3-Methyl-6-nitroindazole Chemical Properties

Melting point:

187-188°C

Boiling point:

384.9±22.0 °C(Predicted)

Density 

1.437

storage temp. 

Sealed in dry,Room Temperature

solubility 

Chloroform (Slightly), Methanol (Slightly)

form 

Solid

pka

11.47±0.40(Predicted)

color 

Beige to Dark Yellow

InChI

InChI=1S/C8H7N3O2/c1-5-7-3-2-6(11(12)13)4-8(7)10-9-5/h2-4H,1H3,(H,9,10)

InChIKey

FUNWSYKLFDLUIZ-UHFFFAOYSA-N

SMILES

N1C2=C(C=CC([N+]([O-])=O)=C2)C(C)=N1

CAS DataBase Reference

6494-19-5

Safety Information

Risk Statements 

20/21/22

Safety Statements 

24/25-36/37

HS Code 

29339900

3-Methyl-6-nitroindazole Usage And Synthesis

Description

3-Methyl-6-nitroindazole is an important organic reagent or pharmaceutical intermediate compound used in the preparation of key intermediates of pazopanib. In experimental studies, it is mostly used for solubility determination, correlation and molecular interaction analysis studies in different pure and mixed solvents. The results showed that in the temperature range of (278.15 ~ 328.15)K, the molar fraction solubility of 3-Methyl-6-nitroindazole increased with increasing temperature in both pure and mixed solvent systems, and was maximum in pure N, N-dimethylformamide and minimum in water.

Chemical Properties

Brown solid

Uses

3-Methyl-6-nitroindazole a reactant used in the preparation of Pazopanib (P210925), an oral angiogenesis inhibitor targeting VEGFR and PDGFR.

Synthesis

Step 1: The general procedure for the synthesis of 3-methyl-6-nitro-1H-indazole from 2-ethyl-5-nitroaniline is referenced in Organic Synthesis 1955, Coll. Vol. 3, 660; 1940, 20, 73. 2-Ethyl-5-nitroaniline (1.021 g, 6.14 mmol) was dissolved in glacial acetic acid (40 ml) ) and the mixture was cooled to 0 °C. Subsequently, a solution of sodium nitrite (1 equiv, 424 mg) in water (1 ml) was added all at once. Stirring of the reaction mixture was continued for 15 min at 25 °C. After 3 h, the residual solid was removed by filtration and the filtrate was allowed to stand at room temperature for 3 days. After that, the solution was concentrated under vacuum and the residue was diluted with 2 ml of water and stirred vigorously. The solid product was collected by filtration and washed thoroughly with cold water. Finally, purification by fast chromatography (4:1 hexane/ethyl acetate) gave 3-methyl-6-nitro-1H-indazole (436 mg, 40.5% yield) as a solid.

References

[1] Li, Wanxin et al. “3-Methyl-6-nitroindazole in some aqueous co-solvent mixtures: Solubility determination, preferential solvation and solvent effect analysis.” The Journal of Chemical Thermodynamics 34 1 (2020): 0.
[2] Li Wang. “Solubility Measurement, Correlation, and Molecular Interactions of 3-Methyl-6-nitroindazole in Different Neat Solvents and Mixed Solvents from T = 278.15 to 328.15 K.” Journal of Chemical & Engineering Data 64 8 (2019): 3260–3269.

Physical properties

3-Methyl-6-nitroindazole, a slightly yellow to tawny powder with a molecular weight of 177.16, is one critical intermediate of Pazopanib. The chemical structure of 3-methyl-6-nitroindazole is shown below. Wang et al. measured the solubility of 3-methyl-6-nitroindazole in eight pure solvents [i.e., N, N-dimethylformamide (DMF), tetrahydrofuran (THF), acetone, ethyl acetate (EA), ethanol, acetonitrile, n-propanol, water] and three mixed solvents (DMF + water, THF + cyclohexane, acetone + water) at temperatures T = 278.15 to 328.15 K and under atmosphere pressure. Whether in a pure solvent or a mixed system, the results show that mole fraction solubilities of 3-methyl-6-nitroindazole increased with increasing temperature. Among the three groups of mixed solvents measured, the molar fraction of 3-methyl-6-nitroindazole in the (DMF + water) system is the maximum[1-2].

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