Water → 6-chloro-N5-(2,2-difluoroethyl)-1-ethyl-N2-{2,2,2-trifluoro-1-[4-fluoro-3-(trifluoromethyl)phenyl]ethyl}-1H-indole-2,5-dicarboxamide

HRID 514246Notes

Reaction equation

HRID 514246 reaction equation
[F:1][CH:2]([F:5])[CH2:3][NH2:4].C[Al](C)C.ClC1[CH:19]=[C:18]2[C:14]([CH:15]=[C:16]([C:22](=[O:40])[NH:23][CH:24]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[C:31]([C:36]([F:39])([F:38])[F:37])[CH:30]=3)[C:25]([F:28])([F:27])[F:26])[N:17]2[CH2:20][CH3:21])=[CH:13][C:12]=1[C:41]([O:43]CC)=O.O.Cl[CH2:48][Cl:49]>>[Cl:49][C:48]1[CH:19]=[C:18]2[C:14]([CH:15]=[C:16]([C:22]([NH:23][CH:24]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[C:31]([C:36]([F:37])([F:38])[F:39])[CH:30]=3)[C:25]([F:28])([F:26])[F:27])=[O:40])[N:17]2[CH2:20][CH3:21])=[CH:13][C:12]=1[C:41]([NH:4][CH2:3][CH:2]([F:5])[F:1])=[O:43]

Participants

6

Reactant 5

HCID 962WaterHCID 6344Dichloromethane3×HCID 1362742,2-DifluoroethanamineHCID 16682925TrimethylaluminumHCID 86713970ethyl 6-chloro-1-ethyl-2-({2,2,2-trifluoro-1-[4-fluoro-3-(trifluoromethyl)phenyl]ethyl}carbamoyl)-1H-indole-5-carboxylate

Product 1

HCID 867139716-chloro-N5-(2,2-difluoroethyl)-1-ethyl-N2-{2,2,2-trifluoro-1-[4-fluoro-3-(trifluoromethyl)phenyl]ethyl}-1H-indole-2,5-dicarboxamideYield 81%

Procedure

2,2-Difluoroethanamine (0.12 g, 1.42 mmol) was dissolved under argon in dichloromethane (2 ml). At room temperature, a solution of trimethylaluminium in dichloromethane (0.71 ml, 1.42 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 30 min and then a solution of ethyl 6-chloro-1-ethyl-2-({2,2,2-trifluoro-1-[4-fluoro-3-(trifluoromethyl)phenyl]ethyl}carbamoyl)-1H-indole-5-carboxylate (0.078 g, 0.14 mmol) in dichloromethane (2 ml) was added dropwise. The reaction mixture was heated under reflux for 16 h and, after cooling, water was added. The aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulphate and the solvent was removed under reduced pressure. The residue was chromatographed with cyclohexane/ethyl acetate (4/1) and gave 0.065 g (81% of theory) of 6-chloro-N5-(2,2-difluoroethyl)-1-ethyl-N2-{2,2,2-trifluoro-1-[4-fluoro-3-(trifluoromethyl)phenyl]ethyl}-1H-indole-2,5-dicarboxamide.

Workup

  1. temperatureThe reaction mixture was heated
  2. temperatureunder reflux for 16 h
  3. temperatureafter cooling
  4. extractionThe aqueous phase was extracted three times with ethyl acetate
  5. dry with materialThe combined organic phases were dried over sodium sulphate
  6. customthe solvent was removed under reduced pressure
  7. customThe residue was chromatographed with cyclohexane/ethyl acetate (4/1)

Sources & evidence

ORD record
ord-d36805a538d3439096a2867929ae4c45
Source dataset
uspto-grants-2015_08
Patent number
US09107411B2

Reaction notes

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