CN104098561B - A kind of method preparing high-optical-purity Moxifloxacin hydrochloride of applicable suitability for industrialized production - Google Patents
A kind of method preparing high-optical-purity Moxifloxacin hydrochloride of applicable suitability for industrialized production Download PDFInfo
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- CN104098561B CN104098561B CN201310123679.9A CN201310123679A CN104098561B CN 104098561 B CN104098561 B CN 104098561B CN 201310123679 A CN201310123679 A CN 201310123679A CN 104098561 B CN104098561 B CN 104098561B
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- 0 *=C(C1C2NCCC1)N(Cc1ccccc1)C2=O Chemical compound *=C(C1C2NCCC1)N(Cc1ccccc1)C2=O 0.000 description 4
- WGQKYBSKWIADBV-UHFFFAOYSA-N NCc1ccccc1 Chemical compound NCc1ccccc1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 1
- SPOPKWOPBJMODQ-SOFGYWHQSA-N O/C(/c1c(C(O)=O)nccc1)=C1/OC1 Chemical compound O/C(/c1c(C(O)=O)nccc1)=C1/OC1 SPOPKWOPBJMODQ-SOFGYWHQSA-N 0.000 description 1
- DWUBVULEMQOCPO-UHFFFAOYSA-N O=C(c1c2nccc1)N(Cc1ccccc1)C2=O Chemical compound O=C(c1c2nccc1)N(Cc1ccccc1)C2=O DWUBVULEMQOCPO-UHFFFAOYSA-N 0.000 description 1
- MCQOWYALZVKMAR-UHFFFAOYSA-N O=C(c1c2nccc1)OC2=O Chemical compound O=C(c1c2nccc1)OC2=O MCQOWYALZVKMAR-UHFFFAOYSA-N 0.000 description 1
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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Abstract
The invention provides a kind of method preparing high-optical-purity Moxifloxacin hydrochloride of applicable suitability for industrialized production: namely to contain the Moxifloxacin hydrochloride of 0.2 ~ 5% optical isomer for raw material, prepare optical siomerism body burden & lt; The optical purity Moxifloxacin hydrochloride (type I compound) of 0.01%.Novel method provided by the invention avoids the method that conventional chiral reagent splits, and utilizes himself alkalescence strong and weak different, by the method for acid-base neutralisation, can obtain high optically pure Moxifloxacin hydrochloride, product cost is low, and yield is high, technique is simple, is applicable to suitability for industrialized production.
Description
Technical field
The present invention relates to a kind of preparation method for improving medicine industry pharmaceutical active compound Moxifloxacin hydrochloride optical purity.
Technical background
Moxifloxacin hydrochloride (moxifloxacinhydrochloride), chemistry 1-cyclopropyl-7-[(S by name, S)-2,8-diazonium-two ring [4.3.0] nonanal-8-group] the fluoro-8-methoxy-1 of-6-, 4-dihydro-4-oxygen-3-quinoline carboxylic acid hydrochloride, its structural formula is such as formula (I).This medicine is wide spectrum flouroquinolone drugs of new generation, all has anti-microbial activity widely to gram-positive and negative pathogens (comprising anerobe, intracellular pathogen and the bacterial strain to beta-lactam or Macrolide antimicrobial drug resistance).Be used for the treatment of the adult suffering from the upper respiratory tract and lower respiratory infection clinically.Moxifloxacin hydrochloride is developed by German Bayer company, and in September, 1999, December in the same year was examined by U.S. FDA first in Germany's listing, approval listing, successively in Britain, the U.S., Mexico's application.China to be gone on the market Moxifloxacin tablet in 2002 by Bayer, listing Moxifloxacin sodium chloride injection in 2004.
There are two chiral centres in Moxifloxacin hydrochloride molecular structure, are chipal compounds, belong to chiral drug.
Large quantity research and clinical practice show, two kinds of enantiomorphs of chiral drug usually have different biologic activity and function, restriction chiral drug DL body is produced, and exploitation single enantiomer medicine, has become the set policy of various countries' medical control decision-making section and pharmaceutical industry.Therefore strictly must control the content of isomer, how efficiently the obtained individual isomer of highly selective is the challenge that pendulum is huge in face of us.
Synthesis mainly quinoline carboxylic acid's parent nucleus and the chiral side chain condensation preparation under protection or unprotected condition of the Moxifloxacin hydrochloride of bibliographical information:
Disclosed in patent EP1832587, the synthetic method of Moxifloxacin hydrochloride is as follows:
Disclosed in patent WO2005012285, WO2008059223, the synthetic method of Moxifloxacin hydrochloride is as follows:
Moxifloxacin hydrochloride chirality is introduced by chiral side chain ((S, S)-2,8-diazabicyclo [4,3,0] nonane), and in the preparation method of above-mentioned report, chiral side chain ee value is 100%, isomer-free.(S, S)-2,8-diazabicyclo [4,3,0] nonane synthesis are as follows:
(S, S)-2,8-diazabicyclo [4,3,0] nonane preparation in need through chiral separation, split weak effect, product yield is low.Domestic market is sold (S, S)-2,8-diazabicyclo [4,3,0] nonane product content of isomer be 0.1 ~ 5%.Isomer is brought in the finished product Moxifloxacin hydrochloride with reaction.Such product cannot reach medicinal standard.
As the Moxifloxacin hydrochloride of more high-optical-purity will be obtained, chiral side chain or Moxifloxacin chiral separation can only be carried out.Chiral side chain is small molecules saturated alkane, weak with resolution reagent bonding force, and split weak effect, product yield is low, and therefore improve with purity, product price sharply increases.
Patent EP1992626 uses L-TARTARIC ACID, fumaric acid, L-bis-pairs of toluoyltartaric to split the Moxifloxacin hydrochloride containing 3 ~ 5% isomer in N ' dinethylformamide (DMF) respectively, splits efficiency as following table:
| Resolution reagent | Content of isomer before splitting | Content of isomer after splitting | Yield |
| L-TARTARIC ACID | 3～5％ | 0.04％ | 90.2％ |
| Fumaric acid | 3～5％ | 3～5％ | 89.2％ |
| L-bis-pairs of toluoyltartaric | 3～5％ | 0.1％ | 81.9％ |
The method preparing Moxifloxacin hydrochloride of above-mentioned bibliographical information needs to split with chiral selectors, this method exist product cost high, need the problem such as chiral separation, DMF organic solvent aftertreatment trouble, restriction Moxifloxacin hydrochloride suitability for industrialized production.
Summary of the invention
In order to improve the optical purity of Moxifloxacin hydrochloride product, reduce production cost, we are in Moxifloxacin hydrochloride preparation research process, develop a kind of method of raising Moxifloxacin hydrochloride optical purity of applicable suitability for industrialized production, present invention process is simple, cost is low, yield is high, without the need to chiral selectors, optical purity of products is high.
Whether Moxifloxacin alkalescence is relevant with the raw conjugation of quinoline environment-development to side chain 8 nitrogen-atoms lone electron pairs, owing to being subject to steric interference, (S, S) configuration moxifloxacin side chain 8-nitrogen-atoms lone electron pair can not with quinoline ring conjugation, and (R, R) configuration moxifloxacin side chain 8-nitrogen-atoms lone electron pair can with quinoline ring conjugation.By conjugative effect, side chain 8-nitrogen-atoms cloud density is reduced, and alkalescence strengthens, Moxifloxacin steric configuration is as follows:
The technical solution adopted in the present invention is: by the Moxifloxacin hydrochloride containing 0.2 ~ 5% isomer in organic solvent, add alkali, by soda acid principle,displacement, by controlling the consumption of alkali, first by weakly alkaline (S, S) configuration Moxifloxacin hydrochloride is transformed into the dissolving of Moxifloxacin base form in organic solvent, and alkaline (R, R) configuration Moxifloxacin hydrochloride does not react, and is still insoluble to organic solvent, filters, filtering insolubles, filtrate adds concentrated hydrochloric acid, then is transformed into hydrochloride form precipitation, is prepared into high optical purity Moxifloxacin hydrochloride.
The invention provides a kind of method preparing high-optical-purity Moxifloxacin hydrochloride, its step is as follows:
By the Moxifloxacin hydrochloride containing 0.2 ~ 5% isomer in organic solvent, add alkali, be converted into Moxifloxacin base form, make it dissolve in organic solvent, filter, the solid salt that filtering is insoluble, filtrate adds concentrated hydrochloric acid, adjust pH to 1, stirring and crystallizing, is prepared into high optical purity Moxifloxacin hydrochloride.
Described organic solvent is any one or multiple mixed solvent etc. in ethanol, methyl alcohol, acetone, Virahol, acetonitrile, preferred alcohol, more preferably dehydrated alcohol.
Described alkali is organic bases or mineral alkali, and particularly preferred is sodium hydroxide, triethylamine, ammoniacal liquor.
Described dissolving mineral alkali agents useful for same is anhydrous organic reagent.
Described in and the molar fraction ratio of Moxifloxacin hydrochloride alkali be 1: 0.9 ~ 1: 1.2, particularly preferred ratio is 1: 1.
Beneficial effect
Compared with prior art, improvements of the present invention are not by the method that chiral reagent splits, and by conventional soda acid neutralization method, prepare the Moxifloxacin hydrochloride of high-optical-purity.The present invention greatly can reduce the production cost of product: (1) (S, S)-2,8-diazabicyclo [4,3,0] nonane product price is relevant with content of isomer, content of isomer more low price is more expensive, and the present invention uses the high and low optical purity chiral side chain of content of isomer to prepare the Moxifloxacin hydrochloride of low optical purity for raw material, low price.(2) without chiral separation, avoid the chiral selectors using price high, use conventional organic solvent, be convenient to recycle and reuse.
Meanwhile, Moxifloxacin hydrochloride optical purity prepared by this law high (ee% > 99.8%), product yield is high, and technique is simple, and reaction conditions gentleness is easy to control, and aftertreatment energy consumption is low, is applicable to suitability for industrialized production.
Accompanying drawing explanation
Fig. 1 raceme Moxifloxacin hydrochloride HPLC schemes
Before Fig. 2 process, Moxifloxacin hydrochloride HPLC schemes
Moxifloxacin hydrochloride HPLC prepared by Fig. 3 embodiment 1 schemes
Moxifloxacin hydrochloride HPLC prepared by Fig. 4 embodiment 2 schemes
Moxifloxacin hydrochloride HPLC prepared by Fig. 5 embodiment 3 schemes
The Moxifloxacin hydrochloride HPLC that Fig. 6 is prepared according to patent EP1992626 schemes
Specific implementation method
Should be appreciated that, those skilled in the art, based on content disclosed in this, can carry out variously not departing from various amendment in spirit and scope of the invention and improvement to the present invention.They should drop in the scope of patent protection of patent requirements definition of the application.In addition, should be appreciated that, embodiment provided herein only for illustration of object of the present invention, and should not be construed as restriction of the present invention.
Embodiment 1: the preparation of Moxifloxacin hydrochloride
In 50L reactor, add dehydrated alcohol 20L, add Moxifloxacin hydrochloride 2kg, under the condition of stirring, instillation sodium hydrate methanol solution (1L, NaOH182.6g), stirring at room temperature 0.5h, filters, filtrate adjusts pH ≈ 1 with concentrated hydrochloric acid, stirring at room temperature 1h, filters, obtains Moxifloxacin hydrochloride 1.92kg.
Yield: 96.0%
Content of isomer: 0.01%
Embodiment 2: the preparation of Moxifloxacin hydrochloride
In 50L reactor, add dehydrated alcohol 20L, add Moxifloxacin hydrochloride 2kg, under the condition of stirring, instillation triethylamine 632mL, is heated to 60 DEG C of stirring reactions 30 minutes, is chilled to 20 ~ 25 DEG C, filter, filtrate adjusts pH ≈ 1, stirring at room temperature 1h with concentrated hydrochloric acid, filters, obtains Moxifloxacin hydrochloride 1.78kg.
Yield is 89.0%.
Content of isomer: do not detect
Embodiment 3: the preparation of Moxifloxacin hydrochloride
In 50L reactor, add dehydrated alcohol 20L, add Moxifloxacin hydrochloride 2kg, under the condition of stirring, instillation strong aqua 280mL, stirring at room temperature 0.5h, filters, and filtrate adjusts pH ≈ 1, stirring at room temperature 1h with concentrated hydrochloric acid, filters, obtains Moxifloxacin hydrochloride 1.69kg.
Yield: 84.5%
Content of isomer: 0.01%
Comparative example 1: patent EP1992626 method for splitting
Add 50g Moxifloxacin in 750mlDMF solution, 18.7gL-(+)-tartrate, stirring reaction 3 hours at 75 ~ 80 DEG C, be cooled to 25 ~ 30 DEG C after reaction terminates and stir 10 ~ 12 hours.Suction filtration, solid 100mlDMF washs, 75 DEG C of vacuum-dryings, obtains tartrate Moxifloxacin 67.3g (98.08%).
50g tartrate Moxifloxacin is added in 250ml ethanol and the 250ml aqueous solution, stir, 16.6ml concentrated hydrochloric acid is added at 25 ~ 30 DEG C, stirring reaction 1 hour at this temperature, suction filtration, filter cake 100ml washing with alcohol, 50 ~ 55 DEG C of vacuum-drying 3 hours, obtains Moxifloxacin hydrochloride 35.10g (88.3%).
Yield: 86.61%
Content of isomer: 0.05%
Analytical procedure
Get the product obtained in above-described embodiment 1 to 3 and comparative example 1 appropriate, add moving phase and dissolve and dilute the solution made about containing 1.0mg in every 1ml, as need testing solution.Measure according to high performance liquid chromatography (Chinese Pharmacopoeia version in 2010 two annex VD).Be weighting agent with octadecylsilane chemically bonded silica, (copper sulfate 1g and L-Phe 1.32g is got with copper sulfate L-Phe solution, after the 1000ml that adds water dissolves, regulating pH to 3.5 with sodium hydroxide test solution)-methyl alcohol (71: 29) is moving phase; Flow velocity is 1.0ml/min; Column temperature is 35 DEG C, and determined wavelength is 293nm.Cancel and revolve Moxifloxacin hydrochloride reference substance in right amount, add moving phase and dissolve in right amount and dilute the solution made about containing 0.2mg in every 1ml, get 10 μ l injection liquid chromatographies, record color atlas, dextrorotatory isomer, Moxifloxacin flow out successively, and resolution should meet the requirements.Precision measures need testing solution 10 μ l, injection liquid chromatography, and record color atlas, calculates by normalization method.
Accordingly result sees the following form
| Content of isomer (%) before process | Content of isomer after process | Yield (%) | |
| Embodiment 1 | 1.21 | 0.01 | 96.00 |
| Embodiment 2 | 1.21 | 0 | 89.00 |
| Embodiment 3 | 1.21 | 0.01 | 84.50 |
| Comparative example 1 | 1.21 | 0.05 | 86.61 |
Claims (4)
1. prepare the method for high-optical-purity Moxifloxacin hydrochloride for one kind, it is characterized in that: with the Moxifloxacin hydrochloride containing 0.2 ~ 5% optical isomer for raw material, alkali is added in dehydrated alcohol, Moxifloxacin hydrochloride is transformed into Moxifloxacin base form, filter, filtering insolubles, adds concentrated hydrochloric acid in organic phase, filter, obtain high optically pure Moxifloxacin hydrochloride.
2. the method for claim 1, wherein alkali described in it is the one in sodium hydroxide, triethylamine, ammoniacal liquor.
3. the method for claim 1, the molfraction of Moxifloxacin hydrochloride and alkali is than being 1:(1-1.2).
4. the method for claim 1, wherein starting raw material Moxifloxacin is hydrochloride form.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US20060264635A1 (en) * | 2003-08-05 | 2006-11-23 | Chava Satyanarayana | Process for the preparation of moxifloxacin hydrochloride |
| ES2284380B1 (en) * | 2006-03-10 | 2008-11-01 | Quimica Sintetica S.A. | PROCEDURE FOR THE PREPARATION OF MOXIFLOXACINO AND MOXIFLOXACINO CHLORHYDRATE. |
| KR20150048920A (en) * | 2006-11-13 | 2015-05-07 | 씨아이피엘에이 엘티디. | Process for the synthesis of moxifloxacin hydrochloride |
| EP1992626A1 (en) * | 2007-05-10 | 2008-11-19 | Sandoz AG | Process for the preparation of moxifloxacin hydrochloride |
| CN102675313A (en) * | 2011-10-12 | 2012-09-19 | 郭峰 | Preparation method of moxifloxacin hydrochloride |
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Effective date of registration: 20191211 Address after: Xinluo Avenue high tech Zone of Ji'nan City, Shandong Province, No. 989 250101 Patentee after: Pharmaceutical Sciences, Shandong Province Address before: Xinluo Avenue high tech Zone of Ji'nan City, Shandong Province, No. 989 250101 Patentee before: SHANDONG PROVINCE BIOMEDICAL ACADEMY OF SCIENCES |