CN110372487B - 3-sodium hydroxybutyrate product and preparation method thereof - Google Patents
3-sodium hydroxybutyrate product and preparation method thereof Download PDFInfo
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Abstract
The invention relates to the technical field of chemical drug engineering, and provides a sodium 3-hydroxybutyrate and a preparation method thereof, wherein the crystallinity of the sodium 3-hydroxybutyrate is more than 90%, and the 2 theta angle of an X-ray spectrogram of a crystal form at least has obvious characteristic diffraction peaks at 6.80, 13.69, 21.77, 25.25, 25.67, 25.82, 30.17, 31.21, 31.47, 34.84, 36.72, 41.85, 42.15, 44.55, 45.08, 48.46 and 48.59. The preparation method comprises the following steps: A. dissolving 3-hydroxy ethyl butyrate in a mixed solvent of an organic solvent and water, controlling the stirring temperature at 5-25 ℃, controlling the stirring speed at 500rpm, adding 1.05 equivalent of sodium hydroxide solid in batches, and continuing to react for 1-5 hours at 5-25 ℃ after the addition is finished; B. heating the reaction system to 50-80 ℃, slowly cooling after the sodium hydroxide solid is completely dissolved, wherein the stirring speed is controlled at 50-500rpm, and the cooling speed is controlled at 0.5-2.0 ℃/min; C. and (3) cooling the reaction system to 0-25 ℃, continuing stirring for 20-50 minutes, and filtering, washing, blasting or vacuum drying to obtain the sodium 3-hydroxybutyrate product.
Description
Technical Field
The invention relates to the technical field of chemical drug engineering, in particular to a sodium 3-hydroxybutyrate product and a preparation method thereof.
Background
Beta-hydroxybutyrate (BHB) is a natural metabolite formed during fat digestion and metabolism, called ketone body, is an energy-intensive molecule that, as a dietary supplement ingredient, functions primarily to naturally provide energy to the brain, heart and muscles without the involvement of glucose and the intake of low carbohydrates. Sodium 3-Hydroxybutyrate (3-Hydroxybutyrate Sodium) as a stable mineral Sodium salt donor for BHB is usually reconstituted into dry powder with calcium 3-Hydroxybutyrate and magnesium 3-Hydroxybutyrate and is decomposed into free Beta-Hydroxybutyrate and mineral ions to be absorbed by human body after being ingested.
3-hydroxy butyric acid and its sodium salt as the main ketone body can offer the energy source for most tissues of the body, have very large using value and prospect in health care products, food and pharmaceutical industry, including: accelerating the weight loss; stimulating the expression of various health-promoting genes; reducing the incidence of inflammatory complications; the exercise performance and the training efficiency are improved, and the metabolic efficiency is enhanced; providing optimal energy for the heart and reducing the incidence of cardiovascular diseases; increase insulin sensitivity; preventing cancer and related diseases caused by glucose metabolism disorder; enhancing cognitive ability, preventing senile dementia, prolonging life, etc.
At present, sodium 3-hydroxybutyrate is mainly prepared by a chemical method, ethyl 3-hydroxybutyrate is adopted as a raw material, deionized water is adopted as a solvent, and ethyl 3-hydroxybutyrate and sodium hydroxide react to form salt; then decolorizing with active carbon, and evaporating water to obtain the finished product of the 3-sodium hydroxybutyrate.
In the salification reaction process, only water is used as a solvent, recrystallization operation cannot be realized, and recrystallization can be realized only after water is evaporated to dryness, so that the steps are complex, and the prepared product has no crystal form or low crystallinity, is easy to absorb moisture and agglomerate, and is not beneficial to later application or storage. In addition, a large amount of ethanol is generated in the process, high additional cost is generated in the process of recycling and discharging water, and the process is also environment-friendly; in the evaporation process, spray drying and vacuum rake drying are mainly used at present, but both methods have the defects of large equipment volume and high energy consumption.
Disclosure of Invention
The invention aims to solve the problems and provides a sodium 3-hydroxybutyrate product and a preparation method thereof aiming at the defects of low crystallinity and easy moisture absorption of a sodium 3-hydroxybutyrate finished product in the prior art.
In a first aspect of the invention, a sodium 3-hydroxybutyrate product is provided, the crystallinity of the sodium 3-hydroxybutyrate product is more than 90%, and the 2 theta angle of an X-ray spectrogram of a crystal form has obvious characteristic diffraction peaks at least at 6.80, 13.69, 21.77, 25.25, 25.67, 25.82, 30.17, 31.21, 31.47, 34.84, 36.72, 41.85, 42.15, 44.55, 45.08, 48.46 and 48.59.
The sodium 3-hydroxybutyrate product of the present invention is a loose powder, and the crystallinity of the sodium 3-hydroxybutyrate product of the present invention can reach 98% at the maximum according to the description of the detailed description.
The invention carries out X-ray measurement of the crystal form through CuK alpha ray, and the test conditions are as follows: the instrument model is as follows: bruker D8advance XRD; diffraction line: CuK α (40kV,40 mA); scanning rate: 4 °/min (2 θ value); scanning range: 5 DEG to 60 DEG (2 theta value).
In a second aspect of the invention, a preparation method of a sodium 3-hydroxybutyrate product is provided, which comprises the following steps:
A. dissolving 3-hydroxy ethyl butyrate in a mixed solvent of an organic solvent and water, controlling the stirring temperature at 5-25 ℃, controlling the stirring speed at 500rpm, adding 1.05 equivalent of sodium hydroxide solid in batches, and continuing to react for 1-5 hours at 5-25 ℃ after the addition is finished;
B. heating the reaction system to 50-80 ℃, slowly cooling after the sodium hydroxide solid is completely dissolved, wherein the stirring speed is controlled at 50-500rpm, and the cooling speed is controlled at 0.5-2.0 ℃/min;
C. and (3) cooling the reaction system to 0-25 ℃, continuing stirring for 20-50 minutes, and filtering, washing, blasting or vacuum drying to obtain the sodium 3-hydroxybutyrate product.
In the salification reaction process of the steps A and B, the mixture of the organic solvent and the water is used as the solvent which is not only used as a reaction medium, but also used as a recrystallization solvent, so that the salification reaction and the crystallization are realized by a one-step method, the process is simplified, the cost is saved, and the product quality is improved.
In addition, a byproduct ethanol is generated in the salification reaction process, and experiments prove that the multi-component solvent has no influence on the reaction, and can show a good crystallization effect in the subsequent recrystallization step of the step C, so that the product ethanol does not need to be separated when the solvent is recovered after the reaction is finished, and the solvent recovery cost is favorably saved.
Preferably, in step a, the organic solvent is a lower chain alcohol or a water-compatible low boiling point organic solvent, the lower chain alcohol is selected from any one of methanol, ethanol, n-propanol and isopropanol, and the water-compatible low boiling point organic solvent is acetonitrile or tetrahydrofuran, preferably ethanol.
In the mixed solvent, the mass ratio of the organic solvent is 20-98%, the preferable mass ratio is 80-98%, and when the organic solvent is ethanol, the mass fraction of the ethanol in the mixed solvent is 85-95%.
The mass ratio of the ethyl 5-hydroxybutyrate to the mixed solvent is 0.5-0.8: 1, and preferably 0.5: 1.
Preferably, in the step B, the temperature reduction rate and the stirring rate have larger influence on the crystallinity and the crystal habit, in the preparation process, the stirring rate is preferably controlled at 150rpm of 100, and the temperature reduction rate is preferably controlled at 0.5-1.0 ℃/min;
preferably, in the step C, the reaction system is cooled to 0-10 ℃ and then is continuously stirred for 30 minutes; the selected washing liquid is absolute ethyl alcohol, isopropanol or acetonitrile, and the absolute ethyl alcohol is preferred; the drying mode is preferably vacuum drying, the drying temperature is 30-90 ℃, preferably 30-70 ℃, and the drying time is 6-10 hours, preferably 8 hours.
The maximum crystallinity of the sodium 3-hydroxybutyrate product obtained according to the preparation method is 98.1 percent, the yield is 95 percent, and the crystal form results identified by X-ray diffraction are shown in Table 1 and figure 1. According to the X-ray spectrogram of the crystal form, the 2 theta angle has obvious characteristic diffraction peaks at least 6.80, 13.69, 21.77, 25.25, 25.67, 25.82, 30.17, 31.21, 31.47, 34.84, 36.72, 41.85, 42.15, 44.55, 45.08, 48.46 and 48.59.
Through the moisture absorption and agglomeration comparison experiments of products with different degrees of crystallinity, the sodium 3-hydroxybutyrate product with high degree of crystallinity has more stable crystal form and is less prone to moisture absorption and agglomeration.
The invention has the following beneficial guarantee and effects:
compared with the prior art, in the preparation method of the sodium 3-hydroxybutyrate product, water and alcohol are used as mixed solvents in salt forming reaction, so that two processes of preparation and crystallization are completed by one step, the mixed solvents can be recycled for 5-10 times, the energy consumption is greatly reduced, the cost is reduced, the process operation is simple and environment-friendly, the product purity is higher, and the preparation method is suitable for industrial amplification production;
the sodium 3-hydroxybutyrate product obtained by the preparation method has no crystal form report, and compared with the existing product, the sodium 3-hydroxybutyrate product has high crystallinity, stable crystal form and difficult moisture absorption and caking.
Drawings
FIG. 1 is an X-ray diffraction pattern of the sodium 3-hydroxybutyrate product of the first example of this invention.
Detailed Description
The present invention will now be described in detail with reference to examples, but the practice of the present invention is not limited thereto.
The reagents and starting materials used in the present invention are commercially available or can be prepared according to literature procedures. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out according to conventional conditions or according to conditions recommended by the manufacturers. Percentages and parts are by volume unless otherwise indicated.
Example one
Dissolving 26.4g of ethyl 3-hydroxybutyrate in a mixed solution of 53g of ethanol and water (the mass ratio of ethanol to water is 95: 5), controlling the temperature of a system to be 5-25 ℃, and controlling the stirring speed to be about 400 rpm; slowly adding 8.4g of sodium hydroxide solid powder into the system, controlling the temperature to be not more than 10 ℃, raising the temperature of the system to 25 ℃, and continuously stirring and reacting for 1 hour after the addition is finished; after the GC detection reaction is finished, raising the temperature of the system to 70 ℃, slowly cooling the system after the system is dissolved and cleared, controlling the cooling rate to be 0.5-1.0 ℃/min, controlling the stirring rate to be 150rpm in the cooling process, reducing the temperature of the system to 10 ℃, continuously stirring and crystallizing for 2 hours, filtering, washing a filter cake by 20g of absolute ethyl alcohol, and carrying out vacuum drying for 8 hours at 50 ℃ to obtain 23.9g of white 3-hydroxy sodium butyrate crystals with the yield of 95%.
The powder crystal form is identified by X-ray diffraction, and the specific test conditions are as follows:
the instrument model is as follows: bruker D8advance XRD
Diffraction line: CuK alpha (40kV,40mA)
Scanning rate: 4 °/min (2 θ value)
Scanning range: 5 DEG-60 DEG (2 theta value)
Peak Search Report(51Peaks,Max P/N＝227.7)
PEAK:29-pts/Parabolic Filter,Threshold＝3.0,Cutoff＝0.1％,BG＝3/1.0,Peak-Top＝Summit
The specific test result and XRD pattern are shown in Table 1 and FIG. 1 respectively, and the crystallinity of the product is 98.1%.
TABLE 1X-ray diffraction test results
Example two
Dissolving 26.4g of ethyl 3-hydroxybutyrate in 52g of a mixed solution of isopropanol and water (the mass ratio of isopropanol to water is 90:10), controlling the temperature of a system to be 5-25 ℃, and controlling the stirring speed to be about 400 rpm; slowly adding 8.4g of sodium hydroxide solid powder into the system, controlling the temperature to be not more than 10 ℃, raising the temperature of the system to 25 ℃, and continuously stirring and reacting for 1 hour after the addition is finished; after the GC detection reaction is finished, raising the temperature of the system to 65 ℃, slowly cooling the system after the system is dissolved and cleared, controlling the cooling rate to be 0.5-1.0 ℃/min, controlling the stirring rate to be 150rpm in the cooling process, reducing the temperature of the system to 0 ℃, continuously stirring and crystallizing for 1 hour, filtering, washing a filter cake by 20g of absolute ethyl alcohol, and carrying out vacuum drying at 50 ℃ for 8 hours to obtain 19.4g of white sodium 3-hydroxybutyrate crystals, wherein the yield is 77%, the crystal form is consistent with that prepared in the first embodiment through powder X-ray diffraction identification, and the crystallinity is 97.3%.
EXAMPLE III
26.4g of ethyl 3-hydroxybutyrate was dissolved in a mixed solution of 52g of acetonitrile and water (mass ratio, acetonitrile: water: 80: 20), the system temperature was controlled to 5 to 25 ℃, and the stirring rate was controlled to about 400 rpm. Slowly adding 8.4g of sodium hydroxide solid powder into the system, controlling the temperature to be not more than 10 ℃, raising the temperature of the system to 25 ℃, and continuously stirring and reacting for 1 hour after the addition is finished; after the GC detection reaction is finished, raising the temperature of the system to 50 ℃, slowly cooling the system after the system is dissolved and cleared, controlling the cooling rate to be 0.5-1.0 ℃/min, controlling the stirring rate to be 150rpm in the cooling process, reducing the temperature of the system to 0 ℃, continuously stirring and crystallizing for 1 hour, filtering, washing a filter cake by 20g of absolute ethyl alcohol, and carrying out vacuum drying at 50 ℃ for 8 hours to obtain 11.4g of white sodium 3-hydroxybutyrate crystals, wherein the yield is 45%, the crystal form is consistent with that of the first crystal form prepared in the example through powder X-ray diffraction identification, and the crystallinity is 92.7%.
Comparative example 1
26.4g of ethyl 3-hydroxybutyrate was dissolved in 40g of anhydrous ethanol, and the temperature of the system was controlled to 5 to 25 ℃. Slowly adding 8.4g of sodium hydroxide solid powder into the system, controlling the temperature to be not more than 10 ℃, continuously reacting at 5-10 ℃ for 30 minutes after the addition is finished, then raising the temperature of the system to 25 ℃, continuously stirring and reacting for 1.5 hours, reducing the temperature of the system to 0-5 ℃ after the GC detection reaction is finished, continuously stirring and crystallizing for 30 minutes, filtering, washing a filter cake by 20g of absolute ethyl alcohol, and drying in vacuum at 60 ℃ for 5 hours to obtain 22.3g of white 3-sodium hydroxybutyrate crystals, wherein the yield is 88%, the crystal form is basically consistent with that of the crystal form prepared in the first embodiment through powder X-ray diffraction identification, and the crystallinity is 62.3%.
Comparative example No. two
26.4g of ethyl 3-hydroxybutyrate was dissolved in 30g of anhydrous methanol, and the temperature of the system was controlled to 5 to 25 ℃. Slowly adding 8.4g of sodium hydroxide solid powder into the system, controlling the temperature to be not more than 10 ℃, continuously reacting at 5-10 ℃ for 30 minutes after the addition is finished, then raising the temperature of the system to 25 ℃, continuously stirring and reacting for 1 hour, reducing the temperature of the system to 0 ℃ after the GC detection reaction is finished, continuously stirring and crystallizing for 1 hour, filtering, washing a filter cake by 20g of absolute ethyl alcohol, and carrying out forced air drying at 60 ℃ for 5 hours to obtain 15.1g of white 3-sodium hydroxybutyrate crystals with the yield of 60%, wherein the yield is basically consistent with the crystal form prepared in the first embodiment through powder X-ray diffraction identification, and the crystallinity is 89.7%.
Compared with the three examples, although the preparation procedures of the two comparative examples are similar, the purity, the crystallinity and the crystal form of the product are influenced by adopting absolute ethyl alcohol or absolute methyl alcohol as a solvent, and the main reasons are as follows: firstly, sodium hydroxide is needed to participate in the reaction process, but the solubility of the substance in absolute ethyl alcohol or absolute methyl alcohol is low, so that the reaction can be carried out under heterogeneous conditions, and as the reaction is exothermic, a system can be locally overheated to generate a large amount of byproducts, thereby seriously affecting the yield and the purity of the product; and secondly, the absolute ethyl alcohol or the absolute methyl alcohol has lower solubility to the product, so that the phenomenon of product burst-out can occur in the reaction process, and the purity and the crystallinity of the product are greatly reduced.
EXAMPLE four different crystallinity considerations for moisture absorption and agglomeration of sodium 3-hydroxybutyrate
In the pharmaceutical and health-care product industry, the chemical and physical stability of the active compounds is particularly important, and the stable drugs can avoid using special storage conditions or adding special preparations. In the industrial mass production, the moisture absorption and agglomeration of the compound also have great influence on the manufacture and long-term storage of the medicament in the later period, and the moisture absorption and agglomeration phenomena of the sodium 3-hydroxybutyrate with different crystallinity in the first example, the first comparative example and the second comparative example are further researched by the invention. Temperature: 25 ℃, relative humidity: 60%, the environment was sealed, and the measurement results are shown in table 2:
TABLE 2 comparison of moisture absorption and caking of sodium 3-hydroxybutyrate products with different degrees of crystallinity
The results in Table 2 prove that the sodium 3-hydroxybutyrate product with high crystallinity can still keep very low moisture after being stored for three months, and the sample basically has no agglomeration phenomenon, so that the sodium 3-hydroxybutyrate product with high crystallinity is suitable for the preparation and long-term storage of medicaments.
While the preferred embodiments of the present invention have been described in detail, it will be understood by those skilled in the art that the invention is not limited thereto, and that various changes and modifications may be made without departing from the spirit of the invention, and the scope of the appended claims is to be accorded the full scope of the invention.
Claims (7)
1. A sodium 3-hydroxybutyrate product is characterized in that the crystallinity of the sodium 3-hydroxybutyrate product is more than 90%, and the 2 theta angle of an X-ray spectrogram of a crystal form has obvious characteristic diffraction peaks at least at 6.80, 13.69, 21.77, 25.25, 25.67, 25.82, 30.17, 31.21, 31.47, 34.84, 36.72, 41.85, 42.15, 44.55, 45.08, 48.46 and 48.59.
2. The sodium 3-hydroxybutyrate product of claim 1, wherein:
wherein the sodium 3-hydroxybutyrate product is in a loose powder form.
3. The process for the preparation of the sodium 3-hydroxybutyrate product of claim 1 or 2, which comprises the steps of:
A. dissolving 3-hydroxy ethyl butyrate in a mixed solvent of an organic solvent and water, controlling the stirring temperature at 5-25 ℃, controlling the stirring speed at 500rpm, adding 1.05 equivalent of sodium hydroxide solid in batches, continuing to react for 1-5 hours at 5-25 ℃ after the addition is finished,
the organic solvent is a low-carbon chain alcohol or a low-boiling-point organic solvent compatible with water, the low-carbon chain alcohol is selected from any one of methanol, ethanol, n-propanol and isopropanol, and the low-boiling-point organic solvent compatible with water is acetonitrile or tetrahydrofuran; in the mixed solvent, the mass ratio of the organic solvent is 20-98%, and the mass ratio of the ethyl 3-hydroxybutyrate to the mixed solvent is 0.5-0.8: 1;
B. heating the reaction system to 50-80 ℃, slowly cooling after the sodium hydroxide solid is completely dissolved, wherein the stirring speed is controlled at 50-500rpm, and the cooling speed is controlled at 0.5-2.0 ℃/min;
C. and (3) cooling the reaction system to 0-25 ℃, continuing stirring for 20-50 minutes, and filtering, washing, blasting or vacuum drying to obtain the sodium 3-hydroxybutyrate product.
4. The process for the preparation of the sodium 3-hydroxybutyrate product of claim 3, which comprises:
wherein in the mixed solvent, the mass ratio of the organic solvent is 80-98%
The organic solvent is ethanol, and the mass fraction of the ethanol in the mixed solvent is 85-95%;
the mass ratio of the ethyl 3-hydroxybutyrate to the mixed solvent is 0.5: 1.
5. The process for the preparation of the sodium 3-hydroxybutyrate product of claim 3, which comprises:
wherein, in the step B, the stirring speed is controlled at 100-150rpm, and the cooling speed is controlled at 0.5-1.0 ℃/min;
6. the process for the preparation of the sodium 3-hydroxybutyrate product of claim 3, which comprises:
wherein, in the step C, the reaction system is cooled to 0-10 ℃ and then is continuously stirred for 30 minutes; the selected washing liquid is absolute ethyl alcohol, isopropanol or acetonitrile; the drying temperature is 30-90 ℃, and the drying time is 6-10 hours.
7. The process for the preparation of the sodium 3-hydroxybutyrate product of claim 6, which comprises:
and C, in the step C, the washing liquid is absolute ethyl alcohol, the drying mode is vacuum drying, the drying temperature is 30-70 ℃, and the drying time is 8 hours.
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