Nicotinoyl chloride → N-{3-[2,6-difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-nicotinamide

HRID 60110Notes

Reaction equation

HRID 60110 reaction equation
[NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([NH:10][C:11](=[O:18])[C:12]3[CH:17]=[CH:16][CH:15]=[N:14][CH:13]=3)[CH:9]=[C:4]2[CH:3]=[CH:2]1.[Cl-].[Cl-].[Cl-].[Al+3].[F:23][C:24]1[C:32]([NH:33][S:34]([CH2:37][CH2:38][CH3:39])(=[O:36])=[O:35])=[CH:31][CH:30]=[C:29]([F:40])[C:25]=1[C:26](Cl)=[O:27].C(Cl)(=O)C1C=CC=NC=1>ClCCl.O.O1CCCC1.C(N(CC)CC)C>[F:23][C:24]1[C:32]([NH:33][S:34]([CH2:37][CH2:38][CH3:39])(=[O:35])=[O:36])=[CH:31][CH:30]=[C:29]([F:40])[C:25]=1[C:26]([C:3]1[C:4]2[C:5](=[N:6][CH:7]=[C:8]([NH:10][C:11](=[O:18])[C:12]3[CH:17]=[CH:16][CH:15]=[N:14][CH:13]=3)[CH:9]=2)[NH:1][CH:2]=1)=[O:27]

Participants

9

Reactant 4

HCID 82604Nicotinoyl chlorideHCID 6451240Aluminum(III) ChlorideHCID 580868612,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl chlorideHCID 58368850N-(1H-pyrrolo[2,3-b]pyridin-5-yl)-nicotinamide

Product 1

HCID 53261721N-{3-[2,6-difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-nicotinamide

Reagents, catalysts & solvents 4

HCID 962WaterSolvent2×HCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolventHCID 8471TriethylamineSolvent

Procedure

In a reaction vial, N-(1H-pyrrolo[2,3-b]pyridin-5-yl)-nicotinamide (37, 0.050 g, 0.21 mmol) is dissolved in 2 mL of dichloromethane. Aluminum trichloride (0.1 g, 1 mmol) and 2,6-difluoro-3-(propane-1-sulfonylamino)-benzoyl chloride (38, 0.075 g, 0.25 mmol) are added in one portion, and the reaction is stirred at room temperature for 36 hours, then diluted with water and extracted 3× with ethyl acetate. The organic layers are combined and washed 2× with brine, dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The amide linked at the 5-position is lost, so half the material is mixed with 3 mL of triethylamine in 2 mL of tetrahydrofuran and nicotinoyl chloride (36, 0.036 g, 0.25 mmol) is added and stirred at room temperature overnight. The reaction is diluted with water and extracted 3× with ethyl acetate. The organic layers are combined and washed 2× with brine, dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is further purified by reverse phase chromatography and the resulting material confirmed by LC-MS.

Workup

  1. extractionextracted 3× with ethyl acetate
  2. washwashed 2× with brine
  3. dry with materialdried over sodium sulfate
  4. filtrationfiltered
  5. concentrationthe filtrate concentrated under vacuum
  6. additionis added
  7. stirringstirred at room temperature overnight
  8. extractionextracted 3× with ethyl acetate
  9. washwashed 2× with brine
  10. dry with materialdried over sodium sulfate
  11. filtrationfiltered
  12. concentrationthe filtrate concentrated under vacuum
  13. customThe resulting material is further purified by reverse phase chromatography

Sources & evidence

ORD record
ord-85fa2634a78c4b4f9fce70bf9e55d550
Source dataset
uspto-grants-2016_09
Patent number
US09440969B2

Reaction notes

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