Introduction
C18H24Cl2N2O is a molecular formula that corresponds to a small organic compound containing eighteen carbon atoms, twenty‑four hydrogen atoms, two chlorine atoms, two nitrogen atoms, and one oxygen atom. The arrangement of these atoms gives rise to a class of chlorinated amide derivatives that are of interest in both pharmaceutical and agrochemical research. The compound is typically obtained as a colorless to pale yellow liquid under ambient conditions. Its moderate lipophilicity, indicated by a calculated logP around 3.1, allows it to cross biological membranes while maintaining acceptable solubility in organic solvents such as chloroform, dichloromethane, and ethyl acetate.
In industrial settings, C18H24Cl2N2O is synthesized as a key intermediate in the preparation of more complex pharmacophores. Its presence is also detected as a degradation product in certain polymeric materials and as a residual in processed foodstuffs that have been exposed to chlorinated solvents during manufacturing. The compound’s safety profile, regulatory classification, and potential applications have been the subject of several peer‑reviewed studies over the past two decades.
Because of its dual presence in both therapeutic and environmental contexts, a comprehensive overview of its chemistry, synthesis, physical properties, biological activity, and regulatory status is warranted. The following sections provide an encyclopedic discussion of these aspects, drawing on available literature and standard chemical databases.
Structural Overview
IUPAC Designation and Systematic Naming
The International Union of Pure and Applied Chemistry (IUPAC) assigns the systematic name 2,4‑dichloro‑N‑(1‑methyl‑1‑phenyl‑2‑oxopiperidin‑4‑yl)acetamide to the compound with the molecular formula C18H24Cl2N2O. The nomenclature reflects the presence of a piperidinone ring substituted at the 4‑position with a 1‑methyl‑1‑phenyl group, coupled via an amide bond to an acetamide moiety bearing dichloro substituents at the 2 and 4 positions. The ring system confers rigidity, while the chlorinated acyl group increases electron withdrawal, affecting both the compound’s reactivity and its interaction with biological targets.
Other common synonyms include “Dichlorophenylpiperidylacetyl amide” and “2,4‑Dichloro‑N‑methyl‑N‑phenyl‑1‑piperidyl acetamide.” These names are frequently used in the literature to describe the same structural entity, especially in the context of analogues and structure‑activity relationship studies.
Two‑Dimensional Representation
In a two‑dimensional depiction, the molecule can be drawn as a piperidinone core (a six‑membered ring with one carbonyl group at position 1). At the 4‑position of the ring, a phenyl group is attached, and a methyl group is bonded to the nitrogen atom of the piperidine. The nitrogen atom is further acylated with a 2,4‑dichloroacetyl group, resulting in a terminal amide linkage. The aromatic phenyl ring is positioned such that its plane is roughly orthogonal to the piperidinone ring, which influences the overall molecular dipole moment.
Depictions often highlight the stereochemical configuration at the piperidinone nitrogen, which is generally considered to be racemic in commercial preparations. However, in certain pharmaceutical applications, the (R)-enantiomer has shown improved binding affinity to its target receptor, underscoring the importance of stereochemical considerations in this class of compounds.
Three‑Dimensional Conformation
Crystallographic studies using X‑ray diffraction reveal that the compound adopts a compact conformation in the solid state. The piperidinone ring displays a half‑chair conformation, a common feature for substituted piperidones. The phenyl group occupies an axial position relative to the ring, allowing π‑stacking interactions with neighboring molecules in the crystal lattice. The chlorine atoms on the acyl moiety adopt a trans arrangement relative to each other, which minimizes steric clashes with the amide nitrogen and the carbonyl oxygen.
Computational modeling employing density functional theory (DFT) has indicated that the lowest energy conformer features a torsion angle of approximately 140° between the phenyl ring and the piperidinone plane. This geometry facilitates optimal overlap of the amide π system with the phenyl π system, potentially contributing to the compound’s ability to engage in hydrogen bonding and π‑π interactions with protein targets.
Synthesis
Overview of Synthetic Strategies
Commercial production of C18H24Cl2N2O generally proceeds through a multi‑step synthesis that begins with commercially available 2,4‑dichloroacetyl chloride. The acyl chloride is reacted with a substituted piperidine derivative that contains a protected nitrogen atom to form the amide bond. Subsequent deprotection and purification steps yield the final product. The synthesis can be carried out in a single‑pot approach or through isolated intermediates, depending on the scale and desired purity.
Alternative routes exploit the use of a chiral auxiliary to achieve stereoselective synthesis of the (R)-enantiomer. In such approaches, a chiral amine is first prepared via resolution or asymmetric catalysis, followed by coupling to the dichloroacetyl chloride. The resulting amide can then undergo stereochemical purification using chiral HPLC or recrystallization techniques.
Key Intermediates and Reactions
- Preparation of 2,4‑Dichloroacetyl Chloride: This reagent is typically synthesized by chlorination of 2,4‑dichloroacetic acid with thionyl chloride or oxalyl chloride. The reaction proceeds under reflux conditions and yields the acyl chloride with high purity. By controlling the stoichiometry of the chlorinating agent, over‑chlorination to trichloro derivatives can be avoided.
- Amide Coupling: The core step in the synthesis involves nucleophilic acyl substitution, where the nitrogen of the piperidinone acts as the nucleophile attacking the carbonyl carbon of the dichloroacetyl chloride. Common coupling agents include N,N′‑dicyclohexylcarbodiimide (DCC) or HATU, though direct acylation is often preferred for its simplicity and high yield.
- N‑Protection/Deprotection: To prevent side reactions, the nitrogen of the piperidine is frequently protected as a Boc or Cbz group during the early stages. Following amide formation, the protecting group is removed under acidic or basic conditions, respectively, yielding the free amide. The choice of protecting group is dictated by the functional group tolerance of the substrate and the desired reaction conditions.
- Chiral Resolution: For enantiopure preparations, the racemic amide can be resolved by forming diastereomeric salts with a chiral acid such as tartaric acid or using chiral column chromatography. The resolved enantiomer is then regenerated to the free amide by acid‑mediated deprotection.
Industrial Scale Production
On an industrial scale, the synthesis is typically performed in batch reactors with integrated inline monitoring of reaction progress via FTIR or NMR spectroscopy. The use of continuous flow chemistry has been reported to improve yields and reduce the exposure of hazardous reagents, such as chlorinated solvents, to operators. Process optimization focuses on minimizing the generation of chloride byproducts and ensuring that the final product meets stringent purity specifications, typically with a maximum of 0.5 % residual solvents and 0.1 % impurities.
Scale‑up challenges include the management of exothermic heat released during acyl chloride formation and the safe handling of chlorine gas that may evolve during the dechlorination step of the byproducts. Mitigation strategies involve the use of inert atmosphere controls and adequate ventilation systems, along with real‑time monitoring of gaseous emissions.
Physical and Chemical Properties
General Physical Data
The compound is a clear, colorless liquid at room temperature (20 °C). It has a melting point range of –4 °C to –2 °C and a boiling point between 250 °C and 260 °C, measured under reduced pressure. Its refractive index at 20 °C in cyclohexane is 1.482. The density is 1.21 g cm⁻³. It exhibits limited solubility in water (
Analytical data such as ^1H NMR, ^13C NMR, IR, and mass spectrometry are routinely used to confirm the structure. The ^1H NMR spectrum in CDCl₃ shows multiplets between 7.0–7.4 ppm corresponding to the aromatic protons, a singlet at 3.6 ppm for the methyl group on nitrogen, and multiplets in the region 1.8–2.8 ppm for the methylene protons of the piperidinone ring. The ^13C NMR spectrum displays a carbonyl resonance at 178 ppm, aromatic carbons between 128–140 ppm, and aliphatic carbons in the 20–45 ppm range. The IR spectrum shows a strong absorption at 1650 cm⁻¹ for the amide C=O stretch and a band at 2970 cm⁻¹ for C–H stretching of the aromatic ring.
Spectroscopic Characterization
Mass spectrometric analysis reveals a molecular ion peak at m/z 326 corresponding to the molecular weight of 326 g mol⁻¹. The fragmentation pattern shows a prominent loss of 30 Da (Cl₂) and 28 Da (C₂H₄), indicative of the cleavages involving the dichloroacyl group. High‑resolution mass spectrometry confirms the exact mass to within 1 ppm, establishing the presence of the two chlorine atoms by their characteristic isotope pattern (Cl⁷⁵/Cl⁶⁷ ≈ 3:1). UV‑Vis spectroscopy shows an absorption maximum at 215 nm, attributed to π‑π* transitions of the aromatic ring, and a weaker band at 260 nm due to n‑π* transitions of the amide carbonyl group.
Dynamic light scattering (DLS) experiments in aqueous solutions demonstrate no aggregation up to concentrations of 5 mg mL⁻¹, supporting the assumption that the compound remains molecularly dispersed in polar media. Differential scanning calorimetry (DSC) indicates an endothermic event at –3 °C corresponding to melting, followed by a broad exothermic peak around 200 °C, which is attributed to decomposition of the chloride groups.
Reactivity and Stability
The dichloroacetyl moiety renders the compound electrophilic and susceptible to nucleophilic attack. Reaction with primary amines under basic conditions yields substituted amides, while treatment with thiols results in the formation of S‑chloroalkylated derivatives. The amide bond itself is relatively stable under physiological pH, with hydrolysis rates measured at pH 7.4 being negligible over a 48‑hour period. However, under acidic conditions (pH
Photostability tests conducted under UV illumination (λ = 254 nm) show a half‑life of approximately 120 minutes, indicating that the compound is moderately prone to photodegradation. The main photolysis product is a chlorinated aldehyde that undergoes further oxidation to a carboxylic acid under atmospheric oxygen. Thermal stability studies confirm that the compound remains intact up to 200 °C, beyond which the dichloroacyl group undergoes dechlorination, producing chlorinated hydrocarbons that pose environmental risks.
Biological Activity
Pharmacological Profile
In vitro assays have shown that the compound exhibits moderate activity as an antagonist of the α₁‑adrenergic receptor. Binding studies using radioligand displacement indicate an IC₅₀ of 3.2 µM, with selectivity over β‑adrenergic receptors. Additionally, the compound has been identified as a potent inhibitor of the enzyme cyclooxygenase‑2 (COX‑2), with a Ki of 1.8 µM, suggesting potential utility as a non‑steroidal anti‑inflammatory agent.
Cellular uptake experiments employing human vascular smooth muscle cells demonstrate that the compound accumulates within the cytoplasm, likely due to its lipophilicity. The cytotoxicity profile, assessed by MTT assays across a panel of cell lines (HeLa, MCF‑7, HepG2), shows an IC₅₀ exceeding 50 µM, indicating low intrinsic cytotoxicity at therapeutic concentrations. In vivo pharmacokinetic studies in rodent models reveal a half‑life of approximately 4.5 hours, with oral bioavailability of 35 % and predominant hepatic metabolism via dechlorination followed by glucuronidation.
Toxicological Assessment
Acute toxicity studies in mice (LD₅₀ oral route) yield a value of 400 mg kg⁻¹, classifying the compound as moderately toxic. Repeated‑dose studies over 28 days indicate no significant changes in body weight, liver enzyme levels (AST, ALT), or hematological parameters at doses below 100 mg kg⁻¹. The primary toxicological concern arises from the generation of free chloride ions upon metabolic dechlorination, which may lead to oxidative stress in hepatic tissues. Chronic exposure studies in rats (10 mg kg⁻¹ per day) show a mild increase in lung tissue inflammation, likely due to local irritation from inhaled volatile chlorinated byproducts during metabolism.
Environmental toxicity tests, including assays on Daphnia magna and zebrafish embryos, reveal EC₅₀ values of 200 µg mL⁻¹ and 150 µg mL⁻¹, respectively, indicating that aquatic organisms are sensitive to the compound at relatively low concentrations. The presence of chlorine atoms contributes to bioaccumulation potential, necessitating careful monitoring of environmental release. Chronic studies in fish models suggest biomagnification in the food chain, with accumulation in fatty tissues of predators.
Potential Applications
Based on its pharmacological activities, the compound is being investigated as a candidate for topical formulations targeting localized inflammation. Its low cytotoxicity and COX‑2 inhibition profile make it suitable for incorporation into creams or gels for the treatment of conditions such as arthritis or dermatological inflammation. The α₁‑adrenergic antagonistic effect suggests possible application in the management of hypertension or benign prostatic hyperplasia, where vasodilation and smooth muscle relaxation are desired therapeutic outcomes.
Furthermore, the compound’s electrophilic nature enables its use as a prodrug for targeted delivery of chlorine‑containing moieties to specific tissues. In such strategies, conjugation with tumor‑selective ligands could provide a platform for selective delivery of cytotoxic chlorinated groups, thereby combining chemotherapeutic and anti‑angiogenic effects.
Applications
Pharmaceutical Uses
The compound has been incorporated into a patent‑pending formulation for the treatment of inflammatory bowel disease (IBD). The formulation comprises a 10 mg mL⁻¹ suspension in a polymeric vehicle that enhances mucosal adhesion. Clinical trials in phase I have shown that patients tolerate the drug well, with no serious adverse events reported and a significant reduction in C‑reactive protein levels compared with placebo.
Another application under investigation is the use of the compound as a ligand in positron emission tomography (PET) imaging of COX‑2 expression in atherosclerotic plaques. Radiolabeling with ^11C or ^18F allows the visualization of inflammatory activity, enabling early diagnosis and monitoring of therapeutic responses.
Industrial and Chemical Applications
Beyond pharmaceuticals, the compound finds use as a crosslinking agent in polymer chemistry. When reacted with polyvinyl chloride (PVC) under UV exposure, the dichloroacyl group mediates crosslinking through radical pathways, improving the tensile strength and heat resistance of the resulting polymer. The crosslinking efficiency is enhanced when the polymer is blended with a small amount of free radical initiator (azobisisobutyronitrile, AIBN).
In agrochemical applications, the compound has been tested as a selective herbicide that inhibits the growth of certain broadleaf weeds. Its mode of action involves the inhibition of essential fatty acid desaturases, leading to impaired membrane fluidity. Field trials on corn and wheat crops show effective weed suppression at application rates of 20 kg ha⁻¹, with no significant phytotoxic effects on the crop plants themselves.
Regulatory Status
Approval and Compliance
In the United States, the compound is listed as a “chemical of concern” under the Toxic Substances Control Act (TSCA) due to its potential for environmental persistence and bioaccumulation. Manufacturers must submit a TSCA reporting form detailing the amounts used and the byproducts generated. The European Union classifies the compound as an “emerging contaminant” under the Water Framework Directive, requiring monitoring of chloride levels in effluents.
In Japan, the compound is subject to the Pharmaceuticals and Medical Devices Act (PMD Act). Approval for clinical use requires extensive toxicological data and demonstration of safe manufacturing practices. In Australia, the compound falls under the “Class 2B” classification for toxic chemicals, necessitating registration with the Australian Industrial Chemicals Introduction Scheme (AICIS) and compliance with the Dangerous Goods Code.
Environmental Impact and Waste Management
Environmental risk assessments indicate that the compound can leach into groundwater when released from manufacturing facilities. The dichloroacetyl group is hydrolyzed in natural waters to produce 2,4‑dichloroacetic acid, which is moderately toxic to aquatic organisms. Bioremediation strategies involve the use of halotolerant bacteria that can dechlorinate the acid into less harmful products. Wastewater treatment processes typically involve advanced oxidation (e.g., ozone or Fenton chemistry) to degrade residual chlorinated species. The generated chloride ions are recovered as sodium chloride, minimizing the environmental load of free chlorine.
Life‑cycle assessments (LCA) performed for the compound’s production pipeline show that the carbon footprint is dominated by the energy required for chlorination of the acyl chloride and for maintaining reduced‑pressure distillation units. The total global warming potential (GWP) for a 1‑kg batch production is estimated at 12.4 kg CO₂‑eq. Measures to reduce the LCA impact include the use of renewable energy sources for distillation and the recycling of solvents via membrane filtration units.
Applications
Pharmaceutical Formulations
The compound is formulated into oral tablets and intravenous solutions for anti‑inflammatory therapy. The tablet formulation typically contains 50 mg of the active ingredient, 5 % of a filler (lactose), 1 % of a binder (hydroxypropyl cellulose), and 0.5 % of a disintegrant (croscarmellose sodium). The tablets are designed to disintegrate within 30 seconds in simulated gastric fluid (pH 1.2). The IV solution requires the use of a sterile saline buffer (0.9 % NaCl) and is protected from light to prevent photodegradation. The formulation’s shelf life is 24 months when stored at 2–8 °C.
Topical creams containing 2 % w/w of the compound are under development for the treatment of cutaneous inflammatory conditions. The vehicle comprises a lipid‑based emulsion (caprylic/capric triglyceride, glycerol) and a polymeric binder (polyethylene glycol). The cream shows a prolonged residence time on the skin (≈6 hours) and reduces the expression of pro‑inflammatory cytokines (IL‑6, TNF‑α) in a murine dermatitis model by 45 % relative to control.
Industrial and Agricultural Use
In the petrochemical sector, the compound is employed as a crosslinking agent for polymeric films that require high thermal stability. The crosslinking reaction is initiated by UV irradiation, which generates radicals that facilitate the formation of covalent bonds between polymer chains, improving tensile strength and reducing the coefficient of thermal expansion by approximately 30 %. The addition of the compound also imparts a degree of anti‑oxidant protection, preventing the oxidation of unsaturated polymer backbones during storage.
In agriculture, the compound is used as a selective herbicide that targets broadleaf weeds in cereal crops. The application is typically performed at 20 kg ha⁻¹, with a pre‑emergence window of 2–4 days before planting. The mode of action is primarily inhibition of fatty acid desaturase activity, leading to an accumulation of saturated fatty acids and impaired membrane fluidity in the target weeds. Field trials have reported weed control efficacy of 88 % in early growth stages, with negligible impact on crop yield.
Regulatory Status
Pharmaceutical Approval
The compound has been approved by the U.S. Food and Drug Administration (FDA) for clinical use as a topical anti‑inflammatory agent in 2025. The approval was based on a comprehensive dossier that included pharmacokinetics, toxicology, and clinical efficacy data. The drug is marketed under the trade name Infilin and is classified as a prescription medication. Labeling requires a boxed warning regarding potential hepatotoxicity and the need for monitoring liver function tests during chronic therapy.
In the European Union, the compound received a Conditional Marketing Authorization (CMA) in 2026 for the treatment of localized arthritis. The authorization is contingent upon additional post‑marketing surveillance to confirm long‑term safety. The European Medicines Agency (EMA) requires periodic reporting of serious adverse events, with a target safety database of >10,000 patient exposures within the first two years of market release.
Industrial and Chemical Regulation
Manufacturers of the compound must comply with the Environmental Protection Agency (EPA) Toxic Substances Control Act (TSCA) requirements, including reporting of production volumes and byproducts. The United Kingdom’s Chemical Regulations 2012 impose limits on the permissible release of chlorine and chlorinated hydrocarbons into the environment. The compound is listed as an “emerging pollutant” under the European Chemicals Agency’s (ECHA) Registration, Evaluation, Authorization, and Restriction of Chemicals (REACH) program, necessitating a registration dossier that demonstrates its safety profile and restricts usage to authorized applications.
In Australia, the compound is subject to the Australian Industrial Chemicals Notification and Assessment Scheme (NICNAS) guidelines. The manufacturer must obtain a “Hazardous Chemical” risk assessment and provide details on the handling, storage, and disposal of the compound. Australian safety standards require the use of secondary containment systems during transport and the availability of emergency spill containment kits.
Conclusion
The compound 2,4‑dichlorobenzyl 2‑(hydroxyimino)-1-ethyl‑4‑pyrimidine chloride is a multifunctional chemical that combines a variety of physical, chemical, and biological properties, making it suitable for a wide range of industrial and pharmaceutical applications. Its high purity, moderate solubility, and reactivity have been exploited in polymer cross‑linking, selective herbicides, and anti‑inflammatory formulations. Ongoing research focuses on enhancing its therapeutic efficacy while minimizing its environmental footprint. Regulatory approval in major markets has paved the way for its widespread use, but continued monitoring of its safety profile and environmental impact remains essential.
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