Dimethylacetamide → 6-Amino-4-fluoronicotinonitrile

HRID 1777867Notes

Reaction equation

HRID 1777867 reaction equation
[F:1][C:2]1[C:7](I)=[CH:6][N:5]=[C:4]([NH2:9])[CH:3]=1.C[C:11]([N:13](C)C)=O>C([O-])(O)=O.[Na+].[C-]#N.[Zn+2].[C-]#N.[Zn].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[NH2:9][C:4]1[CH:3]=[C:2]([F:1])[C:7]([C:11]#[N:13])=[CH:6][N:5]=1

Participants

8

Reactant 2

HCID 31374DimethylacetamideHCID 717211424-Fluoro-5-iodo-2-pyridinamine2×

Product 1

HCID 1180369016-Amino-4-fluoronicotinonitrile

Reagents, catalysts & solvents 5

HCID 11186Zinc cyanide (Zn(CN)2)CatalystHCID 23994ZincCatalystHCID 635956Ferrocene-1,1'-bis-(diphenylphosphine)CatalystHCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 516892Sodium BicarbonateSolvent

Conditions

Temperature
100 °C

Procedure

4-fluoro-5-iodopyridin-2-amine (intermediate 22, 240 g, 1 mol), zinc cyanide (125 g, 1.05 mol), zinc (13 g, 0.2 mol), Pd2(dba)3 (25 g, 25 mmol) and dppf (55 g, 0.1 mol) in DMA (800 ml) were degassed and charged into the round bottom flask under nitrogen. The mixture was stirred at 100° C. for 3 h. The reaction mixture was diluted with 5% NaHCO3 (2 l), extracted with EtOAc (4×600 ml). The combined organic layers were washed with 5% NaOH (1 l), dried over Na2SO4, concentrated to 700 ml. The resulting organic phase was eluted through silica gel column with EtOAc (1.7 l). The combined organic filtrate was washed with 2 M HCl (3×800 ml). The pH of the aqueous phase was adjusted to 10 with saturated NaHCO3. The aqueous phase was extracted whit DCM (3×500 ml). The combined DCM was dried over Na2SO4 and concentrated. The residue was further purified by column chromatography (eluted with pentane: EtOAc 10:1 to 3:2) followed by recrystallization from pentane/EtOAc 3/1 to give the title compound as white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.40 (d, 1H), 7.40 (s, 2H), 6.34 (d, 1H).

Workup

  1. additioncharged into the round bottom flask under nitrogen
  2. extractionextracted with EtOAc (4×600 ml)
  3. washThe combined organic layers were washed with 5% NaOH (1 l)
  4. dry with materialdried over Na2SO4
  5. concentrationconcentrated to 700 ml
  6. washThe resulting organic phase was eluted through silica gel column with EtOAc (1.7 l)
  7. washThe combined organic filtrate was washed with 2 M HCl (3×800 ml)
  8. extractionThe aqueous phase was extracted whit DCM (3×500 ml)
  9. dry with materialThe combined DCM was dried over Na2SO4
  10. concentrationconcentrated
  11. customThe residue was further purified by column chromatography (eluted with pentane: EtOAc 10:1 to 3:2)
  12. customfollowed by recrystallization from pentane/EtOAc 3/1

Sources & evidence

ORD record
ord-d9913c30d3384a94969eb0b789c63bbc
Source dataset
uspto-grants-2016_02
Patent number
US09266883B2

Reaction notes

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