1-(Tert-butyl) 2-methyl (R)-6-oxopiperidine-1,2-dicarboxylate → methyl(R)-2-tert-butoxycarbonylamino-6-(3,4-difluorophenyl)-6-oxohexanoate

HRID 553976Notes

Reaction equation

HRID 553976 reaction equation
[CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][CH2:8][C:7](=[O:11])[N:6]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:4].[F:19][C:20]1[CH:21]=[C:22]([Mg]Br)[CH:23]=[CH:24][C:25]=1[F:26]>C1COCC1>[C:15]([O:14][C:12]([NH:6][C@H:5]([CH2:10][CH2:9][CH2:8][C:7]([C:23]1[CH:22]=[CH:21][C:20]([F:19])=[C:25]([F:26])[CH:24]=1)=[O:11])[C:3]([O:2][CH3:1])=[O:4])=[O:13])([CH3:18])([CH3:17])[CH3:16]

Participants

4

Reactant 2

HCID 107298291-(Tert-butyl) 2-methyl (R)-6-oxopiperidine-1,2-dicarboxylateHCID 178505835HCID 178505835, compound

Product 1

HCID 67461441methyl(R)-2-tert-butoxycarbonylamino-6-(3,4-difluorophenyl)-6-oxohexanoate

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a solution of (R)-6-oxopiperidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (820 mg) in THF (12 mL), 3,4-difluorophenylmagnesium bromide (0.5 M solution in THF, 7.0 mL) was added in a nitrogen atmosphere at −78° C. over 20 minutes. The reaction solution was stirred at −78° C. to −10° C. for two hours, and then quenched with a saturated ammonium chloride solution at −10° C. Water was added to the reaction solution, followed by extraction with ethyl acetate. The resulting extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain methyl (R)-2-tert-butoxycarbonylamino-6-(3,4-difluorophenyl)-6-oxohexanoate (850 mg). A solution of 4 N hydrochloric acid in ethyl acetate (25 mL) was added to a solution of methyl (R)-2-tert-butoxycarbonylamino-6-(3,4-difluorophenyl)-6-oxohexanoate (2.45 g) in ethyl acetate (25 mL) at room temperature, and the reaction solution was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was made basic with a saturated sodium bicarbonate solution. Then, chloroform was added to the residue, and the mixture was stirred at room temperature for two hours. The organic layer was separated, dried over magnesium sulfate, and then concentrated under reduced pressure. 10% palladium-carbon (150 mg) was added to a solution of the residue in methanol (30 mL), and the reaction solution was stirred in a hydrogen atmosphere at room temperature for two hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 1.25 g of the title compound. The property values of the compound are as follows.

Workup

  1. customquenched with a saturated ammonium chloride solution at −10° C
  2. additionWater was added to the reaction solution
  3. extractionfollowed by extraction with ethyl acetate
  4. extractionThe resulting extract
  5. dry with materialwas dried over magnesium sulfate
  6. concentrationconcentrated under reduced pressure
  7. customThe residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system)

Sources & evidence

ORD record
ord-5080411b5c2e4065b8ec8761f9932dee
Source dataset
uspto-grants-2011_11
Patent number
US08048878B2

Reaction notes

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