1-Hydroxybenzotriazole → (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-[N-[(1S)-1-phenyl-1-ethyl]amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile

HRID 227984Notes

Reaction equation

HRID 227984 reaction equation
[CH2:1]([O:8][C:9]([N:11]([CH2:23][C:24]([N:26]1[CH2:30][C@@H:29]([F:31])[CH2:28][C@H:27]1[C:32]#[N:33])=[O:25])[C:12]12[CH2:19][CH2:18][C:15]([C:20]([OH:22])=O)([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[C:56]1([C@@H:62]([NH2:64])[CH3:63])[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1>CN(C)C=O>[CH2:1]([O:8][C:9]([N:11]([CH2:23][C:24]([N:26]1[CH2:30][C@@H:29]([F:31])[CH2:28][C@H:27]1[C:32]#[N:33])=[O:25])[C:12]12[CH2:17][CH2:16][C:15]([C:20]([NH:64][C@H:62]([C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)[CH3:63])=[O:22])([CH2:18][CH2:19]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1

Participants

6

Reactant 4

HCID 757711-HydroxybenzotriazoleHCID 758181-Phenethylamine, (-)-HCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 68842664(2S,4S)-1-[[N-Benzyloxycarbonyl-N-[4-carboxybicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile

Product 1

HCID 68843742(2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-[N-[(1S)-1-phenyl-1-ethyl]amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

(2S,4S)-1-[[N-Benzyloxycarbonyl-N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (40.0 mg) and 1-hydroxybenzotriazole (20.1 mg) were dissolved in N,N-dimethylformamide (0.8 mL). While the solution was chilled in an ice bath, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (41.9 mg) was added and the mixture was stirred at room temperature for 2 hours. Subsequently, (1S)-1-phenylethylamine (14.5 μL) was added and the mixture was further stirred at room temperature for 16.5 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was dissolved in dichloromethane (2 mL). The dichloromethane solution washed sequentially with 0.1 mol/L hydrochloric acid, saturated aqueous sodium bicarbonate solution and saturated brine. The solution then was dried over anhydrous sodium sulfate and was concentrated under reduced pressure. The resulting residue was purified by a silica gel column (eluant:ethyl acetate) to give ((2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-[N-[(1S)-1-phenyl-1-ethyl]amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (51.5 mg).

Workup

  1. temperatureWhile the solution was chilled in an ice bath
  2. stirringthe mixture was further stirred at room temperature for 16.5 hours
  3. concentrationThe reaction mixture was concentrated under reduced pressure
  4. dissolutionthe resulting residue was dissolved in dichloromethane (2 mL)
  5. washThe dichloromethane solution washed sequentially with 0.1 mol/L hydrochloric acid, saturated aqueous sodium bicarbonate solution and saturated brine
  6. dry with materialThe solution then was dried over anhydrous sodium sulfate
  7. concentrationwas concentrated under reduced pressure
  8. customThe resulting residue was purified by a silica gel column (eluant:ethyl acetate)

Sources & evidence

ORD record
ord-09685a7f407c4e7a915e58436cb2a932
Source dataset
uspto-grants-2009_07
Patent number
US07560569B2

Reaction notes

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