312751,4-DioxaneSolvent

Procedure

6-tert-Butyl-3,4-dihydro-2H-isoquinolin-1-one (4 g, 19.67 mmol), Acetic acid 2,6-dibromo-benzyl ester (12.1 g, 2 eq), potassium phosphate tribasic (8.35 g, 2 eq) and copper iodide (787 mg, 0.2 eq) were taken up in dioxane (40 mL). Finally added N,N′-Dimethyl-cyclohexane-1,2-diamine (1.24 mL, 0.4 eq) and the resulting mixture was heated to reflux for 24 hours, after which time more copper iodide (394 mg, 0.1 eq) and N,N′-Dimethyl-cyclohexane-1,2-diamine (0.62 mL, 0.2 eq) were added. Stirred an additional 64 hours and then added more copper iodide (400 mg, 0.1 eq). Continued to stir at reflux for a total of 168 hours. Cooled to room temperature and then added ethylacetate (300 mL) and water (100 mL), partitioned and separated the layers. Washed with further water (2×100 mL) and then finally washed with brine (1×100 mL). The ethyl acetate layer was dried over magnesium sulfate, filtered and concentrated to give 4.45 g of crude product. Purification on a 240 g Analogix column afforded the title compound as a white foamy solid (516 mg) ((M+H)+=431) and recovered 6-tert-Butyl-3,4-dihydro-2H-isoquinolin-1-one (2.188 g).

Workup

  1. temperatureto reflux for 24 hours
  2. stirringContinued to stir
  3. temperatureat reflux for a total of 168 hours
  4. customadded ethylacetate (300 mL) and water (100 mL), partitioned
  5. customseparated the layers
  6. washWashed with further water (2×100 mL)
  7. washfinally washed with brine (1×100 mL)
  8. dry with materialThe ethyl acetate layer was dried over magnesium sulfate
  9. filtrationfiltered
  10. concentrationconcentrated
  11. customto give 4.45 g of crude product
  12. customPurification on a 240 g Analogix column

Sources & evidence

ORD record
ord-957feac6e1d849c3a42654a61558ede1
Source dataset
uspto-grants-2012_10
Patent number
US08299077B2

Linked notes

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