Hydrochloric Acid → 1-(Tert-butoxycarbonyl)-4-(4-chloro-3-fluorophenyl)piperidine-4-carboxylic acid

HRID 2200289Notes

Reaction equation

HRID 2200289 reaction equation
[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:21]#N)[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[F:23].Cl.[OH-:25].[Na+].CC(OC(OC(OC(C)(C)C)=O)=O)(C)C.[OH2:42]>O1CCOCC1>[C:17]([O:16][C:14]([N:11]1[CH2:12][CH2:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([F:23])[CH:4]=2)([C:21]([OH:42])=[O:25])[CH2:9][CH2:10]1)=[O:15])([CH3:20])([CH3:19])[CH3:18]

Participants

7

Reactant 5

HCID 313Hydrochloric AcidHCID 962WaterHCID 14798Sodium HydroxideHCID 90495Di-tert-butyl dicarbonateHCID 66618032Tert-butyl 4-(4-chloro-3-fluorophenyl)-4-cyanopiperidine-1-carboxylate

Product 1

HCID 666180441-(Tert-butoxycarbonyl)-4-(4-chloro-3-fluorophenyl)piperidine-4-carboxylic acidYield 43.96%

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

Procedure

Tert-butyl 4-(4-chloro-3-fluorophenyl)-4-cyanopiperidine-1-carboxylate (1.96 g, 5.785 mmol) was dissolved in concentrated HCl (48.21 mL, 578.5 mmol), heated to reflux, and then stirred over the weekend (approximately 60 hours). The reaction mixture was cooled to room temperature, transferred to a separatory funnel, and washed with ether. The aqueous layer was concentrated on a rotary evaporator and dried on a high vacuum line. The resulting solids were dissolved in 10% NaOH (9.255 g, 23.14 mmol), dioxane (40 mL) was added, followed by a Boc2O addition (1.326 g, 6.074 mmol). The reaction mixture was stirred at room temperature overnight (16 hours). The reaction mixture was then diluted with H2O and washed with ether. The aqueous layer was acidified with solid KHSO4, and then extracted with DCM. The combined extracts were dried (Na2SO4), filtered, concentrated and dried on a high vacuum line to give 1-(tert-butoxycarbonyl)-4-(4-chloro-3-fluorophenyl)piperidine-4-carboxylic acid (0.910 g, 43.96% yield) as a foam. LC/MS (APCI−) m/z 713 [2M−H]−.

Workup

  1. temperatureheated
  2. temperatureto reflux
  3. customtransferred to a separatory funnel
  4. washwashed with ether
  5. concentrationThe aqueous layer was concentrated on a rotary evaporator
  6. customdried on a high vacuum line
  7. stirringThe reaction mixture was stirred at room temperature overnight (16 hours)
  8. washwashed with ether
  9. extractionextracted with DCM
  10. dry with materialThe combined extracts were dried (Na2SO4)
  11. filtrationfiltered
  12. concentrationconcentrated
  13. customdried on a high vacuum line

Sources & evidence

ORD record
ord-7dcfc38e660e480fa45144705fcc7be2
Source dataset
uspto-grants-2016_06
Patent number
US09359340B2

Reaction notes

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