Triethylamine → 2-(3-Fluoro-4-(trifluoromethyl)benzyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid

HRID 1963334Notes

Reaction equation

HRID 1963334 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[C:23]([F:26])([F:25])[F:24])[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>C(#N)C.O>[F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[C:23]([F:26])([F:24])[F:25])[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

6

Reactant 3

HCID 8471TriethylamineHCID 82050Lithium BromideHCID 66734842Dimethyl 2-(3-fluoro-4-(trifluoromethyl)benzyl)piperidine-1,4-dicarboxylate

Product 1

HCID 667322622-(3-Fluoro-4-(trifluoromethyl)benzyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acidYield 95%

Reagents, catalysts & solvents 2

HCID 962WaterSolvent2×HCID 6342AcetonitrileSolvent

Procedure

To a solution of dimethyl 2-(3-fluoro-4-(trifluoromethyl)benzyl)piperidine-1,4-dicarboxylate (7.17 g, 19.00 mmol) in acetonitrile (60 mL) and water (1.2 mL) was added lithium bromide (13.20 g, 152.02 mmol) and triethylamine (10.54 mL, 76.01 mmol). The resulting mixture was heated under reflux for 2 h, then cooled to room temperature. Water was added and acetonitrile removed by evaporation. The aqueous layer was further diluted with water, then washed with MTBE. The organic layer was extracted with water. The combined aqueous layers were acidified with 3.8 M HCl, a colorless precipitate formed. The solids were extracted with DCM 6 times. The aqueous layer was extracted twice again with DCM. The combined organic layers were dried over MgSO4 and evaporated. 2-(3-Fluoro-4-(trifluoromethyl)benzyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (6.56 g, 95%) was isolated as an off-white solid. MS m/z 364 (M+H)+

Workup

  1. temperatureThe resulting mixture was heated
  2. temperatureunder reflux for 2 h
  3. customacetonitrile removed by evaporation
  4. additionThe aqueous layer was further diluted with water
  5. washwashed with MTBE
  6. extractionThe organic layer was extracted with water
  7. customa colorless precipitate formed
  8. extractionThe solids were extracted with DCM 6 times
  9. extractionThe aqueous layer was extracted twice again with DCM
  10. dry with materialThe combined organic layers were dried over MgSO4
  11. customevaporated

Sources & evidence

ORD record
ord-f371030e65bc42adbd915fd3ffd5d920
Source dataset
uspto-grants-2013_04
Patent number
US08415378B2

Reaction notes

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