CN110878017A - Refining and purifying method of L-malic acid for injection - Google Patents
Refining and purifying method of L-malic acid for injection Download PDFInfo
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- CN110878017A CN110878017A CN201811032760.5A CN201811032760A CN110878017A CN 110878017 A CN110878017 A CN 110878017A CN 201811032760 A CN201811032760 A CN 201811032760A CN 110878017 A CN110878017 A CN 110878017A
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- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 title claims abstract description 62
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 title claims abstract description 31
- 229940116298 l- malic acid Drugs 0.000 title claims abstract description 31
- 235000011090 malic acid Nutrition 0.000 title claims abstract description 31
- 238000000034 method Methods 0.000 title claims abstract description 28
- 238000007670 refining Methods 0.000 title claims abstract description 26
- 238000002347 injection Methods 0.000 title claims abstract description 20
- 239000007924 injection Substances 0.000 title claims abstract description 20
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 111
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 47
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims abstract description 12
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000003960 organic solvent Substances 0.000 claims abstract description 12
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims abstract description 12
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims abstract description 6
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 claims abstract description 6
- 239000001530 fumaric acid Substances 0.000 claims abstract description 6
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims abstract description 6
- 239000011976 maleic acid Substances 0.000 claims abstract description 6
- 238000003756 stirring Methods 0.000 claims description 23
- 239000008213 purified water Substances 0.000 claims description 21
- 238000000605 extraction Methods 0.000 claims description 20
- 239000007787 solid Substances 0.000 claims description 18
- 238000001914 filtration Methods 0.000 claims description 12
- 239000012065 filter cake Substances 0.000 claims description 8
- 238000004821 distillation Methods 0.000 claims description 7
- 238000001035 drying Methods 0.000 claims description 7
- 239000007788 liquid Substances 0.000 claims description 2
- 239000012535 impurity Substances 0.000 abstract description 25
- XUKUURHRXDUEBC-SXOMAYOGSA-N (3s,5r)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-SXOMAYOGSA-N 0.000 abstract description 3
- 238000001514 detection method Methods 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract description 2
- 150000007524 organic acids Chemical class 0.000 abstract description 2
- 238000000638 solvent extraction Methods 0.000 abstract description 2
- 235000005985 organic acids Nutrition 0.000 abstract 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 17
- 238000000746 purification Methods 0.000 description 12
- IAVAUMSRZIHIMD-UHFFFAOYSA-N C(C=CC(=O)O)(=O)O.C(C=C/C(=O)O)(=O)O.C(CCC(=O)O)(=O)O Chemical compound C(C=CC(=O)O)(=O)O.C(C=C/C(=O)O)(=O)O.C(CCC(=O)O)(=O)O IAVAUMSRZIHIMD-UHFFFAOYSA-N 0.000 description 6
- 239000012071 phase Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 4
- 238000010268 HPLC based assay Methods 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000001384 succinic acid Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 230000000813 microbial effect Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000004537 pulping Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- -1 compound amino acid Chemical class 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 230000005976 liver dysfunction Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 230000035764 nutrition Effects 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
- C07C51/48—Separation; Purification; Stabilisation; Use of additives by liquid-liquid treatment
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
- C07C51/43—Separation; Purification; Stabilisation; Use of additives by change of the physical state, e.g. crystallisation
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Crystallography & Structural Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a refining and purifying method of L-malic acid for injection. The method adopts an organic solvent extraction mode to remove organic acids such as succinic acid, fumaric acid, maleic acid and the like, and adopts a 2.5% water/ethyl acetate system to remove unknown impurities. The obtained L-malic acid reaches the standard of injection use, and succinic acid, fumaric acid, maleic acid, unknown impurity A and unknown impurity B are all lower than the detection limit. The process is simple to operate, mild in condition and easy for industrial production.
Description
Technical Field
The invention relates to a refining and purifying method of L-malic acid, in particular to a refining and purifying method of injection-grade L-malic acid, belonging to the field of chemical purification.
Background
L-malic acid is widely distributed in animal and plant and microbial cells, plays an important role in the biological metabolism process, and is often matched with compound amino acid injection (important nutrition medicine after operation) to improve the utilization rate of amino acid, which is particularly important for patients with postoperative weakness and liver dysfunction.
At present, the method for artificially preparing the L-malic acid is mainly a microbial fermentation method, an enzymatic conversion method and a chemical synthesis method. The content of succinic acid in medicinal adjuvant-grade L-malic acid related substances is not limited in the fourth part of the 2015 edition of Chinese pharmacopoeia, and the content of succinic acid sold in the market is generally higher than 0.2 percent and cannot meet the requirement of injection.
CN 106220493 discloses a refining method of L-malic acid, which can effectively remove succinic acid by adopting a conventional extraction chemical means. However, the method still has the following two defects: 1. purified water is used as a solvent, water is required to be distilled out in the subsequent steps to obtain a product, experiments show that related substances such as succinic acid, fumaric acid, maleic acid and the like can reach the standard of an injection under given experimental conditions, but two unknown impurities which seriously exceed the standard appear in the process of distilling out water, and the longer the distillation time is, the higher the contents of the two unknown impurities are; 2. one or a mixture of isopropyl ether, n-butanol and ethyl acetate is adopted for final refining, and two unknown impurities cannot be removed but are increased. There is no report on the removal method of these two unknown impurities.
Disclosure of Invention
The invention aims to provide a preparation method of L-malic acid for injection, which adopts purified water as a solvent, removes organic acid impurities such as succinic acid, fumaric acid, maleic acid and the like by an organic solvent extraction method, and removes unknown impurities (unknown impurity A and unknown impurity B) by a method of pulping hydrous ethyl acetate. The method has the characteristics of simple operation, mild conditions, easy industrial production and the like, and the quality of the product meets the use standard of the injection.
In order to achieve the purpose, the invention adopts the technical means as follows:
the refining and purifying method of the L-malic acid for injection is characterized by comprising the following steps:
(1) dissolving a sample: dissolving an L-malic acid sample to be purified into purified water, and stirring to completely dissolve;
(2) and (3) extraction: adding an organic solvent, stirring, standing and separating liquid;
(3) and (3) continuously extracting: continuously adding the organic solvent into the water phase for extraction, and repeating the step (2) until the succinic acid, the maleic acid and the fumaric acid meet the quality standard;
(4) and (3) reduced pressure distillation: after filtering the water phase, distilling under reduced pressure to remove water, and adding a corresponding organic solvent to carry out residual water to obtain a solid;
(5) and (3) finally refining: and (4) adding the solid obtained in the step (4) into ethyl acetate, adding purified water, stirring, filtering, and drying a filter cake to obtain the L-malic acid for injection.
Preferably, the organic solvent in step (1) is ethyl acetate.
Preferably, the dosage of the ethyl acetate used in each extraction in the steps (2) and (3) is 1-5 times of the weight of the sample; more preferably, the amount of ethyl acetate used in each extraction in steps (2) and (3) is 2 times the weight of the sample.
Preferably, the amount of the ethyl acetate used in the step (5) is 1-5 times of the weight of the solid obtained in the step (4); more preferably, the amount of ethyl acetate used in step (5) is 2 times the weight of the solid obtained in step (4).
Preferably, the amount of the purified water in the step (5) is 1-5% of the weight of the ethyl acetate; more preferably, the amount of the purified water used in the step (5) is 2-2.5% by weight of the ethyl acetate.
Compared with the prior art, the invention has the beneficial effects that:
the methods of the prior art not only fail to remove unknown impurity a and unknown impurity B, but increase them significantly beyond the injection level. According to the invention, a water/ethyl acetate system (generally, the two are considered to be immiscible, and a certain solubility of water in ethyl acetate is ignored) is adopted for the final refining of the L-malic acid, a small amount of water plays a key role in removing two unknown impurities, the two unknown impurities can be effectively removed, and the two unknown impurities of the L-malic acid can meet the standard requirements of the injection.
Drawings
FIG. 1 is a HPLC chart of a sample before purification according to the present invention;
FIG. 2 is a HPLC chart of comparative example 1 of the present invention after purification;
FIG. 3 is a HPLC chart after refining in example 1 of the present invention;
FIG. 4 is a HPLC chart after refining in example 2 of the present invention;
FIG. 5 is a HPLC chart after refining in example 3 of the present invention;
FIG. 6 is a HPLC chart after refining in example 4 of the present invention;
FIG. 7 is a HPLC chart after refining in example 5 of the present invention.
Detailed Description
The invention will be further described with reference to specific embodiments, and the advantages and features of the invention will become apparent as the description proceeds. These examples are illustrative only and do not limit the scope of the present invention in any way. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention, and that such changes and modifications may be made without departing from the spirit and scope of the invention.
COMPARATIVE EXAMPLE 1(CN 106220493)
Adding 200g of purified water into a single-mouth bottle, adding a 100g L-malic acid sample under stirring, continuing stirring until the solution is clear, adding 400g of ethyl acetate for extraction, and continuously extracting for 3 times. The aqueous phase was filtered through a 0.45 μm filter and then distilled at 60-63 ℃ under reduced pressure, and when there was substantially no fraction, 50g of ethyl acetate was added again and again to carry out three times of distillation to remove residual water.
Sampling, and monitoring the water content of the system to be less than 0.44%. Adding 250g of ethyl acetate, transferring the mixture into a clean and dry 500ml three-neck bottle, pulping the mixture for 1 hour at the temperature of between 0 and 25 ℃, and then carrying out suction filtration. The filter cake is dried in vacuum at 50-60 ℃ to constant weight to obtain 74.0g, and the yield is 74%.
The impurity content of the sample before and after purification was measured by HPLC, and the results are shown in Table 1.
TABLE 1 HPLC TEST RESULTS FROM AND FROM REFINING COMPARATIVE EXAMPLE 1 SAMPLE
| Impurities | Succinic acid | Fumaric acid | Maleic acid | Unknown A | Unknown B |
| Sample (I) | 0.38 | 0.02 | Not detected out | 0.28 | 0.11 |
| After refining | 0.05 | Not detected out | Not detected out | 0.31 | 0.37 |
Example 1
Adding 200g of purified water into a single-mouth bottle, adding a 100g L-malic acid sample under stirring, continuously stirring until the solution is clear, adding 200g of ethyl acetate for extraction, continuously extracting for 5 times, taking a little water layer after each extraction, removing water, and carrying out HPLC detection. The aqueous phase was filtered and distilled under reduced pressure at 60-63 ℃ and, when there was substantially no distillate, 50g of ethyl acetate was added to take out the residual water to give a solid.
The resulting solid was dried at 50-55 ℃ under reduced pressure to constant weight, yielding 71.0 g. Adding 142g of ethyl acetate and 1.42g of purified water, stirring for 6 hours, filtering, collecting a filter cake, and drying at 50-55 ℃ under reduced pressure to constant weight to obtain 56.0g of L-malic acid for injection with the yield of 56%.
The impurity content of the sample before and after purification was measured by HPLC, and the results are shown in Table 2.
Table 2 example 1 HPLC assay results before and after sample purification
| Impurities | Succinic acid | Fumaric acid | Maleic acid | Unknown A | Unknown B |
| Sample (I) | 0.38 | 0.02 | Not detected out | 0.28 | 0.11 |
| EA extraction once | 0.13 | Not detected out | Not detected out | 0.29 | 0.11 |
| EA extraction twice | 0.08 | Not detected out | Not detected out | 0.31 | 0.14 |
| EA extraction three times | 0.06 | Not detected out | Not detected out | 0.28 | 0.10 |
| EA extraction four times | 0.05 | Not detected out | Not detected out | 0.30 | 0.11 |
| After refining | Not detected out | Not detected out | Not detected out | 0.06 | 0.08 |
Example 2
Adding 200g of purified water into a single-mouth bottle, adding a 100g L-malic acid sample under stirring, continuing stirring until the solution is clear, adding 200g of ethyl acetate for extraction, and continuously extracting for 3 times. The aqueous phase was filtered and distilled under reduced pressure at 60-63 ℃ and, when there was substantially no distillate, 50g of ethyl acetate was added to take out the residual water to give a solid.
The resulting solid was dried at 50-55 ℃ under reduced pressure to constant weight, yielding 75.0 g. Adding 150g of ethyl acetate and 3.75g of purified water, stirring for 6 hours, filtering, collecting a filter cake, and drying at 50-55 ℃ under reduced pressure to constant weight to obtain 64.0g of L-malic acid for injection with the yield of 64%.
The impurity content of the sample before and after purification was measured by HPLC, and the results are shown in Table 3.
Table 3 example 2 HPLC assay results before and after sample purification
| Impurities | Succinic acid | Fumaric acid | Maleic acid | Unknown A | Unknown B |
| Sample (I) | 0.38 | 0.02 | Not detected out | 0.28 | 0.11 |
| After refining | 0.04 | Not detected out | Not detected out | 0.06 | 0.04 |
Example 3
Adding 200g of purified water into a single-neck bottle, adding a 100g L-malic acid sample under stirring, continuously stirring until the solution is clear, adding 100g of ethyl acetate for extraction, continuously extracting for 3 times, filtering the water phase, carrying out reduced pressure distillation at 60-63 ℃, adding 50g of ethyl acetate when no fraction is generated basically, and taking out residual water to obtain a solid.
The resulting solid was dried at 50-55 ℃ under reduced pressure to constant weight, yielding 82.0 g. Adding 164g of ethyl acetate and 4.0g of purified water, stirring for 6 hours, filtering, collecting a filter cake, and drying at 50-55 ℃ under reduced pressure to constant weight to obtain 68.0g of L-malic acid for injection with the yield of 68%.
The impurity content of the sample before and after purification was measured by HPLC, and the results are shown in Table 4.
Table 4 example 3 HPLC assay results before and after sample purification
| Impurities | Succinic acid | Fumaric acid | Maleic acid | Unknown A | Unknown B |
| Sample (I) | 0.38 | 0.02 | Not detected out | 0.28 | 0.11 |
| After refining | 0.11 | Not detected out | Not detected out | 0.08 | 0.05 |
Example 4
Adding 200g of purified water into a single-neck bottle, adding a 100g L-malic acid sample under stirring, continuously stirring until the solution is clear, adding 200g of ethyl acetate for extraction, continuously extracting for 3 times, filtering the water phase, carrying out reduced pressure distillation at 60-63 ℃, adding 50g of ethyl acetate when no fraction is generated basically, and taking out residual water to obtain a solid.
The resulting solid was dried at 50-55 ℃ under reduced pressure to constant weight, yielding 76.0 g. Adding 152g of ethyl acetate and 7.6g of purified water, stirring for 6 hours, filtering, collecting a filter cake, and drying at 50-55 ℃ under reduced pressure to constant weight to obtain 30.0g of L-malic acid for injection with the yield of 30%.
The impurity content of the sample before and after purification was measured by HPLC, and the results are shown in Table 5.
TABLE 5 example 4 HPLC TEST RESULTS FROM AND FROM SAMPLE REFINING
| Impurities | Succinic acid | Fumaric acid | Maleic acid | Unknown A | Unknown B |
| Sample (I) | 0.38 | 0.02 | Not detected out | 0.28 | 0.11 |
| After refining | 0.03 | Not detected out | Not detected out | 0.04 | 0.03 |
Example 5
Adding 20kg of purified water into a reaction kettle, adding 10kg of L-malic acid sample under stirring, continuously stirring until the L-malic acid sample is dissolved, adding 20kg of ethyl acetate for extraction, continuously extracting for 3 times, filtering a water phase, performing reduced pressure distillation at 60-63 ℃, adding 5kg of ethyl acetate when no fraction exists basically, and taking out residual water to obtain a solid.
The resulting solid was dried at 50-55 deg.C under reduced pressure to constant weight, yielding 8.2 kg. Adding 16.4kg of ethyl acetate and 410g of purified water, stirring for 6 hours, filtering, collecting a filter cake, and drying at 50-55 ℃ under reduced pressure to constant weight to obtain 6.6kg of L-malic acid for injection with the yield of 66%.
The impurity content of the sample before and after purification was measured by HPLC, and the results are shown in Table 7.
TABLE 6 HPLC TEST RESULTS FROM AND AFTER REFINING SAMPLE OF EXAMPLE 5
| Impurities | Succinic acid | Fumaric acid | Maleic acid | Unknown A | Unknown B |
| Sample (I) | 0.38 | 0.02 | Not detected out | 0.28 | 0.11 |
| After refining | 0.04 | Not detected out | Not detected out | 0.05 | 0.04 |
Claims (8)
1. A refining and purifying method of L-malic acid for injection is characterized by comprising the following steps:
(1) dissolving a sample: dissolving an L-malic acid sample to be purified into purified water, and stirring to completely dissolve;
(2) and (3) extraction: adding an organic solvent, stirring, standing and separating liquid;
(3) and (3) continuously extracting: continuously adding the organic solvent into the water phase for extraction, and repeating the step (2) until the succinic acid, the maleic acid and the fumaric acid meet the quality standard;
(4) and (3) reduced pressure distillation: after filtering the water phase, distilling under reduced pressure to remove water, and adding a corresponding organic solvent to carry out residual water to obtain a solid;
(5) and (3) finally refining: and (4) adding the solid obtained in the step (4) into ethyl acetate, adding purified water, stirring, filtering, and drying a filter cake to obtain the L-malic acid for injection.
2. The method according to claim 1, wherein the organic solvent in step (1) is ethyl acetate.
3. The method of claim 1, wherein the amount of the organic solvent used in each of the extraction steps (2) and (3) is 1 to 5 times the weight of the sample.
4. The method of claim 3, wherein the amount of organic solvent used in each of the extractions of steps (2) and (3) is 2 times the weight of the sample.
5. The method according to claim 1, wherein the amount of ethyl acetate used in step (5) is 1 to 5 times the weight of the solid obtained in step (4).
6. The process according to claim 5, wherein the amount of ethyl acetate used in step (5) is 2 times the weight of the solid obtained in step (4).
7. The method according to claim 1, wherein the purified water used in step (5) is 1-5% by weight of ethyl acetate.
8. The method according to claim 5, wherein the amount of the purified water used in step (5) is 2 to 2.5% by weight based on ethyl acetate.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106045848A (en) * | 2016-05-26 | 2016-10-26 | 河南精康制药有限公司 | Method for preparing medicinal-level L-malic acid |
| CN106220493A (en) * | 2016-07-22 | 2016-12-14 | 南京正大天晴制药有限公司 | A kind of process for purification of L malic acid |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106045848A (en) * | 2016-05-26 | 2016-10-26 | 河南精康制药有限公司 | Method for preparing medicinal-level L-malic acid |
| CN106220493A (en) * | 2016-07-22 | 2016-12-14 | 南京正大天晴制药有限公司 | A kind of process for purification of L malic acid |
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