CN103012452B - The preparation method of a kind of Moxifloxacin and hydrochloride thereof - Google Patents
The preparation method of a kind of Moxifloxacin and hydrochloride thereof Download PDFInfo
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- CN103012452B CN103012452B CN201210569399.6A CN201210569399A CN103012452B CN 103012452 B CN103012452 B CN 103012452B CN 201210569399 A CN201210569399 A CN 201210569399A CN 103012452 B CN103012452 B CN 103012452B
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Abstract
The invention discloses the preparation method of a kind of Moxifloxacin and hydrochloride thereof.There is following defect in current technique: adopt one kettle way feed in raw material exist temperature rise suddenly and cause punching material and blast potential safety hazard; In the sepn process of borine inner complex, all adopt frozen water to carry out crystallization process be separated inner complex, produce a large amount of waste water.The invention is characterized in, in chelatropic reaction, solid boric acid adopts continuous charging mode to add in aceticanhydride, Reactive Synthesis sequestrant, described sequestrant and 1-cyclopropyl-6, borine inner complex is prepared in 7-difluoro-8-methoxyl-Isosorbide-5-Nitrae-dihydro-4-Oxoquinoline-3-carboxylic acid ethyl ester reaction, adopts organic solvent Crystallization Separation purification borine inner complex.Present invention process is simple, mild condition, chelatropic reaction process safety, solves a large amount of wastewater problem in inner complex preparation process and improves inner complex quality.The method yield that the present invention adopts is high, and selectivity is good, and product purity is high, is applicable to technology and produces.
Description
Technical field
The present invention relates to medicinal chemistry art, specifically a kind of safety, environmental protection, highly selective prepare the method for Moxifloxacin and hydrochloride thereof.
Background technology
Moxifloxacin hydrochloride: the fluoro-7-([S of 1-cyclopropyl-6-, S]-2,8-diazacyclo [4.3.0]-nonanal-8-group)-8-methoxyl group-4-oxo-Isosorbide-5-Nitrae-dihydro-3-quinoline carboxylic acid hydrochloride is wide spectrum and the 8-methoxy fluoroquinolone class antimicrobial drug with anti-microbial activity.It is as the antibacterials of human and animal, effectively can treat the infection that various bacteria causes, demonstrate the excellent activity to gram positive organism and atypical pathogens (as mycoplasma, chlamydozoan, legionella and anerobe etc.), than Sparfloxacin and Ciprofloxacin, there is better anti-microbial activity.Structural formula is as follows:
EP0550903 discloses and adopts 1-cyclopropyl-6,7-difluoro-8-methoxyl-4-oxo-1,4-dihydro-3-quinoline carboxylic acid and (S, S)-2,8-diazacyclo [4.3.0] nonane is under triethylamine does acid binding agent condition, directly carry out the substitution reaction of 7-position, prepare Moxifloxacin and carry out salify with hydrochloric acid, preparing Moxifloxacin hydrochloride.The method technique is simple, but is difficult to avoid C
6-F and C
7the competitive substitution of-F, has quite a few C
6-F replaces by product and generates, and is difficult to be separated, have impact on separation yield and the purity of Moxifloxacin.
JP1990178765 discloses and adopts boric acid and aceticanhydride to react, and prepares sequestrant, then carries out the inner complex that chelating prepares quinolone parent nucleus with quinolone parent nucleus, this inner complex again with (S, S)-2,8-diazacyclo [4.3.0] nonane condensation, greatly can improve C
7the selectivity of-F substitution reaction, thus avoid C
6-F replaces by product and generates, and improves the selectivity of quinolones condensation reaction.
WO2008059223 discloses propionic anhydride and acid reaction prepares sequestrant, sequestrant and 1-cyclopropyl-6,7-difluoro-8-methoxyl-4-oxo-1, inner complex is prepared in the reaction of 4-dihydro-3-quinoline carboxylic acid ethyl ester, with (S, S)-2, methyl alcohol is added and hydrochloric acid removes chelation group in acid condition after the condensation reaction of 8-diazacyclo [4.3.0] nonane, adjust neutral with ammoniacal liquor, dichloromethane extraction free alkali Moxifloxacin, again use hydrochloric acid salify in methanol solvent system, filtering separation hydrochloric acid Moxifloxacin.
After Moxifloxacin hydrochloride synthetic method disclosed in WO2005012285 still adopts and prepares inner complex, inner complex and (S, S)-2,8-diazacyclo [4.3.0] nonane carries out condensation, after separating condensed thing, directly add hydrochloric acid in alcohol solvent, carry out acidolysis removing chelation group Moxifloxacin hydrochloride prepared by salify.
The above is prepared Moxifloxacin hydrochloride technique and there is following defect:
all do not mention the heat effect in sequestrant preparation process, in fact have very large heat effect preparing in sequestrant process, and its reaction initiation temperature is higher, adopt one kettle way to feed in raw material to exist temperature to rise suddenly and the potential safety hazard that causes punching material and blast;
in inner complex sepn process, all adopt frozen water to carry out crystallization process be separated inner complex, produce a large amount of waste water, moisture in drying process inner complex is difficult to completely dry, and have moiety chelates thing in drying process and be hydrolyzed, cause coming off of chelation group, thus affect the quality of inner complex, be embodied in yield in condensation reaction and decline, condensation reaction solution impurity increases.
Summary of the invention
Technical problem to be solved by this invention is the defect overcoming the existence of above-mentioned prior art, provides a kind of reaction conditions gentleness, safety, environmental protection, the finished product content and yield all higher and the preparation method of applicable industrial Moxifloxacin and hydrochloride thereof.
For this reason, the present invention adopts following technical scheme: the preparation method of a kind of Moxifloxacin and hydrochloride thereof, it is characterized in that, in chelatropic reaction, solid boric acid adopts and adds continuously in aceticanhydride, Reactive Synthesis sequestrant, described sequestrant and 1-cyclopropyl-6, borine inner complex is prepared in 7-difluoro-8-methoxyl-Isosorbide-5-Nitrae-dihydro-4-Oxoquinoline-3-carboxylic acid ethyl ester reaction, adopts organic solvent Crystallization Separation purification borine inner complex.
The concrete steps of the preparation method of above-mentioned Moxifloxacin and hydrochloride thereof are as follows:
A) borine inner complex is synthesized
Aceticanhydride stirs and is warming up to 90 DEG C, and solid boric acid adds in aceticanhydride continuously, at 90-120 DEG C of reaction 2-3h, be cooled to 70-80 DEG C, add 1-cyclopropyl-6,7-difluoro-8-methoxyls-Isosorbide-5-Nitrae-dihydro-4-Oxoquinoline-3-carboxylic acid ethyl ester, be warming up to 100-110 DEG C of stirring reaction 1-2h, be cooled to 50-80 DEG C, the reaction solution obtained slowly proceeded in organic solvent and stirs, crystallisation by cooling, filter, washing and drying obtains borine inner complex;
B) borine condenses is synthesized
In acetonitrile, add the borine inner complex of mineral alkali and above-mentioned preparation, stir at 15-45 DEG C of temperature, Moses's side chain (S after dropping dilution in acetonitrile, S)-2,8-diazacyclo [4.3.0] nonane, react after 2-4 hour, after filtration, borine condenses is obtained after washing, reclaim under reduced pressure acetonitrile: the fluoro-7-([S of 1-cyclopropyl-6-, S]-2,8-diazacyclo [4.3.0]-nonanal-8-group)-8-methoxyl group-Isosorbide-5-Nitrae-dihydro-4-Oxoquinoline-3-carboxylic acid ethyl ester aceticanhydride borine inner complex;
C) Moxifloxacin is synthesized
Described borine condenses inorganic base aqueous solution stirs hydrolysis 2-4h at 25-45 DEG C, with hydrolyzed solution 1-2 time of toluene extraction gained, aqueous phase with concentrated hydrochloric acid adjust pH to 7.0-8.5, then halogenated alkane aqueous phase extracted 2-4 time is used, halogenated alkane extraction phase merges, and reclaims halogenated alkane and obtains free alkali Moxifloxacin;
D) preparation of moxifloxacin hydrochloride and recrystallization
The first mixed solvent is added in described free alkali Moxifloxacin, reflux is dissolved, add decolorizing with activated carbon, heat filtering removing gac, cooling 15-45 DEG C, add hydrochloric acid and stir into salt, crystallisation by cooling, filtration, crude product moxifloxacin hydrochloride is obtained with the organic phase washing leaching cake in the first mixed solvent, add the second mixed solvent in dry crude product moxifloxacin hydrochloride and be warming up to 70-80 DEG C of stirring and dissolving, crystallisation by cooling, filtration, with the organic solvent washing filter cake in the second mixed solvent, the moxifloxacin hydrochloride that filter cake vacuum drying must be refined;
The first described mixed solvent is the mixed solvent of any two or two or more solvent composition in alcohol, ketone, water; The second mixed solvent is the mixed solvent of alcohol and water, and wherein the massfraction of water is 5-40%.
Further, step a) in, boric acid and aceticanhydride temperature of reaction are preferably at 90-100 DEG C.
Further, step a) in, the organic solvent that crystallization adopts be do not react with acetic acid or aceticanhydride and boiling point at the organic solvent of 50-150 DEG C, described borine inner complex indissoluble or be slightly soluble in described organic solvent.
Further, step a) in, the boiling point of described organic solvent preferably at 50-100 DEG C, its be preferably C
1-C
8alkane and naphthenic hydrocarbon, C
6-C
9aromatic hydrocarbon and substituent, C
1-C
4ketones solvent, C
1-C
8ether solvent, C
1-C
4alcoholic solvent, C
2-C
8esters solvent in the mixture of one or more.
Further, step a) in, described organic solvent is more preferably the mixture of one or more in acetone, ethyl acetate, Virahol, ethanol, methyl alcohol.
Further, step b) in, described mineral alkali is preferably salt of wormwood, and its molar equivalent is borine inner complex 1.5-3.0 times.
Further, step c) in, described halogenated alkane is preferably methylene dichloride or trichloromethane; Described inorganic base aqueous solution is preferably sodium hydroxide or the potassium hydroxide aqueous solution of 3-10%, and hydrolysis temperature is preferably 25-35 DEG C.
Further, steps d) in, the first described mixed solvent is preferably C
1-C
4the mixed solvent of alcohols, ketones solvent and water composition; Described the second mixed solvent is preferably C
1-C
4alcoholic solvent and water composition mixed solvent.
Further, steps d) in, the first described mixed solvent is more preferably the mixed solvent of methyl alcohol or second alcohol and water composition, and wherein the massfraction of water is 5-40%; Described the second mixed solvent is more preferably the mixed solvent of methyl alcohol or second alcohol and water composition.
The present invention adopts solid continuous charging in inner complex preparation process, solves the heat effect in sequestrant preparation process, ensure that the security of production process; In inner complex sepn process, adopt organic solvent to carry out crystallization treatment, achieve the zero release of waste water, ensure that the quality of inner complex better simultaneously, indirectly improve yield and the selectivity of follow-up condensation reaction, and reduce impurity, thus improve the purity of subsequent product; Follow-uply carry out a salify and a recrystallization just can prepare the moxifloxacin hydrochloride product meeting pharmacopoeial requirements.
Embodiment
In order to illustrate better the present invention, enumerate following examples:
embodiment 1
(a) synthesis borine inner complex
Taking 73.6g aceticanhydride joins in 250ml four-hole boiling flask, stirring is warming up to 90 DEG C, add 13.6g boric acid continuously, control temperature of reaction system 90-95 DEG C, 90 DEG C of insulation 2h after adding, cool to 80 DEG C, add 64.6g parent nucleus (1-cyclopropyl-6,7-difluoro-8-methoxyls-Isosorbide-5-Nitrae-dihydro-4-Oxoquinoline-3-carboxylic acid ethyl ester) stirring and be warmed up to 105 DEG C, 60 DEG C are cooled to after reaction 2h, reaction solution is slowly poured in 600ml dehydrated alcohol to stir and separate out solid, filter, filter cake 120ml ice washing with alcohol, oven dry is weighed: 80.7g, yield 95.5%.
(b) synthesis borine condenses
By the 80.7g inner complex obtained in previous step, join in 500ml there-necked flask, then add 39.5g salt of wormwood and 300ml acetonitrile, 25 DEG C of stirrings, take 25.9g side chain (S, S)-2,8-diazacyclo [4.3.0] nonane, be added drop-wise in there-necked flask with after 50ml dilution in acetonitrile, reaction 4h, filters, with 50ml acetonitrile wash filter cake, collection filtrate decompression reclaims to do and to obtain borine condenses 93.45g, yield 92.6%.
(c) synthesis Moxifloxacin
3%KOH solution 1056.0g is joined in borine condenses, stirring and dissolving, 25 DEG C of insulation reaction 4h, react by 100ml*2 toluene extracting twice, with concentrated hydrochloric acid adjust pH to 7.0, and then with 500ml*3 dichloromethane extraction four times, to reclaim after methylene dichloride to obtain Moxifloxacin 69.77g, yield 98.5%.
D () synthetic hydrochloric acid Moxifloxacin is also refining
It is in 60% methanol aqueous solution 558.2ml that the Moxifloxacin obtained to step (c) joins mass ratio, 75 DEG C of dissolvings, add 1.4g activated carbon decolorizing 30min simultaneously, be cooled to 45 DEG C of filtrations, add 21.7g concentrated hydrochloric acid salify, stirring and crystallizing,-10 DEG C of crystallisation by cooling 12h, filter, filter cake 45ml methanol wash post-drying, obtain crude product Moxifloxacin hydrochloride 69.9g, yield 92.0%.It is carry out recrystallization in the methanol aqueous solution 699ml of 85% that 69.9g crude product joins mass ratio, is heated to 70-80 DEG C and is back to solid and all dissolves rear stirring and be cooled to room temperature, a large amount of solid separate out after-10 DEG C of crystallisation by cooling 12h, filter, washing and drying, obtains product 62.96g, yield 90.0%.In inner complex total yield of products 75.5%, product content 99.93%, maximum list assorted 0.04%.
embodiment 2
A () prepares borine inner complex
Taking 73.6g aceticanhydride joins in 250ml four-hole boiling flask, stirs and is warming up to 90 DEG C, add 13.6g boric acid in batches, control temperature of reaction system and be stabilized in 90-100 DEG C, after adding, 90 DEG C of insulation 3h, cool to 70 DEG C after completion of the reaction, add 64.6g parent nucleus, stirring is warmed up to 105 DEG C, cool to 50 DEG C after reaction 1.5h and slowly pour reaction solution in 600ml Virahol vigorous stirring precipitation solid, suction filtration, filter cake 120ml ice washed with isopropyl alcohol, oven dry is weighed: 81.0g, yield 95.7%.
(b) synthesis borine condenses
By the 81.0g inner complex obtained in previous step, join in 500ml there-necked flask, add 52.8g salt of wormwood and 300ml acetonitrile again, 30 DEG C of stirrings, take side chain 26.0g, be added drop-wise in there-necked flask with after 50ml dilution in acetonitrile, reaction 3h, filters, with 50ml acetonitrile wash filter cake, collection filtrate decompression reclaims to do and to obtain borine condenses 96.43g, yield 95.2%.
(c) synthesis Moxifloxacin
5%NaOH solution 656.3g is joined in borine condenses, stirring and dissolving, 30 DEG C of insulation reaction 3h, by 100ml*2 toluene extracting twice, adjust pH value to 8.5,500ml*3 dichloromethane extraction three times with concentrated hydrochloric acid, reclaim methylene dichloride and obtain Moxifloxacin 70.98g, yield 97.1%.
D () synthetic hydrochloric acid Moxifloxacin is also refining
The methanol aqueous solution 1065ml that mass ratio is 95% is added in the Moxifloxacin that step (c) obtains, 75 DEG C of dissolvings, add 1.4g activated carbon decolorizing 30min simultaneously, are cooled to 30 DEG C of filtrations, add 24.0g concentrated hydrochloric acid salify, stirring and crystallizing ,-10 DEG C of crystallisation by cooling 12h, filter, filter cake 45ml methanol wash, finally dry, obtain crude product Moxifloxacin hydrochloride 69.8g, yield 90.3%.In gained 69.8g crude product, add the aqueous ethanolic solution 698ml recrystallization that mass ratio is 85%, be heated to 70-80 DEG C and be back to solid and all dissolve rear stirring and be cooled to room temperature, a large amount of solid separate out after-10 DEG C of crystallisation by cooling 12h, filter, washing and drying, obtains product 62.65g, yield 89.7%.Total yield of products 74.87%, product content 99.89%, maximum list assorted 0.07%.
embodiment 3
(a) synthesis borine inner complex
Taking 73.6g aceticanhydride joins in 250ml four-hole boiling flask, stirring is warming up to 90 DEG C, adds 13.6g boric acid in batches, ensures that temperature-stable is at 95-100 DEG C, 90 DEG C of insulation 2h after adding, cool to 75 DEG C after completion of the reaction, add the stirring of 64.6g parent nucleus and be warmed up to 110 DEG C, after reaction 1h, cool to 70 DEG C, reaction solution is slowly poured into vigorous stirring in 600ml ethyl acetate and separate out solid, filter, filter cake 120ml glacial acetic acid ethyl ester washing, oven dry is weighed: 80.0g.Yield 94.6%.
(b) synthesis borine condenses
By the 80.0g inner complex obtained in previous step, join in 500ml there-necked flask, add 78.3g salt of wormwood and 300ml acetonitrile again, 45 DEG C of stirrings, are added drop-wise in there-necked flask after taking 25.7g side chain 50ml dilution in acetonitrile, reaction 2h, react filtration, with 50ml acetonitrile wash filter cake, collection filtrate decompression reclaims to do and to obtain borine condenses 96.2g, yield 96.2%.
(c) synthesis Moxifloxacin
10%NaOH solution 327g is joined in above-mentioned borine condenses, stirring and dissolving, 35 DEG C of insulation reaction 2h, react and added 100ml*2 toluene extracting twice, with concentrated hydrochloric acid adjust pH to 7.5, and then with the chloroform extraction three times of 500ml*3, collect the distilled water wash of organic phase 150ml once, reclaim trichloromethane and obtain Moxifloxacin 71.97g, yield 98.7%.
D () synthetic hydrochloric acid Moxifloxacin is also refining
The aqueous ethanolic solution 575.7ml that mass ratio is 60% is added in the Moxifloxacin that step (c) obtains, 75 DEG C of dissolvings, add 1.4g activated carbon decolorizing 30min simultaneously, are cooled to 60 DEG C of filtrations, add 26.4g concentrated hydrochloric acid salify, stirring and crystallizing ,-10 DEG C of crystallisation by cooling 12h, filter, filter cake 45ml washing with alcohol, finally dry, obtain crude product Moxifloxacin hydrochloride 72.5g, yield 92.5%.It is recrystallization in the aqueous ethanolic solution 1087.5ml of 95% that 72.5g crude product Moxifloxacin hydrochloride joins mass ratio, be heated to 70-80 DEG C to be back to solid and all to dissolve rear stirring and be cooled to room temperature, rear-5 DEG C of crystallisation by cooling 12h separated out by a large amount of solid, filter, washing and drying, obtains Moxifloxacin hydrochloride 63.0g, yield 87.0%, product content 99.82%, maximum list assorted 0.08%.
embodiment 4
(a) synthesis borine inner complex
Taking 73.6g aceticanhydride joins in 250ml four-hole boiling flask, stirs and is warming up to 90 DEG C, add 13.6g boric acid in batches, control temperature of reaction system 90-95 DEG C, after adding, 90 DEG C of insulation 2h, cool to 70-80 DEG C, add 64.6g parent nucleus, stirring is warmed up to 105 DEG C, cool to 60 DEG C after reaction 2h, reaction solution is slowly poured in 600ml acetone to stir and separate out solid, filter, the washing with acetone that filter cake cools with 120ml, oven dry is weighed: 78.75g.Yield 93.1%.
embodiment 5
(a) synthesis borine inner complex
Taking 73.6g aceticanhydride joins in 250ml four-hole boiling flask, stirs and is warming up to 90 DEG C, add 13.6g boric acid in batches, control temperature of reaction system 90-95 DEG C, after adding, 90 DEG C of insulation 2h, cool to 70-80 DEG C, add 64.6g parent nucleus, stirring is warmed up to 105 DEG C, cool to 60 DEG C after reaction 2h, reaction solution is slowly poured in 600ml methyl alcohol to stir and separate out solid, filter, the methanol wash that filter cake cools with 120ml, oven dry is weighed: 78.34g.Yield 92.6%.
Claims (7)
1. the preparation method of a Moxifloxacin and hydrochloride thereof, it is characterized in that, in chelatropic reaction, solid boric acid adopts continuous charging mode to add in aceticanhydride, Reactive Synthesis sequestrant, described sequestrant and 1-cyclopropyl-6,7-difluoro-8-methoxyl-1, borine inner complex is prepared in the reaction of 4-dihydro-4-Oxoquinoline-3-carboxylic acid ethyl ester, adopts organic solvent Crystallization Separation purification borine inner complex;
Above-mentioned preparation method comprises the following steps:
A) borine inner complex is synthesized
Aceticanhydride stirs and is warming up to 90 DEG C, and solid boric acid adds in aceticanhydride continuously, at 90-120 DEG C of reaction 2-3h, be cooled to 70-80 DEG C, add 1-cyclopropyl-6,7-difluoro-8-methoxyls-Isosorbide-5-Nitrae-dihydro-4-Oxoquinoline-3-carboxylic acid ethyl ester, be warming up to 100-110 DEG C of stirring reaction 1-2h, be cooled to 50-80 DEG C, the reaction solution obtained slowly proceeded in organic solvent and stirs, crystallisation by cooling, filter, washing and drying obtains borine inner complex;
B) borine condenses is synthesized
In acetonitrile, add the borine inner complex of salt of wormwood and above-mentioned preparation, stir at 15-45 DEG C of temperature, (S, the S)-2 after dropping dilution in acetonitrile, 8-diazacyclo [4.3.0] nonane, react after 2-4 hour, after filtration, washing, after reclaim under reduced pressure acetonitrile borine condenses: 1-cyclopropyl-6-fluoro-7-([S, S]-2,8-diazacyclo [4.3.0]-nonanal-8-group)-8-methoxyl group-Isosorbide-5-Nitrae-dihydro-4-Oxoquinoline-3-carboxylic acid ethyl ester aceticanhydride borine inner complex;
C) Moxifloxacin is synthesized
Described borine condenses inorganic base aqueous solution stirs hydrolysis 2-4h at 25-45 DEG C, with hydrolyzed solution 1-2 time of toluene extraction gained, aqueous phase with concentrated hydrochloric acid adjust pH to 7.0-8.5, then halogenated alkane aqueous phase extracted 2-4 time is used, halogenated alkane extraction phase merges, and reclaims halogenated alkane and obtains free alkali Moxifloxacin;
D) preparation of moxifloxacin hydrochloride and recrystallization
The first mixed solvent is added in described free alkali Moxifloxacin, reflux is dissolved, add decolorizing with activated carbon, heat filtering removing gac, cooling 15-45 DEG C, add hydrochloric acid and stir into salt, crystallisation by cooling, filtration, crude product moxifloxacin hydrochloride is obtained with the organic phase washing leaching cake in the first mixed solvent, add the second mixed solvent in dry crude product moxifloxacin hydrochloride and be warming up to 70-80 DEG C of stirring and dissolving, crystallisation by cooling, filtration, with the organic solvent washing filter cake in the second mixed solvent, the moxifloxacin hydrochloride that filter cake vacuum drying must be refined;
The first described mixed solvent is the mixed solvent of any two or two or more solvent composition in alcohol, ketone, water; The second mixed solvent is the mixed solvent of alcohol and water, and wherein the massfraction of water is 5-40%;
Step a) in, the organic solvent that crystallization adopts be do not react with acetic acid or aceticanhydride and boiling point at the organic solvent of 50-150 DEG C, described borine inner complex indissoluble or be slightly soluble in described organic solvent;
Step c) in, described halogenated alkane is methylene dichloride or trichloromethane.
2. preparation method according to claim 1, is characterized in that, step a) in, boric acid and aceticanhydride temperature of reaction are at 90-100 DEG C.
3. preparation method according to claim 1, is characterized in that, step a) in, the boiling point of described organic solvent is at 50-100 DEG C, and it is C
1-C
8alkane and naphthenic hydrocarbon, C
6-C
9aromatic hydrocarbon and substituent, C
1-C
4ketones solvent, C
1-C
8ether solvent, C
1-C
4alcoholic solvent, C
2-C
8esters solvent in the mixture of one or more.
4. preparation method according to claim 3, is characterized in that, step a) in, described organic solvent is the mixture of one or more in sherwood oil, normal hexane, hexanaphthene, isopropyl ether, toluene, acetone, ethyl acetate, ethanol, methyl alcohol.
5. preparation method according to claim 1, is characterized in that, step b) in, the molar equivalent of described salt of wormwood is borine inner complex 1.5-3.0 times.
6. preparation method according to claim 1, is characterized in that, steps d) in, the first described mixed solvent is C
1-C
4the mixed solvent of alcohols, ketones solvent and water composition; Described the second mixed solvent is C
1-C
4alcoholic solvent and water composition mixed solvent.
7. preparation method according to claim 6, is characterized in that, steps d) in, the first described mixed solvent is the mixed solvent of methyl alcohol or second alcohol and water composition, and wherein the massfraction of water is 5-40%; Described the second mixed solvent is the mixed solvent of methyl alcohol or second alcohol and water composition.
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| CN108690021A (en) * | 2018-07-09 | 2018-10-23 | 宋雪萍 | A kind of preparation method and its pharmaceutical composition of moxifloxacin hydrochloride |
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| CN103315972B (en) * | 2013-07-09 | 2015-08-05 | 山东新时代药业有限公司 | A kind of Moxifloxacin hydrochloride tablet and preparation method thereof |
| CN106928217A (en) * | 2015-12-31 | 2017-07-07 | 江苏天时制药有限公司 | A kind of Analogue of moxifloxacin and preparation method thereof, purposes |
| CN106478624A (en) * | 2016-09-14 | 2017-03-08 | 苏州天马精细化学品股份有限公司 | A kind of purification process of moxifloxacin hydrochloride |
| CN106916155A (en) * | 2017-03-27 | 2017-07-04 | 陕西必康制药集团控股有限公司 | The acidifying of moxifloxacin hydrochloride and preparation method |
| CN110563725B (en) * | 2019-09-27 | 2021-06-18 | 哈尔滨珍宝制药有限公司 | Preparation process of moxifloxacin |
| CN112010851A (en) * | 2020-06-30 | 2020-12-01 | 浙江美诺华药物化学有限公司 | Preparation method of moxifloxacin hydrochloride |
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