ethyl 2-(4,6,7-trifluoro-1H-benzoimidazol-2-yl)propionate → ethyl 2-(2-{2-[1-(4,6,7-trifluoro-1H-benzoimidazol-2-yl)ethyl]-3-methyl-3H-benzoimidazol-5-carbonylamino}ethoxy}benzoate

HRID 412729Notes

Reaction equation

HRID 412729 reaction equation
[F:1][C:2]1[C:10]2[N:9]=[C:8]([CH:11]([CH3:17])[C:12](OCC)=O)[NH:7][C:6]=2[C:5]([F:18])=[C:4]([F:19])[CH:3]=1.[NH2:20][C:21]1[CH:43]=[CH:42][C:24]([C:25]([NH:27][CH2:28][CH2:29][O:30][C:31]2[CH:41]=[CH:40][CH:39]=[CH:38][C:32]=2[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:26])=[CH:23][C:22]=1[NH:44][CH3:45]>CN1C(=O)N(C)CCC1>[F:1][C:2]1[C:10]2[N:9]=[C:8]([CH:11]([C:12]3[N:44]([CH3:45])[C:22]4[CH:23]=[C:24]([C:25]([NH:27][CH2:28][CH2:29][O:30][C:31]5[CH:41]=[CH:40][CH:39]=[CH:38][C:32]=5[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:26])[CH:42]=[CH:43][C:21]=4[N:20]=3)[CH3:17])[NH:7][C:6]=2[C:5]([F:18])=[C:4]([F:19])[CH:3]=1

Participants

4

Reactant 2

HCID 18537794ethyl 2-(4,6,7-trifluoro-1H-benzoimidazol-2-yl)propionateHCID 18537992Ethyl 2-[2-(4-amino-3-methylaminobenzoylamino)ethoxy]benzoate

Product 1

HCID 18537795ethyl 2-(2-{2-[1-(4,6,7-trifluoro-1H-benzoimidazol-2-yl)ethyl]-3-methyl-3H-benzoimidazol-5-carbonylamino}ethoxy}benzoateYield 49%

Reagents, catalysts & solvents 1

HCID 816462(1H)-Pyrimidinone, tetrahydro-1,3-dimethyl-Solvent

Conditions

Temperature
195 °C

Procedure

Ethyl 2-(4,6,7-trifluoro-1H-benzoimidazol-2-yl)propionate (988 mg, 3.63 mmol) and ethyl 2-[2-(4-amino-3-methylaminobenzoylamino)ethoxy]benzoate (1.3 g, 3.63 mmol) were combined and placed under vacuum for 4 hours and then further combined with DMPU (4 ml). The mixture was stirred until in solution, evacuated overnight under high vacuum to remove residual gases, heated to 195° C. under a nitrogen stream for 4 hours, cooled to room temperature and partitioned between ethyl acetate and water. The organic layer was separated and washed with brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica (stepwise gradient of 100% hexane to 100% ethyl acetate) and further purified by crystallization from MeOH/THF/water to provide ethyl 2-(2-{2-[1-(4,6,7-trifluoro-1H-benzoimidazol-2-yl)ethyl]-3-methyl-3H-benzoimidazol-5-carbonylamino}ethoxy}benzoate (1.0 g, 49%) as a white crystalline solid:

Workup

  1. customevacuated overnight under high vacuum
  2. customto remove residual gases
  3. temperaturecooled to room temperature
  4. custompartitioned between ethyl acetate and water
  5. customThe organic layer was separated
  6. washwashed with brine
  7. dry with materialdried over sodium sulfate
  8. concentrationconcentrated
  9. customThe residue was purified by chromatography on silica (stepwise gradient of 100% hexane to 100% ethyl acetate) and
  10. customfurther purified by crystallization from MeOH/THF/water

Sources & evidence

ORD record
ord-99b895b1d69643d581a6e128ad22344b
Source dataset
uspto-grants-2003_05
Patent number
US06562854B2

Reaction notes

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