Lithium Hydroxide → 1,1-Dimethylethyl 3-(5-bromo-1-isoquinolinyl)propanoate

HRID 2192490Notes

Reaction equation

HRID 2192490 reaction equation
[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6](C(C1C=CC=CC=1)=O)[CH:7]2[C:12]#N.BrC[CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].[H-].[Na+].[OH-].[Li+]>C1COCC1.O>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[C:7]2[CH2:12][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]

Participants

7

Reactant 4

HCID 3939Lithium HydroxideHCID 24758Sodium hydrideHCID 256128tert-Butyl 3-bromopropionateHCID 112677672-Benzoyl-5-bromo-1-cyano-1,2-dihydroisoquinoline

Product 1

HCID 581499231,1-Dimethylethyl 3-(5-bromo-1-isoquinolinyl)propanoateYield 69.6%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-10 °C

Procedure

A solution of 5-bromo-2-(phenylcarbonyl)-1,2-dihydro-1-isoquinolinecarbonitrile (D10; 70 g, 206 mmol) and 1,1-dimethylethyl 3-bromopropanoate (Aldrich; 37.9 ml, 227 mmol) in dry, degassed DMF (250 ml) was added dropwise over 40 mins to a suspension of sodium hydride (60%; 24.76 g, 619 mmol) in dry, degassed DMF (750 ml) at −10° C. under nitrogen. The mixture was stirred at −10° C. for 10 mins, then allowed to warm to room temp over 3 h. Water (1500 ml) was cautiously added and the mixture extracted with ethyl acetate (3×500 ml). The combined organic extracts were washed with brine (5×500 ml) and dried (MgSO4). The solvent was evaporated to give a brown oil. The crude intermediate was dissolved in THF (700 ml) and lithium hydroxide (24.71 g, 1032 mmol) in water (100 ml) (note: not all soluble) was added. The mixture was vigorously stirred for 30 h, then stored in the fridge over the weekend. The mixture was partitioned between water (700 ml) and ethyl acetate (3×500 ml) and the combined organic extracts washed with brine (2×500 ml) and dried (MgSO4). The solvent was evaporated and the residue was purified by chromatography on silica eluting with 5-15% ethyl acetate in isohexane gave the title compound (48.2 g)

Workup

  1. customdegassed DMF (250 ml)
  2. customin dry
  3. customdegassed DMF (750 ml) at −10° C. under nitrogen
  4. temperatureto warm to room temp over 3 h
  5. additionWater (1500 ml) was cautiously added
  6. extractionthe mixture extracted with ethyl acetate (3×500 ml)
  7. washThe combined organic extracts were washed with brine (5×500 ml)
  8. dry with materialdried (MgSO4)
  9. customThe solvent was evaporated
  10. customto give a brown oil
  11. stirringThe mixture was vigorously stirred for 30 h
  12. customThe mixture was partitioned between water (700 ml) and ethyl acetate (3×500 ml)
  13. washthe combined organic extracts washed with brine (2×500 ml)
  14. dry with materialdried (MgSO4)
  15. customThe solvent was evaporated
  16. customthe residue was purified by chromatography on silica eluting with 5-15% ethyl acetate in isohexane

Sources & evidence

ORD record
ord-33f88e4561354d4e80cf6a477d5d3314
Source dataset
uspto-grants-2012_12
Patent number
US08329730B2

Reaction notes

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