Toluene → 2-benzyl 3-methyl (2S,3S,5S)-1-benzyl-5-(1-ethoxyethoxy)piperidine-2,3-dicarboxylate

HRID 61452Notes

Reaction equation

HRID 61452 reaction equation
[CH2:1]([N:8]([CH2:25][C@@H:26]([O:39][CH:40]([O:42][CH2:43][CH3:44])[CH3:41])[CH2:27]OS(C1C=CC(C)=CC=1)(=O)=O)[C@@H:9]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>O1CCCC1>[CH2:1]([N:8]1[CH2:25][C@@H:26]([O:39][CH:40]([O:42][CH2:43][CH3:44])[CH3:41])[CH2:27][C@H:20]([C:21]([O:23][CH3:24])=[O:22])[C@H:9]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1

Participants

5

Reactant 3

HCID 1140TolueneHCID 2733832Lithium HexamethyldisilazideHCID 873488361-benzyl 4-methyl (2S)-2-[benzyl((2R)-2-(1-ethoxyethoxy)-3-[(4-methylphenyl)sulfonyl]oxypropyl)amino]succinate

Product 1

HCID 1317319282-benzyl 3-methyl (2S,3S,5S)-1-benzyl-5-(1-ethoxyethoxy)piperidine-2,3-dicarboxylateYield 78.2%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-78 °C

Procedure

To a solution of 1-benzyl 4-methyl(2S)-2-[benzyl((2R)-2-(1-ethoxyethoxy)-3-[(4-methylphenyl)sulfonyl]oxypropyl)amino]succinate (34.30 g, 0.05464 mol) in a mixture of tetrahydrofuran (90.0 mL, 1.11 mol) and toluene (470.0 mL, 4.412 mol) at −78 Celsius was added 1.00 M of Lithium hexamethyldisilazide in tetrahydrofuran (65.6 mL). The resulting mixture was stirred at −78 Celsius overnight, and then allowed to warm up to at 0 Celsius gradually and stirred at 0 Celsius for 30 min. After quenched with aq ammonium chloride, the mixture was extracted with ethyl acetate. The combined organic layers were washed with water, brine, and dried (sodium sulfate), and concentrated to dry. The residue was purified on silica gel column, eluting with 0 to 20% EtOAc in hexane, to yield the cyclized product (19.47 g, 78.2%). MS (ESI): (M+H)+=456.0.

Workup

  1. temperatureto warm up to at 0 Celsius gradually
  2. stirringstirred at 0 Celsius for 30 min
  3. customAfter quenched with aq ammonium chloride
  4. extractionthe mixture was extracted with ethyl acetate
  5. washThe combined organic layers were washed with water, brine
  6. dry with materialdried (sodium sulfate)
  7. concentrationconcentrated
  8. customto dry
  9. customThe residue was purified on silica gel column
  10. washeluting with 0 to 20% EtOAc in hexane

Sources & evidence

ORD record
ord-954034158db24faeac6e39a8e152233f
Source dataset
uspto-grants-2016_09
Patent number
US09440958B2

Reaction notes

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