Triethylamine → 4-[2-(5-Bromo-4-fluoro-2-methyl-phenyl)-acetylamino]-1-methoxy-piperidine-4-carboxylic acid methyl ester

HRID 1962375Notes

Reaction equation

HRID 1962375 reaction equation
[Br:1][C:2]1[C:3]([F:13])=[CH:4][C:5]([CH3:12])=[C:6]([CH2:8][C:9]([OH:11])=O)[CH:7]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.C(N(CC)CC)C.Cl.[CH3:34][O:35][C:36]([C:38]1([NH2:46])[CH2:43][CH2:42][N:41]([O:44][CH3:45])[CH2:40][CH2:39]1)=[O:37]>O1CCCC1>[CH3:34][O:35][C:36]([C:38]1([NH:46][C:9](=[O:11])[CH2:8][C:6]2[CH:7]=[C:2]([Br:1])[C:3]([F:13])=[CH:4][C:5]=2[CH3:12])[CH2:43][CH2:42][N:41]([O:44][CH3:45])[CH2:40][CH2:39]1)=[O:37]

Participants

6

Reactant 4

HCID 8471TriethylamineHCID 682631,1'-CarbonyldiimidazoleHCID 596146012-(5-Bromo-4-fluoro-2-methylphenyl)acetic acidHCID 666317834-Amino-1-methoxy-piperidine-4-carboxylic acid methyl ester hydrochloride

Product 1

HCID 596145984-[2-(5-Bromo-4-fluoro-2-methyl-phenyl)-acetylamino]-1-methoxy-piperidine-4-carboxylic acid methyl ester

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

A suspension of (5-bromo-4-fluoro-2-methyl-phenyl)-acetic acid (preparation example P5.3) (8.0 g) and 1,1′-carbonyldiimidazole (5.8 g) in tetrahydrofuran (150 ml) was heated at reflux for 30 minutes. Upon cooling to room temperature, triethylamine (9.0 ml) and 4-amino-1-methoxy-piperidine-4-carboxylic acid methyl ester hydrochloride salt (preparation example P1, step P1.3) (13.8 g) were added and warming at reflux was continued for 3 hours. The cold reaction mixture was poured on water/ethyl acetate, the layers separated, the organic phase washed with brine, dried over sodium sulfate and concentrated. The residue was solubilised in ethyl acetate/cyclohexane 3:1 and purified by filtration on alumina. Yield: 6.83 g of 4-[2-(5-bromo-4-fluoro-2-methyl-phenyl)-acetylamino]-1-methoxy-piperidine-4-carboxylic acid methyl ester as a solid, mp: 192-193° C.

Workup

  1. temperaturewas heated
  2. temperatureat reflux for 30 minutes
  3. temperaturewarming
  4. temperatureat reflux
  5. customThe cold reaction mixture
  6. additionwas poured on water/ethyl acetate
  7. customthe layers separated
  8. washthe organic phase washed with brine
  9. dry with materialdried over sodium sulfate
  10. concentrationconcentrated
  11. filtrationpurified by filtration on alumina

Sources & evidence

ORD record
ord-726aca880f3e4f55afcd3871a43e90be
Source dataset
uspto-grants-2013_04
Patent number
US08415369B2

Reaction notes

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