Hydrochloric Acid → 6-chloro-N5-(1-cyanocyclopropyl)-1-cyclopropyl-N2-{2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}-1H-indole-2,5-dicarboxamide

HRID 514269Notes

Reaction equation

HRID 514269 reaction equation
[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([NH:13][CH:14]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[C:15]([F:18])([F:17])[F:16])=[O:12])[NH:8]2)=[CH:4][C:3]=1[C:29]([NH:31][C:32]1([C:35]#[N:36])[CH2:34][CH2:33]1)=[O:30].[CH:37]1(B(O)O)[CH2:39][CH2:38]1.C(=O)([O-])[O-].[Na+].[Na+].N1C=CC=CC=1C1C=CC=CN=1.Cl>CN(C)C=O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([NH:13][CH:14]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:28])[F:27])[CH:20]=3)[C:15]([F:16])([F:18])[F:17])=[O:12])[N:8]2[CH:37]2[CH2:39][CH2:38]2)=[CH:4][C:3]=1[C:29]([NH:31][C:32]1([C:35]#[N:36])[CH2:34][CH2:33]1)=[O:30]

Participants

8

Reactant 5

HCID 313Hydrochloric AcidHCID 14742,2'-BipyridineHCID 10340Sodium CarbonateHCID 2760897Cyclopropylboronic acidHCID 867139856-chloro-N5-(1-cyanocyclopropyl)-N2-{2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}-1H-indole-2,5-dicarboxamide

Product 1

HCID 867139876-chloro-N5-(1-cyanocyclopropyl)-1-cyclopropyl-N2-{2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}-1H-indole-2,5-dicarboxamideYield 6.7%

Reagents, catalysts & solvents 2

HCID 8895Cupric acetateCatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
70 °C

Procedure

6-Chloro-N5-(1-cyanocyclopropyl)-N2-{2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}-1H-indole-2,5-dicarboxamide (0.20 g, 0.34 mmol), cyclopropylboronic acid (0.063 g, 0.69 mmol) and sodium carbonate (0.074 g, 0.69 mmol) were initially charged as a suspension in N,N-dimethylformamide (1 ml), and a hot solution of copper(II) acetate (0.064 g, 0.34 mmol) and 2,2′-bipyridyl (0.054 g, 0.34 mmol) was added. The reaction mixture was stirred at 70° C. over 16 h. After cooling, hydrochloric acid (10 ml, 1 mol/l) was added and the organic phase was removed. The aqueous phase was extracted with ethyl acetate (3×) and the combined organic phases were washed with saturated sodium chloride solution and dried over magnesium sulphate, and the solvent was removed under reduced pressure. The residue is purified by means of preparative HPLC (Kromasil100, C18 250×20; eluent: acetonitrile in water, gradient: 10-100%) to obtain 0.013 g (6% of theory) of 6-chloro-N5-(1-cyanocyclopropyl)-1-cyclopropyl-N2-{2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}-1H-indole-2,5-dicarboxamide.

Workup

  1. temperatureAfter cooling
  2. customthe organic phase was removed
  3. extractionThe aqueous phase was extracted with ethyl acetate (3×)
  4. washthe combined organic phases were washed with saturated sodium chloride solution
  5. dry with materialdried over magnesium sulphate
  6. customthe solvent was removed under reduced pressure
  7. customThe residue is purified by means of preparative HPLC (Kromasil100, C18 250×20

Sources & evidence

ORD record
ord-b10ab9aee39640d3a895b53bd726ecbb
Source dataset
uspto-grants-2015_08
Patent number
US09107411B2

Reaction notes

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