Proton sponge → HCID 18408893, compound

HRID 993043Notes

Reaction equation

HRID 993043 reaction equation
Cl.Cl.[O:3]=[C:4]1[CH2:9][N:8]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH2:7][CH2:6][N:5]1[CH2:16][C:17]([C:19]1[CH:31]=[CH:30][C:22]([O:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:21][CH:20]=1)=[O:18].CN(C1C2C(N(C)C)=CC=CC=2C=CC=1)C.Cl[C:49]([O:51][CH:52]([Cl:56])[CH:53](C)C)=[O:50]>C(Cl)Cl.C(OCC)(=O)C.O>[Cl:56][CH:52]([O:51][C:49]([N:13]1[CH2:12][CH2:11][CH:10]([N:8]2[CH2:7][CH2:6][N:5]([CH2:16][C:17]([C:19]3[CH:31]=[CH:30][C:22]([O:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:21][CH:20]=3)=[O:18])[C:4](=[O:3])[CH2:9]2)[CH2:15][CH2:14]1)=[O:50])[CH3:53]

Participants

7

Reactant 3

HCID 88675Proton spongeHCID 27333261-Chloro-2-Methylpropyl ChloroformateHCID 18408903HCID 18408903, compound

Product 1

HCID 18408893HCID 18408893, compoundYield 77.7%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6344DichloromethaneSolvent2×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
-40 °C

Procedure

To a solution of 0.75 g of ethyl 4-[[2-oxo-4-(piperidin-4-yl)-piperazin-1-yl]acetyl]phenoxyacetate dihydrochloride synthesized according to the method described in WO962503 in 16 ml of methylene chloride was added 1.11 g of proton sponge under ice-cooling. After stirring for 5 minutes, the mixture was cooled to −40° C., and a solution of 0.322 g of 1-chloro-2-methylpropyl chloroformate in 2 ml of methylene chloride. After stirring for 45 minutes, the reaction mixture was diluted with ethyl acetate and water, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate. The organic layer collected was washed with saturated aqueous saline, dried over sodium sulfate, and the solvent was removed by distillation. The residue was purified by chromatography on a silica gel column (methylene chloride:methanol=50:1-40:1) to give 0.624 g (74%) of ethyl 4-[[4-[1-(1-chloroethoxycarbonyl)piperidin-4-yl]-2-oxopiperazin-1-yl]acetyl]phenoxyacetate.

Workup

  1. temperaturecooling
  2. stirringAfter stirring for 45 minutes
  3. customthe organic layer was separated
  4. extractionThe aqueous layer was extracted with ethyl acetate
  5. customThe organic layer collected
  6. washwas washed with saturated aqueous saline
  7. dry with materialdried over sodium sulfate
  8. customthe solvent was removed by distillation
  9. customThe residue was purified by chromatography on a silica gel column (methylene chloride:methanol=50:1-40:1)

Sources & evidence

ORD record
ord-a467cc34290f4d8f90f9cc90b731fc2c
Source dataset
uspto-grants-2002_10
Patent number
US06472397B1

Reaction notes

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