CN104628720A - Refining method of moxifloxacin hydrochloride - Google Patents
Refining method of moxifloxacin hydrochloride Download PDFInfo
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- CN104628720A CN104628720A CN201310571399.4A CN201310571399A CN104628720A CN 104628720 A CN104628720 A CN 104628720A CN 201310571399 A CN201310571399 A CN 201310571399A CN 104628720 A CN104628720 A CN 104628720A
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- moxifloxacin
- tartaric acid
- moxifloxacin hydrochloride
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- C—CHEMISTRY; METALLURGY
- 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
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Abstract
The invention discloses a refining method of moxifloxacin hydrochloride. The method comprises the following steps: performing reaction on a moxifloxacin hydrochloride crude product and L-tartaric acid to obtain L-tartaric acid moxifloxacin; adding hydrochloric acid into L-tartaric acid moxifloxacin solution; stirring for crystallizing; filtering; washing; drying to obtain moxifloxacin hydrochloride. The method is easy to operate, mild in condition, high in yield and high in product purity and can be put into industrialization easily; the obtained moxifloxacin hydrochloride is high in solubility, relatively low in solution light turbidity and high in physical property.
Description
Technical field
The invention belongs to medical art, be specifically related to the process for purification of Moxifloxacin hydrochloride.
Background technology
Moxifloxacin hydrochloride (Avelox, Avalox) is the super broad spectrum quinolone class medicine of Bayer A.G's development, trade(brand)name: visit multiple pleasure.Moxifloxacin hydrochloride structural formula is as follows:
Moxifloxacin demonstrates gram positive organism, gram-negative bacteria, anerobe, acid fast bacteria and atypical microorganism in vitro as mycoplasma, chlamydozoan and legionella have broad spectrum antibiotic activity.Antibacterial mechanisms is interference II, IV topoisomerase.Topoisomerase is control DNA topological sum DNA replication dna, repair and transcribe in key enzyme.Moxifloxacin is active high in vivo.Can almost be absorbed completely very soon after moxifloxacin oral, absolute bioavailability amounts to about 91%, when reaching peak 0.5 ~ 4 hour.Moxifloxacin administration does not affect by feed, and the transformation period reaches 12 hours, without cytochrome P 450 enzymes metabolism, decrease the possibility of drug drug interaction, renal metabolism 45%, liver metabolism 52%, the patient of kidney function damage and slight hepatic insufficiency is without the need to adjusting dosage.
Be suitable for medicinal raw material need Moxifloxacin hydrochloride crude product to refine to obtain.The crystallization processes of the moxifloxacin hydrochloride reported at present need to improve on productive rate, product purity and physico-chemical property.
Summary of the invention
The object of the present invention is to provide a kind of simple to operate, mild condition, yield are high, product purity is high and be easy to the process for purification of industrialized moxifloxacin hydrochloride.
The process for purification of moxifloxacin hydrochloride provided by the present invention, comprises the following steps:
(1) Moxifloxacin hydrochloride crude product and L-TARTARIC ACID are reacted, obtain L-TARTARIC ACID Moxifloxacin;
(2) in L-TARTARIC ACID Moxifloxacin solution, add hydrochloric acid, stirring and crystallizing, filter, washing, drying obtains moxifloxacin hydrochloride.
The process of above-mentioned process for purification can as follows shown in reaction formula:
Step (1) is under organic bases triethylamine existent condition, is solvent with dimethyl formamide, Moxifloxacin hydrochloride crude product and L-TARTARIC ACID is reacted and generates L-TARTARIC ACID Moxifloxacin.Concrete, the Moxifloxacin hydrochloride crude product of step (1) by 30-40 weight part, the DMF(dimethyl formamide of 200-300 weight part), the mixing of the triethylamine of 9-15 weight part, slowly be warming up to 70-90 DEG C, add the L-TARTARIC ACID of 11-13 weight part, 65-75 DEG C of insulation reaction 2-4 hour.Reaction end is cooled to room temperature, stirs 5-10h.Centrifuging, a small amount of DMF washes, dry, obtains L-TARTARIC ACID Moxifloxacin.
L-TARTARIC ACID Moxifloxacin is dissolved in the mixing solutions of second alcohol and water by step (2), then adds hydrochloric acid, separates out moxifloxacin hydrochloride.Concrete, the L-TARTARIC ACID Moxifloxacin of 30-40 weight part step (1) prepared adds in the mixing solutions of the ethanol of 70-90 weight part and the water of 150-200 weight part, and intensification stirring and dissolving, adds activated carbon decolorizing, filters; Filtrate under agitation adds hydrochloric acid needs to add 19-21 weight part usually commercially available concentrated hydrochloric acid to pH≤0.5(), stirring at room temperature 1-3 hour, yellow solid is had to separate out, be cooled to 0 ~ 5 DEG C, stir 0.5-2 hour, centrifuging, a small amount of ethanol/water drip washing filter cake, dry, dry, obtain moxifloxacin hydrochloride finished product.
The advantage of technical solution of the present invention is:
1: the chiral auxiliary L-TARTARIC ACID that the present invention adopts raw material easily to obtain is as the brand-new hand-type resolution reagent of Moxifloxacin, the cheap cost of this chiral selectors raw material is lower, therefore, compared with the method (CN98811444.5) reported at present, method of the present invention is more suitable for the industrialized production of Moxifloxacin;
2: the Moxifloxacin product that method of the present invention obtains, compared with the crystallization processes of currently reported (CN989104574.0), the selection of productive rate and enantiomorph has clear superiority;
3: the Moxifloxacin product that the present invention obtains not containing any solvent and recrystallisation solvent thing, is the form of hydrochloride compared with currently reported (CN96123220.X);
4: the moxifloxacin hydrochloride that the present invention obtains is well water-soluble, compared with the moxifloxacin hydrochloride of currently reported (CN00811427.7, CN99811509.6), there is better solvability, this moxifloxacin hydrochloride solution light turbidity is lower simultaneously, is more suitable for the mode of fluid administration;
5: moxifloxacin hydrochloride of the present invention has excellent physical property, make it in bioavailability and bioequivalence, have more significantly advantage, compared with currently reported (CN99813124.5), especially more obvious when it takes solid form delivery system, the consumption of various auxiliary material can be reduced.
Embodiment
The invention will be further described by the following examples, but this is not limitation of the present invention, those skilled in the art, according to basic thought of the present invention, can make various amendment or improvement, but only otherwise depart from basic thought of the present invention, all within the scope of the present invention.
Embodiment 1:
Step 1: the preparation (Chiral Separation) of tartrate Moxifloxacin
34.0kg Moxifloxacin hydrochloride crude product, 238kg DMF, 9.9kg triethylamine are added in reactor and stirs, be slowly warming up to about 80 DEG C, add L-TARTARIC ACID 12.1kg, 65-75 DEG C of insulation reaction 3 hours.Reaction end is cooled to room temperature, stirs 6h.Centrifuging, a small amount of DMF washes, and dry (vacuum-0.07 ~-0.08MPa, the temperature inside the box 60 ~ 70 DEG C, dry 7.0 ~ 8.0 hours) obtain L-TARTARIC ACID Moxifloxacin 37.1kg.Yield is the purity that 87.15%, HPLC records L-TARTARIC ACID Moxifloxacin is 99.83%.
Step 2: the preparation of Moxifloxacin hydrochloride finished product
Add in dissolving vessel by 40kg L-TARTARIC ACID Moxifloxacin, 90kg dehydrated alcohol and 200kg water, intensification stirring and dissolving, add activated carbon decolorizing 30min, press filtration enters in finished product crystallizer, adds 20kg concentrated hydrochloric acid to pH≤0.5 under stirring.Stirring at room temperature 2 hours, has yellow solid to separate out, and is cooled to 0 ~ 5 DEG C, stirs 1hr.Centrifuging, with a small amount of ethanol/water (volume ratio 2.2:1) drip washing filter cake, dries.Discharging, dry (vacuum-0.07 ~-0.08MPa, the temperature inside the box 40 ~ 50 DEG C, dry 5.0 ~ 6.0 hours) obtain Moxifloxacin hydrochloride finished product 24.12kg.Yield is 81.88%, and product (entirely examining) is qualified.
Embodiment 2:
Step 1: the preparation (Chiral Separation) of tartrate Moxifloxacin
40kg Moxifloxacin hydrochloride crude product, 300kg DMF, 15kg triethylamine are added in reactor and stirs, be slowly warming up to about 80 DEG C, add L-TARTARIC ACID 13kg, 65-75 DEG C of insulation reaction 3 hours.Reaction end is cooled to room temperature, stirs 6h.Centrifuging, a small amount of DMF washes, and dry (vacuum-0.07 ~-0.08MPa, the temperature inside the box 60 ~ 70 DEG C, dry 7.0 ~ 8.0 hours) obtain L-TARTARIC ACID Moxifloxacin 37.1kg.Yield is the purity that 87.15%, HPLC records L-TARTARIC ACID Moxifloxacin is 99.83%.
Step 2: the preparation of Moxifloxacin hydrochloride finished product
Add in dissolving vessel by 37.0kg L-TARTARIC ACID Moxifloxacin, 84.5kg dehydrated alcohol and 186.0kg water, intensification stirring and dissolving, add activated carbon decolorizing 30min, press filtration enters in finished product crystallizer, adds 19.5kg concentrated hydrochloric acid to pH≤0.5 under stirring.Stirring at room temperature 2 hours, has yellow solid to separate out, and is cooled to 0 ~ 5 DEG C, stirs 1hr.Centrifuging, with a small amount of ethanol/water (volume ratio 2.2:1) drip washing filter cake, dries.Discharging, dry (vacuum-0.07 ~-0.08MPa, the temperature inside the box 40 ~ 50 DEG C, dry 5.0 ~ 6.0 hours) obtain Moxifloxacin hydrochloride finished product 24.12kg.Yield is 81.88%, and product (entirely examining) is qualified.
Embodiment 3:
Step 1: the preparation (Chiral Separation) of tartrate Moxifloxacin
30kg Moxifloxacin hydrochloride crude product, 200kg DMF, 9kg triethylamine are added in reactor and stirs, be slowly warming up to about 80 DEG C, add L-TARTARIC ACID 11kg, 65-75 DEG C of insulation reaction 3 hours.Reaction end is cooled to room temperature, stirs 6h.Centrifuging, a small amount of DMF washes, and dry (vacuum-0.07 ~-0.08MPa, the temperature inside the box 60 ~ 70 DEG C, dry 7.0 ~ 8.0 hours) obtain L-TARTARIC ACID Moxifloxacin 37.1kg.Yield is the purity that 87.15%, HPLC records L-TARTARIC ACID Moxifloxacin is 99.83%.
Step 2: the preparation of Moxifloxacin hydrochloride finished product
Add in dissolving vessel by 30kg L-TARTARIC ACID Moxifloxacin, 70kg dehydrated alcohol and 150kg water, intensification stirring and dissolving, add activated carbon decolorizing 30min, press filtration enters in finished product crystallizer, adds 19kg concentrated hydrochloric acid to pH≤0.5 under stirring.Stirring at room temperature 2 hours, has yellow solid to separate out, and is cooled to 0 ~ 5 DEG C, stirs 1hr.Centrifuging, with a small amount of ethanol/water (volume ratio 2.2:1) drip washing filter cake, dries.Discharging, dry (vacuum-0.07 ~-0.08MPa, the temperature inside the box 40 ~ 50 DEG C, dry 5.0 ~ 6.0 hours) obtain Moxifloxacin hydrochloride finished product 24.12kg.Yield is 81.88%, and product (entirely examining) is qualified.
Experimental example 1: Moxifloxacin bulk drug solubleness compares
Measuring method: take the trial-product that is ground into fine powder or measure liquid trial-product; be placed in the solvent of certain capacity, in powerful jolting 30 second every 5 minutes, observe the dissolving situation in 30 minutes; as without visual visible particles of solute or drop, be namely considered as dissolving completely.
Under 5 DEG C and different concns sodium-chlor existent condition, moxifloxacin hydrochloride solubleness is as shown in the table:
Claims (5)
1. a process for purification for moxifloxacin hydrochloride, comprises the following steps:
1) Moxifloxacin hydrochloride crude product and L-TARTARIC ACID are reacted, obtain L-TARTARIC ACID Moxifloxacin;
2) in L-TARTARIC ACID Moxifloxacin solution, add hydrochloric acid, stirring and crystallizing, filter, washing, drying obtains moxifloxacin hydrochloride.
2. process for purification according to claim 1, is characterized in that, step 1), under organic bases triethylamine existent condition, is solvent with dimethyl formamide, Moxifloxacin hydrochloride crude product and L-TARTARIC ACID is reacted and generates L-TARTARIC ACID Moxifloxacin.
3. process for purification according to claim 1, it is characterized in that, the triethylamine of the Moxifloxacin hydrochloride crude product of 30-40 weight part, the dimethyl formamide of 200-300 weight part and 9-15 weight part mixes by step 1), slowly be warming up to about 70-90 DEG C, add the L-TARTARIC ACID of 11-13 weight part, 65-75 DEG C of insulation reaction 2-4 hour; Reaction end is cooled to room temperature, stirs 5-10h; Centrifuging, washing, dry, obtain L-TARTARIC ACID Moxifloxacin.
4. process for purification according to claim 1, is characterized in that, step 2) L-TARTARIC ACID Moxifloxacin is dissolved in the mixing solutions of second alcohol and water, then under agitation add hydrochloric acid, separate out moxifloxacin hydrochloride.
5. process for purification according to claim 1, it is characterized in that, step 2) the L-TARTARIC ACID Moxifloxacin of 30-40 weight part is added in the mixing solutions of the ethanol of 70-90 weight part and the water of 150-200 weight part, intensification stirring and dissolving, add activated carbon decolorizing, filter; Filtrate under agitation adds hydrochloric acid to pH≤0.5, and stirring at room temperature 1-3 hour has yellow solid to separate out, and is cooled to 0 ~ 5 DEG C, stirs 0.5-2 hour, centrifuging, and washing is dry, obtains moxifloxacin hydrochloride.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105503864A (en) * | 2015-12-17 | 2016-04-20 | 江苏阿尔法药业有限公司 | Preparing method for moxifloxacin intermediate |
| CN108276402A (en) * | 2018-02-13 | 2018-07-13 | 北京博全健医药科技有限公司 | A kind of preparation method of moxifloxacin hydrochloride |
| CN108840867A (en) * | 2018-07-26 | 2018-11-20 | 哈尔滨珍宝制药有限公司 | A kind of preparation method of new alkali Moxifloxacin |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008138759A1 (en) * | 2007-05-10 | 2008-11-20 | Sandoz Ag | Process for the preparation of moxifloxacin hydrochloride |
| CN102675313A (en) * | 2011-10-12 | 2012-09-19 | 郭峰 | Preparation method of moxifloxacin hydrochloride |
| CN103159759A (en) * | 2013-01-17 | 2013-06-19 | 浙江普洛康裕制药有限公司 | Preparation method of moxifloxacin hydrochloride |
-
2013
- 2013-11-13 CN CN201310571399.4A patent/CN104628720A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008138759A1 (en) * | 2007-05-10 | 2008-11-20 | Sandoz Ag | Process for the preparation of moxifloxacin hydrochloride |
| CN102675313A (en) * | 2011-10-12 | 2012-09-19 | 郭峰 | Preparation method of moxifloxacin hydrochloride |
| CN103159759A (en) * | 2013-01-17 | 2013-06-19 | 浙江普洛康裕制药有限公司 | Preparation method of moxifloxacin hydrochloride |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105503864A (en) * | 2015-12-17 | 2016-04-20 | 江苏阿尔法药业有限公司 | Preparing method for moxifloxacin intermediate |
| CN105503864B (en) * | 2015-12-17 | 2017-03-22 | 江苏阿尔法药业有限公司 | Preparing method for moxifloxacin intermediate |
| CN108276402A (en) * | 2018-02-13 | 2018-07-13 | 北京博全健医药科技有限公司 | A kind of preparation method of moxifloxacin hydrochloride |
| CN108840867A (en) * | 2018-07-26 | 2018-11-20 | 哈尔滨珍宝制药有限公司 | A kind of preparation method of new alkali Moxifloxacin |
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Application publication date: 20150520 |