CN101838238A - Method for synthesizing quinolone main cycle compound - Google Patents
Method for synthesizing quinolone main cycle compound Download PDFInfo
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- CN101838238A CN101838238A CN 201010160812 CN201010160812A CN101838238A CN 101838238 A CN101838238 A CN 101838238A CN 201010160812 CN201010160812 CN 201010160812 CN 201010160812 A CN201010160812 A CN 201010160812A CN 101838238 A CN101838238 A CN 101838238A
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Abstract
The invention discloses a method for synthesizing a quinolone main cycle compound shown in a formula (I), which comprises the following steps of: (1) performing amino exchange reaction on alpha-substituted aroyl-beta-dimethylaminoethyl acrylate shown in a formula (II) and amines shown in the formula (A) in an organic solvent, introducing CO2 to perform reaction with a byproduct dimethylamine, and after the reaction is finished, distilling reaction liquid to recycle a dimethylamine complex compound shown in the formula (B) to obtain residual mother liquid; and (2) performing ring-closure reaction on the residual mother liquid and an acid-binding agent 1, and after the reaction is finished, separating reaction products to prepare the carbstyril main-ring compound shown in the formula (I). In the method, a raw material reutilizing method is adopted to recycle and apply mechanically the reaction byproduct dimethylamine with relatively greater influence on the environment, so the reaction can be cyclically performed; and as the gas CO2 is introduced in the amino exchange reaction to make the byproduct dimethylamine form the dimethylamine complex compound which has a relatively lower boiling point and is easy to separate, the reaction is performed in a positive direction and the yield is further improved.
Description
(1) technical field
The present invention relates to the key intermediate of a class antibacterials quinolone, i.e. the synthetic method of main cyclic quinoline compound.
(2) background technology
Quinolone is class chemosynthesis antibacterials, development always rapidly since coming out, owing to it has that has a broad antifungal spectrum, anti-microbial activity are strong, convenient drug administration, untoward reaction are little, do not have the first-selection that advantage such as cross resistance becomes clinical drug combination with other microbiotic, consumption has surpassed cephalosporin analog antibiotic, becomes first antibiotic medication.
Quinolones has become the focus that current people competitively research and develop, had many bibliographical informations synthesizing of main cyclic quinoline compound, but the synthetic method of being reported all exists weak points such as step is long, yield is not high, three wastes generation is bigger.At present; the domestic synthesis technique that generally adopts is to be starting raw material with adjacent halogen aroyl chloride; make alpha-substitution aroyl-β-dimethylamino acrylate through reactions such as aminations; make main cyclic quinoline compound through amine exchange, ring-closure reaction again; with levofloxacin main ring compound is example, and technology is as follows:
The topmost shortcoming of this technology is: 1) amine exchange reaction exists the molecular balance relation, and reaction not exclusively; The processing of the dimethylamine that produces when 2) amine exchanges is extremely difficult, and conventional method is to make dimethylamine become the dimethylamine hydrochloride aqueous solution with hydrochloric acid to separate, but the dimethylamine in this solution almost can not be by the degradation by bacteria in the biochemistry pool; Other method is to remove moisture content to make it become the dimethylamine hydrochloride solid, because purity is not high, does not have further utility value, therefore finally still can become can not be degraded, to the great amine nitrogen pollutant of environmental influence.
The present invention is under this background, further the synthetic method of quinolones key intermediate is studied, and adopts the method for recycle raw material to prepare main cyclic quinoline compound, is a kind of yield height, green synthesis method that three waste discharge is few.
(3) summary of the invention
The technical problem to be solved in the present invention is the dimethylamine that amine exchange in the existing main cyclic quinoline compound preparation produces to be reclaimed recycling prepare main cyclic quinoline compound.
For reaching goal of the invention the technical solution used in the present invention be:
A kind of synthetic method suc as formula the main cyclic quinoline compound shown in (I); said method comprising the steps of: the aminated compounds shown in the alpha-substitution aroyl-β shown in (1) formula (II)-dimethylamino acrylate and the formula (A) carries out amine exchange reaction in organic solvent, and feeds CO
2React with the by product dimethylamine, reaction finishes afterreaction liquid distillation recovery and obtains remaining mother liquor suc as formula the dimethylamine complex compound shown in (B), (2) residue mother liquor and acid binding agent 1 carry out ring-closure reaction, and reaction finishes afterreaction product separating treatment and makes suc as formula the main cyclic quinoline compound shown in (I);
In formula (I), formula (II) or the formula (A): R
1Be H or C
1～C
4Alkyl, be preferably methyl or ethyl; R
2Be H, halogen or nitro, be preferably H, F, Cl or nitro; R
3Be halogen, be preferably F or Cl; R
4Be halogen, nitro, amino, piperazinyl, N methyl piperazine base, 2-methylpiperazine base, 3-methylpiperazine base, 3,5-lupetazin base, 1-substituted cyclopropane alkyl, pyrryl, 3-amino-pyrroles base or methylpyrrole base, be preferably F, Cl, N methyl piperazine base, 2-methylpiperazine base, 3-methylpiperazine base, 3,5-lupetazin base or 1-substituted cyclopropane alkyl; Z is N or C-R
5, R wherein
5Be H, hydroxyl, methyl, methoxyl group, halogen, nitro or cyano group, be preferably H, F, Cl, methyl, methoxyl group, nitro or cyano group; R
6Be C
1～C
4Alkyl, C
3～C
6Cycloalkyl, 2-fluoro ethyl, fluoro cyclopropyl, phenyl or halogenophenyl, described halogenophenyl is the phenyl that F, Cl, Br or I replace, R
6Be preferably ethyl, cyclopropyl, sec.-propyl, 2-fluoro ethyl, fluoro cyclopropyl, 4-fluorophenyl or 2,4 difluorobenzene base;
In the formula (II), X is a halogen, is preferably F or Cl; Described acid binding agent 1 is inorganic base substance or organic basic material;
Described halogen is F, Cl, Br or I.
Described acid binding agent 1 is for being inorganic base substance or organic basic material, be preferably yellow soda ash, salt of wormwood, sodium hydroxide, potassium hydroxide, pyridine, N, N-Dimethylamino pyridine, triethylamine or triethylene diamine, more preferably salt of wormwood, yellow soda ash, sodium hydroxide or potassium hydroxide.
The ratio of the amount of substance of the aminated compounds shown in alpha-substitution aroyl-β of the present invention-dimethylamino acrylate, the formula (A), acid binding agent 1 is 1: 1～4: 1～10, preferred 1: 1～2: 1～2; Described feeding CO
2, the control reaction pressure is 1～8atm.
Organic solvent of the present invention is dimethyl sulfoxide (DMSO) (DMSO), N, dinethylformamide (DMF), benzene,toluene,xylene, N-Methyl pyrrolidone, acetonitrile, propionitrile, tetrahydrofuran (THF) (THF), methylene dichloride, chloroform or tetracol phenixin are preferably toluene, benzene, DMSO or DMF.
The method of reaction product separating treatment of the present invention is one of following: after (A) reaction finishes, reaction product cooling back filtration under diminished pressure is got filter cake and is washed with water, uses the recrystallization solvent recrystallization, obtain described main cyclic quinoline compound, described recrystallization solvent is ethanol or Virahol; (B) after reaction finished, reaction product added water washing again through distillating recovering solvent, filtered, and got filter cake recrystallization solvent recrystallization, obtained described main cyclic quinoline compound, and described recrystallization solvent is ethanol or Virahol.
Comparatively concrete; described method may further comprise the steps: (1) is in organic solvent; aminated compounds shown in alpha-substitution aroyl-β shown in the adding formula (II)-dimethylamino acrylate and the formula (A); controlled temperature carries out amine exchange reaction for-10～80 ℃; the tracking monitor reaction; usually react with the HPLC tracking monitor, and feed CO
2, the control reaction pressure is 1～8atm, and reaction finishes the dimethylamine complex compound shown in the afterreaction liquid distillation recovery type (B), and it is standby to get the residue mother liquor; (2) in another reaction vessel; add acid binding agent 1 with the identical organic solvent of step (1); be warming up to 30～160 ℃; add described residue mother liquor; the insulated and stirred reaction; tracking monitor is to reacting completely; usually with the reaction of HPLC tracking monitor; reaction finishes afterreaction product separating treatment and makes suc as formula the main cyclic quinoline compound shown in (I), and the ratio of the amount of substance of the aminated compounds shown in described alpha-substitution aroyl-β-dimethylamino acrylate, the formula (A), acid binding agent 1 is 1: 1～4: 1～10.
The consumption of organic solvent is counted 3～10mL/g with the quality of alpha-substitution aroyl-β-dimethylamino acrylate in the described step (1); Be preferably 4～8mL/g.
In the described step (1), the reaction times is generally 0.2～2 hour.
In the described step (1), feed CO
2Be in order to react with the by product dimethylamine, to feed CO in reaction beginning back usually
2, perhaps when amine exchange reaction is finished, feed CO
2, feed CO
2The time, the control reaction pressure is 1～8atm.
In institute's step of telling (2), the time of insulated and stirred reaction is generally 1～6 hour.
The new consumption that adds organic solvent is counted 1～6mL/g with the quality of alpha-substitution aroyl-β-dimethylamino acrylate in the described step (2); Be preferably 2～4mL/g.
In the step of the present invention (2), the residue mother liquor that step (1) obtains can further distill removes organic solvent, adds organic solvent A then, proceeds reaction, and this step can be changed the solvent in the reaction, is all known method of those skilled in the art.
Comparatively concrete; described method may further comprise the steps: (1) is in organic solvent; aminated compounds shown in alpha-substitution aroyl-β shown in the adding formula (II)-dimethylamino acrylate and the formula (A); controlled temperature carries out amine exchange reaction for-10～80 ℃; the tracking monitor reaction, and feed CO
2, the control reaction pressure is 1～8atm, and reaction finishes the dimethylamine complex compound shown in the afterreaction liquid distillation recovery type (B), and it is standby to get the residue mother liquor; (2) get the described residue mother liquor of step (1); continue distillation and remove organic solvent; under 30～160 ℃ of temperature; add in acid binding agent 1 and the organic solvent A; the insulated and stirred reaction; tracking monitor is to reacting completely; reaction finishes afterreaction product separating treatment and makes suc as formula the main cyclic quinoline compound shown in (I); described alpha-substitution aroyl-β-dimethylamino acrylate; aminated compounds shown in the formula (A); the ratio of the amount of substance of acid binding agent 1 is 1: 1～4: 1～10; described organic solvent A is for being different from one of following solvent of the described organic solvent of step (1): dimethyl sulfoxide (DMSO); N, dinethylformamide; benzene; toluene; dimethylbenzene; N-Methyl pyrrolidone; acetonitrile; propionitrile; tetrahydrofuran (THF); methylene dichloride; chloroform or tetracol phenixin.
The new consumption of organic solvent A that adds is for to count 4～16mL/g with the quality of alpha-substitution aroyl-β-dimethylamino acrylate in the described step (2); Be preferably 6～12mL/g.。
Further, described suc as formula the alpha-substitution aroyl-β shown in (II)-dimethylamino acrylate by the N shown in the formula (III), adjacent halogen aroyl chloride shown in N-dimethylamino acrylate and the formula (IV) carries out acylation reaction and makes in organic solvent B in the presence of acid binding agent 2;
In the formula (III), R
1Be H or C
1～C
4Alkyl;
In the formula (IV), R
2Be H, halogen or nitro; R
3Be halogen; R
4Be halogen, nitro, amino, piperazinyl, N methyl piperazine base, 2-methylpiperazine base, 3-methylpiperazine base, 3,5-lupetazin base, 1-substituted cyclopropane alkyl, pyrryl, 3-amino-pyrroles base or methylpyrrole base; Z is N or C-R
5, R wherein
5Be H, hydroxyl, methyl, methoxyl group, halogen, nitro or cyano group; X is a halogen; Described halogen is F, Cl, Br or I.
Described organic solvent B is following any one or two or more mixing with arbitrary proportion: toluene, benzene, dimethylbenzene, normal heptane, hexanaphthene, pentane, methylene dichloride, ether, isopropyl ether, ethyl acetate, butylacetate, tetrahydrofuran (THF), acetone, butanone, N-Methyl pyrrolidone, N, dinethylformamide, dimethyl sulfoxide (DMSO), methyl alcohol, ethanol, Virahol, hexalin or butyleneglycol.
Described acid binding agent 2 is inorganic base substance or organic basic material, is preferably triethylamine, Tributylamine, salt of wormwood, yellow soda ash, pyridine, N, N-Dimethylamino pyridine or triethylene diamine, and more preferably triethylamine, Tributylamine or pyridine most preferably are Tributylamine.
N shown in adjacent halogen aroyl chloride shown in the described formula (IV) and the formula (III), the ratio of the amount of substance of N-dimethylamino acrylate, acid binding agent 2 is 1: 1～4: 1～6.
Comparatively concrete, described preparing by the following method: in organic solvent B suc as formula the alpha-substitution aroyl-β shown in (II)-dimethylamino acrylate, N shown in the adding formula (III), N-dimethylamino acrylate, adjacent halogen aroyl chloride and acid binding agent 2 shown in the formula (IV), temperature of reaction is 10～100 ℃ (preferred 20～60 ℃), stirring reaction 0.1～5 hour (preferred 2～3 hours), reaction finishes the reaction solution washing, get organic layer, steam and remove the mixed solution that residual moisture obtains containing the alpha-substitution aroyl-β shown in the formula (II)-dimethylamino acrylate, described adjacent halogen aroyl chloride, N, N-dimethylamino acrylate is 1: 1～4: 1～6 (preferred 1: 1～2: 1～2) with the ratio of the amount of substance of acid binding agent 2; The volumetric usage of described organic solvent B is counted 5～15mL/g with the quality of adjacent halogen aroyl chloride.
Further, the N shown in the described formula (III), N-dimethylamino acrylate are fully reacted in organic solvent B by the dimethylamine complex compound shown in malonaldehydic acid ester alkali metal salt shown in the formula (C) and the formula (B) and make;
In the formula (C), M is a basic metal, is preferably sodium and potassium, R
1Be H or C
1～C
4Alkyl.
Comparatively concrete, N shown in the described formula (III), N-dimethylamino acrylate prepares by the following method: in organic solvent B, adding is suc as formula the dimethylamine complex compound shown in malonaldehydic acid ester alkali metal salt shown in (C) and the formula (B), controlled temperature is-30～40 ℃ (preferred-10～20 ℃), stirring reaction 0.1～3 hour (preferred 0.5～1 hour), reaction finishes the reaction solution washing, getting the organic layer distillation makes suc as formula the N shown in (III), N-dimethylamino acrylate, the N that contains in described malonaldehydic acid ester alkali metal salt and the dimethylamine complex compound, the ratio of the amount of substance of N-dimethylamino are 1: 1～6 (be preferably 1: 1～4); The volumetric usage of described organic solvent B is counted 6～20mL/g with the quality of malonaldehydic acid ester alkali metal salt.
Further, the synthetic method step that the present invention recommended is as follows:
(a) in organic solvent B, adding is suc as formula the dimethylamine complex compound shown in malonaldehydic acid ester alkali metal salt shown in (C) and the formula (B), controlled temperature is-30～40 ℃ (preferred-10～20 ℃), stirring reaction 0.1～3 hour (preferred 0.5～1 hour), reaction finishes the reaction solution washing, getting the organic layer distillation makes suc as formula the N shown in (III), N-dimethylamino acrylate, the N that contains in described malonaldehydic acid ester alkali metal salt and the dimethylamine complex compound, the ratio of the amount of substance of N-dimethylamino are 1: 1～6 (preferred 1: 1～4); Described organic solvent B is one of following: dimethyl sulfoxide (DMSO), N, dinethylformamide, benzene,toluene,xylene, N-Methyl pyrrolidone, tetrahydrofuran (THF), methylene dichloride, the volumetric usage of organic solvent B is counted 6～20mL/g with the quality of malonaldehydic acid ester alkali metal salt described in the step (a);
(b) in organic solvent B, add the N that step (a) makes, N-dimethylamino acrylate, adjacent halogen aroyl chloride and acid binding agent 2 shown in the formula (IV), temperature of reaction is 10～100 ℃ (preferred 20～60 ℃), stirring reaction 0.1～5 hour (preferred 2～3 hours), reaction finishes the reaction solution washing, get organic layer, steam and remove the mixed solution that residual moisture obtains containing the alpha-substitution aroyl-β shown in the formula (II)-dimethylamino acrylate, described adjacent halogen aroyl chloride, N, N-dimethylamino acrylate is 1: 1～4: 1～6 (preferred 1: 1～2: 1～2) with the ratio of the amount of substance of acid binding agent 2; The volumetric usage of organic solvent B is counted 5～15mL/g with the quality of adjacent halogen aroyl chloride described in the step (b);
(c) get the mixed solution that contains the alpha-substitution aroyl-β shown in the formula (II)-dimethylamino acrylate that step (b) makes; controlled temperature is-10～80 ℃; aminated compounds shown in the adding formula (A) carries out amine exchange reaction, the tracking monitor reaction, and feed CO
2, the control reaction pressure is 1～8atm, and reaction finishes the dimethylamine complex compound shown in the reaction solution distillation recovery type (B), and it is standby to get the residue mother liquor; In another reaction vessel; add acid binding agent 1 with the identical organic solvent of organic solvent B of step (b); the new consumption that adds organic solvent is counted 1～6mL/g with the quality of alpha-substitution aroyl-β-dimethylamino acrylate; be warming up to 30～160 ℃ (preferred 90～120 ℃); add described residue mother liquor; the insulated and stirred reaction; tracking monitor is to reacting completely; reaction finishes afterreaction product separating treatment and makes suc as formula the main cyclic quinoline compound shown in (I) described alpha-substitution aroyl-β-dimethylamino acrylate; aminated compounds shown in the formula (A); the ratio of the amount of substance of acid binding agent 1 is 1: 1～4: 1～10 (preferred 1: 1～2: 1～2).
In the described step (c), the amount of substance of alpha-substitution aroyl-β-dimethylamino acrylate calculates with the amount of substance of adjacent halogen aroyl chloride.
Of the present inventionly can make as follows: dimethylamine and CO suc as formula the dimethylamine complex compound shown in (B)
2Gas is in airtight reaction flask, and in solvent-free existence or organic solvent B, pressure is that (preferred 1～5atm), under the condition of temperature of reaction-20～80 ℃ (preferred 0～20 ℃), fully reaction makes described CO to 1～10atm
2With the ratio of the amount of substance of dimethylamine be 1: 1.2～2.5.
Of the present inventionly can prepare as follows: in reactor suc as formula the malonaldehydic acid ester alkali metal salt shown in (C), alkali metal ethoxide and organic solvent B shown in ethyl formate shown in acetic ester shown in the adding formula (D), the formula (E), the formula (F), under the airtight stirring, controlled temperature is 0～180 ℃ (being preferably 50～90 ℃), pressure rises to 2～80atm and (is preferably 6～25atm), reacted 4～10 hours, make the mixed solution that contains suc as formula the malonaldehydic acid ester alkali metal salt shown in (C), be cooled to-10～40 ℃ standby; The ratio of the amount of substance of described acetic ester, ethyl formate, alkali metal ethoxide is 1: 1～4: 1～1.6;
Described containing suc as formula the mixed solution of the malonaldehydic acid ester alkali metal salt shown in (C) can isolate suc as formula the pure product of malonaldehydic acid ester alkali metal salt shown in (C), be used for the N shown in the further preparation formula (III), N-dimethylamino acrylate, also can react with the dimethylamine complex compound shown in the formula (B) directly to contain mixed solution suc as formula the malonaldehydic acid ester alkali metal salt shown in (C).Common those skilled in the art are synthesis step for simplicity, be directly to carry out next step reaction with the mixed solution that contains suc as formula the malonaldehydic acid ester alkali metal salt shown in (C), the amount of substance of malonaldehydic acid ester alkali metal salt wherein then calculates with the amount of substance of the acetic ester shown in the formula (D).
The possible principle of the synthetic method of main cyclic quinoline compound of the present invention is as follows:
To be example suc as formula the Gatifloxacin main ring compound shown in (VI), concrete described method is as follows:
(1) the dimethylamine complex compound is dissolved in the toluene solvant, controlled temperature is-10～20 ℃, the mixed solution that adds malonaldehydic acid ethyl ester sodium salt and toluene again, stirring reaction 0.5～1 hour is after reaction finishes, reaction solution is through washing, get the organic layer distillation, make N, N-dimethylamino ethyl propenoate, the N that contains in described malonaldehydic acid ester alkali metal salt and the dimethylamine complex compound, the ratio of the amount of substance of N-dimethylamino is 1: 1～4;
(2) with N, N-dimethylamino ethyl propenoate and Tributylamine are added in the toluene solvant, controlled temperature is 20～60 ℃, stir, with 2,4,5-three fluoro-3-methoxy benzoyl chlorides add in the reaction solution again, stirring reaction 2～3 hours, reaction finishes reaction solution through washing, gets organic layer, steams except that residual moisture makes to contain α-(2,4,5-three fluoro-3-methoxyl groups) toluene mixture liquid of benzoyl-β-dimethylamino ethyl propenoate, described 2,4,5-three fluoro-3-methoxy benzoyl chloride and N, N-dimethylamino ethyl propenoate, the amount of substance of Tributylamine is 1: 1～2: 1～2;
(3) toluene mixture liquid that contains α-(2,4,5-three fluoro-3-methoxyl groups) benzoyl-β-dimethylamino ethyl propenoate that above-mentioned steps (2) makes; controlled temperature is 0～25 ℃, adds cyclopropylamine, carries out amine exchange reaction; the tracking monitor reaction feeds CO in the reaction process
2Gas, the control reaction pressure is 1～8atm, reaction finishes the back distillation and reclaims N, the N dimethylamine complex compound, it is standby to get the residue mother liquor.In another reaction flask, add K
2CO
3And toluene, be heated to 90～120 ℃, described residue mother liquor is added in the reaction solution; the insulated and stirred reaction, tracking monitor is to reacting completely filtration under diminished pressure behind the reaction end postcooling; the filter cake washing; add ethyl alcohol recrystallization, get Gatifloxacin main ring compound, described α-(2; 4; 5-three fluoro-3-methoxyl groups) benzoyl-β-dimethylamino ethyl propenoate (with 2,4, the amount of substance meter of 5-three fluoro-3-methoxy benzoyl chlorides), cyclopropylamine, K
2CO
3The ratio of amount of substance is 1: 1～2: 1～2.
The present invention also provides a kind of synthetic method of the main cyclic quinoline compound shown in formula V; described method is: the aminated compounds shown in the alpha-substitution aroyl-β shown in the formula (II)-dimethylamino acrylate and the formula (D) carries out amine exchange reaction in organic solvent C, and feeds CO
2React with the by product dimethylamine, reaction finishes the distillation of afterreaction liquid and reclaims suc as formula the dimethylamine complex compound shown in (B), add acid binding agent 3 in the residue mother liquor and carry out ring-closure reaction, reaction end afterreaction product separating treatment makes the main cyclic quinoline compound shown in formula V;
In formula (II), formula (D) or the formula V, R
1Be H or C
1～C
4Alkyl; R
2Be H, halogen or nitro; R
3Be halogen; R
4Be halogen, nitro, amino, piperazinyl, N methyl piperazine base, 2-methylpiperazine base, 3-methylpiperazine base, 3,5-lupetazin base, 1-substituted cyclopropane alkyl, pyrryl, 3-amino-pyrroles base or methylpyrrole base; Z is C-R
5, R wherein
5Be H, hydroxyl, methyl, methoxyl group, halogen, nitro or cyano group;
In formula V or the formula (D), R
7For-CH
2-,-CH
2CH
2-,-CH
2CH (CH
3)-or-CH (CH
3) CH
2-; Y is O, S or SO
2
Described organic solvent C is: dimethyl sulfoxide (DMSO), N, dinethylformamide, benzene,toluene,xylene, N-Methyl pyrrolidone, acetonitrile, propionitrile, tetrahydrofuran (THF), methylene dichloride, chloroform or tetracol phenixin;
Described acid binding agent 3 is yellow soda ash, salt of wormwood, sodium hydroxide, potassium hydroxide, pyridine, N, N-Dimethylamino pyridine, triethylamine or triethylene diamine.
Main cyclic quinoline compound of the present invention promptly makes the quinolone bulk drug through the piperazine reaction of contracting again through being hydrolyzed into quinolone carboxylic acid.
The said acid binding agent 1 of the present invention, acid binding agent 2, acid binding agent 3 all be meant and be used for the alkaline matter of the acid that generates in the absorption reaction system on the ordinary meaning, just is used for distinguishing the acid binding agent that is in the differential responses step with 1,2,3, and they can be identical or different.
The beneficial effect of the synthetic method of main cyclic quinoline compound of the present invention is mainly reflected in: 1) adopt the method for recycle raw material, recovery set makes this reaction to circulate and carries out repeatedly with the byproduct of reaction dimethylamine that has greater environmental impacts; 2) feed gas CO during amine exchange reaction
2Make the by product dimethylamine form lower, the segregative dimethylamine complex compound of boiling point, promote reaction forward to carry out, yield is further improved, solved the common problem that forms unmanageable amine nitrogenous wastes in the present domestic production technique that generally adopts by dimethylamine simultaneously; 3) acid binding agent 2 preferred Tributylamines form the Tributylamine hydrochloride in reaction, easily thoroughly separate with organic layer during washing, just can obtain highly purified Tributylamine after adding alkaline purification, can directly apply mechanically.
(4) embodiment
The present invention is described further below in conjunction with specific embodiment, but protection scope of the present invention is not limited in this:
The preparation of dimethylamine complex compound: with dimethylamine and CO
2Gas feeds in the airtight reaction flask simultaneously, and pressure is 1～2atm, exothermic heat of reaction, and with the ice-water bath cooling, controlled temperature is 0～20 ℃, when feeding 30g CO
2During with the 56g dimethylamine, just make 86g[Me
2NH
2]
+[Me
2N-CO
2]
-Liquid complex compound.
Embodiment 1:
The preparation of formyl radical ethyl acetate sodium salt: in the reactor of agitator is housed; add 22g ethyl acetate, 38g ethyl formate successively; 200mL toluene and 17g sodium ethylate; stir down and slowly be warming up to 70 ℃; pressure rises to 8atm simultaneously, and afterreaction finished in 6 hours, made the mixed solution that contains formyl radical ethyl acetate sodium salt; be cooled to 0 ℃ standby, wherein the amount of substance of malonaldehydic acid ethyl ester sodium salt is counted 0.23mol.
In reaction flask, add 15.4g dimethylamine complex compound and 150mL toluene; cryosel is bathed and is cooled to 0～5 ℃; be added dropwise to the above-mentioned mixed solution that contains formyl radical ethyl acetate sodium salt again; stirring reaction 40 minutes stops, and reaction solution is got the organic layer distillation after washing; get 118～121 ℃ of (7.5mmHg) cut 30.0g; be N, N-dimethylamino ethyl propenoate, yield 91.2%.
With above-mentioned N; N-dimethylamino ethyl propenoate and 40.0g Tributylamine are added in the 200mL toluene; stir; controlled temperature is 40 ℃; with 44.9g 2,4, the mixed solution of 5-three fluoro-3-methoxy benzoyl chlorides and 200mL toluene is added dropwise in the reaction solution again; stirring reaction 1 hour; stopped reaction, reaction solution are got organic layer and are steamed except that residual moisture through washing; make and contain α-(2; 4,5-three fluoro-3-methoxyl groups) toluene mixture liquid of benzoyl-β-dimethylamino ethyl propenoate is transferred to another reaction flask; drip the 11.5g cyclopropylamine under the control room temperature, feed CO
2Gas, the control reaction pressure is 2atm, and HPLC follows the tracks of, and reacts after 1 hour, and N is reclaimed in distillation, the N dimethylamine complex compound, the N that must reclaim, N dimethylamine complex compound 14.8g, the residue mother liquor is standby.
In another reaction flask, add 28.0g K
2CO
3With 150mL toluene, be heated to 110～115 ℃, above-mentioned residue mother liquor is added drop-wise in the reaction solution, the insulated and stirred reaction, HPLC tracks to and reacts completely, cooling back filtration under diminished pressure, water thorough washing filter cake, add 180mL Virahol recrystallization again, vacuum-drying makes 55.0g Gatifloxacin main ring compound, i.e. 1-cyclopropyl-6,7-two fluoro-8-methoxyl group-1,4-dihydro generation-4-oxo-quinolyl-3-carboxylic acid, ethyl ester.With 2,4,5-three fluoro-3-methoxy benzoyl chlorides are starting raw material, and overall yield of reaction is 85.1%.
1HNMR (CDCl
3) δ: 1.07 (2H, m, CH
2), 1.23 (2H, m, CH
2), 1.41 (3H, t, J=6.9Hz ,-OCH
2CH
3), 3.73 (3H, s ,-OCH
3), 4.00 (1H, m, cyclopropyl tertiary carbon H), 4.39 (2H, q, J=6.9Hz ,-OCH
2CH
3), 8.03 (1H, m, ArH), 8.61 (1H, s, CH=C).
Embodiment 2:
The preparation of formyl radical ethyl acetate sodium salt: in the reactor of agitator is housed; add 22g ethyl acetate, 38g ethyl formate successively; 200mL toluene and 17g sodium ethylate; stir down and slowly be warming up to 70 ℃; pressure rises to 8atm simultaneously, and afterreaction finished in 6 hours, made the mixed solution that contains formyl radical ethyl acetate sodium salt; be cooled to 0 ℃ standby, wherein the amount of substance of malonaldehydic acid ethyl ester sodium salt is counted 0.23mol.
In reaction flask, add 15.4g dimethylamine complex compound and 150mL toluene; cryosel is bathed and is cooled to 0～5 ℃; be added dropwise to the above-mentioned mixed solution that contains formyl radical ethyl acetate sodium salt again; stirring reaction 40 minutes stops, and reaction solution is got the organic layer distillation after washing; get 118～121 ℃ of (7.5mmHg) cut 30.0g; be N, N-dimethylamino ethyl propenoate, yield 91.2%.
With 30g N; N-dimethylamino ethyl propenoate and 40g Tributylamine are added in the 200mL toluene; stir; controlled temperature is 45 ℃; mixed solution with 42.5g phenyl tetrafluoride formyl chloride and 200mL toluene is added dropwise in the reaction solution again; stirring reaction 40 minutes; stopped reaction; reaction solution is through washing; get organic layer and steam, make the toluene mixture liquid that contains α-tetra fluoro benzene formyl radical-β-dimethylamino ethyl propenoate, be transferred to another reaction flask except that residual moisture; drip 15.2g L-aminopropanol under the control room temperature, feed CO
2Gas, the control reaction pressure is 2atm, HPLC follows the tracks of, and reacts after 1 hour, and distill and reclaim N, the N dimethylamine complex compound, the N that must reclaim, N dimethylamine complex compound 15.0g, after the continuation of residue mother liquor was steamed and desolventized toluene, adding 300mL DMSO was standby.
In another reaction flask, add 30g K
2CO
3And 200mLDMSO, be heated to 110～115 ℃, above-mentioned standby mother liquor is added drop-wise in the reaction solution, insulated and stirred is carried out ring-closure reaction, and HPLC tracks to and reacts completely, and reaction solution is through distillating recovering solvent, add water thorough washing, filtration again, get filter cake and add 170mL ethyl alcohol recrystallization, vacuum-drying, make 51.5g levofloxacin main ring compound, i.e. (S)-(-)-9,10-two fluoro-2,3-dihydro-3-methyl-7-oxo-7-pyridinium hydroxide also [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid, ethyl ester.With the phenyl tetrafluoride formyl chloride is starting raw material, and overall yield of reaction is 83.3%.
1HNMR(CDCl
3)δ：1.42(3H，t，J＝7Hz，CH
3)，1.61(3H，d，J＝7Hz，CH
3)，4.37(2H，q，OCH
2CH
3)，4.44～4.48(3H，m，OCH
2CHCH
3)，7.79(1H，dd，ArH)，8.39(1H，s，CH＝C)。
Embodiment 3:
With one of raw material 2,4,5-three fluoro-3-methoxy benzoyl chlorides change 45.5g 2 into, 4-two chloro-5-fluorobenzoyl chlorides, other conditions make 52.6g Ciprofloxacin main ring compound with embodiment 1, i.e. 1-cyclopropyl-6-fluoro-7-chloro-1,4-dihydro generation-4-oxo-quinolyl-3-carboxylic acid, ethyl ester, yield is 85.0%.
1MR(CDCl
3)δ：1.2～1.6(4H，m，CH
2)，1.43(3H，m，-OCH
2CH
3)，3.53(1H，m)，4.46(2H，m，-OCH
2CH
3)，8.07(1H，d，ArH)，8.15(1H，d，ArH)，8.54(1H，s，CH＝C)。
Embodiment 4:
With one of raw material 2,4,5-three fluoro-3-methoxy benzoyl chlorides change the 42.5g phenyl tetrafluoride formyl chloride into, other conditions make main cyclic quinoline compound 1-cyclopropyl-6,7 with embodiment 1,8-three fluoro-1,4-dihydro generation-4-oxo-quinolyl-3-carboxylic acid, ethyl ester 53.2g, yield is 85.5%.
1MR (CDCl
3) δ: 1.07 (2H, m, CH
2), 1.23 (2H, m, CH
2), 1.41 (3H, t, J=6.9Hz ,-OCH
2CH
3), 4.00 (1H, m, cyclopropyl tertiary carbon H), 4.39 (2H, q, J=6.9Hz ,-OCH
2CH
3), 8.03 (1H, m, ArH), 8.61 (1H, s, CH=C).
Embodiment 5:
The preparation of formyl radical ethyl acetate sodium salt: in the reactor of agitator is housed; add 14.3g ethyl acetate, 25g ethyl formate successively; 150mL toluene and 14g sodium ethylate; stir down and slowly be warming up to 70 ℃; pressure rises to 8atm simultaneously, and afterreaction finished in 6 hours, made the mixed solution that contains formyl radical ethyl acetate sodium salt; be cooled to 0 ℃ standby, wherein the amount of substance of malonaldehydic acid ethyl ester sodium salt is counted 0.15mol.
Get the N that reclaims among the 10g embodiment 1; the N dimethylamine complex compound adds 80mL toluene, and cryosel is bathed and is cooled to 0～5 ℃; be added dropwise to the above-mentioned mixed solution that contains formyl radical ethyl acetate sodium salt again; stirring reaction 40 minutes stops, and reaction solution is got the organic layer distillation after washing; get 118～121 ℃ of (7.5mmHg) cut 19.2g; be N, N-dimethylamino ethyl propenoate, yield 90.2%.
The preparation of formyl radical ethyl acetate sodium salt: in the reactor of agitator is housed; add 21g ethyl acetate, 37g ethyl formate successively; 200mL toluene and 17g sodium ethylate; stir down and slowly be warming up to 70 ℃; pressure rises to 8atm simultaneously, and afterreaction finished in 6 hours, made the mixed solution that contains formyl radical ethyl acetate sodium salt; be cooled to 0 ℃ standby, wherein the amount of substance of malonaldehydic acid ethyl ester sodium salt is counted 0.22mol.
Get the N that reclaims among the 15g embodiment 2; the N dimethylamine complex compound adds 100mL toluene, and cryosel is bathed and is cooled to 0～5 ℃; be added dropwise to the above-mentioned mixed solution that contains formyl radical ethyl acetate sodium salt again; stirring reaction 40 minutes stops, and reaction solution is got the organic layer distillation after washing; get 118～121 ℃ of (7.5mmHg) cut 28.1g; be N, N-dimethylamino ethyl propenoate, yield 91.0%.
Embodiment 6:
N with 30g embodiment 5 preparations; N-dimethylamino ethyl propenoate and 40g Tributylamine are added in the 200mL toluene; stir; controlled temperature is 40 ℃; mixed solution with 42.5g phenyl tetrafluoride formyl chloride and 150mL toluene is added dropwise in the reaction solution again; about 40 minutes of stirring reaction; stopped reaction; reaction solution adds water washing 3 times, and separatory is got organic layer and steamed except that residual moisture; obtain containing the toluene mixture liquid of α-tetra fluoro benzene formyl radical-β-dimethylamino ethyl propenoate; be transferred to another reaction flask, drip 15.2g L-aminopropanol under the control room temperature, feed CO
2Gas, the control reaction pressure is 2atm, and HPLC follows the tracks of, and reacts after 1 hour, and N is reclaimed in distillation, and N dimethylamine complex compound, residue mother liquor are after steaming desolventizes toluene, and adding 300mL DMSO is standby.
In another reaction flask, add 30g K
2CO
3With 200mL DMSO, be heated to 110～115 ℃, above-mentioned standby mother liquor is added drop-wise in the reaction solution, the insulated and stirred reaction is to reacting completely, and reaction solution adds water thorough washing, filtration again through distillating recovering solvent, add the 170mL ethyl alcohol recrystallization again, vacuum-drying makes 51.0g levofloxacin main ring compound, and yield is 82.6%.
Embodiment 7:
Under the control room temperature, drip the 15.2g aminopropanol in the α that makes by embodiment 2 methods-tetra fluoro benzene formyl radical-β-dimethylamino ethyl propenoate toluene mixture liquid, stirring reaction began to feed CO after 1 hour
2Gas, HPLC track to and react completely, and N is reclaimed in distillation, and N dimethylamine complex compound, residue mother liquor are after steaming desolventizes toluene, and adding 300mL DMSO is standby.
In another reaction flask, add 30g K
2CO
3With 200mL DMSO, be heated to 110～115 ℃, above-mentioned standby mother liquor is added drop-wise in the reaction solution, the insulated and stirred reaction is to reacting completely, and reaction solution adds water thorough washing, filtration again through distillating recovering solvent, add the 170mL ethyl alcohol recrystallization again, vacuum-drying makes 51.4g Ofloxacine USP 23 main ring compound, and yield is 83.2%.
Embodiment 8:
With 30g K among the embodiment 2
2CO
3Change 25g Na into
2CO
3, other conditions make 50.4g levofloxacin main ring compound with embodiment 2, and yield is 81.5%.
Embodiment 9-12:
Change the solvent DMSO of ring-closure reaction among the embodiment 2 into following solvent, ring-closure reaction temperature such as following table, other operations and condition are with embodiment 2, and reaction result sees the following form:
Embodiment 13:
Change 110～115 ℃ of ring-closure reaction temperature among the embodiment 2 into 85～90 ℃, other conditions make 50.6g levofloxacin main ring compound with embodiment 2, and yield is 81.9%.
Embodiment 14:
To feed CO among the embodiment 1
2During gas, reaction pressure is controlled to be 8atm, and other conditions are with embodiment 1, and yield is 85.0%.
Embodiment 15:
Change acid binding agent 40g Tributylamine among the embodiment 2 into the 22g triethylamine, other conditions are with embodiment 2, and yield is 82.0%.
Embodiment 16:
Change the reaction solvent toluene except that the cyclization reaction among the embodiment 2 into isopropyl ether, other operations and condition are with embodiment 2, and reaction yield is 82.6%.
Embodiment 17:
With N; the input amount of N-dimethylamino ethyl propenoate changes 42.9g into; N; the preparation method of N-dimethylamino ethyl propenoate is as follows: the preparation of formyl radical ethyl acetate sodium salt: in the reactor of agitator is housed; add 30.8g ethyl acetate, 25g ethyl formate successively; 250mL toluene and 22.5g sodium ethylate; stir down and slowly be warming up to 70 ℃; pressure rises to 8atm simultaneously; afterreaction finished in 6 hours; make the mixed solution that contains formyl radical ethyl acetate sodium salt, be cooled to 0 ℃ standby, wherein the amount of substance of malonaldehydic acid ethyl ester sodium salt is counted 0.33mol.
In reaction flask, add 22g dimethylamine complex compound and 200mL toluene; cryosel is bathed and is cooled to 0～5 ℃; be added dropwise to the above-mentioned mixed solution that contains formyl radical ethyl acetate sodium salt again; stirring reaction 40 minutes stops, and reaction solution is got the organic layer distillation after washing; get 118～121 ℃ of (7.5mmHg) cut 42.9g; be N, N-dimethylamino ethyl propenoate, yield 91.2%.
With 42.9g N, N-dimethylamino ethyl propenoate is proceeded reaction according to embodiment 2, and wherein the input amount of Tributylamine changes 74.0g into, and other conditions make levofloxacin main ring compound with embodiment 2, and yield is 83.5%.
Embodiment 18:
Preparation method according to embodiment 1 prepares 30.0g N, N-dimethylamino ethyl propenoate.
With 30g N; N-dimethylamino ethyl propenoate and 40g Tributylamine are added in the 200mL toluene; stir; controlled temperature is 45 ℃; mixed solution with 42.5g phenyl tetrafluoride formyl chloride and 200mL toluene is added dropwise in the reaction solution again; stirring reaction 40 minutes; stopped reaction; reaction solution is through washing; get organic layer and steam, make the toluene mixture liquid that contains α-tetra fluoro benzene formyl radical-β-dimethylamino ethyl propenoate, be transferred to another reaction flask except that residual moisture; drip 15.6g 2-aminoothyl mercaptan under the control room temperature, feed CO
2Gas, the control reaction pressure is 2atm, HPLC follows the tracks of, and reacts after 1 hour, and distill and reclaim N, the N dimethylamine complex compound, after the continuation of residue mother liquor was steamed and desolventized toluene, 300mLTHF was standby in adding.
In another reaction flask, add 30g K
2CO
3And 200mLTHF, be heated to 60～65 ℃, above-mentioned standby mother liquor is added drop-wise in the reaction solution, insulated and stirred is carried out ring-closure reaction, and HPLC tracks to and reacts completely, cooling back filtration under diminished pressure, water thorough washing filter cake adds the 170mL ethyl alcohol recrystallization, vacuum-drying again, make 50.4g rufloxacin main ring compound, promptly 9,10-two fluoro-2,3-dihydro-7-oxo-7-pyridinium hydroxide also [1,2,3-de] [1,4] benzothiazine-6-carboxylic acid, ethyl ester.With the phenyl tetrafluoride formyl chloride is starting raw material, and overall yield of reaction is 81.0%.
1HNMR(CDCl
3)δ：1.36(3H，t，J＝7Hz，CH
3)，4.19(2H，q，OCH
2CH
3)，3.42(2H，t，S
CH 2 CH
2)，3.82(2H，t，S
CH 2 CH 2 )，7.76(1H，dd，ArH)，8.36(1H，s，CH＝C)。
Embodiment 19:
The preparation of levofloxacin carboxylic acid:
In reaction flask, add the levofloxacin main ring compound that 65g water, 270g acetic acid, 9g sulfuric acid and 50g embodiment 2 make successively, under the mechanical stirring, be warming up to 102～104 ℃ and react, the vinyl acetic monomer that constantly fractionates out generation in the reaction process is to keep temperature of reaction.HPLC tracks to the raw material afterreaction that disappears substantially to be finished.Be cooled to 25 ℃, left standstill 1～2 hour.Decompress filter, filter cake are washed to filtrate neutrality again, drain back 75 ℃ of oven dry, make levofloxacin carboxylic acid 44g, yield 96.8%.
The preparation of levofloxacin:
In reaction flask, add 14.1g (0.05mol) levofloxacin carboxylic acid, 13mL N methyl piperazine, 37.5mL DMSO successively, be heated to 130 ℃ of reaction 6h, DMSO and excessive N-methylpiperazine are reclaimed in underpressure distillation, thick product ethyl alcohol recrystallization, make levofloxacin 15.7g, yield: 86.7%.
1HNMR (DMSO-d6) δ: 15.21 (1H, br s ,-COOH), 8.92 (1H, s, 5-H), 7.47 (1H, d, 8-H), 4.92 (1H, d, 3-H), 4.60 (1H, d, 2 β H), (4.33 1H, d, 2 α H), 3.24～3.38 (4H, m, 1,1 ' piperazine ring proton), 2.39 (4H, br, s, 2,2 ' piperazine ring proton), 2.16 (3H, s, N-CH
3), 1.53 (3H, d, 3-CH
3).
Claims (13)
1. synthetic method suc as formula the main cyclic quinoline compound shown in (I); it is characterized in that said method comprising the steps of: the aminated compounds shown in the alpha-substitution aroyl-β shown in (1) formula (II)-dimethylamino acrylate and the formula (A) carries out amine exchange reaction in organic solvent, and feeds CO
2React with the by product dimethylamine, reaction finishes afterreaction liquid distillation recovery and obtains remaining mother liquor suc as formula the dimethylamine complex compound shown in (B), (2) residue mother liquor and acid binding agent 1 carry out ring-closure reaction, and reaction finishes afterreaction product separating treatment and makes suc as formula the main cyclic quinoline compound shown in (I);
In formula (I) or the formula (II): R
1Be H or C
1～C
4Alkyl; R
2Be H, halogen or nitro; R
3Be halogen; R
4Be halogen, nitro, amino, piperazinyl, N methyl piperazine base, 2-methylpiperazine base, 3-methylpiperazine base, 3,5-lupetazin base, 1-substituted cyclopropane alkyl, pyrryl, 3-amino-pyrroles base or methylpyrrole base; Z is N or C-R
5, R wherein
5Be H, hydroxyl, methyl, methoxyl group, halogen, nitro or cyano group; R in formula (I) or the formula (A)
6Be C
1～C
4Alkyl, C
3～C
6Cycloalkyl, 2-fluoro ethyl, fluoro cyclopropyl, phenyl or halogenophenyl, described halogenophenyl is the phenyl that F, Cl, Br or I replace;
In the formula (II), X is a halogen; Described acid binding agent 1 is inorganic base substance or organic basic material;
Described halogen is F, Cl, Br or I.
2. the method for claim 1 is characterized in that described R
1Be methyl or ethyl; R
2Be H, F, Cl or nitro; R
3Be F or Cl; R
4Be F or Cl, N methyl piperazine base, 2-methylpiperazine base, 3-methylpiperazine base, 3,5-lupetazin base or 1-substituted cyclopropane alkyl; Z is N or C-R
5, R
5Be H, F, Cl, methyl, methoxyl group, nitro or cyano group; R
6Be ethyl, cyclopropyl, sec.-propyl, 2-fluoro ethyl, fluoro cyclopropyl, 4-fluorophenyl or 2,4 difluorobenzene base.
3. the method for claim 1 is characterized in that described acid binding agent 1 is yellow soda ash, salt of wormwood, sodium hydroxide, potassium hydroxide, pyridine, N, N-Dimethylamino pyridine, triethylamine or triethylene diamine.
4. the method for claim 1 is characterized in that the ratio of the amount of substance of the aminated compounds shown in described alpha-substitution aroyl-β-dimethylamino acrylate, the formula (A), acid binding agent 1 is 1: 1～4: 1～10; Described feeding CO
2, the control reaction pressure is 1～8atm.
5. the method for claim 1, it is characterized in that described organic solvent is dimethyl sulfoxide (DMSO), N, dinethylformamide, benzene,toluene,xylene, N-Methyl pyrrolidone, acetonitrile, propionitrile, tetrahydrofuran (THF), methylene dichloride, chloroform or tetracol phenixin.
6. the method for claim 1; it is characterized in that described method is: (1) is in organic solvent; aminated compounds shown in alpha-substitution aroyl-β shown in the adding formula (II)-dimethylamino acrylate and the formula (A); controlled temperature carries out amine exchange reaction for-10～80 ℃; the tracking monitor reaction, and feed CO
2, the control reaction pressure is 1～8atm, and reaction finishes the dimethylamine complex compound shown in the afterreaction liquid distillation recovery type (B), and it is standby to get the residue mother liquor; (2) in another reaction vessel, add acid binding agent 1 with the identical organic solvent of step (1), be warming up to 30～160 ℃, add described residue mother liquor, the insulated and stirred reaction, tracking monitor is to reacting completely, and reaction finishes afterreaction product separating treatment and makes suc as formula the main cyclic quinoline compound shown in (I), and the new consumption that adds organic solvent is counted 1～6mL/g with the quality of alpha-substitution aroyl-β-dimethylamino acrylate in the step (2); The ratio of the amount of substance of the aminated compounds shown in described alpha-substitution aroyl-β-dimethylamino acrylate, the formula (A), acid binding agent 1 is 1: 1～4: 1～10.
7. the method for claim 1; it is characterized in that described method is: (1) is in organic solvent; aminated compounds shown in alpha-substitution aroyl-β shown in the adding formula (II)-dimethylamino acrylate and the formula (A); controlled temperature carries out amine exchange reaction for-10～80 ℃; the tracking monitor reaction, and feed CO
2, the control reaction pressure is 1～8atm, and reaction finishes the dimethylamine complex compound shown in the afterreaction liquid distillation recovery type (B), and it is standby to get the residue mother liquor; (2) get the described residue mother liquor of step (1); continue distillation; remove organic solvent; under 30～160 ℃ of temperature; add in acid binding agent 1 and the organic solvent A; the insulated and stirred reaction; tracking monitor is to reacting completely; reaction finishes afterreaction product separating treatment and makes suc as formula the main cyclic quinoline compound shown in (I); described alpha-substitution aroyl-β-dimethylamino acrylate; aminated compounds shown in the formula (A); the ratio of the amount of substance of acid binding agent 1 is 1: 1～4: 1～10; described organic solvent A is for being different from one of following solvent of the described organic solvent of step (1): dimethyl sulfoxide (DMSO); N; dinethylformamide; benzene; toluene; dimethylbenzene; N-Methyl pyrrolidone; acetonitrile; propionitrile; tetrahydrofuran (THF); methylene dichloride; chloroform or tetracol phenixin, the consumption of organic solvent A is counted 4～16mL/g with the quality of alpha-substitution aroyl-β-dimethylamino acrylate.
8. as claim 6 or 7 described methods, the method that it is characterized in that described reaction product separating treatment is one of following: after (A) reaction finishes, reaction product cooling back filtration under diminished pressure, getting filter cake washes with water, use the recrystallization solvent recrystallization, obtain described main cyclic quinoline compound, described recrystallization solvent is ethanol or Virahol; (B) after reaction finished, reaction product added water washing again through distillating recovering solvent, filtered, and got filter cake recrystallization solvent recrystallization, obtained described main cyclic quinoline compound, and described recrystallization solvent is ethanol or Virahol.
9. as the described method of one of claim 1～7, it is characterized in that described suc as formula the alpha-substitution aroyl-β shown in (II)-dimethylamino acrylate by the N shown in the formula (III), adjacent halogen aroyl chloride shown in N-dimethylamino acrylate and the formula (IV) carries out acylation reaction and makes in organic solvent B in the presence of acid binding agent 2;
In the formula (III), R
1Be H or C
1～C
4Alkyl;
In the formula (IV), R
2Be H, halogen or nitro; R
3Be halogen; R
4Be halogen, nitro, amino, piperazinyl, N methyl piperazine base, 2-methylpiperazine base, 3-methylpiperazine base, 3,5-lupetazin base, 1-substituted cyclopropane alkyl, pyrryl, 3-amino-pyrroles base or methylpyrrole base; Z is N or C-R
5, R wherein
5Be H, hydroxyl, methyl, methoxyl group, halogen, nitro or cyano group; X is a halogen; Described halogen is F, Cl, Br or I;
Described organic solvent B is following any one or two or more mixing with arbitrary proportion: toluene, benzene, dimethylbenzene, normal heptane, hexanaphthene, pentane, methylene dichloride, ether, isopropyl ether, ethyl acetate, butylacetate, tetrahydrofuran (THF), acetone, butanone, N-Methyl pyrrolidone, N, dinethylformamide, dimethyl sulfoxide (DMSO), methyl alcohol, ethanol, Virahol, hexalin or butyleneglycol
Described acid binding agent 2 is inorganic base substance or organic basic material.
10. method as claimed in claim 9 is characterized in that described acid binding agent 2 is triethylamine, Tributylamine, salt of wormwood, yellow soda ash, pyridine, N, N-Dimethylamino pyridine or triethylene diamine; N shown in adjacent halogen aroyl chloride shown in the described formula (IV) and the formula (III), the ratio of the amount of substance of N-dimethylamino acrylate, acid binding agent 2 is 1: 1～4: 1～6; The volumetric usage of described organic solvent B is counted 5～15mL/g with the quality of adjacent halogen aroyl chloride.
11. method as claimed in claim 9 is characterized in that the N shown in the described formula (III), N-dimethylamino acrylate is fully reacted in organic solvent B by the dimethylamine complex compound shown in malonaldehydic acid ester alkali metal salt shown in the formula (C) and the formula (B) and makes;
In the formula (C), M is a basic metal, R
1Be H or C
1～C
4Alkyl.
12. the method for claim 1 is characterized in that described method may further comprise the steps:
(a) in organic solvent B, adding is suc as formula the dimethylamine complex compound shown in malonaldehydic acid ester alkali metal salt shown in (C) and the formula (B), controlled temperature is-30～40 ℃, stirring reaction 0.1～3 hour, reaction finishes the reaction solution washing, getting the organic layer distillation makes suc as formula the N shown in (III), N-dimethylamino acrylate, the N that contains in described malonaldehydic acid ester alkali metal salt and the dimethylamine complex compound, the ratio of the amount of substance of N-dimethylamino is 1: 1～6, described organic solvent B is one of following: dimethyl sulfoxide (DMSO), N, dinethylformamide, benzene, toluene, dimethylbenzene, N-Methyl pyrrolidone, tetrahydrofuran (THF) or methylene dichloride, the volumetric usage of organic solvent B is counted 6～20mL/g with the quality of malonaldehydic acid ester alkali metal salt described in the step (a);
(b) in organic solvent B, add the N that step (a) makes, N-dimethylamino acrylate, adjacent halogen aroyl chloride and acid binding agent 2 shown in the formula (IV), temperature of reaction is 10～100 ℃, stirring reaction 0.1～5 hour, reaction finishes the reaction solution washing, get organic layer, steam and remove the mixed solution that residual moisture obtains containing the alpha-substitution aroyl-β shown in the formula (II)-dimethylamino acrylate, described adjacent halogen aroyl chloride, N, N-dimethylamino acrylate is 1: 1～4: 1～6 with the ratio of the amount of substance of acid binding agent 2, and the volumetric usage of organic solvent B is counted 5～15mL/g with the quality of adjacent halogen aroyl chloride described in the step (b);
(c) get the mixed solution that contains the alpha-substitution aroyl-β shown in the formula (II)-dimethylamino acrylate that step (b) makes; controlled temperature is-10～80 ℃; aminated compounds shown in the adding formula (A) carries out amine exchange reaction, the tracking monitor reaction, and feed CO
2, the control reaction pressure is 1～8atm, and reaction finishes the dimethylamine complex compound shown in the afterreaction liquid distillation recovery type (B), and it is standby to get the residue mother liquor; In another reaction vessel; add acid binding agent 1 with the identical organic solvent of organic solvent B of step (b); be warming up to 30～160 ℃; add described residue mother liquor; the insulated and stirred reaction; tracking monitor is to reacting completely; reaction finishes afterreaction product separating treatment and makes suc as formula the main cyclic quinoline compound shown in (I); described alpha-substitution aroyl-β-dimethylamino acrylate; aminated compounds shown in the formula (A); the ratio of the amount of substance of acid binding agent 1 is 1: 1～4: 1～10, and the consumption that newly adds organic solvent is counted 1～6mL/g with the quality of alpha-substitution aroyl-β-dimethylamino acrylate.
13. the synthetic method of the main cyclic quinoline compound shown in formula V; it is characterized in that described method is: the aminated compounds shown in the alpha-substitution aroyl-β shown in the formula (II)-dimethylamino acrylate and the formula (D) carries out amine exchange reaction in organic solvent C, and feeds CO
2React with the by product dimethylamine, reaction finishes the distillation of afterreaction liquid and reclaims suc as formula the dimethylamine complex compound shown in (B), add acid binding agent 3 in the residue mother liquor and carry out ring-closure reaction, reaction end afterreaction product separating treatment makes the main cyclic quinoline compound shown in formula V;
In formula (II), formula (D) or the formula V, R
1Be H or C
1～C
4Alkyl; R
2Be H, halogen or nitro; R
3Be halogen; R
4Be halogen, nitro, amino, piperazinyl, N methyl piperazine base, 2-methylpiperazine base, 3-methylpiperazine base, 3,5-lupetazin base, 1-substituted cyclopropane alkyl, pyrryl, 3-amino-pyrroles base or methylpyrrole base; Z is C-R
5, R wherein
5Be H, hydroxyl, methyl, methoxyl group, halogen, nitro or cyano group;
In formula V or the formula (D), R
7For-CH
2-,-CH
2CH
2-,-CH
2CH (CH
3)-or-CH (CH
3) CH
2-; Y is O, S or SO
2
Described organic solvent C is: dimethyl sulfoxide (DMSO), N, dinethylformamide, benzene,toluene,xylene, N-Methyl pyrrolidone, acetonitrile, propionitrile, tetrahydrofuran (THF), methylene dichloride, chloroform or tetracol phenixin;
Described acid binding agent 3 is yellow soda ash, salt of wormwood, sodium hydroxide, potassium hydroxide, pyridine, N, N-Dimethylamino pyridine, triethylamine or triethylene diamine.
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Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102086158A (en) * | 2009-12-31 | 2011-06-08 | 杭州广林生物医药有限公司 | Method for synthesizing 3-(N,N-2-substituted amino)-2-substituted acrylic esters |
| WO2012100419A1 (en) * | 2011-01-26 | 2012-08-02 | 杭州广林生物医药有限公司 | Process for synthesis of 3-(n,n-disubstituted-amino)-2- substituted acrylate |
| CN105367431A (en) * | 2014-08-12 | 2016-03-02 | 吉林普瑞特生物科技有限公司 | 3-N,N-dimethylamino ethyl acrylate preparation method |
| CN107163063A (en) * | 2017-06-19 | 2017-09-15 | 太仓弘杉环保科技有限公司 | A kind of method for preparing high-quality lavo-ofloxacin hydrochloride |
| WO2018233111A1 (en) * | 2017-06-19 | 2018-12-27 | 太仓卡斯特姆新材料有限公司 | Environmentally friendly method for preparing levofloxacin hydrochloride |
| CN109232528A (en) * | 2018-09-11 | 2019-01-18 | 河南精康制药有限公司 | A kind of high efficiente callback of Sparfloxacin condensed mother liquor utilizes method |
| US10500568B2 (en) * | 2017-07-05 | 2019-12-10 | Hangzhou Normal University | Core-shell structure supported tungsten composite catalyst and preparation method and use thereof |
| CN110794046A (en) * | 2019-09-30 | 2020-02-14 | 珠海润都制药股份有限公司 | Method for detecting 2,4, 5-trifluoro-3-methoxybenzoyl chloride in moxifloxacin intermediate |
| CN111349094A (en) * | 2020-04-23 | 2020-06-30 | 杭州师范大学 | 6H-imidazo [4,5,1-ij ] quinolone and synthesis method and application thereof |
| 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 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1239094A (en) * | 1998-06-12 | 1999-12-22 | 拜尔公司 | Process for preparing quinolone- and naphthyridonecarboxylic acids and esters thereof |
| CN101020658A (en) * | 2007-02-14 | 2007-08-22 | 杭州师范学院 | Synthesis process of main cyclic quinoline compound |
-
2010
- 2010-04-30 CN CN2010101608124A patent/CN101838238B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1239094A (en) * | 1998-06-12 | 1999-12-22 | 拜尔公司 | Process for preparing quinolone- and naphthyridonecarboxylic acids and esters thereof |
| CN101020658A (en) * | 2007-02-14 | 2007-08-22 | 杭州师范学院 | Synthesis process of main cyclic quinoline compound |
Non-Patent Citations (1)
| Title |
|---|
| 《浙江大学学报（理学版）》 20050131 顾海宁 等 盐酸加替沙星的合成研究 66-68，74 1-13 第32卷, 第1期 2 * |
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| CN102086158A (en) * | 2009-12-31 | 2011-06-08 | 杭州广林生物医药有限公司 | Method for synthesizing 3-(N,N-2-substituted amino)-2-substituted acrylic esters |
| WO2012100419A1 (en) * | 2011-01-26 | 2012-08-02 | 杭州广林生物医药有限公司 | Process for synthesis of 3-(n,n-disubstituted-amino)-2- substituted acrylate |
| CN105367431A (en) * | 2014-08-12 | 2016-03-02 | 吉林普瑞特生物科技有限公司 | 3-N,N-dimethylamino ethyl acrylate preparation method |
| CN105367431B (en) * | 2014-08-12 | 2017-07-14 | 吉林普瑞特生物科技有限公司 | 3 N of one kind, the preparation method of N dimethylamino ethyl acrylates |
| CN107163063A (en) * | 2017-06-19 | 2017-09-15 | 太仓弘杉环保科技有限公司 | A kind of method for preparing high-quality lavo-ofloxacin hydrochloride |
| WO2018233111A1 (en) * | 2017-06-19 | 2018-12-27 | 太仓卡斯特姆新材料有限公司 | Environmentally friendly method for preparing levofloxacin hydrochloride |
| US10500568B2 (en) * | 2017-07-05 | 2019-12-10 | Hangzhou Normal University | Core-shell structure supported tungsten composite catalyst and preparation method and use thereof |
| CN109232528A (en) * | 2018-09-11 | 2019-01-18 | 河南精康制药有限公司 | A kind of high efficiente callback of Sparfloxacin condensed mother liquor utilizes method |
| CN110794046A (en) * | 2019-09-30 | 2020-02-14 | 珠海润都制药股份有限公司 | Method for detecting 2,4, 5-trifluoro-3-methoxybenzoyl chloride in moxifloxacin intermediate |
| CN110794046B (en) * | 2019-09-30 | 2022-05-06 | 珠海润都制药股份有限公司 | Method for detecting 2,4, 5-trifluoro-3-methoxybenzoyl chloride in moxifloxacin intermediate |
| CN111349094A (en) * | 2020-04-23 | 2020-06-30 | 杭州师范大学 | 6H-imidazo [4,5,1-ij ] quinolone and synthesis method and application thereof |
| 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 |
| 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 |
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