Citric Acid → benzyl (2S)-2-(4,4,4-trifluorobutanoylamino)propanoate

HRID 1045781Notes

Reaction equation

HRID 1045781 reaction equation
Cl.[CH2:2]([O:9][C:10](=[O:14])[C@H:11]([CH3:13])[NH2:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[F:47][C:48]([F:55])([F:54])[CH2:49][CH2:50][C:51](O)=[O:52].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl>[F:47][C:48]([F:55])([F:54])[CH2:49][CH2:50][C:51]([NH:12][C@@H:11]([CH3:13])[C:10]([O:9][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[O:14])=[O:52]

Participants

8

Reactant 6

HCID 311Citric AcidHCID 81531DiisopropylethylamineHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 27770854,4,4-Trifluorobutanoic acidHCID 27960291-Hydroxybenzotriazole hydrateHCID 12210893L-Alanine, phenylmethyl ester, hydrochloride (1:1)

Product 1

HCID 71244635benzyl (2S)-2-(4,4,4-trifluorobutanoylamino)propanoateYield 94%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

Add successively L-alanine benzyl ester hydrochloride (7.00 g, 32.5 mmol), diisopropylethylamine (28.30 mL, 162.3 mmol), 1-hydroxybenzotriazole hydrate (7.46 g, 48.7 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (9.33 g 48.7 mmol) to a solution of 4,4,4-trifluorobutyric acid (7.131 g, 48.7 mmol) in dichloromethane (162 mL) at ambient temperature under nitrogen and stir for 20 hours. Add a 20% aqueous solution of citric acid (150 mL, 162 mmol), stir mixture for 5 minutes and separate layers. Extract from aqueous with dichloromethane (100 mL). Wash combined organics with saturated aqueous solution of sodium bicarbonate (150 mL), dry over magnesium sulfate and concentrate. Purify the residue by flash chromatography, eluting with hexane:ethyl acetate (4:1 to 2:1) to give the title compound as a white solid (9.22 g, 30.4 mmol, 94%). MS (m/z): 304 (M+1); [α]N825=−44.6° (c=5.0, methanol).

Workup

  1. stirringstir mixture for 5 minutes
  2. customseparate layers
  3. extractionExtract from aqueous with dichloromethane (100 mL)
  4. washWash
  5. dry with materialdry over magnesium sulfate
  6. concentrationconcentrate
  7. customPurify the residue by flash chromatography
  8. washeluting with hexane:ethyl acetate (4:1 to 2:1)

Sources & evidence

ORD record
ord-d82a5c1a78f84864a19befbedf8acea8
Source dataset
uspto-grants-2013_10
Patent number
US08569286B2

Reaction notes

Loading…