Synthesis and Analysis of Ketoprofen 1,4-Sorbitan Ester

Abstract

This study presents the synthesis and comprehensive characterization of ketoprofen 1,4-sorbitan ester, a novel compound with potential applications in drug delivery. The compound was synthesized through a two-step process involving the acid-catalyzed dehydration of D-Glucose to form 1,4-sorbitan, followed by esterification with ketoprofen. The structures of ketoprofen 1,4-sorbitan ester and the reference compound, ketoprofen methyl ester, were rigorously analyzed using a combination of advanced analytical techniques. High-resolution accurate mass liquid chromatography–mass spectrometry was used to determine the precise molecular mass and elemental composition of the synthesized compounds. ¹H and ¹³C nuclear magnetic resonance spectroscopy provided detailed information on the molecular structure and atomic connectivity to identify the specific functional groups and confirm the formation of ester bonds.

1. Introduction

Ketoprofen, a widely used non-steroidal anti-inflammatory drug, has been extensively employed for the treatment of various inflammatory conditions, including arthritis [1]. However, its use is often limited by poor solubility and potential gastrointestinal side effects [2]. To address these challenges, novel drug delivery systems have been explored to enhance ketoprofen’s efficacy and safety [3]. In recent years, interest in the development of ester prodrugs with improved physicochemical properties has been growing. Esters have shown promise in enhancing drug solubility, stability, and bioavailability [4]. Among the various esterification approaches, the use of sugar alcohols as carriers has gained attention, owing to their biocompatibility and potential to modify drug release profiles. Sorbitan, a cyclic sugar alcohol derived from sorbitol, is used in pharmaceutical formulations as a surfactant and emulsifier. The unique structure of sorbitan, particularly the 1,4-isomer, exhibits potential for the development of novel ester prodrugs with improved pharmacokinetic properties [5].

The synthesis and characterization of ester prodrugs often involve a multistep process that requires careful consideration of the reaction conditions and analytical techniques [6]. Advanced spectroscopic methods, including nuclear magnetic resonance (NMR) spectroscopy, mass spectrometry (MS), and infrared (IR) spectroscopy, play crucial roles in elucidating the structures and purities of newly synthesized compounds [7,8]. In this study, we present the synthesis and comprehensive characterization of ketoprofen 1,4-sorbitan ester, a novel compound designed to enhance ketoprofen delivery and efficacy [9]. We aim to contribute to the growing body of knowledge on innovative drug delivery systems and to provide insights into the potential applications of sugar alcohol-based ester prodrugs in pharmaceutical development [10,11]. The two-step synthesis involved the acid-catalyzed dehydration of D-glucose to form 1,4-sorbitan, followed by esterification with ketoprofen [12]. The resulting compound was subjected to rigorous structural analysis using a combination of advanced analytical techniques, including liquid chromatography–mass spectrometry (LC-MS), NMR spectroscopy, and IR spectroscopy [13]. This study not only demonstrates the successful synthesis of ketoprofen 1,4-sorbitan ester but also provides a detailed characterization of its structure and properties [14,15]. Our findings lay the groundwork for future investigations into the physicochemical properties, stability, and potential pharmaceutical applications of this novel ester prodrug, opening new avenues for the design of more effective and targeted drug delivery systems for the treatment of inflammatory conditions [16].

2. Results

In our previous work, we used protonated chiral 1,2-diamines as organocatalysts to perform asymmetric aldol reactions between cyclic ketones and aldehydes [17] and synthesized N-selective asymmetric compounds through the interaction of cyclic ketones and nitrosobenzene compounds [18]. This synthesis was applied to the condensation of new aldehydes with alcohols (2) (Scheme 1).

In addition, we reacted compound 2, which we previously synthesized, with ketoprofen. In this study, we used 4-dimethylaminopyridine (DMAP) and N,N′-dicyclohexylcarbodiimide (DCC) as catalysts and coupling reagents. The synthesis of 1,4-sorbitan and ketoprofen using DMAP and DCC was successful, affording (R)-2-((2R,3R,4S)-3,4-dihydroxytetrahydrofuran-2-yl)-2-hydroxyethyl 2-(3-benzoylphenyl)propanoate(4) (Scheme 2).

The reaction was completed in 22 h, and the target product was obtained in 93% yield. Compound 4 is an example of a ketoprofen-based analog that combines ketoprofen and a 1,4-sorbitan molecular scaffold. The HPLC analysis of the purified ketoprofen 1,4-sorbitan ester showed a single major peak with a purity of more than 93%, indicating the high purity of the synthesized compound. These results collectively confirm the successful synthesis and characterization of the ketoprofen 1,4-sorbitan ester and provide a solid foundation for further studies on its physicochemical properties and potential pharmacological applications.

3. Discussion

The successful synthesis and characterization of the ketoprofen 1,4-sorbitan ester represent a significant advancement in the development of novel drug delivery systems for NSAIDs. This study demonstrates the feasibility of combining ketoprofen with a sugar alcohol-based carrier to potentially enhance its pharmacological properties. The two-step synthesis approach effectively produced the target compound with satisfactory yields. The use of sulfuric acid as a catalyst in the first step facilitated the efficient dehydration of D-glucose to 1,4-sorbitan. The subsequent esterification reaction, employing DCC and DMAP as coupling agents, successfully linked ketoprofen to the 1,4-sorbitan moiety. Also, the comprehensive characterization using LC-MS and NMR spectroscopy provided unequivocal evidence for the structure of the synthesized ester. The NMR data, showing characteristic peaks for both ketoprofen and sorbitan moieties, further confirms the successful linkage of these components.

4. Materials and Methods

4.1. Reagents and Materials

Ketoprofen (≥98% purity), D-glucose (≥98% purity), and sulfuric acid (95–98%) were purchased from Sigma–Aldrich (St. Louis, MO, USA). All other reagents and solvents were of analytical grade and obtained from commercial sources. The solvents were filtered and used at high purity for the UHPLC and LC-MS analyses.

4.2. UHPLC Analysis

UHPLC was performed with UV detection. The samples were filtered through a 0.45 μm filter before analysis. The analysis was conducted using a C18 reverse-phase column (150 mm × 4.6 mm, 5 μm) with a gradient elution of water and acetonitrile. Each sample was injected at 20 μL and analyzed over a 20 min period at a UV wavelength of 233 nm.

4.3. High-Resolution Accurate Mass Liquid Chromatography Mass Spectrometry

HRAM LC-MS was used to precisely identify the impurities detected. The mass spectrometer was equipped with an electrospray ionization source, and the mass range was set to m/z 100–1000. This allowed for the measurement of molecular weights and the deduction of the molecular formulas and chemical structures of the impurities.

4.4. Synthesis of 1,4-Sorbitan

D-Glucose (10 g) was dissolved in 50 mL of deionized water in a round-bottom flask, along with sulfuric acid (0.5 mL) and 10 mol% of (R, R)-1.2-diphenyl ethylenediamine as a catalyst. The mixture was then heated to 90 °C and stirred for 2 h under reflux. The reaction was then cooled to room temperature, and the pH was adjusted to 7.0 using a sodium hydroxide solution. The product was extracted using ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield 1,4-sorbitan.

4.5. Synthesis of the Ketoprofen 1,4-Sorbitan Ester

Ketoprofen (2.54 g, 10 mmol) and 1,4-sorbitan (1.64 g, 10 mmol) were dissolved in anhydrous dichloromethane (30 mL). N,N′-Dicyclohexylcarbodiimide (DCC, 2.27 g, 11 mmol) and 4-dimethylaminopyridine (DMAP, 0.12 g, 1 mmol) were added as coupling agents. The reaction mixture was stirred at room temperature for 22 h under a nitrogen atmosphere. The precipitated dicyclohexylurea was removed via filtration, and the filtrate was washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified via silica gel column chromatography using a gradient elution of chloroform and methanol to yield the ketoprofen 1,4-sorbitan ester.

4.6. Characterization

4.6.1. Liquid Chromatography–Mass Spectrometry

The LC-MS analysis was performed using a Thermo Scientific Q Exactive hybrid quadrupole-Orbitrap mass spectrometer coupled to a Dionex UltiMate 3000 UHPLC system. The column was a Thermo Scientific Hypersil GOLD C18 (100 mm × 2.1 mm, 1.9 μm). The mobile phases consisted of 0.1% formic acid in water (A) and 0.1% formic acid in acetonitrile (B). The gradient elution was performed at a flow rate of 0.3 mL/min. The mass spectrometer was operated in positive ionization mode with a spray voltage of 3.5 kV.

4.6.2. Nuclear Magnetic Resonance Spectroscopy

The ¹H and ¹³C NMR spectra were recorded using a Bruker Avance III 500 MHz spectrometer. Samples were dissolved in deuterated dimethyl sulfoxide (DMSO-d₆). Chemical shifts were reported in parts per million (ppm) relative to tetramethylsilane (TMS) as an internal standard.

4.6.3. Data Analysis

Spectral data were processed and analyzed using the appropriate software packages, including Xcalibur 4.1 (Thermo Scientific) for the LC-MS data, TopSpin 3.6(Bruker) for the NMR spectroscopy data. Structures were determined and validated by comparing the spectral data with the theoretical predictions and literature values.