4-Amino-2-chloropyrimidine
[CAS# 7461-50-9]

Identification

• Classification: Pharmaceutical intermediate >> Heterocyclic compound intermediate >> Pyrimidine compound >> Chloropyrimidine
• Name: 4-Amino-2-chloropyrimidine
• Synonyms: 2-Chloro-4-aminopyrimidine
• Molecular Formula: C₄H₄ClN₃
• Molecular Weight: 129.55
• CAS Registry Number: 7461-50-9
• EC Number: 627-766-4
• SMILES: C1=CN=C(N=C1N)Cl

Properties

• Density: 1.4±0.1 g/cm³ Calc.^*
• Melting point: 197 - 205 °C (Expl.)
• Boiling point: 338.8±15.0 °C 760 mmHg (Calc.)^*
• Flash point: 158.7±20.4 °C (Calc.)^*
• Index of refraction: 1.618 (Calc.)^*

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

Safety Data

• Hazard Symbols: GHS07 Warning
• Risk Statements: H302-H319
• Safety Statements: P264-P264+P265-P270-P280-P301+P317-P305+P351+P338-P330-P337+P317-P501

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Eye irritation	Eye Irrit.	2	H319
Acute toxicity	Acute Tox.	4	H302
Skin irritation	Skin Irrit.	2	H315
Specific target organ toxicity - single exposure	STOT SE	3	H335
Acute toxicity	Acute Tox.	4	H312
Acute toxicity	Acute Tox.	4	H332

Discovery and Applications

4-Amino-2-chloropyrimidine is a halogenated pyrimidine derivative characterized by an amino group at the fourth position and a chlorine atom at the second position of the pyrimidine ring. Pyrimidines, as six-membered nitrogen-containing heterocycles, have long been studied for their roles in nucleic acid chemistry and as scaffolds for synthetic organic chemistry. Halogenated pyrimidines, including 4-amino-2-chloropyrimidine, were developed to provide reactive intermediates for the preparation of functionalized heterocycles and biologically active compounds. The introduction of chlorine at the 2-position enhances the electrophilic character of the ring, making it suitable for nucleophilic substitution reactions, while the amino group at the 4-position offers a nucleophilic site for further derivatization.

The compound is typically synthesized via halogenation of 4-aminopyrimidine precursors or through condensation reactions involving amidines and β-dicarbonyl compounds, followed by selective chlorination at the 2-position. Careful control of reaction conditions, including temperature, solvent, and halogenating agent, is required to achieve high selectivity and yield. The resulting 4-amino-2-chloropyrimidine is usually obtained as a crystalline solid with good stability under ambient conditions. Its halogenated and amino functionalities make it highly versatile in subsequent chemical transformations, which has led to its widespread adoption in research laboratories as a building block for heterocyclic synthesis.

4-Amino-2-chloropyrimidine is predominantly employed as a key intermediate in the preparation of substituted pyrimidines, which are important in pharmaceuticals, agrochemicals, and specialty chemicals. The chlorine atom at the 2-position can undergo nucleophilic aromatic substitution with various nucleophiles, including amines, thiols, and alkoxides, to generate a wide range of functionalized derivatives. This versatility enables the systematic construction of heterocyclic frameworks that serve as scaffolds for biologically active molecules. The amino group at the 4-position further enhances the compound’s utility, allowing formation of amide bonds, ureas, and other nitrogen-containing linkages, which is particularly valuable in drug discovery and medicinal chemistry research.

In pharmaceutical research, 4-amino-2-chloropyrimidine has been used in the synthesis of kinase inhibitors, antiviral agents, and other bioactive molecules. The combination of a reactive halogen and a nucleophilic amino group provides chemists with the ability to introduce structural diversity efficiently, facilitating structure–activity relationship studies and optimization of pharmacological properties. In agrochemical development, it has been incorporated into herbicidal and fungicidal molecules, where substituted pyrimidine rings contribute to biological activity and environmental stability.

Beyond its applications in active compound synthesis, 4-amino-2-chloropyrimidine serves as a model substrate for studying reactivity patterns of halogenated pyrimidines. Its behavior under nucleophilic substitution, oxidation, and coupling reactions has been examined to understand electronic effects, steric influences, and regioselectivity in pyrimidine chemistry. Such studies provide guidance for the design of new heterocyclic molecules and the development of synthetic methodologies.

Physically, 4-amino-2-chloropyrimidine is a stable solid with good solubility in polar organic solvents, allowing for convenient handling in laboratory settings. It can be stored under ambient conditions when protected from moisture and strong acids or bases. Its stability, combined with its versatile reactivity, makes it a reliable intermediate for multistep synthetic sequences and a valuable building block for heterocyclic chemistry.

Overall, 4-amino-2-chloropyrimidine is an important halogenated pyrimidine derivative widely used as a synthetic intermediate. Its dual functionalization with an amino group and a halogen atom provides multiple avenues for chemical modification, making it a cornerstone in the synthesis of diverse biologically and chemically active compounds.

References

2024. Synthesis of 6-dialkylaminopyrimidine carboxamide analogues and their anti-tubercular properties. Medicinal Chemistry Research, 33(10).
DOI: 10.1007/s00044-024-03319-8

2018. Synthesis and evaluation of new 2-chloro-4-aminopyrimidine and 2,6-dimethyl-4-aminopyrimidine derivatives as tubulin polymerization inhibitors. Bioorganic & Medicinal Chemistry Letters, 28(11).
DOI: 10.1016/j.bmcl.2018.04.026