1-Hydroxybenzotriazole → N-(5-chloropyridin-2-yl)-3-hydroxy-2-{[4-(1-methyl-4-oxo-1,4-dihydropyridin-3-yl)benzoyl]amino}benzamide hydrochloride

HRID 910621Notes

Reaction equation

HRID 910621 reaction equation
Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[NH2:23][C:24]1[C:39]([OH:40])=[CH:38][CH:37]=[CH:36][C:25]=1[C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][N:30]=1)=[O:27].[CH3:41][N:42]1[CH:47]=[CH:46][C:45](=[O:48])[C:44]([C:49]2[CH:57]=[CH:56][C:52]([C:53](O)=[O:54])=[CH:51][CH:50]=2)=[CH:43]1>O.CN(C)C=O.C(N(CC)CC)C>[ClH:35].[Cl:35][C:32]1[CH:33]=[CH:34][C:29]([NH:28][C:26](=[O:27])[C:25]2[CH:36]=[CH:37][CH:38]=[C:39]([OH:40])[C:24]=2[NH:23][C:53](=[O:54])[C:52]2[CH:51]=[CH:50][C:49]([C:44]3[C:45](=[O:48])[CH:46]=[CH:47][N:42]([CH3:41])[CH:43]=3)=[CH:57][CH:56]=2)=[N:30][CH:31]=1

Participants

8

Reactant 4

HCID 757711-HydroxybenzotriazoleHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 180011272-amino-N-(5-chloro-2-pyridinyl)-3-hydroxybenzamideHCID 575840694-(1-Methyl-4-oxo-1,4-dihydropyridin-3-yl)benzoic acid

Product 1

HCID 67392177N-(5-chloropyridin-2-yl)-3-hydroxy-2-{[4-(1-methyl-4-oxo-1,4-dihydropyridin-3-yl)benzoyl]amino}benzamide hydrochlorideYield 104.8%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 8471TriethylamineSolvent

Procedure

1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (72 mg), 1-hydroxybenzotriazole (62 mg), triethylamine (64 μl) and 2-amino-N-(5-chloro-2-pyridinyl)-3-hydroxybenzamide (121 mg) were added to an N,N-dimethylformamide solution (3 ml) of 4-(1-methyl-4-oxo-1,4-dihydropyridin-3-yl)benzoic acid (88 mg), followed by stirring at room temperature for 14 hours. After this, water (30 ml) was added to the reaction solution, and the precipitated insoluble solid was collected by filtration. The resulting solid was dried at 60° C. under reduced pressure, then tetrahydrofuran (5 ml), N,N-dimethylformamide (1 ml) and acetic acid (104 μl) were added to the solid, followed by stirring under heating at 60° C. for 2 days. After this, the reaction solution was concentrated under reduced pressure, an aqueous saturated sodium hydrogencarbonate solution (30 ml) was added to the residue, followed by extraction with ethyl acetate. The organic layer was washed with an aqueous saturated sodium hydrogencarbonate solution and saturated brine, dried with magnesium sulfate, and concentrated under reduced pressure. The residue was purified by NH-silica gel column chromatography (chloroform:methanol=97:3). The purified product was suspended in ethanol, 1 M hydrochloric acid (324 μl) was added, followed by concentration under reduced pressure. The residue was recrystallized from ethanol to obtain N-(5-chloropyridin-2-yl)-3-hydroxy-2-{[4-(1-methyl-4-oxo-1,4-dihydropyridin-3-yl)benzoyl]amino}benzamide hydrochloride (123 mg).

Workup

  1. filtrationthe precipitated insoluble solid was collected by filtration
  2. customThe resulting solid was dried at 60° C. under reduced pressure
  3. additiontetrahydrofuran (5 ml), N,N-dimethylformamide (1 ml) and acetic acid (104 μl) were added to the solid
  4. stirringby stirring
  5. temperatureunder heating at 60° C. for 2 days
  6. concentrationAfter this, the reaction solution was concentrated under reduced pressure
  7. additionan aqueous saturated sodium hydrogencarbonate solution (30 ml) was added to the residue
  8. extractionfollowed by extraction with ethyl acetate
  9. washThe organic layer was washed with an aqueous saturated sodium hydrogencarbonate solution and saturated brine
  10. dry with materialdried with magnesium sulfate
  11. concentrationconcentrated under reduced pressure
  12. customThe residue was purified by NH-silica gel column chromatography (chloroform:methanol=97:3)
  13. addition1 M hydrochloric acid (324 μl) was added
  14. concentrationfollowed by concentration under reduced pressure
  15. customThe residue was recrystallized from ethanol

Sources & evidence

ORD record
ord-133b185c8fb344a99f002d741e8f4d25
Source dataset
uspto-grants-2011_09
Patent number
US08022208B2

Reaction notes

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