CN116396163A - A kind of method of solid acid catalyst one-step catalytic synthesis (R)-3-hydroxybutyric acid oligomer - Google Patents

Abstract

The invention belongs to the technical field of chiral chemical R-3-hydroxybutyrate utilization, and relates to a method for synthesizing (R) -3-hydroxybutyrate oligomer by one-step catalysis by using a solid acid catalyst. The method comprises the following steps: stirring (R) -3-hydroxybutyrate, a solid acid catalyst and ultrapure water in an open mode under the flowing air condition and hydrolyzing until insoluble substances begin to appear in the aqueous solution, carrying out solid-liquid separation after the reaction is finished, and carrying out vacuum drying on a liquid product to obtain a water-soluble (R) -3-hydroxybutyrate oligomer; and (3) filtering and separating the solid after cleaning to recycle the solid as a solid acid catalyst. The invention solves the technical problems of multiple process steps, complicated conditions and high energy consumption in the synthesis process of the (R) -3-hydroxybutyric acid oligomer in the prior art, and the catalyst can be reused in the reaction process, and has the advantages of simple process, convenient operation, environmental protection and industrial application value.

Description

One-step catalytic synthesis of (R)-3-hydroxybutyric acid oligomers by a solid acid catalyst method

technical field

The invention belongs to the technical field of utilization of chiral chemical R-3-hydroxybutyrate, and relates to a method for one-step catalytic synthesis of (R)-3-hydroxybutyric acid oligomers by a solid acid catalyst.

Background technique

(R)-3-Hydroxybutyric acid is the structural monomer of green renewable poly-3-hydroxybutyric acid (PHB), which can be obtained by acid-catalyzed hydrolysis of PHB. (R)-3-Hydroxybutyrate is an important ketone body in the body that fuels the brain and is used by skeletal and cardiac muscles. At present, (R)-3-hydroxybutyric acid has been researched and used by special personnel such as athletes and soldiers who enter extreme physiological states in an emergency. In addition, (R)-3-hydroxybutyric acid is also considered as a healthy solid drink (such as ketogenic diet pills), which has a wide market. However, (R)-3-hydroxybutyric acid has certain limitations in the direct application process, mainly including two aspects, one is (R)-3-hydroxybutyric acid is an organic acid, so the human body The amount and concentration of β-hydroxybutyric acid provided during the intake process is limited; the second is that (R)-3-hydroxybutyric acid has poor stability and is not easy to store, and it is easy to decompose the harmful substance croton under normal temperature storage conditions acid. In order to solve problems such as acidity and stability, some companies have developed (R)-3-hydroxybutyrate products (such as sodium, magnesium, calcium and potassium salts). These (R)-3-hydroxybutyrates raise some other problems, such as the potential danger of metal ion overload. In addition, the absorption and metabolism of (R)-3-hydroxybutyric acid and its salts in the human body is too fast, it is difficult to maintain a high concentration in the human body for a long time, and the onset time is too short.

Patent CN110776425A and several academic research results have disclosed that (R)-3-hydroxybutyric acid oligomer can not only prolong the action time to achieve the effect of sustained release, but also reduce the risk of acidosis and metal ion overload. For this reason, (R)-3-hydroxybutyric acid oligomer has the potential to become a high-quality ketone body with high safety, low side effects and long-term effect. Patent CN110776425A discloses the synthetic method of (R)-3-hydroxybutyric acid oligomer at the same time, with (R)-3-hydroxybutyrate obtained by PHB alcoholysis as raw material, (R)-3-hydroxybutyrate catalyzes After hydrolysis, obtain (R)-3-hydroxybutyric acid [preferred base catalysis (such as sodium hydroxide), the homogeneous base catalysis process has environmental pollution risks, and requires post-treatment operations such as acidification, extraction, distillation], and then (R )-3-hydroxybutyric acid is polymerized under complex conditions [higher temperature (100~150°C), inert gas protection, negative pressure (0.001~0.05Mpa) conditions] to obtain (R)-3-hydroxybutyric acid oligomers. The patented process involves two independent reactions, with many process steps, complicated conditions and high energy consumption. Similar to (R)-3-hydroxybutyric acid oligomers, water-soluble (R)-3-hydroxybutyric acid polymers can also theoretically overcome the acidity and instability problems of (R)-3-hydroxybutyric acid , and overcome the problem of high salt content of (R)-3-hydroxybutyrate compounds. Therefore, it is of great significance to develop a new green technology to convert (R)-3-hydroxybutyrate into water-soluble R-3-hydroxybutyrate oligomers through a simple reaction process.

Contents of the invention

Aiming at the technical problems of many process steps, complicated conditions and high energy consumption in the synthesis process of (R)-3-hydroxybutyric acid polymer in the prior art, the present invention proposes a solid acid catalyst to catalyze the synthesis of (R)-3- A method for hydroxybutyric acid oligomers. In the reaction process, the catalyst can be reused, and the catalytic process is simple, convenient to operate and environmentally friendly, and has industrial application value.

In order to achieve the above object, the technical solution of the present invention is achieved in that:

A kind of solid acid catalyst one-step catalytic synthesis method of (R)-3-hydroxybutyric acid oligomer, (R)-3-hydroxybutyrate, solid acid catalyst and ultrapure water are added in open bottle, open The mouth bottle is placed in flowing air conditions to accelerate the evaporation of by-product methanol and water. Turn on mechanical stirring, then hydrolyze at 65~100°C until insoluble matter begins to appear in the aqueous solution. The reaction product is subjected to solid-liquid separation, and a solid acid catalyst and a liquid product are recovered. The liquid product was vacuum-dried to obtain a water-soluble (R)-3-hydroxybutyric acid oligomer. The recovered solid acid catalyst was washed with ultrapure water, separated by suction filtration and reused.

The (R)-3-hydroxybutyrate used in the present invention is mainly (R)-3-hydroxybutyrate methyl and (R)-3-hydroxybutyrate ethyl.

The catalyst used in the present invention is a strongly acidic solid particle catalyst with good stability in aqueous solution below 100°C, including Amberlyst-36, Amberlyst-315, Nafion® NR50, HND-34 solid superacid catalyst, etc.

The mass ratio of (R)-3-hydroxybutyrate in the present invention to the solid acid catalyst is (1~2):1.

According to the present invention, 2-20 mL of ultrapure water needs to be added for every 1-2 g of (R)-3-hydroxybutyrate.

The solid acid catalyst developed by the present invention catalyzes the method for synthesizing (R)-3-hydroxybutyric acid oligomers in one step, which can realize the one-step conversion of (R)-3-hydroxybutyrate into water-soluble (R)-3-Hydroxybutyric acid oligomer. In this reactor, a possible mechanism involves two hydrolytic equilibrium reactions. One is (R)-3-hydroxybutyrate [(R)-3-hydroxybutyrate methyl ester or (R)-3-hydroxybutyrate ethyl ester] is hydrolyzed under solid acid catalysis to generate (R)-3 -Hydroxybutyric acid and alcohol (methanol or ethanol), the resulting methanol or ethanol is removed from the reactor by distillation under heated conditions, thereby promoting the hydrolysis of (R)-3-hydroxybutyrate and (R) - Generation of 3-hydroxybutyric acid. The second is that the generated (R)-3-hydroxybutyric acid undergoes intermolecular (the hydroxyl group of one molecule (R)-3-hydroxybutyric acid and the other molecule (R)-3-hydroxybutyric acid) under the catalysis of solid acid. The catalyzed esterification reaction of the carboxyl group of the acid) finally generates (R)-3-hydroxybutyric acid oligomers. As the reaction progressed, solvent water was removed from the reactor by distillation, further promoting the formation of (R)-3-hydroxybutyric acid oligomers. When insoluble matter begins to appear, stop reaction immediately, in order to avoid generating water-insoluble high polymer, reduce the utilization efficiency of raw material (R)-3-hydroxybutyrate.

For this reason, the key factor that promotes the good effect of the technology of the present invention has three:

(1) The reactor is not airtight during the reaction, and 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-hydroxybutyrate Acid and (R)-3-hydroxybutyric acid further oligomerize to generate (R)-3-hydroxybutyric acid oligomers.

(2) The granular solid acid catalyst is used in the reaction process, and the catalytic performance of the solid acid catalyst will not change too much due to the reduction of solvent water evaporation during the reaction process, and the granular solid acid catalyst will not change much after the reaction ends. Afterwards, it is easy to separate from the product, which greatly simplifies the post-treatment process of (R)-3-hydroxybutyric acid oligomer product and realizes the reuse of the catalyst; in addition, the strong acidic solid acid catalyst is conducive to reducing the (R)-3- The polymerization reaction temperature of hydroxybutyric acid realizes the generation of (R)-3-hydroxybutyric acid oligomers at a mild temperature, which is beneficial to reduce energy consumption and avoid possible high-temperature oxidation of (R)-3-hydroxybutyric acid. For this reason, no inert gas protection is required during the reaction.

(3) Control the reaction time. When insoluble matter begins to appear in the aqueous solution, stop the reaction immediately to ensure that the polymer obtained from the reaction is water-soluble.

The present invention has the following beneficial effects:

The invention provides a method for one-step catalytic synthesis of (R)-3-hydroxybutyric acid oligomers by a solid acid catalyst. The process adopts a simple reaction device with an open door, the reaction temperature is mild (65~100°C), and no inert gas protection conditions are required; the obtained polymer is water-soluble, which is conducive to the application of the product in the preparation of water-based products (such as solid beverages); The solid acid catalyst is adopted, which promotes the reaction and is easy to recycle and reuse. Obviously, the technical process of the present invention is simple, convenient to operate, low in energy consumption, and the whole process is green and environment-friendly, and has broad industrial application prospects.

Description of drawings

In order to more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the following will briefly introduce the drawings that need to be used in the description of the embodiments or the prior art. Obviously, the accompanying drawings in the following description are only These are some embodiments of the present invention. Those skilled in the art can also obtain other drawings based on these drawings without creative work.

Fig. 1 is a schematic diagram of process steps in Embodiment 1 of the present invention.

Fig. 2 is the actual picture of the white solid obtained in Example 1 of the present invention.

Fig. 3 is the mass spectrum analysis of the white solid obtained in Example 1 of the present invention.

Fig. 4 is a GC-MS analysis diagram of the white solid alcoholysis product in Example 1 of the present invention.

Detailed ways

The following will clearly and completely describe the technical solutions in the embodiments of the present invention with reference to the accompanying drawings in the embodiments of the present invention. Obviously, the described embodiments are only some, not all, embodiments of the present invention. Based on the embodiments of the present invention, all other embodiments obtained by persons of ordinary skill in the art without making creative efforts belong to the protection scope of the present invention.

Example 1

This example is a solid acid-catalyzed method for synthesizing water-soluble (R)-3-hydroxybutyric acid oligomers. The steps are as follows (see Figure 1 for the schematic diagram):

(1) Take 20g of methyl R-3-hydroxybutyrate, 10g of Nafion®NR50 solid acid catalyst and 100mL of water into a 250mL open beaker with mechanical stirring. The open beaker was placed in a fume hood, and the fume hood was in a draft state to speed up the methanol and water vapor generated during the volatilization reaction. Turn on the mechanical stirring 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 the reaction process, methyl R-3-hydroxybutyrate is hydrolyzed under the catalysis of Nafion®NR50 solid acid catalyst to generate R-3-hydroxybutyric acid and methanol, and the generated methanol (boiling point 64.7°C) is heated under ( At the reaction temperature of 75°C), it is first evaporated and removed, thereby accelerating the hydrolysis of R-3-hydroxybutyric acid methyl ester to generate R-3-hydroxybutyric acid. Under the exhaust state of the fume hood, the water in the open beaker also gradually evaporates to form a high concentration of R-3-hydroxybutyric acid, thereby promoting the polymerization of R-3-hydroxybutyric acid under the catalysis of a solid acid catalyst to form R-3 -Hydroxybutyric acid oligomers.

(2) The product obtained in step (1) is recovered by solid-liquid separation to obtain Nafion®NR50 solid acid catalyst and liquid product, wherein Nafion®NR50 solid acid catalyst can be reused after being washed with water. The liquid product was put into a vacuum drying oven and dried at 50°C to obtain a white solid (see Figure 2). The white solid is easily soluble in water and is a water-soluble polymer; it also indicates that the degree of polymerization of the solid is not high (because poly-3-hydroxybutyrate with a high degree of polymerization is insoluble in water). The white solid was dissolved in ethanol for mass spectrometry analysis, and the molecular ion peak was found to be 258 (see Figure 3), which happened to be the intermolecular dehydration of three R-3-hydroxybutyric acid (molecular weight 104) (A total of 3 waters were removed, and the molecular weight of water was 18) The value of polymerization (104*3-18*3=258) further verified that the white solid was (R)-3-hydroxybutyric acid oligomer. Take 0.5g of the white solid and 5mL of 2% methanolic sulfuric acid solution into a digestion tube for alcoholysis reaction (reaction at 100°C for 1h). After GC-MS analysis (see Figure 4), the main product is R-3-hydroxybutyric acid methyl ester, indicating that the solid can be re-hydrolyzed into R-3-hydroxybutyrate methyl ester, further proving that the solid product is a water-soluble R-3-hydroxybutyrate oligomer.

Example 2

This embodiment is a method for solid acid catalyzed synthesis of water-soluble (R)-3-hydroxybutyric acid oligomers, the steps are as follows:

Take 50g of methyl R-3-hydroxybutyrate, 25g of Amberlyst-36 solid acid catalyst and 100mL of water into a 250mL open beaker with mechanical stirring. The open beaker was placed in a fume hood, and the fume hood was in a draft state to speed up the methanol and water vapor generated during the volatilization reaction. Turn on the mechanical stirring at 300rpm, and heat the open beaker to 65°C, then react at this temperature until insoluble matter begins to appear, and stop the reaction immediately. The resulting product is recovered through solid-liquid separation to obtain Amberlyst-36 solid acid catalyst and liquid product, wherein the Amberlyst-36 solid acid catalyst can be reused after being washed with water. Put the liquid product into a vacuum drying oven to dry at 50° C. to obtain a water-soluble R-3-hydroxybutyric acid oligomer.

Example 3

This embodiment is a method for solid acid catalyzed synthesis of water-soluble (R)-3-hydroxybutyric acid oligomers, the steps are as follows:

Take 10g of methyl R-3-hydroxybutyrate, 5g of Nafion®NR50 solid acid catalyst and 100mL of water into a 250mL open beaker with mechanical stirring. The open beaker was placed in a fume hood, and the fume hood was in a draft state to accelerate the methanol and water vapor generated during the reaction. Turn on the mechanical stirring at 300rpm, and heat the open beaker to 100°C, then react at this temperature until insoluble matter begins to appear, and stop the reaction immediately. The obtained product is recovered by solid-liquid separation to obtain Nafion®NR50 solid acid catalyst and liquid product, wherein Nafion®NR50 solid acid catalyst can be reused after being washed with water. Put the liquid product into a vacuum drying oven to dry at 50° C. to obtain a water-soluble R-3-hydroxybutyric acid oligomer.

Example 4

This embodiment is a method for solid acid catalyzed synthesis of water-soluble (R)-3-hydroxybutyric acid oligomers, the steps are as follows:

Take 50g of methyl R-3-hydroxybutyrate, 25g of Amberlyst-15 solid acid catalyst and 100mL of water and add it to a 250mL open beaker with mechanical stirring. The open beaker was placed in a fume hood, and the fume hood was in a draft state to speed up the methanol and water vapor generated during the volatilization reaction. Turn on the mechanical stirring at 300rpm, and heat the open beaker to 80°C, then react at this temperature until insoluble matter begins to appear, and stop the reaction immediately. The resulting product is recovered through solid-liquid separation to obtain Amberlyst-36 solid acid catalyst and liquid product, wherein the Amberlyst-36 solid acid catalyst can be reused after being washed with water. The liquid product is put into a vacuum drying oven for drying to obtain a water-soluble R-3-hydroxybutyric acid oligomer.

Example 5

This embodiment is a method for solid acid catalyzed synthesis of water-soluble (R)-3-hydroxybutyric acid oligomers, the steps are as follows:

Take 50g R-3-hydroxybutyrate methyl ester, 50g HND-34 solid superacid catalyst and 100mL water and join in a 250mL open beaker with mechanical stirring. The open beaker was placed in a fume hood, and the fume hood was in a draft state to speed up the methanol and water vapor generated during the volatilization reaction. Turn on the mechanical stirring at 300rpm, and heat the open beaker to 90°C, then react at this temperature until insoluble matter begins to appear, and stop the reaction immediately. The resulting product is recovered by solid-liquid separation to obtain HND-34 solid superacid catalyst and liquid product, wherein the HND-34 solid superacid catalyst can be reused after being washed with water. The liquid product is put into a vacuum drying oven for drying to obtain a water-soluble R-3-hydroxybutyric acid oligomer.

The above descriptions are only preferred embodiments of the present invention, and are not intended to limit the present invention. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included in the scope of the present invention. within the scope of protection.

Claims (7)

1. a method for solid acid catalyst one-step catalytic synthesis of (R)-3-hydroxybutyric acid oligomers, characterized in that: under flowing air conditions, (R)-3-hydroxybutyrate, solid acid catalyst Stir openly with ultrapure water and hydrolyze until insoluble matter begins to appear in the aqueous solution. After the reaction, separate the solid from the liquid and dry the liquid product to obtain water-soluble (R)-3-hydroxybutyric acid oligomers; wash the solid After that, it is separated by suction filtration and recycled as a solid acid catalyst. 2. the method for one-step catalytic synthesis of (R)-3-hydroxybutyric acid oligomer by solid acid catalyst according to claim 1, is characterized in that: described (R)-3-hydroxybutyrate comprises (R) -methyl 3-hydroxybutyrate or ethyl (R)-3-hydroxybutyrate. 3. the method for one-step catalytic synthesis of (R)-3-hydroxybutyric acid oligomers by the solid acid catalyst according to claim 1, characterized in that: the solid acid catalyst has good stability in an aqueous solution below 100°C strongly acidic solid particle catalyst. 4. the method for one-step catalytic synthesis of solid acid catalyst according to claim 3 (R)-3-hydroxybutyric acid oligomer, is characterized in that: described solid acid catalyst comprises Amberlyst-36, Amberlyst-15, Nafion® Any one of NR50 or HND-34 solid superacid catalyst. 5. the method for one-step catalytic synthesis of (R)-3-hydroxybutyric acid oligomers according to the solid acid catalyst described in any one of claims 1-4, is characterized in that: described (R)-3-hydroxybutyric acid The mass ratio of ester to solid acid catalyst is (1~2):1. 6. the method for solid acid catalyst one-step catalytic synthesis (R)-3-hydroxybutyric acid oligomer according to claim 5, is characterized in that: described every 1～2 g (R)-3-hydroxybutyric acid Esters need to add 2~20 mL ultrapure water. 7. according to the method for one-step catalytic synthesis of (R)-3-hydroxybutyric acid oligomers of the solid acid catalyst described in any one of claim 1-4 or 6, it is characterized in that: the temperature of described hydrolysis is 65～100 ℃.

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