CN104292159B - A kind of preparation method of norfloxacin, ciprofloxacin and enrofloxacin - Google Patents
A kind of preparation method of norfloxacin, ciprofloxacin and enrofloxacin Download PDFInfo
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- CN104292159B CN104292159B CN201410532023.7A CN201410532023A CN104292159B CN 104292159 B CN104292159 B CN 104292159B CN 201410532023 A CN201410532023 A CN 201410532023A CN 104292159 B CN104292159 B CN 104292159B
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
- C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
Abstract
The present invention discloses the preparation method of a kind of norfloxacin, ciprofloxacin and enrofloxacin.The method is 1 ethyl 6 fluorine 7 chlorine 4 oxo 1,4 dihydroquinoline 3 carboxylates or 1 cyclopropyl 6 fluorine 7 chlorine 4 oxo 1,4 dihydroquinoline 3 carboxylates directly react with piperazine (or N ethyl piperazidine), more post-treated prepare corresponding target product norfloxacin (or ciprofloxacin or enrofloxacin).Reactions steps of the present invention is short, easy to operate, small investment, beneficially industrialized production；Reduce the consumption of more than half piperazine (or N ethyl piperazidine)；Under Louis acid catalysis effect, reaction temperature is low, and by-product is few, and yield is high, low cost；Avoid a large amount of use mineral acid and inorganic base, decrease pollution.
Description
Technical field
The invention belongs to technical field of medicine synthesis, relate to the synthetic method of fluoroquinolones, tool
Say the preparation method relating to a kind of norfloxacin, ciprofloxacin and enrofloxacin body.
Technical background
Quinolinones is class chemosynthesis antibacterials, has quickly grown, due to it since coming out always
Have that has a broad antifungal spectrum, antibacterial activity be strong, convenient drug administration, untoward reaction is little and other antibiotic are without handing over
Pitch the advantages such as drug resistance and become the first-selection of combined clinical medication.Quinolones has become works as forefathers
The focus competitively researched and developed, existing many documents report the synthetic method of such medicine, but generally deposit
The weak point such as longer in step, yield is the highest, three wastes generation amount is bigger, therefore people are being always
Seek to operate the synthetic method simpler, yield is higher, technique is more environmentally friendly and unremitting effort.Tie below
Close norfloxacin, ciprofloxacin and enrofloxacin to briefly introduce.
Norfloxacin (Norfloxacin), has another name called norfloxacin, chemical name: 1-ethyl-6-fluorin-4-oxygen
Generation-Isosorbide-5-Nitrae-dihydro-7-(1-piperazinyl)-3-quinoline carboxylic acid, is the 3rd generation carbostyril family antibacterial drugs, tool
There is broad-spectrum antibacterial action, to escherichia coli, pneumobacillus, aerobacteria, bacillus cloacae, deformed rod
The distant tree planting Cordycepps such as bacterium, Salmonella, Shigella, citrobacter genus and Serratia
Antibacterial has powerful antibacterial action.Norfloxacin is external also has antibacterial activity to multi-drug resistant bacteria.Right
The Diplococcus gonorrhoeae of Penicillin-resistant, hemophilus influenza and moraxelle catarrhalis also have good antibacterial action.
Owing to norfloxacin has, bioavailability is high, tissue permeability is good resistance to without intersecting with other antibiotics
The features such as the property of medicine, side effect be little and oral absorption is fast, are widely used in treating caused by sensitive organism clinically
The infectious disease such as urinary system, intestinal, respiratory system, surgery, gynecological, department of eye and department of dermatologry.
Structure is as follows:
Ciprofloxacin (Ciprofloxacin), has another name called ciprofloxacin, chemical name: 1-cyclopropyl
The fluoro-7-of-6-(1-piperazine howl base-Isosorbide-5-Nitrae-dihydro-4-oxo-3-quinoline carboxylic acid.It is the eighties Germany Bayer
The strongly active antimicrobial drug of quinolones of new generation that company develops, have wide spectrum, efficiently, toxic and side effects little
Have specially good effect etc. feature, the especially pathogen to resistant to many antibiotic, be at present preferably antibacterials it
One, in multinational listing, become world's best-selling drugs.Its Antibacterial mechanism is the DNA rotation of suppression antibacterial
Turn enzyme, make DNA duplication, transcribe, reparation etc. is obstructed, and reaches the antibacterial and effect of sterilization.For
Urogenital infections, respiratory tract infection, alimentary infection, fowl cholera, avian typhoid, bone and joint
Infection, skin soft-tissue infection, septicemia etc..Structure is as follows:
Enrofloxacin, chemical name: 1-cyclopropyl-7-(4-ethyl-1-piperazinyl) the fluoro-Isosorbide-5-Nitrae of-6--dihydro-4-
Oxo-3-quinoline carboxylic acid, for the third generation carbostyril family antibacterial drugs of synthesis, has another name called ENR,
Enrofloxacin.Obtain FDA approval on October 4th, 1996, resist for the special quinolones of poultry and Aquatic product
Bacterium medicine.There is broad spectrum antibiotic activity and the strongest permeability, gram negative bacteria is had the strongest killing
The effect of going out, also has good antibacterial action to gram positive bacteria and mycoplasma, and oral absorption is good, blood
Concentration is high and stable, and its metabolite is ciprofloxacin, still has powerful antibacterial action.Can significantly drop
Low actual, ill domestic animal restores fast, and growth is rapidly.Sterilization mode is direct and unique, directly acts on thin
The nucleus of bacterium, suppresses DNA of bacteria gyrase, causes antibacterial quick death, be not likely to produce drug resistance.
Structure is as follows:
The synthesis of quinolones, currently mainly uses first cyclization to carry out 7 substituted methods again.
Above-mentioned norfloxacin, ciprofloxacin and enrofloxacin have identical main cyclic quinoline structure, can use
Identical initiation material synthesizes.For main cyclic quinoline (cyclized ester) synthetic method, Chinese patent
The method of 2010101608124 pairs of Bayer patent US6229017 reports is improved, and solves
The shortcoming of dimethylamine by-product, makes dimethylamine form complex and reclaims and make it in whole main ring synthesizes
Recycled, this process recovery ratio is high, and three waste discharge is few, the most in Duo Jia quinolinones manufacturing enterprise
Popularization and application.The last two steps in the synthesis of norfloxacin, ciprofloxacin and enrofloxacin, i.e. cyclized ester
Hydrolysis and piperazine replace, relatively common has 3 kinds of methods: 1, use hydrochloric acid, glacial acetic acid, sulphuric acid
Obtain carboxylic acid Deng acid water solution cyclized ester, then carry out replacement with piperazine and obtain target product, weak point
Being to need to use substantial amounts of glacial acetic acid and sulphuric acid does solvent and reagent, the method cost high pollution is big.2、
Use the alkali water solution cyclized ester such as sodium hydroxide, potassium hydroxide, then adjust with hydrochloric acid, sulphuric acid or glacial acetic acid
PH is to acid, then puts in the reaction of final step contracting piperazine.Although the method can be avoided making with glacial acetic acid
For solvent, but in post processing, have employed acid readjustment pH generate free carboxylic acid, then sucking filtration to acid
Obtain the step of carboxylic acid.Chinese patent 201210200823X reports with levofloxacin or oxygen
The cyclized ester of Flucloxacillin is raw material, uses equal to or more than the alkali of cyclized ester mole, in a solvent one
Pot method synthesis target product.Hereafter the method is adjusted by Chinese patent 2013106498800,
The alkali and the N methyl piperazine that i.e. use catalytic amount are hydrolyzed and obtain carboxylate, then the contracting piperazine one kettle way that heats up
Synthesis target product.Technique after adjustment N methyl piperazine increases the alkalescence of system, decreases alkali
Consumption, but add the consumption of N methyl piperazine.3, after using combinative enzyme hydrolysis cyclized ester to become carboxylic acid
Contracting piperazine obtains target molecule, mild condition again, and three waste discharge is few, but has that efficiency is low, productivity is low
Shortcoming.
In existing document, the synthetic method of quinolones has 2 kinds, one: first synthesis quinolinones master
Ring i.e. cyclized ester, then it is hydrolyzed into carboxylic acid retraction piperazine；Its two: cyclized ester first contracting piperazine hydrolyzes again.This
Bright provide the 3rd kind of synthetic method, the most first synthesis main cyclic quinoline carboxylate (organic salt), more directly
Contracting piperazine obtains target product, the method overcomes the deficiencies in the prior art, is suitable for industrialized production.
Summary of the invention
It is an object of the invention to for the deficiencies in the prior art, it is provided that the preparation of a kind of norfloxacin
Method.
The method is: in a solvent, the fluoro-7-of 1-ethyl-6-chloro-4-oxo-Isosorbide-5-Nitrae-dihydro-quinoline-3-
There is substitution reaction in carboxylate (I) and piperazine, more post-treated prepared target is produced at a certain temperature
Thing norfloxacin, synthetic reaction formula is as follows:
Shown in Formulas I, M is preferably Na, K, Li, Rb or Cs；
The described fluoro-7-of 1-ethyl-6-chloro-4-oxo-1,4-dihydro-quinoline-3-carboxylate (I) with
The mol ratio of piperazine is 1:1～6；
Described substitution reaction also can add catalyst lewis acid, and described lewis acid is preferably
AlCl3、ZnCl2Or SnCl4；Lewis acidic addition and the fluoro-7-of 1-ethyl-6-chloro-4-oxo-1,4-
The mol ratio of dihydro-quinoline-3-carboxylate (I) is 0.01～0.6:1；
Described solvent is preferably alcohols solvent, more preferably ethanol, isopropanol or isoamyl alcohol, consumption with
The fluoro-7-of 1-ethyl-6-chloro-4-oxo-Isosorbide-5-Nitrae-dihydro-quinoline-3-carboxylate (I) quality meter, every gram
The fluoro-7-of 1-ethyl-6-chloro-4-oxo-1,4-dihydro-quinoline-3-carboxylate (I) add solvent 2～
20ml；
The reaction temperature of described substitution reaction is preferably 70～140 DEG C；
The concrete preparation method of norfloxacin be the fluoro-7-of 1-ethyl-6-chloro-4-oxo-1,4-dihydro-
Addition piperazine, lewis acid, solvent in quinoline-3-carboxylation (I), control temperature 70～140 DEG C,
Insulation reaction 8～10 hours, after piperazine replaces completely, cooling, filter to obtain solid, solid is the most molten
Solution, in dilute hydrochloric acid, through alkali regulation pH value to 7.2～7.3, stands, filters to obtain crude product, through ethanol
Recrystallization obtains norfloxacin.
The described fluoro-7-'s of 1-ethyl-6-chloro-4-oxo-1,4-dihydro-quinoline-3-carboxylate (I)
Synthetic method is as follows: 2,4-bis-chloro-5-fluorobenzoyl chloride is warp and N, N-diformazan under the effect of acid binding agent
After amino acrylates reaction, carry out amine exchange reaction with ethamine in organic solvent and prepare intermediate (I
-1), intermediate (I-1) obtains the 1-fluoro-7-of ethyl-6-under the effect of inorganic base after ring-closure reaction
Chloro-4-oxo-Isosorbide-5-Nitrae-dihydro-quinoline-3-carboxylate (I), synthetic reaction formula is as follows:
Described 2,4-bis-chloro-5-fluorobenzoyl chloride, acid binding agent, N, N-dimethylamino acrylate with
The mol ratio of ethamine is 1:1～1.5:1～1.2:0.8～1.2, preferably 1:1.1:1:1.1；
Described acid binding agent is preferably tri-n-butylamine or triethylamine, and described N, N-dimethylamino acrylate is excellent
Elect N, N-dimethylamino ethyl acrylate or N-dimethylamino acrylic acid methyl ester. as；
Described inorganic base is preferably sodium hydroxide, potassium hydroxide, Lithium hydrate, Cesium hydrate., hydrogen
Rubidium oxide, sodium carbonate, potassium carbonate or cesium carbonate, more preferably sodium hydroxide or potassium hydroxide；Inorganic
Alkali is 1.5～2.5:1 with the mol ratio of 2,4-bis-chloro-5-fluorobenzoyl chloride；
Described organic solvent is preferably dimethylbenzene, toluene or dimethyl sulfoxide, consumption with 2,4-dichloro
-5-fluorobenzoyl chloride quality meter, every gram of 2,4-bis-chloro-5-fluorobenzoyl chloride adds organic solvent 4～50
ml；
Concrete grammar is:
Step (1). under room temperature, by 2,4-bis-chloro-5-fluorobenzoyl chloride, acid binding agent add reaction bulb,
Adding N, N-dimethylamino acrylate under stirring, react heat release voluntarily, cold water cooling controls reaction temperature
Spending 40～100 DEG C, insulated and stirred 1 hour again after temperature stabilization, reaction terminates；In reactant liquor
Adding organic solvent and distilled water (volume ratio 2:1), with salt acid for adjusting pH value to 1～2, separatory takes
Organic layer, is washed to neutrality, is transferred to another reaction bulb after residual moisture is evaporated off, and controls temperature and keeps
At 0～20 DEG C, drip ethamine, and be passed through CO2Gas, controlling reaction pressure is 1～2atm, HPLC
Follow the tracks of, after reaction completely, Distillation recovery N, N dimethylamine complex, obtain intermediate (I-1) mother solution
Standby；
The addition of step (1) organic solvent is with step (1) 2,4-bis-chloro-5-fluorobenzoyl chloride quality
Meter, every gram of 2,4-bis-chloro-5-fluorobenzoyl chloride adds organic solvent 2～25ml；
Step (2). in another reaction bulb, add organic solvent and inorganic base, be warming up to 125～130 DEG C,
Stirring is lower drips above-mentioned standby intermediate (I-1) mother solution, steams the low of reaction generation while dropping
Boiling thing, insulation reaction, after HPLC tracks to reaction completely, then recovered under reduced pressure organic solvent is to dry,
To the fluoro-7-of 1-ethyl-6-chloro-4-oxo-1,4-dihydro-quinoline-3-carboxylate (I)；
The addition of step (2) organic solvent is with step (1) 2,4-bis-chloro-5-fluorobenzoyl chloride quality
Meter, every gram of 2,4-bis-chloro-5-fluorobenzoyl chloride adds organic solvent 2～25ml；
Another object of the present invention is for the deficiencies in the prior art, it is provided that the system of a kind of ciprofloxacin
Preparation Method.
The method is: in a solvent, the fluoro-7-of 1-cyclopropyl-6-chloro-4-oxo-Isosorbide-5-Nitrae-dihydro-quinoline-3-
There is substitution reaction in carboxylate (II) and piperazine, more post-treated prepared target is produced at a certain temperature
Thing ciprofloxacin, synthetic reaction formula is as follows:
M ' shown in Formula II is preferably Na, K, Li, Rb or Cs；
The described fluoro-7-of 1-cyclopropyl-6-chloro-4-oxo-1,4-dihydro-quinoline-3-carboxylate (II)
It is 1:1～6 with the mol ratio of piperazine；
Described substitution reaction also can add catalyst lewis acid, and described lewis acid is preferably
AlCl3、ZnCl2Or SnCl4；Lewis acidic addition and the fluoro-7-of 1-cyclopropyl-6-chloro-4-oxo
The mol ratio of-1,4-dihydro-quinoline-3-carboxylate (II) is 0.01～0.6:1；
Described solvent is preferably alcohols solvent, more preferably ethanol, isopropanol or isoamyl alcohol, consumption with
The fluoro-7-of 1-cyclopropyl-6-chloro-4-oxo-Isosorbide-5-Nitrae-dihydro-quinoline-3-carboxylate (II) quality meter, often
Gram fluoro-7-of 1-cyclopropyl-6-chloro-4-oxo-1,4-dihydro-quinoline-3-carboxylate (II) adds solvent
2～20ml；
Described reaction temperature is preferably 70～140 DEG C；
The concrete preparation method of ciprofloxacin is at the fluoro-7-of 1-cyclopropyl-6-chloro-4-oxo-1,4-dihydro
Addition piperazine, lewis acid, solvent in-quinoline-3-carboxylation (II), control temperature 70～140 DEG C,
Insulation reaction 8～10 hours, after piperazine replaces completely, cooling, filter to obtain solid, solid is the most molten
Solution, in dilute hydrochloric acid, through alkali regulation pH value to 7.2～7.3, stands, filters to obtain crude product, through ethanol
Recrystallization obtains ciprofloxacin.
The described fluoro-7-of 1-cyclopropyl-6-chloro-4-oxo-1,4-dihydro-quinoline-3-carboxylate (II)
Synthetic method as follows: 2,4-bis-chloro-5-fluorobenzoyl chloride under the effect of acid binding agent through and N, N-bis-
After methylamino acrylate reactions, carry out amine exchange reaction with cyclopropylamine in organic solvent and prepare middle
Body (II-1), intermediate (II-1) obtains 1-cyclopropyl under the effect of inorganic base after ring-closure reaction
The fluoro-7-of-6-chloro-4-oxo-Isosorbide-5-Nitrae-dihydro-quinoline-3-carboxylate (II), synthetic reaction formula is as follows:
Described 2,4-bis-chloro-5-fluorobenzoyl chloride, acid binding agent, N, N-dimethylamino acrylate with
The mol ratio of cyclopropylamine is 1:1～1.5:1～1.2:0.8～1.2, preferably 1:1.1:1:1.1；
Described acid binding agent is preferably tri-n-butylamine or triethylamine, and described N, N-dimethylamino acrylate is excellent
Elect N, N-dimethylamino ethyl acrylate or N-dimethylamino acrylic acid methyl ester. as；
Described inorganic base is preferably sodium hydroxide, potassium hydroxide, Lithium hydrate, Cesium hydrate., hydrogen
Rubidium oxide, sodium carbonate, potassium carbonate or cesium carbonate, more preferably sodium hydroxide or potassium hydroxide；Inorganic
Alkali is 1.5～2.5:1 with the mol ratio of 2,4-bis-chloro-5-fluorobenzoyl chloride；
Described organic solvent is preferably dimethylbenzene, toluene or dimethyl sulfoxide, consumption with 2,4-dichloro
-5-fluorobenzoyl chloride quality meter, every gram of 2,4-bis-chloro-5-fluorobenzoyl chloride adds organic solvent 4～50
ml；
The fluoro-7-'s of 1-cyclopropyl-6-chloro-4-oxo-1,4-dihydro-quinoline-3-carboxylate (II) is concrete
Preparation method is:
Step (1). under room temperature, by 2,4-bis-chloro-5-fluorobenzoyl chloride, acid binding agent add reaction bulb,
Adding N, N-dimethylamino acrylate under stirring, react heat release voluntarily, cold water cooling controls reaction temperature
Spending 40～100 DEG C, insulated and stirred 1 hour again after temperature stabilization, reaction terminates；In reactant liquor
Adding organic solvent and distilled water, with salt acid for adjusting pH value to 1～2, separatory takes organic layer, washing
To neutral, after residual moisture is evaporated off, it is transferred to another reaction bulb, controls temperature and be maintained at 0～60 DEG C
Dropping cyclopropylamine, and it is passed through CO2Gas, controlling reaction pressure is 1～2atm, and HPLC follows the tracks of, reaction
After Wan Quan, Distillation recovery N, N dimethylamine complex, obtain intermediate (II-2) mother solution standby；
The addition of step (1) organic solvent is with step (1) 2,4-bis-chloro-5-fluorobenzoyl chloride quality
Meter, every gram of 2,4-bis-chloro-5-fluorobenzoyl chloride adds organic solvent 2～25ml；
Step (2). in another reaction bulb, add organic solvent and inorganic base, be warming up to 125～130 DEG C,
Drip intermediate (II-2) mother solution that above-mentioned steps (1) prepares under stirring, while dropping, steam reaction
The low-boiling-point substance produced, insulation reaction, after HPLC tracks to reaction completely, then recovered under reduced pressure dimethylbenzene is extremely
Dry, obtain 1-cyclopropyl-6-fluoro-7-chloro-4-oxo-Isosorbide-5-Nitrae-dihydro-quinoline-3-carboxylate (II)；
The addition of step (2) organic solvent is with step (1) 2,4-bis-chloro-5-fluorobenzoyl chloride quality
Meter, every gram of 2,4-bis-chloro-5-fluorobenzoyl chloride adds organic solvent 2～25ml.
A further object of the present invention is for the deficiencies in the prior art, it is provided that the system of a kind of enrofloxacin
Preparation Method.
The method is: in a solvent, the fluoro-7-of 1-cyclopropyl-6-chloro-4-oxo-Isosorbide-5-Nitrae-dihydro-quinoline-3-
There is substitution reaction in carboxylate (II) and NEP, more post-treated prepared at a certain temperature
Target product enrofloxacin, synthetic reaction formula is as follows:
The described fluoro-7-of 1-cyclopropyl-6-chloro-4-oxo-1,4-dihydro-quinoline-3-carboxylate (II)
It is 1:1～6 with the mol ratio of NEP；
Described substitution reaction also can add catalyst lewis acid, and described lewis acid is preferably
AlCl3、ZnCl2Or SnCl4；Lewis acidic addition and the fluoro-7-of 1-cyclopropyl-6-chloro-4-oxo
The mol ratio of-1,4-dihydro-quinoline-3-carboxylate (II) is 0.01～0.6:1；
Described solvent is preferably alcohols solvent, more preferably ethanol, isopropanol or isoamyl alcohol, consumption with
The fluoro-7-of 1-cyclopropyl-6-chloro-4-oxo-Isosorbide-5-Nitrae-dihydro-quinoline-3-carboxylate (II) quality meter, often
Gram fluoro-7-of 1-cyclopropyl-6-chloro-4-oxo-1,4-dihydro-quinoline-3-carboxylate (II) adds solvent
2～20ml；
Described reaction temperature is preferably 70～140 DEG C；
The concrete preparation method of enrofloxacin is:
The fluoro-7-of 1-cyclopropyl-6-chloro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid is added in reaction bulb
Salt (II), NEP, lewis acid, solvent, control temperature 70～140 DEG C, insulation reaction 8～
10 hours, after NEP replaces completely, cooling, filter to obtain solid, solid is re-dissolved in dilute
In hydrochloric acid, through alkali regulation pH value to 7.2～7.3, stand, filter to obtain crude product, through ethyl alcohol recrystallization
Obtain enrofloxacin.
The described fluoro-7-of 1-cyclopropyl-6-chloro-4-oxo-1,4-dihydro-quinoline-3-carboxylate (II)
Preparation method described above.
The beneficial effects are mainly as follows: 1) use main cyclic quinoline carboxylate (organic salt),
Directly contracting piperazine obtains target product, and yield is high, and consumption of raw materials is few, it is to avoid the difficulty of traditional method generation
The waste water containing ammonia-nitrogen processed, decreases the discharge of the three wastes；2) sodium hydroxide, potassium hydroxide etc. are used
Inorganic alkali as a catalyst catalyzed cyclization simultaneously reacts and hydrolysis, and gained organic salt (1-after reaction
The fluoro-7-of ethyl-6-chloro-4-oxo-1,4-dihydro-quinoline-3-carboxylate I or the fluoro-7-of 1-cyclopropyl-6-
Chloro-4-oxo-1,4-dihydro-quinoline-3-carboxylate II) directly send out with piperazine (or NEP)
Raw substitution reaction, post-reaction treatment is without adding water and alkali process, and product directly separates out from reaction system,
Reaction dissolvent and the complete piperazine (or NEP) of unreacted can directly apply mechanically, it is to avoid makes in a large number
With mineral acid and inorganic base, reduce the consumption of more than half piperazine (or NEP), also reduce
The formation of half inorganic salt, decreases pollution；3) under Louis acid catalysis effect, reaction temperature is low, secondary
Product is few, and yield is high, low cost；4) reactions steps is short, easy to operate, small investment, beneficially work
Industry metaplasia is produced.
Detailed description of the invention
Below in conjunction with embodiment, the invention will be further described, but protection scope of the present invention not only limiting
In this.
Embodiment 1.
Under step (1) room temperature, by 2,4-bis-chloro-5-fluorobenzoyl chloride 40g (0.176mol), three positive fourths
Amine 36g (0.195mol) adds reaction bulb, adds N, N-dimethylamino ethyl acrylate 25.5g under stirring
(0.178mol), reacting heat release voluntarily, cold water cooling controls reaction temperature about 70 DEG C, treats temperature
Insulated and stirred 1 hour again after Wen Ding, reaction terminates.Reactant liquor adds dimethylbenzene 100ml and distillation
Water 50ml, salt adding acid for adjusting pH to 1～2, separatory takes organic layer, is washed to neutrality, and residue is evaporated off
It is transferred to another reaction bulb after moisture, drips cyclopropylamine 11g (0.194mol) at controlling 15 DEG C, and lead to
Enter CO2Gas, control reaction pressure is that 2atm, HPLC follow the tracks of, after reaction completely, Distillation recovery N, N-
Dimethylamine complex, obtains mother solution standby.
Step (2) adds dimethylbenzene 100ml and sodium hydroxide 15g (0.375mol) in reaction bulb,
It is warming up to 125～130 DEG C, under stirring, above-mentioned prepared mother solution is added drop-wise in reactant liquor, dropping same
Time steam the low-boiling-point substance that reaction produces, insulation reaction, after HPLC tracks to reaction completely, then reduce pressure back
Receive dimethylbenzene the most dry, obtain organic salt (the fluoro-7-of 1-cyclopropyl-6-chloro-4-oxo-Isosorbide-5-Nitrae-dihydro-quinoline
-3-carboxylate II) 65g；Above-mentioned organic salt (the fluoro-7-of 1-cyclopropyl-6-chloro-4-oxo-1,4-dihydro-
Quinoline-3-carboxylation II) middle addition piperazine 15.1g (0.176mol), AlCl3Solid 2g (0.015mol)
With ethanol 200ml, control temperature 85 DEG C, insulation reaction 8 hours, after piperazine replaces completely, cool down,
Filtering to obtain solid, solid is re-dissolved in dilute hydrochloric acid, regulates pH7.2～7.3 through alkali, stands, filters
Obtaining crude product, obtain ciprofloxacin finished product 45g through ethyl alcohol recrystallization, with 2,4-bis-chloro-5-fluorobenzoyl chloride is
Initiation material meter, yield 77.2.
In embodiment 1, raw material 2,4-bis-chloro-5-fluorobenzoyl chloride is 1:1 with the mol ratio of piperazine.
Embodiment 2.
Under step (1) room temperature, by 2,4-bis-chloro-5-fluorobenzoyl chloride 40g (0.176mol), three positive fourths
Amine 36g (0.195mol) adds reaction bulb, adds N, N-dimethylamino ethyl acrylate 25.5g under stirring
(0.178mol), reacting heat release voluntarily, cold water cooling controls reaction temperature about 70 DEG C, treats temperature
Insulated and stirred 1 hour again after Wen Ding, reaction terminates.Reactant liquor adds dimethylbenzene 100ml and distillation
Water 50ml, salt adding acid for adjusting pH to 1～2, separatory takes organic layer, is washed to neutrality, and residue is evaporated off
It is transferred to another reaction bulb after moisture, drips cyclopropylamine 11g (0.194mol) at controlling 15 DEG C, and lead to
Enter CO2Gas, control reaction pressure is that 2atm, HPLC follow the tracks of, after reaction completely, Distillation recovery N, N-
Dimethylamine complex, obtains mother solution standby.
Step (2) adds dimethylbenzene 100ml and sodium hydroxide 15g (0.375mol) in reaction bulb, rises
Above-mentioned prepared mother solution, to 125～130 DEG C, is added drop-wise in reactant liquor, while dropping under stirring by temperature
Steam the low-boiling-point substance that reaction produces, insulation reaction, after HPLC tracks to react completely, then recovered under reduced pressure
Dimethylbenzene, to dry, obtains organic salt (the fluoro-7-of 1-cyclopropyl-6-chloro-4-oxo-Isosorbide-5-Nitrae-dihydro-quinoline-3-
Carboxylate II) 65g；Piperazine 15.1g (0.176mol) and ethanol 200ml is added in above-mentioned organic salt,
Control temperature 85 DEG C, insulation reaction 8 hours, after piperazine replaces completely, cool down, filter to obtain solid,
Solid is re-dissolved in dilute hydrochloric acid, regulates pH7.2～7.3 through alkali, stands, filters to obtain crude product, through second
Alcohol recrystallization obtains ciprofloxacin finished product 37.9g, and with 2,4-bis-chloro-5-fluorobenzoyl chloride is initiation material meter,
Yield 65.
In embodiment 2, raw material 2,4-bis-chloro-5-fluorobenzoyl chloride is 1:1 with the mol ratio of piperazine.
Embodiment 3.
Under step (1) room temperature, by 2,4-bis-chloro-5-fluorobenzoyl chloride 40g (0.176mol), three positive fourths
Amine 32.7g (0.176mol) adds reaction bulb, adds N, N-dimethylamino ethyl acrylate under stirring
25.2g (0.176mol), reacts heat release voluntarily, and cold water cooling controls reaction temperature about 40 DEG C, treats
Insulated and stirred 1 hour again after temperature stabilization, reaction terminates.Reactant liquor adds dimethylbenzene 80ml and steaming
Distilled water 40ml, salt adding acid for adjusting pH to 1～2, separatory takes organic layer, is washed to neutrality, is evaporated off remaining
It is transferred to another reaction bulb after remaining moisture, drips cyclopropylamine 8g (0.141mol) at controlling 0 DEG C, and lead to
Enter CO2Gas, control reaction pressure is that 1atm, HPLC follow the tracks of, after reaction completely, Distillation recovery N, N-
Dimethylamine complex, obtains mother solution standby.
Step (2) adds dimethylbenzene 80ml and potassium hydroxide 14.8g (0.264mol) in reaction bulb,
It is warming up to 125 DEG C, under stirring, above-mentioned prepared mother solution is added drop-wise in reactant liquor, steam while dropping
Go out the low-boiling-point substance that reaction produces, insulation reaction, after HPLC tracks to react completely, then recovered under reduced pressure two
Toluene, to dry, obtains organic salt (the fluoro-7-of 1-cyclopropyl-6-chloro-4-oxo-Isosorbide-5-Nitrae-dihydro-quinoline-3-
Carboxylate II) 65g；Piperazine 30.2g (0.352mol), ZnCl is added in above-mentioned organic salt2Solid
14.4g (0.106mol) and isoamyl alcohol 1300ml, controls temperature 70 C, insulation reaction 10 hours, treats
After piperazine replaces completely, cooling, filter to obtain solid, solid is re-dissolved in dilute hydrochloric acid, regulates through alkali
PH7.2～7.3, stands, filters to obtain crude product, obtains ciprofloxacin finished product 41.9g through ethyl alcohol recrystallization,
With 2,4-bis-chloro-5-fluorobenzoyl chloride is initiation material meter, yield 71.9.
In embodiment 3, raw material 2,4-bis-chloro-5-fluorobenzoyl chloride is 1:2 with the mol ratio of piperazine.
Embodiment 4.
Under step (1) room temperature, by 2,4-bis-chloro-5-fluorobenzoyl chloride 40g (0.176mol), three positive fourths
Amine 48.8g (0.264mol) adds reaction bulb, adds N, N-dimethylamino ethyl acrylate under stirring
30.3g (0.212mol), reacts heat release voluntarily, and cold water cooling controls reaction temperature about 100 DEG C,
Insulated and stirred 1 hour again after temperature stabilization, reaction terminates.Reactant liquor adds dimethylbenzene 1000ml
With distilled water 500ml, salt adding acid for adjusting pH to 1～2, separatory takes organic layer, is washed to neutrality, steams
Except being transferred to another reaction bulb after residual moisture, at controlling 60 DEG C, drip cyclopropylamine 12g (0.212mol),
And it is passed through CO2Gas, control reaction pressure is that 1.5atm, HPLC follow the tracks of, after reaction completely, distillation
Reclaim N, N dimethylamine complex, obtain mother solution standby.
Step (2) adds dimethylbenzene 1000ml and Lithium hydrate 10.56g (0.44mol) in reaction bulb,
It is warming up to 130 DEG C, under stirring, above-mentioned prepared mother solution is added drop-wise in reactant liquor, steam while dropping
Go out the low-boiling-point substance that reaction produces, insulation reaction, after HPLC tracks to react completely, then recovered under reduced pressure two
Toluene, to dry, obtains organic salt (the fluoro-7-of 1-cyclopropyl-6-chloro-4-oxo-Isosorbide-5-Nitrae-dihydro-quinoline-3-
Carboxylate II) 60.2g；Piperazine 90.8g (1.056mol), SnCl is added in above-mentioned organic salt4Solid
0.52g (0.002mol) and isoamyl alcohol 120.4ml, control temperature 140 DEG C, insulation reaction 8 hours,
After piperazine replaces completely, cooling, filter to obtain solid, solid is re-dissolved in dilute hydrochloric acid, adjusts through alkali
Joint pH to 7.2～7.3, stands, filters to obtain crude product, obtain ciprofloxacin finished product 42g through ethyl alcohol recrystallization,
With 2,4-bis-chloro-5-fluorobenzoyl chloride is initiation material meter, yield 72.1.
In embodiment 4, raw material 2,4-bis-chloro-5-fluorobenzoyl chloride is 1:6 with the mol ratio of piperazine.
Embodiment 5.
Under step (1) room temperature, by 2,4-bis-chloro-5-fluorobenzoyl chloride 40g (0.176mol), three positive fourths
Amine 36g (0.195mol) adds reaction bulb, adds N, N-dimethylamino ethyl acrylate 25.5g under stirring
(0.178mol), reacting heat release voluntarily, cold water cooling controls reaction temperature about 70 DEG C, treats temperature
Insulated and stirred 1 hour again after Wen Ding, reaction terminates.Reactant liquor adds dimethylbenzene 500ml and distillation
Water 250ml, salt adding acid for adjusting pH to 1～2, separatory takes organic layer, is washed to neutrality, and residue is evaporated off
It is transferred to another reaction bulb after moisture, drips cyclopropylamine 11g (0.194mol) at controlling 15 DEG C, and lead to
Enter CO2Gas, control reaction pressure is that 2atm, HPLC follow the tracks of, after reaction completely, Distillation recovery N, N-
Dimethylamine complex, obtains mother solution standby.
Step (2) adds dimethylbenzene 300ml and Cesium hydrate. 56.2 (0.375mol) in reaction bulb,
It is warming up to 125～130 DEG C, under stirring, above-mentioned prepared mother solution is added drop-wise in reactant liquor, dropping same
Time steam the low-boiling-point substance that reaction produces, insulation reaction, after HPLC tracks to reaction completely, then reduce pressure back
Receive dimethylbenzene the most dry, obtain organic salt (the fluoro-7-of 1-cyclopropyl-6-chloro-4-oxo-Isosorbide-5-Nitrae-dihydro-quinoline
-3-carboxylate II) 105g；NEP 20.1g (0.176mol) is added in above-mentioned organic salt,
AlCl3Solid 3.2g (0.024mol) and ethanol 325ml, controls temperature 85 DEG C, and insulation reaction 8 is little
Time, after NEP replaces completely, cooling, filter to obtain solid, solid is re-dissolved in dilute hydrochloric acid
In, regulate pH7.2～7.3 through alkali, stand, filter to obtain crude product, obtain enrofloxacin through ethyl alcohol recrystallization
Finished product 48.7g, with 2,4-bis-chloro-5-fluorobenzoyl chloride is initiation material meter, yield 77.1.
In embodiment 5, raw material 2,4-bis-chloro-5-fluorobenzoyl chloride is 1 with the mol ratio of NEP:
1。
Embodiment 6.
Under step (1) room temperature, by 2,4-bis-chloro-5-fluorobenzoyl chloride 40g (0.176mol), triethylamine
19.7g (0.195mol) adds reaction bulb, adds N, N-dimethylamino acrylic acid methyl ester. 23g under stirring
(0.178mol), reacting heat release voluntarily, cold water cooling controls reaction temperature about 70 DEG C, treats temperature
Insulated and stirred 1 hour again after Wen Ding, reaction terminates.Reactant liquor adds toluene 500ml and distilled water
250ml, salt adding acid for adjusting pH to 1～2, separatory takes organic layer, is washed to neutrality, is evaporated off remaining water
It is transferred to another reaction bulb after Fen, drips cyclopropylamine 11g (0.194mol) at controlling 15 DEG C, and be passed through
CO2Gas, control reaction pressure is that 2atm, HPLC follow the tracks of, after reaction completely, Distillation recovery N, N-
Dimethylamine complex, obtains mother solution standby.
Step (2) adds toluene 300ml and Cesium hydrate. 56.2 (0.375mol) in reaction bulb, rises
Above-mentioned prepared mother solution, to 125～130 DEG C, is added drop-wise in reactant liquor, while dropping under stirring by temperature
Steam the low-boiling-point substance that reaction produces, insulation reaction, after HPLC tracks to react completely, then recovered under reduced pressure
Toluene, to dry, obtains organic salt (the fluoro-7-of 1-cyclopropyl-6-chloro-4-oxo-Isosorbide-5-Nitrae-dihydro-quinoline-3-
Carboxylate II) 105g；NEP 20.1g (0.176mol) and second is added in above-mentioned organic salt
Alcohol 325ml, control temperature 85 DEG C, insulation reaction 8 hours, after NEP replaces completely,
Cooling, filters to obtain solid, and solid is re-dissolved in dilute hydrochloric acid, regulates pH7.2～7.3 through alkali, stand,
Filter to obtain crude product, obtain enrofloxacin finished product 41.1g through ethyl alcohol recrystallization, with 2,4-bis-chloro-5-fluorobenzene first
Acyl chlorides is initiation material meter, yield 65.
In embodiment 6, raw material 2,4-bis-chloro-5-fluorobenzoyl chloride is 1 with the mol ratio of NEP:
1。
Embodiment 7.
Under step (1) room temperature, by 2,4-bis-chloro-5-fluorobenzoyl chloride 40g (0.176mol), three positive fourths
Amine 32.7g (0.176mol) adds reaction bulb, adds N, N-dimethylamino ethyl acrylate under stirring
25.2g (0.176mol), reacts heat release voluntarily, and cold water cooling controls reaction temperature about 40 DEG C, treats
Insulated and stirred 1 hour again after temperature stabilization, reaction terminates.Reactant liquor adds dimethylbenzene 80ml and steaming
Distilled water 40ml, salt adding acid for adjusting pH to 1～2, separatory takes organic layer, is washed to neutrality, is evaporated off remaining
It is transferred to another reaction bulb after remaining moisture, at controlling 0 DEG C, drips cyclopropylamine 10g (0.176mol), and
It is passed through CO2Gas, control reaction pressure is that 1atm, HPLC follow the tracks of, after reaction completely, Distillation recovery
N, N dimethylamine complex, obtain mother solution standby.
Step (2) adds dimethylbenzene 80ml and rubidium hydroxide 26.9g (0.264mol) in reaction bulb,
It is warming up to 125 DEG C, under stirring, above-mentioned prepared mother solution is added drop-wise in reactant liquor, steam while dropping
Go out the low-boiling-point substance that reaction produces, insulation reaction, after HPLC tracks to react completely, then recovered under reduced pressure two
Toluene, to dry, obtains organic salt (the fluoro-7-of 1-cyclopropyl-6-chloro-4-oxo-Isosorbide-5-Nitrae-dihydro-quinoline-3-
Carboxylate II) 84g；NEP 40.1g (0.352mol), ZnCl is added in above-mentioned organic salt2
Solid 14.4g (0.106mol) and isoamyl alcohol 168ml, control temperature 70 C, insulation reaction 10 hours,
After NEP replaces completely, cooling, filter to obtain solid, solid is re-dissolved in dilute hydrochloric acid,
Regulate pH7.2～7.3 through alkali, stand, filter to obtain crude product, obtain enrofloxacin finished product through ethyl alcohol recrystallization
45.4g, with 2,4-bis-chloro-5-fluorobenzoyl chloride is initiation material meter, yield 71.8.
In embodiment 7, raw material 2,4-bis-chloro-5-fluorobenzoyl chloride is 1 with the mol ratio of NEP:
2。
Embodiment 8.
Under step (1) room temperature, by 2,4-bis-chloro-5-fluorobenzoyl chloride 40g (0.176mol), three positive fourths
Amine 48.7g (0.264mol) adds reaction bulb, adds N, N-dimethylamino ethyl acrylate under stirring
30.3g (0.212mol), reacts heat release voluntarily, and cold water cooling controls reaction temperature about 100 DEG C,
Insulated and stirred 1 hour again after temperature stabilization, reaction terminates.Reactant liquor adds dimethylbenzene 1000ml
With distilled water 500ml, salt adding acid for adjusting pH to 1～2, separatory takes organic layer, is washed to neutrality, steams
Except being transferred to another reaction bulb after residual moisture, at controlling 60 DEG C, drip cyclopropylamine 12g (0.212mol),
And it is passed through CO2Gas, control reaction pressure is that 1.5atm, HPLC follow the tracks of, after reaction completely, distillation
Reclaim N, N dimethylamine complex, obtain mother solution standby.
Step (2) adds dimethylbenzene 1000ml and sodium carbonate 46.7g (0.44mol) in reaction bulb, rises
Above-mentioned prepared mother solution, to 130 DEG C, is added drop-wise in reactant liquor under stirring, steams while dropping by temperature
The low-boiling-point substance that reaction produces, insulation reaction, after HPLC tracks to reaction completely, then recovered under reduced pressure diformazan
Benzene, to dry, obtains organic salt (the fluoro-7-of 1-cyclopropyl-6-chloro-4-oxo-Isosorbide-5-Nitrae-dihydro-quinoline-3-carboxylic acid
Salt II) 90g；NEP 120.4g (1.056mol), SnCl is added in above-mentioned organic salt4
Solid 0.52g (0.002mol) and isoamyl alcohol 1800ml, controls temperature 140 DEG C, and insulation reaction 8 is little
Time, after NEP replaces completely, cooling, filter to obtain solid, solid is re-dissolved in dilute hydrochloric acid
In, regulate pH to 7.2～7.3 through alkali, stand, filter to obtain crude product, through ethyl alcohol recrystallization get En Nuo
Husky star finished product 45.6g, yield 72.2.
In embodiment 8, raw material 2,4-bis-chloro-5-fluorobenzoyl chloride is 1 with the mol ratio of NEP:
6。
Embodiment 9.
Under step (1) room temperature, by 2,4-bis-chloro-5-fluorobenzoyl chloride 40g (0.176mol), three positive fourths
Amine 36g (0.195mol) adds reaction bulb, adds N, N-dimethylamino ethyl acrylate 25.5g under stirring
(0.178mol), reacting heat release voluntarily, cold water cooling controls reaction temperature about 70 DEG C, treats temperature
Insulated and stirred 1 hour again after Wen Ding, reaction terminates.Reactant liquor adds dimethylbenzene 200ml and distillation
Water 100ml, salt adding acid for adjusting pH to 1～2, separatory takes organic layer, is washed to neutrality, and residue is evaporated off
It is transferred to another reaction bulb after moisture, drips ethamine 8.7g (0.194mol) at controlling 15 DEG C, and be passed through
CO2Gas, control reaction pressure is that 2atm, HPLC follow the tracks of, after reaction completely, Distillation recovery N, N-
Dimethylamine complex, obtains mother solution standby.
Step (2) adds dimethylbenzene 200ml and sodium hydroxide 15g (0.375mol) in reaction bulb, rises
Above-mentioned prepared mother solution, to 125～130 DEG C, is added drop-wise in reactant liquor, while dropping under stirring by temperature
Steam the low-boiling-point substance that reaction produces, insulation reaction, after HPLC tracks to react completely, then recovered under reduced pressure
Dimethylbenzene, to dry, obtains organic salt (the fluoro-7-of 1-ethyl-6-chloro-4-oxo-Isosorbide-5-Nitrae-dihydro-quinoline-3-
Carboxylate I) 63g；Piperazine 15.1g (0.176mol), AlCl is added in above-mentioned organic salt3Solid
2g (0.015mol) and ethanol 200ml, controls temperature 85 DEG C, insulation reaction 8 hours, treats that piperazine takes
Generation completely after, cooling, filter to obtain solid, solid is re-dissolved in dilute hydrochloric acid, through alkali regulation pH7.2～
7.3, stand, filter to obtain crude product, obtain norfloxacin finished product 43.4g, yield 77.3 through ethyl alcohol recrystallization
?.
In embodiment 9, raw material 2,4-bis-chloro-5-fluorobenzoyl chloride is 1:1 with the mol ratio of piperazine.
Embodiment 10.
Under step (1) room temperature, by 2,4-bis-chloro-5-fluorobenzoyl chloride 40g (0.176mol), three positive fourths
Amine 36g (0.195mol) adds reaction bulb, adds N, N-dimethylamino ethyl acrylate 25.5g under stirring
(0.178mol), reacting heat release voluntarily, cold water cooling controls reaction temperature about 70 DEG C, treats temperature
Insulated and stirred 1 hour again after Wen Ding, reaction terminates.Reactant liquor adds dimethylbenzene 200ml and distillation
Water 100ml, salt adding acid for adjusting pH to 1～2, separatory takes organic layer, is washed to neutrality, and residue is evaporated off
It is transferred to another reaction bulb after moisture, drips ethamine 8.7g (0.194mol) at controlling 15 DEG C, and be passed through
CO2Gas, control reaction pressure is that 2atm, HPLC follow the tracks of, after reaction completely, Distillation recovery N, N-
Dimethylamine complex, obtains mother solution standby.
Step (2) adds dimethylbenzene 200ml and sodium hydroxide 15g (0.375mol) in reaction bulb, rises
Above-mentioned prepared mother solution, to 125～130 DEG C, is added drop-wise in reactant liquor, while dropping under stirring by temperature
Steam the low-boiling-point substance that reaction produces, insulation reaction, after HPLC tracks to react completely, then recovered under reduced pressure
Dimethylbenzene, to dry, obtains organic salt (the fluoro-7-of 1-ethyl-6-chloro-4-oxo-Isosorbide-5-Nitrae-dihydro-quinoline-3-
Carboxylate I) 63g；Piperazine 15.1g (0.176mol) and ethanol 200ml is added in above-mentioned organic salt,
Control temperature 85 DEG C, insulation reaction 8 hours, after piperazine replaces completely, cool down, filter to obtain solid,
Solid is re-dissolved in dilute hydrochloric acid, regulates pH7.2～7.3 through alkali, stands, filters to obtain crude product, through second
Alcohol recrystallization obtains norfloxacin finished product 36.6g, yield 65.2.
In embodiment 10, raw material 2,4-bis-chloro-5-fluorobenzoyl chloride is 1:1 with the mol ratio of piperazine.
Embodiment 11.
Under step (1) room temperature, by 2,4-bis-chloro-5-fluorobenzoyl chloride 40g (0.176mol), three positive fourths
Amine 32.7g (0.176mol) adds reaction bulb, adds N, N-dimethylamino ethyl acrylate under stirring
25.2g (0.176mol), reacts heat release voluntarily, and cold water cooling controls reaction temperature about 40 DEG C, treats
Insulated and stirred 1 hour again after temperature stabilization, reaction terminates.In reactant liquor add dimethylbenzene 1000ml with
Distilled water 500ml, salt adding acid for adjusting pH to 1～2, separatory takes organic layer, is washed to neutrality, is evaporated off
It is transferred to another reaction bulb after residual moisture, at controlling 0 DEG C, drips ethamine 6.3g (0.141mol), and
It is passed through CO2Gas, control reaction pressure is that 1atm, HPLC follow the tracks of, after reaction completely, Distillation recovery
N, N dimethylamine complex, obtain mother solution standby.
Step (2) adds dimethylbenzene 1000ml and potassium carbonate 36.4g (0.264mol) in reaction bulb,
It is warming up to 125 DEG C, under stirring, above-mentioned prepared mother solution is added drop-wise in reactant liquor, steam while dropping
Go out the low-boiling-point substance that reaction produces, insulation reaction, after HPLC tracks to react completely, then recovered under reduced pressure two
Toluene, to dry, obtains organic salt (the fluoro-7-of 1-ethyl-6-chloro-4-oxo-Isosorbide-5-Nitrae-dihydro-quinoline-3-carboxylic acid
Salt I) 78g；Piperazine 15.1g (0.176mol), ZnCl is added in above-mentioned organic salt2Solid 14.4g
(0.106mol) with isopropanol 1560ml, control temperature 70 C, insulation reaction 10 hours, treat piperazine
After replacing completely, cooling, filter to obtain solid, solid is re-dissolved in dilute hydrochloric acid, through alkali regulation pH7.2～
7.3, stand, filter to obtain crude product, obtain norfloxacin finished product 39.6g, yield 70.5 through ethyl alcohol recrystallization
?.
In embodiment 11, raw material 2,4-bis-chloro-5-fluorobenzoyl chloride is 1:1 with the mol ratio of piperazine.
Embodiment 12.
Under step (1) room temperature, by 2,4-bis-chloro-5-fluorobenzoyl chloride 40g (0.176mol), three positive fourths
Amine 48.7g (0.264mol) adds reaction bulb, adds N, N-dimethylamino ethyl acrylate under stirring
30.3g (0.212mol), reacts heat release voluntarily, and cold water cooling controls reaction temperature about 100 DEG C,
Insulated and stirred 1 hour again after temperature stabilization, reaction terminates.In reactant liquor add dimethylbenzene 80ml with
Distilled water 40ml, salt adding acid for adjusting pH to 1～2, separatory takes organic layer, is washed to neutrality, is evaporated off
It is transferred to another reaction bulb after residual moisture, at controlling 60 DEG C, drips ethamine 9.5g (0.211mol),
And it is passed through CO2Gas, control reaction pressure is that 1.5atm, HPLC follow the tracks of, after reaction completely, distillation
Reclaim N, N dimethylamine complex, obtain mother solution standby.
Step (2) adds dimethylbenzene 180ml and cesium carbonate 143.3 (0.44mol) in reaction bulb, rises
Above-mentioned prepared mother solution, to 130 DEG C, is added drop-wise in reactant liquor under stirring, steams while dropping by temperature
The low-boiling-point substance that reaction produces, insulation reaction, after HPLC tracks to reaction completely, then recovered under reduced pressure diformazan
Benzene, to dry, obtains organic salt (the fluoro-7-of 1-ethyl-6-chloro-4-oxo-Isosorbide-5-Nitrae-dihydro-quinoline-3-carboxylate
I)180g；Piperazine 90.8g (1.056mol), SnCl is added in above-mentioned organic salt4Solid 0.5g
(0.0019mol) with isoamyl alcohol 360ml, control temperature 140 DEG C, insulation reaction 8 hours, treat piperazine
After replacing completely, cooling, filter to obtain solid, solid is re-dissolved in dilute hydrochloric acid, through alkali regulation pH extremely
7.2～7.3, stand, filter to obtain crude product, obtain norfloxacin finished product 39.2g through ethyl alcohol recrystallization, receive
Rate 69.8.
In embodiment 12, raw material 2,4-bis-chloro-5-fluorobenzoyl chloride is 1:6 with the mol ratio of piperazine.
Embodiment 13.
Under step (1) room temperature, by 2,4-bis-chloro-5-fluorobenzoyl chloride 40g (0.176mol), triethylamine
19.7g (0.195mol) adds reaction bulb, adds N, N-dimethylamino acrylic acid methyl ester. 23g under stirring
(0.178mol), reacting heat release voluntarily, cold water cooling controls reaction temperature about 70 DEG C, treats temperature
Insulated and stirred 1 hour again after Wen Ding, reaction terminates.Reactant liquor adds dimethylbenzene 200ml and distillation
Water 100ml, salt adding acid for adjusting pH to 1～2, separatory takes organic layer, is washed to neutrality, and residue is evaporated off
It is transferred to another reaction bulb after moisture, drips ethamine 8.7g (0.194mol) at controlling 15 DEG C, and be passed through
CO2Gas, control reaction pressure is that 2atm, HPLC follow the tracks of, after reaction completely, Distillation recovery N, N-
Dimethylamine complex, obtains mother solution standby.
Step (2) adds dimethylbenzene 200ml and sodium hydroxide 15g (0.375mol) in reaction bulb, rises
Above-mentioned prepared mother solution, to 125～130 DEG C, is added drop-wise in reactant liquor, while dropping under stirring by temperature
Steam the low-boiling-point substance that reaction produces, insulation reaction, after HPLC tracks to react completely, then recovered under reduced pressure
Dimethylbenzene, to dry, obtains organic salt (the fluoro-7-of 1-ethyl-6-chloro-4-oxo-Isosorbide-5-Nitrae-dihydro-quinoline-3-
Carboxylate I) 63g；Piperazine 15.1g (0.176mol), AlCl is added in above-mentioned organic salt3Solid
2g (0.015mol) and ethanol 200ml, controls temperature 85 DEG C, insulation reaction 8 hours, treats that piperazine takes
Generation completely after, cooling, filter to obtain solid, solid is re-dissolved in dilute hydrochloric acid, through alkali regulation pH7.2～
7.3, stand, filter to obtain crude product, obtain norfloxacin finished product 42.1g, yield 75 through ethyl alcohol recrystallization
?.
In embodiment 13, raw material 2,4-bis-chloro-5-fluorobenzoyl chloride is 1:1 with the mol ratio of piperazine.
Embodiment 14:
Reaction bulb adds pure organic salt (the fluoro-7-of 1-ethyl-6-chloro-4-oxo-1,4-dihydro-
Quinoline-3-carboxylic acid sodium salt) 32.4g (0.111mol), piperazine 9.6g (0.111mol), AlCl3Solid
2g (0.015mol) and isoamyl alcohol 200ml, controls temperature 140 DEG C, insulation reaction 8 hours, treats piperazine
After piperazine replaces completely, cooling, filter to obtain solid, solid is re-dissolved in dilute hydrochloric acid, regulates through alkali
PH7.2～7.3, stands, filters to obtain crude product, obtains norfloxacin finished product 32.2g through ethyl alcohol recrystallization,
Count with organic salt for initiation material, yield 90.9.
Raw material (the fluoro-7-of 1-ethyl-6-chloro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid in embodiment 14
Sodium salt) it is 1:1 with the mol ratio of piperazine.
Comparative example 1:
The fluoro-7-of 1-ethyl-6-chloro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid is put in four-hole boiling flask
30g (0.111mol), piperazine 60g (0.697mol), isoamyl alcohol 75g, AlCl3Solid 1.5g
(0.0112mol), it is warming up to 100 DEG C and is incubated 12 hours, be subsequently adding sodium hydroxide 4.5g
(0.113mol), recovered under reduced pressure, to dry, adds 150g water, sodium hydroxide 4.5g in residue
(0.113mol), 0.1g activated carbon, it is warming up to 90 DEG C and is incubated 30 minutes, filter, the filtrate obtained,
Adjusting pH to neutral, be cooled to room temperature sucking filtration, 100 DEG C of drying of filter cake obtain product norfloxacin 27.6g,
Yield 77.9.
Raw material (the fluoro-7-of 1-ethyl-6-chloro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid) in comparative example 1
It is 1:6.3 with the mol ratio of piperazine.
Embodiment 15
Pure organic salt (the fluoro-7-of 1-cyclopropyl-6-chloro-4-oxo-1,4-dihydro is added in reaction bulb
-quinoline-3-carboxylic acid sodium salt) 33.7g (0.111mol), piperazine 9.6g (0.111mol), AlCl3Solid
2g (0.015mol) and isoamyl alcohol 200ml, controls temperature 140 DEG C, insulation reaction 8 hours, treats piperazine
After piperazine replaces completely, cooling, filter to obtain solid, solid is re-dissolved in dilute hydrochloric acid, regulates through alkali
PH7.2～7.3, stands, filters to obtain crude product, obtains ciprofloxacin finished product 33.5g through ethyl alcohol recrystallization,
Count with organic salt for initiation material, yield 91.2.
Raw material (the fluoro-7-of 1-cyclopropyl-6-chloro-4-oxo-1,4-dihydro-quinoline-3-in embodiment 15
Carboxylic acid sodium salt) it is 1:1 with the mol ratio of piperazine.
Comparative example 2
The fluoro-7-of 1-cyclopropyl-6-chloro-4-oxo-1,4-dihydro-quinoline-3-carboxylic is put in four-hole boiling flask
Acid 31.2g (0.111mol), piperazine 60g (0.697mol), isoamyl alcohol 75g, AlCl3Solid 1.5g
(0.0112mol), it is warming up to 100 DEG C and is incubated 12 hours, be subsequently adding sodium hydroxide 4.5g
(0.113mol), recovered under reduced pressure, to dry, adds 150g water, sodium hydroxide 4.5g in residue
(0.113mol), 0.1g activated carbon, it is warming up to 90 DEG C and is incubated 30 minutes, filter, the filtrate obtained,
Adjusting pH to neutral, be cooled to room temperature sucking filtration, 100 DEG C of drying of filter cake obtain product ciprofloxacin 28.6g,
Yield 77.8.
Raw material (the fluoro-7-of 1-cyclopropyl-6-chloro-4-oxo-1,4-dihydro-quinoline-3-carboxylic in comparative example 2
Acid) it is 1:6.3 with the mol ratio of piperazine.
Embodiment 16
Pure organic salt (the fluoro-7-of 1-cyclopropyl-6-chloro-4-oxo-1,4-dihydro is added in reaction bulb
-quinoline-3-carboxylic acid sodium salt) 33.7g (0.111mol), NEP 12.7g (0.111mol), AlCl3
Solid 2g (0.015mol) and isoamyl alcohol 200ml, control temperature 140 DEG C, insulation reaction 8 hours,
After NEP replaces completely, cooling, filter to obtain solid, solid is re-dissolved in dilute hydrochloric acid,
Regulate pH7.2～7.3 through alkali, stand, filter to obtain crude product, obtain enrofloxacin finished product through ethyl alcohol recrystallization
36.6g, counts with organic salt for initiation material, yield 91.8.
Raw material (the fluoro-7-of 1-cyclopropyl-6-chloro-4-oxo-1,4-dihydro-quinoline-3-in embodiment 16
Carboxylic acid sodium salt) it is 1:1 with the mol ratio of NEP.
Comparative example 3
The fluoro-7-of 1-cyclopropyl-6-chloro-4-oxo-1,4-dihydro-quinoline-3-carboxylic is put in four-hole boiling flask
Acid 31.2g (0.111mol), NEP 79.5g (0.697mol), isoamyl alcohol 75g, AlCl3
Solid 1.5g (0.0112mol), is warming up to 100 DEG C and is incubated 12 hours, be subsequently adding sodium hydroxide
4.5g (0.113mol), recovered under reduced pressure, to dry, adds 150g water, sodium hydroxide 4.5g in residue
(0.113mol), 0.1g activated carbon, it is warming up to 90 DEG C and is incubated 30 minutes, filter, the filtrate obtained,
Adjusting pH to neutral, be cooled to room temperature sucking filtration, 100 DEG C of drying of filter cake obtain product enrofloxacin 30.7g,
Yield 77.
Raw material (the fluoro-7-of 1-cyclopropyl-6-chloro-4-oxo-1,4-dihydro-quinoline-3-carboxylic in comparative example 3
Acid) it is 1:6.3 with the mol ratio of NEP.
Knowable to above-described embodiment 14～16 compares with comparative example 1～3: 1. embodiment 14～16 method
(i.e. the inventive method) decreases the consumption of about 5/6 piperazine (or NEP), is greatly saved
Cost of material in commercial production；2. comparative example 2 method (i.e. the inventive method) uses organic salt shape
Formula is reacted, and post-reaction treatment is without adding water and alkali process, and product directly separates out from reaction system,
Reaction dissolvent and the complete piperazine (or NEP) of unreacted can directly be applied mechanically, for commercial production Central Plains
The great convenience that the recycling of material and post processing bring；3. embodiment 14～16 method is (i.e.
The inventive method) reaction enters without adding alkali again, decreases the consumption of acid used when neutralizing pH,
The cost of material being greatly saved in commercial production；4. embodiment 14～16 method (side the most of the present invention
Method) to count with pure organic salt for raw material, embodiment 14～16 average yield is 91.3, comparison ratio
Example 1～3 average yield is high by 13.7.Whole reaction decreases the consumption of raw material, reduces and produces into
This, decrease the discharge of pollutant simultaneously.
Above-described embodiment is not the restriction for the present invention, and the present invention is not limited only to above-described embodiment,
As long as meeting application claims, belong to protection scope of the present invention.
Claims (18)
1. the preparation method of a norfloxacin, it is characterised in that the method is in alcohols solvent, 1-
The fluoro-7-of ethyl-6-chloro-4-oxo-1,4-dihydro-quinoline-3-carboxylate I and piperazine in temperature 70～
140 DEG C, lewis acid is as substitution reaction, more post-treated prepared target occur under conditions of catalyst
Product norfloxacin, synthetic reaction formula is as follows:
M shown in Formulas I is Na, K, Li, Rb or Cs；
The described fluoro-7-of 1-ethyl-6-chloro-4-oxo-1,4-dihydro-quinoline-3-carboxylate I and piperazine
Mol ratio is 1:1；Described solvent adding amount is the every gram of fluoro-7-of 1-ethyl-6-chloro-4-oxo-1,4-two
Hydrogen-quinoline-3-carboxylation I adds solvent 2～20ml；
Described lewis acidic addition and the fluoro-7-of 1-ethyl-6-chloro-4-oxo-1,4-dihydro-quinoline
The mol ratio of-3-carboxylate I is 0.01～0.6:1；Wherein lewis acid is AlCl3、ZnCl2Or SnCl4。
The preparation method of a kind of norfloxacin the most as claimed in claim 1, it is characterised in that described
Solvent is ethanol, isopropanol or isoamyl alcohol.
The preparation method of a kind of norfloxacin the most as claimed in claim 1, it is characterised in that described
The response time of substitution reaction is 8～10 hours.
The preparation method of a kind of norfloxacin the most as claimed in claim 1, it is characterised in that described
The synthetic method of the fluoro-7-of 1-ethyl-6-chloro-4-oxo-1,4-dihydro-quinoline-3-carboxylate I is as follows:
2,4-bis-chloro-5-fluorobenzoyl chloride warp and N, N-dimethylamino ethyl acrylate under the effect of acid binding agent is anti-
Ying Hou, carries out amine exchange reaction in organic solvent and prepares intermediate compound I-1, intermediate compound I-1 with ethamine
After ring-closure reaction, the fluoro-7-of 1-ethyl-6-chloro-4-oxo-1,4-dihydro-quinoline is obtained under the effect of inorganic base
Quinoline-3-carboxylate I, synthetic reaction formula is as follows:
M shown in Formulas I is Na, K, Li, Rb or Cs；
Described inorganic base be sodium hydroxide, potassium hydroxide, Lithium hydrate, Cesium hydrate., rubidium hydroxide,
Sodium carbonate, potassium carbonate or cesium carbonate.
The preparation method of a kind of norfloxacin the most as claimed in claim 4, it is characterised in that described
2,4-bis-chloro-5-fluorobenzoyl chloride, acid binding agent, N, N-dimethylamino ethyl acrylate and ethamine mole
Ratio is 1:1～1.5:1～1.2:0.8～1.2；Inorganic base and 2,4-bis-chloro-5-fluorobenzoyl chloride
Mol ratio is 1.5～2.5:1；The addition of organic solvent is that every gram of 2,4-bis-chloro-5-fluorobenzoyl chloride adds
Enter organic solvent 4～50ml.
The preparation method of a kind of norfloxacin the most as claimed in claim 4, it is characterised in that described
Acid binding agent is tri-n-butylamine or triethylamine, and organic solvent is dimethylbenzene, toluene or dimethyl sulfoxide.
7. the preparation method of a ciprofloxacin, it is characterised in that the method is in alcohols solvent, 1-
The fluoro-7-of cyclopropyl-6-chloro-4-oxo-1,4-dihydro-quinoline-3-carboxylate II and piperazine in temperature 70～
140 DEG C, lewis acid is as substitution reaction, more post-treated prepared target occur under conditions of catalyst
Product ciprofloxacin, synthetic reaction formula is as follows:
M shown in Formula II is Na, K, Li, Rb or Cs；
The described fluoro-7-of 1-cyclopropyl-6-chloro-4-oxo-1,4-dihydro-quinoline-3-carboxylate II and piperazine
The mol ratio of piperazine is 1:1；The addition of solvent is the every gram of fluoro-7-of 1-cyclopropyl-6-chloro-4-oxo-1,4-
Dihydro-quinoline-3-carboxylate II adds solvent 2～20ml；
Described lewis acidic addition and the fluoro-7-of 1-cyclopropyl-6-chloro-4-oxo-1,4-dihydro-quinoline
The mol ratio of quinoline-3-carboxylate II is 0.01～0.6:1；Wherein lewis acid is AlCl3、ZnCl2Or
SnCl4。
The preparation method of a kind of ciprofloxacin the most as claimed in claim 7, it is characterised in that described
Solvent is ethanol, isopropanol or isoamyl alcohol.
The preparation method of a kind of ciprofloxacin the most as claimed in claim 7, it is characterised in that described
The substitution reaction time is 8～10 hours.
The preparation method of a kind of ciprofloxacin the most as claimed in claim 7, it is characterised in that described
The synthetic method of the fluoro-7-of 1-cyclopropyl-6-chloro-4-oxo-1,4-dihydro-quinoline-3-carboxylate II is as follows:
2,4-bis-chloro-5-fluorobenzoyl chloride warp and N, N-dimethylamino ethyl acrylate under the effect of acid binding agent is anti-
Ying Hou, carries out amine exchange reaction in organic solvent and prepares intermediate II-1, intermediate II-1 with cyclopropylamine
Under the effect of inorganic base after ring-closure reaction the fluoro-7-of 1-cyclopropyl-6-chloro-4-oxo-1,4-dihydro-
Quinoline-3-carboxylation II, synthetic reaction formula is as follows:
M shown in Formula II is Na, K, Li, Rb or Cs；
Described inorganic base be sodium hydroxide, potassium hydroxide, Lithium hydrate, Cesium hydrate., rubidium hydroxide,
Sodium carbonate, potassium carbonate or cesium carbonate.
The preparation method of 11. a kind of ciprofloxacins as claimed in claim 10, it is characterised in that described
2,4-bis-chloro-5-fluorobenzoyl chloride, acid binding agent, N, N-dimethylamino ethyl acrylate and cyclopropylamine
Mol ratio is 1:1～1.5:1～1.2:0.8～1.2；Inorganic base and 2,4-bis-chloro-5-fluorobenzoyl
The mol ratio of chlorine is 1.5～2.5:1；The addition of organic solvent is every gram of 2,4-bis-chloro-5-fluorobenzoyl
Chlorine adds organic solvent 4～50ml.
The preparation method of 12. a kind of ciprofloxacins as claimed in claim 10, it is characterised in that described
Acid binding agent be tri-n-butylamine or triethylamine, organic solvent is dimethylbenzene, toluene or dimethyl sulfoxide.
The preparation method of 13. 1 kinds of enrofloxacins, it is characterised in that the method is in alcohols solvent, 1-
The fluoro-7-of cyclopropyl-6-chloro-4-oxo-1,4-dihydro-quinoline-3-carboxylate II and NEP are in temperature
Spend 70～140 DEG C, lewis acid is as substitution reaction, more post-treated system occur under conditions of catalyst
Obtaining target product enrofloxacin, synthetic reaction formula is as follows:
M shown in Formula II is Na, K, Li, Rb or Cs；
The described fluoro-7-of 1-cyclopropyl-6-chloro-4-oxo-1,4-dihydro-quinoline-3-carboxylate II and N-
The mol ratio of ethyl piperazidine is 1:1；The addition of solvent is the every gram of fluoro-7-of 1-cyclopropyl-6-chloro-4-oxygen
In generation ,-1,4-dihydro-quinoline-3-carboxylate II added solvent 2～20ml；
Described lewis acidic addition and the fluoro-7-of 1-cyclopropyl-6-chloro-4-oxo-1,4-dihydro-
The mol ratio of quinoline-3-carboxylation II is 0.01～0.6:1；Wherein lewis acid is AlCl3、ZnCl2
Or SnCl4。
The preparation method of 14. a kind of enrofloxacins as claimed in claim 13, it is characterised in that described
Solvent is ethanol, isopropanol or isoamyl alcohol.
The preparation method of 15. a kind of enrofloxacins as claimed in claim 13, it is characterised in that described
Response time be 8～10 hours.
The preparation method of 16. a kind of enrofloxacins as claimed in claim 13, it is characterised in that described
The fluoro-7-of 1-cyclopropyl-6-chloro-4-oxo-1,4-dihydro-quinoline-3-carboxylate II synthetic method such as
Under: 2,4-bis-chloro-5-fluorobenzoyl chloride is warp and N, N-dimethylamino acrylic acid second under the effect of acid binding agent
After ester reaction, carry out amine exchange reaction with cyclopropylamine in organic solvent and prepare intermediate II-1, intermediate
II-1 obtains the fluoro-7-of 1-cyclopropyl-6-chloro-4-oxo-1,4-under the effect of inorganic base after ring-closure reaction
Dihydro-quinoline-3-carboxylate II, synthetic reaction formula is as follows:
M shown in Formula II is Na, K, Li, Rb or Cs；
Described inorganic base be sodium hydroxide, potassium hydroxide, Lithium hydrate, Cesium hydrate., rubidium hydroxide,
Sodium carbonate, potassium carbonate or cesium carbonate.
The preparation method of 17. a kind of enrofloxacins as claimed in claim 16, it is characterised in that described
2,4-bis-chloro-5-fluorobenzoyl chloride, acid binding agent, N, N-dimethylamino ethyl acrylate and cyclopropylamine
Mol ratio is 1:1～1.5:1～1.2:0.8～1.2；Inorganic base and 2,4-bis-chloro-5-fluorobenzoyl
The mol ratio of chlorine is 1.5～2.5:1；The addition of organic solvent is every gram of 2,4-bis-chloro-5-fluorobenzoyl
Chlorine adds organic solvent 4～50ml.
The preparation method of 18. a kind of enrofloxacins as claimed in claim 16, it is characterised in that described
Acid binding agent be tri-n-butylamine or triethylamine, organic solvent is dimethylbenzene, toluene or dimethyl sulfoxide.
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| CN106279020A (en) * | 2016-08-10 | 2017-01-04 | 杭州新博思生物医药有限公司 | A kind of norfloxacin form D and preparation method thereof, preparation and application |
| CN106632035B (en) * | 2016-12-01 | 2019-04-23 | 杭州洪桥生物技术有限公司 | A kind of preparation method of antibacterial anti-inflammatory veterinary drug Ciprofloxacin |
| CN107501107A (en) * | 2017-09-26 | 2017-12-22 | 兰亚朝 | The intermediate synthetic method of quinolone medicine |
| CN107445892A (en) * | 2017-09-26 | 2017-12-08 | 兰亚朝 | Norfloxacin chemical industry synthesis method |
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| CN114716373B (en) * | 2022-04-14 | 2023-01-10 | 内蒙古源宏精细化工有限公司 | Preparation method of gatifloxacin cyclized ester |
| CN115385856A (en) * | 2022-09-05 | 2022-11-25 | 常州大学 | Method for synthesizing norfloxacin intermediate by one-pot method |
| CN117486796A (en) * | 2023-12-29 | 2024-02-02 | 山东京新药业有限公司 | Synthesis method of key intermediate of quinolone antibacterial drug |
Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4699992A (en) * | 1984-09-29 | 1987-10-13 | Bayer Aktiengesellschaft | 3-amino-2-benzoylacrylic acid derivatives |
| CN1030911A (en) * | 1987-07-24 | 1989-02-08 | 拜尔公司 | The method for preparing quinolone carboxylic acid |
| CN1239094A (en) * | 1998-06-12 | 1999-12-22 | 拜尔公司 | Process for preparing quinolone- and naphthyridonecarboxylic acids and esters thereof |
| CN101481381A (en) * | 2008-09-28 | 2009-07-15 | 宁波经济技术开发区九胜创新医药工艺开发有限公司 | Method for preparing ciprofloxacin by piperazine reaction |
| CN101781313A (en) * | 2010-03-05 | 2010-07-21 | 浙江京新药业股份有限公司 | Method for synthesizing quinolone medicaments |
| CN102241629A (en) * | 2011-05-12 | 2011-11-16 | 浙江国邦药业有限公司 | Chemical preparation method of norfloxacin |
| CN102850376A (en) * | 2012-06-18 | 2013-01-02 | 浙江大学 | One-step synthesizing method of levofloxacin and ofloxacin |
| CN103755722A (en) * | 2013-12-06 | 2014-04-30 | 浙江大学 | Levofloxacin and ofloxacin synthesis method |
-
2014
- 2014-10-10 CN CN201410532023.7A patent/CN104292159B/en active Active
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4699992A (en) * | 1984-09-29 | 1987-10-13 | Bayer Aktiengesellschaft | 3-amino-2-benzoylacrylic acid derivatives |
| CN1030911A (en) * | 1987-07-24 | 1989-02-08 | 拜尔公司 | The method for preparing quinolone carboxylic acid |
| CN1239094A (en) * | 1998-06-12 | 1999-12-22 | 拜尔公司 | Process for preparing quinolone- and naphthyridonecarboxylic acids and esters thereof |
| CN101481381A (en) * | 2008-09-28 | 2009-07-15 | 宁波经济技术开发区九胜创新医药工艺开发有限公司 | Method for preparing ciprofloxacin by piperazine reaction |
| CN101781313A (en) * | 2010-03-05 | 2010-07-21 | 浙江京新药业股份有限公司 | Method for synthesizing quinolone medicaments |
| CN102241629A (en) * | 2011-05-12 | 2011-11-16 | 浙江国邦药业有限公司 | Chemical preparation method of norfloxacin |
| CN102850376A (en) * | 2012-06-18 | 2013-01-02 | 浙江大学 | One-step synthesizing method of levofloxacin and ofloxacin |
| CN103755722A (en) * | 2013-12-06 | 2014-04-30 | 浙江大学 | Levofloxacin and ofloxacin synthesis method |
Non-Patent Citations (2)
| Title |
|---|
| Regioselective nucleophilic substitution of halogen derivatives of 1-substituted 4-oxo-1,4-dihydroquinoline-3-carboxylic acids;Hermecz Istvan等;《Heterocycles》;19981231;第48卷(第6期);第1111-1116页 * |
| 恩氟沙星的合成;程国侯等;《中国医药工业杂志》;19990731;第30卷(第7期);第291-292页 * |
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