1-Hydroxybenzotriazole → HCID 67026107, compound

HRID 1509522Notes

Reaction equation

HRID 1509522 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([N:14]([C:19]([C:21]2[N:25]([CH2:26][CH2:27][CH2:28][CH2:29][O:30][CH3:31])[C:24]3[CH:32]=[CH:33][CH:34]=[CH:35][C:23]=3[N:22]=2)=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:11][C@@H:10]([C:36]([OH:38])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[NH:40][C:41](=[NH:43])[CH3:42].N1(O)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[CH3:31][O:30][CH2:29][CH2:28][CH2:27][CH2:26][N:25]1[C:24]2[CH:32]=[CH:33][CH:34]=[CH:35][C:23]=2[N:22]=[C:21]1[C:19]([N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C@H:12]1[CH2:11][C@@H:10]([C:36]2[O:38][N:43]=[C:41]([CH3:42])[N:40]=2)[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13]1)=[O:20]

Participants

7

Reactant 5

HCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 58355779(3R,5S)-(tert-butoxycarbonyl)-5-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxylic acidHCID 178465666HCID 178465666, compound

Product 1

HCID 67026107HCID 67026107, compoundYield 114.1%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

(3R,5S)-1-(tert-Butoxycarbonyl)-5-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxylic acid (265 mg), N-hydroxy acetamidine (56 mg), 1H-benzotriazol-1-ol (95 mg) and N,N-diisopropylethylamine (259 μl)) were dissolved in DMF (10 ml), WSC.HCl (144 mg) was added and the mixture was stirred at room temperature for 15 hr. The reaction mixture was concentrated under reduced pressure, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in toluene (15 ml), and the mixture was refluxed under heating for 15 hr. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (1:1) was concentrated under reduced pressure to give tert-butyl (3S,5R)-3-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(3-methyl-1,2,4-oxadiazol-5-yl)piperidine-1-carboxylate (324 mg). The obtained tert-butyl (3S,5R)-3-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(3-methyl-1,2,4-oxadiazol-5-yl)piperidine-1-carboxylate was dissolved in 4M hydrogen chloride-ethyl acetate (5 ml), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated, and the residue was diluted with aqueous sodium bicarbonate, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and a fraction eluted with ethyl acetate was concentrated under reduced pressure. The residue was dissolved in methanol (3 ml), 4M Hydrogen chloride-ethyl acetate (1 ml) was added and the mixture was stirred for 5 min. The solvent was evaporated under reduced pressure to give the object product (74 mg).

Workup

  1. concentrationThe reaction mixture was concentrated under reduced pressure
  2. extractionthe mixture was extracted with ethyl acetate
  3. washThe extract was washed with saturated brine
  4. dry with materialdried over anhydrous magnesium sulfate
  5. customThe solvent was evaporated under reduced pressure
  6. dissolutionThe residue was dissolved in toluene (15 ml)
  7. temperaturethe mixture was refluxed
  8. temperatureunder heating for 15 hr
  9. temperatureThe reaction mixture was cooled to room temperature
  10. concentrationconcentrated under reduced pressure
  11. washa fraction eluted with ethyl acetate-hexane (1:1)
  12. concentrationwas concentrated under reduced pressure

Sources & evidence

ORD record
ord-e04ea8180ea947a994753d6f2ddb5b60
Source dataset
uspto-grants-2015_12
Patent number
US09221836B2

Reaction notes

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