CN117069723A - Refining method of pharmaceutical grade adenine - Google Patents
Refining method of pharmaceutical grade adenine Download PDFInfo
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- CN117069723A CN117069723A CN202311017785.9A CN202311017785A CN117069723A CN 117069723 A CN117069723 A CN 117069723A CN 202311017785 A CN202311017785 A CN 202311017785A CN 117069723 A CN117069723 A CN 117069723A
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- adenine
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- 229930024421 Adenine Natural products 0.000 title claims abstract description 109
- 229960000643 adenine Drugs 0.000 title claims abstract description 109
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 title claims abstract description 107
- 238000007670 refining Methods 0.000 title claims abstract description 45
- 238000000034 method Methods 0.000 title claims abstract description 33
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 30
- 238000001914 filtration Methods 0.000 claims abstract description 28
- 238000003756 stirring Methods 0.000 claims abstract description 21
- 239000008213 purified water Substances 0.000 claims abstract description 20
- 239000012043 crude product Substances 0.000 claims abstract description 18
- 238000010438 heat treatment Methods 0.000 claims abstract description 14
- 239000002904 solvent Substances 0.000 claims abstract description 14
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 8
- 238000001816 cooling Methods 0.000 claims abstract description 8
- 239000003960 organic solvent Substances 0.000 claims abstract description 8
- 238000001035 drying Methods 0.000 claims abstract description 5
- 239000003513 alkali Substances 0.000 claims abstract description 3
- 230000003472 neutralizing effect Effects 0.000 claims abstract description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 25
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 10
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- 238000000746 purification Methods 0.000 claims description 6
- 229960000583 acetic acid Drugs 0.000 claims description 5
- 239000012362 glacial acetic acid Substances 0.000 claims description 5
- 238000006386 neutralization reaction Methods 0.000 claims description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 2
- 239000000463 material Substances 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 239000000047 product Substances 0.000 abstract description 25
- 150000003863 ammonium salts Chemical class 0.000 abstract description 18
- 239000012535 impurity Substances 0.000 abstract description 9
- -1 adenine ammonium salt Chemical class 0.000 abstract description 6
- 150000003839 salts Chemical class 0.000 description 23
- 239000000203 mixture Substances 0.000 description 10
- FDGQSTZJBFJUBT-UHFFFAOYSA-N hypoxanthine Chemical compound O=C1NC=NC2=C1NC=N2 FDGQSTZJBFJUBT-UHFFFAOYSA-N 0.000 description 7
- 235000019441 ethanol Nutrition 0.000 description 6
- 230000000694 effects Effects 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- UGQMRVRMYYASKQ-UHFFFAOYSA-N Hypoxanthine nucleoside Natural products OC1C(O)C(CO)OC1N1C(NC=NC2=O)=C2N=C1 UGQMRVRMYYASKQ-UHFFFAOYSA-N 0.000 description 4
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 201000002364 leukopenia Diseases 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 230000001105 regulatory effect Effects 0.000 description 4
- 230000001954 sterilising effect Effects 0.000 description 4
- 238000001291 vacuum drying Methods 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 231100001022 leukopenia Toxicity 0.000 description 3
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- 239000002126 C01EB10 - Adenosine Substances 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- HYVABZIGRDEKCD-UHFFFAOYSA-N N(6)-dimethylallyladenine Chemical compound CC(C)=CCNC1=NC=NC2=C1N=CN2 HYVABZIGRDEKCD-UHFFFAOYSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- 229960005305 adenosine Drugs 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 238000010668 complexation reaction Methods 0.000 description 2
- 239000008139 complexing agent Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 210000000265 leukocyte Anatomy 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 150000007523 nucleic acids Chemical class 0.000 description 2
- 102000039446 nucleic acids Human genes 0.000 description 2
- 108020004707 nucleic acids Proteins 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- ZKBQDFAWXLTYKS-UHFFFAOYSA-N 6-Chloro-1H-purine Chemical compound ClC1=NC=NC2=C1NC=N2 ZKBQDFAWXLTYKS-UHFFFAOYSA-N 0.000 description 1
- ZKHQWZAMYRWXGA-KQYNXXCUSA-N Adenosine triphosphate Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O ZKHQWZAMYRWXGA-KQYNXXCUSA-N 0.000 description 1
- 201000010000 Agranulocytosis Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 206010018687 Granulocytopenia Diseases 0.000 description 1
- FAIXYKHYOGVFKA-UHFFFAOYSA-N Kinetin Natural products N=1C=NC=2N=CNC=2C=1N(C)C1=CC=CO1 FAIXYKHYOGVFKA-UHFFFAOYSA-N 0.000 description 1
- NWBJYWHLCVSVIJ-UHFFFAOYSA-N N-benzyladenine Chemical compound N=1C=NC=2NC=NC=2C=1NCC1=CC=CC=C1 NWBJYWHLCVSVIJ-UHFFFAOYSA-N 0.000 description 1
- 229930003776 Vitamin B4 Natural products 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- WOZSCQDILHKSGG-UHFFFAOYSA-N adefovir depivoxil Chemical compound N1=CN=C2N(CCOCP(=O)(OCOC(=O)C(C)(C)C)OCOC(=O)C(C)(C)C)C=NC2=C1N WOZSCQDILHKSGG-UHFFFAOYSA-N 0.000 description 1
- 229960003205 adefovir dipivoxil Drugs 0.000 description 1
- 238000005815 base catalysis Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000005515 coenzyme Substances 0.000 description 1
- 230000000536 complexating effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- UQHKFADEQIVWID-UHFFFAOYSA-N cytokinin Natural products C1=NC=2C(NCC=C(CO)C)=NC=NC=2N1C1CC(O)C(CO)O1 UQHKFADEQIVWID-UHFFFAOYSA-N 0.000 description 1
- 239000004062 cytokinin Substances 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 239000009322 erkang Substances 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 208000002672 hepatitis B Diseases 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- QANMHLXAZMSUEX-UHFFFAOYSA-N kinetin Chemical compound N=1C=NC=2N=CNC=2C=1NCC1=CC=CO1 QANMHLXAZMSUEX-UHFFFAOYSA-N 0.000 description 1
- 229960001669 kinetin Drugs 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- ZURGFCUYILNMNA-UHFFFAOYSA-N n-(7h-purin-6-yl)acetamide Chemical compound CC(=O)NC1=NC=NC2=C1NC=N2 ZURGFCUYILNMNA-UHFFFAOYSA-N 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 125000003835 nucleoside group Chemical group 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 231100000572 poisoning Toxicity 0.000 description 1
- 230000000607 poisoning effect Effects 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 238000000859 sublimation Methods 0.000 description 1
- 230000008022 sublimation Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229960004556 tenofovir Drugs 0.000 description 1
- 229960001355 tenofovir disoproxil Drugs 0.000 description 1
- JFVZFKDSXNQEJW-CQSZACIVSA-N tenofovir disoproxil Chemical compound N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N JFVZFKDSXNQEJW-CQSZACIVSA-N 0.000 description 1
- VCMJCVGFSROFHV-WZGZYPNHSA-N tenofovir disoproxil fumarate Chemical compound OC(=O)\C=C\C(O)=O.N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N VCMJCVGFSROFHV-WZGZYPNHSA-N 0.000 description 1
- 235000008979 vitamin B4 Nutrition 0.000 description 1
- 239000011579 vitamin B4 Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
- C07D473/32—Nitrogen atom
- C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
Abstract
The application provides a refining method of medicinal adenine, and relates to the field of pharmacy. A method for refining pharmaceutical grade adenine comprises the following steps: adding a refining solvent into the adenine crude product, heating and stirring, adding a purifying reagent, stirring, concentrating or filtering to obtain an adenine complex; adding an organic solvent into the adenine complex, heating and stirring for refining, cooling to room temperature, and filtering to obtain a refined adenine complex; neutralizing the refined adenine complex in purified water with alkali, crystallizing, filtering and drying to obtain the medicinal adenine. The refining method of the pharmaceutical grade adenine can refine the impurity ammonium salt impurities in the adenine crude product to almost undetected, effectively improve the product purity, meet the pharmaceutical requirement and solve the problem of overproof commercial industrial grade adenine ammonium salt impurities.
Description
Technical Field
The application relates to the technical field of pharmacy, in particular to a refining method of medicinal adenine.
Background
Adenine, chinese name: 6-aminopurine (namely a compound I), and the melting point of adenine is 360-365 ℃ and 220 ℃ for sublimation. Is insoluble in water, boiling water, ethanol, diethyl ether and chloroform. Is an important medical raw material and an intermediate. The phosphate is commonly called vitamin B4, is a constituent of nucleic acid and participates in the synthesis of genetic material. Can promote proliferation of white blood cells, increase the number of white blood cells, and be used for preventing and treating leukopenia caused by various reasons, especially leukopenia caused by tumor chemotherapy, and acute granulocytopenia.
Adenine has begun to find widespread use as a biological product in medicine, microbiology, and organic synthesis. It has the effect of stimulating leucocyte proliferation, so that it can be used for several reasons to produce leukopenia, specially for treating leucopenia resulted from tumor chemotherapy, radiation therapy and benzene medicine poisoning, etc.. Adenine is an active ingredient of nucleic acid and some coenzymes, and therefore, it is also an important intermediate of purine drugs such as 6-benzylaminopurine, kinetin, isopentenyl adenine, benzopyran adenine, ATP, nucleosides, and the like. But also has the physiological effects of cytokinin itself and is widely used in biochemical research. Adenine is also an indispensable raw material for preparing anti-hepatitis B drug adefovir dipivoxil and tenofovir disoproxil (or "tenofovir dipivoxil").
According to the report of CN200710071182.1, the production of adenine utilizes the self acid-base catalysis property of high-temperature liquid water and the property of dissolving organic matters to hydrolyze adenosine to generate adenine; patent CN201110282021.3 discloses: reacting hypoxanthine or acetyl hypoxanthine with phosphorus oxychloride to generate 6-chloropurine, and then ammoniating to obtain adenine crude product. The raw materials of the route are easy to obtain, but the route is long, the pollution is serious, the atom economy is poor, and the adenine crude product prepared by the process contains impurities such as hypoxanthine, tertiary amine hydrochloride, phosphate, metal ions and the like, and the adenine pure product with high purity can be obtained by refining. At present, the main stream is that the adenosine is prepared into acetyl adenine through an acetylation reaction, and then is hydrolyzed in a sodium hydroxide solution to directly prepare adenine, the process is simple and easy to implement, the yield is high, and the method is a novel environment-friendly process suitable for industrial production, and the product mainly contains impurities such as hypoxanthine and the like, and contains a large amount of ammonium salt.
The application adopts outsourced industrial adenine and solves the technical problem of unqualified industrial adenine ammonium salt by a special refining method.
Patent CN201210229904.2 reports an adenine refining method: dissolving adenine crude product in water, adding inorganic acid to adjust pH value to 3-5, adding active carbon, heating for refining, and removing ammonium salt in the product; traditionally, adenine refining is as follows: adding 40-60 times of water and proper amount of active carbon into the prepared adenine crude product, heating to boiling, preserving heat, filtering while hot, cooling for a long time for crystallization, filtering and drying. The method has the advantages that the water consumption is high, the ammonium salt is difficult to remove after refining, the refining method is optimized by Hunan Erkang pharmaceutical Co., ltd in CN201310000056.2, the industrial grade adenine crude product is boiled in water, the temperature is kept for 5 minutes, the centrifugation is carried out, and the solid is washed by hot water until washing liquid does not react with chloride ions. Dissolving the centrifuged solid in water, adding organic acid to adjust the pH value to 2-3, adding medicinal active carbon and EDTA, heating to 90 ℃, carrying out heat preservation reaction, filtering while the mixture is hot, ultrafiltering, cooling the filtrate, adjusting the pH value to 7-8 by using inorganic alkaline substances, uniformly stirring, filtering, washing the filter cake by using cold water, and drying to obtain adenine pure product.
Because ammonium salt is difficult to remove, the application provides a new refining method, and the refining of industrial grade products meets the requirements of pharmaceutical grade.
Disclosure of Invention
The application aims to provide a refining method of medicinal adenine, which aims to solve the problems.
In order to achieve the above purpose, the application adopts the following technical scheme:
a method for refining pharmaceutical grade adenine, comprising:
adding a refining solvent into the adenine crude product, heating and stirring, adding a purifying reagent, stirring, concentrating or filtering to obtain an adenine complex;
adding an organic solvent into the adenine complex, heating and stirring for refining, cooling to room temperature, and filtering to obtain a refined adenine complex;
neutralizing the refined adenine complex in purified water with alkali, crystallizing, filtering and drying to obtain the medicinal adenine.
Preferably, the refining solvent comprises one or more of purified water, ethanol, methanol, isopropanol and acetone, and the mass volume ratio of the adenine crude product to the refining solvent is 1g: (1-5) ml, preferably 1g:3ml.
Alternatively, the mass to volume ratio of the adenine crude product to the refining solvent may be 1g:1ml, 1g:2ml, 1g:3ml, 1g:4ml, 1g:5ml, 1g:6ml, 1g:7ml, 1g:8ml, 1g:9ml, 1g:10ml or 1g: (1-10) ml.
Preferably, the purification reagent comprises hydrochloric acid and/or glacial acetic acid in an amount of 0.8 to 1.2 times, preferably 1 time, the molar amount of the crude adenine product.
Alternatively, the purification reagent comprises hydrochloric acid and/or glacial acetic acid, and the amount can be any value between 0.8 times, 0.9 times, 1.0 times, 1.1 times, 1.2 times, or 0.8-1.2 times the molar amount of the adenine crude product.
Preferably, the organic solvent comprises one or more of ethanol, methanol and isopropanol, and the mass volume ratio of the adenine crude product to the organic solvent is 1g: (1-10) ml.
Alternatively, the mass to volume ratio of the crude adenine to the organic solvent may be 1g:1ml, 1g:2ml, 1g:3ml, 1g:4ml, 1g:5ml, 1g:6ml, 1g:7ml, 1g:8ml, 1g:9ml, 1g:10ml or 1g: (1-10) ml.
Preferably, the refining temperature is 30-80 ℃ and the refining time is 0.5-24h.
Alternatively, the temperature of the refining may be 30, 40, 50, 60, 70, 80, or any value between 30-80 ℃ and the time may be 0.5h, 1h, 2h, 4h, 6h, 8h, 10h, 12h, 14h, 16h, 18h, 20h, 22h, 24h, or any value between 0.5-24h.
Preferably, the base comprises one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate.
Preferably, the end point pH of the neutralization is 7-9.
Alternatively, the end point pH of the neutralization may be 7, 8, 9 or any value between 7 and 9.
Preferably, the mass to volume ratio of the purified adenine complex to the purified water is 1g: (1-15) ml.
Preferably, the mass to volume ratio of the purified adenine complex to the purified water is 1g:5ml.
Alternatively, the mass to volume ratio of the purified adenine complex to the purified water may be 1g:1ml, 1g:2ml, 1g:3ml, 1g:4ml, 1g:5ml, 1g:6ml, 1g:7ml, 1g:8ml, 1g:9ml, 1g:10ml, 1g:11ml, 1g:12ml, 1g:13ml, 1g:14ml, 1g:15ml or 1g: (1-15) ml.
Preferably, the material is subjected to aseptic filtration prior to said neutralization.
Compared with the prior art, the application has the beneficial effects that:
according to the adenine refining method provided by the application, the adenine crude product is heated by a solvent, complexing agent is adopted to complex into salt, the complex salt is refined by a specific refining solvent, and the difference of solubility of related impurity ammonium salt and adenine complex in a solvent system and the difference of seed crystal generation process are utilized to achieve the refining effect of removing ammonium salt, so that the product purity is improved, the refined adenine complex salt is free to finally obtain medicinal grade adenine, and the ammonium salt impurities in the adenine crude product are refined to almost undetected, so that the adenine crude product meets the medicinal requirements.
Detailed Description
Embodiments of the present application will be described in detail below with reference to specific examples, but it will be understood by those skilled in the art that the following examples are only for illustrating the present application and should not be construed as limiting the scope of the present application. The specific conditions are not noted in the examples and are carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
The raw material information and sources used in the following specific examples are shown in table 1:
TABLE 1 reagents and sources
Example 1
500g of adenine is added into a 3000ml three-mouth bottle, 1000ml of purified water is added, the temperature is raised to 50+/-3 ℃, the mixture is fully stirred and kept for 30min, 222g of glacial acetic acid is added, the mixture is stirred until the mixture is dissolved, and the reaction solution is concentrated to obtain an adenine complex; adding 1500ml of ethanol into adenine complex salt, transferring into 3000ml of three-mouth bottle, heating to 77 ℃ and refluxing, stirring for 1h, cooling to room temperature, filtering to obtain refined product salt, transferring the refined salt into 10000ml of three-mouth bottle, adding 5000ml of purified water, stirring at 50 ℃, sterilizing, filtering, regulating pH of filtrate to 8-9 with 30% sodium hydroxide solution, stirring for 1h, filtering, eluting 500ml of purified water for several times, vacuum drying the refined product at 60 ℃ for 6h to obtain medicinal grade adenine 458.6g, yield 91.72%, content 99.8% and ammonium salt less than or equal to 0.0002%.
Example 2
500g adenine is added into a 3000ml three-mouth bottle, 1000ml ethanol is added, the temperature is raised to 50+/-3 ℃, the mixture is fully stirred and kept for 30min, 375.2g of 36% hydrochloric acid is added, the mixture is stirred for about 30min, the temperature is reduced to 0-5 ℃, and adenine complex salt is obtained through filtration; adding 2000ml of methanol into adenine complex salt, transferring to a 3000ml three-mouth bottle, heating to 60 ℃ and stirring for 1h, cooling to room temperature, filtering to obtain refined product salt, transferring the refined salt to a 10000ml three-mouth bottle, adding 800 ml of purified water, stirring at 80 ℃, sterilizing and filtering, regulating pH of filtrate to 8-9 by 30% potassium hydroxide solution, stirring for 1h, filtering, eluting with 500ml of purified water for several times to obtain refined product, vacuum drying the refined product at 55 ℃ for 8h, and obtaining medicinal grade adenine 425.3g with yield 85.06%, content 99.8% and ammonium salt less than or equal to 0.0005%.
Example 3
500g adenine is added into a 3000ml three-mouth bottle, 1000ml isopropanol is added, the temperature is raised to 50+/-3 ℃, the mixture is fully stirred and kept for 30min, 375.2g of 36% hydrochloric acid is added, the mixture is stirred for about 30min, and adenine complex salt is obtained by concentration; adding 2000ml of ethanol into adenine complex salt, transferring into 3000ml of three-mouth bottle, heating to 70 ℃ and stirring for 1h, cooling to room temperature, filtering to obtain refined product salt, transferring the refined salt into 10000ml of three-mouth bottle, adding purified water 3000ml, stirring at 80 ℃, sterilizing and filtering, regulating pH of filtrate to 8-9 by 30% potassium hydroxide solution, stirring for 1h, filtering, eluting with 500ml of purified water for several times to obtain refined product, vacuum drying the refined product at 58 ℃ for 7h to obtain pharmaceutical grade adenine 471.1g, and the yield is 94.22%. The content of ammonium salt is less than or equal to 0.0005 percent of 100.1 percent
It is noted that the embodiment of the application achieves the refining effect of removing ammonium salt by using the solubility difference of relevant impurity ammonium salt and adenine complex in a solvent system and the seed crystal generation process difference under the solvent heating action, and achieves the refining effect of removing ammonium salt by complexing industrial grade adenine crude product with complexing agent to form salt under the solvent heating action, refining ammonium salt impurities in adenine crude product to almost undetected by the dissociation of refined adenine complex salt, thereby meeting the medicinal requirements.
The pharmaceutical grade quality criteria for adenine are shown in table 2 below:
TABLE 2 pharmaceutical grade quality criteria for adenine
To further determine the validity of this patent. Experiments were designed to avoid purification of adenine complex as a salt and to avoid purification of adenine complex as a salt, and examples 4 and 5 were provided therebetween.
Example 5
500g adenine is added into a 3000ml three-mouth bottle, 1000ml purified water is added, the temperature is raised to 100 ℃ and stirred for 1h, the temperature is reduced to room temperature, refined product salt is obtained by filtration, and the refined product is dried in vacuum at 58 ℃ for 7h, thus obtaining 485.6g adenine refined product with the yield of 97.12%. The content is 98.4%, the ammonium salt is more than 0.001%, and the product is unqualified.
Example 6
500g adenine is added into a 3000ml three-mouth bottle, 1000ml absolute ethyl alcohol is added, the temperature is raised to 50+/-3 ℃, the mixture is fully stirred and kept for 30min, 222g glacial acetic acid is added, the mixture is stirred for about 30min, and adenine complex salt is obtained by concentration; transferring the adenine complex salt into 10000ml three-mouth bottle, adding purified water 3000ml, stirring at 80 ℃, sterilizing, filtering, regulating pH of filtrate to 8-9 with 30% potassium hydroxide solution, stirring for 1h, filtering, eluting with 500ml purified water for several times to obtain refined product, vacuum drying the refined product at 58 ℃ for 7h to obtain medicinal grade adenine 482.3g, yield 96.46%. The content is 99.1%, the ammonium salt is more than 0.001%, and the product is unqualified.
Experiments that adenine is not subjected to complexation to form salt for refining and adenine complexation salt refining treatment show that the traditional adenine refining method has no effect on removing ammonium salt, and only a special refining method can be used for effectively. The application successfully develops an effective pharmaceutical grade adenine ammonium salt refining method.
While certain specific embodiments of the application have been described in detail by way of example, it will be appreciated by those skilled in the art that the above examples are for illustration only and are not intended to limit the scope of the application. It will be appreciated by those skilled in the art that modifications may be made to the above embodiments without departing from the scope and spirit of the application. The scope of the application is defined by the appended claims.
Claims (10)
1. A method for refining pharmaceutical grade adenine, comprising:
adding a refining solvent into the adenine crude product, heating and stirring, adding a purifying reagent, stirring, concentrating or filtering to obtain an adenine complex;
adding an organic solvent into the adenine complex, heating and stirring for refining, cooling to room temperature, and filtering to obtain a refined adenine complex;
neutralizing the refined adenine complex in purified water with alkali, crystallizing, filtering and drying to obtain the medicinal adenine.
2. The method for refining pharmaceutical grade adenine according to claim 1, wherein the refining solvent comprises one or more of purified water, ethanol, methanol, isopropanol and acetone, and the mass-to-volume ratio of the crude adenine to the refining solvent is 1g: (1-10) ml.
3. The method for purifying pharmaceutical grade adenine according to claim 1, wherein the purifying reagent comprises hydrochloric acid and/or glacial acetic acid in an amount of 0.8 to 1.2 times the molar amount of the crude adenine.
4. The method for refining pharmaceutical grade adenine according to claim 1, wherein the organic solvent comprises one or more of ethanol, methanol and isopropanol, and the mass-volume ratio of the crude adenine to the organic solvent is 1g: (1-10) ml.
5. The method for purifying pharmaceutical grade adenine according to claim 1, wherein the temperature of the purification is 30-80℃for 0.5-24 hours.
6. The method for purifying pharmaceutical grade adenine according to claim 1, wherein the base comprises one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate.
7. The method for purifying pharmaceutical grade adenine according to claim 6, wherein the neutralization has an end point pH of 7 to 9.
8. The method for purifying pharmaceutical grade adenine according to claim 1, wherein the mass-to-volume ratio of the purified adenine complex to the purified water is 1g: (1-15) ml.
9. The method for purifying pharmaceutical grade adenine according to claim 8, wherein the mass-to-volume ratio of the purified adenine complex to the purified water is 1g:5ml.
10. The process for purification of pharmaceutical grade adenine according to any one of claims 1 to 9, wherein the material is subjected to aseptic filtration prior to said neutralization.
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