3-Methylpyrazole
[CAS# 1453-58-3]

Identification

• Classification: Pharmaceutical intermediate >> API intermediate
• Name: 3-Methylpyrazole
• Synonyms: 5-methyl-1H-pyrazole
• Molecular Formula: C₄H₆N₂
• Molecular Weight: 82.10
• CAS Registry Number: 1453-58-3
• EC Number: 215-925-7
• SMILES: CC1=CC=NN1

Properties

• Density: 1.1±0.1 g/cm³ Calc.^*, 1.017 g/mL (Expl.)
• Melting point: 36.5 °C (Expl.)
• Boiling point: 204.0 °C 760 mmHg (Calc.)^*, 203 - 205 °C (Expl.)
• Flash point: 87.4±11.7 °C (Calc.)^*, 93 °C (Expl.)
• Index of refraction: 1.523 (Calc.)^*, 1.496 (Expl.)
• Water solubility: miscible

^* Calculated using Advanced Chemistry Development (ACD/Labs) Software.

Safety Data

• Hazard Symbols: GHS05;GHS07;GHS08 Danger
• Risk Statements: H302-H314:-H318:-H360D:-H373:
• Safety Statements: P203-P260-P264-P264+P265-P270-P280-P301+P317-P301+P330+P331-P302+P361+P354-P304+P340-P305+P354+P338-P316-P317-P318-P319-P321-P330-P363-P405-P501

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Acute toxicity	Acute Tox.	4	H302
Skin irritation	Skin Irrit.	2	H315
Eye irritation	Eye Irrit.	2	H319
Specific target organ toxicity - single exposure	STOT SE	3	H335
Specific target organ toxicity - repeated exposure	STOT RE	2	H373
Serious eye damage	Eye Dam.	1	H318
Reproductive toxicity	Repr.	1B	H360
Skin corrosion	Skin Corr.	1	H314
Reproductive toxicity	Repr.	2	H361
Acute toxicity	Acute Tox.	4	H312
Acute toxicity	Acute Tox.	3	H331
Acute toxicity	Acute Tox.	4	H332
Reproductive toxicity	Repr.	1B	H360D

Discovery and Applications

3-Methylpyrazole is a heterocyclic organic compound with the molecular formula C₄H₆N₂. It is a substituted pyrazole, consisting of a five-membered aromatic ring containing two adjacent nitrogen atoms (at positions 1 and 2) and a methyl group at the 3-position. This structure imparts both basic and nucleophilic properties to the molecule, which appears as a colorless to pale yellow liquid under ambient conditions and has a characteristic amine-like odor.

The discovery of pyrazole derivatives dates back to the 19th century during systematic investigations of nitrogen-containing heterocycles. 3-Methylpyrazole itself can be synthesized by the condensation of hydrazine with 3-methyl-1,3-dicarbonyl compounds or β-ketoesters under acidic or basic conditions. A common laboratory route involves cyclization of 3-methyl-1-phenyl-1,3-propanedione with hydrazine hydrate, yielding the desired pyrazole derivative after work-up and purification.

3-Methylpyrazole has gained particular attention for its biological and pharmaceutical relevance. It is best known for its use as a potent inhibitor of alcohol dehydrogenase (ADH), the enzyme responsible for oxidizing ethanol to acetaldehyde in the human liver. This property is the basis for its use in medicine, particularly in the treatment of methanol or ethylene glycol poisoning. When administered, 3-methylpyrazole (under the generic name fomepizole) competitively inhibits ADH, slowing the formation of toxic metabolites and allowing time for elimination of the parent compounds from the body.

In this medical application, 3-methylpyrazole is administered intravenously and is generally well tolerated when used in recommended doses. It offers a safer alternative to ethanol therapy, which was traditionally used to compete with methanol or ethylene glycol for ADH binding. Unlike ethanol, 3-methylpyrazole has fewer central nervous system effects and a more predictable pharmacokinetic profile, making it a preferred antidote in clinical toxicology.

Outside of its therapeutic use, 3-methylpyrazole serves as a building block in organic synthesis. Its ring system is a common motif in medicinal chemistry and agrochemical development due to its aromaticity and capacity to engage in hydrogen bonding and coordination with metal centers. It is used as a ligand in coordination chemistry, particularly in the synthesis of metal complexes where the nitrogen atoms of the pyrazole ring act as donor sites. These complexes can exhibit useful catalytic, magnetic, or electronic properties.

In industrial applications, 3-methylpyrazole is used in the production of specialty chemicals, intermediates for pharmaceuticals, and heterocyclic compounds used in research. It can be modified through electrophilic substitution reactions, N-alkylation, and other functionalization methods to introduce desired properties for chemical libraries or structure–activity relationship (SAR) studies.

3-Methylpyrazole is also utilized in analytical chemistry, including the formulation of derivatization agents and as a component in reagent kits. In laboratory settings, it can serve as a model compound for studying the behavior of pyrazole derivatives under various chemical and physical conditions.

Standard safety precautions apply when handling 3-methylpyrazole. Although it has relatively low acute toxicity, it can cause irritation upon contact with the skin or mucous membranes. Proper storage includes keeping the substance in tightly closed containers in a well-ventilated, cool, and dry environment, away from strong oxidizers or acids.

In summary, 3-methylpyrazole is a substituted aromatic heterocycle with important roles in both medical and chemical applications. It is most notably used as an antidote for alcohol poisoning through its inhibition of alcohol dehydrogenase and also serves as a versatile synthetic intermediate, ligand, and pharmacophore in various areas of research and industry.

References

2024. Green Synthesis of Alkenes as Antimicrobial Agents from the Corresponding Formyl Pyrazoles in Aqueous Medium and Insights from Molecular Docking. Chemistry Africa, 7(8).
DOI: 10.1007/s42250-024-01054-6

2024. Trifluoroacetaldehyde N-tosylhydrazone in [3+2] cycloaddition reaction for the synthesis of 5-(trifluoromethyl)pyrazolines. Russian Chemical Bulletin, 73(4).
DOI: 10.1007/s11172-024-4215-9

2021. Quinolinyl-pyrazoles: synthesis and pharmacological evolution in the recent decennial. Journal of the Iranian Chemical Society, 18(12).
DOI: 10.1007/s13738-020-02152-1