Hydrochloric Acid → 5,7-Dichlorospiro[isoindoline-1,4'-piperidin]-3-one

HRID 390140Notes

Reaction equation

HRID 390140 reaction equation
C(OC([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=O)(C)(C)C.COC1C=CC(C[NH2:22])=CC=1.[Cl:25][C:26]1[C:27](I)=[C:28]([CH:32]=[C:33]([Cl:35])[CH:34]=1)[C:29](Cl)=[O:30].CCN(CC)CC.Cl>C1(C)C=CC=CC=1>[Cl:25][C:26]1[CH:27]=[C:28]2[C:32](=[C:33]([Cl:35])[CH:34]=1)[C:11]1([CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)[NH:22][C:29]2=[O:30]

Participants

7

Reactant 5

HCID 313Hydrochloric AcidHCID 8471TriethylamineHCID 754524-MethoxybenzylamineHCID 735900tert-Butyl 4-oxopiperidine-1-carboxylateHCID 141743723,5-Dichloro-2-iodobenzoyl chloride

Product 1

HCID 582957645,7-Dichlorospiro[isoindoline-1,4'-piperidin]-3-oneYield 118.5%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Procedure

A 500-mL flask was charged with 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (7.0 g, 35 mmol), 4-methoxy-benzylamine (4.8 g, 35 mmol) and 120 mL of toluene. The mixture was heated to reflux for 12 h. The yellow-orange solution was allowed to cool to ambient and then evaporated. The residue was used directly in the next step without further purification. It was dissolved in 150 mL of toluene. Then 3,5-dichloro-2-iodobenzoyl chloride (9.4 g, 28 mmol) and Et3N (4.5 g, 44 mmol) was added. The mixture was heated to reflux overnight. The mixture was acidified with 0.5 N aq HCl, and the layers were separated. The organic layer was washed with brine, dried and concentrated to give the crude product. It was purified by column chromatography (PE:EtOAc=15:1) to give the desired product (9.0 g, 42%).

Workup

  1. temperatureThe mixture was heated
  2. temperatureto reflux for 12 h
  3. temperatureto cool to ambient and
  4. customthen evaporated
  5. customThe residue was used directly in the next step without further purification
  6. dissolutionIt was dissolved in 150 mL of toluene
  7. temperatureThe mixture was heated
  8. temperatureto reflux overnight
  9. customthe layers were separated
  10. washThe organic layer was washed with brine
  11. customdried
  12. concentrationconcentrated
  13. customto give the crude product
  14. customIt was purified by column chromatography (PE:EtOAc=15:1)

Sources & evidence

ORD record
ord-ca81a611696f40a4b2d2b11cc0f754a0
Source dataset
uspto-grants-2013_02
Patent number
US08383629B2

Reaction notes

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