CN107778335B - Topiramate refining method - Google Patents
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- C07H9/00—Compounds containing a hetero ring sharing at least two hetero atoms with a saccharide radical
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- C—CHEMISTRY; METALLURGY
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- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
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- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
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Abstract
The invention relates to a refining method for preparing pharmaceutical grade topiramate, which effectively realizes that the single impurity of a product is less than 0.1 percent and the total impurity is less than 0.5 percent by one-step refining, and meets the industrial production requirement of the pharmaceutical grade topiramate. The method avoids complicated multi-step purification operation, shortens production period, has simple requirement on production equipment, and improves economy and safety.
Description
Technical Field
The invention belongs to the field of pharmacy, and relates to a refining method for preparing pharmaceutical grade topiramate.
Background
Topiramate (topiramate), tradename tolatate (Topamax), chemical name 2,3:4, 5-bis-O- (1-methylethylidene) - β -D-fructopyranose sulfamate, structural formula as follows:
it was developed by the united states department of intense pharmaceutical companies (Johnson & Johnson) and was marketed in the united kingdom in 1995, and approved by the FDA for the treatment of adult primary partial epilepsy in 1996 and for pediatric epilepsy treatment in 2000. In 2004, the FDA approved the drug for the prevention of migraine in adults. The FDA approved compound weight-reducing drug Qsymia containing topiramate and phentermine of Vivus pharmaceutical company in us at 7 months of 2012, and is the 2 nd new weight-reducing drug passed in us for 13 years.
Topiramate, as a novel antiepileptic drug, has ideal pharmacokinetic characteristics and has a large market share in the sale of antiepileptic drugs. Medical studies have shown that topiramate is effective in preventing migraine attacks, and in particular, is also useful in the treatment of migraine in children, and because of its precise efficacy, topiramate is FDA approved for the prevention of migraine in adults. Medical research shows that topiramate can enhance satiety, and phentermine with different induction mechanisms can play a synergistic role in reducing the dosage and improving the safety and tolerance, so that the FDA approves the Qsymia which is a compound weight-reducing drug containing topiramate and phentermine to be marketed. Another study shows that topiramate has a protective effect on brain injury caused by ischemia, trauma, epilepsy and the like, and is safe and effective for treating alcoholism. Based on the continuous research confirmation and FDA approval of new topiramate indications, the great market potential of the bulk drug is shown, and the development of new pharmaceutical preparation processes thereof again attracts extensive attention of researchers.
The methods for preparing topiramate can be mainly classified into an esterification method, an ammonolysis method, a catalytic hydrogenation method and a hydrolysis method according to the difference of precursors. The main method for industrial application is an ammonolysis method, which takes 2,3:4, 5-bis-O- (1-methylethylidene) -beta-D-fructopyranose chlorosulfonate as a precursor to obtain topiramate through ammonolysis reaction. The method has the advantages that the raw materials are cheap and easy to obtain, chlorosulfonyl isocyanate (CSI) with high toxicity and strong corrosivity can be effectively avoided, and special equipment is not needed. U.S. Pat. No. 4, 5387700 of 1995 provides a process for the preparation of topiramate, see the following formula.
The method selects ammonia gas as an ammonia source, removes a solvent after ammonolysis under a pressurized condition to obtain an oily substance, adds n-hexane, heats and stirs the oily substance, crystallizes the oily substance to obtain a crude product of the topiramate, and recrystallizes the topiramate by ethanol-water to obtain the topiramate. The method adopts two-time refining and purifying of the product, has long crystallization time, and increases the steps of drying materials and the like, so that the production period is longer and the energy consumption is increased. 486-487 in 1999, 30(11) improves the method, ammonolyzes at normal temperature and pressure, removes the solvent, adds ether to refine to obtain a crude product of topiramate, and recrystallizes with ethanol-water to obtain topiramate. The method also adopts twice refining to purify the product, and uses ether to replace n-hexane as a first refining solvent, thereby increasing the danger of industrial production.
In 2007, Chinese patent CN 200710068357.3 provided a method for preparing topiramate, which is shown in the following formula.
The method uses ammonia water as an ammonia source, ammonolyzes in cyclohexane without controlling anhydrous conditions, and performs alkali washing, water washing and solvent removal on post-treatment to obtain the topiramate. The method directly concentrates and removes the solvent after washing the reaction solvent, and the product has high single impurity content and relatively low purity.
In 2010, chinese patent CN 201010287475.5 provided a method for preparing topiramate, see the following formula.
The process uses (NH)4)2CO3Performing ammonolysis reaction in a mixed solvent as an ammonia source, removing the solvent after the reaction, adding ethyl acetate, heating, decoloring by using activated carbon, filtering, removing the ethyl acetate, and then adding isopropanol and n-hexane for crystallization to obtain the topiramate. The method has more purification operation steps, and particularly, if the method is applied to production, the operations of filter pressing and reduced pressure distillation for removing ethyl acetate are added, the production equipment and the energy consumption are increased.
In conclusion, the preparation methods successfully synthesize topiramate by using different ammonia sources, the product purity can reach more than 99.0 percent, and the research progress with high success is achieved, however, degradation impurities with retention time of 7.6min and 31min are generated in each preparation method in the ammonolysis reaction process, and although multi-step purification treatment is performed in each method in the purification process, the requirement that the single impurity content is less than 0.1 percent cannot be met, so that the purification technology of each existing preparation method cannot meet the requirement of producing medicinal topiramate.
Disclosure of Invention
The invention aims to provide a new refining method which is suitable for preparing medicinal grade topiramate, and the method can effectively realize single impurity of a product through one-step refining, particularly the medicinal requirement that the peak at 31min is less than 0.1 percent, and simultaneously reduce the content of the impurity at 7.6min (the requirement is less than 0.3 percent).
The purpose of the invention is realized by the following technical scheme:
after 2,3:4, 5-bis-O- (1-methylethylidene) -beta-D-fructopyranose chlorosulfonate reacts with an aminolysis agent, the solvent is removed to obtain crude oily liquid of topiramate, and the crude oily liquid of topiramate is added with organic solvents such as alcohol solvents, ether and the like for crystallization, and the specific operation is as follows:
firstly, adding 2,3:4, 5-bis-O- (1-methylethylidene) -beta-D-pyranose fructose sulfamate oily liquid into an alcohol solvent, heating and refluxing to dissolve, then cooling to 55-65 ℃, and adjusting the pH value to 9-10 by using ammonia water to obtain a system I;
secondly, dropwise adding an ether solvent into the system I in the first step under stirring, naturally cooling to room temperature after dropwise adding, and standing for crystallization for 8-12 hours to obtain a system II;
and thirdly, filtering the system II in the second step, putting the filter cake into an ether solvent, quickly stirring and grinding, filtering, and drying in vacuum to obtain the pure topiramate crystal.
Wherein, the alcohol in the alcohol solvent is selected from at least one of methanol, ethanol, propanol, isopropanol and glycol;
the ether solvent is at least one selected from petroleum ether, ethylene glycol dimethyl ether and methyl tert-butyl ether;
the ratio of the volume (L) of the alcohol solvent to the weight (kg) of the crude topiramate is 1-8, preferably 4-6.
The ratio of the volume (L) of the ether solvent to the weight (kg) of the crude topiramate in the second step is 1-10, preferably 3-5.
The ratio of the volume (L) of the ether solvent to the weight (kg) of the crude topiramate in the third step is 1-10, preferably 1-5.
And dropwise adding an ether solvent into the topiramate alcoholic solution at the temperature of 50-65 ℃.
Compared with the prior art, the technical scheme of the invention has the following progressive characteristics:
1) the technical scheme of the invention can realize one-step refining, the yield is more than 90%, the medicinal requirement that the peak at 31min of the product is less than 0.1% is effectively realized, even the content of impurities (required to be less than 0.3%) at 7.6min is reduced to be less than 0.1%, the single impurities are less than 0.1%, the total impurities are less than 0.5%, the requirement of industrial production of medicinal grade topiramate is met, and the generation of side effects of the medicament is greatly reduced.
2) The method avoids complicated multi-step purification operation, shortens production period, has simple requirement on production equipment, and improves economy and safety.
The specific implementation mode is as follows:
the following is a more detailed description of the present invention in connection with specific preferred embodiments, and it is not to be construed that the practice of the present invention is limited to these descriptions. For those skilled in the art to which the present invention pertains, several simple deductions or substitutions can be made without departing from the concept of the present invention, and all of the techniques and indexes used in the present invention but not described are the prior art.
The crude product of topiramate used in the examples is oily liquid of crude topiramate obtained by removing a solvent after reacting 2,3:4, 5-bis-O- (1-methylethylidene) -beta-D-fructopyranose chlorosulfonate with an aminolysis agent in the prior art (refer to the reference, journal of Chinese medical industry, 1999, 30(11): 486-.
Topiramate was tested using USP34 standard.
Example 1
Taking a topiramate crude product, and refining according to the following steps:
adding 0.5L of methanol and 0.5L of ethanol into 1kg of 2,3:4, 5-bis-O- (1-methylethylidene) -beta-D-fructopyranose sulfamate oily liquid, heating and refluxing to dissolve, then cooling to 55 ℃, and adjusting the pH to 9.0 by using ammonia water with the mass fraction of 20% to obtain a system I;
stirring, keeping the temperature at 50 ℃, dropwise adding 10L of petroleum ether into the system I, naturally cooling to room temperature after dropwise adding for 1.5h, and standing for crystallization for 8 h to obtain a system II;
and (3) filtering the system II, putting the filter cake into 1L of petroleum ether, quickly stirring and grinding, filtering, and drying in vacuum to obtain a pure topiramate crystal product with the yield of 93.8%. HPLC detection is carried out on the obtained pure topiramate crystal, and the result shows that the purity is 99.86% by calculation with an external standard method, and the impurities with retention time of 7.6min and 31min are respectively 0.05% and 0.06%, and are both less than 0.1%.
Example 2
Taking a topiramate crude product, and refining according to the following steps:
adding 1kg of 2,3:4, 5-bis-O- (1-methylethylidene) -beta-D-fructopyranosyl sulfamate oily liquid into 4L of propanol, heating and refluxing to dissolve, then cooling to 55 ℃, and adjusting the pH value to 9.2 by using 20% ammonia water to obtain a system I;
stirring, keeping the temperature at 52 ℃, dropwise adding 5L of ethylene glycol dimethyl ether into the system I, naturally cooling to room temperature after dropwise adding for 1.2h, and standing for crystallization for 9 h to obtain a system II;
and (3) filtering the system II, putting the filter cake into 3L of ethylene glycol dimethyl ether, quickly stirring and grinding, filtering, and drying in vacuum to obtain a pure product of the topiramate crystal, wherein the yield is 95.1%. HPLC detection is carried out on the obtained pure topiramate crystal, and the result shows that the purity is 99.85% by the calculation of an out-of-plane standard method, and the impurities with the retention time of 7.6min and 30.7min are respectively 0.03% and 0.04%, and are both less than 0.1%.
Example 3
Taking a topiramate crude product, and refining according to the following steps:
adding 1kg of 2,3:4, 5-bis-O- (1-methylethylidene) -beta-D-fructopyranosyl sulfamate oily liquid into 5L of ethanol, heating and refluxing to dissolve, then cooling to 57 ℃, and adjusting the pH to 9.5 by using 25% ammonia water to obtain a system I;
stirring, keeping the temperature at 55 ℃, dropwise adding 3L of petroleum ether into the system I, naturally cooling to room temperature after dropwise adding is completed within 1.2h, and standing for crystallization for 10 hours to obtain a system II;
and (3) filtering the system II, putting filter cakes into 5L of petroleum ether, glycol dimethyl ether and methyl tert-butyl ether, quickly stirring and grinding, filtering, and drying in vacuum to obtain a pure topiramate crystal product with the yield of 92.2%. HPLC detection is carried out on the obtained pure topiramate crystal, and the result shows that the purity of topiramate calculated by an external standard method is 99.92%, and the impurities with retention time of 7.6min and 30.7min are respectively 0.03% and 0.04%, and are both less than 0.1%.
Example 4
Taking a topiramate crude product, and refining according to the following steps:
adding 1kg of 2,3:4, 5-bis-O- (1-methylethylidene) -beta-D-fructopyranosyl sulfamate oily liquid into 6L of isopropanol, heating and refluxing to dissolve, then cooling to 60 ℃, and adjusting the pH to 10 by using 28% ammonia water to obtain a system I;
stirring, keeping the temperature at 60 ℃, dropwise adding 1L of methyl tert-butyl ether into the system I, naturally cooling to room temperature after 1h of dropwise adding, and standing for crystallization for 11 h to obtain a system II;
and (3) filtering the system II, putting the filter cake into 8L of methyl tert-butyl ether, quickly stirring and grinding, filtering, and drying in vacuum to obtain a pure topiramate crystal product with the yield of 92.0%. HPLC detection is carried out on the obtained pure topiramate crystal, and the result shows that the purity is 99.93% by calculation with an external standard method, and the impurities with retention time of 7.6min and 30.7min are respectively 0.04% and 0.03%, and are both less than 0.1%.
Example 5
Taking a topiramate crude product, and refining according to the following steps:
adding 8L of ethylene glycol into 1kg of 2,3:4, 5-bis-O- (1-methylethylidene) -beta-D-fructopyranosyl sulfamate oily liquid, heating and refluxing to dissolve, then cooling to 60 ℃, and adjusting the pH to 10 by using 28% ammonia water to obtain a system I;
stirring, keeping the temperature at 60 ℃, dropwise adding 1L of petroleum ether into the system I, naturally cooling to room temperature after 1h of dropwise adding, and standing for crystallization for 12 h to obtain a system II;
and filtering the system II, putting 10L of petroleum ether into the filter cake, quickly stirring and grinding, filtering, and drying in vacuum to obtain a pure topiramate crystal product with the yield of 91.6%. HPLC detection is carried out on the obtained pure topiramate crystal, and the result shows that the purity is 99.80% by calculation with an external standard method, and the impurities with retention time of 7.6min and 30.7min are respectively 0.07% and 0.05%, and are both less than 0.1%.
Claims (9)
1. A refining method of crude oily liquid of topiramate obtained by removing a solvent after 2,3:4, 5-bis-O- (1-methylethylidene) -beta-D-fructopyranose chlorosulfonate reacts with an aminolysis agent is characterized by comprising the following steps:
firstly, adding 2,3:4, 5-bis-O- (1-methylethylidene) -beta-D-pyranose fructose sulfamate oily liquid into an alcohol solvent, heating and refluxing to dissolve, then cooling to 55-65 ℃, and adjusting the pH value to 9-10 by using ammonia water to obtain a system I;
secondly, dropwise adding an ether solvent into the system I in the first step under stirring, naturally cooling to room temperature after dropwise adding, and standing for crystallization for 8-12 hours to obtain a system II;
thirdly, filtering the system II in the second step, putting a filter cake into an ether solvent for rapid pulping, filtering and vacuum drying to obtain a pure topiramate crystal;
wherein the alcohol solvent is at least one of methanol, ethanol, propanol, isopropanol and glycol, and the weight ratio of the volume of the alcohol solvent to the crude product of topiramate is 1-8; the ether solvent is at least one of petroleum ether, ethylene glycol dimethyl ether and methyl tert-butyl ether.
2. The method of claim 1, wherein the alcoholic solvent is at least one of ethanol, propanol, isopropanol, and ethylene glycol.
3. The method of claim 1, wherein the ethereal solvent is at least one of petroleum ether and ethylene glycol dimethyl ether.
4. The method for refining topiramate as claimed in any one of claims 1 to 3, wherein the ratio of the volume of the alcohol solvent to the weight of the crude topiramate is 4 to 6.
5. The method for refining topiramate according to any one of claims 1 to 3, wherein the ratio of the volume of the ether solvent to the weight of the crude topiramate in the second step is 1 to 10.
6. The refining method of topiramate according to claim 5, wherein the ratio of the volume of the ether solvent to the weight of the crude topiramate in the second step is 3-5.
7. The method for refining topiramate according to any one of claims 1 to 3, wherein the ratio of the volume of the ether solvent to the weight of the crude topiramate in the third step is 1 to 10.
8. The refining method of topiramate according to claim 7, wherein the ratio of the volume of the ether solvent to the weight of the crude topiramate in the third step is 1-5.
9. The method for purifying topiramate according to any one of claims 1 to 3, wherein the temperature of the ether solvent to be dropped into the topiramate alcohol solution is 50 to 65 ℃.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101450951A (en) * | 2007-11-30 | 2009-06-10 | 重庆凯林制药有限公司 | Method for producing topiramate |
| CN102725301A (en) * | 2010-02-05 | 2012-10-10 | 台湾神隆股份有限公司 | Process for the preparation and purification of topiramate |
| CN105566405A (en) * | 2014-11-11 | 2016-05-11 | 华东师范大学 | Preparation method of high-purity topiramate |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101450951A (en) * | 2007-11-30 | 2009-06-10 | 重庆凯林制药有限公司 | Method for producing topiramate |
| CN102725301A (en) * | 2010-02-05 | 2012-10-10 | 台湾神隆股份有限公司 | Process for the preparation and purification of topiramate |
| CN105566405A (en) * | 2014-11-11 | 2016-05-11 | 华东师范大学 | Preparation method of high-purity topiramate |
Non-Patent Citations (3)
| Title |
|---|
| Dynamic stereochemistry of Topiramate (anticonvulsant drug) in solution:theoretical approaches and experimental validation;Mina Ghiasi，et al.;《Carbohydrate Research》;20111119;第348卷;第47-54页 * |
| 托吡酯合成工艺研究;陈滔，等;《现代药物与临床》;20120930;第27卷(第5期);第449-450页 * |
| 托吡酯的合成研究进展;苗宇，等;《中国现代应用药学》;20130430;第30卷(第4期);第453-456页 * |
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Denomination of invention: A refining method of topiramate Effective date of registration: 20230117 Granted publication date: 20210702 Pledgee: Industrial and Commercial Bank of China Limited Linyi Shizhong Sub-branch Pledgor: LUNNAN BETTER PHARMACEUTICAL Co.,Ltd. Registration number: Y2023980031096 |