(3-(3-Chlorophenethyl)pyridin-2-yl)(1-methylpiperidin-4-yl)methanone hydrochloride

(3-(3-Chlorophenethyl)pyridin-2-yl)(1-methylpiperidin-4-yl)methanone hydrochloride, also known by its CAS number 119770-60-4, is a compound with significant relevance in pharmaceutical chemistry. It is primarily recognized as an impurity in the synthesis of Loratadine, an antihistamine used to treat allergies. This article reviews the biological activity of this compound, highlighting its pharmacological properties, mechanisms of action, and relevant research findings.

• Molecular Formula : C20H24Cl2N2O
• Molecular Weight : 379.323 g/mol
• Melting Point : 183-185 °C

The compound exhibits biological activity through its interaction with various neurotransmitter systems. Its structure suggests potential affinities for dopamine and serotonin receptors, which are critical in modulating mood and behavior. The presence of the piperidine moiety is indicative of compounds that often exhibit psychoactive properties.

Antihistaminic Activity

Research indicates that this compound may possess antihistaminic properties similar to Loratadine. Studies have shown that derivatives of this compound can inhibit histamine release from mast cells, thereby reducing allergic responses.

Neurotransmitter Receptor Interaction

Studies involving receptor binding assays have demonstrated that this compound has a notable affinity for serotonin receptors (5-HT2A and 5-HT2C) and dopamine D2 receptors. This suggests potential applications in treating mood disorders and schizophrenia, although further studies are necessary to elucidate these effects fully.

Case Study 1: Antiallergic Effects

A study published in the Journal of Medicinal Chemistry explored the antihistaminic effects of related compounds. The results indicated that modifications to the piperidine ring could enhance receptor binding affinity and improve therapeutic efficacy against allergy symptoms .

Case Study 2: Neuropharmacological Assessment

In a neuropharmacological assessment, researchers evaluated the effects of this compound on animal models exhibiting anxiety-like behaviors. The findings suggested a reduction in anxiety levels, correlating with increased serotonin receptor activity .

Data Summary

Basic Questions

Q. What are the standard synthetic routes for this compound, and what methodological considerations are critical?

The compound is synthesized via multi-step reactions involving pyridine and piperidine intermediates. A representative method includes:

• Step 1 : Coupling of 3-chlorophenethyl groups to pyridine rings using NaOH in dichloromethane (DCM) under reflux .
• Step 2 : Piperidine functionalization via nucleophilic substitution or reductive amination, followed by HCl salt formation .
• Purification : Column chromatography or recrystallization to isolate the hydrochloride salt. Key considerations include maintaining anhydrous conditions, controlling reaction temperature, and verifying intermediate purity via TLC or HPLC .

Q. How is the compound’s purity assessed in academic research?

Purity is evaluated using:

• HPLC : Retention time analysis at 206 nm with a C18 column; purity ≥98% is typical .
• 1H NMR : Detection of impurities (e.g., residual solvents like acetone at δ 2.1 ppm) and integration of proton signals .
• Melting Point : Consistency with literature values (e.g., 175–177°C for structurally related compounds) .

Q. What safety protocols are recommended for handling this compound?

Safety measures include:

• PPE : Gloves, lab coats, and goggles to prevent skin/eye contact .
• Ventilation : Use of fume hoods to avoid inhalation of dust or vapors .
• Storage : In airtight containers, protected from light and moisture at 2–8°C .
• Spill Management : Neutralization with inert absorbents (e.g., sand) and disposal as hazardous waste .

Q. What spectroscopic methods are used for structural characterization?

• X-ray Crystallography : SHELX software (e.g., SHELXL) for refining crystal structures and resolving bond angles/distances .
• 1H/13C NMR : Assigning peaks for pyridine (δ 7.5–8.5 ppm) and piperidine (δ 1.5–3.0 ppm) moieties .
• IR Spectroscopy : Confirming carbonyl (C=O) stretches near 1650–1750 cm⁻¹ .

Advanced Research Questions

Q. How can researchers optimize the synthesis to improve yield and purity?

Optimization strategies include:

• Catalyst Screening : Testing Pd-based catalysts for coupling reactions to reduce byproducts .
• Solvent Selection : Replacing DCM with polar aprotic solvents (e.g., DMF) to enhance reaction efficiency .
• DoE (Design of Experiments) : Varying temperature (50–100°C), reaction time (12–24 hrs), and stoichiometry to identify optimal conditions .

Q. How should discrepancies in crystallographic data (e.g., bond lengths/angles) be analyzed and resolved?

• Software Cross-Validation : Compare SHELXL refinements with alternative programs (e.g., Olex2) to check for systematic errors .
• Twinned Data Analysis : Use the TwinRotMat tool in SHELXL to refine datasets affected by crystal twinning .
• Complementary Techniques : Validate results with DFT calculations or NMR-derived distance constraints (e.g., NOESY) .

Q. What strategies are effective in resolving conflicting pharmacological data (e.g., receptor binding vs. functional assays)?

• Orthogonal Assays : Perform radioligand binding and calcium flux assays to cross-verify target engagement .
• Dose-Response Curves : Assess compound efficacy (EC50) and potency (IC50) across multiple replicates to identify outliers .
• Metabolite Screening : Use LC-MS to rule out degradation products interfering with assay results .

Q. How can stability studies under varying conditions inform storage and handling protocols?

• Accelerated Stability Testing : Expose the compound to 40°C/75% RH for 4 weeks and monitor degradation via HPLC .
• Photostability : UV/Vis spectroscopy under ICH Q1B guidelines to assess light sensitivity .
• pH Stability : Incubate in buffered solutions (pH 3–9) and track salt formation or hydrolysis .

Comparison with Structurally Similar Compounds

Key Structural Features for Comparison:

Pyridine/phenyl substitutions : Position and type of halogen (e.g., Cl, F) or alkyl chains.

Piperidine modifications : Methylation position or replacement with other heterocycles (e.g., pyrrolidine).

Ketone bridge : Presence or absence of a carbonyl linker.

Table 1: Physicochemical and Pharmacological Comparison

*logP values estimated via computational models.

Key Findings:

Fluorine substitution reduces molecular weight but may decrease receptor affinity in certain targets (e.g., dopamine D₂).

Piperidine vs. Pyrrolidine :

• Replacing 1-methylpiperidine with pyrrolidine lowers molecular weight and logP, increasing solubility. However, this reduces conformational rigidity, possibly explaining the higher 5-HT₂A receptor affinity in the pyrrolidine analog.

Methylation Impact: The 1-methyl group on the piperidine ring in the target compound improves solubility (15 mg/mL) compared to the non-methylated variant (8 mg/mL), critical for formulation stability.

Ketone Bridge :

• Removal of the ketone (e.g., in ether-linked analogs) significantly reduces receptor binding potency, underscoring its role in molecular recognition.