4-Bromoisoquinoline → 1-Tert-butoxycarbon-yl-4-(isoquinolin-4-yl)-4-hydroxypiperidine

HRID 1066071Notes

Reaction equation

HRID 1066071 reaction equation
Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4][CH:3]=1.C([Li])(CC)C.[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>O1CCCC1>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][C:27]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[N:4][CH:3]=2)([OH:30])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]

Participants

5

Reactant 3

HCID 737434-BromoisoquinolineHCID 735900tert-Butyl 4-oxopiperidine-1-carboxylateHCID 178418400CID 53628100

Product 1

HCID 177895011-Tert-butoxycarbon-yl-4-(isoquinolin-4-yl)-4-hydroxypiperidineYield 39%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

A solution of 6.46 gm (31.1 mMol) 4-bromoisoquinoline in 80 mL tetrahydrofuran was cooled to −100° C. under a nitrogen atmosphere. To this solution was added dropwise 28.7 mL (37.3 mmol) sec-butyllithium (1.3 M in hexanes) and the reaction mixture was allowed to stir for 1.5 hours. To the reaction mixture was then added dropwise a solution of 1-tert-butoxycarbonyl-4-piperidone in 20 mL tetrahydrofuran dropwise. The reaction mixture was then stirred for 18 hours at room temperature. The reaction mixture was then partitioned between ethyl acetate and 2N sodium hydroxide. The phases were separated and the aqueous phase extracted well with ethyl acetate. The organic phases were combined, washed saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with 9:1 dichloromethane:methanol. Fractions containing product were combined and concentrated under reduced pressure to provide 3.95 gm (39%) 1-tert-butoxycarbonyl-4-(isoquin-olin-4-yl)-4-hydroxypiperidine as a yellow solid.

Workup

  1. stirringThe reaction mixture was then stirred for 18 hours at room temperature
  2. customThe reaction mixture was then partitioned between ethyl acetate and 2N sodium hydroxide
  3. customThe phases were separated
  4. extractionthe aqueous phase extracted well with ethyl acetate
  5. washwashed saturated aqueous sodium chloride
  6. dry with materialdried over sodium sulfate
  7. concentrationconcentrated under reduced pressure
  8. washeluting with 9:1 dichloromethane
  9. additionFractions containing product
  10. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-b388d7a64f2440c28d10a991bda66947
Source dataset
uspto-grants-2001_06
Patent number
US06242450B1

Reaction notes

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