CN102260261A - Method for purifying entecavir - Google Patents
Method for purifying entecavir Download PDFInfo
- Publication number
- CN102260261A CN102260261A CN 201010198419 CN201010198419A CN102260261A CN 102260261 A CN102260261 A CN 102260261A CN 201010198419 CN201010198419 CN 201010198419 CN 201010198419 A CN201010198419 A CN 201010198419A CN 102260261 A CN102260261 A CN 102260261A
- Authority
- CN
- China
- Prior art keywords
- entecavir
- purification process
- crude product
- methyl alcohol
- alcoholic solvent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 229960000980 entecavir Drugs 0.000 title claims abstract description 23
- YXPVEXCTPGULBZ-WQYNNSOESA-N entecavir hydrate Chemical compound O.C1=NC=2C(=O)NC(N)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)C1=C YXPVEXCTPGULBZ-WQYNNSOESA-N 0.000 title claims abstract description 23
- 238000000034 method Methods 0.000 title abstract description 7
- 239000002904 solvent Substances 0.000 claims abstract description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 5
- 238000001953 recrystallisation Methods 0.000 claims abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- 238000000746 purification Methods 0.000 claims description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 11
- 239000012043 crude product Substances 0.000 claims description 8
- 230000001476 alcoholic effect Effects 0.000 claims description 7
- 238000005406 washing Methods 0.000 claims description 6
- 239000012065 filter cake Substances 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 2
- 230000000694 effects Effects 0.000 abstract description 2
- 239000012452 mother liquor Substances 0.000 abstract description 2
- 150000001298 alcohols Chemical class 0.000 abstract 1
- 238000005360 mashing Methods 0.000 abstract 1
- 239000012535 impurity Substances 0.000 description 7
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 239000007787 solid Substances 0.000 description 4
- 238000010009 beating Methods 0.000 description 3
- 238000009835 boiling Methods 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000011347 resin Substances 0.000 description 2
- 229920005989 resin Polymers 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 208000000419 Chronic Hepatitis B Diseases 0.000 description 1
- 241000700721 Hepatitis B virus Species 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 208000002672 hepatitis B Diseases 0.000 description 1
- 230000008676 import Effects 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
Landscapes
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a method for purifying entecavir, comprising the steps of using alcohols for mashing and using water for recrystallization to obtain the purified entecavir. The invention has the advantages of simple operation, obvious effects, and small amounts of solvent, and the mother liquor is recyclable.
Description
Technical field
The invention belongs to the pharmaceutical chemistry field, relate to the purification process of Entecavir.
Background technology
Entecavir is becoming a line medication of treatment chronic hepatitis B, and market outlook are very considerable, also attracts increasing mechanism and enterprise to participate in research.Entecavir is as hepatitis B virus resisting medicine of new generation, and preparation and process for refining are all very complicated, and technical requirements is higher.Require single impurity level less than 0.1% to related substance in its preparation import standard, the total impurities amount is less than 0.3%, only this this requirement becomes the technology barriers of many Entecavir research, bibliographical information has resin method wash-out purifying Entecavir, but this method cost is higher, complicated operation, a large amount of eluting solvents of follow-up generation, cause certain environmental protection pressure, be difficult to promote.
Therefore, the purpose of this invention is to provide a kind of new Entecavir purification process.
Summary of the invention
The purification process of Entecavir provided by the invention may further comprise the steps: (1) adopts alcoholic solvent to the washing of pulling an oar of Entecavir crude product shown in the formula 1
(2) with filter cake water recrystallization.
The present invention screens various alcoholic solvents, and the solvent that can be applied to Entecavir purification process of the present invention comprises methyl alcohol, ethanol, Virahol, propyl carbinol and the trimethyl carbinol.Methyl alcohol even more preferably wherein.
The present invention, comprises that every gram Entecavir uses 5ml, 10ml, 15ml, 20ml, 30ml, 40ml alcoholic solvent, and quality, the volume ratio of alcoholic solvent is optimized the washing of pulling an oar of Entecavir crude product with various quality, volume ratio.Be preferably and select 20ml.
Purification process of the present invention carries out being selected under 0-5 ℃, 5-10 ℃, 10-20 ℃, 20-30 ℃, 30-40 ℃ and the temperature condition more than 40 ℃, and temperature condition is optimized.Be preferably and select 30-40 ℃.
The present invention has overcome the shortcoming of resin elution method in the past, directly washs making beating with solvent, utilizes impurity to be separated with the solvability difference of finished product in alcohol, use simple to operate, effect is obvious, and the solvent for use amount is little, mother liquor is recovery set usefulness repeatedly, economic environmental protection.
Embodiment
The present invention is further elaborated with embodiment below, but this embodiment has any restriction to the present invention absolutely not.Any change that those skilled in the art are done in to the invention process under the enlightenment of this specification sheets all will drop in the scope of claims.
Embodiment 1
Raw material is Entecavir crude product (a HPLC purity 98.5%).
Get a 500ml single port bottle, add 200ml methyl alcohol, add 10g Entecavir crude product again,, filter then, filter cake washed with methanol 3 times, each 10ml 30-40 ℃ of stirring.Repeat 2 washing making beating so again, obtain off-white color solid 8.6g, HPLC purity reaches 99.6%.
Solid with previous step is dissolved in the 200ml boiling water again, and crystallization to be cooled filters and obtains white or off-white color crystal, and HPLC detects maximum single impurity level 0.05%, total impurities amount 0.25%.
Embodiment 2
Raw material is Entecavir crude product (a HPLC purity 98.5%).
Get a 500ml single port bottle, add 200ml ethanol, add 10g Entecavir crude product again, 20-30 ℃ of stirring, filter then, filter cake cleans 3 times with ethanol, each 20ml.Repeat 2 washing making beating so again, obtain off-white color solid 8.4g, HPLC purity reaches 99.2%.
Solid with previous step is dissolved in the 200ml boiling water again, and crystallization to be cooled filters and obtains white or off-white color crystal, and HPLC detects maximum single impurity level 0.05%, total impurities amount 0.25%.
Claims (7)
1. the purification process of Entecavir is characterized in that:
(1) adopt alcoholic solvent to the washing of pulling an oar of Entecavir crude product shown in the formula 1
(2) with filter cake water recrystallization.
2. purification process according to claim 1, wherein said alcohol is selected from methyl alcohol, ethanol, Virahol, propyl carbinol and the trimethyl carbinol.
3. as purification process as described in the claim 2, wherein said alcohol is methyl alcohol.
4. as purification process as described in the claim 2, wherein said alcoholic solvent to the washing of pulling an oar of Entecavir crude product, comprises that every gram Entecavir uses 5ml, 10ml, 15ml, 20ml, 30ml, 40ml alcoholic solvent with various quality, volume ratio.
5. as purification process as described in the claim 4, the consumption of wherein said methyl alcohol is 20ml.
6. as the described purification process of one of claim 1-5, described purifying carries out being selected under 0-5 ℃, 5-10 ℃, 10-20 ℃, 20-30 ℃, 30-40 ℃ and the temperature condition more than 40 ℃.
7. purification process as claimed in claim 6, wherein said temperature are 30-40 ℃.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201010198419 CN102260261A (en) | 2010-06-10 | 2010-06-10 | Method for purifying entecavir |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201010198419 CN102260261A (en) | 2010-06-10 | 2010-06-10 | Method for purifying entecavir |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN102260261A true CN102260261A (en) | 2011-11-30 |
Family
ID=45007124
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 201010198419 Pending CN102260261A (en) | 2010-06-10 | 2010-06-10 | Method for purifying entecavir |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102260261A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102786524A (en) * | 2012-09-04 | 2012-11-21 | 湖南协力药业有限公司 | Refining method of entecavir for treating hepatitis B |
| CN113121466A (en) * | 2019-12-31 | 2021-07-16 | 成都迪康药业股份有限公司 | Recrystallization solvent of acotiamide hydrochloride and refining method thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1660846A (en) * | 2004-12-20 | 2005-08-31 | 美德（江西）生物科技有限公司 | Entecavir in non crystallization kenel |
| CN101245068A (en) * | 2007-02-14 | 2008-08-20 | 浙江医药股份有限公司新昌制药厂 | Crystallization type entecavir, method of producing the same, pharmaceutical composition and uses thereof |
| CN101337962A (en) * | 2007-07-04 | 2009-01-07 | 北京新领先医药科技发展有限公司 | Method for preparing entikawei |
-
2010
- 2010-06-10 CN CN 201010198419 patent/CN102260261A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1660846A (en) * | 2004-12-20 | 2005-08-31 | 美德（江西）生物科技有限公司 | Entecavir in non crystallization kenel |
| CN101245068A (en) * | 2007-02-14 | 2008-08-20 | 浙江医药股份有限公司新昌制药厂 | Crystallization type entecavir, method of producing the same, pharmaceutical composition and uses thereof |
| CN101337962A (en) * | 2007-07-04 | 2009-01-07 | 北京新领先医药科技发展有限公司 | Method for preparing entikawei |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102786524A (en) * | 2012-09-04 | 2012-11-21 | 湖南协力药业有限公司 | Refining method of entecavir for treating hepatitis B |
| CN102786524B (en) * | 2012-09-04 | 2016-08-03 | 湖南千金协力药业有限公司 | A kind of process for purification of hepatitis B therapeutic medicament entecavir |
| CN113121466A (en) * | 2019-12-31 | 2021-07-16 | 成都迪康药业股份有限公司 | Recrystallization solvent of acotiamide hydrochloride and refining method thereof |
| CN113121466B (en) * | 2019-12-31 | 2023-12-15 | 成都迪康药业股份有限公司 | Recrystallizing solvent of acotiamide hydrochloride and refining method thereof |
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| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20111130 |