Hydrochloric Acid → N-(4,4-dimethylcyclohexyl)-4,6-difluoro-1H-indole-2-carboxamide

HRID 62660Notes

Reaction equation

HRID 62660 reaction equation
[F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:12]([OH:14])=O)[NH:6]2.[CH3:15][C:16]1([CH3:23])[CH2:21][CH2:20][CH:19]([NH2:22])[CH2:18][CH2:17]1.Cl.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:15][C:16]1([CH3:23])[CH2:21][CH2:20][CH:19]([NH:22][C:12]([C:5]2[NH:6][C:7]3[C:3]([CH:4]=2)=[C:2]([F:1])[CH:10]=[C:9]([F:11])[CH:8]=3)=[O:14])[CH2:18][CH2:17]1

Participants

7

Reactant 5

HCID 313Hydrochloric AcidHCID 81531DiisopropylethylamineHCID 4210544,4-Dimethylcyclohexan-1-amineHCID 34514414,6-difluoro-1H-indole-2-carboxylic acidHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)

Product 1

HCID 72711190N-(4,4-dimethylcyclohexyl)-4,6-difluoro-1H-indole-2-carboxamide

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

A mixture of 4,6-difluoro-1H-indole-2-carboxylic acid (5 g, 25.36 mmol×4 batches) and 4,4-dimethylcyclohexylamine.HCl (I-6b: 4.6 g, 28.10 mmol, for each batch) in dry DMF (75 mL) was cooled to 0° C. and HATU (11.62 g, 30.57 mmol, for each batch) was added followed by DIPEA (22 mL, 127.9 mmol, for each batch) drop-wise and the mixture was stirred under inert atmosphere at room temperature for 17h. Ice-cold water (50 mL) was added to the reaction mixture with vigorous stirring. The precipitated solid was collected by filtration and dried thoroughly. The crude compound obtained from combining all the batches was purified by column chromatography over silica gel (100-200 mesh) using a solvent gradient of 30%-40% ethyl acetate in hexanes as eluent to afford 23 g of off-white solid. It was triturated with ether/hexanes (3:7) in five cycles to afford 20.6 g (66.2%) of 4,6-difluoro-N-(4,4-dimethylcyclohexyl)-1H-indole-2-carboxamide (2A) as an white solid.

Workup

  1. filtrationThe precipitated solid was collected by filtration
  2. customdried thoroughly
  3. customThe crude compound obtained
  4. customwas purified by column chromatography over silica gel (100-200 mesh)

Sources & evidence

ORD record
ord-abc1b8fcc0b841ddae7184ed5c8b7e43
Source dataset
uspto-grants-2016_09
Patent number
US09447039B2

Reaction notes

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