Synthesis Routes and Detailed Analysis of 3-Methyl-6-nitro-1H-Indazole

Alias: 3-Methyl-6-nitro-1H-indazole

CAS No: 6494-19-5

Molecular Formula: C8H7N3O2

Molecular Weight: 177.16

Physical State: Solid powder

Melting Point: 187-188°C

Boiling Point: 384.9±22.0 °C (Predicted)

Density: 1.437

Applications: Used as an organic intermediate and pharmaceutical intermediate.

3-methyl-6-nitro-1H-indazole   is an important organic intermediate widely used in pharmaceuticals, pesticides, and materials science. The choice of synthesis method directly affects the quality and yield of the target product. This article will detail several common synthesis routes with illustrations for reference in research and industrial production.

 

1. Direct Nitration Method

The direct nitration method uses 3-methylindazole as the starting material. In a mixed acid system of nitric acid and sulfuric acid, nitration is carried out to introduce a nitro group at position 6 of the indazole ring.

Synthesis Steps:

- Starting Material: 3-Methylindazole (readily available, reasonably priced).

- Nitration Reaction: Dissolve 3-methylindazole in concentrated sulfuric acid, and slowly add nitric acid under low-temperature conditions (0–5°C).

- Post-treatment: After the reaction, purify the product through neutralization, extraction, and recrystallization.

Reaction Diagram:

3-Methylindazole + HNO₃/H₂SO₄ → 3-methyl-6-nitro-1H-indazole 

Advantages:

- Simple process and easy to operate.

- Suitable for small-scale laboratory preparation.

Disadvantages:

- Requires strict control of temperature and acid ratios.

- Nitration by-products may affect the purity of the target product.

 

2. Indirect Nitration Method

The indirect nitration method involves first functionalizing the indazole framework and then introducing the nitro group at position 6, providing higher selectivity.

Synthesis Steps:

- Cyclization Reaction: Using o-amino toluene as the starting material, cyclization is carried out to prepare indazole.

- Nitration: Ammonium nitrate or a mixed acid system is used as a nitration reagent to selectively introduce the nitro group at the target position.

- Post-treatment: Purify the product by extraction and distillation to increase the purity of the target product.

Reaction Diagram:

o-Aminotoluene → Indazole → 3-methyl-6-nitro-1H-indazole 

Advantages:

- High selectivity for the product.

- Fewer side reactions.

Disadvantages:

- Complex process with multiple steps.

- Overall yield may be slightly lower.

 3. One-Pot Synthesis Method

The one-pot synthesis method integrates multiple steps into a single reaction system, making it suitable for large-scale production.

Synthesis Steps:

- Starting Material: Pyrazole derivatives or related compounds.

- Nitration Reaction: Under the effect of a catalyst (such as benzoyl peroxide) and ammonium nitrate, the target product is generated in a single step.

- Post-treatment: After the reaction, the product is extracted using organic solvents and purified by vacuum distillation to obtain high-purity product.

Reaction Diagram:

Pyrazole Derivative + Nitration Reagent → 3-methyl-6-nitro-1H-indazole 

Advantages:

- High reaction efficiency, short process time.

- More suitable for industrial-scale applications.

Disadvantages:

- Higher control requirements for reaction conditions.

- Catalyst and reagent costs may increase.

Direct Nitration Method:

- Starting Material: 3-Methylindazole

- Nitration Reagents: Nitric Acid/Sulfuric Acid

- Target Product: 3-methyl-6-nitro-1H-indazole 

 Indirect Nitration Method:

- Starting Material: o-Aminotoluene

- Cyclization Reagent: Sulfonyl Chloride

- Nitration Reagents: Mixed Acid

The above are the common synthesis routes for 3-Methyl-6-nitro-1H-Indazole, including the direct nitration method, indirect nitration method, and one-pot synthesis method. Depending on production needs, an appropriate process route can be chosen, balancing yield, purity, and cost. Additionally, future optimization of catalysts and eco-friendly processes can further improve yield and reduce environmental impact.