Abstract

Canertinib, systematically named N-{4-(3-chloro-4-fluoroanilino)-7-[3-(morpholin-4-yl)propoxy]quinazolin-6-yl}prop-2-enamide (C₂₄H₂₅ClFN₅O₃), represents a synthetic quinazoline derivative with significant chemical and pharmacological interest. This heterocyclic organic compound exhibits a molecular mass of 485.94 g·mol⁻¹ and manifests as a white to off-white crystalline solid under standard conditions. The molecular architecture incorporates multiple pharmacophoric elements including a quinazoline core, acrylamide functionality, morpholine substituent, and halogenated aniline moiety. Canertinib demonstrates limited aqueous solubility but exhibits good solubility in polar organic solvents such as dimethyl sulfoxide and dimethylformamide. The compound's chemical behavior is characterized by its reactivity as an electrophile through the acrylamide group, enabling covalent interactions with biological nucleophiles. Thermal analysis reveals a melting point range of 198-202 °C with decomposition observed above 250 °C.

Introduction

Canertinib (development codes CI-1033, PD-183805) belongs to the chemical class of 4-anilinoquinazolines, a family of synthetic heterocyclic compounds first developed in the late 1990s. This organic molecule represents a structurally advanced derivative of earlier quinazoline-based compounds, incorporating multiple functional groups that confer distinctive chemical properties. The compound emerged from systematic structure-activity relationship studies aimed at developing irreversible enzyme inhibitors through strategic incorporation of Michael acceptor functionality.

As a purely synthetic compound, canertinib does not occur naturally and requires multi-step organic synthesis for production. The molecular structure exemplifies modern medicinal chemistry principles, combining a planar quinazoline heterocycle with flexible side chains containing hydrogen bond acceptors and donors. This architectural arrangement creates a molecule with both hydrophobic and hydrophilic regions, influencing its solubility and reactivity characteristics.

Molecular Structure and Bonding

Molecular Geometry and Electronic Structure

The canertinib molecule (C₂₄H₂₅ClFN₅O₃) exhibits a complex three-dimensional architecture with defined conformational preferences. X-ray crystallographic analysis reveals that the quinazoline core maintains planarity with a root-mean-square deviation of less than 0.05 Å from the mean plane. The dihedral angle between the quinazoline system and the aniline ring measures approximately 35-40°, indicating moderate conjugation between these aromatic systems.

The morpholine ring adopts a chair conformation with the nitrogen atom positioned equatorially. The propoxy linker connecting the morpholine to the quinazoline core exhibits flexibility, with preferred rotameric states around the C-O bonds. The acrylamide group projects from the 6-position of the quinazoline ring, with the carbonyl oxygen and vinyl group adopting orientations that maximize resonance stabilization.

Electronic structure analysis using density functional theory calculations indicates highest occupied molecular orbital (HOMO) electron density localized primarily on the quinazoline π-system and the aniline nitrogen, while the lowest unoccupied molecular orbital (LUMO) shows significant density on the acrylamide carbonyl and vinyl system. This electronic distribution supports the compound's electrophilic character at the β-carbon of the acrylamide group.

Chemical Bonding and Intermolecular Forces

Canertinib exhibits diverse bonding patterns characteristic of complex heterocyclic systems. The quinazoline core contains alternating single and double bonds with bond lengths typical of aromatic heterocycles: C-N bonds measure 1.33-1.35 Å, while C-C bonds range from 1.38-1.42 Å. The exocyclic C-N bond connecting the aniline to the quinazoline measures approximately 1.37 Å, indicating partial double bond character due to resonance with the quinazoline ring system.

Intermolecular forces in crystalline canertinib include multiple hydrogen bonding interactions. The secondary amide functionality serves as both hydrogen bond donor (N-H) and acceptor (C=O), forming extended chains in the solid state. The morpholine oxygen and quinazoline nitrogen atoms act as additional hydrogen bond acceptors. van der Waals interactions between hydrophobic regions and dipole-dipole interactions between polar groups further stabilize the crystal packing.

The molecular dipole moment, calculated at the B3LYP/6-31G* level, measures 5.2 Debye, oriented from the morpholine region toward the halogenated aniline moiety. This significant polarity influences solubility behavior and intermolecular interactions in various solvent environments.

Physical Properties

Phase Behavior and Thermodynamic Properties

Canertinib manifests as a white to off-white crystalline powder under standard conditions. The compound exhibits polymorphism with at least two characterized crystalline forms. Form I, the thermodynamically stable polymorph at room temperature, crystallizes in the monoclinic space group P2₁/c with unit cell parameters a = 15.23 Å, b = 12.87 Å, c = 18.45 Å, and β = 102.7°. Form II, obtained under specific crystallization conditions, displays orthorhombic symmetry with space group Pbca.

The melting point of the stable polymorph occurs at 198-202 °C with decomposition observed above 250 °C. Differential scanning calorimetry shows a sharp endothermic peak at 200 °C corresponding to melting, followed by exothermic decomposition events. The heat of fusion measures 38.5 kJ·mol⁻¹ ± 1.2 kJ·mol⁻¹. The compound sublimes under reduced pressure (0.1 mmHg) at temperatures above 180 °C.

The density of crystalline canertinib measures 1.32 g·cm⁻³ ± 0.02 g·cm⁻³ at 25 °C. The refractive index of the crystalline material is 1.62 ± 0.01 at the sodium D-line. Specific heat capacity at 25 °C measures 1.21 J·g⁻¹·K⁻¹ ± 0.05 J·g⁻¹·K⁻¹.

Spectroscopic Characteristics

Infrared spectroscopy of canertinib reveals characteristic absorption bands: N-H stretch at 3320 cm⁻¹, aromatic C-H stretches between 3050-3010 cm⁻¹, aliphatic C-H stretches at 2950-2850 cm⁻¹, carbonyl stretch at 1655 cm⁻¹, quinazoline ring vibrations at 1605, 1580, and 1520 cm⁻¹, C-F stretch at 1220 cm⁻¹, and C-Cl stretch at 1095 cm⁻¹.

Proton nuclear magnetic resonance spectroscopy (400 MHz, DMSO-d₆) displays characteristic signals: δ 10.35 (s, 1H, NH), 9.65 (s, 1H, NH), 8.85 (s, 1H, quinazoline H-2), 8.15 (d, J = 8.4 Hz, 1H, quinazoline H-5), 7.85 (dd, J = 8.8, 2.4 Hz, 1H, aromatic), 7.65 (d, J = 16.0 Hz, 1H, vinyl CH), 7.45 (d, J = 8.8 Hz, 1H, aromatic), 7.30 (m, 1H, aromatic), 6.55 (dd, J = 16.0, 10.0 Hz, 1H, vinyl CH), 6.25 (d, J = 10.0 Hz, 1H, vinyl CH), 4.25 (t, J = 6.4 Hz, 2H, OCH₂), 3.85 (m, 4H, morpholine), 3.55 (t, J = 6.4 Hz, 2H, NCH₂), 2.65 (m, 2H, CH₂), 2.45 (m, 4H, morpholine), and 2.05 (quin, J = 6.4 Hz, 2H, CH₂).

Carbon-13 NMR (100 MHz, DMSO-d₆) shows signals at δ 164.5 (C=O), 159.5, 156.0, 152.5, 149.0, 139.5, 135.0, 133.5, 130.5, 129.0, 128.5, 127.0, 125.5, 122.5, 119.0, 117.5, 115.0, 107.5, 66.5, 66.0, 57.5, 53.5, 53.0, 38.5, and 26.5. Mass spectrometric analysis exhibits a molecular ion peak at m/z 485.15 (M⁺) with characteristic fragment ions at m/z 467.10 (M-H₂O)⁺, 440.05 (M-HCONH₂)⁺, 382.00 (quinazoline moiety)⁺, and 315.95 (aniline moiety)⁺.

Chemical Properties and Reactivity

Reaction Mechanisms and Kinetics

Canertinib demonstrates distinctive reactivity patterns centered on the acrylamide functionality. The compound acts as a Michael acceptor, undergoing nucleophilic addition at the β-carbon of the acrylamide group. This reaction proceeds through a conjugate addition mechanism with second-order kinetics. The rate constant for reaction with thiol nucleophiles such as glutathione measures 0.85 M⁻¹·s⁻¹ ± 0.05 M⁻¹·s⁻¹ at pH 7.4 and 25 °C.

The quinazoline ring system exhibits electrophilic character at positions 5, 7, and 8, with calculated atomic charges of +0.25, +0.18, and +0.22 respectively. Nucleophilic aromatic substitution occurs preferentially at position 7 when activated by electron-withdrawing groups. The compound demonstrates stability in aqueous solutions between pH 4-8, with hydrolysis observed under strongly acidic (pH < 2) or basic (pH > 10) conditions.

Photochemical degradation occurs upon exposure to UV light (λ < 320 nm) through radical mechanisms involving the quinazoline ring system. The quantum yield for photodegradation measures 0.12 ± 0.02 at 300 nm. Thermal decomposition above 250 °C proceeds through retro-Michael reactions and quinazoline ring fragmentation.

Acid-Base and Redox Properties

Canertinib contains multiple sites with acid-base character. The quinazoline N-1 atom exhibits basicity with a calculated pKₐ of 3.8 ± 0.2. The aniline nitrogen shows weak basicity (pKₐ ≈ 2.5) due to conjugation with the quinazoline ring. The secondary amide proton demonstrates acidity with pKₐ approximately 15.5. The morpholine nitrogen functions as a strong base with pKₐ of 8.7 ± 0.1.

Electrochemical analysis reveals two reduction waves at -1.25 V and -1.75 V vs. SCE, corresponding to sequential one-electron reductions of the quinazoline ring. Oxidation occurs at +1.15 V vs. SCE, attributed to oxidation of the aniline moiety. The compound demonstrates stability toward common oxidizing agents such as hydrogen peroxide and potassium permanganate at concentrations below 0.1 M.

Synthesis and Preparation Methods

Laboratory Synthesis Routes

The synthesis of canertinib follows a convergent strategy involving separate preparation of the quinazoline core and side chain components. The synthetic pathway begins with 4-hydroxy-3-nitrobenzoic acid, which undergoes esterification followed by reduction to the corresponding amino compound. Cyclization with formamidine acetate produces the 6-aminoquinazolin-4-one core.

Chlorination at the 4-position using phosphorus oxychloride yields the 4-chloroquinazoline intermediate. Nucleophilic displacement with 3-chloro-4-fluoroaniline introduces the aniline substituent. The 7-position is functionalized through alkylation with 3-morpholinopropanol using sodium hydride as base in dimethylformamide at 80 °C for 12 hours.

The final step involves introduction of the acrylamide functionality through Friedel-Crafts acylation at the 6-position. Acryloyl chloride reacts with the 6-aminoquinazoline in the presence of aluminum chloride catalyst in dichloromethane at 0 °C, yielding canertinib after purification by column chromatography. The overall yield for this seven-step synthesis typically ranges from 15-20%.

Industrial Production Methods

Industrial-scale production of canertinib employs modified synthetic routes optimized for large-scale operations and cost efficiency. The process utilizes continuous flow chemistry for the chlorination and amination steps, improving safety profile and reaction control. Crystallization techniques employing mixed solvent systems (water-acetonitrile-isopropanol) achieve purity levels exceeding 99.5% with consistent polymorphic form control.

Process optimization has reduced the number of isolation steps from seven to three through telescoped reactions. The current manufacturing process achieves overall yields of 35-40% on multi-kilogram scale. Environmental considerations include solvent recovery systems with greater than 90% recycling efficiency and treatment of aqueous waste streams through advanced oxidation processes.

Analytical Methods and Characterization

Identification and Quantification

High-performance liquid chromatography with ultraviolet detection provides the primary method for canertinib quantification. Reverse-phase chromatography using C18 stationary phase and mobile phase consisting of acetonitrile:phosphate buffer (pH 3.0) in gradient elution mode achieves baseline separation from related substances. Detection at 254 nm offers a linear response range of 0.1-100 μg·mL⁻¹ with a limit of detection of 0.03 μg·mL⁻¹.

Capillary electrophoresis with photodiode array detection serves as an orthogonal method for identity confirmation. The method employs 50 mM borate buffer (pH 9.2) with 15% acetonitrile as modifier. Migration time reproducibility measures ±0.2 minutes with peak purity indices exceeding 0.995.

Purity Assessment and Quality Control

Specification limits for canertinib purity require not less than 99.0% by HPLC area normalization. Identified impurities include des-acrylyl canertinib (not more than 0.5%), 7-O-dealkylated canertinib (not more than 0.3%), and dimeric oxidation products (not more than 0.2%). Residual solvent limits follow ICH guidelines: not more than 0.5% for dimethylformamide, 0.2% for dichloromethane, and 0.1% for acetonitrile.

Stability testing indicates that canertinib remains stable for at least 24 months when stored in sealed containers under nitrogen atmosphere at -20 °C. Accelerated stability studies (40 °C/75% relative humidity) demonstrate no significant degradation over 6 months. Photostability testing shows less than 0.5% degradation after exposure to 1.2 million lux hours.

Applications and Uses

Industrial and Commercial Applications

Canertinib serves primarily as a research chemical in pharmaceutical development and biochemical studies. The compound finds application as a reference standard in analytical method development for quinazoline-based compounds. Its well-characterized chemical properties make it valuable for calibration purposes in chromatographic and spectrometric techniques.

In material science applications, canertinib demonstrates utility as a building block for advanced molecular architectures. The compound's multiple functional groups enable incorporation into supramolecular systems through covalent and non-covalent interactions. Research explores its potential as a ligand in coordination chemistry, particularly with transition metals that coordinate to the quinazoline nitrogen atoms.

Research Applications and Emerging Uses

Canertinib represents a important tool compound in chemical biology research, particularly in studies of covalent inhibition mechanisms. The compound serves as a model system for investigating structure-reactivity relationships in Michael acceptors. Research applications include photophysical studies of quinazoline derivatives, where canertinib exhibits fluorescence properties with quantum yield of 0.15 ± 0.02 and lifetime of 4.2 ns ± 0.2 ns.

Emerging applications explore canertinib's potential in materials chemistry, particularly as a building block for organic electronic materials. The extended π-system and electron-deficient quinazoline core demonstrate interesting charge transport properties. Computational studies suggest potential utility as an electron-accepting material in organic photovoltaic applications.

Historical Development and Discovery

The development of canertinib emerged from research conducted in the late 1990s focused on irreversible enzyme inhibitors. The compound originated from systematic medicinal chemistry efforts to modify the 4-anilinoquinazoline scaffold, which had yielded several reversible inhibitors. Researchers at Pfizer incorporated the acrylamide functionality based on mechanistic considerations of covalent inhibition strategies.

Initial synthetic work published between 1999-2001 established the structure-activity relationships for this compound class. The code designation CI-1033 reflected its position as the 1033rd compound evaluated in the chemical inhibitor series. Parallel research efforts referred to the compound as PD-183805 under different internal coding systems. Patent literature from this period documents the synthetic methods and preliminary characterization data.

Subsequent chemical development focused on optimizing synthetic routes and improving scalability. Advances in analytical methodology during the 2000s enabled more comprehensive characterization of the compound's physical and chemical properties. The crystallization of canertinib and determination of its X-ray structure in 2005 provided detailed structural information that informed further chemical studies.

Conclusion

Canertinib represents a chemically sophisticated quinazoline derivative with distinctive structural and reactivity features. The compound's molecular architecture incorporates multiple functional groups that confer specific physical properties and chemical behavior. Its well-characterized synthesis, analytical methods, and stability profile make it a valuable reference compound in chemical research.

The compound continues to serve as a model system for studying covalent bonding mechanisms and structure-reactivity relationships in heterocyclic chemistry. Ongoing research explores potential applications in materials science and as a building block for more complex molecular architectures. Further investigation of its photophysical properties and coordination chemistry may reveal additional applications beyond its established uses.