Potassium Hydroxide → 4-{[3-[[(5-Chloro-2-thienyl)sulfonyl]({[2-(trimethylsilyl)ethyl]oxy}methyl)amino]-4-(methyloxy)-1H-indazol-1-yl]methyl}-N,N-dimethylbenzamide

HRID 1892939Notes

Reaction equation

HRID 1892939 reaction equation
[Cl:1][C:2]1[S:6][C:5]([S:7]([N:10]([C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][C:26]=3[O:28][CH3:29])[NH:21][N:20]=2)[CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])(=[O:9])=[O:8])=[CH:4][CH:3]=1.Cl[CH2:31][C:32]1[CH:44]=[CH:43][C:35]([C:36]([N:38]([CH2:41]C)[CH2:39]C)=[O:37])=[CH:34][CH:33]=1.[OH-].[K+]>>[Cl:1][C:2]1[S:6][C:5]([S:7]([N:10]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:16])[CH3:17])[C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][C:26]=3[O:28][CH3:29])[N:21]([CH2:31][C:32]3[CH:44]=[CH:43][C:35]([C:36]([N:38]([CH3:39])[CH3:41])=[O:37])=[CH:34][CH:33]=3)[N:20]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1

Participants

4

Reactant 3

HCID 14797Potassium HydroxideHCID 30416634-(Chloromethyl)-N,N-diethylbenzamideHCID 580544435-chloro-N-[4-(methyloxy)-1H-indazol-3-yl]-N-({[2-(trimethylsilyl)ethyl]oxy}methyl)-2-thiophenesulfonamide2×

Product 1

HCID 666646294-{[3-[[(5-Chloro-2-thienyl)sulfonyl]({[2-(trimethylsilyl)ethyl]oxy}methyl)amino]-4-(methyloxy)-1H-indazol-1-yl]methyl}-N,N-dimethylbenzamideYield 61.5%

Conditions

Temperature
50 °C

Procedure

A solution of 5-chloro-N-[4-(methyloxy)-1H-indazol-3-yl]-N-({[2-(trimethylsilyl)ethyl]oxy}methyl)-2-thiophenesulfonamide (Intermediate 8) (150 mg, 0.32 mmol) was treated with 4-(chloromethyl)-N,N-diethylbenzamide (86 mg, 0.38 mmol) and potassium hydroxide (21.3 mg, 0.38 mmol), and the mixture was heated to 50° C. overnight. Reaction mixture was partitioned between DCM (3 mL) and water (3 mL). The organic phase was separated and the aqueous layer was further extracted with 2 mL of DCM. The combined organic solutions were dried (hydrophobic frit) and concentrated under a nitrogen stream in a blowdown unit. The residue was purified by chromatography using a Flash Master system (Solo machine), on a 50 g silica cartridge, eluting with 0 to 100% A in B, A being a 20% EtOAC in DCM solution and B being neat DCM over 60 min. Evaporation of the appropriate fractions gave the title compound (125 mg, 60%) LCMS (System A) RT=1.52 min, ES+ve m/z 680/682 (M+NH4)+.

Workup

  1. customReaction mixture
  2. customwas partitioned between DCM (3 mL) and water (3 mL)
  3. customThe organic phase was separated
  4. extractionthe aqueous layer was further extracted with 2 mL of DCM
  5. customThe combined organic solutions were dried (hydrophobic frit)
  6. concentrationconcentrated under a nitrogen stream in a blowdown unit
  7. customThe residue was purified by chromatography
  8. washon a 50 g silica cartridge, eluting with 0 to 100% A in B
  9. customover 60 min
  10. customEvaporation of the appropriate fractions

Sources & evidence

ORD record
ord-44da87f344c74d82829c96f22bdd2ba9
Source dataset
uspto-grants-2013_08
Patent number
US08507543B2

Reaction notes

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