A process for the preparation of a solid of (r)-3-hydroxybutyric acid

Abstract

This invention belongs to the field of compound processing technology and provides a method for preparing solid (R)-3-hydroxybutyric acid. The method involves first mixing an (R)-3-hydroxybutyric acid solution with an adsorbent, filtering, collecting the solid, drying, eluting, and vacuum distilling to obtain solid (R)-3-hydroxybutyric acid. A polar adsorption resin is used as the adsorbent. The adsorbent is first vacuum dried to remove moisture, then eluted and vacuum distilled to remove the solvent, precipitating solid (R)-3-hydroxybutyric acid with low water content. Furthermore, this invention uses a polar adsorption resin for specific adsorption of the (R)-3-hydroxybutyric acid solution. This polar adsorption resin possesses polar functional groups, enabling hydrogen bonding adsorption of (R)-3-hydroxybutyric acid containing carboxyl groups, resulting in high adsorption efficiency and avoiding the use of strongly basic anion exchange resins for adsorbing (R)-3-hydroxybutyric acid.

Description

Technical Field

[0001] This invention relates to the field of compound processing technology, and more specifically, to a method for preparing (R)-3-hydroxybutyric acid solid. Background Technology

[0002] 3-Hydroxybutyric acid (3-HB) is the monomeric form of the natural polymer poly(R)-3-hydroxybutyric acid (hereinafter referred to as PHB), existing naturally in its pure R configuration. As an important ketone body in the body, 3-hydroxybutyric acid is produced by the degradation of long-chain fatty acids in the liver, transported through the bloodstream to peripheral tissues, and plays a regulatory role in bodily functions. 3-Hydroxybutyric acid has significant application value and prospects in the health supplement, food, and pharmaceutical industries, including: accelerating weight loss; stimulating the expression of various health-promoting genes; reducing the occurrence of inflammatory complications; improving exercise performance and training efficiency; enhancing metabolic efficiency; providing optimal energy for the heart and reducing the incidence of cardiovascular disease; improving insulin sensitivity; preventing cancer and diseases related to glucose metabolism disorders; increasing cognitive ability, preventing Alzheimer's disease, and extending lifespan.

[0003] Solid beverages are popular due to their non-perishable ingredients, long shelf life, small size, and ease of carrying and transportation. The preparation of solid beverages containing 3-hydroxybutyric acid (3-Hydroxybutyric acid) requires the use of solid 3-Hydroxybutyric acid. Solid beverages generally require a water content below 5 wt%. Currently, commercially available (R)-3-hydroxybutyric acid is mainly available in the form of its salt powders, primarily sodium, magnesium, and calcium salts. However, these salts have a high cationic content, making them unsuitable for high-dose use. Excessive intake of (R)-3-hydroxybutyrate can lead to excessive salt intake, which is detrimental to human health.

[0004] The commonly used method for preparing high-content (R)-3-hydroxybutyric acid crystals is the direct chemical synthesis method (liquid-phase oxidation method). The specific principle is as follows: 3-hydroxybutyraldehyde and oxygen are used as the main raw materials, cobalt acetate is used as a catalyst, and ethyl acetate is used as a solvent. After the reaction, the relatively low-boiling-point ethyl acetate and 3-hydroxybutyraldehyde are removed by concentration. However, the cobalt acetate catalyst and the high-boiling-point butenoic acids (3-butenoic acid and 2-butenoic acid) produced by the side reaction are difficult to remove. In particular, the cobalt acetate catalyst is a carcinogen. If used as a food ingredient, the residual byproducts and cobalt acetate pose a safety hazard. Therefore, (R)-3-hydroxybutyric acid prepared by this method is not suitable for use in food or health products. The main and side reactions involved are shown below:

[0005] Main reaction:

[0006] 2CH3CH(OH)CH2CHO+O2→2CH3CH(OH)CH2COOH

[0007] Side reaction:

[0008] CH3CH(OH)CH2CHO→CH3CH-CHCHO+H2O

[0009] 2CH3CH-CHCHO+O2→2CH3CH-CHCOOH

[0010] CH3CH(OH)CH2COOH→CH3CH-CHCOOH+H2O

[0011] CH3CH(OH)CH2COOH→CH2=CHCH2COOH+H2O

[0012] In addition, (R)-3-hydroxybutyric acid can also be prepared by degrading PHB, mainly through the following three routes: (1) Alkaline degradation method: first, PHB is hydrolyzed with a strong alkali to prepare 3-hydroxybutyrate, and then neutralized with acid to obtain (R)-3-hydroxybutyric acid. (2) Acid-catalyzed hydrolysis method: PHB is hydrolyzed with acid to prepare (R)-3-hydroxybutyric acid. (3) PHB is first alcoholized to produce 3-hydroxybutyrate, and then 3-hydroxybutyrate is hydrolyzed to prepare 3-hydroxybutyric acid. Although the above three methods avoid the impurities brought about by the high content of 3-hydroxybutyric acid crystals obtained by direct chemical synthesis, the 3-hydroxybutyric acid products prepared are all 3-hydroxybutyric acid aqueous solutions, in which the 3-hydroxybutyric acid content is low (generally less than 50%), and the liquid (R)-3-hydroxybutyric acid has poor stability due to its high water content and cannot be used as a raw material for solid beverages. If the prepared 3-hydroxybutyric acid aqueous solution is directly concentrated, not only will the solid content of the 3-hydroxybutyric acid aqueous solution be difficult to reach more than 80%, resulting in a liquid substance, but during the concentration process, 3-hydroxybutyric acid undergoes condensation and dehydration, forming some by-products, 3-hydroxybutyrate oligomers (the hydroxyl and carboxyl groups have undergone esterification). If an adsorbent is used to adsorb the active ingredient, it is generally eluted directly with an eluent. However, during the elution process, other impurities are introduced into the system, resulting in insufficient purity of the finished product. In addition, for the adsorption and separation of active ingredients of organic acids, strongly basic ion exchange resins are currently commonly used for adsorption and separation, utilizing the principle of positive and negative charge adsorption to increase the adsorption capacity. However, they also adsorb highly polar molecules such as water, so in the subsequent elution process, concentration is still required to remove them, turning the solution into a viscous substance, which increases the viscosity of the system, and it is still impossible to completely remove water directly through concentration. Furthermore, strong basic ion exchange resins exist in two forms: hydroxyl (OH-) and chloride (Cl-). If a hydroxyl-form strong basic ion exchange resin is used to adsorb (R)-3-hydroxybutyric acid, a neutralization reaction occurs, producing a large amount of water. After adsorption, a significant amount of water remains. Additionally, even food-grade hydroxyl-form resins have a strong odor, which negatively impacts the quality of the final (R)-3-hydroxybutyric acid. Conversely, using a chloride-form strong basic ion exchange resin introduces a large amount of chloride ions into the final (R)-3-hydroxybutyric acid solid, hindering its subsequent applications.

[0013] Therefore, there is an urgent need to develop a method for preparing (R)-3-hydroxybutyric acid solid with low water content and high purity (free from oligomers, other impurities in the system, harmful substances, etc.) to meet the requirements for preparing solid beverages. Summary of the Invention

[0014] This invention aims to solve at least one of the technical problems existing in the prior art. To this end, this invention proposes a method for preparing (R)-3-hydroxybutyric acid solid. By improving the preparation process of (R)-3-hydroxybutyric acid solid, this invention results in a solid with low water content (≤1 wt%), avoids the generation of oligomers during dehydration, is free of toxic impurities (no heavy metals detected), and has high purity, thus solving the current problem that (R)-3-hydroxybutyric acid solid is difficult to apply in solid dosage forms (such as solid beverages).

[0015] The first aspect of the present invention provides a method for preparing (R)-3-hydroxybutyric acid solid.

[0016] Specifically, a method for preparing (R)-3-hydroxybutyric acid solid includes the following steps:

[0017] The (R)-3-hydroxybutyric acid solution and the adsorbent were mixed, filtered, the solid was collected and dried, eluted, and distilled under reduced pressure to obtain the (R)-3-hydroxybutyric acid solid.

[0018] The adsorbent is a polar adsorption resin.

[0019] This invention first utilizes the principle of hydrogen bonding adsorption, employing an adsorbent to adsorb (R)-3-hydroxybutyric acid from a solution. The adsorbent is then filtered, and the resulting solid is dried to remove residual water. Following elution, a solution containing (R)-3-hydroxybutyric acid is obtained. The solvent is then removed by vacuum distillation, precipitating high-purity (R)-3-hydroxybutyric acid solid with low water content. Existing conventional adsorption separation methods typically involve directly eluting the adsorbent after adsorption, which inevitably introduces impurities and reintroduces moisture. This invention, however, first vacuum-dries the adsorbent to remove moisture before elution and vacuum distillation to precipitate (R)-3-hydroxybutyric acid solid, thus significantly reducing water content. In addition, the present invention employs a polar adsorption resin to specifically adsorb (R)-3-hydroxybutyric acid solution. The polar adsorption resin has polar functional groups (e.g., ester bonds, cyano groups, amide groups, etc., which contain polar functional groups such as nitrogen and sulfur), which can perform hydrogen bond adsorption on (R)-3-hydroxybutyric acid containing carboxyl groups. This results in high adsorption efficiency and avoids the need to use strongly basic anion exchange resins to adsorb (R)-3-hydroxybutyric acid.

[0020] Preferably, the polar adsorption resin is a food-grade polar adsorption resin, and / or the polar adsorption resin is a polar adsorption resin containing carboxyl groups.

[0021] More preferably, the polar adsorption resin is at least one of the following: a polar adsorption resin containing a methacrylic acid-2-methacrylic acid copolymer, a polar adsorption resin containing a polyacrylic acid resin, and a polar adsorption resin containing a methacrylic acid-amide resin.

[0022] More preferably, the polar adsorption resin is at least one of the polar adsorption resins of type HP2MGL, type AB-8, and type LSI-960.

[0023] Preferably, the drying is vacuum drying, and / or the drying temperature is 50-70°C, and / or the drying time is 5-10 hours.

[0024] Preferably, the elution is solvent boiling reflux elution. Using solvent boiling reflux elution can reduce the amount of solvent used, increase the subsequent vacuum distillation volume, and reduce energy consumption.

[0025] Preferably, the eluent used for elution is at least one selected from anhydrous methanol, anhydrous ethanol, acetone, methyl formate, ethyl formate, and ethyl acetate.

[0026] More preferably, the eluent used in the elution is anhydrous ethanol.

[0027] Preferably, the eluent used in the elution is a food-grade solvent.

[0028] Preferably, the relative vacuum pressure of the vacuum distillation is below -0.09 MPa, and / or the temperature of the vacuum distillation is 50-70°C, and / or the time of the vacuum distillation is 0.5-2 hours.

[0029] Preferably, the water content of the (R)-3-hydroxybutyric acid solid is ≤1wt%.

[0030] A second aspect of the present invention provides a solid beverage.

[0031] A solid beverage, wherein the components of the solid beverage include (R)-3-hydroxybutyric acid solid, the (R)-3-hydroxybutyric acid solid being prepared by the above-described preparation method.

[0032] Preferably, the water content in the solid beverage is ≤5 wt%.

[0033] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0034] This invention first mixes (R)-3-hydroxybutyric acid solution and adsorbent, filters, collects the solid, dries it, elutes it, and distills it under reduced pressure to obtain solid (R)-3-hydroxybutyric acid. A polar adsorption resin is used as the adsorbent. This invention first utilizes the principle of electrostatic adsorption, using an adsorbent to adsorb (R)-3-hydroxybutyric acid from the solution. Then, it is filtered, and the filtered solid is dried to remove residual water, followed by elution to obtain a solution containing (R)-3-hydroxybutyric acid. The solvent is removed by reduced pressure distillation, precipitating solid (R)-3-hydroxybutyric acid. The solution has low water content, high purity (98.43-99.04 wt%), and an optical purity of 95.18-96.18%. Arsenic, lead, mercury, and cadmium heavy metals are undetectable. This invention first vacuum-dries the adsorbent after adsorption to remove moisture, then elutes and distills under reduced pressure to remove the solvent, precipitating (R)-3-hydroxybutyric acid solid with low water content. Furthermore, this invention employs a polar adsorption resin for specific adsorption of (R)-3-hydroxybutyric acid solution. This polar adsorption resin possesses polar functional groups, enabling hydrogen bonding adsorption of (R)-3-hydroxybutyric acid containing carboxyl groups, resulting in high adsorption efficiency and avoiding the use of strongly basic anion exchange resins for adsorbing (R)-3-hydroxybutyric acid. Moreover, the polar adsorption resin eluted from the solvent in this invention can be reused, making it more environmentally friendly and cost-effective. Attached Figure Description

[0035] Figure 1 This is a schematic diagram of the solvent boiling circulation reflux device used in this invention. Detailed Implementation

[0036] To enable those skilled in the art to more clearly understand the technical solutions described in this invention, the following embodiments are provided for illustration. It should be noted that the following embodiments do not constitute a limitation on the scope of protection claimed by this invention.

[0037] Unless otherwise specified, the raw materials, reagents or devices used in the following examples are available from conventional commercial sources or can be obtained by existing known methods.

[0038] The raw materials and testing methods involved in the embodiments and comparative examples of this invention are as follows:

[0039] (R)-3-hydroxybutyric acid solution: The mass concentration of (R)-3-hydroxybutyric acid is 42.80 wt%, model D3HB50, food grade, manufacturer: Zhuhai Maidefa Biotechnology Co., Ltd.

[0040] Polar adsorption resin: Model HP2MGL, food grade; Manufacturer: Mitsubishi Chemical Resin.

[0041] Polar adsorption resin: Model AB-8, food grade; Manufacturer: Xi'an Lanxiao Technology New Materials Co., Ltd.

[0042] Polar adsorption resin: Model LSI-960, food grade; Manufacturer: Xi'an Lanxiao Technology New Materials Co., Ltd.

[0043] Hydroxide-type strong basic anion exchange resin: Model 201ⅹ7, food grade; Manufacturer: Hebi Haige Chemical Technology Co., Ltd.

[0044] Chlorine-type strong basic anion exchange resin: Model 201ⅹ7, food grade; Manufacturer: Hebi Haige Chemical Technology Co., Ltd.

[0045] Non-polar adsorption resin: Model D-101, food grade; Manufacturer: Xi'an Lanxiao Technology New Materials Co., Ltd.

[0046] Methods for testing optical purity: Refer to GB / T 613-2007.

[0047] The method for detecting heavy metal content is as follows: refer to Method I of GB 5009.268-2016.

[0048] Example 1

[0049] A method for preparing (R)-3-hydroxybutyric acid solid includes the following steps:

[0050] (1) Adsorption and filtration: Take 300g of (R)-3-hydroxybutyric acid solution (D3HB50, content 42.80wt%), add it to a 1000mL beaker, stir, and add 200mL of polar adsorption resin HP2MGL while stirring, stir for 1h; filter, and use liquid chromatography to detect the filtrate, (R)-3-hydroxybutyric acid should be undetectable; if there is residual (R)-3-hydroxybutyric acid in the filtrate, use polar adsorption resin to adsorb the (R)-3-hydroxybutyric acid until it is completely adsorbed;

[0051] (2) Drying: Place the filtered polar adsorption resin on a petri dish, spread it out, cover it with a layer of 200-mesh food-grade nylon filter cloth, and then place it in a vacuum drying oven at 60°C and a relative vacuum pressure of -0.1 MPa for 8 hours.

[0052] (3) Elution: Assemble the solvent boiling circulation reflux device ( Figure 1The following steps are performed by connecting a spherical condenser, a constant pressure funnel, a three-necked round-bottom flask, and a heater, from top to bottom. 600 mL of anhydrous ethanol is added to the three-necked round-bottom flask. A piece of medical cotton is placed at the bottom of the constant pressure funnel to prevent the adsorbent from flowing into the round-bottom flask. The dried adsorbent is then loaded into the constant pressure funnel, followed by boiling and reflux for 3 hours. If (R)-3-hydroxybutyric acid residue remains in the adsorbent, boiling and reflux should continue until the (R)-3-hydroxybutyric acid is completely eluted (take 10 mL of adsorbent and soak it in 20 mL of anhydrous ethanol for 30 minutes; then, use high-performance liquid chromatography to detect whether the soaking solution contains (R)-3-hydroxybutyric acid to determine whether there is (R)-3-hydroxybutyric acid residue in the adsorbent. The following examples and comparative examples all use this method to determine whether there is (R)-3-hydroxybutyric acid residue in the adsorbent).

[0053] (4) Removal of solvent by vacuum distillation: The ethanol solution containing (R)-3-hydroxybutyric acid after rinsing was subjected to vacuum distillation using a rotary evaporator at 60°C and a relative vacuum pressure of -0.09 MPa until no fraction was obtained, which took about 1 hour. A clear solid of (R)-3-hydroxybutyric acid was obtained, weighing 122.20 g, with a content of 98.65 wt% (possibly residual water and (R)-3-hydroxybutyric acid oligomers), a yield of about 93.89%, a chloride ion content of 0.085 wt%, and a water content of 0.55 wt%. The optical purity was tested using a specific polarimeter, and the optical purity of (R)-3-hydroxybutyric acid was 96.18%, with no detectable heavy metals such as arsenic, lead, mercury, and cadmium.

[0054] Example 2

[0055] A method for preparing (R)-3-hydroxybutyric acid solid differs from Example 1 in that, in step (1), the polar adsorption resin is replaced with polar adsorption resin AB-8. A clear (R)-3-hydroxybutyric acid solid was finally obtained, weighing 121.89 g, with a content of 99.04 wt%, a yield of approximately 94.02%, a chloride ion content of 0.081%, and a water content of 0.45 wt%. Optical purity was determined using a specific polarimeter; the optical purity of (R)-3-hydroxybutyric acid was 95.45%, and heavy metals such as arsenic, lead, mercury, and cadmium were not detected.

[0056] Example 3

[0057] A method for preparing (R)-3-hydroxybutyric acid solid differs from Example 1 in that, in step (1), the polar adsorption resin is replaced with polar adsorption resin LSI-960. A clear (R)-3-hydroxybutyric acid solid was finally obtained, weighing 121.13 g, with a content of 98.43 wt%, a yield of approximately 92.86%, a chloride ion content of 0.083%, and a water content of 0.64 wt%. Optical purity was determined using a specific polarimeter; the optical purity of (R)-3-hydroxybutyric acid was 95.23%, and heavy metals such as arsenic, lead, mercury, and cadmium were not detected.

[0058] Example 4

[0059] A method for preparing (R)-3-hydroxybutyric acid solid differs from Example 1 in that, in step (1), the polar adsorption resin is replaced with the recovered polar adsorption resin from Example 1. A clear (R)-3-hydroxybutyric acid solid was finally obtained, weighing 121.04 g, with a content of 98.76 wt%, a yield of approximately 93.10%, a chloride ion content of 0.081%, and a water content of 0.67 wt%. Optical purity was determined using a specific polarimeter; the optical purity of (R)-3-hydroxybutyric acid was 95.18%, and heavy metals such as arsenic, lead, mercury, and cadmium were not detected.

[0060] Comparative Example 1 (Direct Concentration Method)

[0061] A method for preparing (R)-3-hydroxybutyric acid solid includes the following steps:

[0062] (1) Take 300g of (R)-3-hydroxybutyric acid solution (D3HB50, content 42.80wt%);

[0063] (2) Vacuum distillation was performed using a rotary evaporator at 60°C and a relative vacuum pressure below -0.09 MPa until no fraction remained, taking approximately 4 hours, resulting in a viscous liquid. The temperature was then raised to 95°C, and vacuum distillation continued until no fraction remained, taking approximately 2 hours. The liquid remained viscous, and solid (R)-3-hydroxybutyric acid could not be obtained. The content of (R)-3-hydroxybutyric acid was 78.25 wt%, the chloride ion content was 0.072%, and the water content was 21.50 wt%.

[0064] In Comparative Example 1, the solution of (R)-3-hydroxybutyric acid was directly concentrated by vacuum distillation, which only yielded a viscous liquid and could not produce solid (R)-3-hydroxybutyric acid.

[0065] Comparative Example 2 (using hydroxide-type strong basic anion exchange resin)

[0066] A method for preparing (R)-3-hydroxybutyric acid solid differs from Example 1 in that, in step (1), the polar adsorption resin is replaced with a hydroxide-type strong basic anion exchange resin (model 201ⅹ7). The final distillation under reduced pressure until no fraction remains, taking approximately 3 hours, yields a viscous substance. The temperature is then raised to 95°C, and distillation under reduced pressure continues until no fraction remains, taking approximately 2 hours, resulting in a highly viscous substance with no flowability, difficult to pour from the rotary flask, and exhibiting a distinct odor of amine. The content of (R)-3-hydroxybutyric acid is 89.25 wt%, the chloride ion content is 0.85%, and the water content is 10.56 wt%.

[0067] Compared with Example 1, Comparative Example 2 used a hydroxide-type strong basic anion exchange resin, which resulted in a high water content in the final (R)-3-hydroxybutyric acid product, making it difficult to prepare solid beverages, and it also had an odor of amine.

[0068] Comparative Example 3 (using a chloride-form strong basic anion exchange resin)

[0069] A method for preparing (R)-3-hydroxybutyric acid solid differs from Example 1 in that, in step (1), the polar adsorption resin is replaced with a chloride-type strong basic anion exchange resin (model 201ⅹ7). The final distillation under reduced pressure until no fraction remains, taking approximately 3 hours, yields a viscous substance. The temperature is then raised to 95°C, and distillation under reduced pressure continues until no fraction remains, taking approximately 2 hours, resulting in a highly viscous substance with no flowability, difficult to pour from the rotary evaporator flask. The content of (R)-3-hydroxybutyric acid is 89.55 wt%, the chloride ion content is 2.1%, and the water content is 10.20 wt%.

[0070] Compared with Example 1, Comparative Example 3 used a chlorine-type strong basic anion exchange resin, which resulted in a high water content and high chloride ion content in the final (R)-3-hydroxybutyric acid product, making it difficult to prepare solid beverages.

[0071] Comparative Example 4

[0072] A method for preparing (R)-3-hydroxybutyric acid solid includes the following steps:

[0073] (1) Take 300g of (R)-3-hydroxybutyric acid solution (D3HB50, content 42.80wt%) and add it to a 1000mL beaker. Then, stir and add 200mL of adsorption resin (model HP2MGL) while stirring. Stir for 1h. Filter. The (R)-3-hydroxybutyric acid in the filtrate should be undetectable by liquid chromatography. If there is residue in the filtrate, use an adsorbent to adsorb the (R)-3-hydroxybutyric acid.

[0074] (2) Assemble the solvent boiling circulation reflux device. Add 600 mL of anhydrous ethanol to a three-necked round-bottom flask. Place a piece of medical cotton at the bottom of the constant pressure funnel to prevent the adsorbent from flowing into the round-bottom flask. Then, put the dried adsorbent into the constant pressure funnel, boil and reflux, and rinse for 3 hours. If there is (R)-3-hydroxybutyric acid residue in the adsorbent, continue boiling and reflux to wash away the (R)-3-hydroxybutyric acid in the adsorbent.

[0075] (3) The ethanol solution containing (R)-3-hydroxybutyric acid after rinsing was subjected to vacuum distillation using a rotary evaporator at 60°C and a relative vacuum pressure below -0.09 MPa until no fraction remained, which took approximately 3 hours and resulted in a viscous substance. The temperature was then raised to 95°C, and vacuum distillation was continued until no fraction remained, which took approximately 2 hours, yielding a highly viscous substance with no flowability that was difficult to pour out of the rotary evaporator flask. The content of (R)-3-hydroxybutyric acid was 91.15 wt%, the chloride ion content was 0.05%, and the water content was 8.44 wt%.

[0076] Comparative Example 4 used HP2MGL adsorption resin. The filtered adsorption resin was not dried before being directly eluted by solvent boiling circulation. Because HP2MGL adsorption resin contains a polar methacrylate skeleton structure, it also adsorbs a lot of water during the adsorption of (R)-3-hydroxybutyric acid. If the adsorption is not dried to remove the water before elution, the water in the adsorbent will also be eluted and mixed into the product. Ultimately, this will prevent the subsequent preparation of solid (R)-3-hydroxybutyric acid.

Claims

1. A method for preparing (R)-3-hydroxybutyric acid solid, characterized in that, Includes the following steps: The (R)-3-hydroxybutyric acid solution and the adsorbent were mixed, filtered, and the solid was taken and dried under vacuum at 50-70℃ for 5-10 h. After elution and vacuum distillation, the (R)-3-hydroxybutyric acid solid was obtained. The adsorbent is a polar adsorption resin, selected from at least one of HP2MGL type polar adsorption resin, AB-8 type polar adsorption resin, and LSI-960 type polar adsorption resin. The eluent used for elution is at least one of anhydrous methanol, anhydrous ethanol, acetone, methyl formate, ethyl formate, and ethyl acetate. The water content of the (R)-3-hydroxybutyric acid solid is ≤1wt%.

2. The preparation method according to claim 1, characterized in that, The polar adsorption resin is a food-grade polar adsorption resin.

3. The preparation method according to claim 1, characterized in that, The elution is performed by solvent boiling and reflux elution.

4. The preparation method according to claim 1, characterized in that, The eluent is a food-grade solvent.

5. The preparation method according to claim 1, characterized in that, The relative vacuum pressure of the vacuum distillation is below -0.09 mPa.

6. The preparation method according to claim 5, characterized in that, The vacuum distillation is carried out at a temperature of 50-70℃ for 0.5-2 hours.

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