methyl 2-(chloromethyl)-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate
[CAS# 2230200-76-5]

Identification

• Classification: Organic raw materials >> Heterocyclic compound >> Imidazoles
• Name: methyl 2-(chloromethyl)-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate
• Molecular Formula: C₁₄H₁₅ClN₂O₃
• Molecular Weight: 294.73
• CAS Registry Number: 2230200-76-5
• SMILES: COC(=O)C1=CC2=C(C=C1)N=C(N2C[C@@H]3CCO3)CCl

Properties

• Density: 1.4±0.1 g/cm³, Calc.^*
• Index of Refraction: 1.640, Calc.^*
• Boiling Point: 470.9±25.0 °C (760 mmHg), Calc.^*
• Flash Point: 238.6±23.2 °C, Calc.^*

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

Safety Data

• Hazard Symbols: GHS07 Warning
• Risk Statements: H315-H319-H335
• Safety Statements: P261-P305+P351+P351-P302+P352

Discovery and Applications

Methyl 2-(chloromethyl)-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate is a benzimidazole derivative that has emerged as a key intermediate in the development of glucagon-like peptide‑1 receptor (GLP-1R) agonists. The benzimidazole core provides a rigid, planar scaffold that is compatible with receptor-binding motifs, while the 2-(chloromethyl) and 3-[(2S)-oxetan-2-yl]methyl substituents allow further functionalization to optimize potency, selectivity, and pharmacokinetic properties. The methyl ester at the 5-position serves as a versatile handle for derivatization into carboxylic acids or amides as required in downstream medicinal chemistry.

The discovery of this compound was motivated by the need for orally available GLP-1R agonists, which are of significant therapeutic interest for the treatment of type 2 diabetes and obesity. Researchers focused on designing indole and benzimidazole derivatives capable of mimicking key interactions of peptide ligands with the GLP-1 receptor while exhibiting enhanced metabolic stability and oral bioavailability. Structural optimization studies identified methyl 2-(chloromethyl)-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate as a privileged intermediate that could be elaborated into potent agonists with desirable pharmacodynamic profiles.

In synthetic terms, the compound is constructed via functionalization of the benzimidazole ring, incorporating stereocontrolled installation of the oxetane substituent to provide a defined three-dimensional topology. The chloromethyl group at the 2-position serves as an electrophilic site for nucleophilic substitution, enabling the introduction of diverse substituents that modulate receptor binding and solubility. Optimization of these structural elements has been guided by structure-activity relationship (SAR) studies, which allowed fine-tuning of lipophilicity, hydrogen-bonding interactions, and steric complementarity to the GLP-1 receptor binding site.

Applications of methyl 2-(chloromethyl)-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate are largely in the context of drug discovery. The compound functions as an intermediate in the synthesis of orally available GLP-1R agonists, such as Danuglipron, facilitating the construction of multi-functionalized molecules capable of eliciting insulinotropic and glucose-lowering effects. Beyond medicinal chemistry, its benzimidazole framework and functional handles make it potentially useful in the preparation of analogues for SAR exploration, formulation studies, and structure-guided drug design campaigns.

Overall, methyl 2-(chloromethyl)-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate exemplifies a strategically designed synthetic intermediate that combines the stability and planarity of a benzimidazole ring with stereochemically defined substituents to enable access to highly potent and orally bioavailable GLP-1 receptor agonists. Its role in medicinal chemistry demonstrates the utility of modular, functionalized heterocycles in modern drug development programs, where small structural variations can lead to significant improvements in pharmacological properties.

References

Zhang Y, Li X, Chen J, et al. (2025) Discovery and optimization of novel indolecarboxylic acid derivative as potent glucagon-like peptide‑1 receptor agonists. Molecular Diversity, 29 May 2025. DOI: 10.1007/s11030-025-11213-7

Maas R, De Vries H, Smit M, et al. (2022) Synthesis of Danuglipron: An Orally Available GLP-1R Agonist. Synfacts 18 August 2022. DOI: 10.1055/s-0041-1738304