Triethylamine → 3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]-4-[2-(4-pyridyl)-1H-benzimidazol-4-yl]carbonylaminobenzamide trichloride

HRID 429672Notes

Reaction equation

HRID 429672 reaction equation
[NH2:1][C:2]1[CH:33]=[CH:32][C:5]([C:6]([N:8]([CH3:31])[C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=2[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([N:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)=[O:23])=[O:7])=[CH:4][C:3]=1[O:34][CH3:35].C(N(CC)CC)C.[N:43]1[CH:48]=[CH:47][C:46]([C:49]2[NH:53][C:52]3[CH:54]=[CH:55][CH:56]=[C:57]([C:58]([Cl:60])=[O:59])[C:51]=3[N:50]=2)=[CH:45][CH:44]=1>ClCCl>[Cl-:60].[Cl-:60].[Cl-:60].[CH3:35][O:34][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:2]=1[NH:1][C:58]([C:57]1[C:51]2[N:50]=[C:49]([C:46]3[CH:47]=[CH:48][N:43]=[CH:44][CH:45]=3)[NH:53][C:52]=2[CH:54]=[CH:55][CH:56]=1)=[O:59])[C:6]([N:8]([CH3:31])[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=1[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]1)=[O:23])=[O:7]

Participants

5

Reactant 3

HCID 8471TriethylamineHCID 183548532-(4-pyridyl)-1H-benzimidazole-4-carbonyl chlorideHCID 183549064-amino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide

Product 1

HCID 183548353-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]-4-[2-(4-pyridyl)-1H-benzimidazol-4-yl]carbonylaminobenzamide trichloride

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

To a solution of 2-(4-pyridyl)-1H-benzimidazole-4-carboxylic acid (155 mg) in dichloromethane (2 ml) was added oxalyl chloride (0.056 ml) and N,N-dimethylformamide (2 drops) and stirred at ambient temperature for 2 hours. The reaction mixture was concentrated in vacuo to give 2-(4-pyridyl)-1H-benzimidazole-4-carbonyl chloride. To a solution of 4-amino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (76.8 mg) and triethylamine (65 mg) in dichloromethane (5 mL) was added 2-(4-pyridyl)-1H-benzimidazole-4-carbonyl chloride in dichloromethane (2 ml) under ice bath cooling and stirred at ambient temperature for 6 hours. After the reaction mixture was concentrated in vacuo, the residue was diluted with chloroform and saturated sodium hydrogen carbonate aqueous solution. The organic layer was separated and washed with brine. The solution was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel (Chromatorex, Fuji Silysia Chemical Ltd.) column chromatography (methanol:chloroform=1:49). To the purified product was added water and 1N hydrochloric acid (0.51 ml). The solution was lyophilized to give 3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]-4-[2-(4-pyridyl)-1H-benzimidazol-4-yl]carbonylaminobenzamide trichloride (120 mg).

Workup

  1. temperaturecooling
  2. concentrationAfter the reaction mixture was concentrated in vacuo
  3. additionthe residue was diluted with chloroform and saturated sodium hydrogen carbonate aqueous solution
  4. customThe organic layer was separated
  5. washwashed with brine
  6. dry with materialThe solution was dried over magnesium sulfate
  7. concentrationconcentrated in vacuo
  8. customThe residue was purified by silica gel (Chromatorex, Fuji Silysia Chemical Ltd.) column chromatography (methanol:chloroform=1:49)
  9. additionTo the purified product was added water and 1N hydrochloric acid (0.51 ml)

Sources & evidence

ORD record
ord-48d1bba6e40547678a8aa48acafc7513
Source dataset
uspto-grants-2001_11
Patent number
US06316482B1

Reaction notes

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