Lithium Hydroxide → (2S)-2-[[2-(3,5-difluorophenyl)acetyl]amino]propanoic acid

HRID 2267599Notes

Reaction equation

HRID 2267599 reaction equation
[OH-].[Li+].C[O:4][C:5](=[O:20])[C@H:6]([CH3:19])[NH:7][C:8](=[O:18])[CH2:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=1>O.O1CCOCC1>[F:16][C:14]1[CH:15]=[C:10]([CH2:9][C:8]([NH:7][C@H:6]([C:5]([OH:20])=[O:4])[CH3:19])=[O:18])[CH:11]=[C:12]([F:17])[CH:13]=1

Participants

5

Reactant 2

HCID 3939Lithium HydroxideHCID 68605046HCID 68605046, compound

Product 1

HCID 12135350(2S)-2-[[2-(3,5-difluorophenyl)acetyl]amino]propanoic acidYield 97.2%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Procedure

To a stirred solution of 3,5-difluorophenylacetic acid (6.02 g, 34.97 mmol), L-alanine methyl ester hydrochloride (4.88 g, 34.96 mmol) and HOBt (5.20 g, 38.48 mmol) in dichloromethane (200 mL) under nitrogen at 0° C. was added NMM (8.84 g, 87.39 mmol) and EDAC-HCl (7.38 g, 38.49 mmol). The mixture was allowed to warm gradually to ambient temperature and stir overnight. The reaction was diluted with ethyl acetate and extracted sequentially with aqueous sodium bicarbonate, 1N aqueous HCl and brine. The organic phase was dried, filtered and evaporated. The residue was purified by flash chromatography on silica gel eluting with 1:1 (v/v) hexanes:ethyl acetate to afford N-[(3,5-difluorophenyl)acetyl]-L-alanine methyl ester (7.91 g, 88% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ 1.39 (d, 3H, J=7.0 Hz), 3.54 (s, 2H), 3.75 (s, 3H), 4.59 (m, 1H), 6.02 (br 1H), 6.67-6.87 (m, 3H). MS APCI, m/z=258 (M+1). LC/MS: 1.68 min. Lithium hydroxide (1.40 g, 33.33 mmol) in water (60 mL) was added dropwise to a solution of N-[(3,5-difluorophenyl)acetyl]-L-alanine methyl ester (7.79 g, 30.28 mmol) in 1,4-dioxane (150 mL). After 2 h the solvent was evaporated. The residue was dissolved in water and the solution extracted with diethyl ether. The aqueous phase was acidified with 1N aqueous HCl and extracted with ethyl acetate three times. The combined ethyl acetate extracts were dried, filtered and evaporated to afford the title compound (7.16 g, 97% yield) as a white solid. 1H NMR (300 MHz, d6-DMSO) δ 1.28 (d, 3H, J=7.4 Hz), 3.51 (s, 2H), 4.20 (m, 1H), 6.93-7.12 (m, 3H), 8.44 (d, 1H, J=7.0 Hz), 12.46 (br, 1H). HPLC Method A: 2.12 min.

Workup

  1. custom1.68 min
  2. customAfter 2 h the solvent was evaporated
  3. dissolutionThe residue was dissolved in water
  4. extractionthe solution extracted with diethyl ether
  5. extractionextracted with ethyl acetate three times
  6. dry with materialThe combined ethyl acetate extracts were dried
  7. filtrationfiltered
  8. customevaporated

Sources & evidence

ORD record
ord-861e414162764603a5479132fd484949
Source dataset
uspto-grants-2010_12
Patent number
US07858776B2

Reaction notes

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