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

HRID 1093687Notes

Reaction equation

HRID 1093687 reaction equation
C([O:3][C:4](=[O:22])[CH2:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[CH2:10][CH2:9]1)=[O:7])C.CO.O.O[Li].O>C1COCC1>[Cl:21][C:16]1[CH:17]=[CH:18][CH:19]=[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:22])=[O:3])[CH2:13][CH2:12]1

Participants

6

Reactant 4

HCID 887MethanolHCID 962WaterHCID 168937Lithium hydroxide, monohydrateHCID 66592017HCID 66592017, compound

Product 1

HCID 578744033-[4-(2-Chloro-phenoxy)-piperidin-1-yl]-3-oxo-propionic acidYield 75%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a stirred solution of malonic acid monoethyl ester (1.2 g, 0.0089 mole) in DMF (10 mL) was added DIPEA (2.5 g, 0.02 mole), HOBt (1.3 g, 0.0097 mole) and EDCI.HCl (1.9 g, 0.0097 mole). After 2 minutes 4-(2-chloro-phenoxy)-piperidine hydrochloride (2 g, 0.0081 mole) was added 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. The resulting residue was purified by column chromatography using silica gel 60-120 mesh (60% ethyl acetate in hexane) to afford 1.1 g (42%) of 3-[4-(2-chloro-phenoxy)-piperidin-1-yl]-3-oxo-propionic acid ethyl ester. LC-MS purity: 326.11 (M+1)+, 90.2%. To a stirred solution of 3-[4-(2-chloro-phenoxy)-piperidin-1-yl]-3-oxo-propionic acid ethyl ester (1.1 g, 0.0034 mole) in a mixture of THF (20 mL), methanol (4 mL) and H2O (4 mL) was added LiOH.H2O (0.286 g, 0.0068 mole) at ambient temperature. 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 resulting precipitate was isolated by filtration and dried to afford 0.75 g (75%) of 3-[4-(2-chloro-phenoxy)-piperidin-1-yl]-3-oxo-propionic acid.

Workup

  1. customVolatiles were then evaporated
  2. additionthe resulting residue was diluted with water
  3. customThe resulting precipitate was isolated by filtration
  4. customdried

Sources & evidence

ORD record
ord-c90294791e5646c7b5116f890a31c5bd
Source dataset
uspto-grants-2012_03
Patent number
US08129376B2

Reaction notes

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