Ethyl bromoacetate → HCID 86616394, compound

HRID 1367178Notes

Reaction equation

HRID 1367178 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[NH:14][C:13](=[O:15])[C:12]([CH3:17])([CH3:16])[C@@H:11]([OH:18])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[H-].[Na+].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>C1COCC1>[F:8][C:6]1[CH:5]=[C:4]([C@H:9]2[N:14]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:13](=[O:15])[C:12]([CH3:16])([CH3:17])[C@@H:11]([OH:18])[CH2:10]2)[CH:3]=[C:2]([F:1])[CH:7]=1

Participants

5

Reactant 3

HCID 7748Ethyl bromoacetateHCID 24758Sodium hydrideHCID 66973592cis-6-(3,5-Difluorophenyl)-4-hydroxy-3,3-dimethylpiperidin-2-one

Product 1

HCID 86616394HCID 86616394, compound

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a solution of cis-6-(3,5-difluorophenyl)-4-hydroxy-3,3-dimethylpiperidin-2-one from Step B (17.1 g, 67.0 mmol) in THF (400 mL) at 0° C. was added NaH (60% dispersion in oil, 4.91 g, 73.7 mmol). After 30 min, ethyl bromoacetate (8.20 mL, 73.7 mmol) was added. After 30 min, the reaction mixture was quenched with saturated aqueous NH4Cl (100 mL), diluted with H2O (700 mL) and brine (100 mL) and extracted with EtOAc (700 mL). The organic extract was dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 0:100, to give the alcohol as a mixture of four isomers. Additional purification was achieved by HPLC, using a ChiralPak AD column and eluting with hexane:EtOH:Et2NH—90:10:0.1. The first major peak to elute was a mixture of ethyl [(4S,6S)-6-(3,5-difluorophenyl)-4-hydroxy-3,3-dimethyl-2-oxopiperidin-1-yl]acetate and ethyl [(4S,6R)-6-(3,5-difluorophenyl)-4-hydroxy-3,3-dimethyl-2-oxopiperidin-1-yl]acetate (ca. 5:1). The second major peak to elute was a mixture of ethyl [(4R,6R)-6-(3,5-difluorophenyl)-4-hydroxy-3,3-dimethyl-2-oxopiperidin-1-yl]acetate and ethyl [(4R,6S)-6-(3,5-difluorophenyl)-4-hydroxy-3,3-dimethyl-2-oxopiperidin-1-yl]acetate (ca. 3:1). Further purification of the second major peak was achieved by SFC, using a ChiralPak AD column and eluting with CO2:MeOH:Et2NH—90:10:0.1, to give ethyl [(4R,6R)-6-(3,5-difluorophenyl)-4-hydroxy-3,3-dimethyl-2-oxopiperidin-1-yl]acetate, which eluted first, and ethyl [(4R,6S)-6-(3,5-difluorophenyl)-4-hydroxy-3,3-dimethyl-2-oxopiperidin-1-yl]acetate, which eluted second. Further purification of the first major peak was achieved by SFC, using a ChiralPak AD column and eluting with CO2:MeOH:Et2NH—90:10:0.1, to give ethyl [(4S,6R)-6-(3,5-difluorophenyl)-4-hydroxy-3,3-dimethyl-2-oxopiperidin-1-yl]acetate, which eluted first, and ethyl [(4S,6S)-6-(3,5-difluorophenyl)-4-hydroxy-3,3-dimethyl-2-oxopiperidin-1-yl]acetate, which eluted second, the title compound. MS: m/z=342 (M+1).

Workup

  1. waitAfter 30 min
  2. customthe reaction mixture was quenched with saturated aqueous NH4Cl (100 mL)
  3. additiondiluted with H2O (700 mL) and brine (100 mL)
  4. extractionextracted with EtOAc (700 mL)
  5. extractionThe organic extract
  6. dry with materialwas dried over Na2SO4
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. customThe crude product was purified by silica gel chromatography
  10. washeluting with a gradient of hexane

Sources & evidence

ORD record
ord-9c83854fa00643589436f371566edb10
Source dataset
uspto-grants-2011_02
Patent number
US07893079B2

Reaction notes

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