CN100412075C - Process for preparing L-ofloxacin and ofloxacin - Google Patents
Process for preparing L-ofloxacin and ofloxacin Download PDFInfo
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- CN100412075C CN100412075C CNB200410155139XA CN200410155139A CN100412075C CN 100412075 C CN100412075 C CN 100412075C CN B200410155139X A CNB200410155139X A CN B200410155139XA CN 200410155139 A CN200410155139 A CN 200410155139A CN 100412075 C CN100412075 C CN 100412075C
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/06—Peri-condensed systems
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- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
The present invention relates to a preparing method of anti-infection medicines, namely levofloxacin and ofloxacin, which is a synthesizing method using tetrafluorobenzoic acid as raw materials. The present invention is characterized in that the method comprises the following steps: adding solvents into crude products of 2-(2, 3, 4, 5-tetrafluorobenzoyl-3-ethoxy-ethyl acrylate; freezing the solution; dripping L-amino propanol or DL-amino propanol; carrying out heat preservation until complete conversion is finished; adding alkali to react at 50 to 90 DEG C; adding N-methyl piperazine into mother liquid after the reaction is finished; stirring the solution to react for 1 to 3 hours at 55 to 95 DEG C; reducing pressure to reclaim the N-methyl piperazine; raise the reaction temperature to 120 to 130 DEG C; preserving the temperature for 0.1 to 1.0 hour; pouring the reaction liquid into water after the reaction is finished; stirring, cooling and filtering the mixture; adding water and acid into the filtered products; stirring the mixture for reflux until complete hydrolysis is finished; adjusting a pH value to 7.0 by using alkali liquid; adding an extracting agent for extraction; concentrating an extracted layer to obtain levofloxacin and ofloxacin. The method can be used to shorten reaction steps, simplify technology, and bring convenience to concentrated solvent reclamation and reuse.
Description
Technical field
The invention belongs to chemical field, the preparation method of specifically a kind of Levofloxacin and Ofloxacine USP 23.
Background technology
Fluoroquinolones is efficient with it, the antimicrobial characteristic of wide spectrum, low toxicity, is obtaining immense success aspect the clinical anti-infective therapy, and the Ofloxacine USP 23 of Japanese first drugmaker exploitation and Levofloxacin are exactly outstanding kind wherein.Levofloxacin, English name: Leovfloxacin, molecular formula: C
18H
20FN
3O
41/2H
2O, structural formula is as follows:
Ofloxacine USP 23, English name: Floxacin, molecular formula: C
18H
20FN
3O
4, structural formula is as follows:
Levofloxacin synthetic mainly contains following three kinds of methods:
1, Split Method: comprise that high-pressure liquid phase splits EP206283 (1986) and enzyme fractionation (K, Sakano, AginaBiol.chem.:1987,51,1265) this method is not suitable for suitability for industrialized production;
2, begin through the reaction of 7 steps preparation Levofloxacin UP4777253 (1988) by tetrafluorobenzoic aid;
3, be that raw material makes with the trifluoronitrobenzene.EP36841(1990)、EP273399(1988)。
Wherein the one-tenth cyclization established law of method 2 is the comparatively general industrialization synthetic methods that adopt at present.The synthetic route of this method is as shown below:
In said synthesis route, when DL-aminopropanol and 2-(2,3,4,5-tetra fluoro benzene formyl radical)-3-oxyethyl group-ethyl propenoate (below abbreviate compound (V) as) reaction, adopt similar methods, just can make Ofloxacine USP 23, synthetic route is as follows:
In two above-mentioned synthetic routes, this section route by the synthetic final product (Levofloxacin and Ofloxacine USP 23) of compound (V), it forms earlier two rings simultaneously, hydrolysis then, N methyl piperazine base on 10 at last, there is following shortcoming in this section synthetic route: 1) because the solvent difference in each step of reaction (generally adopts N, dinethylformamide or N, N-dimethyl sulfoxide (DMSO) and water), can't operate continuously in same reactor, need to divide a FOUR EASY STEPS, the solid transfer amount is big, dust is many, and is difficult to guarantee that solvent obtains satisfied recovery set rate; 2) go up two rings simultaneously in order to satisfy, reaction is carried out not too easily, and the temperature when making preparation is 120-150 ℃, and the time is 4-5hr, and side reaction takes place the long reaction time under the high temperature easily, and quality product and outward appearance can be affected; 3) need a large amount of glacial acetic acids, production cost is big, the long 5-6hr of hydrolysis time, and the dissolving difficulty, it is complete to be not easy hydrolysis, separation difficulty after the reaction, and bigger to the influence of environment.
Summary of the invention
Technical problem to be solved by this invention is the defective that overcomes above-mentioned prior art, and an operational path from synthetic fast levofloxacin of compound (V) and Ofloxacine USP 23 is provided, and shortens the reaction times, simplifies technology.
Technical scheme of the present invention is such: the preparation method of Levofloxacin, be to be the synthesis method of raw material with the tetrafluorobenzoic aid, it is characterized in that: a) in compound (V) crude product, add solvent, freezing dropping L-aminopropanol, insulation is to conversion fully then, add alkali, 50-90 ℃ of reaction down, after reaction finishes, add N methyl piperazine in the mother liquor, 55-95 ℃ of reclaim under reduced pressure N methyl piperazine after stirring reaction 1-3 hour, temperature of reaction rise to 120-130 ℃ of insulation 0.1-1.0 hour, finish reaction, in reaction solution impouring water, stir, cold filtration gets S-(-) 9-fluoro-3-methyl isophthalic acid 0-(4-methyl isophthalic acid-piperazinyl)-7-oxygen--and 2,3-dihydro-7H-pyrido-[1,2,3 ,-de] [1,4] benzoxazine-6-carboxylic acid, ethyl ester (below abbreviate compound (IX) as); B) add entry, acid in compound (IX), stirring and refluxing is complete to hydrolysis, and transferring PH with alkali lye is 7.0, adds the extraction agent extraction, and concentrated extract layer promptly gets Levofloxacin.
The preparation method of Ofloxacine USP 23, be to be the synthesis method of raw material with the tetrafluorobenzoic aid, it is characterized in that: a) in compound (V) crude product, add solvent, freezing dropping DL-aminopropanol, insulation is to conversion fully then, add alkali, 50-90 ℃ of reaction down, after reaction finishes, add N methyl piperazine in the mother liquor, 55-95 ℃ of reclaim under reduced pressure N methyl piperazine after stirring reaction 1-3 hour, temperature of reaction rise to 120-130 ℃ of insulation 0.1-1.0 hour, finish reaction, in reaction solution impouring water, stir, cold filtration gets 9-fluoro-3-methyl isophthalic acid 0-(4-methyl isophthalic acid-piperazinyl)-7-oxygen--and 2,3-dihydro-7H-pyrido [1,2,3 ,-de] [1,4] benzoxazine-6-carboxylic acid, ethyl ester (below abbreviate compound (X) as); B) add entry, acid in compound (X), stirring and refluxing is complete to hydrolysis, and transferring PH with alkali lye is 7.0, adds the extraction agent extraction, and concentrated extract layer promptly gets Ofloxacine USP 23.
As follows from the reaction mechanism of compound (V) preparation Levofloxacin:
Actual reaction formula is as follows:
In like manner can make Ofloxacine USP 23:
Above-mentioned preparation method, earlier (60-70 ℃) goes up first ring at low temperatures, then goes up the methylpiperazine base, then in high temperature (120-130 ℃) last second ring down, last hydrolysis.Owing to adopt above-mentioned substep to become around-France (the synchronous one-tenth that is different from prior art fully is around-France), promptly form two rings two different temperature, the present invention makes the reaction times short (0.1-1.0 hour) of hot stage, most of reaction times is in 60-80 ℃ low thermophase, and quality product and outward appearance have had tangible improvement.Because what use from compound (V) preparation compound (IX) or reaction process (X) is with a kind of solvent, these three reaction process can be in same reactor a step finish, so involved in the present invention is actually the reaction of two steps from compound (V) preparation final product, shortened the reaction times, after reaction finishes, can concentrate and reclaim solvent and apply mechanically, reduce production cost.In addition, owing to go up the posthydrolysis of methylpiperazine base earlier, hydrolysis is finished under the CL state, and easier hydrolysis is complete, has greatly shortened the reaction times.
The preparation method of described Levofloxacin and Ofloxacine USP 23, solvent is primary isoamyl alcohol, dimethylbenzene, dioxane, N, dinethylformamide (DMF) or N, N-dimethyl sulfoxide (DMSO) (DMSO), different solvents is influential to the yield of reaction.
The preparation method of described Levofloxacin and Ofloxacine USP 23, the alkali of a in the step is salt of wormwood, sodium bicarbonate, triethylamine or pyridine.
The invention provides the preparation method of a kind of Levofloxacin and Ofloxacine USP 23, has following beneficial effect: the 1) temperature of reacting by control, first ring in the elder generation, then go up the methylpiperazine base, go up second ring again, be hydrolyzed at last, reaction is carried out easily, has shortened high-temperature time and entire reaction time; 2) use in the reaction process with a kind of solvent, compound (V) preparation compound (IX) or (X) can be in same reactor a step finish, easy to operate, shortened reactions steps, simplified technology; 3) conveniently concentrate and reclaim solvent and apply mechanically, and good recovery set rate is arranged, reduced production cost; 4) hydrolysis is quick and complete; 5) because high-temperature time is short, quality product and outward appearance have had tangible improvement.
Embodiment
Embodiment 1
A) preparation of compound (IX): in the three-necked bottle of 500ml, drop into 60.0g compound (V), 150ml DMF, be refrigerated to 0 ℃, drip 14.0g L-aminopropanol, after being incubated 0.5 hour then, add 45.0g salt of wormwood, 60-70 ℃ of reaction 3 hours adds the 30.0g N methyl piperazine in the mother liquor, 70-80 ℃ of stirring reaction reclaim under reduced pressure N methyl piperazine after 2 hours.The rising temperature of reaction is to 120-130 ℃, and after 0.5 hour, reaction finishes, and the reaction solution impouring is equipped with in the 1000ml beaker of 500ml water, stirs, and promptly the adularescent solid is separated out, cold filtration, dry 43.0g compound (IX), the yield 57.9% of getting.
B) preparation of Levofloxacin (I): drop into the 50.5g compound (IX), 150ml water, the 50ml concentrated hydrochloric acid that obtain in a step in the three-necked bottle of 500ml successively, stirring and refluxing half an hour, solid dissolves fully, and reaction finishes.It is 7.0 that the alkali lye of solution cold slightly back adding 150ml water and 30.0gNaOH preparation is transferred PH, uses 50ml/ time * 5 times chloroform extraction then, merges to concentrate chloroform layer, gets the 38.5g Levofloxacin, yield 94.2%.
Embodiment 2
Be that with the difference of embodiment 1 adopt primary isoamyl alcohol as solvent, the alkali of adding is sodium bicarbonate, the yield that a step obtains is 45.7%, and the yield that the b step obtains is 92.3%.
Embodiment 3
A) preparation of compound (X): in the three-necked bottle of 500ml, drop into 60.0g compound (V), 150mlDMF successively, be refrigerated to 0 ℃, drip 14.0g DL-aminopropanol, after being incubated 0.5 hour then, add 45.0g salt of wormwood, 60-70 ℃ of reaction 3 hours adds the 30.0g N methyl piperazine in the mother liquor, 70-80 ℃ of stirring reaction reclaim under reduced pressure N methyl piperazine after 2 hours.The rising temperature of reaction is to 120-130 ℃, and after 0.5 hour, reaction finishes, and the reaction solution impouring is equipped with in the 1000ml beaker of 500ml water, stirs, and promptly the adularescent solid is separated out, cold filtration, dry 45.0g, the yield 60.6% of getting.
B) preparation of Ofloxacine USP 23 (XI): drop into the 52.0g solid chemical compound, 150ml water, the 50ml concentrated hydrochloric acid that obtain in a step in the three-necked bottle of 500ml successively, stirring and refluxing half an hour, reaction finishes.The cold slightly back of solution adds 400ml ethanol, promptly separates out a large amount of white solids, stirs freezing after-filtration, dry 41.5g Ofloxacine USP 23, the yield 97.1% of getting.
Embodiment 4
Be that with the difference of embodiment 3 adopt dimethylbenzene as solvent, the alkali of adding is pyridine, the yield that a step obtains is 23.7%, and the yield that the b step obtains is 94.6%.
Claims (4)
1. the preparation method of Levofloxacin is to be the synthesis method of raw material with the tetrafluorobenzoic aid, it is characterized in that: a) at 2-(2,3,4,5-tetra fluoro benzene formyl radical)-and adding solvent in 3-oxyethyl group-ethyl propenoate crude product, described solvent is a primary isoamyl alcohol, dimethylbenzene or N, dinethylformamide, freezing dropping L-aminopropanol, insulation adds alkali to conversion fully then, 50-90 ℃ of reaction down, after reaction finishes, add N methyl piperazine in the mother liquor, 55-95 ℃ of reclaim under reduced pressure N methyl piperazine after stirring reaction 1-3 hour, temperature of reaction rises to 120-130 ℃ of insulation 0.1-1.0 hour, finish reaction, in reaction solution impouring water, stir, cold filtration gets S-(-) 9-fluoro-3-methyl isophthalic acid 0-(4-methyl isophthalic acid-piperazinyl)-7-oxygen-2,3-dihydro-7H-pyrido-[1,2,3,-de] [1,4] benzoxazine-6-carboxylic acid, ethyl ester; B) add entry, concentrated hydrochloric acid in the product of a step gained, stirring and refluxing is complete to hydrolysis, and transferring PH with alkali lye is 7.0, adds chloroform extraction, and concentrated extract layer promptly gets Levofloxacin.
2. the preparation method of Levofloxacin according to claim 1 is characterized in that the alkali of a in the step is salt of wormwood, sodium bicarbonate, triethylamine or pyridine.
3. the preparation method of Ofloxacine USP 23 is to be the synthesis method of raw material with the tetrafluorobenzoic aid, it is characterized in that: a) at 2-(2,3,4,5-tetra fluoro benzene formyl radical)-and adding solvent in 3-oxyethyl group-ethyl propenoate crude product, described solvent is a primary isoamyl alcohol, dimethylbenzene or N, dinethylformamide, freezing dropping DL-aminopropanol, insulation adds alkali to conversion fully then, 50-90 ℃ of reaction down, after reaction finishes, add N methyl piperazine in the mother liquor, 55-95 ℃ of reclaim under reduced pressure N methyl piperazine after stirring reaction 1-3 hour, temperature of reaction rises to 120-130 ℃ of insulation 0.1-1.0 hour, finish reaction, in reaction solution impouring water, stir, cold filtration gets 9-fluoro-3-methyl isophthalic acid 0-(4-methyl isophthalic acid-piperazinyl)-7 oxygen-2,3-dihydro-7H-pyrido-[1,2,3,-de] [1,4] benzoxazine-6-carboxylic acid, ethyl ester; B) add entry, concentrated hydrochloric acid in the product of a step gained, stirring and refluxing is complete to hydrolysis, and transferring PH with alkali lye is 7.0, adds chloroform extraction, and concentrated extract layer promptly gets Ofloxacine USP 23
4. the preparation method of Ofloxacine USP 23 according to claim 3 is characterized in that the alkali of a in the step is salt of wormwood, sodium bicarbonate, triethylamine or pyridine.The no text of this page or leaf
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
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CNB200410155139XA CN100412075C (en) | 2004-06-22 | 2004-06-22 | Process for preparing L-ofloxacin and ofloxacin |
PCT/CN2004/000954 WO2005123746A1 (en) | 2004-06-22 | 2004-08-16 | Methods for preparation of levofloxacin and ofloxacin |
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CNB200410155139XA CN100412075C (en) | 2004-06-22 | 2004-06-22 | Process for preparing L-ofloxacin and ofloxacin |
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CN1594320A CN1594320A (en) | 2005-03-16 |
CN100412075C true CN100412075C (en) | 2008-08-20 |
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CNB200410155139XA Expired - Fee Related CN100412075C (en) | 2004-06-22 | 2004-06-22 | Process for preparing L-ofloxacin and ofloxacin |
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WO (1) | WO2005123746A1 (en) |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
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CN101514208B (en) * | 2008-10-17 | 2011-03-16 | 浙江京新药业股份有限公司 | Green synthesizing process for ofloxacin |
CN101648960B (en) * | 2009-09-04 | 2011-08-10 | 诚达药业股份有限公司 | Method for preparing ofloxacin |
CN103113388B (en) * | 2013-02-01 | 2016-02-10 | 浙江国邦药业有限公司 | A kind of preparation method of levofloxacin |
CN105198904B (en) * | 2014-06-25 | 2017-08-15 | 上虞京新药业有限公司 | The preparation method of lavo-ofloxacin and Ofloxacin |
CN107677735A (en) * | 2016-08-02 | 2018-02-09 | 上海朴颐化学科技有限公司 | A kind of HPLC analysis methods of (S) 2 aminopropanol |
CN112552261A (en) * | 2019-09-26 | 2021-03-26 | 宜昌东阳光长江药业股份有限公司 | Preparation method of levofloxacin and intermediate thereof |
CN114507242B (en) * | 2022-01-26 | 2023-05-19 | 上虞京新药业有限公司 | Preparation method of levofloxacin with high optical purity |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4382892A (en) * | 1980-09-02 | 1983-05-10 | Daiichi Seiyaku Co., Ltd. | Benzoxazine derivatives |
US4777253A (en) * | 1986-04-25 | 1988-10-11 | Abbott Laboratories | Process for preparation of racemate and optically active ofloxacin and related derivatives |
WO2003028664A2 (en) * | 2001-10-03 | 2003-04-10 | Teva Pharmaceutical Industries Ltd. | Preparation of levofloxacin and forms thereof |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
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JPS62215591A (en) * | 1986-03-14 | 1987-09-22 | Dainippon Pharmaceut Co Ltd | Production of pyridobenzoxazine derivative and intermediate therefor |
DE4342186A1 (en) * | 1993-12-10 | 1995-06-14 | Bayer Ag | One-pot process for the production of 3-quinolonecarboxylic acid derivatives |
JP2001031654A (en) * | 1999-07-22 | 2001-02-06 | Fuji Yakuhin:Kk | New quinolinecarboxylic acid derivative and its production and use |
-
2004
- 2004-06-22 CN CNB200410155139XA patent/CN100412075C/en not_active Expired - Fee Related
- 2004-08-16 WO PCT/CN2004/000954 patent/WO2005123746A1/en active Application Filing
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4382892A (en) * | 1980-09-02 | 1983-05-10 | Daiichi Seiyaku Co., Ltd. | Benzoxazine derivatives |
US4777253A (en) * | 1986-04-25 | 1988-10-11 | Abbott Laboratories | Process for preparation of racemate and optically active ofloxacin and related derivatives |
WO2003028664A2 (en) * | 2001-10-03 | 2003-04-10 | Teva Pharmaceutical Industries Ltd. | Preparation of levofloxacin and forms thereof |
Non-Patent Citations (2)
Title |
---|
左旋氧氟沙星不对称合成工艺的研究. 李家明等人.中国药物化学杂志,第10卷第4期. 2000 |
左旋氧氟沙星不对称合成工艺的研究. 李家明等人.中国药物化学杂志,第10卷第4期. 2000 * |
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WO2005123746A1 (en) | 2005-12-29 |
CN1594320A (en) | 2005-03-16 |
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