Citric Acid → (4S)-5-(tert-Butoxy)-4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-5-oxopentanoic acid

HRID 530142Notes

Reaction equation

HRID 530142 reaction equation
[NH2:1][C@H:2]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3][CH2:4][C:5]([OH:7])=[O:6].C(=O)([O-])[O-].[Na+].[Na+].[C:21](Cl)([O:23][CH2:24][CH:25]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]2[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:22].Cl.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCOCC1.O>[CH:36]1[C:37]2[CH:25]([CH2:24][O:23][C:21]([NH:1][C@H:2]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3][CH2:4][C:5]([OH:7])=[O:6])=[O:22])[C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:32]=2[CH:33]=[CH:34][CH:35]=1

Participants

8

Reactant 5

HCID 311Citric AcidHCID 313Hydrochloric AcidHCID 10340Sodium CarbonateHCID 343679-Fluorenylmethyl chloroformateHCID 1175051-(1,1-Dimethylethyl) hydrogen L-glutamate

Product 1

HCID 7017912(4S)-5-(tert-Butoxy)-4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-5-oxopentanoic acidYield 99%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Procedure

To (S)-4-amino-5-tert-butoxy-5-oxopentanoic acid (1.50 g, 7.38 mmol) in 1,4-dioxane (40 mL) chilled to 0° C., sodium carbonate (196 mg, 1.85 mmol) in water (20 mL) was added followed by Fmoc chloride (2.11 g, 8.16 mmol). The reaction was gradually warmed to ambient temperature and stirred at ambient temperature for 16 hours. After this time, the reaction was made slightly acidic (pH=6) with 2 M hydrochloric acid and the pH adjusted to ˜3 with 1 M citric acid (˜80 mL). The resulting mixture was extracted with ethyl acetate (3×100 mL). The combined organics were dried over sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography eluting with hexanes to a 3:2 ethyl acetate/hexane mixture to afford (S)-4-(((9H-fluoren-9-yl)methoxy)carbonylamino)-5-tert-butoxy-5-oxopentanoic acid (3.10 g, 99%) as a white solid: 1H NMR (300 MHz, CDCl3) δ carboxylic acid peak (1H) not observed as it was too broadened out, 7.76 (d, J=7.5 Hz, 2H), 7.61-7.58 (m, 2H), 7.42-7.26 (m, 4H), 5.45 (d, J=7.8 Hz, 1H), 4.48-4.19 (m, 4H), 2.51-2.34 (m, 2H), 2.28-2.14 (m, 1H), 1.99-1.88 (m, 1H), 1.47 (s, 9H); ESI MS m/z=448 [M+Na]+.

Workup

  1. extractionThe resulting mixture was extracted with ethyl acetate (3×100 mL)
  2. dry with materialThe combined organics were dried over sodium sulfate
  3. filtrationfiltered
  4. concentrationthe filtrate concentrated under reduced pressure
  5. customThe residue obtained
  6. customwas purified by silica gel column chromatography
  7. washeluting with hexanes to a 3:2 ethyl acetate/hexane mixture

Sources & evidence

ORD record
ord-1b6e911485a64e70ac4387294aefcbf1
Source dataset
uspto-grants-2016_05
Patent number
US09352049B2

Reaction notes

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