Sodium Methoxide → (3S,4R)-1-(tert-Butoxycarbonyl)-4-(4-fluorophenyl)piperidine-3-carboxylic acid

HRID 2039797Notes

Reaction equation

HRID 2039797 reaction equation
C[O:2][C:3]([C@@H:5]1[C@H:10]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH2:9][CH2:8][N:7]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:6]1)=[O:4].C[O-].[Na+]>C1(C)C=CC=CC=1>[C:21]([O:20][C:18]([N:7]1[CH2:8][CH2:9][C@@H:10]([C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)[C@H:5]([C:3]([OH:4])=[O:2])[CH2:6]1)=[O:19])([CH3:24])([CH3:22])[CH3:23]

Participants

4

Reactant 2

HCID 10942334Sodium MethoxideHCID 58985841(+)-(3R,4R)-4-(4-Fluoro-phenyl)-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester

Product 1

HCID 58985842(3S,4R)-1-(tert-Butoxycarbonyl)-4-(4-fluorophenyl)piperidine-3-carboxylic acidYield 52%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Procedure

A mixture of (+)-(3R,4R)-4-(4-fluoro-phenyl)-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (3.55 g, 10.5 mmol) and sodium methoxide (1.14 g, 21.1 mmol) in 100 ml anhydrous toluene was heated at reflux over night. After cooling to room temperature the reaction mixture was quenched with water and concentrated in vacuo. The residue was dissolved in a mixture of 100 ml 1,4-dioxane and 50 ml 2 M aqueous sodium hydroxide solution. After stirring at RT for 5 h the mixture was diluted with water and washed with two portions of tert-butyl methyl ether. The aqueous layer was cooled to 0° C., acidified to pH 1-2 with ice-cold 1 M aqueous hydrochloric acid solution and extracted with three portions of tert-butyl methyl ether. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. Flash column chromatography and crystallization from heptane/ethyl acetate 9:1 (30 ml) gave the title compound as white crystals (1.76 g, 52%, 97.5% ee).

Workup

  1. temperaturewas heated
  2. temperatureat reflux over night
  3. customwas quenched with water
  4. concentrationconcentrated in vacuo
  5. dissolutionThe residue was dissolved in a mixture of 100 ml 1,4-dioxane and 50 ml 2 M aqueous sodium hydroxide solution
  6. additionwas diluted with water
  7. washwashed with two portions of tert-butyl methyl ether
  8. temperatureThe aqueous layer was cooled to 0° C.
  9. extractionextracted with three portions of tert-butyl methyl ether
  10. dry with materialThe combined organic layers were dried over sodium sulfate
  11. concentrationconcentrated in vacuo
  12. customFlash column chromatography and crystallization from heptane/ethyl acetate 9:1 (30 ml)

Sources & evidence

ORD record
ord-07d3eac5fcfe47d288a8a476d98a928a
Source dataset
uspto-grants-2013_11
Patent number
US08580821B2

Reaction notes

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