3-hydroxybutyric acid derivative

Abstract

Disclosed in the present invention is a 3-hydroxybutyric acid derivative. The 3-hydroxybutyric acid derivative provided by the present invention effectively solves the acid and / or salt load as well as gastrointestinal side effects associated with existing 3-hydroxybutyric acid products, and has excellent taste comfort and stability, and good ketogenic effect, making it a better option as a dietary or nutritional supplement.

Description

3-Hydroxybutyric acid derivatives Technical Field

[0001] The present invention belongs to the technical field of dietary or nutritional supplements, and particularly relates to a 3-hydroxybutyric acid derivative. Background Art

[0002] With the rapid development of economy and science, people's demand for dietary or nutritional supplements is growing, aiming to improve individuals' health and reduce the risk of disease.

[0003] Numerous studies on exogenous ketones have demonstrated that the ingestion of compounds that elevate blood ketone body levels can confer various clinical benefits, including enhanced physical and cognitive performance and the treatment of cardiovascular disease, diabetes, neurodegenerative diseases, and epilepsy. Therefore, it is desirable to directly provide ketone bodies to humans or animals as an energy source. β-Hydroxybutyrate (also known as 3-hydroxybutyrate or BHB) is one source of ingestible exogenous ketones. However, its use is limited by its extremely acidic nature. Due to this acidity, the amount and concentration of β-Hydroxybutyrate that can be used in an ingestible form are limited. Forming β-Hydroxybutyrate into sodium, magnesium, calcium, and potassium salts has addressed the acidity issue in some applications. However, due to the accompanying salt overload and the resulting electrolyte imbalance, the use of ketone salts is limited to very small amounts, and the taste is unpleasant except in small doses.

[0004] Therefore, in order to solve the problems of acid and / or salt load, gastrointestinal side effects, unpleasant taste, etc. associated with existing 3-hydroxybutyric acid products, it is necessary to further seek substances that can effectively avoid or balance the above problems so that they can be better used as ketogenic substances in diets or nutritional supplements. Summary of the Invention

[0005] In one aspect, the present invention provides a 3-hydroxybutyric acid derivative, which is formed by 3-hydroxybutyric acid and any one substance selected from the following: orotic acid, lactic acid or 3-hydroxybutyric acid.

[0006] In some embodiments, the hydroxyl group of 3-hydroxybutyric acid is linked to the carboxyl group of orotic acid, lactic acid, or 3-hydroxybutyric acid.

[0007] In some embodiments, the 3-hydroxybutyric acid derivative has the following structure:

[0008] In some embodiments, the 3-hydroxybutyric acid derivative is an R-3-hydroxybutyric acid derivative and / or an S-3-hydroxybutyric acid derivative.

[0009] In some embodiments, the 3-hydroxybutyric acid derivative comprises not less than 50% of an R-3-hydroxybutyric acid derivative and not more than 50% of an S-3-hydroxybutyric acid derivative; or more than 50% of an S-3-hydroxybutyric acid derivative and less than 50% of an R-3-hydroxybutyric acid derivative.

[0010] In some embodiments, the 3-hydroxybutyric acid derivative has the following structure:

[0011] In some embodiments, orotate-3-hydroxybutyrate has an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 9.43°±0.20°, 17.30°±0.20°, 25.45°±0.20°, and 27.61°±0.20°.

[0012] In some embodiments, the X-ray powder diffraction pattern of orotate further comprises one or more peaks at diffraction angles (2θ) of 9.86°±0.20°, 18.79°±0.20°, and 26.42°±0.20°.

[0013] In some embodiments, the X-ray powder diffraction pattern of orotate further comprises one or more peaks at diffraction angles (2θ) of 16.56°±0.20°, 22.35°±0.20°, and 30.36°±0.20°.

[0014] In some embodiments, the X-ray powder diffraction pattern of orotate-3-hydroxybutyrate is as shown in FIG1 .

[0015] In some embodiments, the infrared spectrum of orotate-3-hydroxybutyrate has the following absorption bands, expressed as the inverse of the wavelength (cm -1 )(±2cm -1 ): 3240, 3132, 1753, 1730, 1694, 1667, 1439, 1408, 1398, 1304, 1261, 1206, 1045, 1016, 937, 853, 837, 806, 773, 540.

[0016] In some embodiments, the 3-hydroxybutyric acid derivative is prepared as a food, a beverage, a supplement, or a nutraceutical.

[0017] In some embodiments, the 3-hydroxybutyric acid derivative is prepared as a solid preparation or a liquid preparation.

[0018] In another aspect, the present invention provides a method for preparing the 3-hydroxybutyric acid derivative as described above, comprising the following steps: adding orotic acid or lactic acid or 3-hydroxybutyric acid, a condensing agent, a 3-hydroxybutyric acid alkyl ester, and a base to a reaction solvent to react; washing the organic phase with water and concentrating it to obtain an intermediate; adding the intermediate to water, adding a hydrolysis agent, and reacting it to obtain a 3-hydroxybutyric acid derivative.

[0019] In some embodiments, the condensing agent is selected from one or more of the following: EDCI, DCC, DIC, HATU, HOSU, HBTU, CDI, T3P, isobutyl chloroformate, pivaloyl chloride, HOBt, 6-Cl-HOBt, HOAt, DMAP; the alkyl 3-hydroxybutyrate is selected from one or more of the following: methyl 3-hydroxybutyrate, ethyl 3-hydroxybutyrate, propyl 3-hydroxybutyrate, isopropyl 3-hydroxybutyrate, butyl 3-hydroxybutyrate, isobutyl 3-hydroxybutyrate, tert-butyl 3-hydroxybutyrate, pentyl 3-hydroxybutyrate; the base is selected from one or more of the following: triethylamine, DIPEA, N-methylmorpholine, pyridine, potassium carbonate.

[0020] In some embodiments, the reaction solvent is selected from one or more of the following: dichloromethane, N,N-dimethylformamide, THF, DMSO, DMAC, NMP, acetonitrile, ethyl acetate.

[0021] In some embodiments, the organic phase is washed with water, concentrated, and then recrystallized. In some embodiments, the recrystallization is performed by adding one or more recrystallization solvents selected from the group consisting of ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, ethanol, acetonitrile, and methyl tert-butyl ether.

[0022] In some embodiments, the hydrolysis agent is selected from one or more of the following: hydrochloric acid, sulfuric acid, sodium hydroxide, potassium hydroxide, enzymes.

[0023] In some embodiments, the hydrolysis temperature is controlled at 20-100°C, 30-90°C, 40-80°C, or 50-70°C.

[0024] In some embodiments, after the hydrolysis reaction, a crystallization solvent is added for slurrying. In some embodiments, the crystallization solvent is selected from one or more of the following: dichloromethane, water, THF, methyl tert-butyl ether, ethanol, acetonitrile, acetone, and ethyl acetate.

[0025] In another aspect, the present invention provides a use of the 3-hydroxybutyric acid derivative as described above for preparing a ketogenic substance for increasing or maintaining the blood ketone level of a subject.

[0026] In some embodiments, the ketogenic substance is a nutritional supplement, an energy treatment, a medical treatment, or a strength and / or endurance sports supplement.

[0027] In another aspect, the present invention provides a composition comprising the 3-hydroxybutyric acid derivative as described above, and 3-hydroxybutyric acid.

[0028] In some embodiments, the proportion of 3-hydroxybutyric acid derivatives is greater than 55%. In some embodiments, the proportion of 3-hydroxybutyric acid derivatives is greater than 60%, 65%, 70%, 75%, 80%, 90%, 99%.

[0029] In some embodiments, the composition further comprises a physiologically acceptable carrier.

[0030] In some embodiments, the composition is prepared as a food, a beverage, a supplement, or a nutraceutical.

[0031] In some embodiments, the composition is prepared as a solid formulation or a liquid formulation.

[0032] In another aspect, the present invention provides use of the composition as described above for preparing a ketogenic substance for increasing or maintaining blood ketone levels in a subject.

[0033] In some embodiments, the ketogenic substance is a nutritional supplement, an energy treatment, a medical treatment, or a strength and / or endurance sports supplement.

[0034] Compared with existing technologies, the present invention can efficiently and stably produce 3-hydroxybutyric acid derivatives, with advantages such as low energy and material consumption. Furthermore, the 3-hydroxybutyric acid derivatives of the present invention are odorless and effectively avoid issues such as acidity, hygroscopicity, salt load, intestinal side effects, and electrolyte imbalance. Compared with other exogenous ketones, 3-hydroxybutyric acid derivatives have excellent adaptability. When administered to subjects, 3-hydroxybutyric acid derivatives exhibit a good overall effect. Therefore, as ketogenic substances, they have broad application prospects in the fields of dietary supplements or foods. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] FIG1 is an XRPD pattern of orotic acid-R-3-hydroxybutyrate of the present invention.

[0036] FIG2 is an IR graph of orotic acid-R-3-hydroxybutyrate of the present invention.

[0037] FIG3 is a Raman spectrum of orotic acid-R-3-hydroxybutyrate of the present invention.

[0038] FIG4 is a TGA diagram of orotic acid-R-3-hydroxybutyrate of the present invention.

[0039] FIG5 is a DSC diagram of orotic acid-R-3-hydroxybutyrate of the present invention.

[0040] Figure 6 shows the ketogenic effect of each group within 4 hours.

[0041] FIG7 shows the cell activities of each group. DETAILED DESCRIPTION

[0042] The preferred embodiments of the present invention will now be described in detail with reference to the embodiments thereof. Although the present invention will be described in conjunction with the preferred embodiments, it should be understood that they are not intended to limit the present invention to these embodiments. On the contrary, the present invention is intended to cover substitutions, modifications and equivalents, which may be included within the spirit and scope of the present invention as defined in the claims. In addition, in the detailed description of the present invention, many specific details are set forth in order to provide a thorough understanding of the present invention. However, it will be apparent to one of ordinary skill in the art that the present invention can be practiced without these specific details. In other cases, well-known methods, procedures, components and other features are not described in detail to avoid unnecessarily obscuring various aspects of the present invention.

[0043] As used herein, the term "or" is intended to include "and" and "or." In other words, the term "or" can also be replaced with "and / or."

[0044] As used herein, the singular forms "a," "an," and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise.

[0045] As used herein, the term "comprises" or "includes" or variations thereof refers to instances where the term is used in its non-limiting sense, meaning that items following the term are included, but items not specifically mentioned are not excluded. It also includes the more restrictive verbs 'consisting essentially of' and 'consisting of.'

[0046] As used herein, the term "physiologically acceptable" refers to pharmaceutically, physiologically, dietary, nutritionally acceptable, and refers to those compositions or agents, materials or combinations of compositions and / or dosage forms thereof that are within the scope of sound medical judgment, suitable for contact with human and animal tissues, compatible with other ingredients of the composition, without excessive toxicity, irritation, allergic response or other problems or complications, and commensurate with a reasonable benefit / risk ratio.

[0047] In some embodiments, the 3-hydroxybutyric acid derivatives of the present invention can be prepared as a composition together with a physiologically acceptable carrier. In the present invention, the administration form of the composition involves a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the composition and not harmful to the subject, i.e., suitable for consumption or nutritionally acceptable.

[0048] In some embodiments, the 3-hydroxybutyric acid derivatives of the present invention can be administered with other supplements, such as vitamins, minerals, nootropics, and other supplements known in the art.

[0049] Administration of the 3-hydroxybutyric acid derivatives and / or compositions of the present invention can increase or maintain blood ketone levels in a subject, acting as ketogenic substances, and produce one or more desired effects, including but not limited to appetite suppression, weight loss, fat loss, lowered blood sugar levels, improved mental alertness, increased physical energy, improved cognitive function, reduced traumatic brain injury, reduced effects of diabetes, improved neurological disorders, reduced cancer, reduced inflammation, anti-aging, anti-glycation, reduced epileptic seizures, improved mood, increased strength, increased muscle mass, or improved body composition.

[0050] The 3-hydroxybutyric acid derivatives and / or compositions of the present invention can be prepared into food and beverage products for human consumption, as well as nutritional supplements, energy treatments, medical treatments, or strength and / or endurance sports supplements, as ketogenic substances, thereby providing a dietary source of exogenous ketones to increase or maintain blood ketone levels in a subject. The resulting products can exhibit reduced acidity, low hygroscopicity, improved taste, good palatability, a uniform appearance, and a well-balanced ketogenic effect, without intestinal side effects, electrolyte imbalance, or high salt load.

[0051] The following examples are illustrative of selected embodiments of the present invention and are not intended to limit the scope of the invention.

[0052] The experimental methods described in the examples are conventional methods unless otherwise specified; the reagents and materials used are commercially available unless otherwise specified.

[0053] Orotic acid (50 g, 1.0 eq), EDCI (73.68 g, 1.2 eq), HOBt (4.33 g, 0.1 eq), and TEA (48.62 g, 1.5 eq) were added to dichloromethane (500 mL) and stirred at room temperature for 0.5 h. Methyl R-3-hydroxybutyrate (37.84 g, 1.0 eq) was added and reacted at room temperature overnight. The reaction of the raw material was completed by TLC and post-processed. The organic phase was washed successively with water, dilute hydrochloric acid, and saturated sodium chloride. Anhydrous sodium sulfate was added for drying, filtered, and distilled under reduced pressure. Ethyl acetate was then added for recrystallization, filtered, and dried to obtain 23.7 g of a white intermediate (molar yield 28.9%).

[0054] The intermediate (20 g, 1.0 eq) and hydrochloric acid (11.25 g, 1.5 eq) were added to water (200 mL) and heated to 60°C for 6 h. The reaction was complete by TLC and post-processing. The product was evaporated under reduced pressure, slurried with dichloromethane, and filtered to dryness to obtain 17.65 g of a white product (98.4% molar yield).

[0055] Quantitative NMR determination of the product content is 98.55%. MS: product molecular formula C9H 10 N2O6, M=242.05; mass spectrometry value [M+H] + =242.9, which is consistent with the product. 1 H NMR (400 MHz, DMSO-d6): δ 12.39 (s, 1H), 11.39 (s, 1H), 11.16 (s, 1H), 6.03 (s, 1H), 5.24-5.37 (m, 1H), 2.60-2.80 (m, 2H), 1.31 (d, 3H). Example 2. Preparation of orotic acid-S-3-hydroxybutyrate

[0056] Orotic acid (50.0 g, 1.0 eq), DCC (79.3 g, 1.2 eq), DMAP (3.9 g, 0.1 eq), and DIPEA (62.1 g, 1.5 eq) were added to ethyl acetate (500 mL) and stirred at room temperature for 0.5 h. Ethyl S-3-hydroxybutyrate (42.3 g, 1.0 eq) was added and the mixture was allowed to react at room temperature overnight. The reaction was complete by TLC and post-processing was performed. The organic phase was washed successively with water, dilute hydrochloric acid, and saturated sodium chloride. Anhydrous sodium sulfate was added to dry the mixture, filtered, and a portion of the solvent was evaporated under reduced pressure. The mixture was recrystallized and filtered to dryness to obtain 24.5 g of a white intermediate (molar yield 29.9%). The intermediate (20 g, 1.0 eq) and sodium hydroxide (3.4 g, 1.1 eq) were added to water (200 mL) and reacted at 20-25°C for 2 h. The reaction was complete by TLC and post-processing was performed. Acetic acid was added to adjust the pH to 5-6, and the mixture was distilled under reduced pressure. Acetone was added to make pulp, and the mixture was filtered and dried to obtain 17.4 g of a white product (molar yield 92.1%). Example 3. Preparation of orotic acid-3-hydroxybutyrate

[0057] Orotic acid (50 g, 1.0 eq), HATU (146.1 g, 1.2 eq), and NMM (48.6 g, 1.5 eq) were added to DMF (300 mL), followed by tert-butyl 3-hydroxybutyrate (51.3 g, 1.0 eq). The reaction was allowed to react at room temperature overnight. The reaction was complete by TLC and post-processing was performed. 900 mL of water was added to the reaction system, and the mixture was extracted three times with 200 mL of dichloromethane. The organic layer was distilled under reduced pressure until no solvent was present. Butyl acetate was then added for recrystallization, and the mixture was filtered and dried to yield 23.1 g of a white intermediate (molar yield 28.2%). The intermediate (20 g, 1.0 eq) and enzyme (5.0 g) were added to water (200 mL), heated to 40-50°C, and incubated for 8 h. The reaction was complete by TLC and post-processing was performed. The insoluble matter was removed by filtration, and the mixture was distilled under reduced pressure. Ethanol was added to make a pulp, and the mixture was filtered and dried to obtain 17.7 g of a white product (molar yield 93.7%).

[0058] Other 3-hydroxybutyric acid derivatives of the present invention were prepared in the same or similar manner as in Examples 1-3. Characterization of 3-hydroxybutyric acid derivatives of the present invention

[0059] The 3-hydroxybutyric acid derivatives of the present invention were subjected to elemental analysis, X-ray powder diffraction (XRPD), infrared spectroscopy (IR), Raman spectroscopy, TGA, DSC, melting point and other tests. Elemental Analysis

[0060] Elemental analysis of orotic acid-R-3-hydroxybutyrate in Example 1 showed C: 44.24%, H: 4.06%, and N: 11.79%. The results of elemental analysis were consistent with the structure of orotic acid-R-3-hydroxybutyrate. X-ray diffraction

[0061] The spectrum was obtained by X-ray powder diffractometer. The XRPD pattern of orotic acid-R-3-hydroxybutyrate of Example 1 is shown in FIG1 , and the data are shown in Table 1. Table 1 Infrared spectroscopy analysis

[0062] The infrared spectrum of orotic acid-R-3-hydroxybutyrate in Example 1 was analyzed by infrared spectrometer. FIG2 is its infrared spectrum (IR) diagram. It can be seen that the orotic acid-R-3-hydroxybutyrate has a peak at 3240 cm -1 、3132cm -1 、3044cm -1 、2997cm -1 、2779cm -1 、1753cm -1 、1730cm -1 、1694cm -1 、1667cm -1 、1499cm -1 、1439cm -1 、1408cm -1 、1398cm -1 、1304cm -1 、1261cm -1 、1206cm -1 、1109cm -1 , 1045cm -1 、1016cm -1 、937cm -1 、853cm -1 、837cm -1 、806cm -1 、773cm -1 , 540cm -1 There is a characteristic absorption peak at . Raman spectroscopy analysis

[0063] The characteristic Raman spectrum of orotic acid-R-3-hydroxybutyrate of Example 1 is shown in Figure 3. -1, 351.74, 431.57, 510.68, 526.41, 589.08, 787.95, 836.65, 852.12, 887.37, 1035.16, 1234.41, 1260.16, 1303.44, 1330.57, 1359.20, 1395.64, 1441.36, 1453.93, 1502.44, 1627.88, 1644.77, 1690.64, 1725.64, 1751.41, 2926.44, 2943.42, 2998.04, and 3135.41 have characteristic absorption peaks, and there is a ±2cm -1 Thermogravimetric analysis (TGA)

[0064] Figure 4 is a TGA graph of orotic acid-R-3-hydroxybutyrate of Example 1, which shows a weight loss of 0.35% when heated from 24.2°C to 110.0°C. Differential Scanning Calorimetry

[0065] Differential scanning calorimetry (DSC) was performed using a TA Q2000 module with a thermal analysis controller. Data were collected and analyzed using TA Instruments Thermal Solutions software. Approximately 1-5 mg of sample was accurately weighed into a custom aluminum crucible with a lid. Samples were analyzed from 40°C to approximately 300°C using a linear heating device at 10°C / min. During use, the DSC cell was purged with dry nitrogen.

[0066] Figure 5 is a DSC spectrum of orotic acid-R-3-hydroxybutyrate of Example 1, including an endothermic peak at 202.62°C ± 3°C.

[0067] The initial melting point of orotic acid-R-3-hydroxybutyrate of Example 1 was detected to be 201.9°C and the final melting point was 202.7°C. Properties of the 3-hydroxybutyric acid derivatives of the present invention Determination of the ketogenic effect of orotic acid-R-3-hydroxybutyrate

[0068] Six-week-old C57BL / 6J mice weighing 18-22 g were selected and housed at 24°C with a 12:12 h light-dark cycle. Food and water were freely available, and the experiment began after acclimatization for one week.

[0069] The mice were randomly divided into the following groups: control group, BHB group, orotic acid group, and orotic acid BHB ester group, with 10 mice in each group. Specific test information is shown in the table below:

[0070] Before the experiment, mice were fasted overnight. After weighing the mice, the drug was administered via gavage at a volume of 0.1 mL / 10 g via a gavage tube. For 4 hours after dosing, blood ketone concentrations were measured every 30 minutes using a blood ketone monitor. The blood ketone concentration data at each time point were recorded for subsequent analysis.

[0071] Based on the measured blood ketone concentration data, the area under the blood ketone concentration curve (AUC) was calculated for each group of mice. Data were analyzed using SPSS statistical software. One-way ANOVA was used for comparisons between multiple groups. If the differences were statistically significant, further pairwise comparisons between groups were performed (using the LSD method). P < 0.05 was considered statistically significant.

[0072] Figure 6 is a graph showing the results of the ketogenic effect within 4 hours. The area under the blood ketone concentration curve (AUC) of the control group was 315.2 mmol / L*mins; the AUC of the BHB group was 572.8 mmol / L*mins; the AUC of the orotic acid group was 431.8 mmol / L*mins; and the AUC of the orotic acid BHB ester group was 596.1 mmol / L*mins. Compared with the control group, the AUC of the orotic acid BHB ester group increased significantly, by 89.12%. This shows that orotic acid-R-3-hydroxybutyrate can effectively increase blood ketone levels and has a ketogenic effect. Example 5 Anti-aging effect of orotic acid-R-3-hydroxybutyrate

[0073] L929 mouse fibroblasts were used as the experimental model. The cells were cultured in an environment containing DMEM medium at a temperature of 37°C and 5% CO2. The experiment was started when the cells were in good condition and in the logarithmic growth phase.

[0074] The experiment was divided into the following groups: control group, BHB group, orotic acid group, and orotic acid BHB ester group, with 6 replicates per group. Specific test information is shown in the table below:

[0075] An appropriate amount of L929 cells were seeded into a 96-well plate, with 5 × 10 cells per well. 3 The cells were cultured in an incubator for 24 hours to allow them to adhere. After the cells adhered, the corresponding concentration of the test compound was added to each well according to the group. The control group was given an equal volume of culture medium. The culture was continued for 48 hours.

[0076] The CCK-8 assay was used to assess cell metabolism and proliferation. After incubation, 10 μL of CCK-8 solution was added to each well of cells, and the 96-well plate was placed in an incubator and incubated for 2 hours. After incubation, the absorbance of each well was measured at a wavelength of 450 nm using a microplate reader. Cell activity was calculated based on the absorbance value using the following formula: Cell activity (%) = (absorbance value of the experimental group - absorbance value of the blank group) / (absorbance value of the control group - absorbance value of the blank group), thereby reflecting the effect of different experimental groups on cell activity.

[0077] SPSS statistical software was used for data analysis. One-way ANOVA was used for comparisons among multiple groups. If the differences were statistically significant, further pairwise comparisons between groups were performed (using the LSD method). P < 0.05 was considered statistically significant.

[0078] Figure 7 shows the cell viability results. The cell viability of the control group was 1.16; the BHB group was 0.89; the orotic acid group was 1.29; and the orotic acid BHB ester group was 1.47. Compared to the control group, the cell viability of the orotic acid BHB ester group increased by 26.72%, demonstrating that orotic acid-R-3-hydroxybutyrate effectively promotes the metabolism and proliferation of L929 mouse fibroblasts, demonstrating its anti-aging properties.

[0079] This invention addresses the acid and / or salt load and gastrointestinal side effects associated with existing 3-hydroxybutyric acid products. It offers a pleasant mouthfeel, excellent stability, and significant ketogenic and anti-aging effects, making it particularly suitable for use in dietary or nutritional supplements. Furthermore, the 3-hydroxybutyric acid derivatives produced by this invention exhibit good bioavailability, a controllable preparation process, low cost, and environmental friendliness.

[0080] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. Any person skilled in the art may make various changes, modifications, substitutions and variations to these embodiments without departing from the principles and purpose of the present invention. The scope of the present invention is defined by the claims and their equivalents.

Claims

1. A 3-hydroxybutyric acid derivative, characterized in that The 3-hydroxybutyric acid derivative is formed by 3-hydroxybutyric acid and any one of the following substances: orotic acid, lactic acid or 3-hydroxybutyric acid.

2. The 3-hydroxybutyric acid derivative according to claim 1, characterized in that The hydroxyl group of the 3-hydroxybutyric acid is linked to the carboxyl group of the orotic acid, lactic acid or 3-hydroxybutyric acid.

3. The 3-hydroxybutyric acid derivative according to claim 1, characterized in that The 3-hydroxybutyric acid derivative has the following structure:

4. The 3-hydroxybutyric acid derivative according to any one of claims 1 to 3, characterized in that The 3-hydroxybutyric acid derivative is an R-3-hydroxybutyric acid derivative and / or an S-3-hydroxybutyric acid derivative.

5. The 3-hydroxybutyric acid derivative according to any one of claims 1 to 4, characterized in that The 3-hydroxybutyric acid derivatives contain not less than 50% of R-3-hydroxybutyric acid derivatives and not more than 50% of S-3-hydroxybutyric acid derivatives; or more than 50% of S-3-hydroxybutyric acid derivatives and less than 50% of R-3-hydroxybutyric acid derivatives.

6. The 3-hydroxybutyric acid derivative according to claim 5, characterized in that The 3-hydroxybutyric acid derivative has the following structure:

7. The 3-hydroxybutyric acid derivative according to any one of claims 1 to 6, characterized in that The X-ray powder diffraction pattern of the orotic acid 3-hydroxybutyrate includes peaks at diffraction angles (2θ) of 9.43°±0.20°, 17.30°±0.20°, 25.45°±0.20°, and 27.61°±0.20°.

8. The 3-hydroxybutyric acid derivative according to claim 7, characterized in that The X-ray powder diffraction pattern of the orotic acid 3-hydroxybutyrate further includes one or more peaks at diffraction angles (2θ) of 9.86°±0.20°, 18.79°±0.20°, and 26.42°±0.20°.

9. The 3-hydroxybutyric acid derivative according to claim 7 or 8, characterized in that The X-ray powder diffraction pattern of the orotic acid 3-hydroxybutyrate further includes one or more peaks located at diffraction angles (2θ) of 16.56°±0.20°, 22.35°±0.20°, and 30.36°±0.20°.

10. The salt according to any one of claims 1 to 9, characterized in that The X-ray powder diffraction pattern of the orotic acid 3-hydroxybutyrate is shown in FIG1 .

11. The 3-hydroxybutyric acid derivative according to any one of claims 1 to 6, characterized in that The infrared spectrum of orotic acid-3-hydroxybutyrate has the following absorption bands, expressed as the reciprocal of the wavelength (cm -1 )(±2cm -1 ): 3240, 3132, 1753, 1730, 1694, 1667, 1439, 1408, 1398, 1304, 1261, 1206, 1045, 1016, 937, 853, 837, 806, 773, 540.

12. The 3-hydroxybutyric acid derivative according to any one of claims 1 to 11, characterized in that The 3-hydroxybutyric acid derivative is prepared into food, beverage, supplement and nutrition product.

13. The 3-hydroxybutyric acid derivative according to any one of claims 1 to 12, characterized in that The 3-hydroxybutyric acid derivative is prepared as a solid preparation or a liquid preparation.

14. A method for preparing a 3-hydroxybutyric acid derivative according to any one of claims 1 to 13, characterized in that: The method comprises the following steps: adding orotic acid or lactic acid or 3-hydroxybutyric acid, a condensing agent, a 3-hydroxybutyric acid alkyl ester and a base into a reaction solvent to react; washing the organic phase with water and concentrating it to obtain an intermediate; adding the intermediate into water, adding a hydrolysis agent and reacting it to obtain the 3-hydroxybutyric acid derivative.

15. The preparation method according to claim 14, characterized in that The condensing agent is selected from one or more of the following: EDCI, DCC, DIC, HATU, HOSU, HBTU, CDI, T3P, isobutyl chloroformate, pivaloyl chloride, HOBt, 6-Cl-HOBt, HOAt, DMAP; the alkyl 3-hydroxybutyrate is selected from one or more of the following: methyl 3-hydroxybutyrate, ethyl 3-hydroxybutyrate, propyl 3-hydroxybutyrate, isopropyl 3-hydroxybutyrate, butyl 3-hydroxybutyrate, isobutyl 3-hydroxybutyrate, tert-butyl 3-hydroxybutyrate, and pentyl 3-hydroxybutyrate; the base is selected from one or more of the following: triethylamine, DIPEA, N-methylmorpholine, pyridine, and potassium carbonate.

16. The preparation method according to claim 14 or 15, characterized in that: The reaction solvent is selected from one or more of the following: dichloromethane, N,N-dimethylformamide, THF, DMSO, DMAC, NMP, acetonitrile, and ethyl acetate.

17. The preparation method according to any one of claims 14 to 16, characterized in that The hydrolysis agent is selected from one or more of the following: hydrochloric acid, sulfuric acid, sodium hydroxide, potassium hydroxide, and enzyme.

18. Use of a 3-hydroxybutyric acid derivative according to any one of claims 1 to 13, characterized in that The 3-hydroxybutyric acid derivative is used to prepare a ketogenic substance for increasing or maintaining the blood ketone level of a subject.

19. The use according to claim 18, characterized in that The ketogenic substance is a nutritional supplement, an energy treatment, a medical treatment, or a strength and / or endurance sports supplement.

20. A composition, characterized in that The composition comprises the 3-hydroxybutyric acid derivative according to any one of claims 1 to 13, and 3-hydroxybutyric acid.

21. The composition according to claim 20, characterized in that The proportion of the 3-hydroxybutyric acid derivative is greater than 55%.

22. The composition according to claim 20 or 21, characterized in that The composition also includes a physiologically acceptable carrier.

23. The composition according to any one of claims 20 to 22, characterized in that The composition is prepared as food, beverage, supplement or nutrition product.

24. The composition according to any one of claims 20 to 23, characterized in that The composition is prepared as a solid preparation or a liquid preparation.

25. Use of the composition according to any one of claims 20 to 24, characterized in that The composition is used for preparing a ketogenic substance for increasing or maintaining the blood ketone level of a subject.

26. The use according to claim 25, characterized in that The ketogenic substance is a nutritional supplement, an energy treatment, a medical treatment, or a strength and / or endurance sports supplement.

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