CN115974679A - Preparation method of alpha-ketoglutarate calcium salt - Google Patents
Preparation method of alpha-ketoglutarate calcium salt Download PDFInfo
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- CN115974679A CN115974679A CN202211640462.0A CN202211640462A CN115974679A CN 115974679 A CN115974679 A CN 115974679A CN 202211640462 A CN202211640462 A CN 202211640462A CN 115974679 A CN115974679 A CN 115974679A
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- Prior art keywords
- alpha
- calcium salt
- ketoglutarate
- preparation
- ketoglutaric acid
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- LADYPAWUSNPKJF-UHFFFAOYSA-L calcium;2-oxopentanedioate Chemical compound [Ca+2].[O-]C(=O)CCC(=O)C([O-])=O LADYPAWUSNPKJF-UHFFFAOYSA-L 0.000 title claims abstract description 24
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- KPGXRSRHYNQIFN-UHFFFAOYSA-N 2-oxoglutaric acid Chemical compound OC(=O)CCC(=O)C(O)=O KPGXRSRHYNQIFN-UHFFFAOYSA-N 0.000 claims abstract description 29
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims abstract description 16
- 238000003756 stirring Methods 0.000 claims abstract description 15
- 239000001110 calcium chloride Substances 0.000 claims abstract description 13
- 229910001628 calcium chloride Inorganic materials 0.000 claims abstract description 13
- 238000000034 method Methods 0.000 claims abstract description 13
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims abstract description 12
- HWXBTNAVRSUOJR-UHFFFAOYSA-N alpha-hydroxyglutaric acid Natural products OC(=O)C(O)CCC(O)=O HWXBTNAVRSUOJR-UHFFFAOYSA-N 0.000 claims abstract description 12
- 229940009533 alpha-ketoglutaric acid Drugs 0.000 claims abstract description 12
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims abstract description 8
- 235000011114 ammonium hydroxide Nutrition 0.000 claims abstract description 8
- 150000007529 inorganic bases Chemical class 0.000 claims abstract description 7
- 239000001569 carbon dioxide Substances 0.000 claims abstract description 6
- 229910002092 carbon dioxide Inorganic materials 0.000 claims abstract description 6
- 239000011259 mixed solution Substances 0.000 claims abstract description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 10
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 239000008367 deionised water Substances 0.000 claims description 5
- 229910021641 deionized water Inorganic materials 0.000 claims description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 5
- 238000005406 washing Methods 0.000 claims description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- 239000000843 powder Substances 0.000 claims description 2
- 239000000047 product Substances 0.000 abstract description 13
- 239000012535 impurity Substances 0.000 abstract description 9
- 238000006386 neutralization reaction Methods 0.000 abstract description 4
- 239000012467 final product Substances 0.000 abstract description 3
- 239000003513 alkali Substances 0.000 abstract description 2
- 238000005516 engineering process Methods 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 11
- 238000006243 chemical reaction Methods 0.000 description 9
- 238000001914 filtration Methods 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- 239000012295 chemical reaction liquid Substances 0.000 description 6
- 239000003651 drinking water Substances 0.000 description 6
- 235000020188 drinking water Nutrition 0.000 description 6
- 239000012065 filter cake Substances 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- KPGXRSRHYNQIFN-UHFFFAOYSA-L 2-oxoglutarate(2-) Chemical compound [O-]C(=O)CCC(=O)C([O-])=O KPGXRSRHYNQIFN-UHFFFAOYSA-L 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- VWPLIFKKLCVFCQ-UHFFFAOYSA-L calcium;2-oxopentanedioate;hydrate Chemical compound O.[Ca+2].[O-]C(=O)CCC(=O)C([O-])=O VWPLIFKKLCVFCQ-UHFFFAOYSA-L 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 230000001376 precipitating effect Effects 0.000 description 3
- 238000009849 vacuum degassing Methods 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 description 2
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 2
- 239000000920 calcium hydroxide Substances 0.000 description 2
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 2
- 159000000007 calcium salts Chemical class 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000002585 base Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 208000029039 cyanide poisoning Diseases 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- YBGBJYVHJTVUSL-UHFFFAOYSA-L disodium;2-oxopentanedioate Chemical compound [Na+].[Na+].[O-]C(=O)CCC(=O)C([O-])=O YBGBJYVHJTVUSL-UHFFFAOYSA-L 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000003859 lipid peroxidation Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of alpha-ketoglutarate calcium salt, relates to the biomedical technology, and aims to solve the problems that the existing preparation method of alpha-ketoglutarate calcium salt is unstable and easily produces impurities in the preparation process to influence the purity of the finished product of alpha-ketoglutarate calcium salt, and the technical scheme has the following key points: adopting low-concentration inorganic base and alpha-ketoglutaric acid to stir and neutralize step by step until the PH value is 5-6 to obtain a mixed solution, then gradually adding ammonia water to adjust the PH value of the mixed solution to 7-7.5 after carbon dioxide is exhausted in a reduced pressure concentration mode, and finally adding calcium chloride to obtain alpha-ketoglutaric acid calcium salt. The invention adopts weaker alkali to neutralize ketoglutaric acid, basically no new impurities are generated in the neutralization process, the purity of the final product reaches more than 99.5 percent, the product quality is ensured, and the preparation is convenient and the cost is low.
Description
Technical Field
The invention relates to a biological medicine technology, in particular to a preparation method of alpha-ketoglutarate calcium salt.
Background
The alpha-ketoglutarate calcium has the physiological functions of reducing the level of lung-formed ammonia, detoxifying common ammonia, protecting lipid peroxidation, protecting nerves from cyanide poisoning and the like.
The preparation of alpha-ketoglutarate calcium salt generally adopts sodium hydroxide to neutralize ketoglutarate to neutrality to form ketoglutarate disodium salt, and then adds calcium chloride to generate alpha-ketoglutarate calcium salt precipitate. The method has the disadvantages that ketoglutaric acid is unstable in the neutralization process, new impurities are easily generated, and calcium salt precipitates can be generated from the impurities, so that the quality of the product is influenced finally.
In addition, calcium hydroxide or calcium carbonate is used for directly neutralizing ketoglutaric acid to generate alpha-ketoglutaric acid calcium salt, but the method is easy to leave calcium hydroxide or calcium carbonate in the product, and the product quality is directly influenced.
Therefore, a new solution is needed to solve this problem.
Disclosure of Invention
Aiming at the defects in the prior art, the invention aims to provide a preparation method of alpha-ketoglutarate calcium salt.
The technical purpose of the invention is realized by the following technical scheme: a preparation method of alpha-ketoglutarate calcium salt comprises the following preparation steps: adopting low-concentration inorganic base and alpha-ketoglutaric acid to stir and neutralize step by step until the PH value is 5-6 to obtain a mixed solution, then gradually adding ammonia water to adjust the PH value of the mixed solution to 7-7.5 after carbon dioxide is exhausted in a reduced pressure concentration mode, and finally adding calcium chloride to obtain calcium alpha-ketoglutarate
The invention is further configured to: the inorganic base comprises sodium bicarbonate or sodium carbonate, and the sodium bicarbonate or the sodium carbonate are anhydrous powder.
The invention is further configured to: the weight ratio of the inorganic base to the alpha-ketoglutaric acid is (0.6-1.2): 1.
The invention is further configured to: the molar ratio of the calcium chloride to the alpha-ketoglutaric acid is (1.15-1.25): 1.
The invention is further configured to: the concentration of the ammonia water is 18-22%.
The invention is further configured to: and washing the calcium chloride with deionized water after adding the calcium chloride to obtain the alpha-ketoglutarate calcium salt.
In conclusion, the invention has the following beneficial effects:
by adopting weaker alkali to neutralize ketoglutaric acid, new impurities are basically not generated in the neutralization process, the purity of the final product reaches more than 99.5 percent, the product quality is ensured, and the preparation is convenient and the cost is low.
Drawings
FIG. 1 shows the HPLC detection results of the product prepared in the first example;
FIG. 2 shows the HPLC detection results of the product prepared in example two;
FIG. 3 shows the HPLC detection results of the product prepared in example III;
Detailed Description
The present invention will be described in detail with reference to examples.
The first embodiment is as follows: a preparation method of alpha-ketoglutaric acid calcium salt comprises adding 100g alpha-ketoglutaric acid into 500mL three-neck flask containing 150mL drinking water, stirring (solid will not be dissolved completely immediately), adding 110g solid sodium bicarbonate in batches, generating bubbles, and adjusting pH to 5.5; after the addition, the vacuum degassing is carried out in a water bath at 60 ℃, carbon dioxide gas is completely removed, specifically, no bubbles are generated and remained in a three-mouth beaker, the normal pressure is recovered, the temperature is cooled to about 25 ℃, the pH value is adjusted to 7.2 by using 20% ammonia water, and finally, the filtration is carried out to remove mechanical impurities, so as to obtain a reaction solution I. Pouring the reaction solution into a clean 500mL three-neck flask for later use.
Adding 91g of anhydrous calcium chloride into a 500mL beaker filled with 200mL of drinking water, stirring to dissolve, and filtering to obtain a second reaction solution for later use.
Under the condition of stirring, adding the prepared reaction liquid II into the reaction liquid I at a constant speed, wherein the molar ratio of calcium chloride to alpha-ketoglutaric acid is 1.21; precipitating, stirring, cooling to about 5 deg.C, and crystallizing at the temperature for more than 2 hr. Filtering to obtain filter cake, washing the filter cake with deionized water three times, drying at 60-70 deg.C for more than 6 hr to obtain 130g of alpha-ketoglutarate calcium salt monohydrate, and detecting by HPLC to obtain product with purity up to 99.6%.
Example two: a method for preparing calcium salt of alpha-ketoglutarate comprises adding 100g of alpha-ketoglutarate into 500mL three-neck flask containing 150mL of drinking water, stirring (solid will not be dissolved completely immediately), adding 64g of anhydrous sodium carbonate in batches, generating bubbles, and adjusting pH to 5; after the addition, the vacuum degassing is carried out in a water bath at 60 ℃, and after carbon dioxide gas is completely removed, the concrete expression is that no bubble is generated and remained in a three-mouth beaker, the normal pressure is recovered, the temperature is cooled to about 25 ℃, and the pH value is adjusted to 7 by using 18 percent ammonia water. Filtering and removing mechanical impurities to obtain a first reaction solution. Pouring the reaction solution into a clean 500mL three-neck flask for later use.
Adding 86.8g of anhydrous calcium chloride into a 500mL beaker filled with 200mL of drinking water, stirring to dissolve, and filtering to obtain a second reaction solution for later use.
Under the condition of stirring, adding the prepared reaction liquid II into the reaction liquid I at a constant speed, wherein the molar ratio of the calcium chloride to the alpha-ketoglutaric acid is 1.15; precipitating, stirring, cooling to about 5 deg.C, and crystallizing at the temperature for more than 2 hr. Filtering to obtain filter cake, washing the filter cake with deionized water for three times, drying at 60-70 deg.c for over 6 hr to obtain 125g of alpha-ketoglutarate calcium salt monohydrate, and HPLC detecting to obtain product with purity over 99.58%.
Example three: adding 100g of alpha-ketoglutaric acid into a 500mL three-neck flask filled with 150mL of drinking water, stirring (solid can not be completely dissolved immediately), then adding 100g of anhydrous sodium carbonate in batches, generating bubbles and keeping the pH value at 6; after the addition, the vacuum degassing is carried out in a water bath at 60 ℃, carbon dioxide gas is completely removed, and the concrete expression is that no bubble is generated and remained in a three-mouth beaker, the normal pressure is recovered, the temperature is cooled to about 25 ℃, the pH value is adjusted to 7.5 by 22 percent ammonia water, and the reaction solution I is obtained after filtration and mechanical impurities are removed. Pouring the reaction solution into a clean 500mL three-neck flask for later use.
Adding 94.5g of anhydrous calcium chloride into a 500mL beaker containing 200mL of drinking water, stirring to dissolve, and filtering to obtain a second reaction solution for later use.
Under the condition of stirring, adding the prepared reaction liquid II into the reaction liquid I at a constant speed, wherein the molar ratio of the calcium chloride to the alpha-ketoglutaric acid is 1.25; precipitating, stirring, cooling to about 5 deg.C, and crystallizing at the temperature for more than 2 hr. And (3) carrying out suction filtration, washing a filter cake for three times by using deionized water, drying for more than 6 hours at the temperature of between 60 and 70 ℃ to obtain 128g of alpha-ketoglutarate calcium salt monohydrate, and detecting the purity of the product by using HPLC (high performance liquid chromatography) to reach 99.52 percent.
As shown in fig. 1 to fig. 3, the HPLC detection results show that, in the process, ketoglutaric acid is neutralized by using weak base, new impurities are not generated substantially in the neutralization process, the purity of the final product reaches over 99.5%, the product quality is ensured, and the preparation is convenient and the cost is low.
The above description is only a preferred embodiment of the present invention, and the protection scope of the present invention is not limited to the above embodiments, and all technical solutions belonging to the idea of the present invention belong to the protection scope of the present invention. It should be noted that modifications and embellishments within the scope of the invention may occur to those skilled in the art without departing from the principle of the invention, and are considered to be within the scope of the invention.
Claims (6)
1. A preparation method of alpha-ketoglutarate calcium salt is characterized by comprising the following steps: the preparation method comprises the following steps: adopting low-concentration inorganic base and alpha-ketoglutaric acid to stir and neutralize step by step until the PH value is 5-6 to obtain a mixed solution, then gradually adding ammonia water to adjust the PH value of the mixed solution to 7-7.5 after carbon dioxide is exhausted in a reduced pressure concentration mode, and finally adding calcium chloride to obtain alpha-ketoglutaric acid calcium salt.
2. The method of producing α -ketoglutarate calcium salt according to claim 1, characterized in that: the inorganic base comprises sodium bicarbonate or sodium carbonate, and the sodium bicarbonate or the sodium carbonate are anhydrous powder.
3. The method of producing α -ketoglutarate calcium salt according to claim 1, characterized in that: the weight ratio of the inorganic base to the alpha-ketoglutaric acid is (0.6-1.2): 1.
4. The method of producing α -ketoglutarate calcium salt according to claim 1, characterized in that: the molar ratio of the calcium chloride to the alpha-ketoglutaric acid is (1.15-1.25): 1.
5. The method of producing α -ketoglutarate calcium salt according to claim 1, characterized in that: the concentration of the ammonia water is 18-22%.
6. The method of producing α -ketoglutarate calcium salt according to claim 1, characterized in that: and washing the calcium chloride with deionized water after adding the calcium chloride to obtain the alpha-ketoglutarate calcium salt.
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| CN202211640462.0A CN115974679A (en) | 2022-12-20 | 2022-12-20 | Preparation method of alpha-ketoglutarate calcium salt |
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| CN202211640462.0A CN115974679A (en) | 2022-12-20 | 2022-12-20 | Preparation method of alpha-ketoglutarate calcium salt |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112955139A (en) * | 2018-09-25 | 2021-06-11 | 庞塞迪利昂健康特定活动公司 | Process for the preparation of calcium alpha-ketoglutarate |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112955139A (en) * | 2018-09-25 | 2021-06-11 | 庞塞迪利昂健康特定活动公司 | Process for the preparation of calcium alpha-ketoglutarate |
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