N-(2-Chloro-4-hydroxyphenyl)-N'-cyclopropyl-urea
[CAS# 796848-79-8]

Identification

• Classification: Chemical reagent >> Organic reagent >> Urea
• Name: N-(2-Chloro-4-hydroxyphenyl)-N'-cyclopropyl-urea
• Synonyms: 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea
• Molecular Formula: C₁₀H₁₁ClN₂O₂
• Molecular Weight: 226.66
• CAS Registry Number: 796848-79-8
• SMILES: C1CC1NC(=O)NC2=C(C=C(C=C2)O)Cl

Properties

• Density: 1.4±0.1 g/cm³ Calc.^*
• Boiling point: 364.6±42.0 °C 760 mmHg (Calc.)^*
• Flash point: 174.3±27.9 °C (Calc.)^*
• Solubility: water: Practically insoluble (0.084 g/L) (25 °C), Calc.
• Index of refraction: 1.638 (Calc.)^*

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

Safety Data

• Hazard Symbols: GHS07 Warning
• Risk Statements: H302-H315-H319
• Safety Statements: P280-P305+P351+P338

Discovery and Applications

N-(2-Chloro-4-hydroxyphenyl)-N'-cyclopropyl-urea is a substituted urea compound characterized by a phenyl ring bearing a chlorine atom at the second position and a hydroxy group at the fourth position, linked through a urea moiety to a cyclopropyl group. The combination of the halogenated aromatic ring, hydroxy functionality, and urea linkage imparts unique chemical reactivity and enables diverse synthetic transformations. Compounds of this type have been explored as intermediates in medicinal chemistry and agrochemical research due to their potential to serve as scaffolds for biologically active molecules. The incorporation of the cyclopropyl group introduces steric rigidity, while the hydroxy and chloro substituents influence electronic distribution, facilitating selective reactions at defined positions.

The synthesis of N-(2-chloro-4-hydroxyphenyl)-N'-cyclopropyl-urea generally involves the reaction of 2-chloro-4-hydroxyaniline with an appropriate isocyanate or carbamoyl derivative containing the cyclopropyl group. Careful control of reaction temperature, solvent, and stoichiometry ensures selective formation of the urea linkage without side reactions such as over-alkylation or hydrolysis. The product is typically isolated as a crystalline solid and can be purified by recrystallization or chromatography. The stability of the compound under ambient conditions allows it to be stored and handled conveniently for further synthetic applications.

This compound is primarily employed as an intermediate in the preparation of more complex molecules with potential biological activity. The urea moiety is a versatile functional group that can participate in hydrogen bonding, allowing modification of molecular recognition properties. The aromatic hydroxy group can be further derivatized, and the chloro substituent can undergo nucleophilic aromatic substitution or metal-catalyzed cross-coupling reactions. These features make N-(2-chloro-4-hydroxyphenyl)-N'-cyclopropyl-urea an attractive building block for medicinal chemistry programs aiming to develop enzyme inhibitors, receptor ligands, or small molecule modulators.

In pharmaceutical research, compounds derived from this urea scaffold have been explored for their activity against various enzymes and protein targets. The presence of the hydroxy and urea functionalities allows the formation of multiple hydrogen bonds with biological macromolecules, enhancing binding specificity and potency. The cyclopropyl group provides conformational constraint, which can improve pharmacokinetic properties and metabolic stability. Researchers utilize such compounds to investigate structure–activity relationships and optimize interactions with target sites while minimizing off-target effects.

Beyond medicinal chemistry, the compound has potential applications in materials chemistry and chemical methodology research. Its functional groups can serve as points for cross-linking, attachment to polymers, or incorporation into supramolecular architectures. The combination of halogenated aromatic systems and urea linkages has been exploited in the design of ligands, catalysts, and functional materials, particularly where hydrogen bonding and steric effects are critical. These applications rely on the predictable reactivity of the functional groups and the structural rigidity imparted by the cyclopropyl substituent.

Physically, N-(2-chloro-4-hydroxyphenyl)-N'-cyclopropyl-urea is a stable solid with moderate solubility in polar organic solvents such as ethanol, dimethylformamide, and dichloromethane. Proper storage away from moisture and strong acids or bases ensures that the compound retains its chemical integrity for use in multistep synthesis. Its combination of reactivity, stability, and steric characteristics makes it a versatile intermediate for constructing diverse chemical entities.

Overall, N-(2-chloro-4-hydroxyphenyl)-N'-cyclopropyl-urea serves as an important functional intermediate in the preparation of structurally complex and biologically relevant molecules. Its halogenated aromatic ring, hydroxy functionality, urea linkage, and cyclopropyl substituent provide multiple avenues for selective chemical modification, making it a valuable scaffold in both synthetic and medicinal chemistry research.

References

2022. A patent review on efficient strategies for the total synthesis of pazopanib, regorafenib and lenvatinib as novel anti-angiogenesis receptor tyrosine kinase inhibitors for cancer therapy. Molecular Diversity, 26(4).
DOI: 10.1007/s11030-022-10406-8

2020. Novel method for the synthesis of lenvatinib using 4-nitrophenyl cyclopropylcarbamate and their pharmaceutical salts. Chemical Papers, 75(4).
DOI: 10.1007/s11696-020-01402-z