4-Methylmorpholine → tert-butyl (S)-3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-oxo-4-(piperidin-1-yl)butanoate

HRID 1482227Notes

Reaction equation

HRID 1482227 reaction equation
[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:20](O)=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.CN1CCOCC1.[NH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>CN(C=O)C.CCCCCC.C(OCC)(=O)C>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:20](=[O:21])[N:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)[CH2:23][C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1

Participants

6

Reactant 3

HCID 79724-MethylmorpholineHCID 8082PiperidineHCID 2724635Fmoc-L-Asp(OtBu)-OH

Product 1

HCID 89668270tert-butyl (S)-3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-oxo-4-(piperidin-1-yl)butanoateYield 102.9%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 21226206Ethyl acetate hexaneSolvent

Procedure

(S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-4-(tert-butoxy)-4-oxobutanoic acid (Compound SP404, Fmoc-Asp(OtBu)-OH) (30 g, 72.9 mmol) was dissolved in DMF (243 mL). N-methylmorpholine (9.6 ml, 87 mmol) and then O-(7-aza-1H-benzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (HATU) (33.3 g, 87 mmol) were added at 0° C., and the mixture was stirred for 10 minutes. Piperidine (7.1 ml, 71.5 mmol) was further added dropwise, and the mixture was stirred for 30 minutes. The reaction mixture was diluted with hexane/ethyl acetate=1/1 (1500 ml), and the organic layer was sequentially washed with a saturated aqueous ammonium chloride solution, a saturated aqueous sodium bicarbonate solution, water and brine. The organic extract was dried over sodium sulfate and then concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1) to afford tert-butyl (S)-3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-oxo-4-(piperidin-1-yl)butanoate (Compound SP403) (35.2 g, 99%).

Workup

  1. stirringthe mixture was stirred for 30 minutes
  2. washthe organic layer was sequentially washed with a saturated aqueous ammonium chloride solution
  3. extractionThe organic extract
  4. dry with materialwas dried over sodium sulfate
  5. concentrationconcentrated under reduced pressure
  6. customthe resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1)

Sources & evidence

ORD record
ord-2e86b613ab0d4b718a43fcf6fad77a77
Source dataset
uspto-grants-2016_08
Patent number
US09409952B2

Reaction notes

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