4-Toluenesulfonyl chloride → 4-Chloro-2-(difluoromethyl)-1-{[5-(6-fluoro-2-pyridinyl)-1,3,4-oxadiazol-2-yl]methyl}-1H-indole-5-carbonitrile

HRID 913417Notes

Reaction equation

HRID 913417 reaction equation
[F:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.Cl.[Cl:23][C:24]1[C:32]([C:33]#[N:34])=[CH:31][CH:30]=[C:29]2[C:25]=1[CH:26]=[C:27]([CH:40]([F:42])[F:41])[N:28]2[CH2:35][C:36]([NH:38][NH2:39])=O.S(Cl)(C1C=CC(C)=CC=1)(=O)=O>CC#N>[Cl:23][C:24]1[C:32]([C:33]#[N:34])=[CH:31][CH:30]=[C:29]2[C:25]=1[CH:26]=[C:27]([CH:40]([F:41])[F:42])[N:28]2[CH2:35][C:36]1[O:10][C:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([F:1])[N:7]=2)=[N:39][N:38]=1

Participants

6

Reactant 4

HCID 73974-Toluenesulfonyl chloride2×HCID 2260276-Fluoropyridine-2-carboxylic acid3×HCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochloride3×HCID 578001332-[4-Chloro-5-cyano-2-(difluoromethyl)-1H-indol-1-yl]acetohydrazide

Product 1

HCID 249859664-Chloro-2-(difluoromethyl)-1-{[5-(6-fluoro-2-pyridinyl)-1,3,4-oxadiazol-2-yl]methyl}-1H-indole-5-carbonitrileYield 31%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Conditions

Temperature
120 °C

Procedure

To a solution of 6-fluoro-2-pyridinecarboxylic acid (0.006 g, 0.043 mmol) in MeCN (2 mL), under N2, was added EDCl (0.0085 g, 0.044 mmol). After 5 min, 2-[4-chloro-5-cyano-2-(difluoromethyl)-1H-indol-1-yl]acetohydrazide (0.012 g, 0.040 mmol) was added. After 1 h, additional 6-fluoro-2-pyridinecarboxylic acid (0.003 g, 0.02 mmol) and EDCl (0.0077 g, 0.040 mmol) were added. After another 15 min, additional 6-fluoro-2-pyridinecarboxylic acid (0.0014 g, 0.01 mmol) and EDCl (0.0046 g, 0.02 mmol) were added. After another 10 min, TsCl (0.009 g, 0.048 mmol) and P-BEMP (loading 2.2 mmol/g, 0.073 g, 0.16 mmol) were added and the mixture was heated at 120° C. for 20 min. Upon cooling, additional TsCl (0.0046 g, 0.024 mmol) and P-BEMP (0.037 g, 0.08 mmol) were added and the mixture was heated at 120° C. for another 20 min. Upon cooling, the resin was filtered off, washed with EtOAc and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (0-50% EtOAc-hexanes gradient) and the product was crystallized from CH2Cl2-hexanes to give the title compound as a white solid (0.005 g, 31% yield): MS (ES) m/z 404 (M+1).

Workup

  1. waitAfter 1 h
  2. waitAfter another 15 min
  3. waitAfter another 10 min
  4. temperatureUpon cooling
  5. temperaturethe mixture was heated at 120° C. for another 20 min
  6. temperatureUpon cooling
  7. filtrationthe resin was filtered off
  8. washwashed with EtOAc
  9. concentrationthe filtrate was concentrated in vacuo
  10. customThe residue was purified by flash chromatography (0-50% EtOAc-hexanes gradient)
  11. customthe product was crystallized from CH2Cl2-hexanes

Sources & evidence

ORD record
ord-031528c470754ba6a56a2e36d79b8778
Source dataset
uspto-grants-2011_09
Patent number
US08026262B2

Reaction notes

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