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

HRID 514267Notes

Reaction equation

HRID 514267 reaction equation
[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11](=[O:28])[NH:12][CH:13]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[C:14]([F:17])([F:16])[F:15])[NH:8]2)=[CH:4][C:3]=1[C:29]([OH:31])=O.Cl.[NH2:33][C:34]1([C:37]#[N:38])[CH2:36][CH2:35]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([NH:12][CH:13]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:26])([F:27])[F:25])[CH:19]=3)[C:14]([F:16])([F:17])[F:15])=[O:28])[NH:8]2)=[CH:4][C:3]=1[C:29]([NH:33][C:34]1([C:37]#[N:38])[CH2:36][CH2:35]1)=[O:31]

Participants

7

Reactant 4

HCID 79724-MethylmorpholineHCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 145863631-Amino-1-cyclopropanecarbonitrile hydrochlorideHCID 867139846-chloro-2-({2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}carbamoyl)-1H-indole-5-carboxylic acid

Product 1

HCID 867139856-chloro-N5-(1-cyanocyclopropyl)-N2-{2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}-1H-indole-2,5-dicarboxamide

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

6-Chloro-2-({2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}carbamoyl)-1H-indole-5-carboxylic acid (2.74 g, 5.07 mmol, 86% pure) was dissolved in N,N-dimethylformamide (14 ml), and 1-aminocyclopropanecarbonitrile hydrochloride (0.78 g, 6.59 mmol), N-[(1H-benzotriazol-1-yloxy)(dimethylamino)methylene]-N-methylmethanaminium hexafluorophosphate (2.12 g, 5.07 mmol) and 4-methylmorpholine (1.54 g, 15.2 mmol) were added. The reaction mixture was stirred at room temperature for 16 h and then ethyl acetate was added. The organic phase was washed with hydrochloric acid (1 mol/l) and the aqueous phase was once again extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution and the portion which was insoluble in both phases was filtered off. The filtercake is triturated with boiling ethyl acetate (15 ml) and the precipitate is washed with warm ethyl acetate. This leaves 2.01 g (74% of theory) of 6-chloro-N5-(1-cyanocyclopropyl)-N2-{2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}-1H-indole-2,5-dicarboxamide.

Workup

  1. washThe organic phase was washed with hydrochloric acid (1 mol/l)
  2. extractionthe aqueous phase was once again extracted with ethyl acetate
  3. washThe combined organic phases were washed with saturated sodium chloride solution
  4. filtrationwas filtered off
  5. customThe filtercake is triturated with boiling ethyl acetate (15 ml)
  6. washthe precipitate is washed with warm ethyl acetate

Sources & evidence

ORD record
ord-b7f3634c7b3c409c912da625c180f480
Source dataset
uspto-grants-2015_08
Patent number
US09107411B2

Reaction notes

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