CN102617568B - Stable moxifloxacin hydrochloride compound and preparation method thereof - Google Patents
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Abstract
The invention discloses a moxifloxacin hydrochloride compound, which is prepared by the steps of: performing Reformatsky reaction on 3-methoxyl-2,4,5-trifluoro benzonitrile to obtain ethyl 3-methoxyl-2,4,5-trifluoro benzoyl acetate, performing enamine formation, amine exchange, nucleophilic substitution, hydrolysis and chelating to obtain (8-methoxyl-1-cyclopropyl-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate) boron difluoride, and performing nucleophilic substitution reaction to obtain moxifloxacin hydrochloride. The preparation method of moxifloxacin hydrochloride compound has the benefits that the operation is easy and simple, and the intermediates obtained in each step are high in purity; the reaction is sufficient, the subsidiary reactions are few, and the purification is easy; and the reaction steps are reduced and the industrialized production is easy to realize.
Description
Technical field
The present invention relates to the medicine in field of medicaments, especially relate to a kind of Moxifloxacin hydrochloride compound, its preparation method of good stability.
Background technology
Along with the even abuse that is widely used of antiseptic-germicide, bacterial drug resistance increases year by year, not only serious harm human health of drug resistant bacterial infections, and become worldwide thorny problem.It is reported, annual ward infection approximately 2,000,000 examples that occur in U.S.'s inpatient, wherein approximately 90,000 examples are dead.More than 70% Nosocomial infection produces resistance to conventional clinically antibacterials, therefore, accelerating research and development, can effectively to tackle the Perorally administrable antimicrobial medicine of the ward infection that the gram positive organism gram-negative bacteria (Pseudomonas aeruginosa and Acinetobacter baumannii etc.) that particularly severe infection and resistance increase progressively due to Methicillin-resistant Staphylococcus aureus (MRSA) causes extremely urgent.
At the beginning of 2006, the U.S. infects disease association (IDSA) and has announced 6 kinds of resistance pathogenic bacterium that human health threatened to maximum, wherein MRSA ranks first, and next coming in order are escherichia coli, klebsiella spp, Acinetobacter baumannii, Vancomycin-resistant Enterococcus faecium and Pseudomonas aeruginosa.More than 60% Nosocomial pneumonia is microbial by Grain-negative.According to statistics, the Klebsiella Pneumoniae of clinical separation of 2002--2003 year to the resistant rate of methoxyimino-β mono-lactam antibiotics (third generation cephalosporin) up to 47%.The ratio of the nosocomial pneumonia being caused by acinetobacter constantly increases, and mortality ratio is up to 20%-50%, and the incidence of the nosocomial pneumonia being caused by Pseudomonas aeruginosa from 1975 9.6% be increased to 2003 18.1%, increase nearly l doubly.
It is the common complication of numerous disease that bacterium infects, and is one of principal element threatening critical patients life.The reasons such as critical patients is due to long-term inpatients, and the state of an illness is critical, has a low resistance, strong to the resistance of antimicrobial drug, Relapse rate outbreak easy infection cause.The lower respiratory infection of critical patients is suitable distinct issues at comprehensive severe ICU (S ICU), account for the more than 50% of all infection according to domestic statistics, this mainly need to set up artificial airway with critical, the many people of the most state of an illness of patient of ICU and carry out mechanical ventilation relevant.
Due to the continuous rising of rate of hospital acquired infection of methicillin-resistant staphylococcus aureus, methicillin-resistant staphylococcus epidermidis and increasing sharply of resistant rate, the Hazard Factor of hospital infection are become.Have data to show, although antibiotic application rolls up, staphylococcic resistant rate is more and more wider, and the scale of kind, dosage, the course for the treatment of and hospital that it and microbiotic use becomes proportional relation.
Moxifloxacin hydrochloride is the 4th generation wide spectrum 8-methoxy fluoroquinolone class antimicrobial drug, is the antibacterials more widely of clinical application in recent years, is also the synthetic antibacterial drug that a class is newer.Moxifloxacin hydrochloride energy facedown streptococcus pneumoniae (the most often causing RTIs), hemophilus influenzae and moraxelle catarrhalis.Different from fluorine caye promise ketone at present used.
Moxifloxacin hydrochloride can strengthen anti-rare G
-the activity of bacterium, comprises that streptococcus aureus, atypia pathogenic agent are as mycoplasma, chlamydozoan and legionella.In addition, also effective to the bacterium of beta-lactam and Macrolide resistance.Yuan Yan company emphasizes, Moxifloxacin hydrochloride can kill bacteria, and effect rapidly, has concentration dependent, only bacterium is played to inhibition growth unlike Macrolide.
Moxifloxacin hydrochloride easy administration, medication every day once can prove effective, thereby has good tolerance.This medicine is without phototoxicity and liver toxicity, identical with other quinolones, and its most obvious side effect is for feeling sick, suffering from diarrhoea.
Another advantage of Moxifloxacin hydrochloride is, more much lower than the resistance degree of other Du-6859a deposits yields.But, use suitable dosage and correct medicining times and interval time.For example, for indication, oral 400mg, qd, is used in conjunction 5-10 days.
popular name:moxifloxacin hydrochloride;
English name: Moxifloxacin Hydrochloride;
chemical name:1-cyclopropyl-7-{(S, S)-2,8-diazonium-bis-encircle [4.3.0] nonanal-8-group }-6-fluoro-8-methoxy-Isosorbide-5-Nitrae-dihydro-4-oxygen-3-quinoline carboxylic acid hydrochloride;
structural formula is:
molecular formula: C
21h
24fN
3o
4hCl
molecular weight: 436.9
physico-chemical property:faint yellow to yellow crystalline powder, slightly water-soluble and methyl alcohol, is slightly soluble in ethanol, is dissolved in hardly acetone.
pharmacology type:moxifloxacin hydrochloride is the 8-methoxy fluoroquinolone class antimicrobial drug with broad spectrum of activity and germicidal action.Moxifloxacin hydrochloride demonstrates in vitro has broad spectrum antibiotic activity to gram positive organism, gram-negative bacteria, anerobe, acid fast bacteria and atypical microorganism as mycoplasma, chlamydozoan and legionella.
mechanism of action:germicidal action mechanism is for disturbing type Ⅱ topoisomerase and IV.Topoisomerase be control DNA topological sum at DNA replication dna, repair and transcribe the enzyme of middle key.Moxifloxacin hydrochloride shows as the fungicidal activity of concentration dependent.Minimum bactericidal concentration and minimum inhibitory concentration are basically identical.Moxifloxacin hydrochloride is also effective to the bacterium of beta-lactam and Macrolide resistance.Confirm by the experimental animal model infecting, Moxifloxacin hydrochloride activity in vivo is high.
indication:the indication of Moxifloxacin hydrochloride is the adult (>=18 years old) that treatment suffers from the upper respiratory tract and lower respiratory infection, as: acute sinusitis, acute episode of chronic bronchitis, community acquired pneumonia, and Skin and soft tissue infection.
usage and dosage:dosage range
:any indication is all recommended a 400mg (1), 1 time on the one.Grownup's instructions of taking: tablet send down with one glass of water, and Time of Administration is not subject to food effect.Treatment time: treatment time should determine according to the severity of symptom or clinical response.The treatment upper respiratory tract and lower respiratory tract.
Can be according to following method when infection: acute episode of chronic tracheitis: 5 days; Community acquired pneumonia: 10 days; Acute sinusitis: 7 days; The recommendation treatment time for the treatment of Skin and soft tissue infection is 7 days; Moxifloxacin hydrochloride 400mg tablet 14 day course for the treatment of of the most multiplex mistake in clinical trial.
The elderly needn't adjust dosage, children and teenager's forbidding; The patient of liver dysfunction needn't adjust the dosage of Moxifloxacin hydrochloride.The dosage that the patient of the impaired renal function of any degree all needn't adjust Moxifloxacin hydrochloride (comprises CrCl≤30ml/min/1.73m
2).Lack at present the pharmacokinetic data of dialysis patient.Needn't adjust drug dose for not agnate.
Moxifloxacin chloride tablets is gone on the market at U.S. FDA by Beyer Co., Ltd in December, 1999, and then Moxifloxacin hydrochloride injection liquid goes on the market in the U.S. calendar year 2001.2002, moxifloxacin chloride tablets was through the SFDA approval of import and in Discussion on Chinese Listed, and trade(brand)name is visitd multiple pleasure
?.The not interior manufacturer production of ratifying state of SFDA at present.
The synthetic method of known Moxifloxacin is as follows:
Patent US4997943 is in synthetic key intermediate compound 6, and with 3-methoxyl group-2,4,5-trifluorobenzonitrile is starting raw material, obtains compound 6 through 8 step reactions, and its synthetic route is as follows.
This method advantage is that raw material is easy to get, but its route is longer, and total recovery is not high and will use thionyl chloride and the diacetyl oxide that toxicity is larger to do reaction reagent.
Patent US2003008894 is in synthetic key intermediate compound 6, and with 3-methoxyl group-2,4,5-trifluoro-benzoic acid is starting raw material, obtains compound 6 through 6 step reactions, and its synthetic route is as follows.
This method advantage is that raw material is easy to get, but its route is longer, and total recovery is not high, and second step need carry out at-10 ℃, has increased operation easier.
Patent US4997943, in synthetic key intermediate compound 6, for raw material, reacts to obtain compound 6 through 5 steps with the fluoro-5-nitrophenols of 2,3-bis-, and synthetic route is as follows.
This method advantage is that reaction scheme is short, but starting raw material is not easy to obtain, and needs to use hypertoxic methyl iodide and dehydrated alcohol in reaction process.
Patent US855292 is in synthetic key intermediate compound 6, and with 3-methoxyl group-2,4,5-trifluoronitrobenzene is starting raw material, reacts to obtain compound 6 through 4 steps, and synthetic route is as follows.
This method advantage is that reaction scheme is shorter, reaction conditions gentleness, but the reaction times is long, and start material is not easy to obtain, and uses anhydrous solvent.
Patent US4855292, US5639886, CN1212256, in synthetic key intermediate compound 6, adopts this route below.
This method advantage is that reaction scheme is shorter, but it has adopted poisonous thionyl chloride and organic bases to do reaction reagent.
In synthetic hydrochloric acid Sitafloxacin, patent CN101941969 adopts compound 6 and compound 8 to carry out nucleophilic substitution reaction under organic bases exists, and this method is directly simple, but generates the impurity that character is close in reaction, be difficult to separate, affected yield and the purity of Moxifloxacin.
Patent WO2008059521 converts the carboxylic acid of compound 6 to acid amides, then reacts with compound 8, using successively sodium hydroxide and salt acid treatment, obtains Moxifloxacin; This method has been used strong carcinogen material DCC and expensive DBU, is unfavorable for suitability for industrialized production.
Patent WO200500970 adopts diethyl ether solution and the compound 6 of boron trifluoride to form inner complex, then reacts with compound 8, and aftertreatment obtains Moxifloxacin.This method has the hydrogen fluoride of a large amount of severe corrosives to generate, and has brought inconvenience to generation.
Patent WO2005012285, WO2008059223 adopts boric acid, acid anhydrides and compound 6 to form inner complex, then reacts with compound 8, then, by mineral alkali and mineral acid treatment, obtains Moxifloxacin.Patent CN101973992, EP1832587 adopts respectively and adds zinc chloride and trimethyl silicane compound to improve it.But it adopts the not high and complex operation of yield, and use more malicious boric acid and acid anhydrides as reaction reagent.CN101830921 with phenylo boric acid directly and compound 6 form inner complex, although simplified operation, its cost is high, is unfavorable for suitability for industrialized production.
The inventor, through studying for a long period of time, makes Moxifloxacin hydrochloride compound, easy and simple to handle, respectively walks intermediate purity all very high.Method of the present invention makes to react carry out abundant, and side reaction is few, and easy purifying.The present invention has reduced reactions steps, is easy to realize suitability for industrialized production.
Summary of the invention
The object of this invention is to provide a kind of method of synthetic hydrochloric acid Moxifloxacin, the above-mentioned defect existing to overcome prior art.
Method of the present invention, comprises the steps:
Reaction equation:
1, compound 2,3-methoxyl group-2,4,5-trifluorobenzonitrile carries out Reformatsky reactionization and obtains compound 3;
2, compound 3,3-methoxyl group-2,4,5-trifluoromethyl benzonitrile ethyl acetoacetic acid ethyl ester reacts and obtains compound 4 with DMF dimethylacetal;
3, compound 4,3-dimethyl amine-2-(3-methoxyl group-2,4,5-trifluoromethyl benzonitrile acyl group) ethyl propenoate carries out amine exchange and obtains compound 5;
4, compound 5,3-cyclopropylamine-2-(3-methoxyl group-2,4,5-trifluoromethyl benzonitrile acyl group) ethyl propenoate passes through nucleophilic substitution and hydrolysis obtains compound 6;
5, compound 6,8-methoxyl group-1-cyclopropyl-6, the fluoro-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-of 7-bis-carboxylic acid chelating obtains compound 7;
6, compound 7, (8-methoxyl group-1-cyclopropyl-6, the fluoro-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-of 7-bis-carboxylic acid) boron difluoride generation nucleophilic substitution reaction obtains Moxifloxacin hydrochloride.
Concrete reaction conditions is:
1, take compound 2: zinc: the mol ratio=1:(1-5 of mineral acid); (0.01-0.5); Compound 2, zinc are joined in solvent, under agitation add acid, be heated to reflux, slowly drip ethyl bromoacetate.Under refluxing, react completely, be cooled to room temperature, add successively 6M hydrochloric acid and water, stir, cooling, filter, dry, obtain compound 3.
Above-mentioned solvent used is tetrahydrofuran (THF), dioxan etc.; Selected acid is organic acid as p-methyl benzenesulfonic acid, methylsulfonic acid etc.; Mineral acid is hydrogen chloride gas etc.; Temperature of reaction is between 40-100 ℃.
2, take mol ratio=1:(1-30 of compound 3:DMFDMA); By compound 3, DMF dimethylacetal and stirring solvent, after room temperature reaction is complete.Concentrating under reduced pressure obtains compound 4, is dissolved in solvent for subsequent use.
Above-mentioned solvent used is methyl alcohol, ethanol, Virahol etc., and temperature is 20-50 ℃.
3, take the mol ratio=1:(0.9-3 of compound 4 and cyclopropylamine); Cyclopropylamine is dissolved in solvent, drips the solution of compound 4, stir until react completely.In reaction solution, add water, stir, leave standstill separatory, organic phase is washed with 10% sodium bicarbonate aqueous solution, separatory.Merge water, water solvent extraction, merges organic phase, and anhydrous sodium sulfate drying filters, and filtrate is concentrated into dry, obtains compound 5.Be dissolved in solvent for subsequent use.
Above-mentioned solvent used is methylene dichloride, tetrahydrofuran (THF) etc., and temperature is 20-50 ℃.
4, take compound 5: the mol ratio=1:(1-10 of mineral alkali); Under agitation, mineral alkali is added in the solution of compound 5, stirs until react completely.Add solvent, stir, filter, filter cake solvent wash, filtrate is concentrated, obtains the solution of intermediate.
Above-mentioned mineral alkali used is salt of wormwood, cesium carbonate, sodium carbonate etc., and temperature is 20-50 ℃, and reaction solvent is dimethyl sulfoxide (DMSO), DMF etc., and cleaning solvent is methylene dichloride, ethyl acetate etc.
Take above-mentioned solution: the mol ratio=1:(3-30 of mineral acid); Under agitation, mineral acid is added in above-mentioned solution, reflux is until react completely.Cooling, adds water, stirs, and filters, and recrystallization obtains intermediate 6.
Above-mentioned mineral acid used is hydrochloric acid etc., and temperature is 80-150 ℃.
5, take compound 6: boron trifluoride: the mol ratio=1:(1-2 of mineral alkali): (1-5); By compound 6, solvent and mineral alkali, under nitrogen protection, stir, drip the diethyl ether solution of boron trifluoride.Heating reacts completely under refluxing.Be down to room temperature, add solvent, stir, filter, solvent washing, drying under reduced pressure, obtains crude product.With solvent making beating, filter, drying under reduced pressure obtains intermediate 7.
Above-mentioned mineral alkali used is salt of wormwood, sodium carbonate, cesium carbonate etc., and solvent for use is tetrahydrofuran (THF), acetonitrile, isopropyl ether, methyl tertiary butyl ether etc.
6, take compound 7: compound 8: the mol ratio=1:(0.95-2 of organic bases): (1-5); By compound 7, compound 8, organic bases and solvent, stir, be heated to be back to and react completely.Cooling, vacuum distillation recovered solvent adds solvent in residue, stirring and dissolving, dripping hydrochloric acid is 2 to pH, stirring at room temperature, stirring and crystallizing at lower than 0 ℃, filters, and 45 ℃ are dry, obtain Moxifloxacin hydrochloride.
Organic bases is triethylamine, pyridine etc., and mineral alkali is salt of wormwood, sodium carbonate etc., and reaction solvent is acetonitrile, tetrahydrofuran (THF) etc., and aftertreatment solvent is ethanol, acetonitrile etc.
the advantage of the design's route:
The invention has the beneficial effects as follows easy and simple to handlely, respectively walk intermediate purity all very high.Method of the present invention makes to react carry out abundant, and side reaction is few, and easy purifying.The present invention has reduced reactions steps, is easy to realize suitability for industrialized production.
1. synthetic compound 3 of the present invention is taked Reformatsky reaction, has avoided using more expensive starting raw material, and has reduced reactions steps, has improved yield, and solvent is tetrahydrofuran (THF) isopolarity aprotic solvent.
2. synthetic compound 4 of the present invention adopts DMF dimethylacetal (DMFDMA), has avoided using poisonous reagent as diacetyl oxide and pyroreaction, has simplified operation.
3. synthetic compound 6 of the present invention, does not purify and can directly obtain compound 6 from compound 3 through simple process in centre.
4. synthetic compound 7 of the present invention occurs under mineral alkali effect, has avoided poisonous organic bases, has improved yield, and solvent is tetrahydrofuran (THF) isopolarity aprotic solvent.
5. the present invention has simplified technological operation, has improved yield.
figure of description:
The reaction equation of Fig. 1 Moxifloxacin hydrochloride compound;
embodiment:
Below in conjunction with embodiment, the present invention is described further, makes professional and technical personnel in the field better understand the present invention.Embodiment is only indicative, never means that it limits the scope of the invention by any way.
embodiment 1
In 3L there-necked flask, add 187g3-methoxyl group-2,4,5-trifluorobenzonitrile, 97.5g zinc and 1L tetrahydrofuran (THF), under agitation add 8.6g p-methyl benzenesulfonic acid, stirring at room temperature 0.5h.Be heated to reflux, slowly drip 217.1g ethyl bromoacetate.Under refluxing, react 2 hours, be cooled to room temperature, add successively 500mL6M hydrochloric acid and 100mL water, stir 2h, be cooled to 5 ℃, have a large amount of solids to separate out, filter, 100 mL alcohol flushings, forced air drying at 40 ℃, obtains 223.5g3-methoxyl group-2,4,5-trifluoromethyl benzonitrile ethyl acetoacetic acid ethyl ester, yield 80.9%, purity 98.5%.
embodiment 2:
In 3L there-necked flask, add 220g3-methoxyl group-2; 4; 5-trifluoromethyl benzonitrile ethyl acetoacetic acid ethyl ester, 1.1L methyl alcohol and 142.8gN; dinethylformamide dimethylacetal; room temperature reaction 2h, TLC demonstration has been reacted, and concentrating under reduced pressure obtains 270g3-dimethyl amine-2-(3-methoxyl group-2; 4,5-trifluoromethyl benzonitrile acyl group) ethyl propenoate.By 270g3-dimethyl amine-2-(3-methoxyl group-2,4,5-trifluoromethyl benzonitrile acyl group) ethyl propenoate is dissolved in 1.35L methylene dichloride for subsequent use.
embodiment 3:
In 5L there-necked flask, add 54.7g cyclopropylamine, 1L methylene dichloride, at room temperature drips 3-dimethyl amine-2-(3-methoxyl group-2,4,5-trifluoromethyl benzonitrile acyl group) dichloromethane solution of ethyl propenoate, stir 1h, TLC detection reaction is complete, stopped reaction.In reaction solution, add 2L water, stir 20 minutes, leave standstill separatory, 1L 10% sodium bicarbonate aqueous solution washing for organic phase, separatory.Merge water, water 1L dichloromethane extraction, merges organic phase, and anhydrous sodium sulfate drying filters, and filtrate is concentrated into dry, obtains 280.5g3-cyclopropylamine-2-(3-methoxyl group-2,4,5-trifluoromethyl benzonitrile acyl group) ethyl propenoate.3-cyclopropylamine-2-(3-methoxyl group-2,4,5-trifluoromethyl benzonitrile acyl group) ethyl propenoate dissolves for subsequent use with 3 L DMSO.
embodiment 4:
In 5L there-necked flask, add 220.8g salt of wormwood, 3-cyclopropylamine-2-(3-methoxyl group-2,4,5-trifluoromethyl benzonitrile acyl group) the DMSO solution of ethyl propenoate, stirring reaction 1 hour under room temperature, TLC detection reaction finishes.Add 1L methylene dichloride, stir 5 minutes, filter, filter cake 2L washed with dichloromethane, filtrate is concentrated steams methylene dichloride.
In 10L there-necked flask, add the solution of dimethyl sulfoxide (DMSO), 200mL concentrated hydrochloric acid, stirs and heats up, back flow reaction 5 hours, and after TLC detection reaction is complete, stopped reaction.Be cooled to room temperature, add 24 L water to reaction solution, stir 1 h, filter, dry, acetonitrile recrystallization obtains 201.6g8-methoxyl group-1-cyclopropyl-6, the fluoro-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-of 7-bis-carboxylic acid, yield 85.4%.
embodiment 5:
In 10L there-necked flask, add 200g8-methoxyl group-1-cyclopropyl-6, the fluoro-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-of 7-bis-carboxylic acid, 2.4L tetrahydrofuran (THF) and 103.2g salt of wormwood stir 10min under nitrogen protection, drip the diethyl ether solution of 153.7mL boron trifluoride.Heating is reacted 4h under refluxing, and HPLC shows that 99% compound 7 has reacted.Be down to room temperature, add 4L methyl tertiary butyl ether and stir 10min, filter, 1L methyl tertiary butyl ether rinses, and drying under reduced pressure (50 ℃ ,-0.095MPa) 2h, obtains crude product 334.5g.With 3.3L acetonitrile 1000mL*3 making beating, filter, drying under reduced pressure (50 ℃ ,-0.095MPa), to constant weight, obtains 225g(8-methoxyl group-1-cyclopropyl-6, the fluoro-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-of 7-bis-carboxylic acid) boron difluoride, yield 96.8%, HPLC purity 99.5%.
embodiment 6:
In there-necked flask, add 220g(8-methoxyl group-1-cyclopropyl-6, the fluoro-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-of 7-bis-carboxylic acid) boron difluoride, 84.7g(4as-be suitable)-octahydro-6
h-pyrrolo-[3,4-b] pyridine, 2.2L acetonitrile and 133.5mL triethylamine, be heated to reflux, and stirs 3h, after TLC detection reaction is complete.Be cooled to 45 ℃, vacuum distillation recovered solvent adds 2.2L ethanol, stirring and dissolving in residue, with 30 ℃ at drip 6moL/L hydrochloric acid to pH be 2, stirring at room temperature 2h then stirs 2h crystallization at lower than 0 ℃, filters, wash with ethanol, 45 ℃ dry, obtains 259.6g Moxifloxacin hydrochloride, yield 92.4%.
Claims (7)
1. a method for synthetic hydrochloric acid Moxifloxacin compound, is characterized in that, comprises the following steps:
Reaction equation:
1). compound 2,3-methoxyl group-2,4,5-trifluorobenzonitrile carries out Reformatsky reactionization and obtains compound 3;
2). compound 3,3-methoxyl group-2,4,5-trifluoromethyl benzonitrile ethyl acetoacetic acid ethyl ester reacts and obtains compound 4 with DMF dimethylacetal;
3). compound 4,3-dimethyl amine-2-(3-methoxyl group-2,4,5-trifluoromethyl benzonitrile acyl group) ethyl propenoate carries out amine exchange and obtains compound 5;
4). compound 5,3-cyclopropylamine-2-(3-methoxyl group-2,4,5-trifluoromethyl benzonitrile acyl group) ethyl propenoate passes through nucleophilic substitution and hydrolysis obtains compound 6;
5). compound 6,8-methoxyl group-1-cyclopropyl-6, the fluoro-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-of 7-bis-carboxylic acid chelating obtains compound 7;
6). compound 7, (8-methoxyl group-1-cyclopropyl-6, the fluoro-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-of 7-bis-carboxylic acid) boron difluoride generation nucleophilic substitution reaction obtains Moxifloxacin hydrochloride.
2. method according to claim 1, is characterized in that, wherein, step 1) comprises the steps: to take compound 2: zinc: the mol ratio=1:1-5:0.01-0.5 of acid; Compound 2, zinc are joined in solvent, under agitation add acid, be heated to reflux, between 40-100 ℃, slowly drip ethyl bromoacetate, under refluxing, react completely, be cooled to room temperature, add successively 6M hydrochloric acid and water, stir, cooling, filter, dry, obtain compound 3.
3. method according to claim 1, is characterized in that, wherein, step 2) comprise the steps: to take mol ratio=1:1-30 of compound 3:DMFDMA; By compound 3, DMF dimethylacetal and stirring solvent, after reacting completely between 20-50 ℃, concentrating under reduced pressure obtains compound 4, is dissolved in solvent for subsequent use.
4. method according to claim 1, is characterized in that, wherein, step 3) comprises the steps: to take compound 4: the mol ratio=1:0.9-3 of cyclopropylamine; Cyclopropylamine is dissolved in solvent, between 20-50 ℃, drips the solution of compound 4, stir until react completely, in reaction solution, add water, stir, leave standstill separatory, organic phase is washed with 10% sodium bicarbonate aqueous solution, and separatory merges water, water solvent extraction, merges organic phase, anhydrous sodium sulfate drying, filter, filtrate is concentrated into dry, obtains compound 5, is dissolved in solvent for subsequent use.
5. method according to claim 1, is characterized in that, wherein, step 4) comprises the steps: to take compound 5: the mol ratio=1:1-10 of mineral alkali; Under 20-50 ℃ of stirring, mineral alkali is added in the solution of compound 5, stir until react completely, add methylene dichloride or ethyl acetate, stir, filter, methylene dichloride or ethyl acetate washing for filter cake, filtrate is concentrated, obtains the solution of intermediate; Take above-mentioned solution: the mol ratio=1:3-30 of mineral acid; Under agitation, mineral acid is added in above-mentioned solution, at 80-150 ℃, reacts completely, cooling, adds water, stirs, and filters, and recrystallization obtains intermediate 6.
6. method according to claim 1, is characterized in that, wherein, step 5) comprises the steps: to take compound 6: boron trifluoride: the mol ratio=1:1-2:1-5 of mineral alkali; By compound 6, solvent and mineral alkali, under nitrogen protection, stir, drip the diethyl ether solution of boron trifluoride, heating reacts completely under refluxing; be down to room temperature, add solvent, stir, filter solvent washing; drying under reduced pressure, obtains crude product, with solvent making beating, filters, and drying under reduced pressure obtains intermediate 7.
7. method according to claim 1, is characterized in that, wherein, step 6) comprises the steps: to take compound 7: compound 8: the mol ratio=1:0.95-2:1-5 of organic bases; By compound 7, compound 8, organic bases and solvent, stir, be heated to be back to and react completely, cooling, vacuum distillation recovered solvent adds solvent, stirring and dissolving in residue, drip hydrochloric acid to pH be 2, stirring at room temperature, stirring and crystallizing at lower than 0 ℃, filters, 45 ℃ dry, obtains Moxifloxacin hydrochloride.
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| CN109651354A (en) * | 2019-01-24 | 2019-04-19 | 广西师范大学 | - 4 (1H) qualone derivative of 3- (2-[4-morpholinodithio base) and its preparation method and application |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4855292A (en) * | 1986-02-25 | 1989-08-08 | Otsuka Pharmaceutical Company, Limited | 1-cyclopropyl-6-fluoro-8-alkyl-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid derivatives |
| US4997943A (en) * | 1986-03-31 | 1991-03-05 | Sankyo Company Limited | Quinoline-3-carboxylic acid derivatives |
| WO2005012285A1 (en) * | 2003-08-05 | 2005-02-10 | Matrix Laboratories Ltd | An improved process for the preparation of moxifloxacin hydrochloride |
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| ATE304539T1 (en) * | 2000-12-14 | 2005-09-15 | Procter & Gamble | ANTIMICROBIAL QUINOLONES |
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2012
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4855292A (en) * | 1986-02-25 | 1989-08-08 | Otsuka Pharmaceutical Company, Limited | 1-cyclopropyl-6-fluoro-8-alkyl-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid derivatives |
| US4997943A (en) * | 1986-03-31 | 1991-03-05 | Sankyo Company Limited | Quinoline-3-carboxylic acid derivatives |
| WO2005012285A1 (en) * | 2003-08-05 | 2005-02-10 | Matrix Laboratories Ltd | An improved process for the preparation of moxifloxacin hydrochloride |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109651354A (en) * | 2019-01-24 | 2019-04-19 | 广西师范大学 | - 4 (1H) qualone derivative of 3- (2-[4-morpholinodithio base) and its preparation method and application |
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