CN110627633A - Preparation method of HMB-Ca - Google Patents
Preparation method of HMB-Ca Download PDFInfo
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Abstract
A preparation method of HMB-Ca comprises the following steps: (1) and (3) chloroform reaction: uniformly dripping 2-3 parts of 40-60 wt% diacetone alcohol aqueous solution into 10-25 wt% oxidant aqueous solution at constant speed for several times, and stirring and reacting for 0.5-1h at the temperature of 18-28 ℃; (2) and (3) refining and purifying a product: acidifying the reaction liquid stock solution until the pH value is 7-8, and concentrating and desalting by using a nanofiltration membrane of 100-; then vacuum distillation is carried out at 60 ℃ and concentration is continued until the mass of the stock solution is 10-20%; cooling to room temperature, stirring for 0.5-1h, and filtering; adding eluent with the mass of 2-3 times of the filtrate, stirring for 1h, filtering, and drying to obtain the HMB-Ca. The invention shortens the process path and improves the conversion rate; the production process is clean, environment-friendly, safe and low in cost.
Description
Technical Field
The invention relates to a preparation method of beta-hydroxy-beta-methylbutanoic acid calcium salt (HMB-Ca), belonging to the technical field of synthesis and refining of organic compounds.
Background
HMB is collectively known as beta-hydroxy-beta-methylbutyrate and is an intermediate metabolite of leucine. HMB was first discovered by doctor Steven Nissen in 1988, and the effects of increasing lean body mass and reducing the decomposition degree of protein molecules were firstly found in animal experiments, and HMB has the functions of increasing fatty acid oxidation and reducing fat of experimental animals.
HMB has been used more widely as a sports supplement and has been a matter of the 21 st century. HMB has a very large number of functions, such as promoting recovery, increasing strength, relieving stress, etc., which are seen in publicity, but it primarily acts on the handler in two ways, namely, promoting protein synthesis and helping to increase muscle; secondly, the protein decomposition is inhibited, and the fat reduction is helped. Both muscle building and fat reduction, and are therefore preferred by the market.
HMB-Ca was GRAS approved by the U.S. food and drug administration in 1995 and was used in the range of medical nutrition and special meals. For the last 20 years, HMB-Ca has been widely used in dairy products, chocolate products, beverages, energy bars and other various food products in the US market. Especially widely applied in the sports nutrition field of the United states, the commodities are widely circulated, and the sports nutritional health-care food is particularly popular among professional athletes and bodybuilders.
Compared with the overseas market, the development time of HMB-Ca in the Chinese market is later. The data show that the demand of the 2016 national market on HMB-Ca raw materials is only 2 tons, and reaches about 20 tons in 2017, and the market demand is estimated to break through 1000 tons in 2025. Of course, the success of HMB-Ca in the Japanese market will continue to encourage the development of products related to domestic brands. Since 2015, domestic enterprises have successively introduced HMB products, such as Likekang high-energy solid beverages introduced by Xianlibang; special force products pushed by Shanghai compound stars; the cornbit HMB muscle building powder enriched type, etc., which have previously been concentrated on sports nutrition foods and special foods sold in hospital channels due to limited use of new food materials. After the technology source group in 2017 finishes the application expansion, HMB-Ca can be used for almost all common food formulations (see 2017.5.31 Wei Shun Notice). This undoubtedly brings unprecedented historical opportunities for numerous food and health product research and development enterprises.
A preparation method of HMB calcium salt belongs to the technical field of organic compound preparation. The preparation route commonly used in the industry is generally based on the reaction of 4-methyl-4-hydroxy-2-pentanone (diacetone alcohol) with an oxidizing agent, and salifying and refining the reaction product to obtain the calcium salt of HMB. In recent years, the application range of HMB is gradually expanding, and many biomedical enterprises have introduced HMB-related products, but there are few reports on methods for synthesizing HMB. In a typical HMB-Ca preparation method, diacetone alcohol and an oxidant are used as reaction raw materials to carry out haloform reaction, then the reaction raw materials are acidified and extracted by an organic solvent to obtain HMB (beta-hydroxy-beta-methylbutyric acid), and then the HMB and the calcium reagent form salt to obtain HMB-Ca, wherein the oxidant is divided into hypohalite and peracetic acid; the organic solvent mostly adopts ethyl acetate, isobutanol and the like; calcium reagents mostly adopt calcium chloride and calcium hydroxide. (CN02151042 and CN 201711166893). However, the synthesis conversion rate of the existing method is low and is not more than 60%, wherein the Yapei company adopts a small-test optimization to mix pure diacetone alcohol and sodium hypochlorite at a low temperature of 3 ℃ for 12.8min and then convert the pure diacetone alcohol and the sodium hypochlorite into 64-78% after flowing out by adopting a continuous tubular reactor, which shows the pyrolysis characteristic of the diacetone alcohol and the essence of the heat release of the chloroform reaction, and the industrial low-temperature controllable continuity and the corrosivity of the raw material sodium hypochlorite have high requirements on equipment, personnel, energy consumption and conditions of the company, so the method is not suitable for the industrial production of small and medium-sized enterprises. And the reaction liquid of the oxidant and the diacetone alcohol which are subjected to the chloroform reaction has large salt content after acidification, and most manufacturers need to adopt an organic solvent extraction method for separation and purification.
Disclosure of Invention
The invention aims to provide a more efficient and environment-friendly HMB-Ca production process.
Based on the purpose, the invention provides a preparation method of HMB-Ca, which comprises the following steps:
(1) and (3) chloroform reaction:
uniformly dripping 2-3 parts of 40-60 wt% diacetone alcohol aqueous solution into 10-25 wt% oxidant aqueous solution at constant speed for several times, and stirring and reacting for 0.5-1h at the temperature of 18-28 ℃;
(2) refining and purifying the product
Acidifying the reaction liquid stock solution in the step (1) until the pH value is 7-8, concentrating and desalting by using a nanofiltration membrane of 100 and 200 daltons until the volume of the concentrated solution is 45% of that of the stock solution, and the membrane operating pressure is 1.5-2.25 MPa; then vacuum distillation is carried out at 60 ℃ and concentration is continued until the mass of the stock solution is 10-20%; cooling to room temperature, stirring for 0.5-1h, and filtering; adding eluent with the mass of 2-3 times of the filtrate, stirring for 1h, filtering, and drying to obtain the HMB-Ca.
The production method of HMB-Ca is practically based on the property of HMB-Ca, adopts a direct synthesis process, and directly synthesizes HMB-Ca without an intermediate of HMB-Na. The traditional synthesis process is changed, the process path is shortened, and the conversion rate is improved to more than 70%; in addition, the use of an organic solvent is effectively avoided in the refining and purification process of the product at the later stage, and high-purity HMB-Ca is obtained; the production process is clean, environment-friendly and safe, and the cost is effectively reduced.
Detailed Description
The invention aims to provide an efficient and environment-friendly HMB-Ca production method. The invention has the advantages of improving the conversion rate of reaction substrates, improving the product quality, reducing the generation of polluting organic solvents and the like.
The preparation method of HMB-Ca is based on the basic production route of chloroform reaction-product fine purification HMB-Ca in the prior art. In the chloroform reaction, the chloroform reaction of the substrate diacetone alcohol and the oxidant is still involved. But in the adding mode of the product, beneficial innovation is carried out, namely, 2-3 parts of 40-60 wt% diacetone alcohol aqueous solution are uniformly dripped into 10-25 wt% oxidant aqueous solution in a sub-step manner at a constant speed, and the mixture is stirred and reacted for 0.5-1h at the temperature of 18-28 ℃.
In order to achieve the technical object of the invention, in particular a sufficient conversion of the substrate, it is a primary technical feature to set a suitable mode of product addition. The specific scheme provided by the invention is that the diacetone alcohol aqueous solution is added in a plurality of times and slowly. In the whole reaction process, the diacetone alcohol aqueous solution serving as a reaction substrate is uniformly divided into 2-3 parts, and the diacetone alcohol aqueous solution is dripped into a reaction system at a constant speed in several times. The dropping speed is 0.3-0.6 ml/min, preferably 0.5 ml/min. The adding time point is selected to ensure that the interval of the starting time points of two adjacent adding times is not less than 15 min. In the scheme of adding for 2 times, the first adding is carried out at the beginning of the reaction, namely the reaction is carried out for 0 min; the second addition is preferably carried out during a reaction time of 30-60 min. Based on the improved technical scheme, the haloform reaction provided by the invention has the advantages that under the condition that the feeding molar ratio of the oxidant to the diacetone alcohol is 2-4:1, the conversion rate of the substrate diacetone alcohol can reach 70% or higher, and under the same technical condition, the value generally does not exceed 60%.
In the chloroform reaction, the oxidant can be selected according to the prior art in the field, and in the invention, calcium hypochlorite, sodium hypoiodate, sodium hypobromite and calcium hypoiodate can be selected but not limited. For sufficient conversion of the reaction substrate, the concentration of the aqueous oxidant solution is 15-20 wt%, wherein wt% refers to mass percent concentration. Also for the purpose of increasing the substrate conversion, the concentration of the aqueous diacetone alcohol solution in our invention is selected to be 50% by weight. However, this is a setting for obtaining the most prominent advantageous effect and is not a limiting condition parameter.
On the basis of improving the conversion rate of the substrate, the technical scheme improvement on the other hand focuses on the purification of the product. The invention replaces the widely adopted organic solvent scheme in the prior art with a solvent-free alternative route: adjusting the pH of the haloform reaction solution to be neutral by acid, and then adding an eluent to wash and crystallize to directly separate and purify the HMB-Ca, so that an HMB-Ca product with the purity of over 95 percent can be obtained, and the yield is 96 percent. The total purity-reduced yield of HMB-Ca in the whole process is over 75 percent. In the specific technical scheme, the product is refined and purified by acidifying the reaction liquid stock solution after the chloroform reaction to the pH value of 7-8, and then concentrating and desalting by using a nanofiltration membrane of 100 and 200 daltons until the volume of the concentrated solution is 45% of that of the stock solution, and the membrane operating pressure is 1.5-2.25 MPa; then vacuum distillation is carried out at 60 ℃ and concentration is continued until the mass of the stock solution is 10-20%; cooling to room temperature, stirring for 0.5-1h, and filtering to obtain filtrate containing HMB-Ca 40-60 wt%; adding eluent with the mass of 2-3 times of the filtrate, stirring for 1h, filtering, and drying to obtain the HMB-Ca. In the step, sulfuric acid, hydrochloric acid or nitric acid is selected as an acidifying agent for acidification; the choice and amount of acidifying agent ensures that the reaction system suppresses salt singleness and ensures that the HMB-Ca is not acidified to HMB. The eluent is selected from methanol, ethanol and ethyl acetate. Ethanol is preferably used. The product obtained by adopting the refining and purifying scheme still does not reach the product with satisfactory purity, and the steps of repeated dissolution-elution can be added to obtain the HMB-Ca product with higher quality label. The repeated dissolution-elution is to prepare the obtained HMB-Ca into 30-50 wt% aqueous solution, add 2-3 times of eluent, stir for 1h and filter. The selection of the eluent is consistent with the scheme so as to ensure the singleness of the solvent and be beneficial to the recovery processing and the reutilization.
The invention is further illustrated by the following non-limiting examples.
In the present specification, unless otherwise specified: and (4) measuring the conversion rate and the HMB-Ca purity by adopting high performance liquid chromatography.
And (3) measuring the effective oxidability of the raw material by adopting a sodium thiosulfate titration method.
Wt% is used herein to denote the mass concentration of the solution.
Example 1
100g of calcium hypochlorite aqueous solution with the mass concentration of 20 percent and 15g of diacetone alcohol aqueous solution with the mass concentration of 50 percent are prepared, 2 parts of diacetone alcohol aqueous solution (namely 7.5 g/part) which is divided into 2 parts are respectively dripped into 100g of calcium hypochlorite aqueous solution at the flow rate of 1.5rpm/min by a peristaltic pump at 0 and 30min, haloform reaction is carried out for 30min at the temperature of 22 ℃, and the conversion rate of the diacetone alcohol is determined to be 73.2 percent.
Acidifying 3kg of reaction liquid after the haloform reaction by hydrochloric acid to pH7.0, and then concentrating and desalting by a nanofiltration membrane with molecular weight cutoff of 200Dalton to obtain 1.35kg of concentrated solution with the mass of the initial reaction liquid, (the HMB loss is less than 1%, the membrane operating pressure is 1.5-2.25 MPa, 1.65kg of salt-containing clear liquid is filtered to obtain concentrated reaction liquid I), continuously concentrating the concentrated reaction liquid I to 0.25kg by vacuum distillation at 60 ℃, cooling to room temperature, stirring for 0.5h, and filtering to obtain HMB-Ca filtrate with the mass content of 57.2%; adding 0.25kg of ethanol into the filtrate, stirring for 1h, filtering, and drying to obtain the HMB-Ca with the purity of 96.1% and the total depurate yield of more than 75%.
Example 2
This example uses the experimental protocols ([0053] - [0056], [0058]) in small trials as provided in CN103857390A for comparison. In CN103857390A, the technical solution optimization in the pilot stage for the chloroform reaction includes: under batch mode, room temperature, bleach-rich operating conditions, 48% -50% HMB yield can be provided by controlled addition of diacetone alcohol; operating conditions in batch mode, room temperature, low bleach generally provide HMB yields of 10% -12% in about 12-20 minutes; under batch mode, low temperature (3 ℃), bleach-rich operating conditions, yields of HMB of 60% to 67% are provided; provides a HMB yield of 16% to 24% under batch mode, low temperature (3 ℃), bleach-lean operating conditions.
Finally, determining that the continuous tubular reactor is adopted to carry out reaction at room temperature and 20 ℃ under the condition of the molar ratio of calcium hypochlorite to diacetone alcohol being 3:1-4:1, and finding that the HMB yield is 46-47% in 6.4-minute residence time and 12.8-minute residence time; an HMB yield of about 52% was achieved at 3 ℃ and 3.2 minutes at low temperature. HMB yield of about 58% -76% at low temperature 3 ℃ and 6.4 minutes residence time. The low temperature of 3 ℃ and 12.8 minutes residence time provided HMB yields of 64% to 78%.
In the technical scheme described in CN103857390A, the batch mode refers to a kettle reaction or a reaction in an oxidation stage; and does not relate to batch feeding or feeding process control.
Adding 80kg of diacetone alcohol into 1200kg of sodium hypochlorite solution (10%), and stirring at room temperature for 4 hours; standing, layering and removing lower-layer liquid; washing the upper layer reaction solution, adding 14kg of sodium bisulfite, controlling the temperature to be 10 ℃, stirring, adding concentrated hydrochloric acid solution, acidifying the solution to pH2.0, then decompressing and concentrating, and filtering to obtain a crude HMB solution; the crude solution was extracted with ethyl acetate, and the combined organic extracts were concentrated at 60 ℃ to give 50kg of HMB. Through detection, the content of the beta-hydroxy-beta-methylbutyric acid in the beta-hydroxy-beta-methylbutyric acid compound product is 98.7%, and the conversion rate is about 61.69%.
Adding 250kg of ethanol into 50kg of HMB, adding 95% equivalent of calcium hydroxide, stirring for 2 hours to obtain a mixed solution, filtering by using a sand core, wherein the aperture of the sand core is 10-20 microns, filling 400-mesh filter cloth, paving diatomite, concentrating the filtrate, and removing water to obtain a solid HMB-Ca crude product; adding 100L of ethanol into the obtained HMB-Ca crude product, raising the temperature to 70 ℃, stirring for 2 hours, and then cooling to room temperature; filtering the cooled mixed solution by using a sand core, wherein the aperture of the sand core is 10-20 microns, concentrating the filtrate, and removing an ethanol solvent to obtain a solid; 100Kg of ethyl acetate is taken, sand core filtration is carried out (the aperture of the sand core is 10-20 microns), then the ethyl acetate is added into the treated solid, the mixture is stirred for 2 hours, filtered and dried, and the HMB-Ca product (95Kg, the yield is 82%) is obtained.
From the comparison of the data, the preparation method for forming salt with calcium reagent after HMB (beta-hydroxy-beta-methylbutyrate) is obtained by taking diacetone alcohol and an oxidant as reaction raw materials to carry out halogen-imitation reaction and then carrying out acidification and organic solvent extraction has the advantages that the synthesis conversion rate is lower and is not more than 62%, the salt content of a reaction liquid of the oxidant and the diacetone alcohol in a chloroform reaction is higher, and the use amount of organic solvent extraction and purification is larger. Wherein CN103857390A is optimized by a small test, pure diacetone alcohol and sodium hypochlorite are converged at a low temperature of 3 ℃ by a continuous tubular reactor for 12.8min and then flow out, and the conversion can reach 64-78%. Nevertheless, in order to achieve the low temperature and controllable continuity described in CN103857390A and the corrosive property of raw material sodium hypochlorite, the requirements of equipment, personnel, energy consumption and company conditions are high, the process steps for synthesizing HMB-Ca are long, and the solution is not suitable for industrial production of small and medium-sized enterprises.
Example 3
An aqueous solution of calcium hypochlorite at a concentration of 20 wt% and an aqueous solution of diacetone alcohol at a concentration of 50 wt% were prepared for the following experiments:
A. under the condition of room temperature, 5g of diacetone alcohol is dripped into 100g of calcium hypochlorite aqueous solution by adopting a peristaltic pump at the flow rate of 1.5rap/min (very low flow rate), the mixture is stirred for 1 hour, and the whole process is cooled in a normal-temperature water bath; after the reaction, the conversion rate of diacetone alcohol is measured by HPLC to be 60 percent; (in-process thermometer monitoring found the temperature of the reaction solution increased by 5-7 ℃ C.)
B. Under the condition of room temperature, 100g of calcium hypochlorite aqueous solution is dripped into 5g of diacetone alcohol by a peristaltic pump at the flow rate of 30rpm/min and stirred for 1h, the conversion rate of the diacetone alcohol is measured by HPLC to be 50% (temperature of reaction liquid is increased by 5-7 ℃ when a thermometer monitors in the process);
C. under the condition of room temperature, dropwise adding 2 parts of diacetone alcohol (namely 2.5 g/part) into 100g of calcium hypochlorite aqueous solution at the flow rate of 1.5rpm/min by using a peristaltic pump at 0 and 30min respectively, stirring for 1h, cooling in a normal-temperature water bath in the whole process, measuring the conversion rate of the diacetone alcohol by HPLC (high performance liquid chromatography) after reaction to be 65 percent, (monitoring and finding that the temperature of the reaction solution rises by 3-5 ℃) and determining the segmented feeding time by taking the initial temperature of the reaction solution for temperature recovery as a standard;
D. under the condition of room temperature, dropwise adding 3 parts of diacetone alcohol (namely 1.7 g/part) into 100g of calcium hypochlorite aqueous solution at the flow rate of 1.5rpm/min by using a peristaltic pump at 0, 20 and 30min respectively, stirring for 1h, cooling in a whole normal-temperature water bath, and measuring the conversion rate of the diacetone alcohol by HPLC (high performance liquid chromatography) after reaction for 65%; in the process, the temperature of the reaction liquid is monitored and found to rise by 3-5 ℃), wherein the time for sectional addition is determined by taking the initial temperature of the reaction liquid as a standard;
E. under the condition of room temperature, a peristaltic pump is adopted to respectively dropwise add 2 parts of diacetone alcohol aqueous solution (namely 7.5 g/part) divided into 2 parts into 100g of calcium hypochlorite aqueous solution at the flow rate of 1.5rpm/min for 0 and 30min, stirring is carried out for 1h, cooling is carried out in a whole normal-temperature water bath, the conversion rate of the diacetone alcohol is measured by HPLC after reaction is 72.5 percent, (the temperature of the reaction solution is monitored and found to rise by 3-5 ℃ by a thermometer in the process), wherein the segmented feeding time is determined by taking the initial temperature of the reaction solution as a standard;
acidifying 3kg of combined reaction liquid A-E by hydrochloric acid until the pH value is 7.0, concentrating and desalting by a nanofiltration membrane with the molecular weight cutoff of 200Dalton to obtain 1.35kg of concentrated solution with the mass of the initial reaction liquid, (the HMB loss is less than 1%, the membrane operation pressure is 1.5-2.25 MPa, 1.65kg of salt-containing clear liquid is filtered to obtain concentrated reaction liquid), carrying out vacuum distillation at 60 ℃ to continuously concentrate 0.25kg of reaction liquid, cooling to room temperature, stirring for 0.5h, and filtering to obtain filtrate containing 54.3% of HMB-Ca by mass; 0.5kg of eluent is added into the filtrate, the mixture is stirred for 1 hour and then filtered, and the purity of HMB-Ca obtained by drying is 95.3 percent, and the total depurative yield is more than 75 percent.
The embodiment provides a partially optimized embodiment, and the results of a-E in embodiment 3 show that:
(1) example 3A illustrates that the drop-wise improvement in conversion of the conventional process is around 60%;
(2) example 3B illustrates that the addition of an oxidizing agent to diacetone alcohol is less effective than the addition of diacetone alcohol to the oxidizing agent;
(3) examples 3C and 3D show that the fractional addition improves the conversion rate compared with the drop addition improvement of the traditional process;
(4) example 3E illustrates that the diluted diacetone alcohol added to the oxidant in portions can increase the conversion of diacetone alcohol to 70% with the best results; and the conversion rate is maintained to be more than 70% after pilot scale amplification.
According to the embodiment, the reaction process can be controlled by the uniform-speed dripping mode provided by the invention, and the decomposition of the raw material diacetone alcohol can be reduced by adding the reaction materials in several times; the mode of adding the diluted raw material diacetone alcohol has a buffering effect on the accumulation of system temperature and the change of pH of a reaction solution, so that the conversion rate can be improved, the solvent-free extraction in the separation and purification step is realized, no special requirements on equipment and the initial temperature of the raw material are required, the cost is reduced, and the green production is realized.
Claims (9)
1. A preparation method of HMB-Ca comprises the following steps:
(1) and (3) chloroform reaction:
uniformly dripping 2-3 parts of 40-60 wt% diacetone alcohol aqueous solution into 10-25 wt% oxidant aqueous solution at constant speed for several times, and stirring and reacting for 0.5-1h at the temperature of 18-28 ℃;
(2) refining and purifying the product
Acidifying the reaction liquid stock solution in the step (1) until the pH value is 7-8, concentrating and desalting by using a nanofiltration membrane of 100 and 200 daltons until the volume of the concentrated solution is 45% of that of the stock solution, and the membrane operating pressure is 1.5-2.25 MPa; then vacuum distillation is carried out at 60 ℃ and concentration is continued until the mass of the stock solution is 10-20%; cooling to room temperature, stirring for 0.5-1h, and filtering; adding eluent with the mass of 2-3 times of the filtrate, stirring for 1h, filtering, and drying to obtain the HMB-Ca.
2. The method of claim 1 wherein said oxidizing agent is selected from the group consisting of calcium hypochlorite, sodium hypoiodate, sodium hypobromite, and calcium hypoiodate.
3. The method of claim 2 wherein said aqueous oxidant solution has a concentration of 15 to 20 wt%.
4. The method of claim 1, wherein said aqueous diacetone alcohol solution has a concentration of 50 wt%.
5. The method of claim 1, wherein the diacetone alcohol aqueous solution is added dropwise at a flow rate of 0.3 to 0.6ml/min in step (1).
6. The method of claim 1, wherein the molar ratio of diacetone alcohol to oxidant is from 1:2 to 4.
7. The method of claim 1, wherein the eluent is selected from the group consisting of methanol, ethanol, and ethyl acetate.
8. The method of claim 1, wherein the acidification in step (2) is sulfuric acid, hydrochloric acid or nitric acid.
9. The method of claim 1, further comprising the steps of: preparing the obtained HMB-Ca into 30-50 wt% aqueous solution, adding 2-3 times of eluent, stirring for 1 hr, and filtering.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103857390A (en) * | 2011-08-15 | 2014-06-11 | 雅培制药有限公司 | Process for manufacturing hmb and salts thereof |
| CN108558641A (en) * | 2018-05-15 | 2018-09-21 | 江苏玺鑫维生素有限公司 | A kind of preparation of beta-hydroxy-Beta-methyl calcium butyrate and purification process |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103857390A (en) * | 2011-08-15 | 2014-06-11 | 雅培制药有限公司 | Process for manufacturing hmb and salts thereof |
| CN108558641A (en) * | 2018-05-15 | 2018-09-21 | 江苏玺鑫维生素有限公司 | A kind of preparation of beta-hydroxy-Beta-methyl calcium butyrate and purification process |
Non-Patent Citations (1)
| Title |
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| 王湛 编: "《膜分离技术基础》", 30 April 2000, 化工工业出版社 * |
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Application publication date: 20191231 |
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| RJ01 | Rejection of invention patent application after publication |