Sodium hydride → 4-(4-Amino-3-fluorophenoxy)pyridin-2-amine

HRID 492734Notes

Reaction equation

HRID 492734 reaction equation
[H-].[Na+].Cl[C:4]1[CH:9]=[CH:8][N:7]=[C:6]([NH2:10])[CH:5]=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]=1[F:19]>CS(C)=O>[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:4]2[CH:9]=[CH:8][N:7]=[C:6]([NH2:10])[CH:5]=2)=[CH:14][C:13]=1[F:19]

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 5818662-Amino-4-chloropyridineHCID 27359194-Amino-3-fluorophenol

Product 1

HCID 71470884-(4-Amino-3-fluorophenoxy)pyridin-2-amineYield 26.3%

Reagents, catalysts & solvents 1

HCID 679Dimethyl SulfoxideSolvent

Procedure

Sodium hydride (1.1 g) was suspended in dimethyl sulfoxide (60 ml) under a nitrogen stream, and 4-chloro-2-pyridinamine (2.9 g) described in WO 02/32872 and then 4-amino-3-fluorophenol (3.6 g, 28 mmol) were added thereto at room temperature while stirring, followed by stirring under a nitrogen stream at 150° C. for 9 hrs. The reaction mixture was cooled down to room temperature, and partitioned between 10% aqueous ammonia (150 ml) and ethyl acetate (350 ml). The organic layer was washed twice with 10% aqueous ammonia (150 ml). The combined aqueous layer was extracted with ethyl acetate (150 ml) again. The combined organic layer was washed twice with a saturated aqueous solution of sodium hydrogencarbonate (100 ml), and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (eluent; hexane:ethyl acetate=1:1, ethyl acetate, then ethyl acetate:methanol=10:1). Crude fractions containing the target compound were concentrated to give a residue, which was then purified by silica gel column chromatography (eluent; ethyl acetate). Fractions containing the target compound were concentrated to provide the titled compound (1.3 g, 26%) as a purple solid.

Workup

  1. stirringby stirring under a nitrogen stream at 150° C. for 9 hrs
  2. temperatureThe reaction mixture was cooled down to room temperature
  3. custompartitioned between 10% aqueous ammonia (150 ml) and ethyl acetate (350 ml)
  4. washThe organic layer was washed twice with 10% aqueous ammonia (150 ml)
  5. extractionThe combined aqueous layer was extracted with ethyl acetate (150 ml) again
  6. washThe combined organic layer was washed twice with a saturated aqueous solution of sodium hydrogencarbonate (100 ml)
  7. dry with materialdried over anhydrous sodium sulfate
  8. customThe solvent was evaporated
  9. customto give a residue, which
  10. customwas then purified by silica gel column chromatography (eluent
  11. additionCrude fractions containing the target compound
  12. concentrationwere concentrated
  13. customto give a residue, which
  14. customwas then purified by silica gel column chromatography (eluent; ethyl acetate)
  15. additionFractions containing the target compound
  16. concentrationwere concentrated

Sources & evidence

ORD record
ord-e9743d4b37ec42b4819b5be314f7bb54
Source dataset
uspto-grants-2009_05
Patent number
US07531532B2

Reaction notes

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