CN115819211B - Separation and purification method of coenzyme Q10 - Google Patents
Separation and purification method of coenzyme Q10 Download PDFInfo
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Abstract
The invention discloses a separation and purification method of coenzyme Q10, which comprises the steps of adding a pH regulator a into coenzyme Q10 fermentation liquor to regulate pH, and carrying out plate frame filtration; collecting mycelium, squeezing, and removing most of water to obtain wet mycelium; taking the wet mycelium, adding an extractant for pulping extraction, wherein the extractant is selected from a combination of a solution a and a solution b, and the extractant a is selected from an aqueous solution containing an antioxidant and having a pH of 8-12; the solvent b is selected from one or two of normal hexane and petroleum ether and comprises a phase transfer extraction additive; by adding a certain proportion of phase transfer solid phase extractant into the pulping extractant, the efficient extraction of wet hyphae can be realized, the extraction efficiency is improved, the extraction time is shortened, the technical problem of low efficiency of extracting wet hyphae by normal hexane is solved, and after the coenzyme Q10 is subjected to multi-step separation and purification by the process disclosed by the invention, the total product yield is obviously improved, and the economic benefit is obvious.
Description
Technical Field
The invention relates to the field of purification methods of organic natural products, in particular to a method for separating and purifying coenzyme Q10 from mycelium obtained by a microbial fermentation method.
Background
Coenzyme Q10, chemical name 2- [ (all-E) 3,7,11,15,19,23,27,31,35,39-decamethyl-2, 6,10, 14,18,22,26,30,34,38-tetradecanyl } -5, 6-dimethoxy-3-methyl-p-benzoquinone, abbreviated as CoQ10, also known as ubiquinone, is a lipid-soluble antioxidant present in all cells of the human body, and its structure is shown in formula I:
coenzyme Q10 can activate human body cells and nutrition of cell energy, has the functions of improving human body immunity, enhancing antioxidation, delaying aging, enhancing human body activity and the like, is widely used for cardiovascular system diseases in medicine, and is widely used for nutritional health care products and food additives at home and abroad. The human body can synthesize coenzyme Q10 by itself, but the synthesis efficiency is also deteriorated with the increase of age, and it is reported that the lack of coenzyme Q10 does not endanger life, but can seriously affect the mechanism of energy generation of the body, and the physical strength is as much as 28 times worse than that of normal people. In addition, a large number of animal researches and human experiments prove that the coenzyme Q10 can effectively reduce muscle injury and inflammatory reaction, can slow down the increase of cell hormone after exercise, improve the antioxidant capacity and have the effect of improving the athletic performance. Therefore, coenzyme Q10 is deeply favored by a wide range of professional athletes and fitness enthusiasts.
The physiological functions of the coenzyme Q10 are continuously and deeply researched and developed, so that the application field of the coenzyme Q10 is continuously widened, the demand market is increased year by year, and researchers are constantly devoted to the development and optimization of the production method and process. The industrialization technology of coenzyme Q10 comprises a microbial fermentation method, a biological extraction method, a cell culture method and a chemical synthesis method, wherein the microbial fermentation method is the most important in the industrialized application.
The production of coenzyme Q10, whether by the initial biological extraction method, cell culture method or the current mainstream microbial fermentation method, requires the separation of the product from the raw materials, and further purification and purification to obtain the coenzyme Q10 product. Therefore, the extraction and purification process of coenzyme Q10 is very critical and important in the industrial production process. The microbial fermentation method generally adopts microbial strains to culture seeds, including primary seeds and secondary seeds, and then carries out large-tank fermentation culture, and nutrient substances and precursor substances are required to be continuously supplemented in the culture process to promote the production of products. Culturing the fermentation liquor to a certain extent, and carrying out tank discharge treatment. The product obtained by the microbial fermentation method is fermentation liquor containing a certain bacterial concentration, the fermentation liquor is filtered or centrifuged to obtain wet mycelium, and the wet mycelium is further treated by the steps of extraction, chromatographic purification, refining and the like after being dried to obtain the product of the coenzyme Q10. The whole separation and purification process is to remove other impurities in the fermentation product, separate and purify to obtain qualified coenzyme Q10 product, and simultaneously reduce the production cost by optimizing the production process.
Because the chemical property of the coenzyme Q10 is unstable, the mycelium is inevitably subjected to the drying process, so that part of products are decomposed, and the yield of the coenzyme Q10 is reduced. Meanwhile, the chemical molecule of the coenzyme Q10 contains a long unsaturated carbon chain, the molecular polarity is small, the coenzyme Q10 belongs to fat-soluble substances, and the extraction solvent commonly used in industry is n-hexane or petroleum ether. N-hexane or petroleum ether is used as an extraction solvent of coenzyme Q10, and has the following advantages: (1) Stable chemical property, no chemical change in the extraction process and no degradation of coenzyme Q10. (2) The boiling point is proper, the solvent can not be evaporated quickly in the extraction process, the accumulation of volatile solvent in a production workshop can not be caused, and the solvent is easy to recycle under the condition of reduced pressure. (3) The cost is low, the solubility of the coenzyme Q10 is high, the solubility of other impurities is low, the subsequent separation and purification are easy after the extraction, and the product with higher purity can be conveniently obtained. Because normal hexane is almost insoluble in water, when wet mycelium is used as a raw material and normal hexane is used for direct extraction, the mixing effect of an extraction solvent and water is poor, and the difficulty of the extraction solvent to 'penetrate' the mycelium coated by a water film is high, so that the extraction efficiency is low, a large amount of extraction solvent and long-time beating and stirring are often needed to enable coenzyme Q10 to fully enter an organic phase.
Disclosure of Invention
The invention mainly aims to solve the technical problem of low extraction efficiency of wet hypha by using normal hexane or petroleum ether as an extractant in the prior art, and provides a better coenzyme Q10 extraction and purification process.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows:
there is provided a method for purifying coenzyme Q10, characterized in that the method comprises the steps of:
(1) Adding a pH regulator a into the coenzyme Q10 fermentation liquor to regulate the pH, and carrying out plate-frame filtration; collecting mycelium, squeezing or squeezing to obtain wet mycelium;
(2) Taking wet mycelia in the step (1), adding an extractant for pulping extraction, wherein the extractant is selected from a combination of a solution a and a solution b, and the extractant a is selected from an aqueous solution containing an antioxidant and having a pH of 8-12; the solvent b is selected from one or two of normal hexane and petroleum ether and comprises a phase transfer extraction additive;
(3) Adding demulsifier after pulping extraction, stirring, standing for layering, separating out lower water phase, washing organic phase with saturated sodium chloride aqueous solution, and drying organic phase with desiccant;
(4) Removing organic solvent of organic phase to obtain extract, purifying with silica gel column chromatography, eluting with mixed solvent of n-hexane and acetone;
(5) Concentrating, and recrystallizing with organic solvent to obtain coenzyme Q10.
Further, in the method for purifying coenzyme Q10 of the invention, the pH adjuster a in the step (1) is an acidic pH adjuster, preferably dilute hydrochloric acid or dilute sulfuric acid; adjusting pH to 3-6, preferably 4-5, heating to 40-60deg.C, and plate-frame filtering; the moisture content of the obtained wet mycelium is 40% -70%.
Further, the antioxidant in the step (2) is selected from one or more of sulfite, citrate and thiosulfate, preferably sodium sulfite or potassium sulfite; the concentration of the antioxidant is 0.02 to 0.1mol/L, preferably 0.04 to 0.08mol/L, preferably 0.05 to 0.07mol/L, preferably 0.06mol/L, and the pH of the extractant a is preferably 9 to 11, more preferably 10.
Further, the phase transfer extraction additive in step (2) is selected from quaternary ammonium salts, preferably the phase transfer extraction additive is selected from benzyltriethylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium bisulfate, tetraoctylammonium chloride, dodecyltrimethylammonium chloride, tetradecyltrimethylammonium chloride.
Further, the mass volume ratio of the phase transfer extraction additive to the n-hexane and petroleum ether in the step (2) is 1-10g/100ml, preferably 2-8g/100ml, or 3-7g/100ml, or 4-6g/100ml or 5g/100ml.
Further, in the step (2), the volume ratio of the solution a to the solution b is 1:1-10, preferably 1:2-8, preferably 1:3-7, preferably 1:4-6, preferably 1:5, a step of; the mass-volume ratio of the wet mycelium to the solution b is 1g/1-10ml, preferably 1g/2-8ml, preferably 1g/3-7ml, preferably 1g/4-6ml, preferably 1g/5ml.
Further, the temperature of the beating extraction in step (2) is 20-60 ℃, preferably 30-50 ℃, preferably 40 ℃; the time of the beating extraction is 4-8 hours, preferably 5-7 hours, and 6 hours.
Further, in the step (3), the demulsifier is selected from saturated sodium chloride solution, and the drying agent is selected from anhydrous sodium chlorate or anhydrous magnesium sulfate or molecular sieve.
Further, the eluent in the step (4) is selected from mixed solvents of 0.8-1.5% of acetone and normal hexane.
Further, the organic solvent for recrystallization in step (5) is selected from ethanol or methanol.
Compared with the prior art, the invention has the following beneficial effects:
1. by adding the phase transfer extractant, the extraction efficiency is improved, the extraction time is shortened, the technical problem of low efficiency of extracting wet mycelia by normal hexane is solved, and after the coenzyme Q10 is subjected to multi-step separation and purification by the process, the total product yield is improved obviously, and the economic benefit is remarkable.
2. In the production process, the operation steps of air flow drying with large dust amount, dry mycelium leaching and the like in the original production process are abandoned, and the environment-friendly and safe effect in the production process is improved by using n-hexane or petroleum ether solvent which has high safety coefficient and low cost and is easy to recycle.
3. The purity of the product is improved to a certain extent to 99.5-99.9%, and the product is completely suitable for medicinal purposes.
Detailed Description
The invention is further described in connection with the following detailed description, in order to make the technical means, the creation characteristics, the achievement of the purpose and the effect of the invention easy to understand.
Experiment preparation:
preparing sodium sulfite aqueous solution with the concentration of 0.05mol/L, and regulating the pH value to 10 by NaOH for later use;
regulating pH of the fermented coenzyme Q10 fermentation liquor to 4-5 with dilute hydrochloric acid, heating to 50 ℃ and carrying out plate-frame filtration; collecting mycelium, squeezing, removing most of water to obtain wet mycelium with water content of about 50%.
Determination of coenzyme Q10 content
The content of coenzyme Q10 is detected by high performance liquid chromatography (internal standard method), and specific detection conditions are as follows:
quantitative detection by HPLC: methanol-absolute ethanol (25:75) (volume ratio), C was used 18 Reverse phase column (4.6 mm. Times.150 mm. Times.5 μm), detection wavelength 275nm, flow rate 1.5ml/min, sample injection amount 10. Mu.l, column temperature 35 ℃.
Example 1
10kg of wet mycelium with the water content of about 60% is weighed, 10L of prepared sodium sulfite aqueous solution is added, beating is carried out under vigorous stirring, 50L of normal hexane and 1kg of dodecyl trimethyl ammonium chloride are added, and beating extraction is carried out continuously for 6 hours under the temperature condition of 40 ℃ after the addition. Adding 1L saturated sodium chloride solution, stirring thoroughly, transferring to a liquid separating device, standing, removing water phase, washing organic phase with saturated sodium chloride aqueous solution (1 L×3), drying organic phase with anhydrous sodium sulfate, filtering, spin-drying solvent to obtain extract, separating extract with 200-300 silica gel column chromatography, separating silica gel 10 times of extract, eluting with mixed solvent of 1% acetone and n-hexane by volume, mixing eluent containing coenzyme Q10, spin-drying solvent, adding 60 deg.C absolute ethanol to dissolve, controlling crystallization temperature to drop 2 deg.C every hour, slowly cooling to 0deg.C and maintaining for 3 hr, filtering, washing, and drying to obtain 108.1g of final product with purity of 99.3%.
Example 2
10kg of wet mycelium with the water content of about 60% is weighed, 10L of prepared sodium sulfite aqueous solution is added, beating is carried out under vigorous stirring, 50L of n-hexane and 1kg of tetradecyl trimethyl ammonium chloride are added, and beating extraction is carried out continuously for 6 hours under the temperature condition of 40 ℃ after the addition. Adding 1L saturated sodium chloride solution, stirring thoroughly, transferring to a liquid separating device, standing, removing water phase, washing organic phase with saturated sodium chloride aqueous solution (1 L×3), drying organic phase with anhydrous sodium sulfate, filtering, spin-drying solvent to obtain extract, separating extract with 200-300 silica gel column chromatography, separating silica gel 10 times of extract, eluting with mixed solvent of 1% acetone and n-hexane by volume, mixing eluent containing coenzyme Q10, spin-drying solvent, adding 60 deg.C absolute ethanol to dissolve again, controlling crystallization temperature to drop 2 deg.C every hour, slowly cooling to 0deg.C and maintaining for 3 hr, filtering, washing, and drying to obtain 107.6g of final product with purity of 99.6%.
Example 3
10kg of wet mycelium with the water content of about 60% is weighed, 10L of prepared sodium sulfite aqueous solution is added, beating is carried out under vigorous stirring, 50L of n-hexane and 0.8kg of tetraoctyl ammonium chloride are added, and beating extraction is carried out continuously for 6 hours under the temperature condition of 40 ℃ after the addition. Adding 1L saturated sodium chloride solution, stirring thoroughly, transferring to a liquid separating device, standing, removing water phase, washing organic phase with saturated sodium chloride aqueous solution (1 L×3), drying organic phase with anhydrous sodium sulfate, filtering, spin-drying solvent to obtain extract, separating extract with 200-300 silica gel column chromatography, separating silica gel 10 times of extract, eluting with mixed solvent of 1% acetone and n-hexane by volume, mixing eluent containing coenzyme Q10, spin-drying solvent, adding 60 deg.C absolute ethanol to dissolve, controlling crystallization temperature to drop 2 deg.C every hour, slowly cooling to 0deg.C and maintaining for 3 hr, filtering, washing, and drying to obtain 97.5g of final product with purity of 99.1%.
Example 4
10kg of wet mycelium with the water content of about 60% is weighed, 10L of prepared sodium sulfite aqueous solution is added, beating is carried out under vigorous stirring, 50L of n-hexane and 0.5kg of tetrabutylammonium bromide are added, and beating extraction is carried out continuously for 6 hours under the temperature condition of 40 ℃ after the addition. Adding 1L saturated sodium chloride solution, stirring thoroughly, transferring to a liquid separating device, standing, removing water phase, washing organic phase with saturated sodium chloride aqueous solution (1 L×3), drying organic phase with anhydrous sodium sulfate, filtering, spin-drying solvent to obtain extract, separating extract with 200-300 silica gel column chromatography, separating silica gel 10 times of extract, eluting with mixed solvent of 1% acetone and n-hexane by volume, mixing eluent containing coenzyme Q10, spin-drying solvent, adding 60 deg.C absolute ethanol to dissolve, controlling crystallization temperature to drop 2 deg.C every hour, slowly cooling to 0deg.C and maintaining for 3 hr, filtering, washing, and drying to obtain 85.3g of final product with purity of 99.7%. Comparative example 1:
10kg of wet mycelium with the water content of about 60% is weighed, 10L of prepared sodium sulfite aqueous solution is added, beating is carried out under vigorous stirring, 50L of n-hexane is added, and beating extraction is carried out continuously for 6 hours under the temperature condition of 40 ℃ after the addition. Adding 1L saturated sodium chloride solution, stirring thoroughly, transferring to a liquid separating device, standing, removing water phase, washing organic phase with saturated sodium chloride aqueous solution (1 L×3), drying organic phase with anhydrous sodium sulfate, filtering, spin-drying solvent to obtain extract, separating extract with 200-300 silica gel column chromatography, separating silica gel 10 times of extract, eluting with mixed solvent of 1% acetone and n-hexane by volume, mixing eluent containing coenzyme Q10, spin-drying solvent, adding 60 deg.C absolute ethanol to dissolve, controlling crystallization temperature to drop 2 deg.C every hour, slowly cooling to 0deg.C and maintaining for 3 hr, filtering, washing, and drying to obtain 13.2g of final product with purity of 99.3%.
Comparative example 2:
10kg of wet mycelium with the water content of about 60% is weighed, 10L of prepared sodium sulfite aqueous solution is added, beating is carried out under vigorous stirring, 50L of n-hexane is added, and beating extraction is carried out continuously for 24 hours under the temperature condition of 40 ℃ after the addition. Adding 1L saturated sodium chloride solution, stirring thoroughly, transferring to a liquid separating device, standing, removing water phase, washing organic phase with saturated sodium chloride aqueous solution (1 L×3), drying organic phase with anhydrous sodium sulfate, filtering, spin-drying solvent to obtain extract, separating extract with 200-300 silica gel column chromatography, separating silica gel 10 times of extract, eluting with mixed solvent of 1% acetone and n-hexane by volume, mixing eluent containing coenzyme Q10, spin-drying solvent, adding 60 deg.C absolute ethanol to dissolve again, controlling crystallization temperature to drop 2 deg.C every hour, slowly cooling to 0deg.C and maintaining for 3 hr, crystallizing to obtain crystal, filtering, washing, and drying to obtain 35.7g of final product with purity of 99.4%.
The above examples and comparative examples show that dodecyl trimethyl ammonium chloride and tetradecyl trimethyl ammonium chloride have the best extraction effect, tetraoctyl ammonium chloride is inferior, and tetrabutylammonium bromide is the worst; when no phase transfer extraction additive is added, the n-hexane can not effectively extract the coenzyme Q10, and the effect of prolonging the extraction time is not obvious.
The foregoing has shown and described the basic principles and main features of the present invention and the advantages of the present invention. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, and that the above embodiments and descriptions are merely illustrative of the principles of the present invention, and various changes and modifications may be made without departing from the spirit and scope of the invention, which is defined in the appended claims. The scope of the invention is defined by the appended claims and equivalents thereof.
Claims (8)
1. A method for purifying coenzyme Q10, characterized in that the method comprises the steps of:
(1) Adding a pH regulator a into the coenzyme Q10 fermentation liquor to regulate the pH, and carrying out plate-frame filtration; collecting mycelium, squeezing or squeezing to obtain wet mycelium; wherein the pH regulator a in the step (1) is an acidic pH regulator; adjusting pH to 3-6, heating to 40-60deg.C, and plate-frame filtering;
(2) Taking wet hypha in the step (1), adding an extracting agent for pulping extraction, wherein the extracting agent is a combination of a solution a and a solution b, the solution a is an aqueous solution with the pH of 8-12 and contains an antioxidant, and the antioxidant is sodium sulfite; the solution b is n-hexane and comprises a phase transfer extraction additive;
(3) Adding demulsifier after pulping extraction, stirring, standing for layering, separating out lower water phase, washing organic phase with saturated sodium chloride aqueous solution, and drying organic phase with desiccant;
(4) Removing organic solvent of organic phase to obtain extract, purifying with silica gel column chromatography, eluting with mixed solvent of n-hexane and acetone;
(5) Concentrating, recrystallizing with organic solvent to obtain coenzyme Q10;
wherein the phase transfer extraction additive is selected from quaternary ammonium salts selected from dodecyl trimethyl ammonium chloride, tetradecyl trimethyl ammonium chloride or tetraoctyl ammonium chloride;
the mass volume ratio of the phase transfer extraction additive to the normal hexane is 1-10g/100 ml.
2. The method for purifying coenzyme Q10 according to claim 1, wherein the moisture content of the obtained wet mycelia is 40% to 70%.
3. The method for purifying coenzyme Q10 according to claim 2, characterized in that the pH adjustor a in the step (1) is dilute hydrochloric acid or dilute sulfuric acid.
4. The method for purifying coenzyme Q10 according to claim 1, characterized in that the concentration of the antioxidant in the step (2) is 0.02 to 0.1 mol/L; the pH of the solution a is 9-11.
5. The method for purifying coenzyme Q10 according to claim 1, characterized in that the volume ratio of the solution a to the solution b in the step (2) is 1:1-10; the mass-volume ratio of the wet mycelium to the solution b is 1g/1-10 ml.
6. The method for purifying coenzyme Q10 according to claim 1, characterized in that the temperature of the beating extraction in step (2) is 30-50 ℃; the pulping and extracting time is 4-8 hours.
7. The method for purifying coenzyme Q10 according to claim 1, characterized in that the demulsifier in step (3) is selected from a saturated sodium chloride solution, and the drying agent is selected from anhydrous sodium sulfate, anhydrous magnesium sulfate or a molecular sieve.
8. The method for purifying coenzyme Q10 according to claim 1, characterized in that the organic solvent for recrystallization in step (5) is selected from ethanol or methanol.
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| KR101341033B1 (en) * | 2007-01-31 | 2013-12-13 | 에스케이이노베이션 주식회사 | Separating and Purifying Method of Coenzyme Q10 |
| CN101314782B (en) * | 2007-05-30 | 2012-05-30 | 宁波天安生物材料有限公司 | Method for fermentation preparation of cozymase Q10 |
| CN101429108B (en) * | 2007-11-09 | 2011-10-19 | 浙江医药股份有限公司新昌制药厂 | Purification method for separation of cozymase Q10 |
| CN111499672B (en) * | 2019-01-30 | 2021-07-20 | 山东新和成精化科技有限公司 | Extraction method for purifying sucralose |
| CN112174796B (en) * | 2020-09-21 | 2023-02-14 | 宁夏泰胜生物科技有限公司 | Method for extracting coenzyme Q10 from coenzyme Q10 fermentation liquor |
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