CN105418587A - Refining method of pradaxa free alkali - Google Patents
Refining method of pradaxa free alkali Download PDFInfo
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- CN105418587A CN105418587A CN201510866833.0A CN201510866833A CN105418587A CN 105418587 A CN105418587 A CN 105418587A CN 201510866833 A CN201510866833 A CN 201510866833A CN 105418587 A CN105418587 A CN 105418587A
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- China
- Prior art keywords
- dabigatran etcxilate
- free alkali
- purification
- virahol
- pradaxa
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
The invention relates to a refining method of pradaxa free alkali, belonging to the technical field of medicine purification. The refining method of pradaxa free alkali comprises the following steps: dissolving the crude product of the pradaxa free alkali with a solvent, crystallizing, filtering and drying, wherein the solvent is isopropanol, and a stabilizing agent is added in the extraction process. According to the invention, the impurity content is reduced, the refining rate is increased, the corresponding increase of the impurity content in the refining process is prevented, the cost is low, and industrialization is easy to realize.
Description
Technical field
The present invention relates to a kind of process for purification of dabigatran etcxilate free alkali, belong to drug purification technical field.
Background technology
Dabigatran etcxilate (commodity are called Pradaxa) is taken the lead in going on the market in Germany and Britain in April, 2008 by German Boehringer Ingelheim company.Dabigatran etcxilate is direct thrombin inhibitor.
Dabigatran etcxilate (I) and mesylate physico-chemical property very special, especially mesylate, refining very difficult, in dabigatran etcxilate capsule import registered standard, the total impurities limitation of allied compound is for≤3.6%, maximum known impurities is≤2.5%, and the low of its standard is very rare in the drug standard.
The difficult point of the refining existence of dabigatran etcxilate (I) and mesylate thereof be following some: 1, refining solvent is difficult to screening; 2, there is multiple obstinate impurity, in treating process, foreign matter content reduces very slow; 3, the foreign matter content had in treating process constantly raises and exceedes criterion of acceptability.
Hexanol, the trimethyl carbinol, toluene, methyl acetate is used to make solvent in WO2014/020546A2, carry out refining to dabigatran etcxilate free alkali (I) and prepare corresponding crystal formation, apart from toluene, refining rate only 60% ~ 70%, repeatedly be refined to qualified after almost there is no yield, the foreign matter content had in treating process constantly raises; Although toluene does solvent treatment rate can reach 85%, almost without refining effect, foreign matter content reduces hardly.The present inventor refines dabigatran etcxilate crude product (I) with reference to above-mentioned document, finds that refining effect is very poor, and the content of the especially obstinate impurity of impurity reduces very slow.The structural formula of dabigatran etcxilate (I) is as follows:
Summary of the invention
The object of the present invention is to provide a kind of process for purification of dabigatran etcxilate free alkali, reduce foreign matter content, improve refining rate, stop the corresponding foreign matter content for the treatment of process to raise, cost is low, is easy to realize industrialization.
The process for purification of dabigatran etcxilate free alkali of the present invention, comprise and adopt dissolution with solvents, crystallization, filtration and drying to dabigatran etcxilate crude free base, solvent for use is Virahol, adds stablizer in dissolution process.
The add-on of described Virahol is 8 ~ 12 times of dabigatran etcxilate free base weight, and the add-on of Virahol is in ml, and dabigatran etcxilate free alkali is in g.
Described stablizer is one or more in triethylamine, ethamine or Monomethylamine.Dabigatran etcxilate is as a kind of ester, and meeting and solvent Virahol generation transesterify, add the pH value that stablizer can improve system, suppresses transesterify to be carried out.
The add-on of described stablizer is 0.05-0.5 times of dabigatran etcxilate free base weight.
The process for purification of described dabigatran etcxilate free alkali, specifically comprises the following steps:
(1) in dabigatran etcxilate crude free base, add Virahol and stablizer, be then heated to 50 ~ 70 DEG C of dissolvings;
(2) solution after dissolving in step (1) is cooled to 30 ~ 50 DEG C of crystallizatioies;
(3) product obtained after crystallization in step (2) is carried out filter and drying, obtain dabigatran etcxilate free alkali fine work.
In step (3), at room temperature filter.
Compared with prior art, the present invention has following beneficial effect:
The present invention uses Virahol to refine dabigatran etcxilate free alkali as Extraction solvent, reduces impurity effective, and refining rate is up to 80%; Add a small amount of stablizer in the present invention, stop the corresponding foreign matter content for the treatment of process to raise.Cost of the present invention is low, is easy to realize industrialization.
Embodiment
Below in conjunction with embodiment, the present invention is further illustrated, but do not limit enforcement of the present invention.
Embodiment 1
By 2.0g (3mmol) dabigatran etcxilate crude free base (I, HPLC content 95%; According to document US8399678B2, prepared by 2013.3.19, Page8-10, lower with), 16ml Virahol and 0.2g triethylamine add in reaction flask, is heated to 50 DEG C of dissolvings.Be cooled to 30 DEG C of crystallizatioies.Be down to that room temperature is filtered, dry dabigatran etcxilate free alkali fine work 1.6g, HPLC content 99.1%, maximum contaminant 0.27%.
Embodiment 2
2.0g (3mmol) dabigatran etcxilate crude free base (I, HPLC content 95%), 24ml Virahol and 0.1g ethamine are added in reaction flask, is heated to 70 DEG C of dissolvings.Be cooled to 50 DEG C of crystallizatioies.Be down to that room temperature is filtered, dry dabigatran etcxilate free alkali fine work 1.6g, HPLC content 99.3%, maximum contaminant 0.21%.
Embodiment 3
By 2.0g (3mmol) dabigatran etcxilate crude free base (I, HPLC content 95%), 20ml adds Virahol and 1.0g Monomethylamine adds in reaction flask, is heated to 60 DEG C of dissolvings.Be cooled to 40 DEG C of crystallizatioies.Be down to that room temperature is filtered, dry dabigatran etcxilate free alkali fine work 1.6g, HPLC content 99.1%, maximum contaminant 0.29%.
Claims (6)
1. a process for purification for dabigatran etcxilate free alkali, comprises and adopts dissolution with solvents, crystallization, filtration and drying to dabigatran etcxilate crude free base, it is characterized in that: solvent for use is Virahol, adds stablizer in dissolution process.
2. the process for purification of dabigatran etcxilate free alkali according to claim 1, is characterized in that: the add-on of Virahol is 8 ~ 12 times of dabigatran etcxilate free base weight, and the add-on of Virahol is in ml, and dabigatran etcxilate free alkali is in g.
3. the process for purification of dabigatran etcxilate free alkali according to claim 1, is characterized in that: stablizer is one or more in triethylamine, ethamine or Monomethylamine.
4. the process for purification of the dabigatran etcxilate free alkali according to claim 1 or 3, is characterized in that: the add-on of stablizer is 0.05-0.5 times of dabigatran etcxilate free base weight.
5. the process for purification of dabigatran etcxilate free alkali according to claim 1, is characterized in that comprising the following steps:
(1) in dabigatran etcxilate crude free base, add Virahol and stablizer, be then heated to 50 ~ 70 DEG C of dissolvings;
(2) solution after dissolving in step (1) is cooled to 30 ~ 50 DEG C of crystallizatioies;
(3) product obtained after crystallization in step (2) is carried out filter and drying, obtain dabigatran etcxilate free alkali fine work.
6. the process for purification of dabigatran etcxilate free alkali according to claim 5, is characterized in that: in step (3), at room temperature filter.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510866833.0A CN105418587B (en) | 2015-11-30 | 2015-11-30 | The process for purification of dabigatran etcxilate free alkali |
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| CN201510866833.0A CN105418587B (en) | 2015-11-30 | 2015-11-30 | The process for purification of dabigatran etcxilate free alkali |
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| CN105418587A true CN105418587A (en) | 2016-03-23 |
| CN105418587B CN105418587B (en) | 2017-12-01 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105859686A (en) * | 2016-05-24 | 2016-08-17 | 浙江华海药业股份有限公司 | Preparation technology of high-purity dabigatran etexilate |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103664882A (en) * | 2012-09-20 | 2014-03-26 | 天津药物研究院 | Dabigatran etexilate in crystal modification form, and preparation method and use of dabigatran etexilate |
| CN103664881A (en) * | 2012-09-20 | 2014-03-26 | 天津药物研究院 | Dabigatran etexilate of crystallized variant form B as well as preparation method thereof and application |
| WO2014192030A2 (en) * | 2013-05-29 | 2014-12-04 | Laurus Labs Private Limited | An improved process for preparation of dabigatran etexilate and pharmaceutically acceptable acid addition salts thereof |
| CN104650037A (en) * | 2014-12-30 | 2015-05-27 | 青岛黄海制药有限责任公司 | Synthesis method of dabigatran etexilate |
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2015
- 2015-11-30 CN CN201510866833.0A patent/CN105418587B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103664882A (en) * | 2012-09-20 | 2014-03-26 | 天津药物研究院 | Dabigatran etexilate in crystal modification form, and preparation method and use of dabigatran etexilate |
| CN103664881A (en) * | 2012-09-20 | 2014-03-26 | 天津药物研究院 | Dabigatran etexilate of crystallized variant form B as well as preparation method thereof and application |
| WO2014192030A2 (en) * | 2013-05-29 | 2014-12-04 | Laurus Labs Private Limited | An improved process for preparation of dabigatran etexilate and pharmaceutically acceptable acid addition salts thereof |
| CN104650037A (en) * | 2014-12-30 | 2015-05-27 | 青岛黄海制药有限责任公司 | Synthesis method of dabigatran etexilate |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105859686A (en) * | 2016-05-24 | 2016-08-17 | 浙江华海药业股份有限公司 | Preparation technology of high-purity dabigatran etexilate |
| CN105859686B (en) * | 2016-05-24 | 2021-10-08 | 浙江华海药业股份有限公司 | Refining method of dabigatran etexilate free alkali |
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| CN105418587B (en) | 2017-12-01 |
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