Citric Acid → N-[(S)-1-[(S)-2-(3-butoxy-3-phenylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethylcarbamoyl]-2-(1H-imidazol-4-yl)ethyl]benzamide

HRID 540370Notes

Reaction equation

HRID 540370 reaction equation
ClCCl.F[C:5](F)(F)[C:6]([OH:8])=O.[C:11]([NH:19][C@@H:20]([CH2:37][C:38]1[N:39]=[CH:40][NH:41][CH:42]=1)[C:21]([NH:23][C@@H:24]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)[C:25]([OH:27])=O)=[O:22])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CN(C(ON1N=NC2[CH:54]=[CH:55][CH:56]=[CH:57][C:52]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C[CH2:66][N:67](C(C)C)[CH:68](C)C.FC(F)(F)C(O)=O.[CH2:81](OC1(C2C=CC=CC=2)CNC1)[CH2:82][CH2:83][CH3:84].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C.C(Cl)Cl.CN(C=O)C>[CH2:81]([O:8][C:6]1([C:5]2[CH:54]=[CH:55][CH:56]=[CH:57][CH:52]=2)[CH2:68][N:67]([C:25](=[O:27])[C@@H:24]([NH:23][C:21]([C@@H:20]([NH:19][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:37][C:38]2[N:39]=[CH:40][NH:41][CH:42]=2)=[O:22])[CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)[CH2:66]1)[CH2:82][CH2:83][CH3:84]

Participants

9

Reactant 6

HCID 311Citric AcidHCID 81531DiisopropylethylamineHCID 2733207O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborateHCID 21863450Trifluoroacetic acid methylene chlorideHCID 669880053-Butoxy-3-phenylazetidine trifluoroacetateHCID 178490239HCID 178490239, compound

Product 1

HCID 178450016N-[(S)-1-[(S)-2-(3-butoxy-3-phenylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethylcarbamoyl]-2-(1H-imidazol-4-yl)ethyl]benzamideYield 60%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 22350042dichloromethane N,N-dimethylformamideSolvent

Procedure

1 ml of a 3/2 dichloromethane/trifluoroacetic acid solution is added to 200 mg (0.343 mmol) of (S)-2-[(S)-2-benzoylamino-3-(1H-imidazol-4-yl)propionylamino]-3-(4-methoxyphenyl)propanoic acid. After stirring at ambient temperature for 1 hour, the solvents are evaporated off. The residue obtained is dissolved in 5 ml of DMF, and 110 mg (0.343 mmol) of TBTU and 2.37 ml of DIEA are added. The reaction medium is left to stir for 15 minutes at ambient temperature. 47 mg (0.147 mmol) of 3-butoxy-3-phenylazetidine trifluoroacetate dissolved in 5 ml of a 1/4 DCM/DMF solution are added dropwise and stirred at ambient temperature for 16 hours. A 5% citric acid solution is added, followed by extraction with dichloromethane. The organic phase is washed with a saturated solution of potassium hydrogen carbonate. The organic phase is dried and evaporated to dryness. The crude product obtained is purified by silica gel chromatography (eluent 9/1 dichloromethane/methanol). 55 mg of N—[(S)-1-[(S)-2-(3-butoxy-3-phenylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethylcarbamoyl]-2-(1H-imidazol-4-yl)ethyl]benzamide are obtained in the form of a white powder with a yield of 60%.

Workup

  1. customthe solvents are evaporated off
  2. customThe residue obtained
  3. waitThe reaction medium is left
  4. stirringto stir for 15 minutes at ambient temperature
  5. additionare added dropwise
  6. stirringstirred at ambient temperature for 16 hours
  7. extractionfollowed by extraction with dichloromethane
  8. washThe organic phase is washed with a saturated solution of potassium hydrogen carbonate
  9. customThe organic phase is dried
  10. customevaporated to dryness
  11. customThe crude product obtained
  12. customis purified by silica gel chromatography (eluent 9/1 dichloromethane/methanol)

Sources & evidence

ORD record
ord-8d996c0ea2cc45998d451dd88a0d9220
Source dataset
uspto-grants-2014_10
Patent number
US08871187B2

Reaction notes

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