Tetrahydrofuran → N-(3-Chloro-4-fluoro-phenyl)-2-{2,6-dichloro-3-[(2,2-dimethyl-propionylamino)-methyl]-phenylamino}-6-(2-fluoroethoxy)-1-methyl-1H-benzimidazole-5-carboxylic acid amide

HRID 410123Notes

Reaction equation

HRID 410123 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:26])[C:11]2[CH:16]=[C:15]([N+:17]([O-])=O)[C:14]([NH:20][CH3:21])=[CH:13][C:12]=2[O:22][CH2:23][CH2:24][F:25])[CH:5]=[CH:6][C:7]=1[F:8].C1COCC1.[Cl:32][C:33]1[C:46]([N:47]=[C:48]=S)=[C:45]([Cl:50])[CH:44]=[CH:43][C:34]=1[CH2:35][NH:36][C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39].CC(C)N=C=NC(C)C>CC#N.[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:11]2[C:12]([O:22][CH2:23][CH2:24][F:25])=[CH:13][C:14]3[N:20]([CH3:21])[C:48]([NH:47][C:46]4[C:45]([Cl:50])=[CH:44][CH:43]=[C:34]([CH2:35][NH:36][C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39])[C:33]=4[Cl:32])=[N:17][C:15]=3[CH:16]=2)=[O:26])[CH:5]=[CH:6][C:7]=1[F:8]

Participants

7

Reactant 4

HCID 8028TetrahydrofuranHCID 12734DiisopropylcarbodiimideHCID 56840192N-[(2,4-dichloro-3-isothiocyanatophenyl)methyl]-2,2-dimethylpropanamideHCID 86669642N-(3-chloro-4-fluorophenyl)-2-(2-fluoroethoxy)-4-methylamino-5-nitro-benzamide

Product 1

HCID 86669641N-(3-Chloro-4-fluoro-phenyl)-2-{2,6-dichloro-3-[(2,2-dimethyl-propionylamino)-methyl]-phenylamino}-6-(2-fluoroethoxy)-1-methyl-1H-benzimidazole-5-carboxylic acid amide

Reagents, catalysts & solvents 2

HCID 23938PalladiumCatalystHCID 6342AcetonitrileSolvent

Procedure

A mixture of N-(3-chloro-4-fluorophenyl)-2-(2-fluoroethoxy)-4-methylamino-5-nitro-benzamide (67.9 mg, 0.176 mmol), Pd/C (15 mg) and 10 mL THF is stirred under a H2-atmosphere (3 bar) for 8 h. The crude mixture is filtered into a flask charged with N-(2,4-dichloro-3-isothiocyanato-benzyl)-2,2-dimethyl-propionamide (59 mg, 0.185 mmol) and concentrated to ˜5 mL. The mixture is stirred for 2 h at rt and concentrated i. vac. The mixture is diluted with MeCN (2.0 mL), DIC (29 μl, 0.186 mmol) is added and it is stirred overnight at rt and 2 h at 60° C. The mixture is cooled to rt and the resulting precipitate is filtered off, washed with MeCN, redissolved in dioxane/MeCN and a few drops of HCOOH and lyophilized.

Workup

  1. filtrationThe crude mixture is filtered into a flask
  2. concentrationconcentrated to ˜5 mL
  3. stirringThe mixture is stirred for 2 h at rt
  4. concentrationconcentrated i
  5. additionis added
  6. stirringit is stirred overnight at rt and 2 h at 60° C
  7. filtrationthe resulting precipitate is filtered off
  8. washwashed with MeCN
  9. dissolutionredissolved in dioxane/MeCN

Sources & evidence

ORD record
ord-e0c0470c2a59449e968e78e9061fe063
Source dataset
uspto-grants-2014_06
Patent number
US08759537B2

Reaction notes

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