Triethylamine → 2-(3,5-Difluorobenzyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid

HRID 1963320Notes

Reaction equation

HRID 1963320 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([CH:20]=[C:21]([F:23])[CH:22]=1)[CH2:5][CH:6]1[CH2:11][CH:10]([C:12]([O:14]C)=[O:13])[CH2:9][CH2:8][N:7]1[C:16]([O:18][CH3:19])=[O:17].[Br-].[Li+].C(N(CC)CC)C.CC(OC)(C)C>C(#N)C.O>[F:23][C:21]1[CH:20]=[C:4]([CH:3]=[C:2]([F:1])[CH:22]=1)[CH2:5][CH:6]1[CH2:11][CH:10]([C:12]([OH:14])=[O:13])[CH2:9][CH2:8][N:7]1[C:16]([O:18][CH3:19])=[O:17]

Participants

7

Reactant 4

HCID 8471TriethylamineHCID 15413tert-Butyl methyl etherHCID 82050Lithium BromideHCID 66734958Dimethyl 2-(3,5-difluorobenzyl)piperidine-1,4-dicarboxylate

Product 1

HCID 667322412-(3,5-Difluorobenzyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acidYield 85%

Reagents, catalysts & solvents 2

HCID 962WaterSolvent2×HCID 6342AcetonitrileSolvent

Procedure

Dimethyl 2-(3,5-difluorobenzyl)piperidine-1,4-dicarboxylate (8.459 g, 25.84 mmol) was dissolved in acetonitrile (85 mL) and water (1.7 mL). Lithium bromide (17.95 g, 206.74 mmol) and triethylamine (14.33 mL, 103.37 mmol) were added. The suspension was heated to reflux 1.5 h before water (100 mL) and MTBE (300 mL) were added. The organic phase was extracted with water (×2). The combined water phases were acidified to pH 1 with 3.8 M HCl and extracted with MTBE (×2). The combined organic phases were washed with water, dried with MgSO4, filtered through celite and concentrated. The crude product was redissolved in MTBE and washed with 0.1 M HCl (×2) and water. The organic phase was dried with MgSO4 and concentrated to give 2-(3,5-difluorobenzyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (6.88 g, 85%). MS m/z 314 (M+H)+

Workup

  1. temperatureThe suspension was heated
  2. additionwere added
  3. extractionThe organic phase was extracted with water (×2)
  4. extractionextracted with MTBE (×2)
  5. washThe combined organic phases were washed with water
  6. dry with materialdried with MgSO4
  7. filtrationfiltered through celite
  8. concentrationconcentrated
  9. dissolutionThe crude product was redissolved in MTBE
  10. washwashed with 0.1 M HCl (×2) and water
  11. dry with materialThe organic phase was dried with MgSO4
  12. concentrationconcentrated

Sources & evidence

ORD record
ord-71881befdbc6466ca158a8b57cc2677b
Source dataset
uspto-grants-2013_04
Patent number
US08415378B2

Reaction notes

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