Description:ONE-POT SYNTHESIS OF QUERCETIN AND ITS DERIVATIVES FOR PHARMACEUTICAL AND NUTRACEUTICAL APPLICATIONS
Field of the Invention
[0001] The disclosed system relates to a one-pot synthesis methodology for generating quercetin and derivatives for pharmaceutical and nutraceutical use.
Background
[0002] The background description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.
[0003] Quercetin is a naturally occurring flavonoid commonly found in various plant-based sources such as onions, apples, and berries. It exhibits multiple therapeutic properties, including antioxidant, anti-inflammatory, antiviral, and cardioprotective effects, making it a valuable bioactive compound in pharmaceutical and nutraceutical industries. Traditional synthetic routes for quercetin involve multi-step chemical processes that require isolation and purification of intermediate compounds, the use of multiple solvents, and harsh reaction conditions that increase production cost, time, and environmental burden. In particular, the multi-step process often includes the synthesis of chalcones followed by cyclization and oxidation to obtain the flavonoid framework. These steps are usually carried out in separate vessels or stages, leading to high solvent consumption and reduced overall efficiency. Furthermore, modification of the quercetin backbone to form its pharmacologically active derivatives requires additional processing, often requiring solvent exchange or drying between steps. Given the increasing demand for high-purity quercetin derivatives and the push towards green chemistry principles, there exists a pressing need for streamlined, solvent-efficient, and scalable synthetic methods that offer both structural flexibility and operational simplicity. Prior art lacks a consolidated one-pot synthesis method that integrates chalcone formation, cyclization, and oxidation steps while simultaneously allowing derivatization, especially under reaction conditions conducive to pharmaceutical-grade yield. Thus, an efficient, reproducible, and sustainable synthetic pathway remains absent in conventional practice.
[0004] All references, including publications, patent applications, and patents, cited herein are hereby incorporated by reference to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein.
Summary
[0005] Various objects, features, and advantages of the disclosed subject matter can be more fully appreciated with reference to the following detailed description of the disclosed subject matter when considered in connection with the following drawings, in which like reference numerals identify like elements.
[0006] The disclosed system relates to a one-pot synthesis methodology for generating quercetin and derivatives for pharmaceutical and nutraceutical use.
[0007] A system and method are disclosed for the one-pot synthesis of quercetin and its derivatives intended for pharmaceutical and nutraceutical applications. The synthesis is initiated by combining a hydroxybenzaldehyde and a dihydroxyacetophenone in a single reaction vessel, in the presence of a catalytic amount of an acid or base under controlled thermal conditions. The in-situ condensation forms an intermediate chalcone compound, which undergoes subsequent ring cyclization and oxidation within the same vessel to form the core flavonoid scaffold. The process eliminates intermediate purification steps and reduces solvent usage, achieving improved reaction efficiency. The solvent medium may be selected from polar alcohols or aprotic solvents, tailored to reaction kinetics and crystallization behavior. Oxidation is induced by air, iodine, or hydrogen peroxide without requiring solvent exchange. Derivatization such as methylation or glycosylation is optionally integrated into the same vessel using post-synthesis modifiers. The process yields high-purity quercetin derivatives which are directly suitable for formulation. An associated system architecture may include a heat-resistant reactor, reflux setup, magnetic stirrer, and thermal controller to facilitate batch or continuous synthesis cycles. This one-pot process supports greener chemistry practices by reducing chemical waste and improving scalability for industrial applications.
Brief Description of the Drawings
[0008] The features and advantages of the present disclosure would be more clearly understood from the following description taken in conjunction with the accompanying drawings in which:
[0009] FIG. 1 illustrates a block diagram representing the integrated one-pot synthesis system architecture comprising reagent input, solvent chamber, catalytic chamber, reaction vessel, reflux condenser, oxidation chamber, crystallization interface, and product outlet.
[00010] FIG. 2 depicts a method flow diagram outlining sequential operations involved in the one-pot synthesis process including reagent mixing, chalcone formation, in-situ cyclization, oxidative conversion, derivatization (optional), and product crystallization.
[00011] FIG. 3 presents a deployment architecture diagram showing the batch and continuous operational setups of the one-pot synthesis system, comprising reagent tanks, thermal control modules, condenser loop, inline derivatization port, and product collection lines across laboratory-scale and industrial-scale environments.
Detailed Description
[00012] The following is a detailed description of exemplary embodiments to illustrate the principles of the invention. The embodiments are provided to illustrate aspects of the invention, but the invention is not limited to any embodiment. The scope of the invention encompasses numerous alternatives, modifications and equivalent; it is limited only by the claims.
[00013] In view of the many possible embodiments to which the principles of the present discussion may be applied, it should be recognized that the embodiments described herein with respect to the drawing figures are meant to be illustrative only and should not be taken as limiting the scope of the claims. Therefore, the techniques as described herein contemplate all such embodiments as may come within the scope of the following claims and equivalents thereof.
[00014] The detailed description is described with reference to the accompanying figures. In the figures, the left-most digit(s) of a reference number identifies the figure in which the reference number first appears. The use of the same reference numbers in different instances in the description and the figures may indicate similar or identical items.
[00015] Pursuant to the "Detailed Description" section herein, whenever an element is explicitly associated with a specific numeral for the first time, such association shall be deemed consistent and applicable throughout the entirety of the "Detailed Description" section, unless otherwise expressly stated or contradicted by the context.
[00016] The disclosed system relates to a one-pot synthesis methodology for generating quercetin and derivatives for pharmaceutical and nutraceutical use.
[00017] Pursuant to the "Detailed Description" section herein, whenever an element is explicitly associated with a specific numeral for the first time, such association shall be deemed consistent and applicable throughout the entirety of the "Detailed Description" section, unless otherwise expressly stated or contradicted by the context.
[00018] FIG. 1 illustrates a block diagram representing the structural arrangement of components involved in the one-pot synthesis system configured for producing quercetin and its derivatives. The diagram begins with the reagent input module, which is operatively configured to allow the controlled introduction of hydroxybenzaldehyde and dihydroxyacetophenone precursors in stoichiometric proportions. Said module may include calibrated feed lines and solenoid-controlled valves for precise dosing. The reagents enter a solvent chamber, wherein polar protic or aprotic solvents such as ethanol or dimethylformamide are premixed with the reactants. The solvent chamber may also include agitation means to enhance miscibility.
[00019] The solvent-reactant mixture flows into a catalytic chamber, wherein a predetermined quantity of a Lewis acid or Brønsted base catalyst is injected. The catalyst chamber is designed to provide uniform dispersion of catalytic species using static mixers or flow baffles. From this chamber, the activated mixture enters a reaction vessel, which is thermally regulated to maintain a temperature between 60°C and 100°C. The vessel includes a magnetic stirrer and heat mantle or oil bath to sustain uniform heat distribution and kinetic activation for chalcone formation. Positioned atop the reaction vessel is a reflux condenser, which prevents solvent loss while allowing volatile components to return to the vessel.
[00020] As the reaction advances, an integrated oxidation chamber introduces oxidants such as air, hydrogen peroxide, or iodine, to facilitate flavone ring closure. The oxidation step is temporally synchronized via an embedded timer or sensor feedback loop based on UV absorbance tracking. Downstream of the oxidation zone, a crystallization interface enables cooling of the mixture, leading to flavonoid precipitation. The final stage is the product outlet module, which may include a vacuum filter assembly and drying unit to yield pharmaceutical-grade quercetin derivatives. The holistic configuration allows sequential progression of chemical transformations without interruption, reducing manual intervention and optimizing operational throughput. The disclosed one-pot synthesis system begins with the introduction of a hydroxybenzaldehyde precursor into a single reaction vessel, where said compound is selected based on the desired substitution pattern on the aromatic ring. Examples include 2,4-dihydroxybenzaldehyde and 3,4-dihydroxybenzaldehyde, which contribute hydroxyl functionalities necessary for downstream flavonoid activity. The precursor is dissolved in a solvent medium selected from ethanol, methanol, or other polar solvents that promote solubility and support the subsequent condensation step. A dihydroxyacetophenone compound is then added to the reaction mixture in a stoichiometric or slightly excess molar ratio, typically ranging from 1:1 to 1:1.5. Stirring is initiated, and a catalyst is introduced, either a Lewis acid such as zinc chloride or a Brønsted base such as potassium carbonate, to activate the carbonyl and aldehyde functionalities for aldol-type condensation.
[00021] The reaction mixture is gradually heated to a temperature range between 60°C and 100°C to initiate the formation of the chalcone intermediate through carbon-carbon bond formation. Reflux conditions may be applied to prevent solvent loss, and magnetic stirring is continuously maintained to ensure homogeneity. Upon formation of the chalcone, the reaction proceeds without isolation to the cyclization step, which is facilitated either by maintaining thermal energy or introducing a mild oxidant such as air oxygen, iodine, or hydrogen peroxide. The ring closure yields a flavone structure, forming the core skeleton of quercetin. The oxidant is added dropwise to prevent over-oxidation, and the temperature is carefully monitored to avoid degradation of the flavonoid core.
[00022] The reaction is allowed to proceed for a duration ranging from two to six hours, depending on the nature of the starting materials and solvent system. Upon completion, the vessel is cooled to ambient temperature, promoting the crystallization of the product directly from the solution. Crystals are then collected by vacuum filtration and optionally subjected to low-pressure drying to yield the final product. Analytical validation using high-performance liquid chromatography (HPLC) or UV-Vis spectroscopy confirms the formation of quercetin or its respective derivatives with purity levels exceeding 95%. The elimination of intermediate workup steps significantly reduces production time and minimizes waste generation.
[00023] In a second embodiment, the process is modified to include a derivatization step without transferring the product to a new vessel. Following the formation of the core quercetin structure, reagents such as methyl iodide, acetic anhydride, or glucose donors are added directly to the same reaction mixture to induce methylation, acetylation, or glycosylation, respectively. These reactions are performed at slightly elevated temperatures, ranging between 40°C and 70°C, under inert atmosphere where necessary. The derivatives thus formed exhibit altered solubility profiles, improved bioavailability, and enhanced antioxidant capacity. This embodiment allows on-demand generation of pharmacologically tuned analogues within a unified synthesis process.
[00024] In a third embodiment, the entire synthesis is carried out in a continuous flow reactor that mimics the batch one-pot synthesis but facilitates industrial throughput. The precursors are introduced via separate feed lines into a pre-heated tubular reactor containing the catalytic bed. The condensation, cyclization, and derivatization occur as the reactants pass through sequential reaction zones with controlled temperature and residence time. Inline spectroscopy monitors the formation of intermediates and products, allowing feedback control of reagent flow rates. This configuration supports automated quercetin synthesis suitable for GMP-compliant production.
[00025] Across all embodiments, the solvent recovery system recaptures used alcohol or aprotic solvent through condensation and recycling mechanisms. Unreacted starting materials are optionally separated and redirected to the reactor to enhance atom economy. The integrated one-pot architecture leads to significant reductions in operational cost, chemical handling, and energy input compared to conventional multi-step synthesis. The system is particularly advantageous for nutraceutical industries requiring bulk quantities of antioxidant compounds with minimal ecological impact. Furthermore, the lack of intermediate purification supports rapid prototyping and formulation trials in pharmaceutical development pipelines.
[00026] FIG. 2 depicts a method flow diagram encapsulating the procedural steps of the one-pot synthesis process. The method initiates with the input of reactants, specifically the selected hydroxybenzaldehyde and dihydroxyacetophenone, introduced into a solvent medium. This stage is denoted as "Reagent Mixing." The reaction proceeds to chalcone formation, activated by a catalytic species under controlled thermal agitation. The chalcone intermediate is not isolated but is retained in the same vessel to undergo in-situ cyclization, where thermal conditions promote intramolecular ring closure. Upon adequate formation of the closed-ring intermediate, the process transitions into the oxidative conversion phase, wherein the addition of oxidizing agents such as iodine or hydrogen peroxide facilitates the transformation into quercetin.
[00027] Following the base compound synthesis, the method optionally proceeds to a derivatization step, which involves introducing methylating, acetylating, or glycosylating agents to modify hydroxyl groups. This derivatization is performed in the same vessel to avoid solvent exchange or compound isolation. The final step is crystallization and collection, wherein the reaction mixture is cooled to precipitate the desired flavonoid product, which is then filtered and dried. Each step flows logically into the next without intermediate transfer, minimizing energy loss and solvent consumption. The unbroken sequence reinforces the method’s alignment with green chemistry principles and its suitability for pharmaceutical-grade batch or continuous operation.
[00028] FIG. 3 provides a deployment architecture diagram representing two configurations of the system: batch processing setup and continuous processing system. In the batch configuration, discrete reaction vessels are equipped with stirring and heating elements, connected to overhead reflux condensers and side-mounted oxidant injectors. Reagent storage tanks deliver pre-calibrated quantities into the vessel, and the crystallization and collection occur in an integrated output module. This configuration is ideal for laboratory-scale synthesis or specialized formulations where volume control and derivatization flexibility are prioritized.
[00029] In contrast, the continuous flow configuration is designed for industrial-scale deployment, involving parallel feed lines for reagents, catalyst, and solvent routed through a tubular reactor segmented into zones for condensation, cyclization, and oxidation. The reactor is jacketed for thermal control and includes real-time sensors for pH, temperature, and UV absorbance to facilitate inline quality monitoring. Post-reaction streams enter a derivatization port, where optional chemical modifiers are injected before the product stream is directed into a cooling crystallizer. A product collection tank with integrated filtration handles the final output. Solvent recovery units are positioned downstream to recirculate ethanol or DMSO. This deployment allows uninterrupted production cycles, scalability, and reduced environmental burden, rendering the system commercially viable for high-throughput nutraceutical manufacturing.
[00030] Further, while operations are depicted in a particular order, this should not be understood as requiring that such operations be performed in the particular order shown or in sequential order, or that all illustrated operations be performed, to achieve desirable results. In certain circumstances, multitasking and parallel processing may be advantageous. Likewise, while several specific implementation details are contained in the above discussions, these should not be construed as limitations on the scope of the subject matter described herein, but rather as descriptions of features that may be specific to particular embodiments. Certain features that are described in this specification in the context of separate embodiments can also be implemented in combination in a single embodiment. Conversely, various features that are described in the context of a single embodiment can also be implemented in multiple embodiments separately or in any suitable sub-combination. Moreover, although features may be described above as acting in certain combinations and even initially claimed as such, one or more features from a claimed combination can in some cases be excised from the combination, and the claimed combination may be directed to a sub-combination or variation of a sub-combination.

Claims
I/We Claim:
CLAIM 1
A one-pot synthesis method for preparing quercetin and its derivatives, comprising the sequential or simultaneous reaction of a hydroxybenzaldehyde precursor, a dihydroxyacetophenone compound, and an acid or base catalyst in a single reaction vessel, under reflux or controlled heating conditions, followed by the in-situ cyclization and oxidation to form a flavonoid backbone, wherein said process eliminates intermediate isolation steps, reduces solvent usage, and facilitates scalability for pharmaceutical and nutraceutical-grade formulation.
CLAIM 2
The method of claim 1, wherein the hydroxybenzaldehyde precursor is selected from the group consisting of 2,4-dihydroxybenzaldehyde, 3,4-dihydroxybenzaldehyde, and 3,5-dihydroxybenzaldehyde, each contributing distinct hydroxyl group positioning, enabling the modulation of final quercetin derivative structures tailored for specific bioactivity profiles.
CLAIM 3
The method of claim 1, wherein the dihydroxyacetophenone compound is selected from 2,4-dihydroxyacetophenone or 2,5-dihydroxyacetophenone, and the molar ratio between hydroxybenzaldehyde and dihydroxyacetophenone is maintained in the range of 1:1 to 1:1.5 to promote optimal condensation kinetics and enhance final yield purity.
CLAIM 4
The method of claim 1, wherein the catalyst is a Lewis acid such as zinc chloride or aluminum chloride, or a Brønsted base such as sodium ethoxide or potassium carbonate, and wherein the catalyst is added in catalytic amounts between 1 mol% and 10 mol% relative to total reactants to enable efficient chalcone intermediate formation without requiring high-temperature decomposition steps.
CLAIM 5
The method of claim 1, wherein the reaction medium is an alcohol-based solvent selected from ethanol, methanol, or isopropanol, or a polar aprotic solvent selected from dimethylformamide or dimethyl sulfoxide, and wherein solvent selection directly influences reaction rate and flavonoid crystallization behavior within the reaction vessel.
CLAIM 6
The method of claim 1, wherein the oxidative cyclization step is achieved in-situ by exposure to air oxygen, hydrogen peroxide, or iodine under mild stirring at temperatures ranging between 50°C and 100°C, facilitating ring closure and formation of the flavone structure with minimal formation of by-products.
CLAIM 7
The method of claim 1, wherein the final product is purified by crystallization directly from the reaction vessel through cooling, followed optionally by vacuum drying or filtration, to yield pharmaceutical-grade quercetin with at least 95% purity as confirmed by HPLC or spectroscopic validation.
CLAIM 8
The method of claim 1, wherein the resulting quercetin derivatives include methylated, acetylated, or glycosylated analogues formed by introducing respective modifying agents during or after the synthesis step in the same vessel, allowing direct derivatization without requiring isolation or solvent exchange between steps.
CLAIM 9
The method of claim 1, wherein the synthesis process is performed under green chemistry principles by minimizing the use of hazardous solvents, reusing the reaction medium, and recovering unreacted starting materials for subsequent cycles, thereby supporting sustainable production for commercial-scale nutraceutical application.
CLAIM 10
A one-pot system for preparing quercetin derivatives comprising a heat-resistant glass reactor with integrated reflux condenser, magnetic stirring apparatus, reagent addition port, and thermal control unit, operatively configured to facilitate sequential reagent addition, condensation, cyclization, and oxidative derivatization steps, wherein said system is operable for batch-wise or continuous production of quercetin compounds in a pharmaceutically compliant setting.

ONE-POT SYNTHESIS OF QUERCETIN AND ITS DERIVATIVES FOR PHARMACEUTICAL AND NUTRACEUTICAL APPLICATIONS
Abstract
A one-pot synthesis method for preparing quercetin and its derivatives is disclosed, involving the condensation of hydroxybenzaldehyde and dihydroxyacetophenone in the presence of acid or base catalyst within a single vessel. The method comprises in-situ chalcone formation, oxidative cyclization, and optional derivatization without intermediate isolation. The process utilizes polar solvents and mild oxidants to achieve high-purity quercetin suitable for pharmaceutical and nutraceutical applications. The method supports sustainable, scalable, and solvent-efficient manufacturing practices. , Claims:Claims
I/We Claim:
CLAIM 1
A one-pot synthesis method for preparing quercetin and its derivatives, comprising the sequential or simultaneous reaction of a hydroxybenzaldehyde precursor, a dihydroxyacetophenone compound, and an acid or base catalyst in a single reaction vessel, under reflux or controlled heating conditions, followed by the in-situ cyclization and oxidation to form a flavonoid backbone, wherein said process eliminates intermediate isolation steps, reduces solvent usage, and facilitates scalability for pharmaceutical and nutraceutical-grade formulation.
CLAIM 2
The method of claim 1, wherein the hydroxybenzaldehyde precursor is selected from the group consisting of 2,4-dihydroxybenzaldehyde, 3,4-dihydroxybenzaldehyde, and 3,5-dihydroxybenzaldehyde, each contributing distinct hydroxyl group positioning, enabling the modulation of final quercetin derivative structures tailored for specific bioactivity profiles.
CLAIM 3
The method of claim 1, wherein the dihydroxyacetophenone compound is selected from 2,4-dihydroxyacetophenone or 2,5-dihydroxyacetophenone, and the molar ratio between hydroxybenzaldehyde and dihydroxyacetophenone is maintained in the range of 1:1 to 1:1.5 to promote optimal condensation kinetics and enhance final yield purity.
CLAIM 4
The method of claim 1, wherein the catalyst is a Lewis acid such as zinc chloride or aluminum chloride, or a Brønsted base such as sodium ethoxide or potassium carbonate, and wherein the catalyst is added in catalytic amounts between 1 mol% and 10 mol% relative to total reactants to enable efficient chalcone intermediate formation without requiring high-temperature decomposition steps.
CLAIM 5
The method of claim 1, wherein the reaction medium is an alcohol-based solvent selected from ethanol, methanol, or isopropanol, or a polar aprotic solvent selected from dimethylformamide or dimethyl sulfoxide, and wherein solvent selection directly influences reaction rate and flavonoid crystallization behavior within the reaction vessel.
CLAIM 6
The method of claim 1, wherein the oxidative cyclization step is achieved in-situ by exposure to air oxygen, hydrogen peroxide, or iodine under mild stirring at temperatures ranging between 50°C and 100°C, facilitating ring closure and formation of the flavone structure with minimal formation of by-products.
CLAIM 7
The method of claim 1, wherein the final product is purified by crystallization directly from the reaction vessel through cooling, followed optionally by vacuum drying or filtration, to yield pharmaceutical-grade quercetin with at least 95% purity as confirmed by HPLC or spectroscopic validation.
CLAIM 8
The method of claim 1, wherein the resulting quercetin derivatives include methylated, acetylated, or glycosylated analogues formed by introducing respective modifying agents during or after the synthesis step in the same vessel, allowing direct derivatization without requiring isolation or solvent exchange between steps.
CLAIM 9
The method of claim 1, wherein the synthesis process is performed under green chemistry principles by minimizing the use of hazardous solvents, reusing the reaction medium, and recovering unreacted starting materials for subsequent cycles, thereby supporting sustainable production for commercial-scale nutraceutical application.
CLAIM 10
A one-pot system for preparing quercetin derivatives comprising a heat-resistant glass reactor with integrated reflux condenser, magnetic stirring apparatus, reagent addition port, and thermal control unit, operatively configured to facilitate sequential reagent addition, condensation, cyclization, and oxidative derivatization steps, wherein said system is operable for batch-wise or continuous production of quercetin compounds in a pharmaceutically compliant setting.