CN101921251B - Refining technique method of zanamivir intermediates - Google Patents
Refining technique method of zanamivir intermediates Download PDFInfo
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- CN101921251B CN101921251B CN2010102885302A CN201010288530A CN101921251B CN 101921251 B CN101921251 B CN 101921251B CN 2010102885302 A CN2010102885302 A CN 2010102885302A CN 201010288530 A CN201010288530 A CN 201010288530A CN 101921251 B CN101921251 B CN 101921251B
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Abstract
The invention discloses a refining technique method of zanamivir intermediates, comprising the following steps: taking a crude zanamivir intermediate compound as shown in formula I as a raw material, and dissolving the crude zanamivir intermediate compound into a methanol water solution; adding acetone to dissolve out solid; and filtering, drip washing the filter cakes by acetone, and drying to obtain the refined zanamivir intermediate compound as shown in formula I. The method of the invention selectively dissolves the organic impurities by utilizing methanol to achieve the purpose of decreasing the impurities, thus effectively decreasing or removing the impurities of the zanamivir intermediate compound as shown in formula I. The water in the invention can effectively remove the impurities, such as inorganic salts in the crude zanamivir intermediate compound as shown in formula I. The method of the invention is beneficial for large-scale production of products, has lower cost, and can recycle the partial solvents.
Description
Technical field
The present invention relates to a kind of preparation method of chemical substance, be specifically related to a kind of refining technique method of zanamivir intermediates.
Background technology
Zanamivir is a kind of compound, and its structural formula is:
Chemistry is by name: 5-acetylaminohydroxyphenylarsonic acid 4-［ (amino imino methyl)-amino ］-2, and 6-hydrogen-3,4,5-three deoxidations-D-glycerol base-D-semi-lactosi-2-bmap acid are a kind of effective influenza virus sialic acid inhibitor.
It is by the neuraminidase of inhibition influenza virus, thus gathering and the release of change influenza virus in cells infected, and in order to the influenza that treatment A type and Type B influenza virus cause, the influenza effect that special treatment causes because of H1N1virus is obvious.According to its pharmaco-kinetic properties, zanamivir is suitable for administration every day, and has good drug effect and security.
R in formula I compound
1Be Ac, R
2Be Me, be formula II compound;
R in formula I compound
1Be H, R
2Be Me, be formula III compound;
R in formula I compound
1Be Ac, R
2Be H, be formula IV compound;
R in formula I compound
1Be H, R
2Be H, be formula V compound.
Formula II compound gets formula III compound through taking off ester, and formula III compound gets formula V compound through demethyl, and 4 guanidine radicalsization of formula V compound get formula VI compound, i.e. zanamivir.
Formula II compound gets formula IV compound through demethyl, and formula IV compound gets formula V compound through taking off ester, and 4 guanidine radicalsization of formula V compound get formula VI compound, i.e. zanamivir.
Formula II compound, formula III compound, formula IV compound are earlier through 4 guanidine radicalsization, and warp or degreasing or demethyl get formula VI compound, i.e. zanamivir again.
As seen from the above, the quality of formula I compound directly has influence on the quality of last zanamivir, and zanamivir intermediate formula I compound refining is an important step in the whole zanamivir technology.
Impurity mainly is made up of organic impurity and inorganic salt impurity that reaction produces in the zanamivir intermediate formula I compound.If it is improper that refining solvent is selected, can make product become oily, perhaps most of curing caused mother liquor to be difficult to separate from system, thereby do not reached refining effect.
Summary of the invention
Technical problem to be solved by this invention provides a kind of refining technique method of zanamivir intermediates, and it can improve the liquid phase purity and the active constituent content of product effectively.
For solving the problems of the technologies described above, the technical solution of refining technique method of zanamivir intermediates of the present invention is:
May further comprise the steps:
With zanamivir intermediate formula I compound crude product is raw material, is dissolved in the methanol aqueous solution; Add acetone then and separate out solid, filter, filter cake acetone drip washing, drying gets zanamivir intermediate formula I compound elaboration;
Zanamivir intermediate formula I compound is:
R in the formula I compound
1Be H or Ac, R
2Be H or Me.
The volume ratio of described methyl alcohol and water is 1:1～10.
The weight ratio of described methanol aqueous solution and formula I compound is 1～10:1.
The weight ratio of described acetone and formula I compound is 5～20:1.
Institute's water is purified water or high purity water in the described purification step.
The technique effect that the present invention can reach is:
The present invention utilizes the selective dissolution of methyl alcohol to organic impurity, reaching the purpose that reduces impurity, thereby can reduce or remove the impurity of zanamivir intermediate formula I compound effectively.
Water among the present invention can be removed the impurity such as inorganic salt in the zanamivir intermediate crude product effectively.
The large-scale production of product also is convenient in the present invention, and cost is lower, and partial solvent can be recycled.
Embodiment
Refining technique method of zanamivir intermediates of the present invention may further comprise the steps:
With zanamivir intermediate formula I compound crude product is raw material, is dissolved in the methanol aqueous solution, and the volume ratio of methyl alcohol and water is 1:1～10, and the weight ratio of methanol aqueous solution and formula I compound is 1～10:1; Add acetone then and separate out solid, the weight ratio of acetone and formula I compound is 5～20:1, filter, and filter cake small amount of acetone drip washing, drying gets zanamivir intermediate formula I compound elaboration.
Zanamivir intermediate formula I compound has following feature:
R in the formula I compound
1Be H or Ac, R
2Be H or Me.
Institute's water is purified water or high purity water, preferred high purity water.
Embodiment 1
Get 20g zanamivir intermediate formula II compound crude product, be dissolved in the 100ml methanol aqueous solution, the methanol-water volume ratio is 1:1, stir the slow down 100ml of adding acetone, solid is separated out in a large number, filters, filter cake is with the drip washing of 2 * 15ml acetone, drying gets zanamivir intermediate formula II compound elaboration 18g, and liquid phase purity is 99.3%.
Embodiment 2
Get 20g zanamivir intermediate formula III compound crude product, be dissolved in the 150ml methanol aqueous solution, the methanol-water volume ratio is 1:5, stir the slow down 200ml of adding acetone, solid is separated out in a large number, filters, filter cake is with the drip washing of 2 * 15ml acetone, drying gets zanamivir intermediate formula III compound elaboration 16g, and liquid phase purity is 99.0%.
Embodiment 3
Get 20g zanamivir intermediate formula IV compound crude product, be dissolved in the 100ml methanol aqueous solution, the methanol-water volume ratio is 1:1, stir the slow down 200ml of adding acetone, solid is separated out in a large number, filters, filter cake is with the drip washing of 2 * 15ml acetone, drying gets zanamivir intermediate formula IV compound elaboration 17g, and liquid phase purity is 99.1%.
Embodiment 4
Get 20g zanamivir intermediate formula V compound crude product, be dissolved in the 60ml methanol aqueous solution, the methanol-water volume ratio is 1:9, stir the slow down 300ml of adding acetone, solid is separated out in a large number, filters, filter cake is with the drip washing of 2 * 15ml acetone, drying gets zanamivir intermediate formula II compound elaboration 18.5g, and liquid phase purity is 99.2%.
Formula V
Claims (7)
1. a refining technique method of zanamivir intermediates is characterized in that, may further comprise the steps:
With zanamivir intermediate formula I compound crude product is raw material, is dissolved in the methanol aqueous solution; Add acetone then and separate out solid, filter, filter cake acetone drip washing, drying gets zanamivir intermediate formula I compound elaboration;
Zanamivir intermediate formula I compound is:
R in the formula I compound
1Be H, R
2Be H.
2. refining technique method of zanamivir intermediates according to claim 1 is characterized in that: the volume ratio of described methyl alcohol and water is 1:1～10.
3. refining technique method of zanamivir intermediates according to claim 1 and 2 is characterized in that: the weight ratio of described methanol aqueous solution and formula I compound is 1～10:1.
4. refining technique method of zanamivir intermediates according to claim 1 and 2 is characterized in that: the weight ratio of described acetone and formula I compound is 5～20:1.
5. refining technique method of zanamivir intermediates according to claim 3 is characterized in that: the weight ratio of described acetone and formula I compound is 5～20:1.
6. refining technique method of zanamivir intermediates according to claim 1 is characterized in that: institute's water is purified water or high purity water in the described purification step.
7. refining technique method of zanamivir intermediates according to claim 1 is characterized in that: institute's water is a high purity water in the described purification step.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010102885302A CN101921251B (en) | 2010-09-21 | 2010-09-21 | Refining technique method of zanamivir intermediates |
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|---|---|---|---|
| CN2010102885302A CN101921251B (en) | 2010-09-21 | 2010-09-21 | Refining technique method of zanamivir intermediates |
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| CN101921251A CN101921251A (en) | 2010-12-22 |
| CN101921251B true CN101921251B (en) | 2011-10-05 |
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| CN2010102885302A Expired - Fee Related CN101921251B (en) | 2010-09-21 | 2010-09-21 | Refining technique method of zanamivir intermediates |
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| WO2015032357A1 (en) * | 2013-09-09 | 2015-03-12 | 中国科学院上海有机化学研究所 | Zanamivir, zanamivir intermediate, and synthesis method |
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Assignee: YUEYANG HUANYU PHARMACEUTICAL Co.,Ltd. Assignor: Xianju Purui Pharmaceutical Co.,Ltd. Contract record no.: 2012430000027 Denomination of invention: Refining technique method of zanamivir intermediates Granted publication date: 20111005 License type: Exclusive License Open date: 20101222 Record date: 20120413 |
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Address after: 317300 modern industrial agglomeration area, Taizhou County, Zhejiang, Xianju Patentee after: ZHEJIANG PURE PHARMACEUTICAL CO.,LTD. Address before: 317300 modern industrial agglomeration area, Taizhou County, Zhejiang, Xianju Patentee before: Xianju Purui Pharmaceutical Co.,Ltd. |
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