Cesium carbonate → 5-(2,6-difluorophenyl)-3-{[1-(ethylsulphonyl)piperidin-4-yl]amino}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]isoquinoline-7-carbaldehyde

HRID 1256248Notes

Reaction equation

HRID 1256248 reaction equation
Br[C:2]1[N:3]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[N:4]=[C:5]2[C:14]3[CH:13]=[CH:12][C:11]([CH:15]=[O:16])=[CH:10][C:9]=3[C:8]([C:17]3[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=3[F:24])=[N:7][C:6]=12.[CH2:33]([S:35]([N:38]1[CH2:43][CH2:42][CH:41]([NH2:44])[CH2:40][CH2:39]1)(=[O:37])=[O:36])[CH3:34].C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[F:24][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]([F:23])[C:17]=1[C:8]1[C:9]2[CH:10]=[C:11]([CH:15]=[O:16])[CH:12]=[CH:13][C:14]=2[C:2]2[N:3]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:30])([CH3:31])[CH3:32])[N:4]=[C:5]([NH:44][CH:41]3[CH2:42][CH2:43][N:38]([S:35]([CH2:33][CH3:34])(=[O:36])=[O:37])[CH2:39][CH2:40]3)[C:6]=2[N:7]=1

Participants

8

Reactant 4

HCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 167761864-Amino-1-ethanesulfonylpiperidineHCID 866649343-bromo-5-(2,6-difluorophenyl)-2-(2-trimethylsilanylethoxymethyl)-2H-pyrazolo[4,3-c]isoquinoline-7-carbaldehyde

Product 1

HCID 866649335-(2,6-difluorophenyl)-3-{[1-(ethylsulphonyl)piperidin-4-yl]amino}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]isoquinoline-7-carbaldehydeYield 45.9%

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Procedure

A 50 ml three-necked flask equipped with a magnetic stirrer and with an argon intake is charged with 350 mg of 3-bromo-5-(2,6-difluorophenyl)-2-(2-trimethylsilanylethoxymethyl)-2H-pyrazolo[4,3-c]isoquinoline-7-carbaldehyde, prepared in step 5 of example 2, in 7.8 ml of 1,4-dioxane. 195 mg of 1-ethylsulphonylpiperidin-4-ylamine, 880 mg of caesium carbonate, 59 mg of 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene and 15 mg of palladium(II) acetate are added. The mixture is heated at reflux for 2 h. After cooling, the mixture is poured into water and extracted with AcOEt. The organic phase is washed with saturated NaCl solution, dried over MgSO4, filtered and concentrated under RP. It is purified by flash chromatography on silica gel (15-40 μm), eluting with a mixture of cyclohexane and AcOEt (75/25 by vol.), to give 195 mg of 5-(2,6-difluorophenyl)-3-{[1-(ethylsulphonyl)piperidin-4-yl]amino}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]isoquinoline-7-carbaldehyde (yellow foam). LC-MS-DAD-ELSD 628=(M−H)(+).

Workup

  1. customA 50 ml three-necked flask equipped with a magnetic stirrer and with an argon intake
  2. temperatureThe mixture is heated
  3. temperatureat reflux for 2 h
  4. temperatureAfter cooling
  5. extractionextracted with AcOEt
  6. washThe organic phase is washed with saturated NaCl solution
  7. dry with materialdried over MgSO4
  8. filtrationfiltered
  9. concentrationconcentrated under RP
  10. customIt is purified by flash chromatography on silica gel (15-40 μm)
  11. washeluting with a mixture of cyclohexane and AcOEt (75/25 by vol.)

Sources & evidence

ORD record
ord-2ac1086e98694ff58ad9eb09df1756fe
Source dataset
uspto-grants-2013_06
Patent number
US08461175B2

Reaction notes

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