CN117924105B - Preparation method of potassium aspartate - Google Patents
Preparation method of potassium aspartate Download PDFInfo
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- CN117924105B CN117924105B CN202410339149.6A CN202410339149A CN117924105B CN 117924105 B CN117924105 B CN 117924105B CN 202410339149 A CN202410339149 A CN 202410339149A CN 117924105 B CN117924105 B CN 117924105B
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- YKZPPPNXRZHVGX-PXYKVGKMSA-L dipotassium;(2s)-2-aminobutanedioate;hydron;hydrate Chemical compound [H+].[H+].O.[K+].[K+].[O-]C(=O)[C@@H](N)CC([O-])=O.[O-]C(=O)[C@@H](N)CC([O-])=O YKZPPPNXRZHVGX-PXYKVGKMSA-L 0.000 title claims abstract description 80
- 229940068988 potassium aspartate Drugs 0.000 title claims abstract description 80
- 238000002360 preparation method Methods 0.000 title claims abstract description 30
- 238000003756 stirring Methods 0.000 claims abstract description 126
- 239000013078 crystal Substances 0.000 claims abstract description 105
- 238000002425 crystallisation Methods 0.000 claims abstract description 90
- 230000008025 crystallization Effects 0.000 claims abstract description 82
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims abstract description 78
- 239000007787 solid Substances 0.000 claims abstract description 72
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 55
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 51
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 claims abstract description 51
- 229960005261 aspartic acid Drugs 0.000 claims abstract description 51
- CKLJMWTZIZZHCS-UHFFFAOYSA-N D-OH-Asp Natural products OC(=O)C(N)CC(O)=O CKLJMWTZIZZHCS-UHFFFAOYSA-N 0.000 claims abstract description 29
- CKLJMWTZIZZHCS-UWTATZPHSA-N L-Aspartic acid Natural products OC(=O)[C@H](N)CC(O)=O CKLJMWTZIZZHCS-UWTATZPHSA-N 0.000 claims abstract description 29
- 238000001914 filtration Methods 0.000 claims abstract description 29
- 239000008213 purified water Substances 0.000 claims abstract description 25
- 238000007790 scraping Methods 0.000 claims abstract description 17
- 238000001816 cooling Methods 0.000 claims abstract description 15
- 239000000706 filtrate Substances 0.000 claims abstract description 13
- 238000010438 heat treatment Methods 0.000 claims abstract description 13
- 239000000047 product Substances 0.000 claims abstract description 10
- 238000002156 mixing Methods 0.000 claims abstract description 8
- 239000000243 solution Substances 0.000 claims description 125
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 44
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 28
- 238000000034 method Methods 0.000 claims description 25
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 20
- 239000007864 aqueous solution Substances 0.000 claims description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- 238000001035 drying Methods 0.000 claims description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims description 10
- 238000004519 manufacturing process Methods 0.000 claims description 9
- 238000005406 washing Methods 0.000 claims description 9
- 239000002904 solvent Substances 0.000 abstract description 11
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 abstract description 6
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 abstract description 3
- 235000003704 aspartic acid Nutrition 0.000 description 21
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 21
- 238000010907 mechanical stirring Methods 0.000 description 18
- 239000012528 membrane Substances 0.000 description 18
- 239000000203 mixture Substances 0.000 description 16
- 238000004090 dissolution Methods 0.000 description 10
- 238000001694 spray drying Methods 0.000 description 10
- 230000000052 comparative effect Effects 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 238000004880 explosion Methods 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 229910001220 stainless steel Inorganic materials 0.000 description 6
- 239000010935 stainless steel Substances 0.000 description 6
- 238000005360 mashing Methods 0.000 description 5
- 239000012535 impurity Substances 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 208000019025 Hypokalemia Diseases 0.000 description 3
- 238000007664 blowing Methods 0.000 description 3
- 230000001276 controlling effect Effects 0.000 description 3
- 239000011549 crystallization solution Substances 0.000 description 3
- 230000006866 deterioration Effects 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 230000006698 induction Effects 0.000 description 3
- 208000024896 potassium deficiency disease Diseases 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 206010003119 arrhythmia Diseases 0.000 description 2
- 230000006793 arrhythmia Effects 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 208000021264 digitalis poisoning Diseases 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003792 electrolyte Substances 0.000 description 2
- 238000007667 floating Methods 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- LVBRFZFUCKKGDJ-HJWRJIQTSA-J magnesium;dipotassium;(2s)-2-aminobutanedioate;hydron Chemical compound [Mg+2].[K+].[K+].OC(=O)[C@@H](N)CC([O-])=O.OC(=O)[C@@H](N)CC([O-])=O.[O-]C(=O)[C@@H](N)CC(O)=O.[O-]C(=O)[C@@H](N)CC(O)=O LVBRFZFUCKKGDJ-HJWRJIQTSA-J 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 239000004810 polytetrafluoroethylene Substances 0.000 description 2
- 229920001343 polytetrafluoroethylene Polymers 0.000 description 2
- 229940111263 potassium magnesium aspartate Drugs 0.000 description 2
- 206010007559 Cardiac failure congestive Diseases 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 208000009525 Myocarditis Diseases 0.000 description 1
- 206010037714 Quadriplegia Diseases 0.000 description 1
- 206010047281 Ventricular arrhythmia Diseases 0.000 description 1
- 238000009098 adjuvant therapy Methods 0.000 description 1
- 238000007605 air drying Methods 0.000 description 1
- 229940009098 aspartate Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- TXXVQZSTAVIHFD-DKWTVANSSA-M potassium;(2s)-2-aminobutanedioate;hydron Chemical compound [K+].[O-]C(=O)[C@@H](N)CC(O)=O TXXVQZSTAVIHFD-DKWTVANSSA-M 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000013049 sediment Substances 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 238000011179 visual inspection Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/38—Separation; Purification; Stabilisation; Use of additives
- C07C227/40—Separation; Purification
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/38—Separation; Purification; Stabilisation; Use of additives
- C07C227/40—Separation; Purification
- C07C227/42—Crystallisation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/10—Process efficiency
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Crystallography & Structural Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The application relates to the technical field of chemistry, and discloses a preparation method of potassium aspartate, which comprises the following steps: mixing L-aspartic acid, purified water and potassium hydroxide in a first container, heating, stirring, filtering, adding filtrate into a second container, then adding first alcohol, stirring, cooling, crystallizing, adhering solids to the inner wall of the second container, stopping stirring, scraping the solids adhered to the inner wall, and continuing stirring to obtain a seed crystal solution; mixing L-aspartic acid, purified water and potassium hydroxide, heating, stirring, and filtering to obtain a crystallization water solution; and adding the seed crystal solution into the second glycol at one time, then dripping the crystallization water solution, continuously stirring for crystallization, and filtering to obtain the product. The application improves the serious wall sticking caused by direct crystallization in the solvent crystallization method, and also improves the problem that the seed crystal is dissolved after the potassium aspartate seed crystal is directly added.
Description
Technical Field
The invention relates to the technical field of chemistry, in particular to a preparation method of potassium aspartate.
Background
Potassium aspartate, all referred to as L-aspartic acid monopotassium salt, molecular formula: c 4H8KNO4, molecular weight: 173.21. the potassium aspartate is mainly used as a bulk drug for potassium aspartate injection and potassium magnesium aspartate injection. Potassium aspartate injection as electrolyte supplementary medicine is used in treating hypokalemia caused by various reasons, periodic quadriplegia caused by hypokalemia and arrhythmia caused by digitalis poisoning. The potassium magnesium aspartate injection can be used as electrolyte supplement for adjuvant treatment of hypokalemia, arrhythmia (mainly ventricular arrhythmia) caused by digitalis poisoning, myocarditis sequelae, congestive heart failure, and myocardial infarction.
The existing preparation method of potassium aspartate mainly comprises two methods, namely a spray drying method and a solvent crystallization method.
The spray drying method is to use potassium hydroxide and aspartic acid to form salt in water, and then to realize the preparation of potassium aspartate through the steps of filtration, concentration, spray drying and the like. GB2008588A reports various spray drying methods of aspartate, and discloses that the preparation of potassium aspartate can be realized by self-made potassium aspartate aqueous solution drying at 95-180 ℃. CN101675921a describes that self-made potassium aspartate aqueous solution forms fog drops through an atomizer, the fog drops are sprayed into a drying chamber, the flow direction of drying air is the same as the spraying direction of feed liquid, the air inlet temperature is 130-200 ℃, the air outlet temperature is 40-120 ℃, and solid sediments of the potassium aspartate bulk drug obtained after drying are collected into a collecting chamber, so that the preparation of aspartic acid can be realized.
The solvent crystallization method generally refers to adding a potassium aspartate aqueous solution into a specific organic solvent for crystallization to prepare potassium aspartate. CN101234992A describes a method for preparing potassium aspartate by solvent crystallization, which is characterized in that potassium salt and aspartic acid are added into water, the pH value is regulated to 6.0-8.0 by salifying, more than 60% of water is removed from the reaction solution, the remainder is added into a nonaqueous solvent which can be mutually dissolved with water and has a certain concentration and temperature to separate out solid, and the solid is centrifugated or filtered and dried to obtain a finished product of potassium aspartate. The method disclosed in the application is a method for preparing potassium aspartate by classical solvent crystallization, and the subsequent CN102875403A, CN103130669A, CN103130669A, CN111302964A and the like report that the potassium aspartate is similarly prepared by the solvent crystallization method.
However, the spray drying process for preparing potassium aspartate has high requirements on the reaction equipment and production site. Meanwhile, the spray drying method generally needs to feed at a higher temperature, and aspartic acid can be degraded at a high temperature, so that the product quality is seriously affected. The spray drying process has no effect on impurity removal, and the product quality is difficult to be improved again. The solvent crystallization method has serious defects in a plurality of experiments, when the potassium aspartate aqueous solution is dripped into the low-temperature alcohol solution, no matter how much potassium aspartate is added, the potassium aspartate is firstly precipitated at the bottom of the reactor in the form of oily matters, the oily matters cannot be immediately separated out of crystals, the oily matters can be completely separated out in a short time in the stirring crystallization process, the separated out solids are adhered to the bottom of the reactor, the hardness is higher, normal potassium aspartate products cannot be obtained, and the phenomenon can lead to direct scrapping of the batch of materials in the process of amplified production.
In general, the above problems can be solved by adding solid seed crystals in the crystallization process, but it is actually found that, firstly, adding potassium aspartate solid seed crystals into a low-temperature alcohol solution, and when dropwise adding a potassium aspartate aqueous solution to stir and crystallize, all the solid seed crystals dissolve oil, so that the effect of the seed crystals is lost, and the problem of seed crystal dissolution is not solved even if the seed crystal dosage is increased, because potassium aspartate solid seed crystals with better forms have better solubility under a crystallization system.
In view of this, the present invention has been made.
Disclosure of Invention
The invention aims to provide a preparation method of potassium aspartate.
The invention is realized in the following way:
In a first aspect, the present invention provides a method for preparing potassium aspartate, comprising:
S1, preparing a seed crystal solution: mixing L-aspartic acid, purified water and potassium hydroxide in a first container, heating, stirring, filtering, adding filtrate into a second container, then adding first alcohol, stirring, cooling, crystallizing, adhering solids to the inner wall of the second container, stopping stirring, scraping the solids adhered to the inner wall, and continuing stirring to obtain a seed crystal solution;
s2, preparing a crystallization aqueous solution: mixing L-aspartic acid, purified water and potassium hydroxide in a third container, heating, stirring and filtering to obtain a crystallization water solution;
S3, preparation of potassium aspartate: adding the second alcohol into the fourth container, stirring and cooling, adding the seed crystal solution at one time, then dripping the crystallization water solution, continuously stirring and crystallizing, and filtering to obtain the product.
In an alternative embodiment, the first container, the second container, the third container, and the fourth container have a volume ratio of 1:4-6:8-12:40-100.
In an alternative embodiment, the mass to volume ratio of L-aspartic acid, the purified water and the potassium hydroxide in step S1 and step S2 is 1g:1.3-1.8ml:0.4-0.5g, wherein the ratio of the mass usage of L-aspartic acid in the step S1 to the volume of the first container is 20-30g:100ml, wherein the ratio of the mass usage of the L-aspartic acid in the step S2 to the volume of the second container is 20-30g:100ml.
In an alternative embodiment, the first alcohol is added in an amount of 1/2 or more of the volume of the second container and the second alcohol is added in an amount of 1/2 or more of the volume of the fourth container.
In an alternative embodiment, the temperature of the heating and stirring in step S1 and step S2 is 35-45 ℃ and the stirring time is 20-60min.
In an alternative embodiment, in step S1, stirring before scraping off the solids adhering to the inner wall comprises stirring with stirring blades at 1/2 or more of the volume of the solution;
in the step S1, stirring after scraping the solids adhered to the inner wall comprises the step of stirring the solution by positioning a stirring blade at more than 1/3 of the volume of the solution;
In step S3, stirring during stirring crystallization comprises stirring the solution by locating the stirring blade at more than 1/3 of the volume of the solution.
In an alternative embodiment, the temperature of the cooling crystallization in the step S1 is-30-10 ℃.
In an alternative embodiment, the temperature of stirring and cooling in the step S3 is reduced to-30 to-15 ℃, and the temperature of stirring and crystallization is-30 to 10 ℃.
In an alternative embodiment, the first alcohol and the second alcohol are each independently selected from at least one of methanol, ethanol, isopropanol, and n-propanol.
In an alternative embodiment, after the filtering in step S3, the method further includes washing with the second glycol, followed by nitrogen air drying.
The invention has the following beneficial effects:
The preparation method of the potassium aspartate provided by the application prepares the potassium aspartate by taking all the solutions in the second container as seed crystal solutions together and adding the seed crystal solutions into a crystallization system for mass production of the potassium aspartate for induced crystallization. The seed crystal solution provided by the application is different from the conventional solid seed crystal, the seed crystal solution is crystallized, a huge number of fine crystal nuclei exist in the solution, meanwhile, the solid in the seed crystal solution is scraped to have larger bulk density, the seed crystal solution is difficult to completely dissolve in amplified crystallization dissolution, the seed crystal can fully play a role in the crystallization process, and meanwhile, the seed crystal solution is easy to be better mixed with the crystallization solution, so that the seed crystal can be prevented from possibly floating on the surface of the solution to lose the seed crystal induction effect. The preparation method of the potassium aspartate provided by the application solves the problems that the high temperature of spray drying possibly causes the deterioration of the potassium aspartate purity and the impurity cannot be removed. Meanwhile, the problem of serious wall sticking caused by direct crystallization of potassium aspartate produced by using an alcohol and water system in a solvent crystallization method is solved, and the problem that seed crystals are dissolved after the potassium aspartate seed crystals are directly added is solved.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention more clear, the technical solutions of the embodiments of the present invention will be clearly and completely described below. The specific conditions are not noted in the examples and are carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
The invention provides a preparation method of potassium aspartate, which comprises the following steps:
S1, preparing a seed crystal solution:
mixing L-aspartic acid, purified water and potassium hydroxide in a first container, heating, stirring, filtering, adding filtrate into a second container, adding first alcohol, stirring, cooling, crystallizing, adhering solids to the inner wall of the second container, stopping stirring, scraping the solids adhered to the inner wall, and continuing stirring to obtain a seed crystal solution.
In the application, the mass volume ratio of L-aspartic acid, purified water and potassium hydroxide is 1g:1.3-1.8ml:0.4-0.5g, wherein the ratio of the mass dosage of L-aspartic acid in the step S1 to the volume of the first container is 20-30g:100ml, the temperature of heating and stirring is 35-45 ℃, and the stirring time is 20-60min. And (3) filtering while the solution is hot after heating and stirring, adding the filtrate into a second container which is larger than the first container, then adding more than 1/2 of the first alcohol of the volume of the second container, crystallizing the filtrate to separate out solids, and cooling to the crystallization temperature of-30-10 ℃. Wherein the volume ratio of the first container to the second container is 1:4-6.
However, the research of the application finds that when the potassium aspartate aqueous solution is dripped into the low-temperature first alcohol solution, no matter how much potassium aspartate is added, the potassium aspartate is firstly precipitated at the bottom of the reactor in the form of oil, crystals cannot be immediately precipitated from the oil, the oil can be subjected to explosion phenomenon in the stirring crystallization process, namely, solids are completely precipitated in a short time, the precipitated solids are adhered to the bottom of the reactor, the hardness is higher, the stirring blade is directly locked, the phenomenon that stirring cannot be performed is caused, and the phenomenon leads to direct scrapping of the batch of materials in the process of amplified production. For this purpose, in the present application, stirring before scraping off the solids stuck to the inner wall includes stirring with stirring blades at 1/2 or more of the volume of the solution; stirring after scraping the solids adhered to the inner wall comprises the step of stirring the solution by positioning a stirring blade at more than 1/3 of the volume of the solution; the stirring operation can avoid locking of the stirring blade in the crystallization process, and simultaneously reduce the position of the stirring blade after scraping after crystallization is finished, so that scraped solids can be crushed in a stirring state. It should be understood that, in the present application, instead of using only the uniformly crystallized particles as crystals, the part of the particles, the solids scraped from the inner wall, and the whole solution are used as a seed crystal solution, wherein the solids scraped from the inner wall may be in a sheet shape or a block shape, and the shape is more irregular after being crushed by the stirring blade, by using the whole system in the second container as the seed crystal, the dissolution of the seed crystal under the crystallization system can be effectively avoided.
The first alcohol is selected from at least one of methanol, ethanol, isopropanol and n-propanol; preferably, the first alcohol is selected from at least one of isopropyl alcohol and n-propyl alcohol.
S2, preparing a crystallization aqueous solution:
Mixing L-aspartic acid, purified water and potassium hydroxide in a third container, heating and stirring at 35-45deg.C for 20-60min, and filtering to obtain crystallization water solution; the mass volume ratio of L-aspartic acid, purified water and potassium hydroxide is 1g:1.3-1.8ml:0.4-0.5g, wherein the ratio of the mass dosage of L-aspartic acid in the step S2 to the volume of the second container is 20-30g:100ml.
The volume ratio of the first container to the second container to the third container is 1:4-6:8-12.
S3, preparation of potassium aspartate:
adding a second alcohol into a fourth container, stirring and cooling to-30 to-15 ℃, adding seed crystal solution at one time, then dropwise adding crystallization water solution, continuing stirring and crystallization, wherein the temperature of low-temperature stirring is-30-10 ℃, stirring during stirring and crystallization comprises stirring the solution with stirring blades positioned above 1/3 of the volume of the solution for 3-6 hours, filtering, washing with the second alcohol, and then drying with nitrogen air blast.
The volume ratio of the first container, the second container, the third container and the fourth container is 1:4-6:8-12:40-100. The addition amount of the second alcohol is more than 1/2 of the volume of the fourth container. The second glycol is at least one selected from methanol, ethanol, isopropanol and n-propanol; preferably, the second alcohol is at least one selected from isopropyl alcohol and n-propyl alcohol, respectively and independently.
As can be seen from the volume changes of the first container, the second container, the third container and the fourth container according to the present application, in the present application, the mixed solution of L-aspartic acid, purified water and potassium hydroxide is prepared in the smaller first container and added into the slightly larger second container to perform crystallization, at this time, the crystallization process in the second container is easy to control, at the same time, the solid-liquid on the inner wall of the second container is also easy to scrape off by means of a scraper, the whole system in the second container is used as a seed crystal solution, at this time, the solid seed crystals therein are not easy to dissolve in the subsequent solution of the second alcohol, the third container is used for preparing a crystallization aqueous solution, and the crystallization aqueous solution is added dropwise into the fourth container containing the second alcohol and the seed crystal solution to induce crystallization, so that the volume of the fourth container is the largest, and at the same time, the expansion production is realized. The method of the application solves the problems that the high temperature of spray drying can cause the deterioration of the purity of potassium aspartate and the impurity cannot be removed. Meanwhile, the problem of serious wall sticking caused by direct crystallization of potassium aspartate produced by using an alcohol and water system in a solvent crystallization method is solved, and the problem that seed crystals are dissolved after the potassium aspartate seed crystals are directly added is solved.
The features and capabilities of the present invention are described in further detail below in connection with the examples.
Example 1
The embodiment provides a preparation method of potassium aspartate, which comprises the following steps:
S1, preparing a seed crystal solution: 26.6g of L-aspartic acid and 40ml of purified water are added into a 100ml three-port bottle, 12.2g of high-purity potassium hydroxide is added in batches under mechanical stirring, the pH value is 7.12, the temperature is raised to 40 ℃ after the addition, the mixture is stirred for 30 minutes, a filter membrane is filled and filtered while the filter membrane is hot, the filtrate is added into a 500ml three-port bottle, 266ml of isopropanol is added, the mixture is stirred by mechanical stirring, a stirring blade is positioned above about 1/2 volume of the solution, and the temperature is reduced to-15 ℃ and the mixture is stirred for crystallization. After stirring for 4 hours, a large amount of solid is adhered to the bottle wall, the hardness is higher, stirring is stopped, a stainless steel scraper is used for scraping the solid adhered to the bottle wall and mashing the solid with a larger block, the stirring blade is lowered to the position of about 1/3 volume of the solution, and stirring is continued for 4 hours, so that the aspartic acid seed crystal solution is obtained.
S2, preparing a crystallization aqueous solution: to 1000ml three-mouth bottle, 266.0g L-aspartic acid and 400ml purified water are added, 122g high-purity potassium hydroxide is added in batches under mechanical stirring, pH is measured to be 7.15, after the addition, the temperature is raised to 40 ℃ and stirring is carried out for 1 hour, a filter membrane is used for filtering while the solution is hot, and crystallization water solution is obtained.
S3, preparation of potassium aspartate: 2.66L of isopropanol is added into a 5000ml three-mouth bottle to obtain isopropanol solution, the temperature is reduced to-15 ℃ under mechanical stirring, a stirring blade is positioned at the bottom of the bottle to the position of about 1/3 of the liquid level, the aspartic acid seed crystal solution is added at one time, the dropwise addition of the crystallization water solution is controlled at-30 ℃, after the dropwise addition, the stirring is carried out for 6 hours, the filtration and the isopropanol washing are carried out, and the potassium aspartate dihydrate 448.0g is obtained through the blowing and drying of 25 ℃ nitrogen flow, and the yield is 98.4%.
After the reaction is finished, the condition that the inner wall of the three-mouth bottle in the step S3 is almost free from solid sticking is solved, namely the problems of aspartic acid explosion and seed crystal dissolution during solid seed crystal addition are solved.
Example 2
The embodiment provides a preparation method of potassium aspartate, which comprises the following steps:
S1, preparing a seed crystal solution: 26.6g of L-aspartic acid and 40ml of purified water are added into a 100ml three-port bottle, 12.2g of high-purity potassium hydroxide is added in batches under mechanical stirring, the pH value is 7.12, the temperature is raised to 40 ℃ after the addition, the mixture is stirred for 30 minutes, a filter membrane is filled and filtered while the filter membrane is hot, the filtrate is added into a 500ml three-port bottle, 266ml of isopropanol is added, the mixture is stirred by mechanical stirring, a stirring blade is positioned above about 1/2 volume of the solution, and the temperature is reduced to-30 ℃ and the mixture is stirred for crystallization. After stirring for 4 hours, a large amount of solid is adhered to the bottle wall, the hardness is higher, stirring is stopped, a stainless steel scraper is used for scraping the solid adhered to the bottle wall and mashing the solid with a larger block, the stirring blade is lowered to the position of about 1/3 volume of the solution, and stirring is continued for 4 hours, so that the aspartic acid seed crystal solution is obtained.
S2, preparing a crystallization aqueous solution: 2.66kg of L-aspartic acid and 4L of purified water are added into a 10L glass reaction kettle, 1.22kg of high-purity potassium hydroxide is added in batches under mechanical stirring, the pH value is measured to be 7.14, the temperature is raised to 40 ℃ after the addition, the stirring is carried out for 1 hour, and a filter membrane is filled and filtered while the solution is hot, so that a crystallization water solution is obtained.
S3, preparation of potassium aspartate: adding 26.6L of isopropanol into a 50L glass reaction kettle to obtain an isopropanol solution, mechanically stirring, cooling to-15 ℃, adding an aspartic acid seed crystal solution at one time, controlling to drop a crystallization water solution at 0 ℃, stirring for 8 hours after dropping, filtering, washing with isopropanol, and drying with nitrogen flow blast at 25 ℃ to obtain 4.01kg of potassium aspartate dihydrate with a yield of 95.9%.
After the reaction is finished, the condition that the inner wall of the three-mouth bottle in the step S3 is almost free from solid sticking is solved, namely the problems of aspartic acid explosion and seed crystal dissolution during solid seed crystal addition are solved.
Example 3
The embodiment provides a preparation method of potassium aspartate, which comprises the following steps:
S1, preparing a seed crystal solution: 26.6g of L-aspartic acid and 40ml of purified water are added into a 100ml three-mouth bottle, 12.2g of high-purity potassium hydroxide is added in batches under mechanical stirring, the pH value is 7.12, the temperature is raised to 40 ℃ after the addition, the mixture is stirred for 30 minutes, a filter membrane is filled and filtered while the filter membrane is hot, the filtrate is added into a 500ml three-mouth bottle, 266ml of n-propanol is added, the mixture is stirred by mechanical stirring, a stirring blade is positioned above about 1/2 volume of the solution, and the temperature is reduced to 10 ℃ and the mixture is stirred for crystallization. After stirring for 4 hours, a large amount of solid is adhered to the bottle wall, the hardness is higher, stirring is stopped, a stainless steel scraper is used for scraping the solid adhered to the bottle wall and mashing the solid with a larger block, the stirring blade is lowered to the position of about 1/3 volume of the solution, and stirring is continued for 4 hours, so that the aspartic acid seed crystal solution is obtained.
S2, preparing a crystallization aqueous solution: to 1000ml three-mouth bottle, 266.0g L-aspartic acid and 400ml purified water are added, 122g high-purity potassium hydroxide is added in batches under mechanical stirring, pH is measured to be 7.00, after the addition, the temperature is raised to 40 ℃ and stirring is carried out for 1 hour, and a filter membrane is used for filtering while the solution is hot, thus obtaining the crystallization water solution.
S3, preparation of potassium aspartate: 2.66L of n-propanol is added into a 5000ml three-mouth bottle to obtain n-propanol solution, the temperature is reduced to minus 15 ℃ under mechanical stirring, a stirring blade is positioned at the bottom of the bottle to the position of about 1/3 of the liquid level, the aspartic acid seed crystal solution is added at one time, the dropwise addition of the crystallization water solution is controlled at minus 30 ℃, after the dropwise addition, stirring is carried out for 6 hours, filtering and n-propanol washing are carried out, and the potassium aspartate dihydrate 444.0g is obtained through blowing and drying by nitrogen flow at 25 ℃, thus the yield is 97.5%.
After the reaction is finished, the condition that the inner wall of the three-mouth bottle in the step S3 is almost free from solid sticking is solved, namely the problems of aspartic acid explosion and seed crystal dissolution during solid seed crystal addition are solved.
Example 4
The embodiment provides a preparation method of potassium aspartate, which comprises the following steps:
S1, preparing a seed crystal solution: 26.6g of L-aspartic acid and 35ml of purified water are added into a 100ml three-port bottle, 10.64g of high-purity potassium hydroxide is added in batches under mechanical stirring, the pH is 7.04, the temperature is raised to 35 ℃ after the addition, the mixture is stirred for 30 minutes, a filter membrane is filled and filtered while the filter membrane is hot, the filtrate is added into a 500ml three-port bottle, 266ml of n-propanol is added, the mixture is stirred by mechanical stirring, a stirring blade is positioned above 1/2 volume of the solution, and the temperature is reduced to 0 ℃ for stirring crystallization. After stirring for 4 hours, a large amount of solid is adhered to the bottle wall, the hardness is higher, stirring is stopped, a stainless steel scraper is used for scraping the solid adhered to the bottle wall and mashing the solid with a larger block, the stirring blade is lowered to the position of about 1/3 volume of the solution, and stirring is continued for 4 hours, so that the aspartic acid seed crystal solution is obtained.
S2, preparing a crystallization aqueous solution: to 1000ml three-mouth bottle, 266.0g L-aspartic acid and 350ml purified water are added, 106.4g high-purity potassium hydroxide is added in batches under mechanical stirring, pH is measured to be 7.50, after the addition, the temperature is raised to 35 ℃ and stirring is carried out for 1 hour, and a filter membrane is used for filtering while the solution is hot, thus obtaining crystallization water solution.
S3, preparation of potassium aspartate: 2.66L of n-propanol is added into a 5000ml three-mouth bottle to obtain n-propanol solution, the temperature is reduced to minus 15 ℃ under mechanical stirring, a stirring blade is positioned at the bottom of the bottle to the position of about 1/3 of the liquid level, the aspartic acid seed crystal solution is added at one time, the dropwise addition of the crystallization water solution is controlled at 10 ℃, after the dropwise addition, stirring is carried out for 6 hours, filtering, washing with n-propanol is carried out, and drying with nitrogen flow blast at 25 ℃ is carried out to obtain 444.0g of potassium aspartate dihydrate, and the yield is 97.5%.
After the reaction is finished, the condition that the inner wall of the three-mouth bottle in the step S3 is almost free from solid sticking is solved, namely the problems of aspartic acid explosion and seed crystal dissolution during solid seed crystal addition are solved.
Example 5
The embodiment provides a preparation method of potassium aspartate, which comprises the following steps:
S1, preparing a seed crystal solution: 26.6g of L-aspartic acid and 47ml of purified water are added into a 100ml three-port bottle, 13.3g of high-purity potassium hydroxide is added in batches under mechanical stirring, the pH value is 7.20, the temperature is raised to 45 ℃ after the addition, the mixture is stirred for 30 minutes, a filter membrane is filled and filtered while the filter membrane is hot, the filtrate is added into a 500ml three-port bottle, 266ml of isopropanol is added, the mixture is stirred by mechanical stirring, a stirring blade is positioned above about 1/2 volume of the solution, and the temperature is reduced to-15 ℃ and the mixture is stirred for crystallization. After stirring for 4 hours, a large amount of solid is adhered to the bottle wall, the hardness is higher, stirring is stopped, a stainless steel scraper is used for scraping the solid adhered to the bottle wall and mashing the solid with a larger block, the stirring blade is lowered to the position of about 1/3 volume of the solution, and stirring is continued for 4 hours, so that the aspartic acid seed crystal solution is obtained.
S2, preparing a crystallization aqueous solution: 47L of purified water and 26.6 kgL-aspartic acid are sequentially added into a 100L reaction kettle, 13.3kg of high-purity potassium hydroxide is added in batches under stirring, the pH value is measured to be 7.3 after the addition, the temperature is raised to 45 ℃ and the mixture is stirred for 2 hours, and a 0.2 mu m filter membrane nitrogen filter pressing is carried out while the mixture is hot, so as to obtain a crystallization water solution.
S3, preparation of potassium aspartate: 266L of isopropanol is added into a 500L reaction kettle to obtain isopropanol solution III, the temperature is reduced to minus 30 ℃ under stirring, an aspartic acid seed crystal solution is added at one time, a crystallization water solution is slowly dripped at minus 30 ℃, 10 percent of the crystallization water solution is firstly dripped, after a large amount of solid is separated out by visual inspection, the rest 90 percent of crystallization water phase II is dripped, after the dripping is finished, the stirring is carried out for 6 hours, the filtration and the isopropanol washing are carried out, and 40.8kg of potassium aspartate dihydrate is obtained by blowing and drying with nitrogen flow at 25 ℃, and the yield is 98.6 percent.
After the reaction is finished, the condition that the inner wall of the three-mouth bottle in the step S3 is almost free from solid sticking is solved, namely the problems of aspartic acid explosion and seed crystal dissolution during solid seed crystal addition are solved.
Comparative example 1
This comparative example provides a process for the preparation of potassium aspartate according to example 1 disclosed in CN 103130669A:
133.1g of aspartic acid were added to 80.0g of purified water, heated to 30℃and stirred until the solid was completely dissolved. Adding 80.0g of potassium hydroxide for reaction, measuring the pH of the reaction solution to be about 8.0, heating the reaction solution to 40 ℃, adding 8.55g of active carbon, cooling to 30 ℃ for decoloration for 30min, filtering while the reaction solution is hot, and respectively performing three-stage filtration through a carbon filter, a1 mu m filter membrane (made of PTFE) and a 0.45 mu m filter membrane (made of PTFE) to obtain filtrate. Transferring the filtrate into a 1L three-mouth bottle, controlling the temperature to minus 10 ℃ to minus 8 ℃, slowly adding 240ml of 95% ethanol, and finding that the solution is gradually turbid. After the addition, keeping the temperature at minus 25 ℃ for 2 hours, finding that oily matters adhere to the bottom of the bottle in the crystallization process, solidifying to form harder solids which adhere to the wall of the bottle, scraping the solids by using a stainless steel scraper, and continuing stirring to obtain the more dispersed solids. The white product was obtained by filtration, washed with a small amount of ethanol solution of 30ml of ethanol, and then dried under reduced pressure at 30℃for 8 hours to obtain 190.64g of potassium aspartate dihydrate in a yield of 92.0%.
Comparative example 2
This comparative example is substantially the same as example 1 except that solid seed crystals were directly added in this comparative example.
S1, preparing seed crystals: the product obtained in example 1, S3, was used as seed.
S2, preparing a crystallization aqueous solution: to 1000ml three-mouth bottle, 266.0g L-aspartic acid and 400ml purified water are added, 122g high-purity potassium hydroxide is added in batches under mechanical stirring, pH is measured to be 7.15, after the addition, the temperature is raised to 40 ℃ and stirring is carried out for 1 hour, a filter membrane is used for filtering while the solution is hot, and crystallization water solution is obtained.
S3, preparation of potassium aspartate: adding 2.66L of isopropanol into a 5000ml three-mouth bottle to obtain isopropanol solution, mechanically stirring, cooling to-15 ℃, positioning a stirring blade at the bottom of the bottle to about 1/3 of the liquid level, adding aspartic acid solid seed crystals, controlling to drop the crystallization water solution at-30 ℃, finding that the solid seed crystals gradually dissolve and become oil when the crystallization water solution is dropped, after dropping, stirring for crystallization, wherein the crystallization process also has solid wall sticking phenomenon, the dissolved seed crystals do not exert seed crystal induced crystallization effect, stirring after hanging the wall sticking solid by using a scraper, filtering, washing with isopropanol, and carrying out blast drying with nitrogen flow at 25 ℃ to obtain 448.0g of potassium aspartate dihydrate with the yield of 98.4%.
In the comparative example, the solid potassium aspartate is used as seed crystal, and after the solid potassium aspartate is added, the solid seed crystal can completely dissolve oil and lose the seed crystal effect when the potassium aspartate aqueous solution is dripped and stirred for crystallization. In example 1 of the present application, all the solutions in the second container are used as seed crystal solutions, and the seed crystals in example 1 and this comparative example are mainly different in that: the seed crystal solution is crystallized, a large number of fine crystal nuclei exist in the solution, meanwhile, the solid in the seed crystal solution is scraped to have larger bulk density, so that the seed crystal solution is difficult to completely dissolve in amplified crystallization dissolution, the seed crystal can fully play a role in crystallization, and meanwhile, the seed crystal solution is easy to mix with the crystallization solution better, and the phenomenon that the seed crystal possibly floats on the surface of the solution to lose the seed crystal induction effect is avoided. Therefore, the embodiment 1 of the application can improve the problems of crystallization and wall adhesion, improve the problem that the seed crystal is dissolved after the potassium aspartate seed crystal is directly added, ensure that the wall adhesion of the reaction vessel is less during industrial mass production, the service cycle of the reaction vessel is long, and the shutdown cleaning frequency is obviously reduced.
In summary, the preparation method of potassium aspartate provided by the application prepares potassium aspartate by taking all the solutions in the second container as seed crystal solutions together, adding the seed crystal solutions into a crystallization system for mass production of potassium aspartate to perform induced crystallization. The seed crystal solution provided by the application is different from the conventional solid seed crystal, the seed crystal solution is crystallized, a huge number of fine crystal nuclei exist in the solution, meanwhile, the solid in the seed crystal solution is scraped to have larger bulk density, the seed crystal solution is difficult to completely dissolve in amplified crystallization dissolution, the seed crystal can fully play a role in the crystallization process, and meanwhile, the seed crystal solution is easy to be better mixed with the crystallization solution, so that the seed crystal can be prevented from possibly floating on the surface of the solution to lose the seed crystal induction effect. The preparation method of the potassium aspartate provided by the application solves the problems that the high temperature of spray drying possibly causes the deterioration of the potassium aspartate purity and the impurity cannot be removed. Meanwhile, the problem of serious wall sticking caused by direct crystallization of potassium aspartate produced by using an alcohol and water system in a solvent crystallization method is solved, and the problem that seed crystals are dissolved after the potassium aspartate seed crystals are directly added is solved.
The above description is only of the preferred embodiments of the present invention and is not intended to limit the present invention, but various modifications and variations can be made to the present invention by those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (3)
1. The preparation method of the potassium aspartate is characterized by comprising the following steps:
S1, preparing a seed crystal solution: mixing L-aspartic acid, purified water and potassium hydroxide in a first container, heating, stirring, filtering, adding filtrate into a second container, then adding first alcohol, stirring, cooling, crystallizing, adhering solids to the inner wall of the second container, stopping stirring, scraping the solids adhered to the inner wall, and continuing stirring to obtain a seed crystal solution;
s2, preparing a crystallization aqueous solution: mixing L-aspartic acid, purified water and potassium hydroxide in a third container, heating, stirring and filtering to obtain a crystallization water solution;
S3, preparation of potassium aspartate: adding a second alcohol into a fourth container, stirring and cooling, adding the seed crystal solution all at once, then dripping the crystallization water solution, continuously stirring and crystallizing, and filtering to obtain a product;
The volume ratio of the first container, the second container, the third container and the fourth container is 1:4-6:8-12:40-100;
The mass-volume ratio of the L-aspartic acid, the purified water and the potassium hydroxide in the step S1 and the step S2 is 1g:1.3-1.8ml:0.4-0.5g, wherein the ratio of the mass usage of L-aspartic acid in the step S1 to the volume of the first container is 20-30g:100ml, wherein the ratio of the mass usage of the L-aspartic acid in the step S2 to the volume of the second container is 20-30g:100ml;
The addition amount of the first alcohol is more than 1/2 of the volume of the second container, and the addition amount of the second alcohol is more than 1/2 of the volume of the fourth container;
the temperature of heating and stirring in the step S1 and the step S2 is 35-45 ℃ and the stirring time is 20-60min;
the temperature of the cooling crystallization in the step S1 is-30-10 ℃;
In the step S3, stirring and cooling to-30 to-15 ℃, wherein the temperature of stirring crystallization is-30 to 10 ℃;
The first alcohol and the second alcohol are respectively and independently at least one selected from methanol, ethanol, isopropanol and n-propanol.
2. The method for producing potassium aspartate according to claim 1, wherein in step S1, stirring before scraping off the solids adhering to the inner wall comprises stirring with stirring blades at 1/2 or more of the volume of the solution;
in the step S1, stirring after scraping the solids adhered to the inner wall comprises the step of stirring the solution by positioning a stirring blade at more than 1/3 of the volume of the solution;
In step S3, stirring during stirring crystallization comprises stirring the solution by locating the stirring blade at more than 1/3 of the volume of the solution.
3. The method according to any one of claims 1 to 2, wherein the filtration in step S3 is followed by washing with the second alcohol and then drying with nitrogen air.
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