Triethylamine → Tert-butyl 3-((2-(4-fluorophenyl)-2-oxoethyl)carbamoyl)piperidine-1-carboxylate

HRID 874995Notes

Reaction equation

HRID 874995 reaction equation
C(N(CC)CC)C.[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH2:18][CH:17]([C:21]([OH:23])=O)[CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].Cl.[NH2:25][CH2:26][C:27]([C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1)=[O:28].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C1COCC1>[F:35][C:32]1[CH:31]=[CH:30][C:29]([C:27](=[O:28])[CH2:26][NH:25][C:21]([CH:17]2[CH2:18][CH2:19][CH2:20][N:15]([C:13]([O:12][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:14])[CH2:16]2)=[O:23])=[CH:34][CH:33]=1

Participants

6

Reactant 4

HCID 8471TriethylamineHCID 111923Propylphosphonic anhydrideHCID 27356471-((Tert-butoxy)carbonyl)piperidine-3-carboxylic acidHCID 132906662-Amino-1-(4-fluorophenyl)ethan-1-one hydrochloride

Product 1

HCID 69935617Tert-butyl 3-((2-(4-fluorophenyl)-2-oxoethyl)carbamoyl)piperidine-1-carboxylateYield 52.8%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

Triethyl amine (1.52 mL, 10.4 mmol) was added dropwise to a solution of piperidine-1,3-dicarboxylic acid 1-tert-butyl ester (600 mg, 2.6 mmol) and 2-amino-1-(4-fluorophenyl)ethanone hydrochloride (500 mg, 2.6 mmol) in THF (12 mL), followed by T3P (propylphosphonic anhydride) (1.7 mL, 2.6 mmol, 50% in EtOAc) at 0° C. The reaction mixture was stirred 30 min, allowed to warm up to room temperature and stirred for an additional 8 h. The reaction mixture was then concentrated under reduced pressure and diluted with EtOAc. The organic layer was washed with aqueous 10% NaHCO3, water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by purified by column chromatography (silica gel 60-120 mesh, eluent 20-25% EtOAc in petroleum ether) to afford tert-butyl 3-((2-(4-fluorophenyl)-2-oxoethyl)carbamoyl)piperidine-1-carboxylate (500 mg, yield 52%). 1H NMR (400 MHz, DMSO-d6) δ 8.33-8.30 (t, J=5.6 Hz, 1H), 8.08-8.04 (dd, J=8.5 Hz, 5.8 Hz, 2H), 7.39-7.35 (t, J=8.7 Hz, 2H), 4.57-4.56 (m, 2H), 3.99-3.86 (m, 2H), 2.39-2.32 (m, 1H), 1.87-1.84 (m, 1H), 1.66-1.62 (m, 1H), 1.56-1.46 (m, 2H), 1.40 (s, 9H), 1.32-1.23 (m, 2H).

Workup

  1. stirringstirred for an additional 8 h
  2. concentrationThe reaction mixture was then concentrated under reduced pressure
  3. additiondiluted with EtOAc
  4. washThe organic layer was washed with aqueous 10% NaHCO3, water and brine
  5. dry with materialdried over anhydrous sodium sulfate
  6. concentrationconcentrated under reduced pressure
  7. customThe crude product was purified
  8. customby purified by column chromatography (silica gel 60-120 mesh, eluent 20-25% EtOAc in petroleum ether)

Sources & evidence

ORD record
ord-14b45816fc0d4840b8b95f002bab951f
Source dataset
uspto-grants-2015_03
Patent number
US08981084B2

Reaction notes

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