Acetic Acid → 6-Fluoro-4-methoxy-1H-indazol-3-amine

HRID 1808584Notes

Reaction equation

HRID 1808584 reaction equation
F[C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6](OC)[C:3]=1[C:4]#[N:5].[OH2:13].[NH2:14][NH2:15].[CH3:16]C(O)=O.C(OCC)(=O)C>C(O)CCC.O>[F:10][C:8]1[CH:9]=[C:2]2[C:3]([C:4]([NH2:5])=[N:14][NH:15]2)=[C:6]([O:13][CH3:16])[CH:7]=1

Participants

7

Reactant 4

HCID 176Acetic AcidHCID 8857Ethyl AcetateHCID 24654Hydrazine hydrate (1:1)HCID 580544482,4-Difluoro-6-methoxybenzonitrile

Product 1

HCID 580545716-Fluoro-4-methoxy-1H-indazol-3-amineYield 21%

Reagents, catalysts & solvents 2

HCID 2631-ButanolSolventHCID 962WaterSolvent

Conditions

Temperature
110 °C

Procedure

2,4-Difluoro-6-methoxybenzonitrile (for a preparation see Intermediate 48) (29.2 g, 0.17 mol) was suspended in n-butanol (250 mL) and hydrazine hydrate (16.6 mL, 0.34 mol) was added. The suspension was heated at 110° C. for 19 h, then 115° C. for 4 h. The reaction was allowed to cool and a solid formed overnight. The solid was collected by filtration, and washed with n-butanol. Solid is mainly an aryl hydrazine by-product (uncyclised or regioisomer). The filtrate was concentrated and azeotroped with toluene to give 15.6 g of crude product (84% by LCMS). The crude product was taken up in ˜400 mL water, ˜5 mL AcOH and ˜350 mL ethyl acetate and any insoluble material was discarded. The organic layer was washed with water, dried (MgSO4) and evaporated. The residue was taken up in hot ethyl acetate (75 mL, 55° C.) and heptane was added (20 mL). The solid was collected by filtration, washed with heptane. This was repeated twice to give the title compound (6.7 g, 21%) as a purple solid.

Workup

  1. temperatureto cool
  2. customa solid formed overnight
  3. filtrationThe solid was collected by filtration
  4. washwashed with n-butanol
  5. concentrationThe filtrate was concentrated
  6. customazeotroped with toluene
  7. customto give 15.6 g of crude product (84% by LCMS)
  8. washThe organic layer was washed with water
  9. dry with materialdried (MgSO4)
  10. customevaporated
  11. customwas taken up in hot ethyl acetate (75 mL, 55° C.)
  12. additionheptane was added (20 mL)
  13. filtrationThe solid was collected by filtration
  14. washwashed with heptane

Sources & evidence

ORD record
ord-04415d86f1144093ae8fe79041835e79
Source dataset
uspto-grants-2013_01
Patent number
US08357716B2

Reaction notes

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