CN117343097A - Method for purifying amifostine crude product - Google Patents
Method for purifying amifostine crude product Download PDFInfo
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- CN117343097A CN117343097A CN202210746121.5A CN202210746121A CN117343097A CN 117343097 A CN117343097 A CN 117343097A CN 202210746121 A CN202210746121 A CN 202210746121A CN 117343097 A CN117343097 A CN 117343097A
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- amifostine
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- JKOQGQFVAUAYPM-UHFFFAOYSA-N amifostine Chemical compound NCCCNCCSP(O)(O)=O JKOQGQFVAUAYPM-UHFFFAOYSA-N 0.000 title claims abstract description 115
- 229960001097 amifostine Drugs 0.000 title claims abstract description 115
- 238000000034 method Methods 0.000 title claims abstract description 27
- 239000012043 crude product Substances 0.000 title claims description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 55
- 239000012535 impurity Substances 0.000 claims abstract description 54
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 53
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 49
- 238000001914 filtration Methods 0.000 claims abstract description 28
- 238000002156 mixing Methods 0.000 claims abstract description 22
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 17
- 239000000203 mixture Substances 0.000 claims abstract description 14
- 238000001035 drying Methods 0.000 claims abstract description 13
- 239000000047 product Substances 0.000 claims description 32
- 238000003756 stirring Methods 0.000 claims description 31
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 24
- 239000000706 filtrate Substances 0.000 claims description 16
- 239000007787 solid Substances 0.000 claims description 10
- 238000001816 cooling Methods 0.000 claims description 9
- 230000001376 precipitating effect Effects 0.000 claims description 9
- 238000004090 dissolution Methods 0.000 claims 1
- 239000002516 radical scavenger Substances 0.000 abstract description 8
- 230000000052 comparative effect Effects 0.000 description 7
- 238000010438 heat treatment Methods 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 1
- 238000009098 adjuvant therapy Methods 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 238000005054 agglomeration Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 230000001120 cytoprotective effect Effects 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000003672 processing method Methods 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/16—Esters of thiophosphoric acids or thiophosphorous acids
- C07F9/165—Esters of thiophosphoric acids
- C07F9/1651—Esters of thiophosphoric acids with hydroxyalkyl compounds with further substituents on alkyl
-
- 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
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a method for purifying a crude amifostine product, which comprises the steps of mixing and dissolving the crude amifostine product with water, then adding a impurity removing agent in batches for removing impurities, and then crystallizing, filtering and drying, wherein the impurity removing agent is a mixture of water and active carbon, and the ratio of the total feeding mass of the active carbon to the feeding mass of the crude amifostine product is (0.01-0.3): 1, a step of; the number of batches is at least two, the time interval between two adjacent times of adding the impurity removing agent is at least 30min, and the mixed system is filtered before the next time of adding the impurity removing agent. According to the invention, the water scavenger is added into the crude amifostine water solution in batches, so that the purity of amifostine can be improved on the basis of not increasing the dosage of the water scavenger.
Description
Technical Field
The invention relates to a method for purifying a crude amifostine product.
Background
Amifostine (ALT), alias An Linting, is a white solid chemical. Amifostine is a normal cytoprotective agent, mainly used for the adjuvant treatment of various cancers, and can scavenge free radicals generated during radiation or drug chemotherapy, thereby protecting normal cells and not significantly affecting the therapeutic effect of the combined drugs. The higher the purity of amifostine, the better its stability and the less adverse side effects. The amifostine synthesized by the existing synthesis method has lower purity and needs to be purified.
Patent CN106674272a discloses a processing method for amifostine, which comprises the steps of dissolving amifostine raw material with water, adding a mixture of water and activated carbon to the solution at one time, crystallizing, filtering and drying to obtain amifostine. The method has simple steps and low cost, but the purity of the amifostine prepared by the method is still not high.
Disclosure of Invention
The invention aims to provide a method for purifying a crude amifostine product, so as to improve the purity of amifostine.
In order to achieve the above purpose, the invention adopts the following technical scheme:
the invention provides a method for purifying a crude amifostine product, which comprises the steps of mixing and dissolving the crude amifostine product with water, then adding a impurity remover in batches for removing impurities, and then crystallizing, filtering and drying, wherein the impurity remover is a mixture of water and active carbon, and the ratio of the total feeding mass of the active carbon to the feeding mass of the crude amifostine product is (0.01-0.3): 1, a step of; the number of times of batch is at least two, the time interval between two adjacent times of adding the impurity removing agent is at least 30min, and the mixed system is filtered before the next time of adding the impurity removing agent.
Preferably, the ratio of the total feeding mass of the activated carbon to the feeding mass of the crude amifostine product is (0.05-0.15): 1, e.g., 0.05:1, 0.06:1, 0.07:1, 0.08:1, 0.09:1, 0.10:1, 0.11:1, 0.12:1, 0.13:1, 0.14:1, etc.
Preferably, the batch times are two times, and in the impurity removing agent added for the first time, the feeding mass ratio of the activated carbon to the crude amifostine product is (0.01-0.1): 1, a step of; in the impurity removing agent added for the second time, the feeding mass ratio of the active carbon to the amifostine crude product is (0.01-0.2): 1.
further preferably, in the impurity removing agent added for the first time, the feeding mass ratio of the activated carbon to the crude amifostine product is (0.03-0.08): 1, e.g., 0.03:1, 0.04:1, 0.05:1, 0.06:1, 0.07:1, etc.
Further preferably, in the impurity removing agent added for the second time, the feeding mass ratio of the activated carbon to the crude amifostine product is (0.02-0.07): 1, e.g., 0.03:1, 0.04:1, 0.05:1, 0.06:1, 0.07:1, etc.
Preferably, in the impurity removing agent added for the first time, the feeding mass ratio of the water to the crude amifostine product is (0.1-0.5): 1, a step of; in the impurity removing agent added for the second time, the feeding mass ratio of the water to the crude amifostine product is (0.05-0.2): 1.
further preferably, in the impurity removing agent added for the first time, the feeding mass ratio of the water to the crude amifostine product is (0.2-0.4): 1, e.g., 0.2:1, 0.25:1, 0.3:1, 0.35:1, 0.4:1, etc.
Further preferably, in the impurity removing agent added for the second time, the feeding mass ratio of the water to the crude amifostine product is (0.1-0.2): 1, e.g., 0.1:1, 0.15:1, 0.2:1, etc.
Preferably, after adding the impurity removing agent, stirring the mixed system, controlling the stirring temperature to be 35-45 ℃, and stirring for more than or equal to 30min.
According to some preferred embodiments, the method comprises in particular the following steps: (1) Mixing and dissolving the crude amifostine product and the water at 35-45 ℃; (2) Adding part of impurity removing agent into the mixed system in the step (1), keeping the temperature of the mixed system unchanged, continuously stirring for at least 30min, and filtering, wherein the feeding mass ratio of the active carbon in the part of impurity removing agent to the amifostine crude product is (0.01-0.1): 1, the mass ratio of water in part of the impurity removing agent to the crude amifostine product is (0.1-0.5): 1, a step of; (3) Adding the rest of impurity removing agent into the filtrate in the step (2), keeping the temperature of the mixed system unchanged, continuously stirring for at least 30min, and filtering, wherein the feeding mass ratio of the active carbon in the rest of impurity removing agent to the amifostine crude product is (0.01-0.2): 1, the mass ratio of water in the rest impurity removing agent to the crude amifostine product is (0.05-0.2): 1, a step of; (4) And (3) adding ethanol into the filtrate obtained in the step (3), stirring at 45-55 ℃, cooling to 5-15 ℃, precipitating solid, filtering, and drying to obtain amifostine.
Further preferably, in the step (1), the feeding mass ratio of the crude amifostine to the water is 1: (1-3), such as 1:1, 1:1.5, 1:2, 1:2.5, etc.
Further preferably, the feeding mass ratio of the ethanol to the amifostine crude product is (3-8): 1, e.g., 3:1, 4:1, 5:1, 6:1, 7:1, etc.
Due to the application of the technical scheme, compared with the prior art, the invention has the following advantages:
according to the invention, the water scavenger is added into the crude amifostine water solution in batches, so that the purity of amifostine can be improved on the basis of not increasing the dosage of the water scavenger.
Detailed Description
The present inventors have unexpectedly found that by adding a water scavenger to a crude aqueous solution of amifostine in batches, the purity of amifostine is improved compared to a single addition of the water scavenger. The schemes of the present application are discussed further below.
According to some specific and preferred embodiments, a process for purifying crude amifostine comprises the steps of:
(1) Mixing and dissolving the crude amifostine product and water at 35-45 ℃, wherein the feeding mass ratio of the crude amifostine product to the water is 1: (1-3);
(2) Adding part of the impurity removing agent into the mixed system in the step (1), keeping the temperature of the mixed system unchanged, continuously stirring for at least 30min, and filtering, wherein the feeding mass ratio of the active carbon in the part of the impurity removing agent to the crude amifostine product is (0.03-0.08): 1, the feeding mass ratio of water in part of the impurity removing agent to the crude amifostine product is (0.2-0.4): 1, a step of;
(3) Adding the rest of impurity removing agent into the filtrate in the step (2), keeping the temperature of the mixed system unchanged, continuously stirring for at least 30min, and filtering, wherein the feeding mass ratio of the activated carbon in the rest of impurity removing agent to the amifostine crude product is (0.02-0.07): 1, the mass ratio of water in the rest impurity removing agent to the crude amifostine product is (0.1-0.2): 1, a step of;
(4) Adding ethanol into the filtrate obtained in the step (3), stirring at 45-55 ℃, cooling to 5-15 ℃, precipitating solid, filtering, and drying to obtain amifostine; wherein, the feeding mass ratio of the ethanol to the amifostine crude product is (3-8): 1.
the scheme of the invention has at least the following advantages:
(1) According to the invention, the water scavenger is added into the amifostine crude product aqueous solution in batches, so that impurities can be effectively removed on the basis of not increasing the dosage of the water scavenger, the purity of the amifostine is improved, and the purity of the amifostine can reach more than 99.9%.
(2) According to the invention, the water and the activated carbon are mixed firstly and then added into the crude amifostine aqueous solution, so that agglomeration caused by direct addition of the activated carbon is avoided, and the purification effect of amifostine is further improved.
(3) According to the invention, before adding the impurity removing agent next time, the part of the impurity removing agent remained in the last batch in the system is filtered and removed, so that the purification effect of the amifostine can be further improved.
(4) The method has the advantages of simple scheme and strong applicability, and is suitable for industrial production.
The invention is further described below with reference to examples. The present invention is not limited to the following examples. The implementation conditions adopted in the embodiments can be further adjusted according to different requirements of specific use, and the implementation conditions which are not noted are conventional conditions in the industry. The technical features of the various embodiments of the present invention may be combined with each other as long as they do not collide with each other.
Without particular explanation, the crude amifostine product in the examples and comparative examples below was self-made, and the same batch was used, and the purity of the crude amifostine product was 98.1% by the self-made method with reference to the prior art.
Example 1
A method for purifying crude amifostine, comprising the steps of:
(1) Mixing 1 part of crude amifostine and 2 parts of water, and controlling the temperature of a mixed system to be 40 ℃ to dissolve the amifostine;
(2) Mixing 0.3 part of water and 0.05 part of activated carbon, adding the mixture into the mixed system in the step (1), keeping the temperature of the mixed system unchanged, continuously stirring for 30min, and filtering;
(3) Mixing 0.2 part of water and 0.03 part of activated carbon, adding the mixture into the filtrate obtained in the step (2), controlling the temperature of the system to be 40 ℃, continuously stirring for 30min, and filtering;
(4) Adding 5 parts of ethanol with the mass concentration of 95% into the filtrate in the step (3), heating the system to 50 ℃, stirring for 1.5h, cooling to 10 ℃, precipitating solids, filtering and drying to obtain amifostine.
In this example, the yield of amifostine was 85.8% and the purity was 99.90%.
Example 2
A method for purifying crude amifostine, comprising the steps of:
(1) Mixing 1 part of crude amifostine and 2 parts of water, and controlling the temperature of a mixed system to be 40 ℃ to dissolve the amifostine;
(2) Mixing 0.3 part of water and 0.07 part of activated carbon, adding the mixture into the mixed system in the step (1), keeping the temperature of the mixed system unchanged, continuously stirring for 30min, and filtering;
(3) Mixing 0.2 part of water and 0.07 part of active carbon, adding the mixture into the filtrate obtained in the step (2), controlling the temperature of the system to be 40 ℃, continuously stirring for 30min, and filtering;
(4) Adding 5 parts of ethanol with the mass concentration of 95% into the filtrate in the step (3), heating the system to 50 ℃, stirring for 1.5h, cooling to 10 ℃, precipitating solids, filtering and drying to obtain amifostine.
In this example, the yield of amifostine was 85.6% and the purity was 99.95%.
Example 3
(1) Mixing 1 part of crude amifostine and 2 parts of water, and controlling the temperature of a mixed system to be 40 ℃ to dissolve the amifostine;
(2) Mixing 0.4 part of water and 0.1 part of activated carbon, adding the mixture into the mixed system in the step (1), keeping the temperature of the mixed system unchanged, continuously stirring for 30min, and filtering;
(3) Mixing 0.2 part of water and 0.05 part of active carbon, adding the mixture into the filtrate obtained in the step (2), controlling the temperature of the system to be 40 ℃, continuously stirring for 30min, and filtering;
(4) Adding 5 parts of ethanol with the mass concentration of 95% into the filtrate in the step (3), heating the system to 50 ℃, stirring for 1.5h, cooling to 10 ℃, precipitating solids, filtering and drying to obtain amifostine.
In this example, the yield of amifostine was 85.5% and the purity was 99.98%.
Comparative example 1
(1) Mixing 1 part of crude amifostine and 2 parts of water, and controlling the temperature of a mixed system to be 40 ℃ to dissolve the amifostine;
(2) Mixing 0.5 part of water and 0.08 part of activated carbon, adding the mixture into the mixed system in the step (1), keeping the temperature of the mixed system unchanged, continuously stirring for 60min, and filtering;
(3) Adding 5 parts of ethanol with the mass concentration of 95% into the filtrate in the step (2), heating to 50 ℃, stirring for 1.5h, cooling to 10 ℃, precipitating solid, filtering and drying to obtain amifostine.
In this comparative example, the yield of amifostine was 84.5% and the purity was 98.50%.
Comparative example 2
(1) Mixing 1 part of crude amifostine and 2 parts of water, and controlling the temperature of a mixed system to be 40 ℃ to dissolve the amifostine;
(2) Mixing 0.6 part of water and 0.2 part of activated carbon, adding the mixture into the mixed system in the step (1), keeping the temperature of the mixed system unchanged, continuously stirring for 60min, and filtering;
(3) Adding 5 parts of ethanol with the mass concentration of 95% into the filtrate in the step (2), heating to 50 ℃, stirring for 1.5h, cooling to 10 ℃, precipitating solid, filtering and drying to obtain amifostine.
In this comparative example, the yield of amifostine was 85.1% and the purity was 99.1%.
Comparative example 3
A method for purifying crude amifostine, comprising the steps of:
(1) Mixing 1 part of crude amifostine and 2 parts of water, and controlling the temperature of a mixed system to be 40 ℃ to dissolve the amifostine;
(2) Mixing 0.3 part of water and 0.05 part of activated carbon, then adding the mixture into the mixed system in the step (1), keeping the temperature of the mixed system unchanged, and continuously stirring for 30min;
(3) Mixing 0.2 part of water and 0.03 part of activated carbon, adding the mixture into the filtrate obtained in the step (2), controlling the temperature of the system to be 40 ℃, continuously stirring for 30min, and filtering;
(4) Adding 5 parts of ethanol with the mass concentration of 95% into the filtrate in the step (3), heating the system to 50 ℃, stirring for 1.5h, cooling to 10 ℃, precipitating solids, filtering and drying to obtain amifostine.
In this comparative example, the yield of amifostine was 85.2% and the purity was 99.35%.
The present invention has been described in detail with the purpose of enabling those skilled in the art to understand the contents of the present invention and to implement the same, but not to limit the scope of the present invention, and all equivalent changes or modifications made according to the spirit of the present invention should be included in the scope of the present invention.
Claims (10)
1. A method for purifying a crude amifostine product, which is characterized in that: the method comprises mixing the crude amifostine with water for dissolution, then adding impurity removing agent for impurity removal in batches, then crystallizing, filtering and drying,
the impurity removing agent is a mixture of water and active carbon, and the ratio of the total feeding mass of the active carbon to the feeding mass of the amifostine crude product is (0.01-0.3): 1, a step of;
the number of times of batch is at least two, the time interval between two adjacent times of adding the impurity removing agent is at least 30min, and the mixed system is filtered before the next time of adding the impurity removing agent.
2. The process for purifying crude amifostine according to claim 1, wherein: the ratio of the total feeding mass of the activated carbon to the feeding mass of the crude amifostine product is (0.05-0.15): 1.
3. the process for purifying crude amifostine according to claim 1, wherein: the batch times are two times, and in the impurity removing agent added for the first time, the feeding mass ratio of the activated carbon to the amifostine crude product is (0.01-0.1): 1, a step of; in the impurity removing agent added for the second time, the feeding mass ratio of the active carbon to the amifostine crude product is (0.01-0.2): 1.
4. a process for purifying crude amifostine according to claim 3, characterized in that: in the impurity removing agent added for the first time, the feeding mass ratio of the active carbon to the amifostine crude product is (0.03-0.08): 1, a step of; in the impurity removing agent added for the second time, the feeding mass ratio of the active carbon to the amifostine crude product is (0.02-0.07): 1.
5. a process for purifying crude amifostine according to claim 3, characterized in that: in the impurity removing agent added for the first time, the feeding mass ratio of the water to the crude amifostine product is (0.1-0.5): 1, a step of; in the impurity removing agent added for the second time, the feeding mass ratio of the water to the crude amifostine product is (0.05-0.2): 1.
6. the method for purifying crude amifostine according to claim 5, wherein: in the impurity removing agent added for the first time, the feeding mass ratio of the water to the crude amifostine product is (0.2-0.4): 1, a step of; in the impurity removing agent added for the second time, the feeding mass ratio of the water to the crude amifostine product is (0.1-0.2): 1.
7. the process for purifying crude amifostine according to claim 1, wherein: and after adding the impurity removing agent, stirring the mixed system, controlling the stirring temperature to be 35-45 ℃, and stirring for more than or equal to 30min.
8. The process for purifying crude amifostine according to claim 1, wherein: the method specifically comprises the following steps:
(1) Mixing and dissolving the crude amifostine product and the water at 35-45 ℃;
(2) Adding part of impurity removing agent into the mixed system in the step (1), keeping the temperature of the mixed system unchanged, continuously stirring for at least 30min, and filtering, wherein the feeding mass ratio of the active carbon in the part of impurity removing agent to the amifostine crude product is (0.01-0.1): 1, the mass ratio of water in part of the impurity removing agent to the crude amifostine product is (0.1-0.5): 1, a step of;
(3) Adding the rest of impurity removing agent into the filtrate in the step (2), keeping the temperature of the mixed system unchanged, continuously stirring for at least 30min, and filtering, wherein the feeding mass ratio of the active carbon in the rest of impurity removing agent to the amifostine crude product is (0.01-0.2): 1, the mass ratio of water in the rest impurity removing agent to the crude amifostine product is (0.05-0.2): 1, a step of;
(4) And (3) adding ethanol into the filtrate obtained in the step (3), stirring at 45-55 ℃, cooling to 5-15 ℃, precipitating solid, filtering, and drying to obtain amifostine.
9. The method for purifying crude amifostine according to claim 8, wherein: in the step (1), the feeding mass ratio of the crude amifostine to the water is 1: (1-3).
10. The method for purifying crude amifostine according to claim 8, wherein: the feeding mass ratio of the ethanol to the amifostine crude product is (3-8): 1.
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| CN202210746121.5A CN117343097A (en) | 2022-06-29 | 2022-06-29 | Method for purifying amifostine crude product |
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