Ammonia → Acumapimod

HRID 884811Notes

Reaction equation

HRID 884811 reaction equation
[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:10]([NH:12][CH:13]2[CH2:15][CH2:14]2)=[O:11])[N:5]=[C:4](OCC)[C:3]=1[C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[Cu](C#N)[C:32]#[N:33].N.C(OCC)(=O)C>CN(C)C=O>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:10]([NH:12][CH:13]2[CH2:15][CH2:14]2)=[O:11])[N:5]=[CH:4][C:3]=1[C:23](=[O:30])[C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([C:32]#[N:33])[CH:29]=1

Participants

6

Reactant 4

HCID 222AmmoniaHCID 8857Ethyl AcetateHCID 11153934HCID 11153934, compoundHCID 178418260HCID 178418260, compound

Product 1

HCID 11338127AcumapimodYield 51%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
80 °C

Procedure

To a stirred solution of iodide 4 (7.4 g, 0.015 mol, 1.0 equiv) in N,N-dimethyl formamide (25 ml) under N2 was added copper cyanide. The resultant suspension was refluxed for 1 hour. The reaction was monitored by TLC and checked for the completion. Heating was discontinued and the reaction mixture was cooled down to 80° C. Ice water (15 ml), 25% aqueous ammonia (15 ml), and ethyl acetate (50 ml) were added to quench the reaction. The mixture was filtered to remove the solids. From the filtrate organic layer was separated. The organic layer was washed with water, saturated brine and dried over anhydrous sodium sulfate. Solvent was removed under reduced pressure and the crude material dried at 60° C. under high vacuum then purified by column with ethyl acetate as eluent to provide the product (3 g, 51%) as an off white solid. HPLC (Waters X-Terra 5 micron C18 column 4.6 mm×250 mm, 1.0 mL/min, mobile phase: 0.1% TEA in H2O/acetonitrile 70/30, 30 min elution) tR 23.70 min, 99.4% purity; 1H NMR (400 MHz, CDCl3) δ 8.10 (t, J=2.9 Hz, 1 H), 8.06 (t, J=2.7 Hz, 1 H), 8.04 (m, 1 H), 7.85 (t, J=2.5 Hz, 1 H), 7.83 (m, 1 H), 7.81 (d, J=1.8 Hz, 1 H), 7.95 (d, J=1.6 Hz, 1 H), 7.37 (s, 1 H), 7.65 (t, J=7.8 Hz, 1 H), 7.45 (d, J=8.0 Hz, 1 H), 6.41 (s, 1 H), 5.94 (s, 2 H), 2.88 (m, 1 H), 2.24 (s, 3 H), 0.86 (dd, J=6.9, 6.1 Hz, 2 H) 0.61 (m, 2 H) ppm; 13C NMR (400 MHz, CDCl3) δ 186.6, 167.2, 151.5, 141.3, 140.7, 140.3, 135.1, 134.5, 134.0, 132.2, 131.8, 129.5, 128.7, 126.2, 118.1, 113.0, 103.7, 30.9, 23.2, 17.7, 6.8 ppm.

Workup

  1. temperatureHeating
  2. customto quench
  3. customthe reaction
  4. filtrationThe mixture was filtered
  5. customto remove the solids
  6. customFrom the filtrate organic layer was separated
  7. washThe organic layer was washed with water, saturated brine
  8. dry with materialdried over anhydrous sodium sulfate
  9. customSolvent was removed under reduced pressure
  10. dry with materialthe crude material dried at 60° C. under high vacuum
  11. customthen purified by column with ethyl acetate as eluent

Sources & evidence

ORD record
ord-ef151b432bd64c6597e5ea842b69c8ef
Source dataset
uspto-grants-2012_08
Patent number
US08242117B2

Reaction notes

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