A method for one-step catalytic synthesis of (R)-3-hydroxybutyric acid oligomers using a solid acid catalyst

Abstract

This invention belongs to the technical field of chiral chemical R-3-hydroxybutyrate utilization, and relates to a method for one-step catalytic synthesis of (R)-3-hydroxybutyric acid oligomers using a solid acid catalyst. The method involves: under flowing air conditions, (R)-3-hydroxybutyrate, a solid acid catalyst, and ultrapure water are stirred and hydrolyzed in an open container until insoluble substances begin to appear in the aqueous solution. After the reaction is complete, solid-liquid separation is performed. The liquid product is vacuum dried to obtain water-soluble (R)-3-hydroxybutyric acid oligomers. The solid is washed and filtered to recover and reuse the solid acid catalyst. This invention solves the technical problems of multiple process steps, cumbersome conditions, and high energy consumption in the synthesis of (R)-3-hydroxybutyric acid oligomers in existing technologies. The catalyst provided in this invention can be reused, and the process is simple, convenient, and environmentally friendly, possessing industrial application value.

Description

Technical Field

[0001] This invention belongs to the technical field of chiral chemical R-3-hydroxybutyrate utilization, and relates to a method for one-step catalytic synthesis of (R)-3-hydroxybutyric acid oligomers using a solid acid catalyst. Background Technology

[0002] (R)-3-hydroxybutyric acid (PHB) is a green, renewable monomer of poly(3-hydroxybutyric acid), obtained through acid-catalyzed hydrolysis. PHB is an important ketone body in the human body, providing fuel for the brain and being used by skeletal and cardiac muscles. Currently, PHB is being researched for use by athletes, military personnel, and other individuals in extreme physiological states. Furthermore, PHB is also considered a beneficial solid beverage (such as a ketogenic diet pill) with a broad market potential. However, the direct application of PHB has certain limitations, primarily in two aspects: firstly, as an organic acid, the amount and concentration of β-hydroxybutyric acid provided by the human body during ingestion are limited; secondly, PHB has poor stability and is difficult to store, easily decomposing into harmful crotonic acid under normal temperature storage conditions. To address issues such as acidity and stability, some companies have developed (R)-3-hydroxybutyrate compounds (e.g., sodium, magnesium, calcium, and potassium salts). However, these (R)-3-hydroxybutyrates have raised other problems, such as the potential danger of metal ion overload. Furthermore, (R)-3-hydroxybutyric acid and its salts are absorbed and metabolized too rapidly in the human body, making it difficult to maintain high concentrations for extended periods and resulting in a short onset of action.

[0003] Patent CN110776425A and several academic research findings have disclosed that (R)-3-hydroxybutyric acid oligomers can prolong the duration of action to achieve a sustained-release effect, while also reducing the risk of acidosis and metal ion overload. Therefore, (R)-3-hydroxybutyric acid oligomers have the potential to become a high-quality ketone body with high safety, low side effects, and a longer duration of action. Patent CN110776425A discloses a method for synthesizing (R)-3-hydroxybutyric acid oligomers. Using (R)-3-hydroxybutyrate ester obtained from the alcoholysis of PHB as a raw material, the (R)-3-hydroxybutyrate ester is catalytically hydrolyzed to obtain (R)-3-hydroxybutyric acid [preferably catalyzed by an alkaline catalyst (such as sodium hydroxide). This homogeneous alkaline catalysis process poses an environmental pollution risk and requires post-processing operations such as acidification, extraction, and distillation]. Then, the (R)-3-hydroxybutyric acid is polymerized under complex conditions [high temperature (100~150℃), inert gas protection, and negative pressure (0.001~0.05 MPa)] to obtain (R)-3-hydroxybutyric acid oligomers. This patented process involves two independent reactions, with numerous steps, complex conditions, and high energy consumption. Similar to (R)-3-hydroxybutyric acid oligomers, water-soluble (R)-3-hydroxybutyric acid polymers can theoretically overcome the acidity and instability issues of (R)-3-hydroxybutyric acid, as well as the high salt content problem of (R)-3-hydroxybutyrate compounds. Therefore, developing green new technologies to convert (R)-3-hydroxybutyrate esters into water-soluble R-3-hydroxybutyric acid oligomers through simple reaction processes is of great significance. Summary of the Invention

[0004] To address the technical problems of numerous process steps, cumbersome conditions, and high energy consumption in the synthesis of (R)-3-hydroxybutyric acid polymers in existing technologies, this invention proposes a one-step catalytic synthesis method for (R)-3-hydroxybutyric acid oligomers using a solid acid catalyst. In this reaction, the catalyst can be reused, and the catalytic process is simple, convenient, and environmentally friendly, possessing industrial application value.

[0005] To achieve the above objectives, the technical solution of the present invention is implemented as follows:

[0006] A method for one-step catalytic synthesis of (R)-3-hydroxybutyric acid oligomers using a solid acid catalyst is disclosed. The method involves adding (R)-3-hydroxybutyrate, a solid acid catalyst, and ultrapure water to an open flask, which is then placed under flowing air to accelerate the evaporation of the byproducts methanol and water. Mechanical stirring is initiated, followed by hydrolysis at 65–100 °C until insoluble substances begin to appear in the aqueous solution. The reaction product is then subjected to solid-liquid separation to recover the solid acid catalyst and the liquid product. The liquid product is vacuum dried to obtain water-soluble (R)-3-hydroxybutyric acid oligomers. The recovered solid acid catalyst is washed with ultrapure water and then separated by filtration for reuse.

[0007] The (R)-3-hydroxybutyrate used in this invention is mainly (R)-3-hydroxybutyrate methyl ester and (R)-3-hydroxybutyrate ethyl ester.

[0008] The catalysts used in this invention are strong acid solid particulate catalysts with good stability in aqueous solutions below 100°C, including Amberlyst-36, Amberlyst-315, Nafion® NR50, HND-34 solid superacid catalysts, etc.

[0009] The mass ratio of (R)-3-hydroxybutyrate to solid acid catalyst in this invention is (1~2):1.

[0010] The present invention requires the addition of 2 to 20 mL of ultrapure water for every 1 to 2 g of (R)-3-hydroxybutyrate.

[0011] The present invention provides a method for one-step catalytic synthesis of (R)-3-hydroxybutyric acid oligomers using a solid acid catalyst. This method enables the one-step conversion of (R)-3-hydroxybutyrate ester into water-soluble (R)-3-hydroxybutyric acid oligomers in an open reactor. The reactor operates on the principle of two hydrolysis equilibrium reactions. First, (R)-3-hydroxybutyrate ester [methyl (R)-3-hydroxybutyrate or ethyl (R)-3-hydroxybutyrate] undergoes hydrolysis under solid acid catalysis to generate (R)-3-hydroxybutyric acid and an alcohol (methanol or ethanol). The generated methanol or ethanol is removed from the reactor by distillation under heating conditions, thereby promoting the hydrolysis of (R)-3-hydroxybutyrate ester and the formation of (R)-3-hydroxybutyric acid. Secondly, the generated (R)-3-hydroxybutyric acid undergoes an intermolecular catalytic esterification reaction (between the hydroxyl group of one molecule of (R)-3-hydroxybutyric acid and the carboxyl group of another molecule of (R)-3-hydroxybutyric acid) under the catalysis of a solid acid, ultimately producing (R)-3-hydroxybutyric acid oligomers. As the reaction proceeds, the solvent water is removed from the reactor by distillation, further promoting the formation of (R)-3-hydroxybutyric acid oligomers. The reaction is immediately stopped when insoluble substances begin to appear to avoid the formation of water-insoluble polymers, which would reduce the utilization efficiency of the raw material (R)-3-hydroxybutyrate.

[0012] Therefore, there are three key factors that contribute to the good results of this invention:

[0013] (1) The reactor is not closed during the reaction process. The alcohol generated by hydrolysis and the reaction solvent water can be removed by evaporation, thereby promoting the hydrolysis of (R)-3-hydroxybutyrate to generate (R)-3-hydroxybutyric acid, and the further oligomerization reaction of (R)-3-hydroxybutyric acid to generate (R)-3-hydroxybutyric acid oligomer.

[0014] (2) The reaction process uses a particulate solid acid catalyst. The catalytic performance of the solid acid catalyst will not change much due to the evaporation of solvent water during the reaction. Moreover, the particulate solid acid catalyst can be easily separated from the product after the reaction, which greatly simplifies the post-processing of (R)-3-hydroxybutyric acid oligomer products and enables the reuse of catalyst. In addition, the strong acid solid acid catalyst is beneficial to reduce the polymerization temperature of (R)-3-hydroxybutyric acid, realizing the generation of (R)-3-hydroxybutyric acid oligomers at a mild temperature. This helps to reduce energy consumption and avoid the possible high-temperature oxidation of (R)-3-hydroxybutyric acid. Therefore, there is no need to introduce inert gas protection during the reaction.

[0015] (3) Control the reaction time. When insoluble substances begin to appear in the aqueous solution, stop the reaction immediately to ensure that the polymer obtained from the reaction is water-soluble.

[0016] The present invention has the following beneficial effects:

[0017] This invention provides a one-step catalytic synthesis method for (R)-3-hydroxybutyric acid oligomers using a solid acid catalyst. The process employs a simple open-top reaction apparatus, with a mild reaction temperature (65-100°C), and requires no inert gas protection. The resulting polymer is water-soluble, which is beneficial for its application in the preparation of aqueous products (such as solid beverages). The use of a solid acid catalyst promotes the reaction and facilitates recovery and reuse. Clearly, this invention features a simple process, convenient operation, low energy consumption, and is environmentally friendly, possessing broad prospects for industrial application. Attached Figure Description

[0018] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0019] Figure 1 This is a schematic diagram of the process steps in Embodiment 1 of the present invention.

[0020] Figure 2 This is a photograph of the white solid obtained in Example 1 of the present invention.

[0021] Figure 3 Mass spectrometry analysis of the white solid obtained in Example 1 of this invention.

[0022] Figure 4 This is a GC-MS analysis diagram of the white solid alcoholysis product in Example 1 of the present invention. Detailed Implementation

[0023] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0024] Example 1

[0025] This embodiment describes a method for synthesizing water-soluble (R)-3-hydroxybutyric acid oligomers using solid acid catalysis. The steps are as follows (see schematic diagram). Figure 1 ):

[0026] (1) Take 20g of methyl R-3-hydroxybutyrate, 10g of Nafion® NR50 solid acid catalyst and 100mL of water and add them to a 250mL open beaker equipped with a mechanical stirrer. Place the open beaker in a fume hood with the fume hood in exhaust mode to accelerate the volatilization of methanol and water vapor generated during the reaction. Turn on the mechanical stirrer at 300rpm and heat the open beaker to 75°C. Then react at this temperature until insoluble matter begins to appear, and stop the reaction immediately. During this reaction, methyl R-3-hydroxybutyrate is hydrolyzed to R-3-hydroxybutyric acid and methanol under the catalysis of Nafion® NR50 solid acid catalyst. The methanol generated (boiling point 64.7°C) is first evaporated and removed under heating conditions (reaction temperature 75°C), thereby accelerating the hydrolysis of methyl R-3-hydroxybutyrate to R-3-hydroxybutyric acid. When the fume hood is in exhaust mode, the water in the open beaker gradually evaporates, forming a high concentration of R-3-hydroxybutyric acid, which promotes the polymerization of R-3-hydroxybutyric acid under the catalysis of a solid acid catalyst to form R-3-hydroxybutyric acid oligomers.

[0027] (2) The product obtained in step (1) was recovered by solid-liquid separation to obtain Nafion® NR50 solid acid catalyst and liquid product. The Nafion® NR50 solid acid catalyst can be reused after washing with water. The liquid product was placed in a vacuum drying oven and dried at 50°C to obtain a white solid (see...). Figure 2 The white solid is readily soluble in water, indicating it is a water-soluble polymer; this also suggests that the solid has a low degree of polymerization (because highly polymerized poly-3-hydroxybutyrate is insoluble in water). Mass spectrometry analysis of the dissolved white solid in ethanol revealed a molecular ion peak at 258 (see...). Figure 3The molecular ion peak is precisely the value of the polymerization of three R-3-hydroxybutyric acids (molecular weight 104) undergoing pairwise dehydration (removing a total of 3 water molecules, with a water molecular weight of 18) (104*3-18*3=258), further verifying that the white solid is an oligomer of (R)-3-hydroxybutyric acid. 0.5g of this white solid and 5mL of 2% sulfuric acid methanol solution were placed in a digestion tube for alcoholysis (reacted at 100℃ for 1h). Analysis by GC-MS (see...) Figure 4 The main product is methyl R-3-hydroxybutyrate, indicating that the solid can be hydrolyzed back to methyl R-3-hydroxybutyrate, further proving that the solid product is a water-soluble oligomer of R-3-hydroxybutyrate.

[0028] Example 2

[0029] This embodiment describes a method for synthesizing water-soluble (R)-3-hydroxybutyric acid oligomers using solid acid catalysis, with the following steps:

[0030] 50g of methyl R-3-hydroxybutyrate, 25g of Amberlyst-36 solid acid catalyst, and 100mL of water were added to a 250mL open beaker equipped with a mechanical stirrer. The open beaker was placed in a fume hood with the exhaust fan engaged to accelerate the evaporation of methanol and water vapor generated during the reaction. The mechanical stirrer was turned on at 300rpm, and the open beaker was heated to 65°C. The reaction was continued at this temperature until insoluble substances began to appear, at which point the reaction was immediately stopped. The resulting product was recovered by solid-liquid separation to obtain the Amberlyst-36 solid acid catalyst and the liquid product. The Amberlyst-36 solid acid catalyst could be reused after washing with water. The liquid product was dried in a vacuum drying oven at 50°C to obtain water-soluble R-3-hydroxybutyric acid oligomers.

[0031] Example 3

[0032] This embodiment describes a method for synthesizing water-soluble (R)-3-hydroxybutyric acid oligomers using solid acid catalysis, with the following steps:

[0033] 10g of methyl R-3-hydroxybutyrate, 5g of Nafion® NR50 solid acid catalyst, and 100mL of water were added to a 250mL open beaker equipped with a mechanical stirrer. The open beaker was placed in a fume hood with the fume hood in exhaust mode to accelerate the reaction and expel methanol and water vapor. The mechanical stirrer was turned on at 300rpm, and the open beaker was heated to 100°C. The reaction was continued at this temperature until insoluble substances began to appear, at which point the reaction was immediately stopped. The resulting product was recovered by solid-liquid separation to obtain the Nafion® NR50 solid acid catalyst and the liquid product. The Nafion® NR50 solid acid catalyst could be reused after washing with water. The liquid product was dried in a vacuum drying oven at 50°C to obtain water-soluble R-3-hydroxybutyric acid oligomers.

[0034] Example 4

[0035] This embodiment describes a method for synthesizing water-soluble (R)-3-hydroxybutyric acid oligomers using solid acid catalysis, with the following steps:

[0036] 50g of methyl R-3-hydroxybutyrate, 25g of Amberlyst-15 solid acid catalyst, and 100mL of water were added to a 250mL open beaker equipped with a mechanical stirrer. The open beaker was placed in a fume hood with the exhaust fan engaged to accelerate the evaporation of methanol and water vapor generated during the reaction. The mechanical stirrer was turned on at 300rpm, and the open beaker was heated to 80°C. The reaction was continued at this temperature until insoluble substances began to appear, at which point the reaction was immediately stopped. The resulting product was recovered by solid-liquid separation to obtain Amberlyst-36 solid acid catalyst and the liquid product. The Amberlyst-36 solid acid catalyst could be reused after washing with water. The liquid product was dried in a vacuum drying oven to obtain water-soluble R-3-hydroxybutyric acid oligomers.

[0037] Example 5

[0038] This embodiment describes a method for synthesizing water-soluble (R)-3-hydroxybutyric acid oligomers using solid acid catalysis, with the following steps:

[0039] 50g of methyl R-3-hydroxybutyrate, 50g of HND-34 solid superacid catalyst, and 100mL of water were added to a 250mL open beaker equipped with a mechanical stirrer. The open beaker was placed in a fume hood with the exhaust fan engaged to accelerate the evaporation of methanol and water vapor generated during the reaction. The mechanical stirrer was turned on at 300rpm, and the open beaker was heated to 90℃. The reaction was continued at this temperature until insoluble substances began to appear, at which point the reaction was immediately stopped. The resulting product was recovered by solid-liquid separation to obtain the HND-34 solid superacid catalyst and the liquid product. The HND-34 solid superacid catalyst could be reused after washing with water. The liquid product was dried in a vacuum drying oven to obtain water-soluble R-3-hydroxybutyric acid oligomers.

[0040] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A method for one-step catalytic synthesis of (R)-3-hydroxybutyric acid oligomers using a solid acid catalyst, characterized in that: Under flowing air conditions, (R)-3-hydroxybutyrate, a solid acid catalyst, and ultrapure water were stirred and hydrolyzed in an open environment until insoluble substances began to appear in the aqueous solution. After the reaction was completed, solid-liquid separation was performed. The liquid product was dried to obtain water-soluble (R)-3-hydroxybutyrate oligomers. The solid was washed and filtered to be recycled as a solid acid catalyst. The (R)-3-hydroxybutyrate includes methyl (R)-3-hydroxybutyrate or ethyl (R)-3-hydroxybutyrate; The solid acid catalyst is a strong acid solid particulate catalyst with good stability in aqueous solutions below 100°C. The solid acid catalyst includes any one of Amberlyst-36, Amberlyst-15, Nafion® NR50, or HND-34 solid superacid catalysts; The mass ratio of (R)-3-hydroxybutyrate to the solid acid catalyst is (1~2):1; Each 1-2 g of (R)-3-hydroxybutyrate requires the addition of 2-20 mL of ultrapure water; The hydrolysis temperature is 65~100℃.

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