Diisopropylethylamine → Methyl 4'-{[(3S)-1-azabicyclo[2.2.2]oct-3-ylcarbonyl]amino}-1,1'-biphenyl-4-carboxylate

HRID 722191Notes

Reaction equation

HRID 722191 reaction equation
[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([C:9](Cl)=[O:10])[CH2:2]2.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([O:27][CH3:28])=[O:26])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1.C(N(CC)C(C)C)(C)C>C1COCC1.ClCCl>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@H:3]([C:9]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([O:27][CH3:28])=[O:26])=[CH:21][CH:20]=3)=[CH:17][CH:18]=1)=[O:10])[CH2:2]2

Participants

6

Reactant 3

HCID 81531DiisopropylethylamineHCID 7376354'-Aminobiphenyl-4-carboxylic acid methyl esterHCID 11672746(3R)-1-azabicyclo[2.2.2]octane-3-carbonyl chloride

Product 1

HCID 69617735Methyl 4'-{[(3S)-1-azabicyclo[2.2.2]oct-3-ylcarbonyl]amino}-1,1'-biphenyl-4-carboxylate

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent

Procedure

679 mg (3.91 mmol) of (3R)-1-azabicyclo[2.2.2]octane-3-carbonyl chloride, 846 mg (3.73 mmol) methyl 4′-amino-1,1′-biphenyl-4-carboxylate, 963 mg (7.45 mmol) of N,N-diisopropylethylamine and 227 mg (1.86 mmol) of 4-N,N-dimethylaminopyridine are dissolved in 5 ml of THF and stirred at RT overnight and then at 50° C. overnight once again. The reaction mixture is taken up in dichloromethane and water, and the aqueous phase is extracted three times with dichloromethane. The crude product is purified by chromatography on silica gel 60 (mobile phase: dichloromethane/triethylamine 100:1→dichloromethane/methanol/triethylamine 50:50:1). The solvent is removed under reduced pressure. The product is taken up in 1N sodium hydroxide solution and extracted a total of three times with ethyl acetate. The organic phase is dried over magnesium sulfate and freed of solvent under reduced pressure. Finally, the last residues of solvent are removed under high vacuum. 50 mg (4% of theory) of the title compound are obtained.

Workup

  1. customat 50° C.
  2. customovernight
  3. extractionwater, and the aqueous phase is extracted three times with dichloromethane
  4. customThe crude product is purified by chromatography on silica gel 60 (mobile phase: dichloromethane/triethylamine 100:1→dichloromethane/methanol/triethylamine 50:50:1)
  5. customThe solvent is removed under reduced pressure
  6. extractionextracted a total of three times with ethyl acetate
  7. dry with materialThe organic phase is dried over magnesium sulfate
  8. customFinally, the last residues of solvent are removed under high vacuum

Sources & evidence

ORD record
ord-cfce49b6ad004828a2490b8e6a3334b6
Source dataset
uspto-grants-2006_11
Patent number
US07138410B2

Reaction notes

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