CN107987074A - A kind of synthetic method of Pradofloxacin - Google Patents
A kind of synthetic method of Pradofloxacin Download PDFInfo
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- CN107987074A CN107987074A CN201711020779.3A CN201711020779A CN107987074A CN 107987074 A CN107987074 A CN 107987074A CN 201711020779 A CN201711020779 A CN 201711020779A CN 107987074 A CN107987074 A CN 107987074A
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- C07—ORGANIC CHEMISTRY
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- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract
The present invention relates to a kind of synthetic method of Pradofloxacin, this method uses compound cheap and easy to get as raw material, and target product Pradofloxacin is obtained through chlorination, acylation, nucleophilic displacement of fluorine, cyclisation, hydrolysis, alkylated reaction.The nucleophilic displacement of fluorine object β substituted amido α substituted benzene formyl acrylate compounds quality of the present invention is good, and for purity more than 98%, yield reaches 80~90%, and more than 10% is improved compared with the prior art；Ester hydrolysis method provided by the invention and good product quality, reaction yield reach 93~98%；Replacing traditional inorganic base by the use of organic base, easy to operate, pollution-free, cost is greatly lowered as cyclization catalyst；Alkylation solvent is used as using halogenated hydrocarbons, reaction temperature is room temperature condition, reaction is gentle easily operated, it is few that the impurity for reacting and being alkylated at high temperature than the prior art and reacting and produce is alkylated at 20~40 DEG C, high income, and halogenated hydrocarbon solvent is easy to recovery of applied, pollution greatly reduces, environmentally friendly.
Description
Technical field
The present invention relates to field of medicine preparing technology, refers specifically to a kind of synthetic method of Pradofloxacin.
Background technology
Pradofloxacin (Pradofloxacin) is by the 3rd generation enhanced spectrum beast of the fluoroquinolones of Beyer Co., Ltd's research and development
Antibiotic is cured, is primarily adapted for use in the prescription medicine for the treatment of dog and cat bacterial infection.Quinolones mainly suppresses DNA gyrases (also referred to as
Type Ⅱ topoisomerase) A subunits, only a small number of medicines act on B subunits, so as to destroy its activity, make deoxyribose core
The synthesis of acid, ribonucleic acid and protein is disturbed, and prevents bacterium from again into line splitting, and plays bactericidal effect.
Entitled 8- cyano group -1- cyclopropyl -7- ((1S, the 6S) -2,8- diazabicyclos-(4.3.0) nonyl of Pradofloxacin chemistry
Alkane -8- bases) the fluoro- Isosorbide-5-Nitraes of -6--dihydro -4- oxo -3- quinoline carboxylic acids, molecular formula C21H21FN4O3, molecular weight 396.41,
Structural formula is：
In the prior art, the synthesis of Pradofloxacin is broadly divided into three steps：
(1) synthesis of fluoquinolone quinoline parent nucleus；
(2) synthesis of hand-type pyrrolidine side chain；
(3) 2 parts connect more than.
Fluoquinolone quinoline parent nucleus structure generally has three kinds of methods：Substituted aniline and ethoxy methylene diethyl malonate
(EMME) cyclization, β-substituted amido-alpha-substituted benzoyl after cyclization, phenyl isothiocyanate and diethyl malonate are condensed after being condensed
The preparation and cyclization of acrylate.Wherein, Pradofloxacin fluoquinolone quinoline parent nucleus passes through β-substituted amido-alpha-substituted benzoyl
In the preparation method of acrylate, β-substituted amido-alpha-substituted benzoyl acrylic acid ester, occur nucleophilic with 1- amino-cyclopropanes again
Purity is relatively low after substitution reaction, carries out cyclization making acid binding agent in higher boiling protonic solvent with inorganic base, post processing produces
Pollution it is very serious.
The content of the invention
The technical problem to be solved by the invention for the present situation of prior art is to provide a kind of purity and high income, step
The synthetic method of rapid simple, environmental-friendly Pradofloxacin.
Technical solution is used by the present invention solves above-mentioned technical problem：A kind of synthetic method of Pradofloxacin, it is special
Sign is to comprise the following steps：
(1) VIII compound of following formula is in varsol or halogenated hydrocarbon solvent, under organic base catalytic among reaction generation
Body formula VII；VII compound of formula obtains intermediate formula VI through nucleophilic displacement of fluorine again；VI compound of body formula occurs with 1- amino-cyclopropanes again
Nucleophilic substitution obtains the solution of intermediate Formula V compound, the adjusted pH of Formula V compound solution, post processing, isolated formula
V compounds；
Wherein, it is above-mentioned it is various in X it is identical, be chlorine atom or fluorine atom；
(2) Formula V compound ring-closure reaction occurs under organic base catalytic obtains IV compound of formula, through cooling down, filtering, dry
Obtain IV compound of formula；
(3) in the in the mixed solvent that lower fatty acid and water are formed with sulfuric acid or methanesulfonic acid hydrolysis occurs for IV compound of formula instead
The precipitation of III compound of formula should be obtained, is cooled to room temperature, filtering, dry III compound of formula；
(4) III compound of formula is alkylated with II compound of formula in halogenated hydrocarbon solvent under the catalysis of acid binding agent
Reaction obtains type I compound solution, and post-treated to obtain type I compound, which is target product.
Preferably, the varsol described in step (1) or halogenated hydrocarbon solvent are toluene, dichloromethane, chloroform, 1,2-
One kind in dichloroethanes, organic base are triethylamine.
As an improvement, being first cooled to room temperature when adjusting pH in step (1), then pH is adjusted to 5.5~6.5.
Preferably, the organic base described in step (2) is selected from pyridine, Trimethylamine, triethylamine, N, N- diisopropyl ethyls
Amine, tert-butylamine, tri-n-butylamine, N-methylmorpholine, N- methyl piperidines.
Preferably, the molar ratio of organic base and substrate described in step (2) is (1.2~5)：1.
Preferably, reaction temperature is 8~120 DEG C in step (2).
Preferably, organic acid described in step (3) is acetic acid, propionic acid one kind.
Improve again, organic acid described in step (3), water, the volume of sulfuric acid or methanesulfonic acid are 10：1：(1~2).
Preferably, the ratio of halogenated hydrocarbons and formula III compound described in step (4) is (10~40) mL：1g.
Preferably, institute's acid binding agent is triethylamine in step (4).
Compared with prior art, the advantage of the invention is that：
(1) nucleophilic displacement of fluorine object β-substituted amido-alpha-substituted benzoyl acrylic acid ester compounds quality of the invention is good,
For purity more than 98%, yield reaches 80~90%, and more than 10% is improved compared with the prior art；Ester hydrolysis method provided by the invention
And good product quality, reaction yield reach 93~98%；
(2) present invention replaces traditional inorganic base as cyclization catalyst by the use of organic base, easy to operate, pollution-free, into
Originally it is greatly lowered；
(3) for the present invention using halogenated hydrocarbons as alkylation solvent, reaction temperature is room temperature condition, and reaction is gentle easily operated,
It is few that the impurity for reacting and being alkylated at high temperature than the prior art and reacting and produce is alkylated at 20~40 DEG C, high income,
And halogenated hydrocarbon solvent is easy to recovery of applied, pollution greatly reduces, environmentally friendly；
(4) overall synthetic method purity of the invention can reach 99.3%~99.8%, it is not necessary to using it is cumbersome, into
This higher column chromatography method purified product and other special installations, are more conducive to industrialization production.
Brief description of the drawings
Fig. 1 is the ESI-MS collection of illustrative plates of step (1) products therefrom in the embodiment of the present invention 1；
Fig. 2 is the HPLC collection of illustrative plates of step (4) products therefrom in the embodiment of the present invention 1；
Fig. 3 is the HPLC collection of illustrative plates of step (4) products therefrom in the embodiment of the present invention 3；
Fig. 4 is the HPLC collection of illustrative plates of step (4) products therefrom in the embodiment of the present invention 4；
Fig. 5 is the HPLC collection of illustrative plates of step (4) products therefrom in the embodiment of the present invention 5；
Fig. 6 is the ESI-MS collection of illustrative plates of step (4) products therefrom in the embodiment of the present invention 6；
Fig. 7 is the HPLC collection of illustrative plates of step (4) products therefrom in the embodiment of the present invention 6.
Embodiment
The present invention is described in further detail below in conjunction with attached drawing embodiment.
Embodiment 1：
The synthetic method of the present embodiment Pradofloxacin comprises the following steps：
(1) 2- (2,4- bis- chloro- 3- cyano group -5- fluoro benzoyls) -3- cyclopropylamino ethyl acrylates, i.e. following formula 5 is prepared
Compound
The chloro- 3- cyano group -5- fluobenzoic acid 24g of 2,4- bis- are put into reaction bulb, add dichloromethane 240mL, chlorine is added dropwise
Change sulfoxide 28.8g；Drop finishes stirring 5 minutes, adds triethylamine 2mL, and stirring is to slowly warm up to 35~40 DEG C, when reflux 3~5 is small；
Reaction finishes, and is cooled to -5~-10 DEG C, and the mixing of 15.2g triethylamines and the 3- dimethylamino ethyl acrylates of 21.5g is added dropwise
Liquid, drop finish be warming up to room temperature the reaction was continued 12 it is small when, the reaction was complete for TLC detection compound of reactions formula 7；Ice bath cool down, 10 DEG C with
Lower addition acetic acid 24mL, stirs 5 minutes, adds 9g1- amino-cyclopropanes, room temperature the reaction was continued 12 it is small when, TLC detection reactions
The reaction was complete for Formula 6；100mL washings are added, 6N salt acid for adjusting pH is 5.5~6.5, and stratification obtains organic layer, 40 DEG C
Dichloromethane is concentrated below, adds ethanol 100ml crystallizations；Decompression filters to obtain wet product；50~60 DEG C are dried under reduced pressure 8 hours to perseverance
Weight, it is 5 compound 2- of formula (2,4- bis- chloro- 3- cyano group -5- fluoro benzoyls) -3- rings third that rewinding, which obtains off-white powder shape solid,
Aminoacrylic acid ethyl ester, dry weight 32.4g, yield 85%.
As shown in Figure 1, the stronger quasi-molecular ions in ESI-MS positive mass spectrum figures at m/z 370.9 corresponds to the [M of sample
+ H]+ion, it can thus be appreciated that the molecular weight of sample is 370；In addition the m/e=392.9 plasmas peak occurred corresponds respectively to [M+
Na]+plasma, there is each fragment peak above；Hence, it can be determined that molecular weight analyte is consistent with 5 molecular weight of formula, 5 structure of formula is just
Really.
(2) the fluoro- Isosorbide-5-Nitraes of the chloro- 8- cyano group -1- cyclopropyl -6- of 7--dihydro -4- oxo -3- quinoline carboxylic acid ethyl esters, i.e. formula 4 is prepared
Compound
150mL acetonitriles, 5 compound 2- of formula (the chloro- 3- cyano group -5- fluoro benzoyls of 2,4- bis-) -3- are put into reaction bulb
Cyclopropylamino ethyl acrylate 25g, triethylamine 20mL, heat up 75-80 DEG C, when insulation reaction 5~7 is small.Reaction finishes, and is cooled to
Room temperature has crystal precipitation, then be stirred at room temperature 2 it is small when filter.50~55 DEG C of wet product is dried under reduced pressure 8 hours to constant weight, and it is white that rewinding obtains class
The fluoro- 1,4- dihydros -4- oxos -3- quinoline carboxylic acid's second of the chloro- 8- amino -1- cyclopropyl -6- of the powdered 4 compound 7- of solid type of color
Ester, dry weight 21.5g, yield 95%.
(3) the fluoro- Isosorbide-5-Nitraes of the chloro- 8- cyano group -1- cyclopropyl -6- of 7--dihydro -4- oxo -3- quinoline carboxylic acids are prepared, i.e. following formula 3 is changed
Compound
In the mixture of 45mL acetic acid, 4.5mL water and the 4.5mL concentrated sulfuric acids by the chloro- 8- cyano group -1- cyclopropyl of the 7- of 15g -
The fluoro- 1,4- dihydros -4- oxos -3- quinoline carboxylic acid ethyl esters of 6- be heated at reflux 3 it is small when.Be cooled to room temperature stirring 1 it is small when, suction filtration
The sediment of deposition, is washed with water, and 60 DEG C of vacuum drying, obtain product 13.5g, yield 98%.
(4) synthesis of Pradofloxacin, i.e. 1 compound of following formula
Under environment temperature, in 100mL dichloromethane, by the chloro- fluoro- Isosorbide-5-Nitraes of 8- cyano group -1- cyclopropyl -6- of the 7- of 10.0g -
(4aS, 7aS)-octahydro -1H- pyrrolo-es [3,4-b] pyridine of dihydro -4- oxo -3- quinoline carboxylic acids (3 compound of formula) and 6.3g
(2 compound of formula) and triethylamine stir together 70 it is small when.All volatile ingredients are removed in vacuum and use ethyl alcohol recrystallization.Pressurization
Filter, washed with ethanol, 60 DEG C of vacuum drying, obtain product 12.5g, yield 95%, HPLC purity 99.84%, such as Fig. 2 institutes
Show.
Embodiment 2：
The present embodiment is different only in that with embodiment 1：Step (3) substitutes acetic acid using propionic acid, with 9mL pyrovinic acid generations
For sulfuric acid, the fluoro- Isosorbide-5-Nitraes of the chloro- 8- cyano group -1- cyclopropyl -6- of 7- finally obtained-dihydro -4- oxo -3- quinoline carboxylic acid's (3 chemical combination of formula
Thing) 13.2g, yield 96%.
Embodiment 3：
The present embodiment is different only in that with embodiment 1：Make acid binding agent using pyridine in step (4), finally obtain pula
Husky star 11.9g, yield 90.3%, HPLC purity 99.33%, as shown in Figure 3.
Embodiment 4：
The present embodiment is different only in that with embodiment 1：N is used in step (4), N- diisopropyl ethyl amines tie up acid
Agent, finally obtains Pradofloxacin 12.1g, yield 92%, HPLC purity 99.60%, as shown in Figure 4.
Embodiment 5：
The present embodiment is different only in that with embodiment 1：Make acid binding agent using N methyl piperazine in step (4), finally
To Pradofloxacin 12.3g, yield 93.7%, HPLC purity 99.47%, as shown in Figure 5.
Embodiment 6：
The synthetic method of the present embodiment Pradofloxacin comprises the following steps：
(1) 2- (3- cyano group -2,4,5- trifluoromethylbenzoyls) -3- cyclopropylamino ethyl acrylates are prepared, i.e. following formula 11 is changed
Compound
3- cyano group -2,4 is put into reaction bulb, 5- trifluoro fluobenzoic acid 20.8g, add dichloromethane 240mL, and chlorine is added dropwise
Change sulfoxide 28.8g.Drop finishes stirring 5 minutes, adds triethylamine 2mL, and stirring is to slowly warm up to 35~40 DEG C, when reflux 3~5 is small.
Reaction finishes, and is cooled to -5~-10 DEG C, and the mixing of 15.2g triethylamines and the 3- dimethylamino ethyl acrylates of 21.5g is added dropwise
Liquid, drop finish be warming up to room temperature the reaction was continued 12 it is small when, the reaction was complete for TLC detections.Ice bath cools down, less than 10 DEG C addition acetic acid
24mL, stirs 5 minutes, adds 9g1- amino-cyclopropanes, room temperature the reaction was continued 12 it is small when, TLC detection compound of reactions formula 12
The reaction was complete.100mL washings are added, 6N salt acid for adjusting pH is 5.5~6.5, and stratification obtains organic layer, less than 40 DEG C concentrations two
Chloromethanes, adds ethanol 100mL crystallizations.Decompression filters to obtain wet product.50~60 DEG C are dried under reduced pressure 8 hours and obtain class to constant weight, rewinding
11 compound 2- of white powdery solids formula (3- cyano group -2,4,5- trifluoromethylbenzoyls) -3- cyclopropylamino ethyl acrylates, do
Weight 28.6g, yield 81.7%.
(2) bis- fluoro- Isosorbide-5-Nitrae of 8- cyano group -1- cyclopropyl -6,7--dihydro -4- oxo -3- quinoline carboxylic acid ethyl esters, i.e. following formula is prepared
10 compounds
150mL acetonitriles, 11 compound 2- of formula (3- cyano-2,4,5-trifluoros formoxyl) -3- rings are put into reaction bulb
Third aminoacrylic acid ethyl ester 22.8g, triethylamine 20mL, heat up 75-80 DEG C, when insulation reaction 5~7 is small.Reaction finishes, and is cooled to
Room temperature has crystal precipitation, then be stirred at room temperature 2 it is small when filter.50~55 DEG C of wet product is dried under reduced pressure 8 hours to constant weight, and it is white that rewinding obtains class
Powdered 10 compound 8- cyano group -1- cyclopropyl -6,7- of solid type, the bis- fluoro- Isosorbide-5-Nitrae-dihydro -4- oxo -3- quinoline carboxylic acid's second of color
Ester, dry weight 19.6g, yield 91.4%.
(3) bis- fluoro- Isosorbide-5-Nitrae of 8- cyano group -1- cyclopropyl -6,7--dihydro -4- oxo -3- quinoline carboxylic acids are prepared, i.e. following formula 9 is changed
Compound
In the mixture of 45mL acetic acid, 4.5mL water and 4.5mL pyrovinic acids by the 8- cyano group -1- cyclopropyl of 14.3g -
The fluoro- 1,4- dihydros -4- oxos -3- quinoline carboxylic acid ethyl esters of 6,7- bis- be heated at reflux 3 it is small when.Be cooled to room temperature stirring 1 it is small when, suction
The sediment of filter deposition, is washed with water, and 50 DEG C of vacuum drying, obtain product 11.98g, yield 96%.
(4) synthesis of Pradofloxacin, i.e. 1 compound of following formula
Under environment temperature, in 100mL dichloromethane, by the bis- fluoro- Isosorbide-5-Nitrae of -8- cyano group -1- cyclopropyl -6,7- of 10.0g -
(4aS, 7aS)-octahydro -1H- pyrrolo-es [3,4-b] pyridine of dihydro -4- oxo -3- quinoline carboxylic acids (9 compound of formula) and 8.7g
(2 compound of formula) and N-methylmorpholine stir together 75 it is small when.All volatile ingredients are removed in vacuum and from ethyl alcohol recrystallization.Add
Pressure filters, and is washed with methanol, and 60 DEG C of vacuum drying, obtain product 12.7g, yield 93%, HPLC purity 99.68%, such as Fig. 7 institutes
Show.
As shown in fig. 6, the stronger quasi-molecular ions in ESI-MS positive mass spectrum figures at m/z 397 corresponds to the [M+ of sample
H]+ion, it can thus be appreciated that the molecular weight of sample shows that structure is correct for 396, ESI-Mass.
Claims (10)
1. a kind of synthetic method of Pradofloxacin, it is characterised in that comprise the following steps：
(1) VIII compound of following formula is in varsol or halogenated hydrocarbon solvent, the reaction generation intermediate formula under organic base catalytic
Ⅶ；VII compound of formula obtains intermediate formula VI through nucleophilic displacement of fluorine again；With 1- amino-cyclopropanes nucleophilic occurs for VI compound of body formula again
Substitution reaction obtains the solution of intermediate Formula V compound, the adjusted pH of Formula V compound solution, post processing, isolated Formula V
Compound；
Wherein, it is above-mentioned it is various in X it is identical, be chlorine atom or fluorine atom；
(2) Formula V compound ring-closure reaction occurs under organic base catalytic obtains IV compound of formula, through cooling down, filtering, dry formula
IV compound；
(3) IV compound of formula is obtained in the in the mixed solvent generation hydrolysis that lower fatty acid and water are formed with sulfuric acid or methanesulfonic acid
To the precipitation of III compound of formula, room temperature is cooled to, filtering, dry III compound of formula；
(4) with II compound of formula in halogenated hydrocarbon solvent under the catalysis of acid binding agent alkylated reaction occurs for III compound of formula
Type I compound solution is obtained, post-treated to obtain type I compound, which is target product,
2. the synthetic method of Pradofloxacin according to claim 1, it is characterised in that：Hydro carbons described in step (1) is molten
Agent or halogenated hydrocarbon solvent are toluene, one kind in dichloromethane, chloroform, 1,2- dichloroethanes, and organic base is triethylamine.
3. the synthetic method of Pradofloxacin according to claim 1, it is characterised in that：It is first when adjusting pH in step (1)
Room temperature is cooled to, then adjusts pH to 5.5~6.5.
4. the synthetic method of Pradofloxacin according to claim 1, it is characterised in that：Organic base described in step (2)
Selected from pyridine, Trimethylamine, triethylamine, N, N- diisopropyl ethyl amines, tert-butylamine, tri-n-butylamine, N-methylmorpholine, N- methyl
Piperidines.
5. the synthetic method of Pradofloxacin according to claim 4, it is characterised in that：Organic base described in step (2) with
The molar ratio of substrate is (1.2~5)：1.
6. the synthetic method of Pradofloxacin according to claim 1, it is characterised in that：In step (2) reaction temperature for 8~
120℃。
7. the synthetic method of Pradofloxacin according to claim 1, it is characterised in that：Organic acid is described in step (3)
Acetic acid, propionic acid are a kind of.
8. the synthetic method of Pradofloxacin according to claim 7, it is characterised in that：Organic acid described in step (3),
The volume of water, sulfuric acid or methanesulfonic acid is 10：1：(1~2).
9. the synthetic method of Pradofloxacin according to claim 1, it is characterised in that：Halogenated hydrocarbons described in step (4) with
The ratio of III compound of formula is (10~40) mL：1g.
10. the synthetic method of Pradofloxacin according to claim 1, it is characterised in that：Institute's acid binding agent is three in step (4)
Ethamine.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108948011A (en) * | 2018-08-14 | 2018-12-07 | 华南农业大学 | A kind of preparation method of the sandy star in pula |
| 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 |
| CN115703757A (en) * | 2021-08-16 | 2023-02-17 | 浙江中欣氟材股份有限公司 | Synthesis method of melafloxacin |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108948011A (en) * | 2018-08-14 | 2018-12-07 | 华南农业大学 | A kind of preparation method of the sandy star in pula |
| 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 |
| 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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| CN107987074B (en) | 2020-12-29 |
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