CN100432087C - Preparation method of topiramate - Google Patents
Preparation method of topiramate Download PDFInfo
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- CN100432087C CN100432087C CNB2007100683573A CN200710068357A CN100432087C CN 100432087 C CN100432087 C CN 100432087C CN B2007100683573 A CNB2007100683573 A CN B2007100683573A CN 200710068357 A CN200710068357 A CN 200710068357A CN 100432087 C CN100432087 C CN 100432087C
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- topiramate
- acid ester
- methyl ethylidene
- pyranofructose
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Abstract
This invention relates to a preparation method of topiramate. It takes 2, 3: 4, 5 - double - O - ( 1 - methyl ethylidene) - D - fructopyranose chlorosulfonic acid ester and ammonia to carry out reaction to prepare topiramate. It uses ammonia to substitute alkaline air to carry out ammonolysis reaction, so the hand le is easy, simple, security, reduce equipment cost. The solvent does not require anhydrous hand ling, and aftertreatment just need extraction. It is benefit for commercial process.
Description
(1) technical field
The present invention relates to a kind of preparation method of epilepsy drug topiramate.
(2) background technology
Topiramate is pharmacy (the Johnson ﹠amp of U.S. Johnson ﹠ Johnson; Johnson) reuptake inhibitor of company exploitation, nineteen ninety-five goes on the market in Britain with trade(brand)name Topamax, clinically is used to control the primary partial epilepsy.
The chemical name of topiramate is: 2, and 3:4,5-pair-O-(1-methyl ethylidene)-β-D-pyrrole sulfamate, structural formula is as follows:
The disclosed preparation method of U.S. Pat 5387700A is shown in Scheme 1:
This method adopts batch process, and the first step is reacted with SULPHURYL CHLORIDE earlier, gets chlorsulfonic acid ester (ROSO
2Cl), the second step chlorsulfonic acid ester and ammonia gas react obtain topiramate.The shortcoming of this method is to adopt batch process, after the first step reaction is finished, removes separated from solvent and goes out product, and isolated solid is dissolving again in second organic solvent, and reaction obtains final product then.Caused needs to separate semi-stability, heat-labile chlorsulfonic acid ester (ROSO thus
2Cl) method of intermediate, and used ammonia in the second step reaction, and the solvent that uses is definitely anhydrous, this just need not have water treatment to solvent, increase workload and cost.
The disclosed preparation method of U.S. Pat 20040158081A is with U.S. Pat 5387700A, different is that it is to prepare topiramate with continuous processing, this has just solved the problem of bringing in the batch process, but it has still used ammonia and absolute anhydrous solvent carries out ammonolysis reaction.And the last aftertreatment of these two patented methods all will just can be taken crystal by the method for multistep recrystallization, has increased post-processing step; And in the suitability for industrialized production, there are more adverse factors in gas ratio liquid: as reaction unit the requirement of comparison strictness is arranged, as the requirement of aspects such as stopping property, crushing resistance; Unnecessary ammonia needs to reclaim, and this just needs gas concentration unit, has increased equipment cost; The operation of gas, transportation, storage do not have the convenience of liquid, safety.
(3) summary of the invention
The purpose of this invention is to provide a kind of method that is different from the prior art for preparing topiramate, this method avoids having used ammonia, make operational safety, easy, avoid using absolute anhydrous solvent, not needing does not have water treatment to solvent, reduce cost, avoided the multistep recrystallization, only needed method of extraction just can obtain solid, and yield is suitable with prior art, suitability for industrialized production.
For reaching goal of the invention the technical solution used in the present invention be:
The method route of preparation topiramate of the present invention is shown in Scheme 2.
This method is compound 2,3:4, and 5-is two-O-(1-methyl ethylidene)-D-pyranofructose chlorsulfonic acid ester and ammoniacal liquor prepared in reaction topiramate.Concrete, under 10～40 ℃, with compound 2,3:4,5-is two-and O-(1-methyl ethylidene)-D-pyranofructose chlorsulfonic acid ester is dissolved in the organic solvent, with ammoniacal liquor reaction after 3～8 hours, leaves standstill separatory, organic layer is used rare inorganic alkali lye and washing respectively, drying, and reconcentration just obtains topiramate to doing.
Organic solvent described here is and the immiscible organic solvent of water, as hydro carbons, and C particularly
5～C
12Hydrocarbon: as pentane, hexane, hexanaphthene, heptane, toluene etc.; C
2-C
6The ester class: as ethyl acetate.
Find in the experiment, effective with the solvent (as tetrahydrofuran (THF), acetone, acetonitrile) that immiscible solvent ratio of water and water dissolve each other, be mainly reflected in the yield height.
Described rare inorganic alkali lye is 1%～10% sodium hydroxide solution, 1%～10% sodium hydrogen carbonate solution etc.
The content of ammonia is 20～37% in the described ammoniacal liquor.
Described 2,3:4,5-is two-and O-(1-methyl ethylidene)-D-pyranofructose chlorsulfonic acid ester is 1: 5～15 with the ratio of the amount of substance of ammoniacal liquor.
Can add phase-transfer catalyst in the described reaction system, reaction effect with do not add comparing of phase-transfer catalyst and do not have clear superiority.
Compound 2,3:4, the preparation of 5-pair-O-(1-methyl ethylidene)-D-pyranofructose chlorsulfonic acid ester can be with reference to U.S. Pat 20040158081A or document " Chinese Journal of Pharmaceuticals ", 1999,30 (11), 486-487.
Preparation method's beneficial effect of topiramate of the present invention is mainly reflected in: with the aqueous ammonia to replace ammonia carry out that ammonolysis reaction brought easy and simple to handle, safety reduce equipment cost, and solvent need not have water treatment, only need extraction just can obtain solid in the aftertreatment, be beneficial to suitability for industrialized production.
(4) embodiment
The present invention is described further below in conjunction with specific embodiment, but protection scope of the present invention is not limited in this:
Embodiment 1:2,3:4, the preparation of 5-pair-O-(1-methyl ethylidene)-D-pyranofructose
In reaction flask, add acetone 250mL, be chilled to-5 ℃, drip vitriol oil 12mL, stir 0.5h, in-5～15 ℃ add in batches D-fructose (20g, 0.111moL), neutralize with diluted sodium hydroxide solution behind the room temperature reaction 3h, filter pressure reducing and steaming partial solvent, cooling crystallization, get white needles thing 2 with the water recrystallization, 3:4,5-pair-O-(1-methyl ethylidene)-D-pyranofructose 17.4g, yield 60.2%.
Embodiment 2:2,3:4, the preparation of 5-pair-O-(1-methyl ethylidene)-D-pyranofructose chlorsulfonic acid ester
In reaction flask, add toluene 100mL, sulfuryl chloride 8mL (0.09moL), stir, under-10 ℃, slowly be added dropwise to and contain 2,3:4,5-pair-O-(1-methyl ethylidene)-D-pyranofructose (20g, 0.077moL) toluene 100mL and the mixing solutions of pyridine 8mL, behind room temperature reaction 3h, add the dilution of 100mL water, tell organic layer dilute hydrochloric acid, after dilute sodium hydroxide aqueous solution and the washing, anhydrous sodium sulfate drying filters, and removes toluene under reduced pressure, get buff syrup (2,3:4,5-pair-O-(1-methyl ethylidene)-D-pyranofructose chlorsulfonic acid ester) 27.1g, yield 98.4%.
Embodiment 3:2,3:4, the preparation of 5-pair-O-(1-methyl ethylidene)-Beta-D-Fructopyranose sulfamate
Under 15 ℃, with 2,3:4,5-pair-O-(1-methyl ethylidene)-D-pyranofructose chlorsulfonic acid ester (20g, 0.056moL) be dissolved in the 200mL hexanaphthene, add 38mL (0.725moL) strong aqua, reaction 5h afterreaction is complete, leave standstill separatory, after organic layer was washed and washed with sig water respectively, dried over sodium sulfate was evaporated to dried white needle-like crystals 13.6g, 50 ℃ of oven dry, yield 72%.122～124 ℃ of mp of m/z 340 (M+1) [α]
D 23=-34.0 ° of (c=0.4 in MeOH) GC content are 99.6%.
Embodiment 4:2,3:4, the preparation of 5-pair-O-(1-methyl ethylidene)-Beta-D-Fructopyranose sulfamate
Press the operation of embodiment 3, (1.7g, 0.0056moL), yield is 73% to add phase-transfer catalyst tetrabutylammonium acetate ammonium.
Embodiment 5:2,3:4, the preparation of 5-pair-O-(1-methyl ethylidene)-Beta-D-Fructopyranose sulfamate
Press the operation of embodiment 3, replace hexanaphthene with normal heptane or toluene, its yield all has about 67%.
Embodiment 6:2,3:4, the preparation of 5-pair-O-(1-methyl ethylidene)-Beta-D-Fructopyranose sulfamate
Press the operation of embodiment 3, replace hexanaphthene with acetone, acetonitrile or tetrahydrofuran (THF), its yield is about 15%.
Embodiment 7:2,3:4, the preparation of 5-pair-O-(1-methyl ethylidene)-Beta-D-Fructopyranose sulfamate
With 2,3:4,5-pair-O-(1-methyl ethylidene)-D-pyranofructose chlorsulfonic acid ester (20g, 0.056moL) be dissolved in the 300mL ethyl acetate, add 43.5mL (0.84moL) strong aqua, 35 ℃ of reaction 6h afterreactions are complete, leave standstill separatory, organic layer is washed with sig water, washing, dried over sodium sulfate is evaporated to dried white needle-like crystals 7.35g, 50 ℃ of oven dry, yield 43.0%.
Embodiment 8:2,3:4, the preparation of 5-pair-O-(1-methyl ethylidene)-Beta-D-Fructopyranose sulfamate
Press the operation of embodiment 7, ethyl acetate is replaced with normal hexane, its yield is 76%.
Embodiment 8:2,3:4, the preparation of 5-pair-O-(1-methyl ethylidene)-Beta-D-Fructopyranose sulfamate
With 2,3:4,5-pair-(20g 0.056moL) is dissolved in the 300mL normal hexane O-(1-methyl ethylidene)-D-pyranofructose chlorsulfonic acid ester, add 15mL (0.29moL) strong aqua, 20 ℃ reaction 3h afterreaction is complete down, leaves standstill separatory, and organic layer is washed with 5% sodium hydroxide solution, wash with water again, be evaporated to dried white needle-like crystals 10.4g, 60 ℃ of oven dry, yield 55.0%.
Embodiment 9:2,3:4, the preparation (Comparative Examples) of 5-pair-O-(1-methyl ethylidene)-Beta-D-Fructopyranose sulfamate
In reaction flask, add 2,3:4,5-pair-O-(1-methyl ethylidene)-D-pyranofructose chlorsulfonic acid ester (20g, 0.056moL), the 100mL anhydrous tetrahydro furan, logical dry ammonia 4h afterreaction is complete under normal temperature, normal pressure, filters, filtrate decompression is concentrated into dried, get crude product with recrystallization in the alcohol-water, the hexanaphthene recrystallization gets white needle-like crystals 12.3g, oven dry about 50 ℃, yield 65%.
Claims (9)
1. the preparation method of a topiramate, described method comprises: with structure suc as formula 2 shown in (II), 3:4,5-is two-O-(1-methyl ethylidene)-D-pyranofructose chlorsulfonic acid ester is dissolved in the organic solvent and reacts with ammoniacal liquor.
2. the preparation method of topiramate according to claim 1 is characterized in that described organic solvent is and the immiscible organic solvent of water.
3. the preparation method of topiramate according to claim 2 is characterized in that described and the immiscible organic solvent of water are C
5～C
12Hydrocarbon.
4. the preparation method of topiramate according to claim 3 is characterized in that described C
5～C
12Hydrocarbon be pentane, hexane, hexanaphthene, heptane.
5. the preparation method of topiramate according to claim 1 is characterized in that the described reaction times is 3-8 hour.
6. the preparation method of topiramate according to claim 1 is characterized in that described temperature of reaction is 10～40 ℃.
7. the preparation method of topiramate according to claim 1, it is characterized in that described reaction finishes after, leave standstill separatory, organic layer is washed with rare inorganic alkali lye, washing, drying, reconcentration is to dried topiramate.
8. the preparation method of topiramate according to claim 1, it is characterized in that described 2,3:4,5-is two-O-(1-methyl ethylidene)-D-pyranofructose chlorsulfonic acid ester is 1: 5～15 with the ratio of the amount of substance of ammoniacal liquor.
9. topiramate preparation method according to claim 1, it is characterized in that 2,3:4,5-is two-O-(1-methyl ethylidene)-D-pyranofructose chlorsulfonic acid ester be dissolved in the immiscible solvent of water in, add strong aqua, 10～40 ℃ are reacted after 3-8 hour down, leave standstill separatory, organic layer is washed with sig water, washing, dried over sodium sulfate is evaporated to dried white needle-like crystals; Described and the immiscible solvent of water is hexanaphthene, normal hexane or normal heptane; Described 2,3:4,5-is two-and O-(1-methyl ethylidene)-D-pyranofructose chlorsulfonic acid ester is 1: 5～15 with the ratio of the amount of substance of ammoniacal liquor.
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Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101979395B (en) * | 2010-09-17 | 2013-04-24 | 南京理工大学 | Method for preparing topiramate |
| CN102936268A (en) * | 2012-11-13 | 2013-02-20 | 江苏吉贝尔药业有限公司 | Process for preparing topiramate midbody acetonylidene |
| CN103910770B (en) * | 2014-03-14 | 2017-01-04 | 天津南开允公医药科技有限公司 | A kind of intermediate crystal form involved in the preparation method of topiramate and the method and preparation method thereof |
| CN106397502A (en) * | 2016-08-31 | 2017-02-15 | 安徽省润生医药股份有限公司 | Synthesis technology of topiramate |
| CN108341844A (en) * | 2018-04-25 | 2018-07-31 | 广州小桔生物科技有限公司 | A kind of preparation method of high-purity Topiramate |
| CN110655541A (en) * | 2018-06-29 | 2020-01-07 | 鲁南制药集团股份有限公司 | 2,3:4, 5-bis-O- (1-methylethylidene) -beta-D-fructopyranose chlorosulfonate crystal form |
| CN110655542A (en) * | 2018-06-29 | 2020-01-07 | 鲁南制药集团股份有限公司 | Crystal form of 2,3:4, 5-bis-O- (1-methylethylidene) -beta-D-fructopyranose chlorosulfonate |
| CN111171084B (en) * | 2020-01-07 | 2021-11-23 | 华东医药（西安）博华制药有限公司 | Improved fructose diacetone reaction liquid post-treatment method |
| CN113999228B (en) * | 2021-11-08 | 2022-11-04 | 南京卓康医药科技有限公司 | Synthesis method of tadalafil |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1646538A (en) * | 2002-02-15 | 2005-07-27 | 奥索-麦克尼尔药品公司 | Topiramate salts and compositions comprising and methods of making and using the same |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1646538A (en) * | 2002-02-15 | 2005-07-27 | 奥索-麦克尼尔药品公司 | Topiramate salts and compositions comprising and methods of making and using the same |
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Effective date of registration: 20090320 Address after: Guangde Economic Development Zone, Anhui, Zhongshan Road Patentee after: Anhui Menovo Pharmaceutical Co., Ltd. Address before: Hangzhou City, Zhejiang Province, Binjiang District Lake Road 1197 7 Building 3 layer Patentee before: Hangzhou Shengmei Medicine Technology Development Co., Ltd. |
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