Water → 4-[2-(1,3-Dioxo-1,3-dihydroisoindol-2-yloxy)ethyl]piperidine-1-carboxylic acid tert-butyl ester

HRID 2112422Notes

Reaction equation

HRID 2112422 reaction equation
[H-].[Na+].[OH:3][N:4]1[C:8](=[O:9])[C:7]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]2[C:5]1=[O:14].[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([CH2:28][CH2:29]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].O>CN(C)C=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([CH2:28][CH2:29][O:3][N:4]2[C:5](=[O:14])[C:6]3[C:7](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]2=[O:9])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]

Participants

8

Reactant 4

HCID 962WaterHCID 10665N-HydroxyphthalimideHCID 24758Sodium hydrideHCID 21936070N-Boc-4-[2-(4-Toluenesulfonyloxy)ethyl]piperidine

Product 1

HCID 576420504-[2-(1,3-Dioxo-1,3-dihydroisoindol-2-yloxy)ethyl]piperidine-1-carboxylic acid tert-butyl esterYield 74.6%

Reagents, catalysts & solvents 3

HCID 67553Tetrabutylammonium IodideCatalystHCID 6228DimethylformamideSolvent2×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

At 0° C., a 60% suspension of sodium hydride in mineral oil (0.69 g, 17.2 mmol) was added to a solution of N-hydroxyphthalimide (2.80 g, 17.2 mmol) in N,N-dimethylformamide (20 ml). The reaction mixture was stirred for 45 min at 0° C. A solution of 4-[2-(toluene-4-sulfonyloxy)ethyl]piperidine-1-carboxylic acid tert-butyl ester (5.99 g, 15.6 mmol) in N,N-dimethylformamide (15 ml) and tetrabutylammonium iodide (0.17 g, 0.47 mmol) were added successively. The reaction mixture was heated to 60° C. for 2 days and cooled to room temperature. Water (5 ml) was added carefully. The reaction mixture was diluted with ethyl acetate (250 ml) and washed with a 10% aqueous solution of sodium hydrogensulphate (200 ml). The aqueous phase was extracted with ethyl acetate (200 ml). The combined organic layers were washed with a saturated aqueous solution of sodium hydrogencarbonate (150 ml) and dried over magnesium sulphate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (80 g), using ethyl acetate/heptane 1:1 as eluent to give 4.36 g of 4-[2-(1,3-dioxo-1,3-dihydroisoindol-2-yloxy)ethyl]piperidine-1-carboxylic acid tert-butyl ester.

Workup

  1. temperatureThe reaction mixture was heated to 60° C. for 2 days
  2. temperaturecooled to room temperature
  3. washwashed with a 10% aqueous solution of sodium hydrogensulphate (200 ml)
  4. extractionThe aqueous phase was extracted with ethyl acetate (200 ml)
  5. washThe combined organic layers were washed with a saturated aqueous solution of sodium hydrogencarbonate (150 ml)
  6. dry with materialdried over magnesium sulphate
  7. customThe solvent was removed in vacuo
  8. customThe crude product was purified by flash chromatography on silica (80 g)

Sources & evidence

ORD record
ord-b6154ee20cec48ca949ed5a2f5aa51ed
Source dataset
uspto-grants-2009_04
Patent number
US07524813B2

Reaction notes

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