CN105859764B - A kind of preparation method of Moxifloxacin important intermediate - Google Patents
A kind of preparation method of Moxifloxacin important intermediate Download PDFInfo
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- CN105859764B CN105859764B CN201610299425.6A CN201610299425A CN105859764B CN 105859764 B CN105859764 B CN 105859764B CN 201610299425 A CN201610299425 A CN 201610299425A CN 105859764 B CN105859764 B CN 105859764B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic System
- C07F5/02—Boron compounds
- C07F5/04—Esters of boric acids
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Abstract
The invention discloses a kind of preparation methods of Moxifloxacin important intermediate, include the following steps：(1) first boric acid, acetic anhydride and zinc chloride are fitted into reaction kettle A, are warming up to reaction temperature, are stirred to react strongly, obtain reaction material liquid；(2) during answering, above-mentioned reaction material liquid with certain flow rate is pumped into and is filled with the continuous except the acetic acid that generation is removed in acid system of plumper, is then pumped into reaction kettle B；(3) 16,7 difluoro of cyclopropyl, 84 oxo of methoxyl group Isosorbide-5-Nitrae dihydro, 3 quinoline carboxylic acid is added in into reaction kettle B, is stirred to react；(4) after reaction, it is concentrated under reduced pressure, crystallization is filtered to get the important intermediate.The present invention is by using continuous deacidification device, remove the acetic acid for being difficult to distill of generation boron ester when institute by-product, so as to be effectively improved the conversion ratio of raw material Moses's parent nucleus, substantially increase the yield of target product I, the operability of technique amplification is enhanced, realizes low energy consumption, simply and rapidly continuous production.
Description
Technical field
The present invention relates to a kind of production Moxifloxacin important intermediate 1- cyclopropyl -6,7- difluoro-8-methoxyls -1,4- two
The method that bis- acetic acid of hydrogen -4- Oxoquinoline-3-carboxylic acids-O3, O4- closes boron ester (I), is related to the moxifloxacin hydrochloride in pharmaceutical field
Technology of preparing.
Background technology
Moxifloxacin hydrochloride is that the forth generation developed by Bayer A.G in 1999 surpasses broad spectrum quinolone class drug, commodity
Entitled " visiing multiple pleasure ".New generation product (especially moxifloxacin hydrochloride) no matter the medicine property moved, security, antibacterial activity or
Antimicrobial spectrum and application aspect are best.Moxifloxacin hydrochloride shows in vitro to gram positive bacteria, gram-negative bacteria, detests
Oxygen bacterium, acid fast bacteria and atypical microorganism such as mycoplasma, Chlamydia and Legionella have broad spectrum antibiotic activity.It is suffered from for treating
Respiratory tract and lower respiratory tract infection (such as community acquired pneumonia, acute sinusitis, acute exacerbation of chronic bronchitis and skin
And soft tissue infection) adult, have antibacterial activity strong, has a broad antifungal spectrum, be not likely to produce drug resistance, to common drug-fast bacteria effectively, half
Many advantages, such as phase length, adverse reaction decline less.With clinical application, curative effect is increasingly affirmed, makes it in pharmaceutical synthesis
Field has high research significance and application value.
Compound I is the important intermediate of synthetic hydrochloric acid Moxifloxacin, is by bis- fluoro- 8- methoxies of 1- cyclopropyl -6,7-
Base-Isosorbide-5-Nitrae-dihydro -4- oxo -3- quinoline carboxylic acids (Moses's parent nucleus) boron esterification obtains, and this method has that cost of material is low, raw
The advantages that production. art is simple, but there is the problems such as product I conversion ratios are not high, and by-product is difficult to separate for the technique.
Since acetic anhydride generates by-product acetic acid by boric acid alcoholysis in reaction, high boiling acetic acid is difficult to amplify in industrialization
It is evaporated off in the process.Therefore the acetic acid of generation how is removed effectively during the reaction, is that can the technique adapt to industrialize
The key point produced greatly.
The content of the invention
Goal of the invention：In order to solve the above technical problem, the present invention provides a kind of Moxifloxacin important intermediate 1- rings
Bis- acetic acid of propyl -6,7- difluoro-8-methoxyl -1,4- dihydro -4- Oxoquinoline-3-carboxylic acids-O3, O4- closes the preparation side of boron ester
Method.
Technical solution：To achieve the above object, the present invention provides a kind of preparation method of Moxifloxacin important intermediate,
Include the following steps：
(1) first boric acid, acetic anhydride and zinc chloride are fitted into reaction kettle A, are warming up to reaction temperature, are stirred to react strongly,
Obtain reaction material liquid；
(2) during answering, above-mentioned reaction material liquid is pumped into continuously removing in acid system for filling plumper with certain flow rate and is removed
The acetic acid of generation is removed, is then pumped into reaction kettle B；
(3) 1- cyclopropyl -6,7- difluoro-8-methoxyl -1,4- dihydro -4- oxo -3- quinoline carboxylics are added in into reaction kettle B
Sour (Moxifloxacin parent nucleus), is stirred to react；
(4) after reaction, it is concentrated under reduced pressure, crystallization, filtering obtains bis- fluoro- 8- first of formula (I) compound 1-cyclopropyl base -6,7-
Oxy-1, bis- acetic acid of 4- dihydro -4- oxo -3- quinoline carboxylic acids-O3, O4- close boron ester, are the important intermediate；
Preferably, the mol ratio of boric acid and acetic anhydride is 1 described in step (1):1~1:4；The boric acid and chlorination
The mol ratio of zinc is 1:1~4:1.
As another preferred embodiment, reaction temperature described in step (1), at 100~150 DEG C, the reaction time is 1~8h.
As another preferred embodiment, the acid system that continuously removes that plumper is loaded described in step (2) is a filling plumper
Acid removal column either two and more than load plumper acid removal column tandem compound or two and more than load plumper
Acid removal column parallel combination.
As another preferred embodiment, plumper is sodium hydroxide, potassium hydroxide, natrium carbonicum calcinatum or hydrogen described in step (2)
Calcium oxide.
As another preferred embodiment, the condition reacted described in step (3) is：Reaction temperature is at 30~70 DEG C, the reaction time
For 1~8h.
As another preferred embodiment, the solvent added in described in step (4) in crystallization include water, methanol, ethyl alcohol, acetone,
Ethyl acetate.
Advantageous effect：Present invention mainly solves raw material Moses's parent nucleus conversion ratio during prior art production compound I is low
The problem of.Compared with the prior art, the present invention removes the by-product second in the boron ester of generation by using continuous deacidification device
Acid so as to be effectively improved the conversion ratio of raw material Moses's parent nucleus, substantially increases the yield of target product I, enhances technique
The operability of amplification realizes low energy consumption, simply and rapidly continuous production, and the yield of obtained target product I is more than 95%,
Chemical purity is more than 98%.
Description of the drawings
Fig. 1：Fig. 1 preparation method flow charts of the present invention, in figure mark for：1. acid esterification reaction kettle, 2. acid removal columns, 3. mothers
Core boron reaction kettle of the esterification, 4. boric acid+acetic anhydride material inlet, 5. parent nucleus material inlets.
Specific embodiment
Embodiment 1
Reaction substrate and product method for qualitative and quantitative detection are：Using Kromasil C18Column (the μ of 12.5cm × 4.6mm × 5
M), mobile phase：Acetonitrile:Phosphate buffer (pH 3.6) (35:65)；UV Detection wavelengths 293nm；Flow velocity：1.0mL/min；Column
35 DEG C of temperature.
First by boric acid, acetic anhydride and zinc chloride according to 1:1:0.25 molar ratio is fitted into reaction kettle A, is warming up to 150 DEG C,
5h is stirred to react strongly, reaction material liquid is pumped into reaction process and is filled with the single-column of sodium hydroxide continuously except being removed in acid system
The acetic acid of generation, and be pumped into reaction kettle B.1- cyclopropyl -6,7- difluoro-8-methoxyls -1,4- two is added in into reaction kettle B
Hydrogen -4- oxo -3- quinoline carboxylic acids (Moses's parent nucleus), 3h is stirred to react at 70 DEG C.After completion of the reaction, it is concentrated under reduced pressure.Add in water
Stirring and crystallizing 20h, filtering, obtains 1- cyclopropyl -6,7- difluoro-8-methoxyl-Isosorbide-5-Nitrae-dihydro -4- oxo -3- quinoline carboxylic acid-O3,
Bis- acetic acid of O4- closes boron ester (I), yield 96.3%, chemical purity 98.7%.
Embodiment 2
Reaction substrate and product method for qualitative and quantitative detection and operation are same as Example 1, change reactant mole
Implementation steps with when each operating parameter are as follows：
First by boric acid, acetic anhydride and zinc chloride according to 1:2:1 molar ratio is fitted into reaction kettle A, is warming up to 100 DEG C, by force
It is strong to be stirred to react 8h, reaction material liquid is pumped into reaction process and is filled with the series connection twin columns of potassium hydroxide continuously except being removed in acid system
The acetic acid of generation is removed, and is pumped into reaction kettle B.1- cyclopropyl -6,7- difluoro-8-methoxyls -1,4- two is added in into reaction kettle B
Hydrogen -4- oxo -3- quinoline carboxylic acids (Moses's parent nucleus), 1h is stirred to react at 50 DEG C.After completion of the reaction, it is concentrated under reduced pressure.Add in first
Alcohol stirring and crystallizing 12h, filtering, obtain 1- cyclopropyl -6,7- difluoro-8-methoxyl-Isosorbide-5-Nitrae-dihydro -4- oxo -3- quinoline carboxylic acids -
Bis- acetic acid of O3, O4- closes boron ester (I), yield 97.4%, chemical purity 99.2%.
Embodiment 3
Reaction substrate and product method for qualitative and quantitative detection and operation are same as Example 1, change reactant mole
Implementation steps with when each operating parameter are as follows：
First by boric acid, acetic anhydride and zinc chloride according to 1:3:0.5 molar ratio is fitted into reaction kettle A, is warming up to 110 DEG C,
3h is stirred to react strongly, reaction material liquid is pumped into reaction process and is filled with the single-column of Anhydrous potassium carbonate continuously except being removed in acid system
The acetic acid of generation is removed, and is pumped into reaction kettle B.1- cyclopropyl -6,7- difluoro-8-methoxyls -1,4- two is added in into reaction kettle B
Hydrogen -4- oxo -3- quinoline carboxylic acids (Moses's parent nucleus), 5h is stirred to react at 30 DEG C.After completion of the reaction, it is concentrated under reduced pressure.Add in second
Alcohol stirring and crystallizing 15h, filtering, obtain 1- cyclopropyl -6,7- difluoro-8-methoxyl-Isosorbide-5-Nitrae-dihydro -4- oxo -3- quinoline carboxylic acids -
Bis- acetic acid of O3, O4- closes boron ester (I), yield 96.8%, chemical purity 99.1%.
Embodiment 4
Reaction substrate and product method for qualitative and quantitative detection and operation are same as Example 1, change reactant mole
Implementation steps with when each operating parameter are as follows：
First by boric acid, acetic anhydride and zinc chloride according to 1:4:0.33 molar ratio is fitted into reaction kettle A, is warming up to 140 DEG C,
1h is stirred to react strongly, reaction material liquid is pumped into the twin columns in parallel for being filled with calcium hydroxide continuously except in acid system in reaction process
The acetic acid of generation is removed, and is pumped into reaction kettle B.1- cyclopropyl -6,7- difluoro-8-methoxyls -1,4- is added in into reaction kettle B
Dihydro -4- oxo -3- quinoline carboxylic acids (Moses's parent nucleus), 8h is stirred to react at 60 DEG C.After completion of the reaction, it is concentrated under reduced pressure.It adds in
Ethyl acetate stirring and crystallizing 18h, filtering, obtains 1- cyclopropyl -6,7- difluoro-8-methoxyl-Isosorbide-5-Nitrae-dihydro -4- oxo -3- quinoline
Bis- acetic acid of carboxylic acid-O3, O4- closes boron ester (I), yield 95.2%, chemical purity 98.5%.
Claims (4)
1. a kind of preparation method of moxifloxacin intermediate, which is characterized in that include the following steps：
(1) first boric acid, acetic anhydride and zinc chloride are fitted into reaction kettle A, are warming up to reaction temperature, are stirred to react strongly, obtain instead
Answer feed liquid；The mol ratio of the boric acid and acetic anhydride is 1:1~1:4；The mol ratio of the boric acid and zinc chloride is 1:1~
4:1；For the reaction temperature at 100~150 DEG C, the reaction time is 1~8h；
(2) in reaction process, above-mentioned reaction material liquid is pumped into continuously removing in acid system for filling plumper with certain flow rate and is removed
The acetic acid of generation is then pumped into reaction kettle B；The continuous of the filling plumper loads removing for plumper except acid system is one
Sour column either two and more than load plumper acid removal column tandem compound or two and more than load plumper deacidification
Column parallel combination；
(3) 1- cyclopropyl -6,7- difluoro-8-methoxyl-Isosorbide-5-Nitrae-dihydro -4- oxo -3- quinoline carboxylic acids are added in into reaction kettle B,
It is stirred to react；
(4) after reaction, be concentrated under reduced pressure, crystallization, filtering, obtain formula (I) compound 1-cyclopropyl base -6,7- difluoro-8-methoxyl -
Isosorbide-5-Nitrae-bis- acetic acid of dihydro -4- oxo -3- quinoline carboxylic acids-O3, O4- closes boron ester, is the important intermediate；
2. the preparation method of moxifloxacin intermediate according to claim 1, which is characterized in that step is removed described in (2)
Sour agent is sodium hydroxide, potassium hydroxide, natrium carbonicum calcinatum or calcium hydroxide.
3. the husky preparation method for wanting intermediate of Moses according to claim 1, which is characterized in that anti-described in step (3)
The condition answered is：For reaction temperature at 30~70 DEG C, the reaction time is 1~8h.
4. the husky preparation method for wanting intermediate of Moses according to claim 1, which is characterized in that step is analysed described in (4)
The solvent added in crystalline substance includes one or more of water, methanol, ethyl alcohol, acetone, ethyl acetate.
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| JPH04243882A (en) * | 1991-01-21 | 1992-08-31 | Ube Ind Ltd | Production of tri-lower alkanoyloxyboron |
| WO2005012285A1 (en) * | 2003-08-05 | 2005-02-10 | Matrix Laboratories Ltd | An improved process for the preparation of moxifloxacin hydrochloride |
| WO2010052726A1 (en) * | 2008-11-06 | 2010-05-14 | Hetero Research Foundation | Novel polymorph of moxifloxacin hydrochloride |
| WO2014087292A1 (en) * | 2012-12-04 | 2014-06-12 | Mankind Research Centre | An improved process for the preparation of moxifloxacin hydrochloride |
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2016
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH04243882A (en) * | 1991-01-21 | 1992-08-31 | Ube Ind Ltd | Production of tri-lower alkanoyloxyboron |
| WO2005012285A1 (en) * | 2003-08-05 | 2005-02-10 | Matrix Laboratories Ltd | An improved process for the preparation of moxifloxacin hydrochloride |
| WO2010052726A1 (en) * | 2008-11-06 | 2010-05-14 | Hetero Research Foundation | Novel polymorph of moxifloxacin hydrochloride |
| WO2014087292A1 (en) * | 2012-12-04 | 2014-06-12 | Mankind Research Centre | An improved process for the preparation of moxifloxacin hydrochloride |
| CN104277059A (en) * | 2013-07-01 | 2015-01-14 | 广东东阳光药业有限公司 | Preparation method of fluoroquinolone antibacterial drug |
| CN105085522A (en) * | 2015-10-12 | 2015-11-25 | 山东罗欣药业集团股份有限公司 | Method for preparing high-purity moxifloxacin hydrochloride |
Non-Patent Citations (3)
| Title |
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| "Synthesis and Crystal Structure of 1-Cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinoline carboxylic acid-(O3,O4)-bis-(acetate-O)borate";FEI LI et al.;《Asian Journal of Chemistry》;20131231;第25卷(第11期);第6079-6082页 * |
| "诺氟沙星(氟哌酸)生产工艺中螯合反应方程式的改正和环合反应的改进";龙良瓒等;《化学世界》;19981231(第5期);第273-274页 * |
| 莫西沙星的合成;翟红等;《化工生产与技术》;20071225;第14卷(第6期);第15-17，41页 * |
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