Methyl 2,4,6-trimethylbenzeneacetate → 3-[1-Methoxy-4-(4-methoxy-benzylsulfanyl)-piperidin-4-yl]-3-oxo-2-(2,4,6-trimethylphenyl)-propionic acid methyl ester

HRID 2035309Notes

Reaction equation

HRID 2035309 reaction equation
C([Li])CCC.[CH3:6][O:7][C:8](=[O:19])[CH2:9][C:10]1[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=1[CH3:18].[CH3:20][O:21][N:22]1[CH2:27][CH2:26][C:25]([S:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=2)([C:28](Cl)=[O:29])[CH2:24][CH2:23]1>C(NC(C)C)(C)C.O1CCCC1>[CH3:6][O:7][C:8](=[O:19])[CH:9]([C:10]1[C:11]([CH3:18])=[CH:12][C:13]([CH3:17])=[CH:14][C:15]=1[CH3:16])[C:28]([C:25]1([S:31][CH2:32][C:33]2[CH:34]=[CH:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=2)[CH2:24][CH2:23][N:22]([O:21][CH3:20])[CH2:27][CH2:26]1)=[O:29]

Participants

6

Reactant 3

HCID 13524810Methyl 2,4,6-trimethylbenzeneacetateHCID 866633001-Methoxy-4-(4-methoxybenzylsulfanyl)-piperidine-4-carbonyl chlorideHCID 178418339Butyllithium

Product 1

HCID 667938903-[1-Methoxy-4-(4-methoxy-benzylsulfanyl)-piperidin-4-yl]-3-oxo-2-(2,4,6-trimethylphenyl)-propionic acid methyl ester

Reagents, catalysts & solvents 2

HCID 7912DiisopropylamineSolventHCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-5 °C

Procedure

In a separate flask, 512 mg diisopropylamine was dissolved in 15 ml tetrahydrofuran, cooled to −5° C., and 2.86 ml n-butyllithium (1.6M in hexane) was added, then stirred at 0° C. for 1 hour. Then 864 mg (2,4,6-trimethyl-phenyl)-acetic acid methyl ester was added, and the mixture stirred for additional 30 minutes at 0° C. The crude 1-methoxy-4-(4-methoxybenzylsulfanyl)-piperidine-4-carbonyl chloride was dissolved in 5 ml tetrahydrofuran and added to the reaction mixture, which was then allowed to warm to room temperature and stirred for 18 hours. The solvent was evaporated, the residue partitioned between half saturated aqueous ammonium chloride and t-butylmethyl ether, the organic layer washed with brine, dried over sodium sulfate, and evaporated. The residue was chromatographed on silica gel with ethyl acetate/cyclohexane (1:9, then 1:5, then 1:2) as a solvent. Thus, 508 mg 3-[1-methoxy-4-(4-methoxy-benzylsulfanyl)-piperidin-4-yl]-3-oxo-2-(2,4,6-trimethylphenyl)-propionic acid methyl ester was obtained.

Workup

  1. stirringthe mixture stirred for additional 30 minutes at 0° C
  2. additionadded to the reaction mixture, which
  3. temperatureto warm to room temperature
  4. stirringstirred for 18 hours
  5. customThe solvent was evaporated
  6. customthe residue partitioned between half saturated aqueous ammonium chloride and t-butylmethyl ether
  7. washthe organic layer washed with brine
  8. dry with materialdried over sodium sulfate
  9. customevaporated
  10. customThe residue was chromatographed on silica gel with ethyl acetate/cyclohexane (1:9

Sources & evidence

ORD record
ord-56e6fc3c0a8f410f85f6fe2437fb5ad8
Source dataset
uspto-grants-2013_11
Patent number
US08574607B2

Reaction notes

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