CN112979706A - Refining method of disodium levoornidazole phosphate impurity - Google Patents
Refining method of disodium levoornidazole phosphate impurity Download PDFInfo
- Publication number
- CN112979706A CN112979706A CN201911312951.1A CN201911312951A CN112979706A CN 112979706 A CN112979706 A CN 112979706A CN 201911312951 A CN201911312951 A CN 201911312951A CN 112979706 A CN112979706 A CN 112979706A
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- CN
- China
- Prior art keywords
- levoornidazole
- disodium
- phosphate
- ethyl acetate
- impurity
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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 System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
- C07F9/6571—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms
- C07F9/6574—Esters of oxyacids of phosphorus
- C07F9/65742—Esters of oxyacids of phosphorus non-condensed with carbocyclic rings or heterocyclic rings or ring systems
Abstract
The invention belongs to the field of chemical preparation, and particularly relates to a refining method of a disodium levoornidazole phosphate impurity. According to the scheme, the yield of the impurity of the disodium levoornidazole phosphate is more than 80% after the disodium levoornidazole phosphate is refined by the ethyl acetate in two steps, the purity of the disodium levoornidazole phosphate is more than 99.6%, the operation steps are few, the cost is saved, and the method is suitable for large-scale production.
Description
Technical Field
The invention belongs to the field of chemical preparation, and particularly relates to a refining method of a disodium levoornidazole phosphate impurity.
Background
The phosphorylation is a common prodrug design method, can improve the water solubility of parent drugs, improve the pharmacokinetic properties, improve the targeting property, reduce the toxic and side effects of drugs, increase the stability of drugs and the like, and is widely regarded and applied in the research and development of modern drugs.
The disodium levoornidazole phosphate is a compound with a novel structure developed according to the principle, and the product is used as a prerequisite medicament of the levoornidazole, has obvious clinical advantages compared with the ornidazole, is in a clinical research stage in recent years, and has potential to be applied to clinic as a new generation of antibacterial medicament.
Research shows that the disodium levoornidazole phosphate and the preparation thereof are easy to degrade in the long-term sample retention process to form trace impurities with the limit of about 2.5 percent, and have important influence on the purity of the raw material of the disodium levoornidazole phosphate and the safety of the preparation. At present, no literature report on the purification aspect of the disodium levoornidazole phosphate corresponding to the formula I is reported in the prior art.
Disclosure of Invention
In view of the defects of the prior art, the invention aims to provide a refining method of a disodium levoornidazole phosphate impurity, so as to improve the yield and purity of the disodium levoornidazole phosphate impurity and reduce the impurity content in a crude product.
The technical scheme of the invention is that after the impurity of the disodium levoornidazole phosphate is dissolved by an organic solvent, hot ethanol, acetone or petroleum ether is used as a crystallization solvent for crystallization. The method specifically comprises the following steps:
adding ethyl acetate, stirring and heating to 50-75 ℃, clarifying the system, filtering insoluble substances, adding a crystallization solvent, standing and crystallizing for 8-18 hours at 15-25 ℃, performing suction filtration, washing with ethanol to obtain a white solid, and drying.
The crystallization solvent is selected from hot ethanol, acetone and petroleum ether, and the hot ethanol is hot ethanol with the temperature of 50-60 ℃.
The impurity yield of the disodium levoornidazole phosphate after the crude product (with the purity of 85%) is refined by a one-step crystallization solvent is over 86.0%, and the purity is over 90.0%.
Volume of ethyl acetate: and (3) crude product quality is 5-10: 1, unit: L/KG.
The crystallization solvent is as follows: ethyl acetate volume 1: 2.
the crystallization solvent is preferably hot ethanol with the temperature of 50-60 ℃.
Preferably, the technical scheme of the invention specifically comprises the following steps:
volume of ethyl acetate: the quality of the crude product of the disodium levoornidazole phosphate impurity is 8: 1, unit: L/KG, stirring and heating to 70 ℃, clarifying the system, filtering insoluble substances, adding hot ethanol, standing at 20 ℃ for crystallization for 16 hours, performing suction filtration, washing with ethanol to obtain a white solid, and drying.
Further preferably, the purification is performed again after the first purification. The method comprises the following specific steps:
1) first purification, volume of ethyl acetate: the quality of the crude product of the disodium levoornidazole phosphate impurity is 8: 1, stirring and heating to 70 ℃, clarifying a system, filtering insoluble substances, adding hot ethanol, standing and crystallizing for 16 hours at 20 ℃, filtering, washing with ethanol to obtain a white solid, and drying.
The second refining step was as above.
The total yield of the impurity of the disodium levoornidazole phosphate after the crude product (with the purity of 85.0%) is refined in two steps is more than 80.0%, and the purity can reach more than 99.6%.
The invention achieves the following beneficial technical effects:
after the refining treatment, the purity of the impurity of the disodium levoornidazole phosphate is greatly improved, the operation steps are few, the cost is saved, the production process technology is simple, the defects of the prior art are overcome, the method is suitable for large-scale laboratory scale, pilot scale and industrial production, and the finished product obtained by the method reaches the high-quality standard required by ICH. As can be seen from the examples, the yield of the impurity of the refined disodium levoornidazole phosphate is above 86.0%, and the purity of the impurity of the refined disodium levoornidazole phosphate is above 90.0%; the purity of the impurity of the disodium levoornidazole phosphate refined in the two steps can reach more than 99.6 percent, and the single impurity is less than 0.1 percent and is higher than the medication standard.
Detailed Description
The present invention is not limited to the following examples.
Example 1
Volume of ethyl acetate: the mass of the crude product of the disodium levoornidazole phosphate impurity is 10: 1, stirring and heating to 45 ℃, clarifying a system, filtering insoluble substances, adding acetone, standing and crystallizing for 20 hours at 8 ℃ with the volume of acetone being half of that of ethyl acetate, carrying out suction filtration, washing with ethanol to obtain a white solid, and drying the product. The yield was 83.7% and the purity was 91.5%.
Example 2
Volume of ethyl acetate: the mass of the crude product of the disodium levoornidazole phosphate impurity is 15: 1, stirring and heating to 70 ℃, clarifying a system, filtering insoluble substances, adding acetone, standing and crystallizing for 20 hours at the temperature of 30 ℃ with the volume of the acetone equal to that of ethyl acetate, carrying out suction filtration, washing with ethanol to obtain a white solid, and drying the product. The yield was 87.1% and the purity was 95.6%.
Example 3
First purification, volume of ethyl acetate: the mass of the crude product of the disodium levoornidazole phosphate impurity is 10: 1, stirring and heating to 45 ℃, clarifying a system, filtering insoluble substances, adding acetone, standing and crystallizing for 20 hours at 8 ℃ with the volume of acetone being half of that of ethyl acetate, carrying out suction filtration, washing with ethanol to obtain a white solid, and drying the product.
The second refining process is carried out in the same manner as above. The yield is 80.9 percent, and the purity is 92.0 percent.
Example 4
First purification, volume of ethyl acetate: the mass of the crude product of the disodium levoornidazole phosphate impurity is 15: 1, stirring and heating to 70 ℃, clarifying a system, filtering insoluble substances, adding acetone, standing and crystallizing for 20 hours at the temperature of 30 ℃ with the volume of the acetone equal to that of ethyl acetate, carrying out suction filtration, washing with ethanol to obtain a white solid, and drying the product.
The second refining process is carried out in the same manner as above. The yield was 75.4% and the purity was 96.9%.
Example 5
Volume of ethyl acetate: the quality of the crude product of the disodium levoornidazole phosphate impurity is 5: 1, stirring and heating to 50 ℃, clarifying a system, filtering insoluble substances, adding hot ethanol, standing at 15 ℃ for crystallization for 18h, performing suction filtration, washing with ethanol to obtain a white solid, and drying. The yield is 97.3 percent, and the purity is 98.7 percent.
Example 6
Volume of ethyl acetate: the mass of the crude product of the disodium levoornidazole phosphate impurity is 10: 1, stirring and heating to 75 ℃, clarifying a system, filtering insoluble substances, adding acetone, standing and crystallizing for 16 hours at 25 ℃ with the volume of acetone being half of that of ethyl acetate, carrying out suction filtration, washing with ethanol to obtain a white solid, and drying the product. The yield was 92.3% and the purity was 97.7%.
Claims (7)
1. A refining method of a crude product of a disodium levoornidazole phosphate impurity is characterized in that after the disodium levoornidazole phosphate impurity is dissolved in an organic solvent, hot ethanol, acetone or petroleum ether is used as a crystallization solvent for crystallization.
2. The refining method according to claim 1, characterized by comprising the following steps: adding ethyl acetate, stirring and heating to 50-75 ℃, clarifying the system, filtering insoluble substances, adding a crystallization solvent, standing and crystallizing for 8-18 hours at 15-25 ℃, performing suction filtration, washing with ethanol to obtain a white solid, and drying.
3. The refining process of claim 1, wherein the ratio of L: kg, volume of ethyl acetate: and (3) crude product quality is 5-10: 1.
4. the refining method according to claim 1, wherein the volume of the crystallization solvent is: volume of ethyl acetate 1: 2.
5. the refining method according to claim 1, wherein the crystallization solvent is hot ethanol at 50 to 60 ℃.
6. The refining method according to any one of claims 1 to 5, characterized by comprising the steps of: volume of ethyl acetate: the quality of the crude product of the disodium levoornidazole phosphate impurity is 8: 1, stirring and heating to 70 ℃, clarifying a system, filtering insoluble substances, adding hot ethanol, standing and crystallizing for 16 hours at 20 ℃, filtering, washing with ethanol to obtain a white solid, and drying.
7. The refining method according to any one of claims 1 to 5, characterized by adopting two refining steps, specifically comprising the following steps:
1) first purification, volume of ethyl acetate: the quality of the crude product of the disodium levoornidazole phosphate impurity is 8: 1, stirring and heating to 70 ℃, clarifying the system, filtering insoluble substances, adding hot ethanol, standing and crystallizing for 16h at 20 ℃, filtering, washing with ethanol to obtain white solid, drying,
2) refining again by the same method as above.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201911312951.1A CN112979706A (en) | 2019-12-18 | 2019-12-18 | Refining method of disodium levoornidazole phosphate impurity |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201911312951.1A CN112979706A (en) | 2019-12-18 | 2019-12-18 | Refining method of disodium levoornidazole phosphate impurity |
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| Publication Number | Publication Date |
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| CN112979706A true CN112979706A (en) | 2021-06-18 |
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| CN201911312951.1A Pending CN112979706A (en) | 2019-12-18 | 2019-12-18 | Refining method of disodium levoornidazole phosphate impurity |
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2019
- 2019-12-18 CN CN201911312951.1A patent/CN112979706A/en active Pending
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Application publication date: 20210618 |