4-Bromoaniline → (3R)-N-(4-bromophenyl)-1-azabicyclo[2.2.2]octane-3-carboxamide

HRID 722176Notes

Reaction equation

HRID 722176 reaction equation
[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([C:9]([OH:11])=O)[CH2:2]2.S(Cl)(Cl)=O.[Br:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Br:16][C:17]1[CH:23]=[CH:22][C:20]([NH:21][C:9]([C@@H:3]2[CH:4]3[CH2:5][CH2:6][N:1]([CH2:8][CH2:7]3)[CH2:2]2)=[O:11])=[CH:19][CH:18]=1

Participants

6

Reactant 4

HCID 78074-BromoanilineHCID 24386Thionyl ChlorideHCID 81531DiisopropylethylamineHCID 1380958(3R)-1-azabicyclo[2.2.2]octane-3-carboxylic acid

Product 1

HCID 58742393(3R)-N-(4-bromophenyl)-1-azabicyclo[2.2.2]octane-3-carboxamide

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

9.17 g (about 47.8 mmol) of (R)-1-azabicyclo[2.2.2]octane-3-carboxylic acid are heated together with 160 ml of thionyl chloride under reflux for 1 h. The excess thionyl chloride is removed under reduced pressure, and residues are removed by azeotropic distillation together with toluene. The crude acid chloride obtained in this way is stirred together with 8.19 g (47.60 mmol) of 4-bromoaniline and 24.6 ml (190.4 mmol) of N,N-diisopropylethylamine in 59 ml of DMF at RT for 72 h. The solvent is removed under reduced pressure. The crude product is purified by chromatography on silica gel 60 (mobile phase: dichloromethane→dichloromethane/methanol/triethylamine 70:30:2). The solvent is removed under reduced pressure. Finally, the last residues of solvent are removed under high vacuum. 5.5 g (37% of theory) of the title compound are obtained. The absolute configuration was assigned by crystal structure analysis of single crystals.

Workup

  1. temperatureunder reflux for 1 h
  2. customThe excess thionyl chloride is removed under reduced pressure, and residues
  3. customare removed by azeotropic distillation together with toluene
  4. customThe crude acid chloride obtained in this way
  5. customThe solvent is removed under reduced pressure
  6. customThe crude product is purified by chromatography on silica gel 60 (mobile phase: dichloromethane→dichloromethane/methanol/triethylamine 70:30:2)
  7. customThe solvent is removed under reduced pressure
  8. customFinally, the last residues of solvent are removed under high vacuum

Sources & evidence

ORD record
ord-8ec25364b7574bffad86b86bc3731c1b
Source dataset
uspto-grants-2006_11
Patent number
US07138410B2

Reaction notes

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