(2,4-Difluoro-phenyl)-hydrazine → 1-(2,4-Difluorophenyl)-4-iodo-1H-pyrazolo[3,4-B]pyridine

HRID 1186801Notes

Reaction equation

HRID 1186801 reaction equation
F[C:2]1[N:9]=[CH:8][CH:7]=[C:6]([I:10])[C:3]=1[CH:4]=O.[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[NH:19][NH2:20]>CN1C(=O)CCC1>[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[N:19]1[C:2]2=[N:9][CH:8]=[CH:7][C:6]([I:10])=[C:3]2[CH:4]=[N:20]1

Participants

4

Reactant 2

HCID 588958(2,4-Difluoro-phenyl)-hydrazineHCID 99923282-Fluoro-4-iodopyridine-3-carbaldehyde

Product 1

HCID 666648441-(2,4-Difluorophenyl)-4-iodo-1H-pyrazolo[3,4-B]pyridineYield 63.7%

Reagents, catalysts & solvents 1

HCID 13387N-methyl-2-pyrrolidoneSolvent

Procedure

To a dry 16×100 mm Chem-Glass reaction tube under N2 was added 2-fluoro-4-iodonicotinaldehyde (5 g, 19.92 mmol), (2,4-difluorophenyl)hydrazine (3.01 g, 20.92 mmol) and anhydrous NMP (35 mL). The reaction mixture was flushed with argon, securely capped, stirred for 20 min at room temp, and then placed in a 180° C. oil bath for 4 h. The reaction mixture was then allowed to stir at room temperature for 72 h. The reaction mixture was diluted with EtOAc (1200 mL) and the organic layer was extracted with water (6×350 mL), brine (1×100 mL), dried over Na2SO4, filtered, and evaporated to dryness. The residue was purified by Biotage Silica gel chromatography on a 300 g Thompson Single Step™ silica cartridge using a linear gradient from 100% hexanes to 100% dichloromethane over 10 column volumes to give 4.53 g (44.6%) of Intermediate 13A, as a light yellow solid that contained 28% of the uncyclized hydrazone intermediate ((E)-3-(2-(2,4-difluorophenyl)hydrazono)methyl)-2-fluoro-4-iodopyridine). 1H NMR (500 MHz, CCl3D) δ ppm 8.21 (1 H, d, J=4.58 Hz), 8.14 (1 H, s), 7.59-7.71 (2 H, m), 7.10 (2 H, td, J=7.55, 3.81 Hz). LC/MS (Condition A): T=3.7 min, (M+H)+ 357.90.

Workup

  1. customTo a dry
  2. custom16×100 mm Chem-Glass reaction tube under N2
  3. customThe reaction mixture was flushed with argon
  4. customsecurely capped
  5. customplaced in a 180° C.
  6. customfor 4 h
  7. stirringto stir at room temperature for 72 h
  8. additionThe reaction mixture was diluted with EtOAc (1200 mL)
  9. extractionthe organic layer was extracted with water (6×350 mL), brine (1×100 mL)
  10. dry with materialdried over Na2SO4
  11. filtrationfiltered
  12. customevaporated to dryness
  13. customThe residue was purified by Biotage Silica gel chromatography on a 300 g Thompson Single Step™ silica cartridge

Sources & evidence

ORD record
ord-da48b4cb38fb458298e4eaeb32de708f
Source dataset
uspto-grants-2014_03
Patent number
US08673922B2

Reaction notes

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