CN101633639B - High-purity fleroxacin compound - Google Patents
High-purity fleroxacin compound Download PDFInfo
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- CN101633639B CN101633639B CN2009100179580A CN200910017958A CN101633639B CN 101633639 B CN101633639 B CN 101633639B CN 2009100179580 A CN2009100179580 A CN 2009100179580A CN 200910017958 A CN200910017958 A CN 200910017958A CN 101633639 B CN101633639 B CN 101633639B
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Abstract
The invention aims at providing a high-purity fleroxacin compound, and the preparation method thereof helps improve the purity and obtain an injected fleroxacin bulk drug.
Description
Technical field
The present invention relates to a kind of highly purified fleroxacin compound, belong to medical technical field.
Background technology
Fleroxacin (Fleroxacin), its chemical name is: 6,8-two fluoro-1-(2-fluoro ethyl) 1,4-dihydro-7-(4-methyl isophthalic acid-piperazinyl)-4-oxygen-3-quinoline carboxylic acid, molecular formula: C
17H
18F
3N
3O
3, molecular weight: 369.34, structural formula is:
Fleroxacin is the FQNS anti-infectives that Japanese Anzurin Pharmaceutical Co., Ltd develops, and is white to little yellow crystalline powder, odorless, mildly bitter flavor.Went on the market in Switzerland first in 1992; Obtained drugs approved by FDA in 1994, domestic in the nineteen ninety-five listing, have has a broad antifungal spectrum; Advantages such as bioavailability height and long half time can be used for treating respiratory tract, urogenital system, skin soft tissue, bone and the infection of joint and typhoid fever etc.
The synthetic route of fleroxacin, what domestic and foreign literature was reported mainly contains 3: (1) is raw material with the trifluoronitrobenzene, after reduction, with the EMME condensation, generates the fluoro ethyl thing with the reaction of tosic acid fluorine ethyl ester again, after the N methyl piperazine condensation, hydrolysis, ammonification.This route has the reaction of tosic acid fluorine ethyl ester, the aftertreatment difficulty; (2) with the trifluoromethyl aniline be raw material, with the EMME condensation after N position fluoro ethylization, cyclization, hydrolysis is again with the N methyl piperazine condensation.Need use the high and dangerous NaH of valency during the cyclization of this route, yield is obviously on the low side; (3) with the 2,3,4,5 tetra fluoro benzoic acid be raw material, with two lithium salts condensations of monoethyl malonate, with the triethyl orthoformate effect, again with the condensation of fluorine ethylamine hydrochloride, cyclization, hydrolysis is with the N methyl piperazine condensation.The starting raw material of this route is domestic still not to have production, and import price is high, and synthetic difficulty is bigger.
The fleroxacin that above-mentioned compound method obtains is oral level, and purity is lower, be not suitable for as the injection raw material, and be an importance that guarantees the injection security and in the preparation of injection, effectively reduce foreign matter content.In the existing compound method; (1) in " Chinese Pharmaceutical Journal " 1999 the 34th the 7th phases of volume " synthesis technique of injection fleroxacin improves ", the refining ammonification step in the 4th step has been passed through 2 dissolvings and backflow; Process is complicated, and is too consuming time and have a strong impact on product yield; (2) " 1999 the 30th volumes the 10th of 1999 the 17th volumes of pharmacy practice journal the 6th phase " synthesis technique of fleroxacin injection raw material " and " Chinese Journal of Pharmaceuticals " are interim; The ammonification purification step in the 4th step needs control reaction temperature and pH value; And this is difficult to accurate control in production practice; And improved cost, particularly its purity and be merely 96.4% (latter does not report), still be unsafe for injection; (3) used a kind of process for purification in the aftertreatment in " research of fleroxacin synthesis technique "; But it is as the method that is only applicable to specific reaction (hydrolysis of alkali formula); The material that not only adds, in proper order different with the present invention; And its purpose only is to eliminate raw material and impurity in this specific reactions, therefore do not have general significance (this article is not reported the yield of this method yet), in literary composition thereafter, also adopted in the subsequent disposal of acid hydrolysis with (2) in method like two pieces of document categories; And this article thinks that alkali formula hydrolysis impurity is more, do not recommend basically.
Therefore, although after fleroxacin preparation, some purification step is provided all in the prior art, they are owing to exist above-mentioned defective, and are difficult to be successfully used to the production practice of injection fleroxacin.This area presses for and addresses the above problem.
Summary of the invention
The purpose of this invention is to provide a kind of process for purification of fleroxacin compound, method is easy, and is with low cost, improved purity very effectively, obtains a kind of injection stage bulk drug of fleroxacin.
In order to realize the foregoing invention purpose, technical scheme of the present invention is following:
The process for purification of the fleroxacin compound of structure shown in a kind of formula (I),
Comprise the steps: in fleroxacin bullion compound, to add acid solution to dissolving fully, decarburization is filtered in the adding charcoal absorption, and filtrating adds alkaline solution again, separates out solid, filter, and washing, drying gets the fleroxacin highly finished product.
Wherein, above-mentioned described method, described acid is selected from one or more in lactic acid, Citric Acid, toxilic acid, oxysuccinic acid, oxalic acid, the tartrate, is preferably lactic acid; Described alkali is sodium hydroxide, Pottasium Hydroxide or ammoniacal liquor.
Above-mentioned described method, the amount that adds gac accounts for the 0.05%-1% (g/ml) of overall solution volume, is preferably 0.1%-0.5% (g/ml).
Above-mentioned described method after separating out solid filtering, is used water washing, dry 2-5 hour of 50 ℃ of-60 ℃ of reduced vacuum.
As embodiment preferred of the present invention, the process for purification of fleroxacin compound provided by the invention comprises the steps: in fleroxacin bullion compound, to add acid solution to dissolving fully; Adding was filtered decarburization with respect to charcoal absorption 20-30 minute of overall solution volume 0.05%-1% (g/ml), and filtrating adds alkaline solution again; Solid is separated out in stirring, filters, and filter cake is used water washing; Dry 2-5 hour of 50 ℃ of-60 ℃ of reduced vacuum, the fleroxacin highly finished product.
The inventor finds, the thick product of fleroxacin is added the acid dissolving, has compared with prior art significantly reduced the consumption of water, is beneficial to refining; Add then adsorbable impurity of gac or colored substance; And then filter and to add alkali, can obtain purity and reach the highly finished product more than 99.8%, thereby improve the security of injection formulations greatly.Simultaneously, method of the present invention is controlled temperature and pH accurately, has reduced the production cost of enterprise, and this all is very favourable for the producers and consumers.
Compare with existing fleroxacin compound preparation method, the inventive method can make highly purified highly finished product, and purity reaches more than 99.8%, and yield surpasses 90%.The inventive method has obtained a kind of fleroxacin of high purity injection stage, thereby safe injection raw material is provided.The inventive method is simple, easy handling, is suitable for large-scale industrial production.
Embodiment
Below further explain or explanation content of the present invention, but embodiment should not be understood that the restriction to protection domain of the present invention through embodiment.
Making with extra care of embodiment 1 fleroxacin
Get the 100g fleroxacin, add 1500ml water and 22g toxilic acid, stir all dissolvings, add 0.85g charcoal absorption 30 minutes; Filter decarburization, filtrating adds the sodium hydroxide solution 10ml of 0.1mol/L again, stirs and separates out solid; Filter filter cake water 30ml * 3 washings, dry 5 hours of 50 ℃ of reduced vacuum; Get fleroxacin highly finished product 93.7g, yield 93.7%, it is 99.94% that the HPLC method detects purity.
Making with extra care of embodiment 2 fleroxacins
Get the 100g fleroxacin, add 1500ml water and 60ml lactic acid, stir all dissolvings, add 17g charcoal absorption 20 minutes; Filter decarburization, filtrating adds 10% ammonia soln 30ml again, stirs and separates out solid; Filter filter cake water 30ml * 3 washings, dry 2 hours of 60 ℃ of reduced vacuum; Get fleroxacin highly finished product 91.6g, yield 91.6%, it is 99.89% that the HPLC method detects purity.
Making with extra care of embodiment 3 fleroxacins
Get the 100g fleroxacin, add 1500ml water and 60ml lactic acid, stir all dissolvings, add 1.7g charcoal absorption 30 minutes; Filter decarburization, filtrating adds the potassium hydroxide solution 15ml of 0.1mol/L again, stirs and separates out solid; Filter filter cake water 30ml * 3 washings, dry 4 hours of 55 ℃ of reduced vacuum; Get fleroxacin highly finished product 92.4g, yield 92.4%, it is 99.92% that the HPLC method detects purity.
Making with extra care of embodiment 4 fleroxacins
Get the 100g fleroxacin, add 1500ml water and 80ml oxysuccinic acid, stir all dissolvings, add 8.5g charcoal absorption 20 minutes; Filter decarburization, filtrating adds 10% ammonia soln 30ml again, stirs and separates out solid; Filter filter cake water 30ml * 3 washings, dry 3 hours of 60 ℃ of reduced vacuum; Get fleroxacin highly finished product 94.1g, yield 94.1%, it is 99.93% that the HPLC method detects purity.
Making with extra care of embodiment 5 fleroxacins
Get the 100g fleroxacin, add 1500ml water and 10g Citric Acid, stir all dissolvings, add 5.1g charcoal absorption 30 minutes; Filter decarburization, filtrating adds 0.5mol/L sodium hydroxide solution 10ml again, stirs and separates out solid; Filter filter cake water 30ml * 3 washings, dry 5 hours of 50 ℃ of reduced vacuum; Get fleroxacin highly finished product 90.8g, yield 90.8%, it is 99.90% that the HPLC method detects purity.
The Test Example structural identification
Ultimate analysis: theoretical value C:55.28%, H:4.91%, N:11.38%, F:15.43%;
Experimental value C:55.33%, H:4.96%, N:11.17%, F:15.39%.
IR(KBr)cm
-1：3420，2797，1718，1626，1479，816；
1H-NMR (CDCl
3) δ: 3.32 (s, 3H ,-CH
3); 3.5-4.18 (m, 8H, 2-CH
2CH
2-); 4.96-5.44 (m, 4h ,-CH
2CH
2-); (8.38 J=11.02 is single hydrogen on the phenyl ring for d, 1H); (9.36 s, 1H, lonely hydrogen on the quinoline ring).
MS (m/z): 369 is molecular ion peak, and 325,254,221 all can obtain reasonably cracking parsing.
Should be appreciated that these embodiment only are the explanations to preferred version of the present invention, and also limit protection scope of the present invention never in any form.Those skilled in the art under the prerequisite that does not deviate from the present invention's spirit and purport, can carry out suitable modification and improvement to the present invention under the instruction of the disclosed content of the present invention, these all will fall within the scope of the present invention.
Claims (1)
1. the process for purification of the fleroxacin compound of structure shown in the formula (I),
It is characterized in that comprising the steps: to get the 100g fleroxacin, add 1500ml water and 22g toxilic acid, stir all dissolvings; Add 0.85g charcoal absorption 30 minutes, filter decarburization, filtrating adds the sodium hydroxide solution 10ml of 0.1mol/L again; Solid is separated out in stirring, filters filter cake water 30ml * 3 washings; Dry 5 hours of 50 ℃ of reduced vacuum, fleroxacin highly finished product 93.7g.
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| CN2009100179580A CN101633639B (en) | 2009-08-26 | 2009-08-26 | High-purity fleroxacin compound |
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| CN2009100179580A CN101633639B (en) | 2009-08-26 | 2009-08-26 | High-purity fleroxacin compound |
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| CN101633639A CN101633639A (en) | 2010-01-27 |
| CN101633639B true CN101633639B (en) | 2012-11-21 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105566217B (en) * | 2016-02-23 | 2019-03-01 | 青岛科技大学 | A kind of purification process of fleraxacin crude product |
| CN109438346A (en) * | 2018-12-30 | 2019-03-08 | 广东新南方青蒿药业股份有限公司 | A kind of piperaquine preparation method of high yield |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1857266A (en) * | 2006-03-17 | 2006-11-08 | 通化东日药业股份有限公司 | Fleroxacin injection and its preparing method |
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2009
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1857266A (en) * | 2006-03-17 | 2006-11-08 | 通化东日药业股份有限公司 | Fleroxacin injection and its preparing method |
Non-Patent Citations (4)
| Title |
|---|
| 丁健等.氟罗沙星的合成.《中国医药工业杂志》.1999,第30卷(第10期),435-436. * |
| 刘波等.氟罗沙星葡萄糖注射液的处方研究.《黑龙江医药》.2007,第20卷(第3期),237-238. * |
| 孙学惠等.注射用氟罗沙星的合成工艺改进.《中国药学杂志》.1999,第34卷(第7期),492-493. * |
| 鄢立刚等.氟罗沙星针剂原料的合成工艺.《药学实践杂志》.1999,第17卷(第6期),349-351. * |
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