Methanol → 3-[4-(2-Chloro-5-fluoro-phenoxy)-piperidin-1-yl]-3-oxo-propionic acid

HRID 1093682Notes

Reaction equation

HRID 1093682 reaction equation
C([O:3][C:4](=[O:23])[CH2:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[Cl:22])[CH2:10][CH2:9]1)=[O:7])C.CO.O.O[Li].O>C1COCC1>[Cl:22][C:16]1[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:15]=1[O:14][CH:11]1[CH2:10][CH2:9][N:8]([C:6](=[O:7])[CH2:5][C:4]([OH:23])=[O:3])[CH2:13][CH2:12]1

Participants

6

Reactant 4

HCID 887MethanolHCID 962WaterHCID 168937Lithium hydroxide, monohydrateHCID 665917293-[4-(2-Chloro-5-fluoro-phenoxy)-piperidin-1-yl]-3-oxo-propionic acid ethyl ester

Product 1

HCID 578744413-[4-(2-Chloro-5-fluoro-phenoxy)-piperidin-1-yl]-3-oxo-propionic acidYield 73.1%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a stirred solution of malonic acid monoethyl ester (0.5 g, 0.00377 mole) in DMF (10 mL) was added DIPEA (1.18 g, 0.0094 mole), HOBt (0.608 g, 0.0045 mole) and EDCI.HCl (0.865 g, 0.0045 mole). After 2 minutes 4-(2-chloro-5-fluoro-phenoxy)-piperidine hydrochloride (1 g, 0.003 7 mole) and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and the product was extracted with ethyl acetate. The organic layers were dried over sodium sulfate and concentrated under reduced pressure to get afford 0.9 g (70%) of 3-[4-(2-chloro-5-fluoro-phenoxy)-piperidin-1-yl]-3-oxo-propionic acid ethyl ester. LC-MS purity: 344.78 (M+1)+, 82.56%. To a stirred solution of 3-[4-(2-chloro-5-fluoro-phenoxy)-piperidin-1-yl]-3-oxo-propionic acid ethyl ester (0.9 g, 0.0026 mole) in a mixture of THF (10 mL), methanol (3 mL) and H2O (2 mL) was added LiOH.H2O (0.218 g, 0.0052 mole) at ambient temperature and the resulting mixture was stirred for 30 minutes. Volatiles were then evaporated and the resulting residue was diluted with water, acidified with 10% aqueous HCl solution. The product was extracted with ethyl acetate, and the organic layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to afford 0.6 g (73%) of 3-[4-(2-chloro-5-fluoro-phenoxy)-piperidin-1-yl]-3-oxo-propionic acid. LC-MS purity: 316.72 (M+1)+, 75.8%.

Workup

  1. customVolatiles were then evaporated
  2. additionthe resulting residue was diluted with water
  3. extractionThe product was extracted with ethyl acetate
  4. washthe organic layer was washed with brine solution
  5. dry with materialdried over sodium sulfate
  6. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-09802ed2d86747c2900f5c53d14f9174
Source dataset
uspto-grants-2012_03
Patent number
US08129376B2

Reaction notes

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