CN105801482A - Method for preparing 1-cyclopropyl-4-oxo-7-bromine-8-difluoromethoxy-1,4-dihydro-quinoline-3-nonanoic acid-ethyl ester - Google Patents
Method for preparing 1-cyclopropyl-4-oxo-7-bromine-8-difluoromethoxy-1,4-dihydro-quinoline-3-nonanoic acid-ethyl ester Download PDFInfo
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- 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
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Abstract
The invention discloses a method for synthesizing 1-cyclopropyl-4-oxo-7-bromine-8-difluoromethoxy-1,4-dihydro-quinoline-3-nonanoic acid-ethyl ester, and belongs to the technical field of chemical synthesis. The method is characterized by comprising the following steps that 1, 2,4-dibromo-3-difluoromethoxy ethyl benzoylacetate is prepared; 2, 3-ethyoxyl-2-(2,4-dibromo-3-difluoromethoxy benzoyl)ethyl acrylate is prepared; 3, 3-amino cyclopropyl-2-(2,4-dibromo-3-difluoromethoxy benzoyl)ethyl acrylate is prepared; 4, 1-cyclopropyl-4-oxo-7-bromo-8-difluoromethoxy-1,4-dihydro-quinoline-3-carboxylic ethyl ester is prepared. The method for synthesizing 1-cyclopropyl-4-oxo-7-bromine-8-difluoromethoxy-1,4-dihydro-quinoline-3-nonanoic acid-ethyl ester has the advantages of that the reaction steps are short, operation is easy, pollution is low, the synthesis yield is high, product quality is good, and is suitable for industrialized application.
Description
Technical field:
The invention belongs to chemosynthesis technical field, specifically, relate to a kind of 1-cyclopropyl-4-oxo-7-bromo-8-difluoro-methoxy-Isosorbide-5-Nitrae-
The preparation method of dihydroquinoline-3-carboxylic acid, ethyl ester.
Background technology:
1-cyclopropyl-4-oxo-7-bromo-8-difluoro-methoxy-1,4-dihydroquinoline-3-carboxylic acid, ethyl ester is that synthesizing new carbostyril family antibacterial drugs adds
The key intermediate of Lei Shaxing.
T-3811 is developed by Japan folic hill chemistry, trade name Geninax, obtains the listing license of MHLW of Japan in August, 2007.
T-3811 is a kind of 6 novel carbostyril medicines removing fluorine, more higher than Gatifloxacin, ciprofloxacin, levofloxacin effect, antibacterial
Compose wider.
At present, the synthetic method of 1-cyclopropyl-4-oxo-7-bromo-8-difluoro-methoxy-Isosorbide-5-Nitrae-dihydroquinoline-3-carboxylic acid, ethyl ester mainly has following two
Kind:
(1), patent WO2013121439, disclose with 3-methyl hydroxybenzoate as raw material, through the method that eight steps are synthesized target compound:
This synthetic method reactions steps is longer, and agents useful for same is expensive to be not easy to obtain, and therefore extensively cannot apply in industrialized production.
(2), patent CN1427815 disclose with 2,4-bis-bromo-3-difluoro-methoxy-benzoic acid is raw material, through chloride, is condensed, replaces, closes
The method of ring four-step reaction synthesising target compound
Though this patent does not provides raw material 2, the synthetic method of 4-bis-bromo-3-difluoro-methoxy-benzoic acid, but its synthesis refers to synthetic route one (patent
WO2013121439), result, it is believed that this synthetic route is the optimization and upgrading to synthetic route one, shortens reactions steps, but still need to through seven steps anti-
Should be from 3-methyl hydroxybenzoate synthesising target compound, simultaneous reactions process need to be through chloride step, chloride reagent used, as
Thionyl chloride, Phosphorous chloride. etc., all can produce substantial amounts of waste gas and waste water, pollute relatively big, these are not enough, all limit this route in industrialization
On extensive application.
Summary of the invention:
It is an object of the invention to provide that a kind of raw material is easy to get, reactions steps is short, simple to operate, pollute less, synthesis yield is high, good product quality
The preparation method of 1-cyclopropyl-4-oxo-7-bromo-8-difluoro-methoxy-1,4-dihydroquinoline-3-carboxylic acid, ethyl ester.
The technical solution used in the present invention is as follows:
A kind of preparation method of 1-cyclopropyl-4-oxo-7-bromo-8-difluoro-methoxy-Isosorbide-5-Nitrae-dihydroquinoline-3-carboxylic acid, ethyl ester, it is characterised in that
Comprise the following steps:
(1), 3-hydroxy acetophenone (I) and bromine react in the presence of organic amine, obtain 2,4-bis-bromo-3-hydroxy acetophenone (II)；
(2), the 2 of step (1) gained, 4-bis-bromo-3-hydroxy acetophenone (II) reacts in the presence of an inorganic base with monochlorodifluoromethane,
To 2,4-bis-bromo-3-difluoro-methoxy 1-Phenylethanone. (III)；
(3), the 2 of step (2) gained, 4-bis-bromo-3-difluoro-methoxy 1-Phenylethanone. (III) and diethyl carbonate react in the presence of highly basic,
Obtain 2,4-bis-bromo-3-difluoro-methoxy benzoyl acetic acid ethyl ester (IV)；
(4), the 2,4-bis-bromo-3-difluoro-methoxy benzoyl acetic acid ethyl ester (IV) of step (3) gained deposits at acetic anhydride with triethyl orthoformate
In lower reaction, obtain 3-ethyoxyl-2-(2,4-bis-bromo-3-difluoro-methoxy benzoyl) ethyl acrylate (V)；
(5), 3-ethyoxyl-2-(the 2,4-bis-bromo-3-difluoro-methoxy benzoyl) ethyl acrylate (V) of step (4) gained and ring third
Amine reacts, and obtains 3-cyclopropylamino-2-(2,4-bis-bromo-3-difluoro-methoxy benzoyl) ethyl acrylate (VI)；
(6), 3-cyclopropylamino-2-(the 2,4-bis-bromo-3-difluoro-methoxy benzoyl) ethyl acrylate (VI) of step (5) gained is at alkali
In the presence of cyclization, obtain 1-cyclopropyl-4-oxo-7-bromo-8-difluoro-methoxy-Isosorbide-5-Nitrae-dihydroquinoline-3-carboxylic acid, ethyl ester (VII).
The synthetic route that the present invention uses can represent with following reaction equation:
The further setting of the present invention is as follows:
In step (1):
There is multiple bromo-reaction site in compound (I), in order to enable to obtain highly purified compound (II) with high yield, it is necessary to bromo-reaction
Condition strictly controls, and the kind of brominated reagent and consumption are the key factors affecting bromo-reaction result.Conventional brominated reagent has N-bromine
For acetamide, N-bromo-succinimide, bromine liquid etc., preferred brominated reagent is bromine, the amount of the material of brominated reagent and compound (I) it
Ratio is: 2.0:1～2.2:1.
Described organic amine, selected from following one or more: triethylamine, triethylenediamine, tert-butylamine, diisopropylamine, preferred organic amine
For tert-butylamine, organic amine with the ratio of the amount of the material of compound (I) is: 2:1～10:1.
Can reaction dissolvent be smoothed out having vital impact to bromo-reaction.Suitably reaction dissolvent can improve the selection of bromo-reaction
Property, suppress the generation of many bromos side reaction, improve product purity.Reaction dissolvent selected from following one or more: dichloromethane, chloroform,
The chlorinated hydrocarbon solvent such as carbon tetrachloride, dichloroethanes, the ether solvent such as diisopropyl ether, methyl tertiary butyl ether(MTBE), oxolane, methyl acetate, acetic acid
The esters solvents such as ethyl ester, isopropyl acetate, tert-butyl acetate, the aromatic hydrocarbon solvent such as toluene, dimethylbenzene.Solvent load is compound (I) quality
1～10 times.
Reaction temperature also has significant impact, too low reaction temperature to the selectivity of bromo-reaction, although can suppress the side reaction of many bromos,
Improving the selectivity of reaction, but response speed is relatively slow, the response time is long, is unfavorable for improving production efficiency, too high reaction temperature, although
The response time can be shortened, but be unfavorable for suppressing the selectivity of the side reaction of many bromos and bromo-reaction, cause product purity to decline, preferably react
Temperature is-30～50 DEG C.
Compound (II) is noval chemical compound, and Structural Identification data are as follows:
1HNMR (400MHz, DMSO-d6) δ 10.18 (br s, 1H), 7.58 (d, J=8.4Hz, 1H), 6.96 (d, J=8.4Hz, 1H), 2.50 (s,
3H)；13CNMR(100MHz,DMSO-d6)δ201.11,151.71,142.81,132.50,120.69,114.30,108.70,30.75。
In step (2):
Step (2) is typical Williamson (williamson) etherification reaction, and reaction need to be carried out in the presence of a base, and preferred alkali is inorganic base.
Described inorganic base selected from following one or more: sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate, potassium bicarbonate, nothing
Machine alkali with the ratio of the amount of the material of compound (II) is: 0.5:1～10:1.
Reaction need to be carried out in suitable solvent, solvent used selected from following one or more: the alcohols solvents such as methanol, ethanol, isopropanol,
The esters solvents such as isopropyl acetate, the ethyl ester tert-butyl ester, the ether solvent such as diisopropyl ether, methyl tertiary butyl ether(MTBE), oxolane, 2-methyltetrahydrofuran,
The aromatic hydrocarbon solvent such as toluene, dimethylbenzene, Yi Jishui.In order to increase inorganic base dissolubility in a solvent, accelerate response speed, preferably react
Solvent is the mixed solvent being made up of organic solvent and water, and this solvent can be homogeneous solvent, it is also possible to be non-homogeneous solvent, organic solvent and water
Mass ratio be 1:10～10:1, the total consumption of solvent is 1～10 times of compound (II) quality.
Monochlorodifluoromethane has another name called chlorodifluoromethane (Freon-22), is gas under room temperature, therefore reacts preferably at the reactor with certain voltage endurance capability
In carry out.Monochlorodifluoromethane is passed through in reaction system in gaseous form, makes reaction system keep certain pressure, preferred reaction pressure be 0～
1.0MPa, monochlorodifluoromethane consumption to guarantee that compound (II) fully reaction is as the criterion, preferred monochlorodifluoromethane and compound (II)
The ratio of the amount of material is: 1:1～10:1.
Reaction temperature has material impact to etherification reaction.Too low reaction temperature makes response speed the slowest, and the response time is long, is unfavorable for carrying
High efficiency, but too high reaction temperature, can then increase the reaction consumption of monochlorodifluoromethane and inorganic base, increase monochlorodifluoromethane and
The consumption of inorganic base, preferred reaction temperature is 10～60 DEG C.
The Structural Identification data of compound (III) are as follows:
1HNM (400MHz, DMSO-d6) δ 7.88 (d, J=8.4Hz, 1H), 7.49 (d, J=8.4Hz, 1H), 7.15 (t, J=71.6Hz, 1H),
2.55(s,3H)；13CNMR(100MHz,DMSO-d6)δ200.52,146.52,143.48,133.75,127.70,120.61,120.20,
118.01,115.40,115.05,30.79。
In step (3):
Diethyl carbonate is in course of reaction, both as reaction raw materials, uses as reaction dissolvent again, preferred diethyl carbonate and compound (III)
The ratio of amount of material be: 1:1～30:1.Use the diethyl carbonate of excess, be possible not only to accelerate response speed, simultaneously as its conduct again
Reaction dissolvent uses, thus avoids the recovery introducing other organic solvent, beneficially reaction dissolvent and apply mechanically, and reduces production cost.
Described highly basic, selected from following one or more: Sodium ethylate, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydride, alkali and compound
(III) ratio of the amount of material is: 1:1～6:1.
Reaction temperature and the kind of alkali used, consumption are relevant.When the increased activity of alkali used, reaction temperature can be fitted the most within the specific limits
Working as reduction, similar, when the consumption of alkali increases, reaction temperature also can the most suitably reduce, preferred reaction temperature
For: 50～130 DEG C.
After reaction terminates, being diluted to by reactant liquor in the sodium bicarbonate of debita spissitudo or the aqueous solution of potassium bicarbonate, cancellation is reacted.Body after cancellation
System, layered, dry, concentration, obtain 2, the concentrated solution of 4-bis-bromo-3-difluoro-methoxy benzoyl acetic acid ethyl ester (IV), it is not necessary to the purest
Change, i.e. can be used for the next step.
In step (4):
Compound (IV) is the concentrated solution of step (1) gained 2,4-bis-bromo-3-difluoro-methoxy benzoyl acetic acid ethyl ester (IV).Compound (IV)
Quantity calculate standard, be to be fully converted into the theoretical yield of compound (IV) by compound (III) in step (3) to calculate.
Acetic anhydride both as reaction reagent, uses as reaction dissolvent again in course of reaction, the amount of the material of preferred acetic anhydride and compound (IV)
Ratio be: 2:1～10:1.Use the acetic anhydride of excess, be possible not only to accelerate response speed, simultaneously as it uses as reaction dissolvent again, from
And avoid introducing other organic solvent, beneficially the recovery of reaction dissolvent with apply mechanically, reduce production cost.
Triethyl orthoformate with the ratio of the amount of the material of compound (IV) is: 1:1～2:1.
Reaction temperature is 80～150 DEG C.
After reaction terminates, decompression distillation removing low-boiling-point substance, concentrated solution adds toluene and dissolves, obtains 3-ethyoxyl-2-(2,4-bis-bromo-3-difluoro first
Epoxide benzoyl) toluene solution of ethyl acrylate (V), through washing, it is dried, for the next step.
In step (5):
Compound (V) is the first of step (4) gained 3-ethyoxyl-2-(2,4-bis-bromo-3-difluoro-methoxy benzoyl) ethyl acrylate (V)
Benzole soln.The quantity of compound (V) calculates standard, is the theoretical product being fully converted into compound (V) by compound (IV) in step (4)
Amount calculates.
Reaction makees solvent with toluene, and toluene used can all be from step (4) for the toluene used by dissolved compound (V), it is also possible to
According to needing use, add extra toluene, to guarantee that reaction system has preferable mobility, enable reaction to be smoothed out.Total consumption of toluene
For compound (V) weight 1～10 times.
Cyclopropylamine uses dropping mode, joins in the toluene solution of compound (V), and cyclopropylamine with the ratio of the amount of the material of compound (V) is:
1:1～2:1.
Reaction temperature is 0～50 DEG C.
After reaction terminates, react with appropriate hydrochloric acid or aqueous sulfuric acid cancellation, stand and separate organic facies, through washing, be dried, obtain 3-ring third
The toluene solution of amino-2-(2,4-bis-bromo-3-difluoro-methoxy benzoyl) ethyl acrylate (VI), for the next step.
In step (6):
Compound (VI) is step (5) gained 3-cyclopropylamino-2-(2,4-bis-bromo-3-difluoro-methoxy benzoyl) ethyl acrylate (VI)
Toluene solution.The quantity of compound (VI) calculates standard, is fully converted into compound (VI) by compound (V) in step (5)
Theoretical yield calculates.
Reaction makees solvent with toluene, and toluene used can all be from step (5) for the toluene used by dissolved compound (VI), it is also possible to
According to needing use, add extra toluene, to guarantee that reaction can be smoothed out.Total consumption of toluene is 1～10 times of compound (VI) weight.
Described alkali, selected from following one or more: sodium carbonate, potassium carbonate, sodium hydride, alkali with the ratio of the amount of the material of compound (VI) is:
1:1～3:1.
Reaction temperature is 0～120 DEG C.
After reaction terminates, add appropriate shrend and go out reaction, the mixture filtration after cancellation, obtain 1-cyclopropyl-4-oxo-7-bromo-8-difluoro first
Oxy-1,4-dihydroquinoline-3-carboxylic acid, ethyl ester (VII) crude product, more scrubbed, dry, the 1-cyclopropyl-4-oxygen of purity more than 99%
Generation-7-bromo-8-difluoro-methoxy-1,4-dihydroquinoline-3-carboxylic acid, ethyl ester (VII).
Six-step process total recovery more than 65%, product (VII) purity more than 99%.
Compared with prior art, its beneficial effect is embodied in the present invention:
(1) devise with 3-hydroxy acetophenone as raw material, through six-step process synthesize 1-cyclopropyl-4-oxo-7-bromo-8-difluoro-methoxy-Isosorbide-5-Nitrae-
The synthetic route of dihydroquinoline-3-carboxylic acid, ethyl ester, this synthetic route not yet has open report；
(2) synthetic method have that reactions steps is short, simple to operate, pollute less, the advantage such as synthesis yield height, good product quality, applicable industrialization
Application.
Below in conjunction with detailed description of the invention, the invention will be further described.
Detailed description of the invention:
Embodiment one:
Adding dichloromethane 140 grams, triethylenediamine 58 grams in 500 milliliters of reaction bulbs, stirring is cooled to-5～0 DEG C, is slowly added into bromine
90 grams, after charging, system is cooled to-25～-30 DEG C, drips 35 grams of 3-hydroxy acetophenones and the mixed solution of 175 grams of dichloromethane, drips
After adding, system, in-20～-25 DEG C of stirring reactions 1 hour, is risen again naturally to room temperature reaction 2 hours.Reactant liquor is quenched to 10% hydrochloric acid
In solution, separating organic facies, aqueous phase dichloromethane extracts secondary, merges organic facies, drying, concentration, obtains 2,4-bis-bromo-3-hydroxy benzenes second
Ketone 74 grams, yield 98%, purity 96.2%.
Embodiment two:
Adding tert-butylamine 100 grams in 250 milliliters of reaction bulbs, be stirred at room temperature, drip bromine 47 grams, after dropping, system stirring is cooled to
-10～-15 DEG C, drip 20 grams of 3-hydroxy acetophenones and the mixed solution of 30 grams of ethyl acetate, after dropping, system is stirred in-10～-15 DEG C
Mix reaction 2 hours, be slowly ramped to 35～40 DEG C and react 1 hour.Reactant liquor is diluted in 25% sulfuric acid solution, separates organic facies, aqueous phase
It is extracted with ethyl acetate secondary, merges organic facies, drying, concentration, obtain 2,4-bis-bromo-3-hydroxy acetophenone 41.7 grams, yield 96.6%,
Purity 95.4%.
Embodiment three:
250 milliliters of reaction bulbs add toluene 75 grams, triethylamine 74 grams, is stirred at room temperature, drip bromine 60 grams, after dropping, system
Stirring is cooled to-5～0 DEG C, drips 25 grams of 3-hydroxy acetophenones and the mixed solution of 75 grams of oxolanes, and after dropping, system is stirred in-5～0 DEG C
Mix reaction 1 hour, be slowly ramped to 45～50 DEG C and react 1 hour.Being diluted to by reactant liquor in 5% hydrochloric acid solution, separate organic facies, aqueous phase is used
Isopropyl acetate extraction secondary, merges organic facies, drying, concentration, obtains 2,4-bis-bromo-3-hydroxy acetophenone 52.7 grams, yield 97.6%,
Purity 96.4%.
Embodiment four:
500 milliliters of reaction bulbs add chloroform 60 grams, diisopropylamine 130 grams, system temperature control 5～10 DEG C, are slowly added into bromine 74 grams,
After charging, system stirring is cooled to-5～-10 DEG C, drip 30 grams of 3-hydroxy acetophenones and the mixed solution of 60 grams of tert-butyl acetates, drips
After, system is reacted 1 hour in-5～-10 DEG C of stirrings, is slowly ramped to 25～30 DEG C and reacts 1 hour.Reactant liquor is diluted to 10% sulfur
In acid solution, separating organic facies, aqueous phase tert-butyl acetate extracts secondary, merges organic facies, drying, concentration, obtains 2,4-bis-bromo-3-hydroxyl
1-Phenylethanone. 63 grams, yield 97.4%, purity 96.9%.
Embodiment five:
Addition ethanol 30 grams in 250 milliliters of pressure reactors, 30 grams of water, 2,4-bis-bromo-3-hydroxy acetophenones 30 grams, sodium hydroxide 20 grams,
Closed reactor, is stirred at room temperature, and is passed through monochlorodifluoromethane gas 88 grams, and system was in 30～40 DEG C of stirring reactions 4 hours.Take out reactant liquor,
Decompression distillation removing ethanol, residue adds water, freezing crystallize, filters, filter cake recrystallization, obtains 2,4-bis-bromo-3-difluoromethoxy phenyl second 30.3
Gram, yield 86.4%, purity 99.3%.
Embodiment six:
500 milliliters of pressure reactors add tert-butyl acetate 40 grams, 160 grams of water, 2,4-bis-bromo-3-hydroxy acetophenones 20 grams, sodium bicarbonate
46 grams, closed reactor, it is stirred at room temperature, is passed through monochlorodifluoromethane gas 12 grams, system was in 50～60 DEG C of stirring reactions 10 hours.Take out
Reactant liquor, separates organic facies, concentrating under reduced pressure, residue recrystallization, obtains 2,4-bis-bromo-3-difluoro-methoxy 1-Phenylethanone. 19.9 grams, yield 85.1%,
Purity 99.4%.
Embodiment seven:
Addition toluene 210 grams in 500 milliliters of pressure reactors, 70 grams of water, 2,4-bis-bromo-3-hydroxy acetophenones 35 grams, potassium carbonate 16 grams, close
Closing reactor, be stirred at room temperature, be passed through monochlorodifluoromethane gas 41 grams, system is stirred at room temperature reaction 7 hours.Take out reactant liquor, separated
Machine phase, concentrating under reduced pressure, residue recrystallization, obtain 2,4-bis-bromo-3-difluoro-methoxy 1-Phenylethanone. 35.8 grams, yield 87.5%, purity 99.1%.
Embodiment eight:
250 milliliters of pressure reactors add methyl tertiary butyl ether(MTBE) 45 grams, 60 grams of water, 2,4-bis-bromo-3-hydroxy acetophenones 15 grams, potassium hydroxide
9 grams, closed reactor, it is passed through monochlorodifluoromethane gas 26 grams, system was in 10～20 DEG C of stirring reactions 10 hours.Take out reactant liquor, point
Go out organic facies, concentrating under reduced pressure, residue recrystallization, obtain 2,4-bis-bromo-3-difluoro-methoxy 1-Phenylethanone. 15.1 grams, yield 86.1%, purity 99.2%.
Embodiment nine:
Addition 2 in 500 milliliters of reaction bulbs, 4-bis-bromo-3-difluoro-methoxy 1-Phenylethanone. 50 grams, diethyl carbonate 300 grams, Sodium ethylate 55 grams,
In 120～130 DEG C of stirring reactions 12 hours.System is cooled to room temperature, is slowly diluted in 300 gram of 30% potassium bicarbonate aqueous solution, stratification,
Separate organic facies, drying, concentration, obtain 2,4-bis-bromo-3-difluoro-methoxy benzoyl acetic acid ethyl ester.
500 milliliters of reactions add the 2 of gained, 4-bis-bromo-3-difluoro-methoxy benzoyl acetic acid ethyl ester, adds triethyl orthoformate 43 grams, vinegar
Acid anhydride 145 grams, stirring is warming up to 80～90 DEG C of insulation reaction 12 hours.By reactant liquor concentrating under reduced pressure, concentrated solution adds toluene 350 grams, stirs molten
Solve, through washing, be dried, obtain the toluene solution of 3-ethyoxyl-2-(2,4-bis-bromo-3-difluoro-methoxy benzoyl) ethyl acrylate.
The toluene of 3-ethyoxyl-2-(the 2,4-bis-bromo-3-difluoro-methoxy benzoyl) ethyl acrylate adding gained in 500 milliliters of reaction bulbs is molten
Liquid, stirring is cooled to 0～10 DEG C, drips cyclopropylamine 8.5 grams, after dropping, is warming up to 40～50 DEG C of insulation reaction 1 hour.System cools down
To room temperature, add 2% aqueous hydrochloric acid solution 100 grams, stand and separate organic facies, through washing, be dried, obtain 3-cyclopropylamino-2-(2,4-dibromos
-3-difluoro-methoxy benzoyl) toluene solution of ethyl acrylate.
500 milliliters of reaction bulbs add the toluene of 3-cyclopropylamino-2-(the 2,4-bis-bromo-3-difluoro-methoxy benzoyl) ethyl acrylate of gained
Solution, adds Anhydrous potassium carbonate 50 grams, and temperature rising reflux reacts 12 hours.System is cooled to room temperature, adds 150 grams of water, filters, filter cake warp
Washing, dry, obtain 1-cyclopropyl-4-oxo-7-bromo-8-difluoro-methoxy-Isosorbide-5-Nitrae-dihydroquinoline-3-carboxylic acid, ethyl ester 48.4 grams, yield 82.8%,
Purity 99.5%.
Embodiment ten:
Addition 2 in 500 milliliters of reaction bulbs, 4-bis-bromo-3-difluoro-methoxy 1-Phenylethanone. 30 grams, diethyl carbonate 300 grams, potassium tert-butoxide 39 grams,
In 100～110 DEG C of stirring reactions 8 hours.System is cooled to room temperature, is slowly diluted in 200 gram of 20% potassium bicarbonate aqueous solution, stratification,
Separate organic facies, drying, concentration, obtain 2,4-bis-bromo-3-difluoro-methoxy benzoyl acetic acid ethyl ester.
250 milliliters of reactions add the 2 of gained, 4-bis-bromo-3-difluoro-methoxy benzoyl acetic acid ethyl ester, add triethyl orthoformate 14.2 grams,
Acetic anhydride 22 grams, stirring is warming up to 140～150 DEG C of insulation reaction 5 hours.By reactant liquor concentrating under reduced pressure, concentrated solution adds toluene 45 grams, stirring
Dissolve, through washing, be dried, obtain the toluene solution of 3-ethyoxyl-2-(2,4-bis-bromo-3-difluoro-methoxy benzoyl) ethyl acrylate.
The toluene of 3-ethyoxyl-2-(the 2,4-bis-bromo-3-difluoro-methoxy benzoyl) ethyl acrylate adding gained in 250 milliliters of reaction bulbs is molten
Liquid, is stirred at room temperature, and drips 7.5 grams of cyclopropylamines and the mixed solution of 10 grams of toluene, and after dropping, system continues reaction 3 hours in room temperature.
Add 10% aqueous hydrochloric acid solution 50 grams, stand and separate organic facies, through washing, be dried, obtain 3-cyclopropylamino-2-(2,4-bis-bromo-3-difluoro first
Epoxide benzoyl) toluene solution of ethyl acrylate.
Adding 60% sodium hydride 3.5 grams, toluene 10 grams in 250 milliliters of reaction bulbs, stirring is cooled to 0～10 DEG C, the 3-cyclopropylamino of dropping gained
The toluene solution of-2-(2,4-bis-bromo-3-difluoro-methoxy benzoyl) ethyl acrylate, after dropping, system is risen again naturally to room temperature reaction 3
Hour.Adding 50 grams of water, filter, filter cake is scrubbed, drying, obtains 1-cyclopropyl-4-oxo-7-bromo-8-difluoro-methoxy-Isosorbide-5-Nitrae-dihydroquinoline
-3-carboxylic acid, ethyl ester 28.2 grams, yield 80.4%, purity 99.4%.
Embodiment 11:
Addition 2 in 250 milliliters of reaction bulbs, 4-bis-bromo-3-difluoro-methoxy 1-Phenylethanone. 40 grams, diethyl carbonate 60 grams, 60% sodium hydride 9 grams,
In 70～80 DEG C of stirring reactions 6 hours.System is cooled to room temperature, is slowly diluted in 80 gram of 30% potassium bicarbonate aqueous solution, stratification, point
Go out organic facies, drying, concentration, obtain 2,4-bis-bromo-3-difluoro-methoxy benzoyl acetic acid ethyl ester.
250 milliliters of reactions add the 2 of gained, 4-bis-bromo-3-difluoro-methoxy benzoyl acetic acid ethyl ester, add triethyl orthoformate 25.8 grams,
Acetic anhydride 48 grams, stirring is warming up to 130～140 DEG C of insulation reaction 5 hours.By reactant liquor concentrating under reduced pressure, concentrated solution adds toluene 165 grams, stirring
Dissolve, through washing, be dried, obtain the toluene solution of 3-ethyoxyl-2-(2,4-bis-bromo-3-difluoro-methoxy benzoyl) ethyl acrylate.
The toluene of 3-ethyoxyl-2-(the 2,4-bis-bromo-3-difluoro-methoxy benzoyl) ethyl acrylate adding gained in 500 milliliters of reaction bulbs is molten
Liquid, is stirred at room temperature, and drips cyclopropylamine 8 grams, after dropping, is warming up to 40～50 DEG C of insulation reaction 1 hour.System is cooled to room temperature, adds
Enter 5% aqueous hydrochloric acid solution 60 grams, stand and separate organic facies, through washing, be dried, obtain 3-cyclopropylamino-2-(2,4-bis-bromo-3-difluoromethoxy
Base benzoyl) toluene solution of ethyl acrylate.
500 milliliters of reaction bulbs add the toluene of 3-cyclopropylamino-2-(the 2,4-bis-bromo-3-difluoro-methoxy benzoyl) ethyl acrylate of gained
Solution, adds natrium carbonicum calcinatum 36 grams, and temperature rising reflux reacts 16 hours.System is cooled to room temperature, adds 150 grams of water, filters, filter cake warp
Washing, dry, obtain 1-cyclopropyl-4-oxo-7-bromo-8-difluoro-methoxy-Isosorbide-5-Nitrae-dihydroquinoline-3-carboxylic acid, ethyl ester 37.7 grams, yield 80.6%,
Purity 99.3%.
Embodiment 12:
Addition 2,4-bis-bromo-3-difluoro-methoxy 1-Phenylethanone. 50 grams, diethyl carbonate 170 grams, 60% sodium hydride 17.5 in 500 milliliters of reaction bulbs
Gram, in 50～60 DEG C of stirring reactions 12 hours.System is cooled to room temperature, is slowly diluted in 400 gram of 10% sodium bicarbonate aqueous solution, stand
Layering, separates organic facies, drying, concentration, obtains 2,4-bis-bromo-3-difluoro-methoxy benzoyl acetic acid ethyl ester.
250 milliliters of reactions add the 2 of gained, 4-bis-bromo-3-difluoro-methoxy benzoyl acetic acid ethyl ester, add triethyl orthoformate 36.6 grams,
Acetic anhydride 89 grams, stirring is warming up to 110～120 DEG C of insulation reaction 8 hours.By reactant liquor concentrating under reduced pressure, concentrated solution adds toluene 140 grams, stirring
Dissolve, through washing, be dried, obtain the toluene solution of 3-ethyoxyl-2-(2,4-bis-bromo-3-difluoro-methoxy benzoyl) ethyl acrylate.
The toluene of 3-ethyoxyl-2-(the 2,4-bis-bromo-3-difluoro-methoxy benzoyl) ethyl acrylate adding gained in 500 milliliters of reaction bulbs is molten
Liquid, stirring is cooled to 0～10 DEG C, drips the mixed solution of cyclopropylamine 16.6 grams and 120 grams of toluene, after dropping, system 0～10 DEG C of insulations
React 3 hours.Add 10% aqueous sulfuric acid 100 grams, stand and separate organic facies, through washing, be dried, obtain 3-cyclopropylamino-2-(2,4-
Two bromo-3-difluoro-methoxy benzoyls) toluene solution of ethyl acrylate.
250 milliliters of reaction bulbs add 60% sodium hydride 7 grams, toluene 20 grams, is stirred at room temperature, the 3-cyclopropylamino-2-(2,4-of dropping gained
Two bromo-3-difluoro-methoxy benzoyls) toluene solution of ethyl acrylate, after dropping, system continues reaction 2 hours in room temperature.Add water
100 grams, filtering, filter cake is scrubbed, drying, obtains 1-cyclopropyl-4-oxo-7-bromo-8-difluoro-methoxy-Isosorbide-5-Nitrae-dihydroquinoline-3-carboxylic acid, ethyl ester
48.6 grams, yield 83.1%, purity 99.5%.
Embodiment 13:
Addition 2 in 500 milliliters of reaction bulbs, 4-bis-bromo-3-difluoro-methoxy 1-Phenylethanone. 35 grams, diethyl carbonate 240 grams, sodium tert-butoxide 44 grams,
In 90～100 DEG C of stirring reactions 15 hours.System is cooled to room temperature, slowly 200 gram of 25% potassium bicarbonate aqueous solution of dropping, stratification, point
Go out organic facies, drying, concentration, obtain 2,4-bis-bromo-3-difluoro-methoxy benzoyl acetic acid ethyl ester.
250 milliliters of reactions add the 2 of gained, 4-bis-bromo-3-difluoro-methoxy benzoyl acetic acid ethyl ester, adds triethyl orthoformate 21 grams, vinegar
Acid anhydride 31 grams, stirring is warming up to 130～140 DEG C of insulation reaction 6 hours.By reactant liquor concentrating under reduced pressure, concentrated solution adds toluene 330 grams, stirs molten
Solve, through washing, be dried, obtain the toluene solution of 3-ethyoxyl-2-(2,4-bis-bromo-3-difluoro-methoxy benzoyl) ethyl acrylate.
The toluene of 3-ethyoxyl-2-(the 2,4-bis-bromo-3-difluoro-methoxy benzoyl) ethyl acrylate adding gained in 500 milliliters of reaction bulbs is molten
Liquid, system temperature control 10～20 DEG C, drip cyclopropylamine 10.5 grams, after dropping, system is stirred at room temperature reaction 2 hours.Add 5% sulphuric acid water
Solution 150 grams, stands and separates organic facies, through washing, is dried, obtains 3-cyclopropylamino-2-(2,4-bis-bromo-3-difluoro-methoxy benzoyl)
The toluene solution of ethyl acrylate.
500 milliliters of reaction bulbs add 60% sodium hydride 6 grams, toluene 100 grams, is stirred at room temperature, the 3-cyclopropylamino-2-(2,4-of dropping gained
Two bromo-3-difluoro-methoxy benzoyls) toluene solution of ethyl acrylate, after dropping, system continues reaction 2 hours in room temperature.Will reaction
Liquid is diluted in 200 grams of water, filters, and filter cake is scrubbed, drying, obtains 1-cyclopropyl-4-oxo-7-bromo-8-difluoro-methoxy-Isosorbide-5-Nitrae-dihydro quinoline
Quinoline-3-carboxylic acid, ethyl ester 33.4 grams, yield 81.6%, purity 99.6%.
Claims (24)
1. the preparation method of 1-cyclopropyl-4-oxo-7-bromo-8-difluoro-methoxy-Isosorbide-5-Nitrae-dihydroquinoline-3-carboxylic acid, ethyl ester, it is characterised in that comprise the following steps:
(1), 3-hydroxy acetophenone and bromine react in the presence of organic amine, obtain 2,4-bis-bromo-3-hydroxy acetophenone；
(2), the 2 of step (1) gained, 4-bis-bromo-3-hydroxy acetophenone reacts in the presence of an inorganic base with monochlorodifluoromethane, obtains 2,4-bis-bromo-3-difluoro-methoxy 1-Phenylethanone.；
(3), the 2 of step (2) gained, 4-bis-bromo-3-difluoro-methoxy 1-Phenylethanone. and diethyl carbonate react in the presence of highly basic, obtain 2,4-bis-bromo-3-difluoro-methoxy benzoyl acetic acid ethyl ester；
(4), the 2 of step (3) gained, 4-bis-bromo-3-difluoro-methoxy benzoyl acetic acid ethyl ester and triethyl orthoformate react in the presence of acetic anhydride, obtain 3-ethyoxyl-2-(2,4-bis-bromo-3-difluoro-methoxy benzoyl) ethyl acrylate；
(5), the 3-ethyoxyl-2-(2 of step (4) gained, 4-bis-bromo-3-difluoro-methoxy benzoyl) ethyl acrylate reacts with cyclopropylamine, obtain 3-cyclopropylamino-2-(2,4-bis-bromo-3-difluoro-methoxy benzoyl) ethyl acrylate；
(6), the 3-cyclopropylamino-2-(2 of step (5) gained, 4-bis-bromo-3-difluoro-methoxy benzoyl) ethyl acrylate cyclization in the presence of a base, obtain 1-cyclopropyl-4-oxo-7-bromo-8-difluoro-methoxy-Isosorbide-5-Nitrae-dihydroquinoline-3-carboxylic acid, ethyl ester.
A kind of 1-cyclopropyl-4-oxo-7-bromo-8-difluoro-methoxy-1 the most according to claim 1, the preparation method of 4-dihydroquinoline-3-carboxylic acid, ethyl ester, it is characterized in that: in step (1), bromine with the ratio of the amount of the material of 3-hydroxy acetophenone is: 2.0:1～2.2:1.
A kind of 1-cyclopropyl-4-oxo-7-bromo-8-difluoro-methoxy-1 the most according to claim 1, the preparation method of 4-dihydroquinoline-3-carboxylic acid, ethyl ester, it is characterized in that: in step (1), described organic amine, selected from following one or more: triethylamine, triethylenediamine, tert-butylamine, diisopropylamine, preferably organic amine is tert-butylamine, and organic amine with the ratio of the amount of the material of 3-hydroxy acetophenone is: 2:1～10:1.
A kind of 1-cyclopropyl-4-oxo-7-bromo-8-difluoro-methoxy-1 the most according to claim 1, the preparation method of 4-dihydroquinoline-3-carboxylic acid, ethyl ester, it is characterized in that: in step (1), reaction dissolvent selected from following one or more: dichloromethane, chloroform, carbon tetrachloride, dichloroethanes, diisopropyl ether, methyl tertiary butyl ether(MTBE), oxolane, methyl acetate, ethyl acetate, isopropyl acetate, tert-butyl acetate, toluene, dimethylbenzene, solvent load is 1～10 times of 3-hydroxy acetophenone quality.
The preparation method of a kind of 1-cyclopropyl-4-oxo-7-bromo-8-difluoro-methoxy-Isosorbide-5-Nitrae-dihydroquinoline-3-carboxylic acid, ethyl ester the most according to claim 1, it is characterised in that: in step (1), reaction temperature is-30～50 DEG C.
A kind of 1-cyclopropyl-4-oxo-7-bromo-8-difluoro-methoxy-1 the most according to claim 1, the preparation method of 4-dihydroquinoline-3-carboxylic acid, ethyl ester, it is characterized in that: in step (2), described inorganic base selected from following one or more: sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate, potassium bicarbonate, inorganic base and 2, the ratio of the amount of the material of 4-bis-bromo-3-hydroxy acetophenone is: 0.5:1～10:1.
A kind of 1-cyclopropyl-4-oxo-7-bromo-8-difluoro-methoxy-1 the most according to claim 1, the preparation method of 4-dihydroquinoline-3-carboxylic acid, ethyl ester, it is characterized in that: in step (2), solvent used is the mixed solvent of organic solvent and water composition, wherein organic solvent selected from following one or more: methanol, ethanol, isopropanol, isopropyl acetate, the ethyl ester tert-butyl ester, diisopropyl ether, methyl tertiary butyl ether(MTBE), oxolane, 2-methyltetrahydrofuran, toluene, dimethylbenzene, organic solvent is 1:10～10:1 with the mass ratio of water, the total consumption of solvent is 2, 1～10 times of 4-bis-bromo-3-hydroxy acetophenone quality.
A kind of 1-cyclopropyl-4-oxo-7-bromo-8-difluoro-methoxy-1 the most according to claim 1, the preparation method of 4-dihydroquinoline-3-carboxylic acid, ethyl ester, it is characterized in that: in step (2), monochlorodifluoromethane and 2, the ratio of the amount of the material of 4-bis-bromo-3-hydroxy acetophenone is: 1:1～10:1.
The preparation method of a kind of 1-cyclopropyl-4-oxo-7-bromo-8-difluoro-methoxy-Isosorbide-5-Nitrae-dihydroquinoline-3-carboxylic acid, ethyl ester the most according to claim 1, it is characterised in that: in step (2), reaction temperature is 10～60 DEG C.
A kind of 1-cyclopropyl-4-oxo-7-bromo-8-difluoro-methoxy-1 the most according to claim 1, the preparation method of 4-dihydroquinoline-3-carboxylic acid, ethyl ester, it is characterized in that: in step (3), diethyl carbonate and 2, the ratio of the amount of the material of 4-bis-bromo-3-difluoro-methoxy 1-Phenylethanone. is: 1:1～30:1.
11. a kind of 1-cyclopropyl-4-oxo-7-bromo-8-difluoro-methoxies-1 according to claim 1, the preparation method of 4-dihydroquinoline-3-carboxylic acid, ethyl ester, it is characterized in that: in step (3), described highly basic, selected from following one or more: Sodium ethylate, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydride, alkali and 2, the ratio of the amount of the material of 4-bis-bromo-3-difluoro-methoxy 1-Phenylethanone. is: 1:1～6:1.
The preparation method of 12. a kind of 1-cyclopropyl-4-oxo-7-bromo-8-difluoro-methoxy-Isosorbide-5-Nitrae-dihydroquinoline-3-carboxylic acid, ethyl esters according to claim 1, it is characterised in that: in step (3), reaction temperature is 50～130 DEG C.
13. a kind of 1-cyclopropyl-4-oxo-7-bromo-8-difluoro-methoxies-1 according to claim 1, the preparation method of 4-dihydroquinoline-3-carboxylic acid, ethyl ester, it is characterized in that: in step (3), after reaction terminates, reactant liquor is diluted in the sodium bicarbonate of debita spissitudo or the aqueous solution of potassium bicarbonate, layered, dry, concentration, obtains 2, the concentrated solution of 4-bis-bromo-3-difluoro-methoxy benzoyl acetic acid ethyl ester, for the next step.
14. a kind of 1-cyclopropyl-4-oxo-7-bromo-8-difluoro-methoxies-1 according to claim 1, the preparation method of 4-dihydroquinoline-3-carboxylic acid, ethyl ester, it is characterized in that: in step (4), acetic anhydride and 2, the ratio of the amount of the material of 4-bis-bromo-3-difluoro-methoxy benzoyl acetic acid ethyl ester is: 2:1～10:1.
15. a kind of 1-cyclopropyl-4-oxo-7-bromo-8-difluoro-methoxies-1 according to claim 1, the preparation method of 4-dihydroquinoline-3-carboxylic acid, ethyl ester, it is characterized in that: in step (4), triethyl orthoformate and 2, the ratio of the amount of the material of 4-bis-bromo-3-difluoro-methoxy benzoyl acetic acid ethyl ester is: 1:1～2:1.
The preparation method of 16. a kind of 1-cyclopropyl-4-oxo-7-bromo-8-difluoro-methoxy-Isosorbide-5-Nitrae-dihydroquinoline-3-carboxylic acid, ethyl esters according to claim 1, it is characterised in that: in step (4), reaction temperature is 80～150 DEG C.
17. a kind of 1-cyclopropyl-4-oxo-7-bromo-8-difluoro-methoxies-1 according to claim 1, the preparation method of 4-dihydroquinoline-3-carboxylic acid, ethyl ester, it is characterized in that: in step (4), after reaction terminates, decompression distillation removing low-boiling-point substance, concentrated solution adds toluene and dissolves, obtain 3-ethyoxyl-2-(2,4-bis-bromo-3-difluoro-methoxy benzoyl) toluene solution of ethyl acrylate, through washing, it is dried, for the next step.
18. a kind of 1-cyclopropyl-4-oxo-7-bromo-8-difluoro-methoxies-1 according to claim 1, the preparation method of 4-dihydroquinoline-3-carboxylic acid, ethyl ester, it is characterized in that: in step (5), cyclopropylamine with the ratio of the amount of the material of 3-ethyoxyl-2-(2,4-bis-bromo-3-difluoro-methoxy benzoyl) ethyl acrylate is: 1:1～2:1.
19. a kind of 1-cyclopropyl-4-oxo-7-bromo-8-difluoro-methoxies-1 according to claim 1, the preparation method of 4-dihydroquinoline-3-carboxylic acid, ethyl ester, it is characterized in that: in step (5), reaction dissolvent is toluene, the consumption of toluene is 1～10 times of 3-ethyoxyl-2-(2,4-bis-bromo-3-difluoro-methoxy benzoyl) ethyl acrylate weight.
The preparation method of 20. a kind of 1-cyclopropyl-4-oxo-7-bromo-8-difluoro-methoxy-Isosorbide-5-Nitrae-dihydroquinoline-3-carboxylic acid, ethyl esters according to claim 1, it is characterised in that: in step (5), reaction temperature is 0～50 DEG C.
21. a kind of 1-cyclopropyl-4-oxo-7-bromo-8-difluoro-methoxies-1 according to claim 1, the preparation method of 4-dihydroquinoline-3-carboxylic acid, ethyl ester, it is characterized in that: in step (5), after reaction terminates, reacting with hydrochloric acid or aqueous sulfuric acid cancellation, organic facies, through washing, being dried, obtains 3-cyclopropylamino-2-(2,4-bis-bromo-3-difluoro-methoxy benzoyl) toluene solution of ethyl acrylate, for the next step.
22. a kind of 1-cyclopropyl-4-oxo-7-bromo-8-difluoro-methoxies-1 according to claim 1, the preparation method of 4-dihydroquinoline-3-carboxylic acid, ethyl ester, it is characterized in that: in step (6), described alkali, selected from following one or more: sodium carbonate, potassium carbonate, sodium hydride, alkali with the ratio of the amount of the material of 3-cyclopropylamino-2-(2,4-bis-bromo-3-difluoro-methoxy benzoyl) ethyl acrylate is: 1:1～3:1.
23. a kind of 1-cyclopropyl-4-oxo-7-bromo-8-difluoro-methoxies-1 according to claim 1, the preparation method of 4-dihydroquinoline-3-carboxylic acid, ethyl ester, it is characterized in that: in step (6), reaction dissolvent is toluene, the consumption of toluene is 1～10 times of 3-cyclopropylamino-2-(2,4-bis-bromo-3-difluoro-methoxy benzoyl) ethyl acrylate weight.
The preparation method of 24. a kind of 1-cyclopropyl-4-oxo-7-bromo-8-difluoro-methoxy-Isosorbide-5-Nitrae-dihydroquinoline-3-carboxylic acid, ethyl esters according to claim 1, it is characterised in that: in step (6), reaction temperature is 0～120 DEG C.
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| CN115703757A (en) * | 2021-08-16 | 2023-02-17 | 浙江中欣氟材股份有限公司 | Synthesis method of melafloxacin |
| CN115703757B (en) * | 2021-08-16 | 2024-04-09 | 浙江中欣氟材股份有限公司 | Synthesis method of melaxacin |
| CN114716373A (en) * | 2022-04-14 | 2022-07-08 | 内蒙古源宏精细化工有限公司 | Preparation method of gatifloxacin cyclized ester |
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