CN101619068B - Novel method for preparing marbofloxacin - Google Patents
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Abstract
The invention mainly discloses a novel method for preparing marbofloxacin, which comprises the following steps: under the protection of inert gases, 2,3,4,5-phenyl tetrafluoride formoxyl alkyl ester forms negative ions with alkali in an inert organic solvent, is condensed with imidic salt to obtain N-dimethyl substitutive enamine derivative, and reacts with N - methyl hydrazide in organic acid to obtain N-methyl-N-acyl substitutive enamine derivative; under the reflux state, the N-methyl-N-acyl substitutive enamine derivative is catalyzed by alkali to obtain quinoline carboxylic ether; the quinoline carboxylic ether takes water as a solvent, is catalyzed with alkali at proper temperature and is neutralized to obtain quinoline carboxylic acid; under the action of an acid-binding agent, the quinoline carboxylic acid is condensed with N-methyl piperazine to obtain a condensed piperazine substance; the condensed piperazine substance is heated to proper temperature in an alkalis hydroxid water solution, is kept at the temperature and is neutralized to obtain hydrolysate; and the hydrolysate takes water as a solvent and is reacted with dialkoxy methane or methylene halide to obtain the marbofloxacin under the catalysis of the catalyzer. The invention has high yield, thereby facilitating industrialized production at large scale.
Description
Technical field
The invention belongs to chemical field, provided a kind of novel method for preparing marbofloxacin specifically, with 2,3,4,5-tetra fluoro benzene carbamoyl ester is a raw material, obtains target compound through series of chemical.
Background technology
Marbofloxacin (Marbofloxacin is to call Compound I in the following text) is the novel fluoroquinolone antibacterial agent of animal specific.By the development of Luo Shi (Roche) company,, successively go on the market the earliest in English, method in nineteen ninety-five after Ve ' toquinol company further develops.Its structural formula is:
Advantages such as marbofloxacin has has a broad antifungal spectrum, and sterilizing power is strong, absorbs soon, and is widely distributed in the body, easy to use with other antibiotic no cross resistances, and untoward reaction is little.Pharmacokinetic studies shows that marbofloxacin is removed long half time in animal body, and bioavailability is near 100%, does not almost have residually in blood, ight soil and the tissue of animal, is well suited for clinically to antibiotic requirement for animals.
Marbofloxacin is a tricyclic compound, comprises Yi oxadiazine ring.The synthetic method of document mainly contains following several:
One, US4801584 has reported two kinds of synthetic routes (square method one, method two) of marbofloxacin.
Method one
Method one is basic identical with method two; all be with 2; 3-two fluoro-6-nitrophenolss are starting raw material, through reduction, contract and, series of chemical such as cyclization, alkylation, amido protecting obtain target compound, difference only is the order difference protected on the phenolic hydroxyl group.
These two kinds of method routes are longer, wherein need to use the reagent of price costlinesses such as EMME, alkylating reagent, easy contaminate environment, are unfavorable for large-scale industrial production.
Two, ZL94190968.9 has reported three kinds of synthetic routes (square method three, method four, method five) of marbofloxacin
Method three
Wherein R represents the alkyl of 1 to 4 carbon atom, preferable methyl or ethyl; M is the positively charged ion of alkali metal hydroxide.
This method is starting raw material with the tetrafluorobenzoic aid, behind the formation monoesters, obtains target compound through reactions such as etherificate, amination, cyclization, the piperazine that contracts, hydrolysis.This method route is moderate, reacts comparatively simple, and overall yield has 32%, but during the potassium hydroxide hydrolysis because the existence of alkoxyl group is arranged, under the effect of potassium hydroxide, be easy to form the by-product that alkoxyl group replaces.
Method four
Still be starting raw material, obtain target compound through reactions such as amine exchange, cyclization, the piperazines that contracts again with XII with the tetrafluorobenzoic aid.The difficult point of this method is the preparation of compounds X II and the reaction of tetrafluorobenzoic aid and XII condensation, has limited its industrial applications.
Method five
Still be starting raw material with the tetrafluorobenzoic aid, direct and XIII condensation, reaction obtains target compound through the number step again.Though this method route is shorter, the preparation of compounds X III is difficulty more, and the tetrafluorobenzoic aid and the productive rate in one step of XIII condensation be the end more, does not have industrial value substantially.
Three, document (Dax SL; Wei CC, Quinolone antibacterials:A hydroxymethylation-intra-molecular cychzation route to pyrio[3,2,1-ij]-1,3,4-benzoxadiazines[J] .J Org Chem, 1992,57 (2): 744-766.) provide a kind of synthetic fiber crops to protect the novel method of Sha Xing oxadiazine ring.
This method is closed ring to adopt the catalysis of tetrabutyl fluoride amine, and with the N methyl piperazine condensation, hydrolysis gets target compound more again.But because the tetrabutyl fluoride amine that uses costs an arm and a leg, and reaction needed carries out under the anhydrous condition of strictness, therefore do not have industrial value.
In sum, in the existing marbofloxacin synthetic route, there are various deficiencies, more or the like as severe reaction conditions, chemical reagent costliness, long, the indivedual reactions steps impurity of reaction scheme.In view of the defective that above-mentioned the whole bag of tricks exists, the inventor has done research trial, invents out a kind of new method for preparing marbofloxacin, and this case produces thus.
Summary of the invention
The structural formula of involved compound is as follows in below describing:
Technical characterictic of the present invention is as follows:
1,2,3,4; 5-tetra fluoro benzene formyl radical alkyl ester (formula II) at inert organic solvents, forms negative ion with the highly basic effect in the preferred toluene under protection of inert gas; with inferior amine salt (formula III) condensation, make the enamine derivates (formula IV) that the N-dimethyl replaces again, need not to separate and purify.
Wherein said alkyl R is the alkyl of 1 to 4 carbon atom, preferred ethyl or methyl; Rare gas element can be argon gas or nitrogen, preferred nitrogen; Inert organic solvents can be acetonitrile, oil of mirbane, chlorobenzene, dimethylbenzene, toluene, preferred toluene; Used highly basic comprises alkalimetal hydrides such as sodium hydride, potassium hydride KH; Alkali-metal lower alkyl oxide compounds such as sodium methylate, potassium methylate, sodium ethylate, potassium ethylate, sodium tert-butoxide, potassium tert.-butoxide; Organo-metallic such as magnesium methylate, magnesium ethylate magnesium compound; And organo-metallic lithium compounds such as butyllithium, di-isopropyl ammonia lithium, benzyl lithium, preferred sodium hydride or sodium ethylate.
2, formula IV and N-methylhydrazide (formula V), with in the feed liquid of step gained, under organic acid catalysis, reaction makes the enamine derivates (compound VI) of N-methyl-N-acyl substituted.
Wherein said R ' can be formyl radical, ethanoyl, trifluoroacetyl group, benzoyl, ethoxycarbonyl, 2,2,2-trichlorine ethoxycarbonyl, benzene oxygen formyl radical, carbobenzoxy, uncle's fourth oxygen formyl radical etc., preferred formyl radical; Described organic acid is acetate, trifluoroacetic acid, Phenylsulfonic acid, tosic acid etc., preferred acetate.
3, formula VI under the preferred reflux state, at base catalysis ShiShimonoseki ring, makes quinoline carboxylic ester (formula VII) in the feed liquid of last step gained.
Described in alkali be the oxyhydroxide of alkaline-earth metal, the carbonate of alkaline-earth metal, the supercarbonate or the lower trialkyl amine of alkaline-earth metal, as sodium hydroxide, potassium hydroxide, yellow soda ash, sodium bicarbonate, salt of wormwood, saleratus, triethylamine etc., preferred yellow soda ash or salt of wormwood.
4, formula VII is solvent with water, at a certain temperature, with an amount of base catalysis, hydrolysis reaction takes place, and with an amount of acid neutralization, filters again, and drying under reduced pressure makes quinoline carboxylic acid (formula VIII).
Wherein said temperature of reaction is 30-100 ℃, preferred 70 ℃; The alkali that is used for catalyzed reaction can be the oxyhydroxide of alkaline-earth metal or the carbonate of alkaline-earth metal, preferred sodium hydroxide; Be used for neutral acid and can be protonic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, acetate, Phenylsulfonic acid, tosic acid, preferred hydrochloric acid.
5, formula VIII rises to certain temperature in organic solvent, under the effect of acid binding agent, with the N methyl piperazine condensation, makes the piperazine thing (formula IX) that contracts.
Wherein said organic solvent can be methyl alcohol, ethanol, Virahol, primary isoamyl alcohol, acetonitrile, toluene, DMSO, DMF, pyridine etc., preferred pyridine; Described acid binding agent can be the carbonate of alkaline-earth metal or rudimentary tri-alkoxy amine such as yellow soda ash, sodium bicarbonate, salt of wormwood, saleratus, triethylamine etc., preferred triethylamine.The temperature of reaction is 30 ℃ of boiling points to solvent, preferred 60 ℃.
6, formula IX rises to certain temperature in certain density alkali metal hydroxide aqueous solution, is incubated to the regular hour, with the acid neutralization, makes hydrolyzate (formula X) again.
Wherein said alkali metal hydroxide is sodium hydroxide or potassium hydroxide, preferred potassium hydroxide; Concentration is 20-40% (weight concentration), preferred 30%; The temperature of reaction is 50-120 ℃, preferred reflux temperature; Reaction times is 10-60 hour, preferred 20 hours; The consumption of alkali metal hydroxide is more than 10 equivalents.
7, formula X is solvent with water, under the catalysis of acid or alkali, reacts with dialkoxy methane or methylene halide (formula XI), is neutralized to pH value=7.0-8.0 with an amount of alkali or acid again, makes Compound I.
Wherein said R " be the lower alkoxy or the halogen atom of carbonatoms 1 to 4, preferred methoxyl group or bromine atoms; If " be lower alkoxy, described to be used for catalytic acid be acetate, hydrochloric acid, sulfuric acid, Phenylsulfonic acid, tosic acid etc., preferably hydrochloric acid R; If R " be halogen atom, described oxyhydroxide or carbonate or the supercarbonate that catalytic alkali is alkaline-earth metal, the preferred sodium hydroxide of being used for; Comparatively the consumption of Shi Yi catalyzer (comprising bronsted lowry acids and bases bronsted lowry) is the 2.0-3.0 equivalent, preferred 2.5 equivalents.
The invention provides a kind of synthetic route of new preparation marbofloxacin, compare, have following characteristics with existing various synthetic routes:
1, total recovery of the present invention is more than 50%, and simple to operate, side reaction is few, reaction conditions gentleness, suitable industrial scale operation.
2, after the present invention sloughs ester group and amino protecting group again with N methyl piperazine generation condensation reaction; because lone-pair electron delocalized influence on carboxyl ionization and the amino in solvent; increase cloud density on the phenyl ring, strengthened the piperazine reactive activity that contracts, improved yield.
3, the present invention reacts in potassium hydroxide aqueous solution after ester group and amino protecting group are sloughed again, has both increased the activity of 8 fluorine atoms, can effectively avoid the existence of alkoxyl group again and the side reaction that causes, has therefore shortened the reaction times, and has improved yield.
4, the invention provides a kind of method of the husky star oxadiazine ring of synthetic fiber crops guarantor of novelty, is cyclizing agent with dialkoxy methane or methylene halide, reacts under the catalysis of acid or alkali, makes marbofloxacin.
5, except that midbody compound VIII need take out, all the other intermediates all can not take out, and directly carry out the next step, are very beneficial for mass preparation.
Embodiment
With 2,3,4, the 5-tetrafluorobenzoyl ethyl is that starting raw material prepares marbofloxacin, and synthetic route chart is as follows:
In order to set forth conveniently, each step of the present invention is called an embodiment, wherein embodiment 1 is the synthetic of 3-(dimethylamino)-2-(2,3,4,5-tetra fluoro benzene formyl radical) ethyl acetate; Embodiment 2 be 3-(2-formyl radical-2-methyl diazanyl)-2-(2,3,4,5-tetra fluoro benzene formyl radical ethyl propenoate synthetic; Embodiment 3 is 6,7,8-three fluoro-1-(N-methyl formamido group)-4-oxo-1,4-dihydroquinoline-3 carboxylic acid, ethyl ester synthetic; Embodiment 4, embodiment 5 and embodiment 6 are 6,7,8-three fluoro-1-(methylamino)-4-oxos-1,4-dihydroquinoline-3 carboxylic acid synthetic; Embodiment 7, embodiment 8 and embodiment 9 are 6,8-two fluoro-1-(methylamino)-7-(4-methyl isophthalic acid-piperazinyl)-4-oxos-1,4-dihydroquinoline-3 carboxylic acid synthetic; Embodiment 10, embodiment 11 and embodiment 12 are 6-fluoro-8-hydroxyl-1-(methylamino) 7-(4-methyl isophthalic acid-piperazinyl)-4-oxos-1,4-dihydroquinoline-3 carboxylic acid synthetic; Embodiment 13, embodiment 14 and embodiment 15 are the synthetic of marbofloxacin.
Synthesizing of embodiment 1,3-(dimethylamino)-2-(2,3,4,5-tetra fluoro benzene formyl radical) ethyl acetate
Input 4g sodium hydride in the 500ml four-hole boiling flask that is full of nitrogen (60%, 0.10mol), about 0 ℃, drip 2,3,4, the toluene solution of 5-tetrafluoro ethyl benzoylacetate (26.42g is dissolved in 60ml toluene) with 200ml toluene.Dripped off in about 2-3 hour, and be incubated 8 hours down in 0 ℃.Other gets 39.85g1, and 1-dimethyl-2-methoxyl group imines mesylate (0.20mol) is added dropwise under 0 ℃ in the above-mentioned solution, drip to finish 0-5 ℃ of following insulation reaction 15 hours.Reaction is finished, decompress filter, and filter cake is bleached with an amount of toluene.Merging filtrate, with deionized water wash twice, each deionized water 40ml uses anhydrous sodium sulfate drying again; the filtering siccative promptly gets 3-(dimethylamino)-2-(2,3; 4,5-tetra fluoro benzene formyl radical) the toluene feed liquid of ethyl acetate need not purifying and is directly used in the next step.
Embodiment 2,3-(2-formyl radical-2-methyl diazanyl)-2-(2,3,4,5-tetra fluoro benzene formyl radical ethyl propenoate synthetic
Upwards go on foot adding 8.6ml glacial acetic acid (0.15mol) in the gained feed liquid, stirred 10 minutes, drip 8.81gN-amino-N-methylformamide (0.10mol) down in 5 ℃.Drip and finish, 5-10 ℃ was reacted 6 hours down.Reaction is finished, and regulates pH value to 6 with an amount of sodium hydroxide solution.Again with frozen water washing three times, 40ml frozen water at every turn.The organic layer anhydrous sodium sulfate drying, the filtering siccative, (2,3,4, the toluene feed liquid of 5-tetra fluoro benzene formyl radical ethyl propenoate need not purifying and is directly used in the next step to get 3-(2-formyl radical-2-methyl diazanyl)-2-.
Embodiment 3,6,7,8-three fluoro-1-(N-methyl formamido group)-4-oxo-1,4-dihydroquinoline-3 carboxylic acid, ethyl ester synthetic
Upwards go on foot adding 6.36g yellow soda ash (0.06mol) in the gained feed liquid, be warming up to backflow, reaction is 4 hours under reflux state.There is product to separate out in the reaction process gradually.Reaction is finished, suction filtration.To neutral, 60 ℃ of following vacuum-dryings again get faint yellow to yellow powder 29.54g (yield 90.0%), fusing point 188-191 ℃ filter cake with rinsed with deionized water.
Embodiment 4,6,7,8-three fluoro-1-(methylamino)-4-oxos-1,4-dihydroquinoline-3 carboxylic acid synthetic
In the 500ml four-hole boiling flask, drop into 32.82g6,7,8-three fluoro-1-(N-methyl formamido group)-4-oxo-1,4-dihydroquinoline-3 carboxylic acid, ethyl ester (0.10mol) and 100ml2N sodium hydroxide solution (0.2mol) are warming up to 70 ℃, react 4 hours.Reaction is finished, and is cooled to room temperature, regulates pH value=7 with the 2N hydrochloric acid soln.Transfer and finish, stirred 30 minutes.Decompress filter, filter cake 100ml deionized water rinsing at twice, 60 ℃ of following vacuum-dryings get pale yellow powder 26.10g (yield 95.9%), fusing point 236-239 ℃.
Embodiment 5,6,7,8-three fluoro-1-(methylamino)-4-oxos-1,4-dihydroquinoline-3 carboxylic acid synthetic
In the 500ml four-hole boiling flask, drop into 32.82g6,7,8-three fluoro-1-(N-methyl formamido group)-4-oxo-1,4-dihydroquinoline-3 carboxylic acid, ethyl ester (0.10mol) and 10.60g yellow soda ash (0.10mol) are warming up to 100 ℃, react 4 hours.Reaction is finished, and is cooled to room temperature, regulates pH value=7 with the 2N hydrochloric acid soln.Transfer and finish, stirred 30 minutes.Decompress filter, filter cake 100ml deionized water rinsing at twice, 60 ℃ of following vacuum-dryings get pale yellow powder 24.50g (yield 90.0%), fusing point 236-239 ℃.
Embodiment 6,6,7,8-three fluoro-1-(methylamino) 4-oxos-1,4-dihydroquinoline-3 carboxylic acid synthetic
In the 500ml four-hole boiling flask, drop into 31.42g6,7,8-three fluoro-1-(N-methyl formamido group)-4-oxo-1,4-dihydroquinoline-3 carboxylate methyl ester (0.10mol) and 8g sodium hydroxide (0.20mol) are warming up to 30 ℃, react 8 hours.Reaction is finished, and is cooled to room temperature, regulates pH value=7 with the 2N hydrochloric acid soln.Transfer and finish, stirred 30 minutes.Decompress filter, filter cake 100ml deionized water rinsing at twice, 60 ℃ of following vacuum-dryings get pale yellow powder 25.04g (yield 92.0%), fusing point 236-239 ℃.
Embodiment 7,6,8-two fluoro-1-(methylamino)-7-(4-methyl isophthalic acid-piperazinyl)-4-oxos-1,4-dihydroquinoline-3 carboxylic acid synthetic
In the 500ml four-hole boiling flask, drop into 27.22g6,7,8-three fluoro-1-(methylamino)-4-oxos-1,4-dihydroquinoline-3 carboxylic acid (0.10mol), 10.12g triethylamine (0.10mol), 11.01g N methyl piperazine (0.11mol) and 150ml pyridine, be warming up to 60 ℃, insulation reaction 4 hours.Reaction is finished, and the evaporated under reduced pressure solvent adds 150ml methylene dichloride and 100ml deionized water, stirs standing demix 30 minutes.Water layer dichloromethane extraction three times, each 40ml.Merge organic layer, deionized water wash twice, each 40ml.Organic layer is used anhydrous sodium sulfate drying again, the filtering siccative, and the filtrate decompression evaporate to dryness gets faint yellow to yellow solid 32.82g (yield 93.1%), fusing point 225-228 ℃.
Embodiment 8,6,8-two fluoro-1-(methylamino)-7-(4-methyl isophthalic acid-piperazinyl)-4-oxos-1,4-dihydroquinoline-3 carboxylic acid synthetic
In the 500ml four-hole boiling flask, drop into 27.22g6,7,8-three fluoro-1-(methylamino)-4-oxos-1,4-dihydroquinoline-3 carboxylic acid (0.10mol), 5.3g yellow soda ash (0.05mol), 11.01g N methyl piperazine (0.11mol) and 150ml Virahol, be warming up to backflow, insulation reaction 6 hours.Reaction is finished, and the evaporated under reduced pressure solvent adds 150ml methylene dichloride and 100ml deionized water, stirs standing demix 30 minutes.Water layer dichloromethane extraction three times, each 40ml.Merge organic layer, deionized water wash twice, each 40ml.Organic layer is used anhydrous sodium sulfate drying again, the filtering siccative, and the filtrate decompression evaporate to dryness gets faint yellow to yellow solid 31.82g (yield 90.3%), fusing point 225-228 ℃.
Embodiment 9,6,8-two fluoro-1-(methylamino)-7-(4-methyl isophthalic acid-piperazinyl)-4-oxos-1,4-dihydroquinoline-3 carboxylic acid synthetic
In the 500ml four-hole boiling flask, drop into 27.22g6,7,8-three fluoro-1-(methylamino)-4-oxos-1,4-dihydroquinoline-3 carboxylic acid (0.10mol), 10.12g triethylamine (0.10mol), 15.02g N methyl piperazine (0.15mol) and 150mlDMF, 30 ℃ of following insulation reaction 6 hours.Reaction is finished, and the evaporated under reduced pressure solvent adds 150ml methylene dichloride and 100ml deionized water, stirs standing demix 30 minutes.Water layer dichloromethane extraction three times, each 40ml.Merge organic layer, deionized water wash twice, each 40ml.Organic layer is used anhydrous sodium sulfate drying again, the filtering siccative, and the filtrate decompression evaporate to dryness gets faint yellow to yellow solid 31.50g (yield 89.4%), fusing point 225-228 ℃.
Embodiment 10,6-fluoro-8-hydroxyl-1-(methylamino)-7-(4-methyl isophthalic acid-piperazinyl)-4-oxo-1,4-dihydroquinoline-3 carboxylic acid synthetic
In the 500ml four-hole boiling flask, drop into 56.11g potassium hydroxide (1.0mol), add the 130.9ml deionized water, after stirring makes dissolving, be chilled to room temperature.Again to wherein adding 35.23g 6,8-two fluoro-1-(methylamino)-7-(4-methyl isophthalic acid-piperazinyl)-4-oxos-1,4-dihydroquinoline-3 carboxylic acid (0.10mol) is warming up to backflow, and reaction is 20 hours under reflux state.Reaction is finished, and is chilled to room temperature, and Dropwise 5 N hydrochloric acid soln is regulated pH value=7-7.5.Transfer and finish, stirred 30 minutes, decompress filter, filter cake 100ml rinsed with deionized water rinsing at twice, 60 ℃ of following vacuum-dryings again get pale powder 29.32g (yield 83.7%).
Embodiment 11,6-fluoro-8-hydroxyl-1-(methylamino)-7-(4-methyl isophthalic acid-piperazinyl)-4-oxo-1,4-dihydroquinoline-3 carboxylic acid synthetic
In the 500ml four-hole boiling flask, drop into 60.00g sodium hydroxide (1.5mol), add the 240ml deionized water, after stirring makes dissolving, be chilled to room temperature.Again to wherein adding 35.23g 6,8-two fluoro-1-(methylamino)-7-(4-methyl isophthalic acid-piperazinyl)-4-oxos-1,4-dihydroquinoline-3 carboxylic acid (0.10mol) is warming up to 120 ℃, insulation reaction 60 hours.Reaction is finished, and is chilled to room temperature, and Dropwise 5 N hydrochloric acid soln is regulated pH value=7-7.5.Transfer and finish, stirred 30 minutes, decompress filter, filter cake 100ml rinsed with deionized water rinsing at twice, 60 ℃ of following vacuum-dryings again get pale powder 29.88g (yield 85.3%).
Embodiment 12,6-fluoro-8-hydroxyl-1-(methylamino)-7-(4-methyl isophthalic acid-piperazinyl)-4-oxo-1,4-dihydroquinoline-3 carboxylic acid synthetic
In the 500ml four-hole boiling flask, drop into 112.22g potassium hydroxide (2.0mol), add the 168.33ml deionized water, after stirring makes dissolving, be chilled to room temperature.Again to wherein adding 35.23g6,8-two fluoro-1-(methylamino)-7-(4-methyl isophthalic acid-piperazinyl)-4-oxos-1,4-dihydroquinoline-3 carboxylic acid (0.10mol) is warming up to 50 ℃, insulation reaction 10 hours.Reaction is finished, and is chilled to room temperature, and Dropwise 5 N hydrochloric acid soln is regulated pH value=7-7.5.Transfer and finish, stirred 30 minutes, decompress filter, filter cake 100ml rinsed with deionized water rinsing at twice, 60 ℃ of following vacuum-dryings again get pale powder 23.56g (yield 67.25%).
Synthesizing of embodiment 13, marbofloxacin
In the 500ml four-hole boiling flask, successively drop into 35.03g6-fluoro-8-hydroxyl-1-(methylamino)-7-(4-methyl isophthalic acid-piperazinyl)-4-oxo-1, the 5N hydrochloric acid soln (0.20mol) of 4-dihydroquinoline-3 carboxylic acid (0.10mol), 240ml deionized water and 40ml, restir add 7.60g formaldehyde dimethyl acetal (0.10mol) down.Be warming up to 50 ℃, reacted 6 hours.Reaction is finished, and is cooled to room temperature, regulates pH value=7.0-8.0 with the 3N sodium hydroxide solution, and ice-water bath is chilled to 0-5 ℃, close stirring, left standstill crystallization 12 hours, suction filtration, the 100ml rinsed with deionized water rinsing at twice of gained filter cake filter cake, 60 ℃ of following drying under reduced pressure get marbofloxacin 33.60g.Yield 92.7%, fusing point 265-268 ℃.
Synthesizing of embodiment 14, marbofloxacin
In the 500ml four-hole boiling flask, successively drop into 35.03g6-fluoro-8-hydroxyl-1-(methylamino base)-7-(4-methyl isophthalic acid-piperazinyl)-4-oxo-1, the 5N hydrochloric acid soln (0.30mol) of 4-dihydroquinoline-3 carboxylic acid (0.10mol), 240ml deionized water and 60ml, restir add 10.42g ethylal (0.10mol) down.Be warming up to 90 ℃, reacted 2 hours.Reaction is finished, and is cooled to room temperature, regulates pH value=7.0-8.0 with the 3N sodium hydroxide solution, and ice-water bath is chilled to 0-5 ℃, close stirring, left standstill crystallization 12 hours, suction filtration, the 100ml rinsed with deionized water rinsing at twice of gained filter cake, 60 ℃ of following drying under reduced pressure get marbofloxacin 32.55g.Yield 89.8%, fusing point 265-268 ℃.
Synthesizing of embodiment 15, marbofloxacin
In the 500ml four-hole boiling flask, successively drop into 35.03g6-fluoro-8-hydroxyl-1-(methylamino)-7-(4-methyl isophthalic acid-piperazinyl)-4-oxo-1, the 5N sodium hydroxide solution (0.25mol) of 4-dihydroquinoline-3 carboxylic acid (0.10mol), 240ml deionized water and 50ml, restir add 17.38g methylene bromide (0.10mol) down.Be warming up to 100 ℃, reacted 4 hours.Reaction is finished, and is cooled to room temperature, regulates pH value=7.0-8.0 with the 3N hydrochloric acid soln, and ice-water bath is chilled to 0-5 ℃, close stirring, left standstill crystallization 12 hours, suction filtration, the 100ml rinsed with deionized water rinsing at twice of gained filter cake, 60 ℃ of following drying under reduced pressure get marbofloxacin 33.10g.Yield 91.3%, fusing point 265-268 ℃.
Claims (12)
1. method for preparing marbofloxacin is characterized in that:
Step 1,2,3,4,5-tetra fluoro benzene formyl radical alkyl ester (formula II) forms negative ion with the highly basic effect in inert organic solvents under protection of inert gas, with inferior amine salt (formula III) condensation, make the enamine derivates (formula IV) that the N-dimethyl replaces again, need not to separate and purify;
R is the alkyl of 1 to 4 carbon atom;
Step 2, in the feed liquid of last step gained, enamine derivates (formula IV) that the N-dimethyl replaces and N-methylhydrazide (formula V), under organic acid catalysis, reaction makes the enamine derivates (formula VI) of N-methyl-N-acyl substituted;
R ' is formyl radical, ethanoyl, trifluoroacetyl group, benzoyl, ethoxycarbonyl, 2,2, any one in 2-trichlorine ethoxycarbonyl, benzene oxygen formyl radical, carbobenzoxy, the uncle's fourth oxygen formyl radical;
Step 3, in the feed liquid of last step gained, the enamine derivates (formula VI) of N-methyl-N-acyl substituted at base catalysis ShiShimonoseki ring, makes quinoline carboxylic ester (formula VII) under reflux state;
Step 4, the quinoline carboxylic ester (formula VII) that step 3 is made is solvent with water, under 30 ℃ of-100 ℃ of temperature, uses base catalysis, and hydrolysis reaction takes place, and with the acid neutralization, filters again, drying under reduced pressure makes quinoline carboxylic acid (formula VIII);
Step 5 makes quinoline carboxylic acid (formula VIII) in organic solvent with step 4, heat up, 30 ℃ to the temperature range of organic solvent boiling point, under the effect of acid binding agent,, make the piperazine thing (formula IX) that contracts with the N methyl piperazine condensation;
Step 6 contracts piperazine thing (formula IX) to what step 5 made in the alkali metal hydroxide aqueous solution of 20%-40% weight concentration, is warming up to 50 ℃-120 ℃, is incubated 10 hours-60 hours, with the acid neutralization, makes hydrolyzate (formula X) again;
Step 7 is solvent with water with the hydrolyzate of step 6 gained, and under the catalysis of catalyzer, XI reacts with formula, is neutralized to pH value=7.0-8.0 again, makes marbofloxacin;
R″(CH
2)R″
XI?，
R " is the lower alkoxy or the halogen atom of carbonatoms 1 to 4.
2. a kind of method for preparing marbofloxacin as claimed in claim 1 is characterized in that: the inert organic solvents described in the step 1 is a toluene; Rare gas element is a nitrogen; The alkyl R of formula II is ethyl or methyl; Used highly basic is alkalimetal hydride, or is sodium ethylate, or is the organo-metallic magnesium compound, or is the organo-metallic lithium compound.
3. a kind of method for preparing marbofloxacin as claimed in claim 1 is characterized in that: organic acid is the wherein a kind of of acetate, trifluoroacetic acid, Phenylsulfonic acid, tosic acid in the described step 2.
4. a kind of method for preparing marbofloxacin as claimed in claim 1 is characterized in that: the alkali described in the step 3 is the oxyhydroxide of alkaline-earth metal, or is the carbonate of alkaline-earth metal, or is the supercarbonate of alkaline-earth metal.
5. a kind of method for preparing marbofloxacin as claimed in claim 1 is characterized in that: preferred 70 ℃ of the temperature of reaction described in the step 4; The alkali that is used for catalyzed reaction is the oxyhydroxide of alkaline-earth metal, or is the carbonate of alkaline-earth metal, and it is wherein a kind of for hydrochloric acid, sulfuric acid, phosphoric acid, acetate, Phenylsulfonic acid, tosic acid to be used for neutral acid.
6. a kind of method for preparing marbofloxacin as claimed in claim 1 is characterized in that: the organic solvent described in the step 5 is that methyl alcohol, ethanol, Virahol, primary isoamyl alcohol, acetonitrile, toluene, DMSO, DMF, pyridine are wherein a kind of; Described acid binding agent is the carbonate of alkaline-earth metal, or triethylamine, and the temperature of reaction is 60 ℃.
7. a kind of method for preparing marbofloxacin as claimed in claim 1 is characterized in that: the alkali metal hydroxide described in the step 6 is sodium hydroxide or potassium hydroxide; Weight concentration is 30%; Temperature of reaction is a reflux temperature; Reaction times is 20 hours; The consumption of alkali metal hydroxide is more than 10 equivalents.
8. a kind of method for preparing marbofloxacin as claimed in claim 1 is characterized in that: R in the step 7 " is lower alkoxy; Described catalyzer is that acetate, hydrochloric acid, sulfuric acid, Phenylsulfonic acid, tosic acid are wherein a kind of.
9. a kind of method for preparing marbofloxacin as claimed in claim 1 is characterized in that: R in the step 7 " is halogen atom; Described catalyzer is that oxyhydroxide, alkaline earth metal carbonate, the alkali metal bicarbonates of alkaline-earth metal is wherein a kind of, and consumption is the 2.0-3.0 equivalent.
10. a kind of method for preparing marbofloxacin as claimed in claim 2 is characterized in that: described alkalimetal hydride is a sodium hydride.
11. a kind of method for preparing marbofloxacin as claimed in claim 8 is characterized in that: described lower alkoxy is a methoxyl group.
12. a kind of method for preparing marbofloxacin as claimed in claim 9 is characterized in that: described halogen atom is a bromine atoms; Described catalyst levels is 2.5 equivalents.
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| CN102617595A (en) * | 2012-03-23 | 2012-08-01 | 江西华士药业有限公司 | Preparation method of fluoroquinolone antibacterial medicament marbofloxacin |
| CN105130892B (en) * | 2015-08-19 | 2016-08-17 | 海门慧聚药业有限公司 | The preparation of Marbofloxacin key intermediate |
| CN107522632A (en) * | 2017-08-29 | 2017-12-29 | 湖北龙翔药业科技股份有限公司 | A kind of preparation method of 3 (N methyl formohydrazide group) ethyl acrylates |
| CN107522718B (en) * | 2017-09-14 | 2019-11-08 | 浙江国邦药业有限公司 | A kind of synthetic method of Marbofloxacin |
| CN110283186A (en) * | 2019-07-19 | 2019-09-27 | 海门慧聚药业有限公司 | A kind of crystal form of Marbofloxacin and preparation method thereof |
| CN115703757B (en) * | 2021-08-16 | 2024-04-09 | 浙江中欣氟材股份有限公司 | Synthesis method of melaxacin |
| CN113912539B (en) * | 2021-12-13 | 2022-03-11 | 山东国邦药业有限公司 | Synthesis method of cyclopropanecarboxylic acid |
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