4-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine
[CAS# 1940180-18-6]

Identification

• Classification: Pharmaceutical intermediate >> Heterocyclic compound intermediate >> Pyrazines
• Name: 4-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine
• Molecular Formula: C₁₀H₈ClN₅
• Molecular Weight: 233.66
• CAS Registry Number: 1940180-18-6
• EC Number: 858-879-9
• SMILES: CN1C=C(C=N1)C2=CN3C(=CC=N3)C(=N2)Cl

Properties

• Density: 1.5±0.1 g/cm³ Calc.^*
• Index of refraction: 1.757 (Calc.)^*

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

Safety Data

• Hazard Symbols: GHS07 Warning
• Risk Statements: H302-H315-H319-H335
• Safety Statements: P261-P264-P264+P265-P270-P271-P280-P301+P317-P302+P352-P304+P340-P305+P351+P338-P319-P321-P330-P332+P317-P337+P317-P362+P364-P403+P233-P405-P501

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Acute toxicity	Acute Tox.	4	H302
Skin irritation	Skin Irrit.	2	H315
Specific target organ toxicity - single exposure	STOT SE	3	H335
Eye irritation	Eye Irrit.	2	H319

Discovery and Applications

4-Chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine is a synthetic heterocyclic compound that integrates multiple nitrogen-rich ring systems within a single molecular framework. It consists of a fused pyrazolo[1,5-a]pyrazine core substituted with a chlorine atom at the 4-position and a 1-methyl-1H-pyrazol-4-yl group at the 6-position. The molecular structure combines aromaticity and heteroatom diversity, contributing to its electronic complexity and potential for interaction with biological targets.

The development of pyrazolo[1,5-a]pyrazine derivatives began in the context of exploring fused bicyclic heterocycles with applications in medicinal chemistry. The incorporation of additional heterocyclic substituents, such as methylated pyrazoles, was pursued to modulate physicochemical properties, enhance solubility, and target specific enzyme or receptor binding domains. Chlorine substitution at electron-deficient positions of the core ring system, such as the 4-position in this compound, is known to facilitate further synthetic elaboration via nucleophilic aromatic substitution reactions.

This compound has been investigated as part of structure–activity relationship studies in the field of kinase inhibition. Fused pyrazolo[1,5-a]pyrazines are recognized scaffolds in medicinal chemistry for their ability to serve as ATP-mimetic cores in the design of inhibitors targeting protein kinases. The presence of a 1-methylpyrazolyl moiety contributes to binding specificity by interacting with hydrophobic pockets or hydrogen-bonding regions within kinase active sites. Substituents at the 6-position, such as the 1-methyl-1H-pyrazol-4-yl group, help orient the molecule within the binding cleft and affect selectivity profiles.

The chloro group at position 4 can be synthetically replaced with a variety of nucleophiles, including amines, thiols, and alkoxides, allowing for the generation of diverse analogs. These transformations are commonly carried out under mild conditions and are used to tailor the compound's physicochemical and pharmacokinetic properties. For example, derivatization can enhance aqueous solubility or improve cell permeability for in vitro and in vivo studies.

Synthetic methods for preparing 4-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine generally involve the cyclization of hydrazine-containing precursors with appropriately substituted diketones or amidines, followed by functionalization steps including chlorination and cross-coupling. Alternatively, pyrazolo[1,5-a]pyrazine cores may be constructed first and subsequently modified at the 4- and 6-positions through electrophilic aromatic substitution and metal-catalyzed coupling reactions.

In pharmaceutical research, this compound and its analogs are employed as molecular probes to investigate signal transduction pathways involving serine/threonine and tyrosine kinases. Their compact, planar structures, combined with nitrogen-rich functionalities, support high-affinity binding in kinase ATP-binding sites while offering opportunities to fine-tune interaction profiles for desired selectivity.

The chemical stability and reactivity of 4-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine make it a versatile building block in heterocyclic chemistry. It continues to be utilized in the development of small-molecule libraries for biological screening and lead optimization, particularly in oncology and inflammatory disease research. The compound's inclusion in various patent disclosures reflects its potential as a core scaffold for drug discovery efforts targeting intracellular signaling mechanisms.

References

2021. Synthesis of PF-06826647. Synfacts, 17(2).
DOI: 10.1055/s-0040-1719324