2,6-Difluorobenzoic acid → N-[3-(2,6-difluorobenzoyl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-7-yl]cyclopropanecarboxamide

HRID 2201850Notes

Reaction equation

HRID 2201850 reaction equation
[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=O.S(Cl)(Cl)=O.[CH3:16][C:17]1[NH:31][C:20]2=[C:21]([NH:25][C:26]([CH:28]3[CH2:30][CH2:29]3)=[O:27])[N:22]=[CH:23][CH:24]=[C:19]2[CH:18]=1.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl.CO>[F:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:2]([F:1])[C:3]=1[C:4]([C:18]1[C:19]2[C:20](=[C:21]([NH:25][C:26]([CH:28]3[CH2:29][CH2:30]3)=[O:27])[N:22]=[CH:23][CH:24]=2)[NH:31][C:17]=1[CH3:16])=[O:6]

Participants

7

Reactant 4

HCID 97962,6-Difluorobenzoic acidHCID 24386Thionyl ChlorideHCID 6451240Aluminum(III) ChlorideHCID 71061496N-(2-methyl-1H-pyrrolo[2,3-c]pyridin-7-yl)cyclopropanecarboxamide

Product 1

HCID 86720654N-[3-(2,6-difluorobenzoyl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-7-yl]cyclopropanecarboxamideYield 42%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
100 °C

Procedure

To a solution of 2,6-difluorobenzoic acid (176 mg, 1.15 mmol) in dry dichloromethane, was added thionyl chloride (5 mL) and heated at 100° C. for about 3 hours. The reaction mass was concentrated under vacuum. The residual mass was dissolved in dry dichloromethane (3 mL) and added to a well stirred solution of N-(2-methyl-1H-pyrrolo[2,3-c]pyridin-7-yl)cyclopropanecarboxamide (120 mg, 0.55 mmol) in aluminium chloride (743 mg, 5.57 mmol) drop wise. The resulting reaction mixture was stirred overnight at room temperature. After completion, methanol (10 mL) was added cautiously to quench the reaction mass followed by concentration under vacuum. The reaction mass was diluted with water and extracted with ethyl acetate. The combined organic layer was neutralized using aq. sodium bicarbonate solution, washed with brine, dried over anhydrous sodium sulfate, and concentrated. Purification by silica gel (100-200) column chromatography using dichloromethane and methanol gradient as eluent afforded N-[3-(2,6-difluorobenzoyl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-7-yl]cyclopropanecarboxamide (80 mg, 42%).

Workup

  1. concentrationThe reaction mass was concentrated under vacuum
  2. dissolutionThe residual mass was dissolved in dry dichloromethane (3 mL)
  3. additionadded to a well
  4. customThe resulting reaction mixture
  5. customto quench the reaction mass
  6. concentrationfollowed by concentration under vacuum
  7. additionThe reaction mass was diluted with water
  8. extractionextracted with ethyl acetate
  9. washwashed with brine
  10. dry with materialdried over anhydrous sodium sulfate
  11. concentrationconcentrated
  12. customPurification by silica gel (100-200) column chromatography

Sources & evidence

ORD record
ord-f7f568d031584a2e9b3b7167febb4c22
Source dataset
uspto-grants-2016_06
Patent number
US09364466B2

Reaction notes

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