CN102070650A - Preparation method for levofloxacin-N-oxide - Google Patents
Preparation method for levofloxacin-N-oxide Download PDFInfo
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- CN102070650A CN102070650A CN 201110030762 CN201110030762A CN102070650A CN 102070650 A CN102070650 A CN 102070650A CN 201110030762 CN201110030762 CN 201110030762 CN 201110030762 A CN201110030762 A CN 201110030762A CN 102070650 A CN102070650 A CN 102070650A
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- Prior art keywords
- levofloxacin
- oxide compound
- reaction
- crystal
- water
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- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- MVLAUMUQGRQERL-JTQLQIEISA-N levofloxacin n-oxide Chemical compound C([C@@H](N1C2=C(C(C(C(O)=O)=C1)=O)C=C1F)C)OC2=C1N1CC[N+](C)([O-])CC1 MVLAUMUQGRQERL-JTQLQIEISA-N 0.000 title abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims abstract description 30
- GSDSWSVVBLHKDQ-JTQLQIEISA-N Levofloxacin Chemical compound C([C@@H](N1C2=C(C(C(C(O)=O)=C1)=O)C=C1F)C)OC2=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-JTQLQIEISA-N 0.000 claims abstract description 27
- 229960003376 levofloxacin Drugs 0.000 claims abstract description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 21
- 238000000034 method Methods 0.000 claims abstract description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 12
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000002904 solvent Substances 0.000 claims abstract description 5
- -1 levofloxacin-N-oxide compound Chemical class 0.000 claims description 40
- 239000013078 crystal Substances 0.000 claims description 27
- 239000012043 crude product Substances 0.000 claims description 12
- 239000000706 filtrate Substances 0.000 claims description 12
- 238000005406 washing Methods 0.000 claims description 12
- 238000001953 recrystallisation Methods 0.000 claims description 11
- 238000002425 crystallisation Methods 0.000 claims description 9
- 238000001914 filtration Methods 0.000 claims description 6
- 239000006210 lotion Substances 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 6
- 230000008025 crystallization Effects 0.000 claims description 3
- 239000012535 impurity Substances 0.000 abstract description 13
- 239000000047 product Substances 0.000 abstract description 9
- 239000002994 raw material Substances 0.000 abstract description 5
- 239000006227 byproduct Substances 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract description 2
- 238000004821 distillation Methods 0.000 abstract 1
- 238000001035 drying Methods 0.000 abstract 1
- 238000002156 mixing Methods 0.000 abstract 1
- 239000000203 mixture Substances 0.000 abstract 1
- GSDSWSVVBLHKDQ-UHFFFAOYSA-N 9-fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid Chemical compound FC1=CC(C(C(C(O)=O)=C2)=O)=C3N2C(C)COC3=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-UHFFFAOYSA-N 0.000 description 4
- 229960001699 ofloxacin Drugs 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000013558 reference substance Substances 0.000 description 3
- 239000003513 alkali Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000005286 illumination Methods 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- SWWQQSDRUYSMAR-UHFFFAOYSA-N 1-[(4-hydroxyphenyl)methyl]-1,2,3,4-tetrahydroisoquinoline-6,7-diol;hydrochloride Chemical group Cl.C1=CC(O)=CC=C1CC1C2=CC(O)=C(O)C=C2CCN1 SWWQQSDRUYSMAR-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000000356 contaminant Substances 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- 229940093181 glucose injection Drugs 0.000 description 1
- 230000008676 import Effects 0.000 description 1
- 229940089519 levaquin Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000008381 oxidative degradant Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- NVKWWNNJFKZNJO-RXMQYKEDSA-N oxygen-fluorine acid Chemical compound N1([C@H](C)CO2)C=C(C(O)=O)C(=O)C3=C1C2=C(F)C(F)=C3 NVKWWNNJFKZNJO-RXMQYKEDSA-N 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
Landscapes
- 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 invention provides a preparation method for levofloxacin-N-oxide and relates to the field of a levofloxacin medicament. The preparation method comprises the following steps of: mixing the levofloxacin and 0.1mol/L hydrochloric acid solution according to a proportion of 0.03mol: 500ml, and dissolving the mixture at the temperature of between 80 and 100 DEG C; adding 100ml of hydrogen peroxide solution having the mass concentration of 30 percent by three times at the temperature of between 60 and 80 DEG C; reacting for 3 to 5 hours each time to obtain reaction solution; drying the reaction solution through distillation; and recrystallizing the residual water. The selection of the raw materials is convenient for the subsequential separating operation; by adding the hydrogen peroxide solution in steps, the progress of the reaction is controlled, the generation of byproducts is reduced, the conversion rate of the levofloxacin-N-oxide is improved and the generation of impurities is reduced; and by the method, the condition is easy to control, the route is simple, the solvent is obtained easily, the yield is 88.7 percent, the cost of the levofloxacin-N-oxide serving as a contrast is reduced greatly, and the product purity is high and over 99.5 percent, so the levofloxacin-N-oxide can be used as a working contrast.
Description
Technical field
The present invention relates to medicine levofloxacin field, the preparation method of particularly a kind of levofloxacin-N-oxide compound.
Background technology
Levofloxacin (Levofloxacin) is the levo form of Ofloxacine USP 23, has has a broad antifungal spectrum, characteristics that anti-microbial effect is strong.Japan Daiichi Pharmaceutical Co., Ltd. in 1993 at Japanese list marketing levofloxacin raw material and tablet, and now in multinational listings such as Britain, the U.S..The Levaquin of present domestic listing mainly contains tablet, little pin, glucose injection and eye drops etc.At present domestic and international more bibliographical information the known impurities of Ofloxacine USP 23, and it is less about the research report of levofloxacin known impurities, but known impurities and synthetic route by Ofloxacine USP 23 can be inferred, levofloxacin contains probably with the different process contaminants of the identical and three-dimensional configuration of Ofloxacine USP 23 structural formula, its steric configuration all should be levo form, and this impurity research to levofloxacin has higher reference value.
The quality standard of levofloxacin is recorded in national standard and import standard at present, all known impurities is not controlled, according to bibliographical information, M. [Lalitha Devi M such as Lalitha Devi, Chandrasekhar K B. A validated stability-indicating RP-HPLC method for levofloxacin in the presence of degradation products, its process related impurities and identification of oxidative degradant[J]. J Pharm Biomed Anal, 2009,50 (5): 710-707] adopt reversed-phased high performace liquid chromatographic, to levofloxacin acid, alkali, oxidation, illumination, high temperature destroys sample and detects, found that levofloxacin is at alkali (0.5N NaOH), high temperature, more stable under the conditions such as illumination, substantially do not detect the generation degraded product, and in acid (0.5N HCL), place after 7 days, micro-degraded product occurred for 70 ℃; H 0.01%
2O
2The middle placement after 12 hours produces tangible degraded product.Wherein at H
2O
2The middle placement in the degraded product that produces contained levofloxacin-N-oxide compound, CAS 178964-53-9, and molecular formula is C
18H
20FN
3O
5, molecular weight is 377, chemical name:
4-[(S) 6-carboxyl-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7
H-pyrido [1,2,3-
De]-1,4-benzoxazine-10-yl]-1-methylpiperazine-1-oxide compound, English name is 4-[(
S)-6-carboxy-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7
H-pyrido[1,2,3-
De]-1,4-benzoxazine-10-yl]-1-methylpiperazine 1-oxide, though the existing abroad bibliographical information of the structural research of this impurity, its preparation method does not still have open report both at home and abroad.
Summary of the invention
In order to overcome the above problems, the invention provides the method that levofloxacin prepares levofloxacin-N-oxide compound of passing through that a kind of technology is simple, product purity is high.
The present invention is achieved by the following measures:
The preparation method of a kind of levofloxacin-N-oxide compound may further comprise the steps:
(1) hydrochloric acid soln of levofloxacin and 0.1mol/L is pressed 0.03mol: the mixed of 500ml is stirred to dissolving under 80～100 ℃ of conditions of temperature;
Add mass concentration under (2) 60～80 ℃ of conditions and be 30% hydrogen peroxide solution 100ml, behind reaction 3～5h, add hydrogen peroxide solution 100ml, reaction 3～5h adds hydrogen peroxide solution 100ml, reaction 3～5h, reaction soln;
(3), and remove residual H with the reaction soln water bath method
2O
2, get residue, with water as solvent residue is carried out recrystallization, get levofloxacin-N-oxide compound.
Recrystallization may further comprise the steps:
(1) crystallization: residue is added the water of 120 times of weight, be heated to 80 ℃, stir and make the residue dissolving, filter, filtrate volume is concentrated into 2/3, puts 4 ℃ of refrigerators and places 2 hours, separate out crystal, filter, crystal washes several times with water, merging filtrate and washing lotion are concentrated into 200ml, put 4 ℃ of refrigerators and place 2 hours, separate out crystal, repeat filtration, washing, crystallisation step 3 times, merge the gained crystal, promptly get levofloxacin-N-oxide compound crude product 1;
(2) recrystallization: get levofloxacin-N-oxide compound crude product 1, add the water of 150 times of weight, be heated to 60 ℃ of stirrings and make levofloxacin-N-oxide compound crude product 1 dissolving, filter, filtrate is concentrated into 2/5, puts 4 ℃ of refrigerators and places 2 hours, separate out crystal, filter, crystal washes several times with water, merging filtrate and washing lotion are concentrated into 200ml, put 4 ℃ of refrigerators and place 2 hours, separate out crystal, repeat filtration, washing, crystallisation step 3 times, merge the gained crystal, promptly get levofloxacin-N-oxide compound crude product 2;
(3) repeating step (2) is 1-2 time, and the gained crystal is levofloxacin-N-oxide compound.
The hydrochloric acid soln of levofloxacin and 0.1mol/L mixes in the reaction flask of prolong is housed.
Reaction formula is as shown in the formula 1:
Method of the present invention is raw material with the levofloxacin, adopts HCL and H
2O
2As oxygenant, accurately control levofloxacin and HCL, levofloxacin and H
2O
2Ratio, and H
2O
2Dividing three times adds, can make oxidizing reaction more abundant, reduce other the oxidized probability of N, control the transformation efficiency of levofloxacin-N-oxide compound, reduce the generation of side reactions (seeing reaction formula 2 and reaction formula 3) such as decarboxylation, demethyl, to improve the purity of gained levofloxacin-N-oxide compound as far as possible as far as possible; Adopt repeatedly water recrystallization, control strength of solution and Tc, the impurity that will contain is removed as wide as possible, has also improved the purity of levofloxacin-N-oxide compound.
Reaction formula 2:
Reaction formula 3:
Beneficial effect of the present invention:
1, with the levofloxacin be raw material, employing HCL is a reaction medium, H
2O
2As oxygenant, HCL and H
2O
2Can pass through heated volatile, not introduce new impurity, be convenient to follow-up mask work, by the substep adding of hydrogen peroxide solution, the progress of control reaction reduces the generation of by product, improves the transformation efficiency of levofloxacin-N-oxide compound, the generation of minimizing impurity;
2, condition of the present invention is easily controlled, and route is simple, and solvent is easy to get, and productive rate is 88.7%, can reduce levofloxacin-N-oxide compound cost of product in contrast greatly;
3, the levofloxacin-N-oxide compound of the present invention's preparation is through the water recrystallization, and products obtained therefrom purity height can reach more than 99.5%, can be used as the work reference substance and uses;
4, synthetic levofloxacin-N-oxide compound not only provides reference substance for the impurity evaluation and the impurity detection of levofloxacin, for the raising of the quality standard of levofloxacin and preparation thereof and the quality control of product provide useful reference, also provide reference for similar compound synthetic.
Description of drawings
The HPLC spectrogram of the levofloxacin that accompanying drawing 1 obtains for the inventive method-N-oxide compound.
Embodiment
Below in conjunction with embodiment method of the present invention is further specified.
(1) get levofloxacin raw material 0.03mol, quality is 10.83g, puts into the reaction flask that prolong is housed, and adds the hydrochloric acid soln 500ml of 0.1mol/L, is stirred to the levofloxacin dissolving under 80～100 ℃ of conditions of temperature;
Add mass concentration in (2) 80～100 ℃ of condition downhill reaction bottles and be 30% hydrogen peroxide solution 100ml, behind reaction 3～5h, add hydrogen peroxide solution 100ml again, reaction 3～5h adds hydrogen peroxide solution 100ml again, reaction 3～5h, reaction soln;
(3), and remove residual HCL and H with the water bath method of reaction soln with 100 ℃
2O
2, get residue 11.2g, with water as solvent residue is carried out recrystallization, get levofloxacin-N-oxide compound.
The step of recrystallization is as follows:
(1) crystallization: residue is added the water of 120 times of weight, be heated to 80 ℃, stir and make the residue dissolving, filter, filtrate volume is concentrated into 2/3, puts 4 ℃ of refrigerators and places 2 hours, separate out crystal, filter, crystal washes several times with water, merging filtrate and washing lotion are concentrated into 200ml, put 4 ℃ of refrigerators and place 2 hours, separate out crystal, repeat filtration, washing, crystallisation step 3 times, merge the gained crystal, promptly get levofloxacin-N-oxide compound crude product 1;
(2) recrystallization: get levofloxacin-N-oxide compound crude product 1, add the water of 150 times of weight, be heated to 60 ℃ of stirrings and make levofloxacin-N-oxide compound crude product 1 dissolving, filter, filtrate is concentrated into 2/5, puts 4 ℃ of refrigerators and places 2 hours, separate out crystal, filter, crystal washes several times with water, merging filtrate and washing lotion are concentrated into 200ml, put 4 ℃ of refrigerators and place 2 hours, separate out crystal, repeat filtration, washing, crystallisation step 3 times, merge the gained crystal, promptly get levofloxacin-N-oxide compound crude product 2;
(3) repeating step (2) is 1-2 time, and gained crystal 10g is levofloxacin-N-oxide compound, and ultimate yield is greater than 88%.
Adopt the HPLC method to the detecting of levofloxacin-N-oxide compound of obtaining by the inventive method, collection of illustrative plates is seen Fig. 1.The purity that draws levofloxacin-N-oxide compound that the inventive method obtains with the peak area normalization method reaches more than 99.5%, satisfies the service requirements as the work reference substance fully.
Claims (3)
1. the preparation method of levofloxacin-N-oxide compound is characterized in that may further comprise the steps:
(1) hydrochloric acid soln of levofloxacin and 0.1mol/L is pressed 0.03mol: the mixed of 500ml is stirred to dissolving under 80～100 ℃ of conditions of temperature;
Add mass concentration under (2) 60～80 ℃ of conditions and be 30% hydrogen peroxide solution 100ml, behind reaction 3～5h, add hydrogen peroxide solution 100ml, reaction 3～5h adds hydrogen peroxide solution 100ml, reaction 3～5h, reaction soln;
(3), and remove residual H with the reaction soln water bath method
2O
2, get residue, with water as solvent residue is carried out recrystallization, get levofloxacin-N-oxide compound.
2. method according to claim 1 is characterized in that recrystallization may further comprise the steps:
(1) crystallization: residue is added the water of 120 times of weight, be heated to 80 ℃, stir and make the residue dissolving, filter, filtrate volume is concentrated into 2/3, puts 4 ℃ of refrigerators and places 2 hours, separate out crystal, filter, crystal washes several times with water, merging filtrate and washing lotion are concentrated into 200ml, put 4 ℃ of refrigerators and place 2 hours, separate out crystal, repeat filtration, washing, crystallisation step 3 times, merge the gained crystal, promptly get levofloxacin-N-oxide compound crude product 1;
(2) recrystallization: get levofloxacin-N-oxide compound crude product 1, add the water of 150 times of weight, be heated to 60 ℃ of stirrings and make levofloxacin-N-oxide compound crude product 1 dissolving, filter, filtrate is concentrated into 2/5, puts 4 ℃ of refrigerators and places 2 hours, separate out crystal, filter, crystal washes several times with water, merging filtrate and washing lotion are concentrated into 200ml, put 4 ℃ of refrigerators and place 2 hours, separate out crystal, repeat filtration, washing, crystallisation step 3 times, merge the gained crystal, promptly get levofloxacin-N-oxide compound crude product 2;
(3) repeating step (2) is 1-2 time, and the gained crystal is levofloxacin-N-oxide compound.
3. method according to claim 1 and 2 is characterized in that the hydrochloric acid soln of levofloxacin and 0.1mol/L mixes in the reaction flask of prolong is housed.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011100307622A CN102070650B (en) | 2011-01-28 | 2011-01-28 | Preparation method for levofloxacin-N-oxide |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011100307622A CN102070650B (en) | 2011-01-28 | 2011-01-28 | Preparation method for levofloxacin-N-oxide |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102070650A true CN102070650A (en) | 2011-05-25 |
| CN102070650B CN102070650B (en) | 2012-06-27 |
Family
ID=44029428
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2011100307622A Expired - Fee Related CN102070650B (en) | 2011-01-28 | 2011-01-28 | Preparation method for levofloxacin-N-oxide |
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| Country | Link |
|---|---|
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102558197A (en) * | 2012-01-11 | 2012-07-11 | 浙江医药股份有限公司新昌制药厂 | Preparation method of levofloxacin-N-oxide |
| CN102775424A (en) * | 2012-07-09 | 2012-11-14 | 浙江司太立制药股份有限公司 | Preparation method for levofloxacin impurity |
| CN106632279A (en) * | 2016-12-01 | 2017-05-10 | 北京万全德众医药生物技术有限公司 | Preparation method for vilazodone monoxide |
| CN107011362A (en) * | 2017-05-24 | 2017-08-04 | 扬子江药业集团江苏海慈生物药业有限公司 | A kind of synthetic method of lavo-ofloxacin isomeric compound |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030144511A1 (en) * | 2001-10-03 | 2003-07-31 | Valerie Niddam-Hildesheim | Methods for the purification of levofloxacin |
| CN1596256A (en) * | 2001-11-29 | 2005-03-16 | 特瓦制药工业有限公司 | Methods for the purification of levofloxacin |
-
2011
- 2011-01-28 CN CN2011100307622A patent/CN102070650B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030144511A1 (en) * | 2001-10-03 | 2003-07-31 | Valerie Niddam-Hildesheim | Methods for the purification of levofloxacin |
| CN1596256A (en) * | 2001-11-29 | 2005-03-16 | 特瓦制药工业有限公司 | Methods for the purification of levofloxacin |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102558197A (en) * | 2012-01-11 | 2012-07-11 | 浙江医药股份有限公司新昌制药厂 | Preparation method of levofloxacin-N-oxide |
| CN102775424A (en) * | 2012-07-09 | 2012-11-14 | 浙江司太立制药股份有限公司 | Preparation method for levofloxacin impurity |
| CN106632279A (en) * | 2016-12-01 | 2017-05-10 | 北京万全德众医药生物技术有限公司 | Preparation method for vilazodone monoxide |
| CN107011362A (en) * | 2017-05-24 | 2017-08-04 | 扬子江药业集团江苏海慈生物药业有限公司 | A kind of synthetic method of lavo-ofloxacin isomeric compound |
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| Publication number | Publication date |
|---|---|
| CN102070650B (en) | 2012-06-27 |
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Inventor after: Shi Guosheng Inventor after: Wang Weijian Inventor after: Li Tao Inventor after: Xie Yuanchao Inventor after: Sui Liya Inventor after: Liu Qi Inventor before: Wang Weijian Inventor before: Li Tao Inventor before: Xie Yuanchao Inventor before: Sui Liya Inventor before: Liu Qi |
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Free format text: CORRECT: INVENTOR; FROM: WANG WEIJIAN LI TAO XIE YUANCHAO SUI LIYA LIU QI TO: SHI GUOSHENG WANG WEIJIAN LI TAO XIE YUANCHAO SUI LIYA LIU QI |
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