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Hydrochloric Acid → 8-Dimethylamino-1-(2-methoxy-ethoxy)-3-(2,4,6-trimethylphenyl)-1,8-diaza-spiro[4.5]decane-2,4-dione

HRID 2367893
Notes
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Reaction equation

HRID 2367893 reaction equation
CO[C:3]([C:5]1([N:14]([OH:27])[C:15](=[O:26])[CH2:16][C:17]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=2[CH3:25])[CH2:10][CH2:9][N:8]([N:11]([CH3:13])[CH3:12])[CH2:7][CH2:6]1)=[O:4].[H-].[Na+].Br[CH2:31][CH2:32][O:33][CH3:34].C[O-].[Na+].[Cl-].[NH4+].Cl>CN(C)C=O>[CH3:12][N:11]([CH3:13])[N:8]1[CH2:7][CH2:6][C:5]2([N:14]([O:27][CH2:31][CH2:32][O:33][CH3:34])[C:15](=[O:26])[CH:16]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=3[CH3:25])[C:3]2=[O:4])[CH2:10][CH2:9]1
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

8

Reactant 6

HCID 313Hydrochloric AcidHCID 24758Sodium hydrideHCID 25517Ammonium ChlorideHCID 809722-Bromoethyl methyl etherHCID 10942334Sodium MethoxideHCID 866713071-Dimethylamino-4-{hydroxy-[2-(2,4,6-trimethyl-phenyl)-acetyl]-amino}-piperidine-4-carboxylic acid methyl ester

Product 1

HCID 672272618-Dimethylamino-1-(2-methoxy-ethoxy)-3-(2,4,6-trimethylphenyl)-1,8-diaza-spiro[4.5]decane-2,4-dioneYield 35.6%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
0 °C

Procedure

420 mg 1-Dimethylamino-4-{hydroxy-[2-(2,4,6-trimethyl-phenyl)-acetyl]-amino}-piperidine-4-carboxylic acid methyl ester (from Step 4) is dissolved in 15 ml dimethylformamide, cooled to 0° C., then 43 mg sodium hydride is added. It is warmed to room temperature, and stirred for 30 minutes. Then, 186 mg 1-Bromo-2-methoxy-ethane is added slowly at ambient temperature. The mixture is stirred for an additional hour, cooled to 0° C., and 180 mg sodium methoxide is added. Stirring is continued for 2 hours at room temperature. Then the mixture is poured into 200 ml aqueous ammonium chloride and the pH is adjusted to 4.3 by the addition of hydrochloric acid. It is extracted three times with ethyl acetate, the organic layer is separated, dried over sodium sulfate, and the solvent is evaporated. The residue is purified by chromatography on silica gel with cyclohexane/acetone as a solvent, from 1:2 to pure acetone. Thus, 160 mg 8-Dimethylamino-1-(2-methoxy-ethoxy)-3-(2,4,6-trimethylphenyl)-1,8-diaza-spiro[4.5]decane-2,4-dione is obtained as a solid, mp 108° C. 1H-NMR (d4-methanol): 6.84 ppm (s, 2H), 4.28 ppm (m, 2H), 3.68 ppm (m, 2H), 3.37 ppm (s, 3H), 2.70 ppm (s, 6H), 2.22 ppm (m, 5H), 2.10 ppm (m, 8H).

Workup

  1. temperatureIt is warmed to room temperature
  2. stirringThe mixture is stirred for an additional hour
  3. temperaturecooled to 0° C.
  4. stirringStirring
  5. waitis continued for 2 hours at room temperature
  6. extractionIt is extracted three times with ethyl acetate
  7. customthe organic layer is separated
  8. dry with materialdried over sodium sulfate
  9. customthe solvent is evaporated
  10. customThe residue is purified by chromatography on silica gel with cyclohexane/acetone as a solvent, from 1:2 to pure acetone

Sources & evidence

ORD record
ord-10b3ba713d3347228eacf7682bd80213
Source dataset
uspto-grants-2014_04
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08703165B2

Reaction notes

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On this pageParticipantsConditionsProcedureWorkupSources & evidenceReaction notes