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4-Methylmorpholine → 1-[2-(4-Fluoro-3-trifluoromethyl-phenyl)-2-oxo-ethylcarbamoyl]-piperidine-4-carboxylic acid tert-butyl ester

HRID 2194477
Notes
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Reaction equation

HRID 2194477 reaction equation
CN1CCOCC1.C(O[C:13]([N:15]1[CH2:20][CH2:19][CH:18]([C:21]([OH:23])=[O:22])[CH2:17][CH2:16]1)=[O:14])(C)(C)C.ClC(O[CH2:28][CH:29]([CH3:31])[CH3:30])=O.Cl.[NH2:33][CH2:34][C:35]([C:37]1[CH:42]=[CH:41][C:40]([F:43])=[C:39]([C:44]([F:47])([F:46])[F:45])[CH:38]=1)=[O:36]>O1CCCC1>[C:29]([O:23][C:21]([CH:18]1[CH2:17][CH2:16][N:15]([C:13](=[O:14])[NH:33][CH2:34][C:35]([C:37]2[CH:42]=[CH:41][C:40]([F:43])=[C:39]([C:44]([F:47])([F:45])[F:46])[CH:38]=2)=[O:36])[CH2:20][CH2:19]1)=[O:22])([CH3:31])([CH3:30])[CH3:28]
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

6

Reactant 4

HCID 79724-MethylmorpholineHCID 62365Isobutyl chloroformateHCID 3928711-(tert-Butoxycarbonyl)-4-piperidinecarboxylic acidHCID 666499872-Amino-1-[4-fluoro-3-(trifluoromethyl)phenyl]ethanone Hydrochloride

Product 1

HCID 666498871-[2-(4-Fluoro-3-trifluoromethyl-phenyl)-2-oxo-ethylcarbamoyl]-piperidine-4-carboxylic acid tert-butyl ester
Yield 70.8%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-10 °C

Procedure

Add N-methylmorpholine (3 equiv; 631.52 mmoles; 69.66 mL) to a solution of piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (1.20 equiv; 252.61 mmoles; 57.92 g) in tetrahydrofuran (THF) (400 mL). Cool the mixture to −10° C. with a dry ice-acetone bath. Add isobutyl chloroformate (1.1 equiv; 231.56 mmoles; 30.26 mL) dropwise while maintaining the temperature below −5° C. After 30 min at −5°-10° C., add 2-amino-1-(4-fluoro-3-trifluoromethyl-phenyl)-ethanone hydrochloride (54.23 g; 1.00 equiv; 210.51 mmoles) suspended in THF (300 mL) and stir the mixture in the bath at −5° C. for 20 min. Stir for 1 hour at RT. Add water and EtOAc, then wash the organic layer with water and saturated aqueous sodium chloride. Dry over MgSO4, filter and remove solvent in vacuo. Suspend the crude in MTBE and stir for 2 hours. Filter the solid and dry in vacuo to give 1-[2-(4-Fluoro-3-trifluoromethyl-phenyl)-2-oxo-ethylcarbamoyl]-piperidine-4-carboxylic acid tert-butyl ester (64.44 g; 70.79% yield).

Workup

  1. stirringStir for 1 hour at RT
  2. washAdd water and EtOAc, then wash the organic layer with water and saturated aqueous sodium chloride
  3. dry with materialDry over MgSO4
  4. filtrationfilter
  5. customremove solvent in vacuo
  6. stirringstir for 2 hours
  7. filtrationFilter the solid
  8. customdry in vacuo

Sources & evidence

ORD record
ord-6c15153f4ced4f64aee210d2a6128428
Source dataset
uspto-grants-2012_12
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08334293B2

Reaction notes

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On this pageParticipantsConditionsProcedureWorkupSources & evidenceReaction notes