CN108017561B - Method for refining carglutamic acid - Google Patents
Method for refining carglutamic acid Download PDFInfo
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- CN108017561B CN108017561B CN201610973321.9A CN201610973321A CN108017561B CN 108017561 B CN108017561 B CN 108017561B CN 201610973321 A CN201610973321 A CN 201610973321A CN 108017561 B CN108017561 B CN 108017561B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C273/00—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C273/18—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas
- C07C273/189—Purification, separation, stabilisation, use of additives
Abstract
The invention relates to a method for refining carglutamic acid. The method comprises the following steps: (1-1) reacting the crude carlstragic acid with alkali in an alcohol solvent containing 1 to 5 carbon atoms to obtain carlstragic acid salt; (2-1) reacting the carglumate obtained in the step (1) with acid to obtain the carglumate again. The problem of low product purity in the traditional process is solved, and the product quality of the carglutamic acid is improved; the content of the product refined by the method can reach more than 99.5 percent, and the impurities are less than 0.1 percent, thereby meeting the product quality of the raw material medicines.
Description
Technical Field
The invention relates to a method for refining carglutamic acid, in particular to a method for preparing the carglutamic acid again by further reacting with acid after a crude product reacts with alkali.
Background
It was reported that 42 children from 28 families were diagnosed with NAGS (N-acetylglutamate synthase) deficiency between 1980 and 2001, of which 8 died because they were not rescued in time. NAGS deficiency, a congenital urea cycle disorder, is a disease. Patients often have too high a blood ammonia concentration due to lack of NAGS, with the possibility of acute death. However, the NAGS deficiency disease is a rare disease, the treatment medicine is less, and the patient is difficult to be effectively cured.
Carglutamic acid, chemical name: N-carbamoyl-L-glutamic acid or (2S) -2- (carbamoylamino) glutaric acid, of formula: c6H10N2O5. The product is mainly used for treating acute or chronic hyperammonemia caused by liver N-acetylglutamate synthase (NAGS) deficiency of children and adultsAnd (4) symptoms. The action mechanism is that the carglumic acid is a synthetic compound with a structure similar to that of N-acetyl glutamic acid (NAG) and is an important allosteric activator for the synthesis of carbamoyl phosphate (CPS1) in liver mitochondria. Whereas CPS1 is the primary enzyme of the ornithine cycle that converts ammonia to urea. NAG is the product of the mitochondrial enzyme acetylglutamate synthase (NAGS). Therefore, carglumic acid replaces NAG in NAGS deficient patients by activating CPS 1. At present, the medicine is sold in the market abroad, and no company is produced at home. The structural formula of the carglutamic acid is:
the conventional process takes L-glutamic acid as a raw material, the L-glutamic acid reacts with potassium cyanate under an alkaline condition, and the obtained crude carglutamic acid product is refined by water to obtain a finished product, but the purity of the finished product obtained by the refining method is low, and particularly the maximum single impurity (single impurity) cannot meet the requirement of less than 0.1 percent, so the quality requirement of the raw material medicine cannot be met.
Disclosure of Invention
As is well known to those skilled in the art, the purity requirement of the target compound in the raw material drug is not only concerned with the total purity, but also the single impurity (single impurity) of the target compound in the raw material drug is below a certain limit, generally less than 0.1%; the traditional refining method can not make the maximum single impurity (single impurity) in the carglutamic acid less than 0.1 percent, so that the carglutamic acid finished product meeting the declared standard can not be obtained by utilizing the traditional method. The invention mainly improves the post-refining process of the carglutamic acid, solves the problem of low product purity in the traditional process, and particularly reduces the maximum single impurity content to a level below 0.1%, so that the quality of the raw material medicine can further declare related medicine products. Therefore, the purification method is fundamentally different from the conventional method, and thus has extremely important practical significance.
In addition, the raw material L-glutamic acid of the product is very cheap and has wide sources. The final product, namely, the carglutamic acid, is relatively high in price as a medicine, so that from the economic aspect, although the yield of the method is reduced compared with that of the traditional method, the purity of the target compound in the raw material medicine is improved by about 0.5%, and particularly the maximum single impurity content is reduced to a level less than 0.1%, so that the method is very necessary and worthy of comprehensive consideration for preparing the carglutamic acid with higher purity.
Specifically, the present invention provides a method for refining carminic acid, which comprises the steps of:
(1-1) reacting the crude carlstragic acid with alkali in an alcohol solvent containing 1 to 5 carbon atoms to obtain carlstragic acid salt;
(2-1) reacting the carglumate obtained in the step (1-1) with acid to obtain the carglumate again.
The alcohol having 1 to 5 carbon atoms means that the number of carbon atoms in the alcohol molecule is 1 to 5 (may be abbreviated as C)1-C5Alcohol (c) of (a).
In a specific embodiment, the carglutaminate is a water soluble carglutaminate.
In one embodiment, the alcohol solvent containing 1 to 5 carbon atoms is selected from at least one of methanol, ethanol, isopropanol and n-propanol.
In one embodiment, the base is selected from at least one of sodium hydroxide, potassium hydroxide, ammonia, lithium hydroxide, magnesium hydroxide, and calcium hydroxide.
In a specific embodiment, the acid is selected from at least one of hydrochloric acid, sulfuric acid, acetic acid, hydrobromic acid, phosphoric acid, and carbonic acid. Among them, it is understood by those skilled in the art that the salt formed in step (2-1) should be water-soluble, such as sodium chloride, potassium chloride, ammonium chloride, magnesium chloride, calcium chloride, sodium sulfate, potassium sulfate, ammonium sulfate, magnesium sulfate, calcium sulfate, sodium acetate, potassium acetate, ammonium acetate, sodium bromide, potassium bromide, ammonium bromide, sodium phosphate, potassium phosphate, and ammonium phosphate, etc. Otherwise, if the salt formed in this step is water-insoluble, it will not be conducive to subsequent purification by crystallization of carglutamic acid.
In a preferred embodiment, the acid is selected from at least one of hydrochloric acid, sulfuric acid and acetic acid.
In one embodiment, in the step (1-1), the reaction is carried out at a temperature of 30 to 50 ℃ for 10 minutes to 3 hours.
In a preferred embodiment, in the step (1-1), the reaction is carried out at a temperature of 35 ℃ to 45 ℃ for 20 minutes to 1 hour.
In one embodiment, after the step (1-1) and before the step (2-1), the method further comprises the step (1-2) of adjusting the reaction solution in the step (1) to 5 ℃ to 30 ℃, and crystallizing for 2 hours to 30 hours.
In a preferred embodiment, in step (1-2) after step (1-1) and before step (2-1), the reaction liquid in step (1) is adjusted to 10 ℃ to 25 ℃ and crystallized for 10 hours to 20 hours.
In a specific embodiment, after the step (2-1), the method further comprises a step (2-2) of adjusting the reaction solution in the step (2) to 0 ℃ to 20 ℃, and crystallizing for 2 hours to 30 hours.
In a preferred embodiment, in the step (2-2) subsequent to the step (2-1), the reaction liquid in the step (2) is adjusted to 0 ℃ to 10 ℃ and crystallized for 10 hours to 20 hours.
In one embodiment, the molar ratio of the crude carglutamic acid to the base is less than 1: 1; preferably, the molar ratio of the crude carglutamic acid to the base is 1:2 to 1: 4.
In one embodiment, the molar ratio of the crude carglutamic acid to the acid is less than 1: 1; preferably, the molar ratio of the crude carglutamic acid to the acid is 1:2 to 1: 4.
In one embodiment, the concentration of carglumate is from 10 wt% to 20 wt%.
In one embodiment, the concentration of the crude carglutamic acid in the alcoholic solvent is from 10% (wt/v) to 30% (wt/v).
In one embodiment, the concentration of the crude carglutamic acid in the alcoholic solvent is from 10% (wt/v) to 20% (wt/v).
In one embodiment, the concentration of the crude carglutamic acid in the alcoholic solvent is from 20% (wt/v) to 25% (wt/v).
In one embodiment, the method further comprises a final step of drying the recovered carglutamic acid; the recovered carglutamic acid is preferably dried at 20 ℃ to 40 ℃.
Detailed Description
The present invention will be described in detail with reference to examples, but the present invention is not limited to these examples.
The raw materials in the examples of the present invention were all purchased from commercial sources unless otherwise specified. The crude carglutamic acid used in the present invention can be obtained by conventional processes or by purchase, for example, by reacting L-glutamic acid as a raw material with potassium cyanate under alkaline conditions.
The method for refining the carglutamic acid comprises the following steps:
(1) dissolving a carglumic acid crude product (wherein the carglumic acid is a compound shown in a formula 1) in a proper alcohol solvent, and adding a proper base (AOH, wherein A is cation) to react to obtain a compound 2.
(2) Reacting compound 2 with a suitable acid to obtain a refined carglumic acid.
Wherein: the alcohol solvent used in step 1 can be methanol, ethanol, isopropanol or n-propanol, and the alkali used can be sodium hydroxide, potassium hydroxide or ammonia water.
The acid used in step 2 may be hydrochloric acid, sulfuric acid and acetic acid.
The purity of the carglutamic acid was checked by HPLC method.
The yield of the carglumic acid is equal to the yield of fine carglumic acid/crude carglumic acid multiplied by 100 percent
Example 1
1.47kg of crude carglumic acid was mixed with 5L of ethanol in a 10L three-necked flask, stirred and warmed to 35 ℃ and a solution prepared from 800g of sodium hydroxide and 3200g of purified water was added thereto. After the addition, the reaction solution was stirred to clarify. Stirring at 35 deg.C for 0.5h, cooling to 15 deg.C, and crystallizing for 10 h. Suction filtration to dryness and drying gave 700g of carminic acid sodium salt. Mixing the above ammonium salt with 6L purified water, adding into 10L three-necked flask, stirring, dissolving, adjusting pH to 1-2 with acid, cooling to 0 deg.C, and crystallizing for 10 h. After crystallization, filtering to dry, and drying at 30 ℃ to obtain 370g of fine carglumic acid product with the purity of 99.8 percent and the maximum single impurity of less than 0.1 percent; the product yield was 25.2%.
Example 2
4.8kg of carglumic acid crude product and 20.4L of ethanol are mixed in a 50L reaction kettle, stirred and heated to 45 ℃, and 13.7kg of strong ammonia water is dripped into the mixture. After the addition, 1.1kg of purified water was continuously added, and the reaction solution was clarified. Stirring at 45 deg.C for 0.5h, cooling to 25 deg.C, and crystallizing for 20 h. Suction filtration to dryness and drying to obtain 2.3kg of ammonium carvoglutamate. Mixing the ammonium salt with 19L of purified water, stirring and dissolving the mixture in a 50L reaction kettle, adjusting the pH value to 1-2 by using acid, cooling to 10 ℃, and crystallizing for 20 hours. Centrifuging and drying at 30 ℃ after crystallization is finished to obtain 1.4kg of fine carglumic acid product with the product content of 99.7 percent and the maximum single impurity content of less than 0.1 percent; the product yield was 29.2%.
Example 3
4.8kg of carglumic acid crude product and 20.4L of ethanol are mixed in a 50L reaction kettle, stirred and heated to 30 ℃, and 13.7kg of strong ammonia water is dripped into the mixture. After the addition, 1.1kg of purified water was continuously added, and the reaction solution was clarified. Stirring at 30 deg.C for 1 hr, cooling to 5 deg.C, and crystallizing for 10 hr. Suction filtration to dryness and drying to obtain 2.3kg of ammonium carvoglutamate. Mixing the ammonium salt with 19L of purified water, stirring and dissolving the mixture in a 50L reaction kettle, adjusting the pH value to 1-2 by using acid, cooling to 0 ℃, and crystallizing for 20 hours. Centrifuging and drying at 30 ℃ after crystallization is finished to obtain 1.24kg of fine carglumic acid product with the product content of 99.8 percent and the maximum single impurity content of less than 0.1 percent; the product yield was 25.8%.
Example 4
4.8kg of carglumic acid crude product and 20.4L of ethanol are mixed in a 50L reaction kettle, stirred and heated to 50 ℃, and 13.7kg of strong ammonia water is dripped into the mixture. After the addition, 1.1kg of purified water was continuously added, and the reaction solution was clarified. Stirring at 50 deg.C for 0.5h, cooling to 30 deg.C, and crystallizing for 30 h. Suction filtration to dryness and drying to obtain 2.3kg of ammonium carvoglutamate. Mixing the ammonium salt with 19L of purified water, stirring and dissolving the mixture in a 50L reaction kettle, adjusting the pH value to 1-2 by using acid, cooling to 10 ℃, and crystallizing for 20 hours. Centrifuging and drying at 30 ℃ after crystallization is finished to obtain 1.32kg of fine carglumic acid product with the product content of 99.7 percent and the maximum single impurity content of less than 0.1 percent; the product yield was 27.5%.
Example 5
4.8kg of carglumic acid crude product and 20.4L of ethanol are mixed in a 50L reaction kettle, stirred and heated to 50 ℃, and 13.7kg of strong ammonia water is dripped into the mixture. After the addition, 1.1kg of purified water was continuously added, and the reaction solution was clarified. Stirring at 50 deg.C for 10 min, cooling to 30 deg.C, and crystallizing for 30 hr. Suction filtration to dryness and drying to obtain 2.3kg of ammonium carvoglutamate. Mixing the ammonium salt with 19L of purified water, stirring and dissolving the mixture in a 50L reaction kettle, adjusting the pH value to 1-2 by using acid, cooling to 20 ℃, and crystallizing for 30 hours. After crystallization, centrifugally drying, and drying at 30 ℃ to obtain 1.36kg of a fine carglutamic acid product with the product content of 99.7 percent and the maximum single impurity content of less than 0.1 percent; the product yield was 28.3%.
Example 6
4.8kg of carglumic acid crude product and 20.4L of ethanol are mixed in a 50L reaction kettle, stirred and heated to 50 ℃, and 13.7kg of strong ammonia water is dripped into the mixture. After the addition, 1.1kg of purified water was continuously added, and the reaction solution was clarified. Stirring at 50 deg.C for 10 min, cooling to 10 deg.C, and crystallizing for 2 hr. Suction filtration to dryness and drying to obtain 2.3kg of ammonium carvoglutamate. Mixing the ammonium salt with 19L of purified water, stirring and dissolving the mixture in a 50L reaction kettle, adjusting the pH value to 1-2 by using acid, cooling to 0 ℃, and crystallizing for 10 hours. Centrifuging and drying at 30 ℃ after crystallization is finished to obtain 1.38kg of fine carglumic acid product with the product content of 99.7 percent and the maximum single impurity content of less than 0.1 percent; the product yield was 28.8%.
Example 7
4.8kg of carglumic acid crude product and 20.4L of ethanol are mixed in a 50L reaction kettle, stirred and heated to 45 ℃, and 13.7kg of strong ammonia water is dripped into the mixture. After the addition, 1.1kg of purified water was continuously added, and the reaction solution was clarified. Stirring at 50 deg.C for 3 hr, cooling to 10 deg.C, and crystallizing for 2 hr. Suction filtration to dryness and drying to obtain 2.3kg of ammonium carvoglutamate. Mixing the ammonium salt with 19L of purified water, stirring and dissolving the mixture in a 50L reaction kettle, adjusting the pH value to 1-2 by using acid, cooling to 0 ℃, and crystallizing for 2 hours. After crystallization, centrifugally drying, and drying at 30 ℃ to obtain 1.33kg of a fine carglutamic acid product with the product content of 99.7 percent and the maximum single impurity content of less than 0.1 percent; the product yield was 27.7%.
Comparative example 1
4.8kg of crude carglumic acid and 62.4kg of purified water are mixed in a 100L reaction kettle, stirred and heated to 60 ℃, and stirred until the carglumic acid is dissolved clearly. After dissolution, the mixture is continuously stirred and cooled to 15-25 ℃, stirred and crystallized for 6 hours at the temperature of 15-25 ℃, discharged, centrifugally dried and dried at the temperature of 40 ℃, and thus 2.6kg of refined carglutamic acid with the product content of 99.3 percent, the maximum single impurity content of more than 0.1 percent and the product yield of 54.2 percent are obtained.
The above description is only for the purpose of illustrating the present invention and is not intended to limit the present invention in any way, and the present invention is not limited to the above description, but rather should be construed as being limited to the scope of the present invention.
Claims (7)
1. A method for refining carglutamic acid, comprising the steps of: mixing 1.47kg of carglumic acid crude product with 5L of ethanol in a 10L three-necked bottle, stirring, heating to 35 ℃, and adding a solution prepared from 800g of sodium hydroxide and 3200g of purified water; after the addition, stirring to clarify the reaction solution; then stirring for 0.5h at the temperature of 35 ℃, cooling to 15 ℃, and crystallizing for 10 h; filtering to dry, and drying to obtain 700g of carvone monosodium glutamate; mixing the sodium salt and 6L of purified water in a 10L three-necked bottle, stirring for dissolving, adjusting the pH to be 1-2 by using acid, cooling to 0 ℃, and crystallizing for 10 hours; after crystallization, the mixture is filtered to be dry, and dried at 30 ℃ to obtain 370g of refined carglutamic acid.
2. A method for refining carglutamic acid, comprising the steps of:
mixing 4.8kg of carglumic acid crude product with 20.4L of ethanol in a 50L reaction kettle, stirring, heating to 45 ℃, and dropwise adding 13.7kg of strong ammonia water into the mixture; after the addition, 1.1kg of purified water is continuously added, and the reaction solution is clarified; stirring at 45 deg.C for 0.5h, cooling to 25 deg.C, and crystallizing for 20 h; filtering to dry, and drying to obtain 2.3kg of ammonium carglutaminate; mixing the ammonium salt and 19L of purified water in a 50L reaction kettle, stirring for dissolving, adjusting the pH to be 1-2 by using acid, cooling to 10 ℃, and crystallizing for 20 hours; and (4) after crystallization, centrifugally drying, and drying at 30 ℃ to obtain 1.4kg of a fine carglutamic acid product.
3. A method for refining carglutamic acid, comprising the steps of:
mixing 4.8kg of carglumic acid crude product with 20.4L of ethanol in a 50L reaction kettle, stirring, heating to 30 ℃, and dropwise adding 13.7kg of strong ammonia water into the mixture; after the addition, 1.1kg of purified water is continuously added, and the reaction solution is clarified; then stirring for 1h at the temperature of 30 ℃, cooling to 5 ℃, and crystallizing for 10 h; filtering to dry, and drying to obtain 2.3kg of ammonium carglutaminate; mixing the ammonium salt and 19L of purified water in a 50L reaction kettle, stirring for dissolving, adjusting the pH to be =1-2 by using acid, cooling to 0 ℃, and crystallizing for 20 hours; and (4) after crystallization, centrifugally drying, and drying at 30 ℃ to obtain 1.24kg of a fine carglutamic acid product.
4. A method for refining carglutamic acid, comprising the steps of:
mixing 4.8kg of carglumic acid crude product with 20.4L of ethanol in a 50L reaction kettle, stirring, heating to 50 ℃, and dropwise adding 13.7kg of strong ammonia water into the mixture; after the addition, 1.1kg of purified water is continuously added, and the reaction solution is clarified; stirring at 50 deg.C for 0.5h, cooling to 30 deg.C, and crystallizing for 30 h; filtering to dry, and drying to obtain 2.3kg of ammonium carglutaminate; mixing the ammonium salt and 19L of purified water in a 50L reaction kettle, stirring for dissolving, adjusting the pH to be 1-2 by using acid, cooling to 10 ℃, and crystallizing for 20 hours; and (4) after crystallization, centrifugally drying, and drying at 30 ℃ to obtain 1.32kg of a fine carglutamic acid product.
5. A method for refining carglutamic acid, comprising the steps of:
mixing 4.8kg of carglumic acid crude product with 20.4L of ethanol in a 50L reaction kettle, stirring, heating to 50 ℃, and dropwise adding 13.7kg of strong ammonia water into the mixture; after the addition, 1.1kg of purified water is continuously added, and the reaction solution is clarified; then stirring for 10 minutes at the temperature of 50 ℃, cooling to 30 ℃, and crystallizing for 30 hours; filtering to dry, and drying to obtain 2.3kg of ammonium carglutaminate; mixing the ammonium salt and 19L of purified water in a 50L reaction kettle, stirring for dissolving, adjusting the pH =1-2 with acid, cooling to 20 ℃, and crystallizing for 30 h; and (4) after crystallization, centrifugally drying, and drying at 30 ℃ to obtain 1.36kg of a fine carglutamic acid product.
6. A method for refining carglutamic acid, comprising the steps of:
mixing 4.8kg of carglumic acid crude product with 20.4L of ethanol in a 50L reaction kettle, stirring, heating to 50 ℃, and dropwise adding 13.7kg of strong ammonia water into the mixture; after the addition, 1.1kg of purified water is continuously added, and the reaction solution is clarified; then stirring for 10 minutes at the temperature of 50 ℃, cooling to 10 ℃ and crystallizing for 2 hours; filtering to dry, and drying to obtain 2.3kg of ammonium carglutaminate; mixing the ammonium salt and 19L of purified water in a 50L reaction kettle, stirring for dissolving, adjusting the pH to be 1-2 by using acid, cooling to 0 ℃, and crystallizing for 10 hours; and (4) after crystallization, centrifugally drying, and drying at 30 ℃ to obtain 1.38kg of a fine carglutamic acid product.
7. A method for refining carglutamic acid, comprising the steps of:
mixing 4.8kg of carglumic acid crude product with 20.4L of ethanol in a 50L reaction kettle, stirring, heating to 45 ℃, and dropwise adding 13.7kg of strong ammonia water into the mixture; after the addition, 1.1kg of purified water is continuously added, and the reaction solution is clarified; then stirring for 3 hours at the temperature of 50 ℃, cooling to 10 ℃ and crystallizing for 2 hours; filtering to dry, and drying to obtain 2.3kg of ammonium carglutaminate; mixing the ammonium salt and 19L of purified water in a 50L reaction kettle, stirring for dissolving, adjusting the pH to be =1-2 by using acid, cooling to 0 ℃, and crystallizing for 2 hours; and (4) after crystallization, centrifugally drying, and drying at 30 ℃ to obtain 1.33kg of a fine carglutamic acid product.
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| CN112028794B (en) * | 2019-06-03 | 2023-07-14 | 武汉武药科技有限公司 | High-purity carboglutamic acid and preparation method thereof |
| CZ308924B6 (en) * | 2020-02-26 | 2021-09-08 | Scale Up Laboratory s.r.o. | Process for purifying carglumic acid and semi-product of this process |
| CN116808013A (en) * | 2020-11-23 | 2023-09-29 | 武汉武药科技有限公司 | Bulk pharmaceutical chemical of carglutamic acid, solid preparation of carglutamic acid and preparation method thereof |
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