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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- pradofloxacin
- synthetic method
- acid
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- LZLXHGFNOWILIY-APPDUMDISA-N pradofloxacin Chemical compound C12=C(C#N)C(N3C[C@H]4NCCC[C@H]4C3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 LZLXHGFNOWILIY-APPDUMDISA-N 0.000 title claims abstract description 28
- 229960001248 pradofloxacin Drugs 0.000 title claims abstract description 28
- 238000010189 synthetic method Methods 0.000 title claims abstract description 19
- 150000001875 compounds Chemical class 0.000 claims abstract description 56
- 238000006243 chemical reaction Methods 0.000 claims abstract description 34
- 150000008282 halocarbons Chemical class 0.000 claims abstract description 12
- 150000007530 organic bases Chemical class 0.000 claims abstract description 12
- 239000002904 solvent Substances 0.000 claims abstract description 11
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 8
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 7
- 230000000269 nucleophilic effect Effects 0.000 claims abstract description 7
- 238000006073 displacement reaction Methods 0.000 claims abstract description 5
- 239000011737 fluorine Substances 0.000 claims abstract description 5
- 230000007062 hydrolysis Effects 0.000 claims abstract 2
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract 2
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 32
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 21
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 21
- 239000002253 acid Substances 0.000 claims description 15
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 11
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 9
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 239000011230 binding agent Substances 0.000 claims description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- 230000003197 catalytic effect Effects 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 4
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 4
- 150000007524 organic acids Chemical class 0.000 claims description 4
- 238000001556 precipitation Methods 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 claims description 4
- HTJDQJBWANPRPF-UHFFFAOYSA-N Cyclopropylamine Chemical class NC1CC1 HTJDQJBWANPRPF-UHFFFAOYSA-N 0.000 claims description 3
- 238000012805 post-processing Methods 0.000 claims description 3
- 235000019260 propionic acid Nutrition 0.000 claims description 3
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 3
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical class CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 claims description 2
- 238000006555 catalytic reaction Methods 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 2
- 239000000194 fatty acid Substances 0.000 claims description 2
- 229930195729 fatty acid Natural products 0.000 claims description 2
- 150000004665 fatty acids Chemical class 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
- 239000012046 mixed solvent Substances 0.000 claims description 2
- 238000006467 substitution reaction Methods 0.000 claims description 2
- 239000000758 substrate Substances 0.000 claims description 2
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 claims description 2
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 claims description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical class ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims 1
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 claims 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims 1
- 229930195733 hydrocarbon Natural products 0.000 claims 1
- 150000002430 hydrocarbons Chemical class 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 5
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 abstract description 4
- -1 benzene formyl acrylate compounds Chemical class 0.000 abstract description 3
- 150000007529 inorganic bases Chemical class 0.000 abstract description 3
- 230000029936 alkylation Effects 0.000 abstract description 2
- 238000005804 alkylation reaction Methods 0.000 abstract description 2
- 239000003054 catalyst Substances 0.000 abstract description 2
- 238000010931 ester hydrolysis Methods 0.000 abstract description 2
- 239000012535 impurity Substances 0.000 abstract description 2
- 238000011084 recovery Methods 0.000 abstract description 2
- 230000010933 acylation Effects 0.000 abstract 1
- 238000005917 acylation reaction Methods 0.000 abstract 1
- 125000003368 amide group Chemical group 0.000 abstract 1
- 238000005660 chlorination reaction Methods 0.000 abstract 1
- 239000002994 raw material Substances 0.000 abstract 1
- 239000000047 product Substances 0.000 description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
- 238000004128 high performance liquid chromatography Methods 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- 235000019441 ethanol Nutrition 0.000 description 5
- 238000001514 detection method Methods 0.000 description 4
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000001291 vacuum drying Methods 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- PLPDHGOODMBBGN-VOTSOKGWSA-N (e)-4-oxo-4-phenylbut-2-enoic acid Chemical class OC(=O)\C=C\C(=O)C1=CC=CC=C1 PLPDHGOODMBBGN-VOTSOKGWSA-N 0.000 description 2
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- 125000003236 benzoyl group Chemical class [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- 230000008021 deposition Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- KUHNQNUSGIAQLQ-UHFFFAOYSA-N ethyl 2-aminoprop-2-enoate Chemical compound CCOC(=O)C(N)=C KUHNQNUSGIAQLQ-UHFFFAOYSA-N 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 238000009413 insulation Methods 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- QKFJKGMPGYROCL-UHFFFAOYSA-N phenyl isothiocyanate Chemical compound S=C=NC1=CC=CC=C1 QKFJKGMPGYROCL-UHFFFAOYSA-N 0.000 description 2
- 210000002381 plasma Anatomy 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000013049 sediment Substances 0.000 description 2
- 238000013517 stratification Methods 0.000 description 2
- 150000003462 sulfoxides Chemical class 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical class CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 1
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 description 1
- ASJSAQIRZKANQN-CRCLSJGQSA-N 2-deoxy-D-ribose Chemical group OC[C@@H](O)[C@@H](O)CC=O ASJSAQIRZKANQN-CRCLSJGQSA-N 0.000 description 1
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- 108010054814 DNA Gyrase Proteins 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N N-phenyl amine Natural products NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 1
- 101710183280 Topoisomerase Proteins 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 239000012491 analyte Substances 0.000 description 1
- 150000001448 anilines Chemical class 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical class ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 229940124307 fluoroquinolone Drugs 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 238000009434 installation Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 description 1
- 229940117953 phenylisothiocyanate Drugs 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 229940126532 prescription medicine Drugs 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 150000007660 quinolones Chemical class 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 229920002477 rna polymer Polymers 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D471/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
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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| 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 |
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| 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 |
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