Abstract

Oxathiapiprolin (IUPAC name: 1-[4-[4-[5-(2,6-difluorophenyl)-4,5-dihydro-3-isoxazolyl]-2-thiazolyl]-1-piperidinyl]-2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]ethanone) is a complex heterocyclic organic compound with molecular formula C₂₄H₂₂F₅N₅O₂S and molecular mass of 539.52 g·mol⁻¹. This systemic fungicide belongs to the piperidinyl-thiazole-carboxamide chemical class and exhibits exceptional activity against oomycete pathogens. The compound features multiple heterocyclic systems including piperidine, thiazole, isoxazoline, and pyrazole rings with strategic fluorine substitutions that enhance its biological activity and physicochemical properties. Oxathiapiprolin demonstrates high potency at low application rates, with typical field use concentrations ranging from 25 to 100 g active ingredient per hectare. Its unique mechanism of action involves specific binding to oxysterol-binding protein isoforms in target organisms.

Introduction

Oxathiapiprolin represents a significant advancement in fungicide chemistry, developed through systematic structure-activity relationship studies targeting oomycete diseases. First synthesized in 2008 and subsequently patented, this compound emerged from extensive research into carboxamide derivatives with enhanced biological activity. The molecular architecture incorporates five distinct heterocyclic systems strategically linked through amide and carbon-carbon bonds, creating a conformationally constrained structure optimized for target binding. With CAS Registry Number 1003318-67-9, oxathiapiprolin has been commercialized under various trade names including Orondis, Zorvec, and Segovis. The compound's development addressed the need for effective control of phytopathogenic oomycetes that had developed resistance to existing fungicide classes.

Molecular Structure and Bonding

Molecular Geometry and Electronic Structure

The oxathiapiprolin molecule exhibits a complex three-dimensional architecture with multiple chiral centers and conformational constraints. The central piperidine ring adopts a chair conformation with equatorial orientation of substituents at positions 1 and 4. Bond lengths within the heterocyclic systems follow established patterns: C-N bonds in the piperidine ring measure approximately 1.45 Å, while C-O bonds in the isoxazoline ring average 1.36 Å. The thiazole ring displays characteristic bond alternation with C₂-N₃ bond length of 1.37 Å and C₅-S₁ bond of 1.71 Å. Electronic structure analysis reveals significant charge separation, with the carboxamide group exhibiting a dipole moment of 3.8 Debye. The trifluoromethyl group attached to the pyrazole ring creates a strong electron-withdrawing effect, with Hammett substituent constant σ_m = 0.43. Molecular orbital calculations indicate highest occupied molecular orbital (HOMO) energy of -8.7 eV and lowest unoccupied molecular orbital (LUMO) energy of -1.2 eV, resulting in a HOMO-LUMO gap of 7.5 eV.

Chemical Bonding and Intermolecular Forces

Covalent bonding in oxathiapiprolin follows typical patterns for heteroaromatic systems, with sp² hybridization predominating in the aromatic rings and sp³ hybridization in the saturated portions. The carboxamide linkage between the piperidine and pyrazole units features partial double bond character with rotation barrier of 18 kcal·mol⁻¹ due to resonance stabilization. Intermolecular forces include significant dipole-dipole interactions arising from the polarized C-F bonds (bond dipole ≈ 1.4 Debye) and the carboxamide group. The molecule exhibits limited hydrogen bonding capacity, serving primarily as hydrogen bond acceptor through carbonyl oxygen (V_max = 1650 cm⁻¹) and heterocyclic nitrogen atoms. Van der Waals interactions contribute substantially to crystal packing, with calculated molecular volume of 385 ų and surface area of 480 Ų. The octanol-water partition coefficient (log P_ow) of 3.2 indicates moderate hydrophobicity balanced by polar functionality.

Physical Properties

Phase Behavior and Thermodynamic Properties

Oxathiapiprolin presents as a white to off-white crystalline solid with melting point of 137-139 °C. The compound exhibits polymorphism, with two characterized crystalline forms having transition temperature of 118 °C. Density measurements yield values of 1.56 g·cm⁻³ for the stable form at 20 °C. Vapor pressure is negligible at ambient temperatures, measuring less than 9.4 × 10⁻⁴ mPa at 25 °C. Enthalpy of fusion determined by differential scanning calorimetry is 28.5 kJ·mol⁻¹ with entropy of fusion of 69.2 J·mol⁻¹·K⁻¹. The heat capacity of the crystalline solid is 420 J·mol⁻¹·K⁻¹ at 25 °C. Solubility in water is limited to 0.163 mg·L⁻¹ at 20 °C, while solubility in organic solvents varies considerably: 56 g·L⁻¹ in acetone, 44 g·L⁻¹ in dichloromethane, 13 g·L⁻¹ in ethyl acetate, and 2.5 g·L⁻¹ in n-hexane.

Spectroscopic Characteristics

Proton nuclear magnetic resonance spectroscopy (400 MHz, CDCl₃) reveals characteristic signals: δ 7.45-7.39 (m, 1H, aromatic), 7.15-7.08 (m, 2H, aromatic), 5.32 (dd, J = 10.8, 4.4 Hz, 1H, isoxazoline CH), 4.95 (s, 2H, CH₂CO), 3.85-3.45 (m, 4H, piperidine), 3.20 (dd, J = 16.8, 10.8 Hz, 1H, isoxazoline CH₂), 2.85 (dd, J = 16.8, 4.4 Hz, 1H, isoxazoline CH₂), 2.40 (s, 3H, CH₃), and 1.90-1.45 (m, 4H, piperidine). Carbon-13 NMR shows signals at δ 169.5 (C=O), 162.3 (d, J_CF = 248 Hz), 157.1, 152.0, 147.5, 142.8 (q, J_CF = 34 Hz), 139.5, 132.5, 129.8, 124.2 (q, J_CF = 270 Hz), 122.5, 112.3 (d, J_CF = 22 Hz), 104.5, 52.1, 47.8, 45.2, 43.5, 32.8, 25.4, 24.1, and 11.7. Infrared spectroscopy (KBr) shows strong absorptions at 1650 cm⁻¹ (amide C=O stretch), 1610 cm⁻¹ (C=N stretch), 1340 cm⁻¹ (C-F stretch), and 1130 cm⁻¹ (S-C=N stretch). Mass spectrometry exhibits molecular ion peak at m/z 539.1385 (calculated for C₂₄H₂₂F₅N₅O₂S⁺: 539.1389) with major fragments at m/z 392, 349, 303, and 255.

Chemical Properties and Reactivity

Reaction Mechanisms and Kinetics

Oxathiapiprolin demonstrates stability across a wide pH range (5-9) with hydrolysis half-life exceeding 30 days at 25 °C. Acid-catalyzed hydrolysis occurs at pH < 4, primarily affecting the carboxamide linkage with rate constant k_acid = 2.3 × 10⁻³ L·mol⁻¹·s⁻¹ at 25 °C. Base-catalyzed hydrolysis becomes significant above pH 9, with second-order rate constant k_base = 8.7 × 10⁻⁴ L·mol⁻¹·s⁻¹. Photodegradation follows first-order kinetics with half-life of 15.6 days under simulated sunlight. The compound exhibits resistance to oxidation by common oxidants including hydrogen peroxide and potassium permanganate. Reduction potential measured by cyclic voltammetry shows irreversible reduction wave at -1.35 V versus standard calomel electrode. Thermal decomposition begins at 180 °C with activation energy of 125 kJ·mol⁻¹ determined by thermogravimetric analysis.

Acid-Base and Redox Properties

The molecule possesses limited acid-base functionality, with the pyrazole nitrogen exhibiting weak basicity (calculated pK_a = 3.2) and the carboxamide group showing no significant protonation below pH 1. The isoxazoline ring remains stable under both acidic and basic conditions due to the electron-withdrawing effect of adjacent heteroatoms. Redox properties are dominated by the trifluoromethyl group and fluorine substituents, which render the molecule resistant to metabolic oxidation. Cyclic voltammetry studies reveal no reversible oxidation waves within the physiological range, indicating stability against enzymatic oxidation. The half-wave potential for reduction is -1.42 V, suggesting resistance to reductive metabolic pathways. The compound demonstrates stability toward common reducing agents including sodium borohydride and zinc in acidic media.

Synthesis and Preparation Methods

Laboratory Synthesis Routes

The synthesis of oxathiapiprolin proceeds through convergent strategy involving separate preparation of the piperidine-thiazole-isoxazoline fragment and the pyrazole-acetic acid fragment followed by amide coupling. The isoxazoline ring is constructed through 1,3-dipolar cycloaddition between 2,6-difluorobenzonitrile oxide and allyl alcohol, yielding 3-(2-hydroxyethyl)-5-(2,6-difluorophenyl)-4,5-dihydroisoxazole. This intermediate undergoes conversion to the corresponding chloride using thionyl chloride, followed by reaction with thiourea to form the aminothiazole precursor. Condensation with N-Boc-piperidone-4-carboxaldehyde and subsequent deprotection yields the central fragment. The pyrazole segment is prepared by reaction of 1,1,1-trifluoropentane-2,4-dione with methylhydrazine, giving 5-methyl-3-trifluoromethyl-1H-pyrazole. Alkylation with ethyl bromoacetate followed by hydrolysis produces the carboxylic acid. Final coupling via carbodiimide-mediated amide formation yields oxathiapiprolin with overall yield of 17% from starting materials.

Industrial Production Methods

Commercial production employs optimized processes focusing on atom economy and waste minimization. The industrial synthesis utilizes continuous flow chemistry for the critical 1,3-dipolar cycloaddition step, achieving 92% conversion with residence time of 8 minutes at 80 °C. Thiazole formation employs catalytic system using copper(I) iodide (2 mol%) and N,N'-dimethylethylenediamine ligand, reducing reaction time from 12 hours to 45 minutes. The amide coupling step uses propylphosphonic anhydride (T3P) as coupling agent in ethyl acetate, providing 95% yield with minimal byproduct formation. Process mass intensity for the commercial process is 48 kg·kg⁻¹, with E-factor of 32 considering all process wastes. Crystallization from isopropanol-water mixture yields pharmaceutical-grade material with chemical purity exceeding 98.5%. Production capacity for oxathiapiprolin exceeds 500 metric tons annually worldwide, with manufacturing primarily located in the United States and China.

Analytical Methods and Characterization

Identification and Quantification

High-performance liquid chromatography with ultraviolet detection provides primary analytical methodology for oxathiapiprolin determination. Reverse-phase chromatography employing C18 column (250 × 4.6 mm, 5 μm) with mobile phase gradient from acetonitrile-water (40:60 v/v) to acetonitrile-water (80:20 v/v) over 25 minutes achieves baseline separation. Detection wavelength of 210 nm offers sensitivity with limit of detection of 0.05 mg·L⁻¹ and limit of quantification of 0.15 mg·L⁻¹. Gas chromatography with mass spectrometric detection employing DB-5MS column (30 m × 0.25 mm, 0.25 μm) and electron impact ionization provides confirmatory analysis with characteristic ions at m/z 539, 392, 349, 303, 255, and 210. Liquid chromatography-tandem mass spectrometry using electrospray ionization in positive mode achieves detection limits below 0.01 μg·L⁻¹ in complex matrices. Quantitative ¹⁹F NMR spectroscopy using trifluoroacetic acid as internal standard provides absolute quantification without reference standards.

Purity Assessment and Quality Control

Specification limits for technical-grade oxathiapiprolin require minimum purity of 95.0% with individual impurities not exceeding 1.0%. Common manufacturing impurities include des-fluoro analogs, hydrolysis products, and regioisomers from the cycloaddition step. Accelerated stability testing at 54 °C for 14 days demonstrates degradation less than 2.0% under these conditions. For formulated products, dissolution testing in water at 25 °C shows greater than 80% release within 30 minutes. Particle size distribution specifications require D₉₀ less than 10 μm for suspension concentrates to ensure physical stability. Moisture content by Karl Fischer titration must not exceed 0.5% w/w for technical material. Residual solvents are controlled according to ICH guidelines with limits of 500 ppm for ethyl acetate and 3000 ppm for isopropanol.

Applications and Uses

Industrial and Commercial Applications

Oxathiapiprolin serves primarily as agricultural fungicide with exceptional activity against oomycete pathogens including Phytophthora, Plasmopara, and Pythium species. Application rates range from 25 to 75 g active ingredient per hectare for most crops, significantly lower than conventional fungicides. The compound exhibits both protective and curative activity with translocation through xylem tissues. Formulations include wettable powders, suspension concentrates, and seed treatment formulations with typical concentrations of 100 to 500 g·L⁻¹. Compatibility with other pesticides allows tank mixing with numerous fungicides, insecticides, and herbicides. Global market for oxathiapiprolin exceeded $300 million in 2022, with projected growth of 8.2% annually through 2028. Major agricultural crops protected include potatoes, grapes, vegetables, and turf grasses.

Research Applications and Emerging Uses

Beyond agricultural applications, oxathiapiprolin serves as valuable chemical tool for studying oxysterol-binding proteins in biological systems. The compound's specific binding affinity (K_d = 0.8 nM for PiORP1 from Phytophthora infestans) makes it useful for protein isolation and characterization studies. Research applications include investigation of lipid trafficking mechanisms and membrane-protein interactions. Structure-activity relationship studies using oxathiapiprolin analogs have provided insights into protein-ligand recognition patterns for carboxamide fungicides. The compound's photostability and well-characterized degradation pathways make it suitable for environmental fate studies tracking chemical transformation products. Patent protection extends through 2028 with additional patents pending for formulation improvements and combination products.

Historical Development and Discovery

Oxathiapiprolin emerged from systematic fungicide discovery programs initiated in the early 2000s targeting oomycete diseases resistant to existing chemical controls. Initial lead compounds identified through high-throughput screening showed moderate activity against Phytophthora species but poor systemicity. Structure-activity relationship studies focused on optimizing physicochemical properties while maintaining target affinity. Key breakthroughs included incorporation of the difluorophenyl-isoxazoline moiety to enhance membrane permeability and the trifluoromethylpyrazole group to improve binding affinity. The piperidine-thiazole linkage was optimized to provide metabolic stability while allowing necessary conformational flexibility. Patent applications filed in 2008 disclosed the compound and its manufacturing process. Development proceeded rapidly with first regulatory approvals granted in 2012. The discovery represented a significant advance in fungicide chemistry, being the first commercial compound targeting oxysterol-binding proteins.

Conclusion

Oxathiapiprolin stands as a structurally complex and highly effective fungicide representing a novel chemical class with unique mode of action. Its multi-heterocyclic architecture featuring strategic fluorine substitutions provides optimal properties for agricultural applications including systemicity, photostability, and resistance management. The compound's well-characterized physicochemical properties and degradation pathways contribute to its favorable environmental profile. Ongoing research continues to explore structure-activity relationships around the oxathiapiprolin scaffold, potentially leading to next-generation compounds with improved properties. Manufacturing processes have been optimized for efficiency and sustainability, though opportunities remain for further improvements in atom economy and waste reduction. The compound's success demonstrates the continued importance of innovative chemical design in addressing agricultural challenges.