CN105859764A - Preparation method of key intermediate of moxifloxacin - Google Patents
Preparation method of key intermediate of moxifloxacin Download PDFInfo
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- CN105859764A CN105859764A CN201610299425.6A CN201610299425A CN105859764A CN 105859764 A CN105859764 A CN 105859764A CN 201610299425 A CN201610299425 A CN 201610299425A CN 105859764 A CN105859764 A CN 105859764A
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- reaction
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- moxifloxacin
- acid
- important intermediate
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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
Abstract
The invention discloses a preparation method of a key intermediate of moxifloxacin. The preparation method includes the steps of (1), filling a reaction kettle A with boracic acid, acetic anhydride and zinc chloride, heating to a reaction temperature and violently stirring to obtain a reactive material liquid; (2), in a reaction process, pumping the reactive material liquid into a continuous disacidifying system filled with a disacidifying agent at a certain flow speed to remove generated acetic acid, and pumping the reactive material liquid into a reaction kettle B; (3), adding 1-cyclopropyl-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxo-3-quinoline carboxylic acid into the reaction kettle B with stirring; (4), after reaction is terminated, conducting vacuum concentration, crystallizing and filtering so as to obtain the key intermediate. The preparation method of the key intermediate of the moxifloxacin has the advantages that a continuous disacidifying device is adopted to remove the byproduct acetic acid difficult to distill when boron ester is generated, so that conversion ratio of raw material (S,S)-2,8-diazabicyclo[4,3,0]nonane is increased effectively, yield of a target product I is increased greatly, technological scale-up operability is enhanced and low-energy-consumption continuous production is achieved simply and quickly.
Description
Technical field
The present invention relates to a kind of production Moxifloxacin important intermediate 1-cyclopropyl-6,7-difluoro-8-methoxyl-1,4-dihydro-4-
Oxoquinoline-3-carboxylic acid-O3, O4-bis-acetic acid close boron ester (I) method, relate to moxifloxacin hydrochloride in pharmaceutical field
Technology of preparing.
Background technology
Moxifloxacin hydrochloride is that the forth generation developed by Bayer A.G for 1999 surpasses broad spectrum quinolone class medicine, commodity
Entitled " visiing multiple pleasure ".New generation product (especially moxifloxacin hydrochloride) no matter at the medicine property moved, safety, antibacterial activity,
Or it is all best in antimicrobial spectrum and application aspect.Moxifloxacin hydrochloride demonstrates in vitro to gram positive bacteria, leather orchid
Negative bacterium, anaerobe, acid fast bacteria and atypical microorganism such as mycoplasma, chlamydia and legionella have broad spectrum antibiotic activity.
Upper respiratory tract and lower respiratory infection is suffered from (such as community acquired pneumonia, acute sinusitis, chronic bronchial for treatment
Scorching acute attack and Skin and soft tissue infection) adult, have that antibacterial activity is strong, has a broad antifungal spectrum, be not likely to produce resistance to
Medicine, to common fastbacteria effectively, the plurality of advantages such as long half time, untoward reaction be few.Along with clinical application, its curative effect
Increasingly affirmed so that it is in pharmaceutical synthesis field, there is high Research Significance and using value.
Compound I is the important intermediate of synthetic hydrochloric acid Moxifloxacin, and it is by 1-cyclopropyl-6,7-difluoro-8-methoxyl
-Isosorbide-5-Nitrae-dihydro-4-oxo-3-quinoline carboxylic acid (Moses's parent nucleus) boron esterification obtains, and the method has cost of material low, raw
The advantages such as production. art is simple, but this technique also exists product, and I conversion ratio is the highest, and by-product is difficult to the problems such as separation.
Owing in reaction, acetic anhydride is produced by-product acetic acid by boric acid alcoholysis, high boiling acetic acid is difficult in industrialization amplified
It is evaporated off in journey.In course of reaction, the most how effectively to remove the acetic acid of generation, be that can this technique adapt to industrialization
The big key point produced.
Summary of the invention
Goal of the invention: in order to solve above-mentioned technical problem, the invention provides a kind of Moxifloxacin important intermediate 1-ring third
Base-6,7-difluoro-8-methoxyl-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid-O3, O4-bis-acetic acid closes the preparation method of boron ester.
Technical scheme: for achieving the above object, the invention provides the preparation method of a kind of Moxifloxacin important intermediate,
Comprise the steps:
(1) first boric acid, acetic anhydride and zinc chloride being loaded in reactor A, be warming up to reaction temperature, strong agitation is anti-
Should, obtain reaction feed liquid；
(2), during answering, above-mentioned reaction feed liquid is pumped into certain flow rate in the continuous deacidification system of filling plumper and remove
Remove the acetic acid generated, be then pumped in reactor B；
(3) in reactor B, 1-cyclopropyl-6,7-difluoro-8-methoxyl-1,4-dihydro-4-oxo-3-quinoline carboxylic acid is added (not
Xisha star parent nucleus), stirring reaction；
(4) after reaction terminates, concentrating under reduced pressure, crystallize, filters, obtains formula (I) compound 1-cyclopropyl base-6, the fluoro-8-of 7-bis-
Methoxyl group-Isosorbide-5-Nitrae-dihydro-4-oxo-3-quinoline carboxylic acid-O3, O4-bis-acetic acid closes boron ester, is described important intermediate；
As preferably, described in step (1), the mol ratio of boric acid and acetic anhydride is 1:1～1:4；Described boric acid and chlorine
The mol ratio changing zinc is 1:1～4:1.
Preferred as another kind, described in step (1), reaction temperature is at 100～150 DEG C, and the response time is 1～8h.
Preferred as another kind, the continuous deacidification system loading plumper described in step (2) is a filling plumper
Acid removal column, or two and the acid removal column tandem compound of above filling plumper, or two and load plumper above
Acid removal column parallel combination.
Preferred as another kind, plumper described in step (2) be sodium hydroxide, potassium hydroxide, natrium carbonicum calcinatum or
Calcium hydroxide.
Preferred as another kind, described in step (3), the condition of reaction is: reaction temperature is at 30～70 DEG C, during reaction
Between be 1～8h.
Preferred as another kind, the solvent added in crystallize described in step (4) include water, methanol, ethanol, third
Ketone, ethyl acetate.
Beneficial effect: present invention mainly solves raw material Moses's parent nucleus conversion ratio during prior art produces compound I low
Problem.Relative to prior art, the present invention, by using continuous deacidification device, removes the by-product second in the boron ester generated
Acid, thus it is effectively improved the conversion ratio of raw material Moses's parent nucleus, substantially increase the productivity of target product I, enhance
The operability that technique is amplified, it is achieved low energy consumption, produce the most continuously, the productivity of the target product I obtained
More than 95%, chemical purity is more than 98%.
Accompanying drawing explanation
Fig. 1: Fig. 1 preparation method flow chart of the present invention, is labeled as in figure: 1. acid esterification reactor, 2. acid removal column,
3. parent nucleus boron reaction kettle of the esterification, 4. boric acid+acetic anhydride material inlet, 5. parent nucleus material inlet.
Detailed description of the invention
Embodiment 1
Reaction substrate and product method for qualitative and quantitative detection be: uses Kromasil C18Post (12.5cm × 4.6mm × 5 μm),
Flowing phase: acetonitrile: phosphate buffer (pH 3.6) (35:65)；UV detects wavelength 293nm；Flow velocity: 1.0mL/min；
Column temperature 35 DEG C.
First boric acid, acetic anhydride and zinc chloride are loaded in reactor A according to the mol ratio of 1:1:0.25, are warming up to 150 DEG C,
Strong agitation reaction 5h, enters to be filled with by reaction material liquid pump in course of reaction in the single-column deacidification system continuously of sodium hydroxide
Remove the acetic acid generated, and pump in reactor B.1-cyclopropyl-6,7-difluoro-8-methoxyl is added in reactor B
-Isosorbide-5-Nitrae-dihydro-4-oxo-3-quinoline carboxylic acid (Moses's parent nucleus), stirring reaction 3h at 70 DEG C.After completion of the reaction, decompression
Concentrate.Add water stirring and crystallizing 20h, filter, obtain 1-cyclopropyl-6,7-difluoro-8-methoxyl-Isosorbide-5-Nitrae-dihydro-4-oxo-3-
Quinoline carboxylic acid-O3, O4-bis-acetic acid close boron ester (I), productivity is 96.3%, and chemical purity is 98.7%.
Embodiment 2
Reaction substrate and product method for qualitative and quantitative detection and operation are the most same as in Example 1, change reactant mole and join
The enforcement step of the most each operating parameter is as follows:
First boric acid, acetic anhydride and zinc chloride are loaded in reactor A according to the mol ratio of 1:2:1, are warming up to 100 DEG C,
Strong agitation reaction 8h, enters reaction material liquid pump to be filled with the series connection twin columns of potassium hydroxide and deacidifies continuously and be in course of reaction
System removes the acetic acid of generation, and pumps in reactor B.The fluoro-8-first of 1-cyclopropyl-6,7-two is added in reactor B
Oxy-1,4-dihydro-4-oxo-3-quinoline carboxylic acid (Moses's parent nucleus), stirring reaction 1h at 50 DEG C.After completion of the reaction,
Concentrating under reduced pressure.Add methanol stirring and crystallizing 12h, filter, obtain 1-cyclopropyl-6,7-difluoro-8-methoxyl-Isosorbide-5-Nitrae-dihydro-4-
Oxo-3-quinoline carboxylic acid-O3, O4-bis-acetic acid closes boron ester (I), and productivity is 97.4%, and chemical purity is 99.2%.
Embodiment 3
Reaction substrate and product method for qualitative and quantitative detection and operation are the most same as in Example 1, change reactant mole and join
The enforcement step of the most each operating parameter is as follows:
First boric acid, acetic anhydride and zinc chloride are loaded in reactor A according to the mol ratio of 1:3:0.5, are warming up to 110 DEG C,
Strong agitation reaction 3h, enters reaction material liquid pump to be filled with the single-column of Anhydrous potassium carbonate and deacidifies continuously system in course of reaction
The middle acetic acid removing generation, and pump in reactor B.The fluoro-8-methoxy of 1-cyclopropyl-6,7-two is added in reactor B
Base-Isosorbide-5-Nitrae-dihydro-4-oxo-3-quinoline carboxylic acid (Moses's parent nucleus), stirring reaction 5h at 30 DEG C.After completion of the reaction, subtract
Pressure concentrates.Add ethanol stirring and crystallizing 15h, filter, obtain 1-cyclopropyl-6,7-difluoro-8-methoxyl-Isosorbide-5-Nitrae-dihydro-4-oxo
-3-quinoline carboxylic acid-O3, O4-bis-acetic acid closes boron ester (I), and productivity is 96.8%, and chemical purity is 99.1%.
Embodiment 4
Reaction substrate and product method for qualitative and quantitative detection and operation are the most same as in Example 1, change reactant mole and join
The enforcement step of the most each operating parameter is as follows:
First boric acid, acetic anhydride and zinc chloride are loaded in reactor A according to the mol ratio of 1:4:0.33, are warming up to 140 DEG C,
Strong agitation reaction 1h, enters reaction material liquid pump to be filled with the twin columns in parallel of calcium hydroxide and deacidifies continuously and be in course of reaction
System removes the acetic acid of generation, and pumps in reactor B.The fluoro-8-first of 1-cyclopropyl-6,7-two is added in reactor B
Oxy-1,4-dihydro-4-oxo-3-quinoline carboxylic acid (Moses's parent nucleus), stirring reaction 8h at 60 DEG C.After completion of the reaction,
Concentrating under reduced pressure.Add ethyl acetate stirring and crystallizing 18h, filter, obtain 1-cyclopropyl-6,7-difluoro-8-methoxyl-Isosorbide-5-Nitrae-dihydro
-4-oxo-3-quinoline carboxylic acid-O3, O4-bis-acetic acid closes boron ester (I), and productivity is 95.2%, and chemical purity is 98.5%.
Claims (7)
1. the preparation method of a Moxifloxacin important intermediate, it is characterised in that comprise the steps:
(1) first boric acid, acetic anhydride and zinc chloride being loaded in reactor A, be warming up to reaction temperature, strong agitation is anti-
Should, obtain reaction feed liquid；
(2), during answering, above-mentioned reaction feed liquid is pumped into certain flow rate in the continuous deacidification system of filling plumper and remove
Remove the acetic acid generated, be then pumped in reactor B；
(3) in reactor B, 1-cyclopropyl-6,7-difluoro-8-methoxyl-1,4-dihydro-4-oxo-3-quinoline carboxylic acid is added (not
Xisha star parent nucleus), stirring reaction；
(4) after reaction terminates, concentrating under reduced pressure, crystallize, filters, obtains formula (I) compound 1-cyclopropyl base-6, the fluoro-8-of 7-bis-
Methoxyl group-Isosorbide-5-Nitrae-dihydro-4-oxo-3-quinoline carboxylic acid-O3, O4-bis-acetic acid closes boron ester, is described important intermediate；
The preparation method of Moxifloxacin important intermediate the most according to claim 1, it is characterised in that step (1)
Described in the mol ratio of boric acid and acetic anhydride be 1:1～1:4；The mol ratio of described boric acid and zinc chloride is 1:1～4:1.
The preparation method of carvedilol intermediate the most according to claim 1, it is characterised in that in step (1)
Described reaction temperature is at 100～150 DEG C, and the response time is 1～8h.
The preparation method of Moxifloxacin important intermediate the most according to claim 1, it is characterised in that step (2)
Described in load the acid removal column that the continuous deacidification system of plumper is a filling plumper, or two and above filling remove
The acid removal column tandem compound of acid agent, or two and the acid removal column parallel combination of above filling plumper.
The preparation method of Moxifloxacin important intermediate the most according to claim 1, it is characterised in that step (2)
Described in plumper be sodium hydroxide, potassium hydroxide, natrium carbonicum calcinatum or calcium hydroxide.
The preparation method of Moxifloxacin important intermediate the most according to claim 1, it is characterised in that step (3)
Described in reaction condition be: reaction temperature is at 30～70 DEG C, and the response time is 1～8h.
The preparation method of Moxifloxacin important intermediate the most according to claim 1, it is characterised in that step (4)
Described in the solvent that added in crystallize include water, methanol, ethanol, acetone, ethyl acetate.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110903194A (en) * | 2019-12-11 | 2020-03-24 | 南京恒道医药科技有限公司 | Method for continuously preparing voriconazole intermediate ethyl 2-fluoro-3-oxopentanoate |
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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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| FEI LI ET AL.: ""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"", 《ASIAN JOURNAL OF CHEMISTRY》 * |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110903194A (en) * | 2019-12-11 | 2020-03-24 | 南京恒道医药科技有限公司 | Method for continuously preparing voriconazole intermediate ethyl 2-fluoro-3-oxopentanoate |
| CN110903194B (en) * | 2019-12-11 | 2022-02-25 | 南京恒道医药科技有限公司 | Method for continuously preparing voriconazole intermediate ethyl 2-fluoro-3-oxopentanoate |
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