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

HRID 913414Notes

Reaction equation

HRID 913414 reaction equation
[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:17]([F:19])[F:18])[N:6]2[CH2:13][C:14]([OH:16])=O.CCN=C=NCCCN(C)C.Cl.[F:32][C:33]1[CH:42]=[C:41]([F:43])[CH:40]=[CH:39][C:34]=1[C:35]([NH:37][NH2:38])=O.S(Cl)(C1C=CC(C)=CC=1)(=O)=O>ClCCCl>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:17]([F:19])[F:18])[N:6]2[CH2:13][C:14]1[O:16][C:35]([C:34]2[CH:39]=[CH:40][C:41]([F:43])=[CH:42][C:33]=2[F:32])=[N:37][N:38]=1

Participants

6

Reactant 4

HCID 73974-Toluenesulfonyl chloride2×HCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 27369222,4-Difluorobenzoic acid hydrazideHCID 57800318[4-chloro-5-cyano-2-(difluoromethyl)-1H-indol-1-yl]acetic acid

Product 1

HCID 249858104-Chloro-2-(difluoromethyl)-1-{[5-(2,4-difluorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-1H-indole-5-carbonitrileYield 38%

Reagents, catalysts & solvents 1

HCID 111,2-DichloroethaneSolvent

Procedure

To a suspension of [4-chloro-5-cyano-2-(difluoromethyl)-1H-indol-1-yl]acetic acid (0.020 g, 0.070 mmol) in DCE (3 mL), under N2, was added EDCl (0.016 g, 0.081 mmol) and stirred at rt. After 5 min, 2,4-difluorobenzohydrazide (0.014 g, 0.081 mmol) was added and stirring was continued at rt. After 30 min, TsCl (0.016 g, 0.084 mmol) and P-BEMP (loading 2.2 mmol/g, 0.127 g, 0.28 mmol) were added and the mixture was heated at 100° C. for 20 min. The reaction was monitored by LC/MS. Subsequently, the mixture was heated at 120° C. for 30 min. Additional TsCl (0.020 g, 0.105 mmol) and P-BEMP (0.127 g, 0.28 mmol) were added and the mixture was heated at 120° C. another 20 min. Upon cooling, the resin was filtered off and washed with EtOAc. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography (10-70% EtOAc-hexanes gradient). The product was crystallized from CH2Cl2-hexanes to afford the title compound as a white solid (0.011 g, 38% yield): MS (ES) m/z 421 (M+1).

Workup

  1. stirringstirring
  2. customwas continued at rt
  3. waitAfter 30 min
  4. temperaturethe mixture was heated at 100° C. for 20 min
  5. temperatureSubsequently, the mixture was heated at 120° C. for 30 min
  6. temperaturethe mixture was heated at 120° C. another 20 min
  7. temperatureUpon cooling
  8. filtrationthe resin was filtered off
  9. washwashed with EtOAc
  10. concentrationThe filtrate was concentrated in vacuo
  11. customthe residue was purified by flash chromatography (10-70% EtOAc-hexanes gradient)
  12. customThe product was crystallized from CH2Cl2-hexanes

Sources & evidence

ORD record
ord-8d63e2764b2c413db51301ff490d1fd9
Source dataset
uspto-grants-2011_09
Patent number
US08026262B2

Reaction notes

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