Sodium hydride → 2-(4-chloro-3-iodo-5-phenyl-pyrazolo[3,4-c]pyridazin-1-yl)-1-[(3R)-3-fluoropyrrolidin-1-yl]ethanone

HRID 588571Notes

Reaction equation

HRID 588571 reaction equation
[H-].[Na+].[Cl:3][C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]=[C:6]2[NH:16][N:17]=[C:18]([I:19])[C:5]=12.Cl[CH2:21][C:22]([N:24]1[CH2:28][CH2:27][C@@H:26]([F:29])[CH2:25]1)=[O:23].[Li+].[Cl-]>CN(C=O)C.C(OCC)(=O)C>[Cl:3][C:4]1[C:9]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[N:8][N:7]=[C:6]2[N:16]([CH2:21][C:22]([N:24]3[CH2:28][CH2:27][C@@H:26]([F:29])[CH2:25]3)=[O:23])[N:17]=[C:18]([I:19])[C:5]=12

Participants

7

Reactant 4

HCID 24758Sodium hydrideHCID 433294Lithium ChlorideHCID 86717264CID 86717264HCID 867172712-chloro-1-[(3R)-3-fluoropyrrolidin-1-yl]ethanone

Product 1

HCID 867172722-(4-chloro-3-iodo-5-phenyl-pyrazolo[3,4-c]pyridazin-1-yl)-1-[(3R)-3-fluoropyrrolidin-1-yl]ethanoneYield 58.1%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

Sodium hydride (60% in mineral oil, 240 mg, 6 mmol) was added to a solution of 4-chloro-3-iodo-5-phenyl-1H-pyrazolo[3,4-c]pyridazine (1.06 g, 3 mmol) and 2-chloro-1-[(3R)-3-fluoropyrrolidin-1-yl]ethanone (740 mg, 4.5 mmol) in dry DMF (20 mL) at room temperature. The reaction mixture was stirred at room temperature for 16 h. 4% LiCl aq. solution and ethyl acetate was added. The layers were separated and the aqueous was extracted with ethyl acetate. The combined organics were dried (MgSO4), filtered and concentrated in vacuo. The residue was partially purified by column chromatography (silica gel, isohexane/ethyl acetate 1:0 to 3:7). The resulting solid was dissolved in minimum CH2Cl2 and diethyl ether was added until a solid precipitated. The solid was collected by filtration to provide Compound It as a solid (846 mg).

Workup

  1. customThe layers were separated
  2. extractionthe aqueous was extracted with ethyl acetate
  3. dry with materialThe combined organics were dried (MgSO4)
  4. filtrationfiltered
  5. concentrationconcentrated in vacuo
  6. customThe residue was partially purified by column chromatography (silica gel, isohexane/ethyl acetate 1:0 to 3:7)
  7. dissolutionThe resulting solid was dissolved in minimum CH2Cl2
  8. additiondiethyl ether was added until a solid
  9. customprecipitated
  10. filtrationThe solid was collected by filtration

Sources & evidence

ORD record
ord-3db8865058a64f8f8897712f7f293d83
Source dataset
uspto-grants-2016_01
Patent number
US09227976B2

Reaction notes

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