CN114195761A - Preparation method of high-purity sitafloxacin 3/2 hydrate - Google Patents
Preparation method of high-purity sitafloxacin 3/2 hydrate Download PDFInfo
- Publication number
- CN114195761A CN114195761A CN202111592708.7A CN202111592708A CN114195761A CN 114195761 A CN114195761 A CN 114195761A CN 202111592708 A CN202111592708 A CN 202111592708A CN 114195761 A CN114195761 A CN 114195761A
- Authority
- CN
- China
- Prior art keywords
- sitafloxacin
- purity
- water
- hydrate
- solvent
- Prior art date
- 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
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The invention discloses a preparation method of high-purity sitafloxacin 3/2 hydrate, which comprises the following steps: mixing the sitafloxacin crude product, water, a solvent and ammonia water, dissolving, filtering, then distilling the filtrate under reduced pressure or introducing inert gas for crystallization, and supplementing a fresh mixed solution of the solvent and the water when the total volume change exceeds 5-15%; when the pH value is 8.0-9.5, cooling, introducing inert gas, and continuing crystallization; and after the crystallization end point is reached, carrying out post-treatment to obtain the high-purity sitafloxacin 3/2 hydrate. The sitafloxacin prepared by the preparation method has high purity, maximum impurities of less than or equal to 0.6 per mill, high content, white appearance and good long-term stability.
Description
Technical Field
The invention belongs to the field of chemical pharmacy, and particularly relates to a preparation method of high-purity sitafloxacin 3/2 hydrate.
Background
Sitafloxacin (sitafloxacin hydrate) was developed by the first three co-company corporation as a quinolone antibacterial agent, and 3/2 hydrate thereof was used clinically. Sitafloxacin is a novel oral antibacterial drug with broad-spectrum antibacterial effect, not only has antibacterial activity on gram-negative bacteria, but also has stronger antibacterial activity on gram-positive bacteria, anaerobic bacteria, mycoplasma, chlamydia and the like, and also has good bactericidal action on a plurality of clinically common fluoroquinolone-resistant strains.
Chemical name of sitafloxacin: 7- [ (7S) -7-amino-5-azaspiro [2.4] hept-5-yl ] -8-chloro-6-fluoro-1- [ (1R,2S) -cis-2-fluorocyclopropyl ] -1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid. The structural formula is as follows:
sitafloxacin is a polymorphic compound, and anhydrous alpha, beta forms, hydrated 1/2 hydrate, 1 hydrate, 3/2 hydrate, in total five crystal forms are reported in the literature [ International Journal of pharmaceuticals (2012)422, 1-8 ]. The crystal form of the clinical medicine is 3/2 hydrate. The three crystal forms of the water-containing compound can be converted into alpha and beta forms by heat treatment.
The original patent CN1106006 discloses a preparation method and parameter ranges of five crystal forms of sitafloxacin, wherein 3/2 hydrate is obtained by recrystallization of ammonia water and a hydrous ethanol solvent. The preparation method of the 3/2 hydrate comprises the following steps: dissolving the crude product in a mixed solvent of ethanol, water and ammonia water, decoloring by using activated carbon, evaporating about half of the solvent under reduced pressure, cooling to room temperature, and drying in vacuum to obtain 3/2 hydrate. The process has the problems that the product obtained by recrystallization has high impurity, poor purity, dark and yellow appearance and high solvent residue.
Patent CN105566287 discloses a method for preparing sitafloxacin 3/2 hydrate by recrystallization under acetic acid system condition, the yield of the product recrystallized by the process is only 86%, and the product stability under acidic condition during enlarged production is poor.
Chinese patent application publication No. CN 103524887 a discloses a preparation method of sitafloxacin and a refining method of sitafloxacin, wherein ethanol and ammonia water are adopted to dissolve sitafloxacin, and acetone is added to precipitate crystals; however, the inventors have repeated this process and found that when ethanol: when the ammonia water is 2:1, sitafloxacin is not easy to dissolve, and the concentration of the used ammonia water is high, so that impurities are increased; meanwhile, the process is accompanied with solidification of oily coagula during crystallization, so that the appearance of the product is uneven and partial yellow; during centrifugal suction filtration, the ammonia gas has a strong taste, and the working environment of a crystallization area is influenced; the product has poor stability and is easy to discolor; in addition, the inventors of the present application, according to the purification method described in the text thereof, increased the purity of sitafloxacin from about 99.4% to about 99.7%, and the yield was only 75%, and the purification efficiency was not high.
In summary, the recrystallization method reported in the existing patents and literatures for preparing sitafloxacin 3/2 hydrate generally has the defects of large amount of impurities, large single impurity, large repeatability difference among batches and dark appearance color of the obtained product.
Disclosure of Invention
The invention provides a preparation method of high-purity sitafloxacin 3/2 hydrate, which has the advantages of high yield, high purity of the obtained product, less impurities and convenient repetition.
A preparation method of high-purity sitafloxacin 3/2 hydrate comprises the following steps:
mixing the crude sitafloxacin hydrate, water, a solvent and ammonia water, dissolving, filtering, distilling the filtrate under reduced pressure or introducing inert gas, supplementing the mixed solvent of the fresh solvent and the water for crystallization when the volume change in the kettle exceeds 5-15%, cooling and introducing the inert gas for continuous crystallization when the pH value is 8.0-9.5, and performing post-treatment to obtain the high-purity sitafloxacin 3/2 hydrate after the crystallization end point is reached.
According to the novel crystallization method of the sitafloxacin 3/2 hydrate, a certain amount of water is additionally supplemented as a solvent besides a crystallization solvent and ammonia water, then ammonia gas in the system is driven out in a reduced pressure distillation or inert gas introduction mode, when a specified pH value is reached, crystallization is continuously carried out in an inert gas introduction mode, sitafloxacin crystals can be stably separated out, and the obtained product is high in purity, few in impurities and white in appearance.
The solvent used in the preparation method of the invention is obtained by a large number of experiments. The solvent used in the experiment process comprises one or a mixture of two of water, ammonia water, methanol, ethanol, isopropanol, n-butanol, acetonitrile, dichloromethane, ethyl acetate, acetone, toluene and tetrahydrofuran, and the most preferable solvent is ethanol.
Preferably, when mixing is carried out in the initial stage, the proportion range of the sitafloxacin crude product, the solvent, the water and the ammonia water is as follows: the weight ratio of the sitafloxacin crude product to the solvent to the water to the ammonia water is 1: (2-5): (3-8): (1-4). Compared with the method without adding water, the addition of water can promote the dissolution of the crude sitafloxacin so as to ensure the smooth proceeding of the subsequent crystallization.
The inert gas introduced by the invention is argon, nitrogen and the like, and nitrogen is generally adopted. The flow rate can be controlled to be 1-10L/h according to the feeding amount. The inert gas can be recycled after being treated and absorbed by acid, and the acid is usually hydrochloric acid, sulfuric acid, acetic acid, phosphoric acid or aqueous solution of nitric acid, and the like.
In the preparation method, the concentration of the used ammonia water is 10-28%, and the preferable application range is that the concentration of the ammonia water is 20-28%. The adding temperature of the ammonia water is usually 30-60 ℃, and preferably 40-60 ℃.
When the volume in the crystallization kettle is controlled to be continuously reduced and distilled or inert gas is introduced for recrystallization, the mixed solution of fresh solvent and water is supplemented to keep the volume in the crystallization kettle constant. The weight ratio of water to the solvent in the fresh mixed solvent is supplemented to be 10: 1-1: 10, and is further preferably controlled to be 6: 1-1: 6. The weight or volume of the added mixed solvent is regulated to be constant within the control kettle by +/-10%.
In the preparation method of the invention, before the pH value reaches 8.0-9.5, the temperature in the crystallization kettle is controlled to be 30-50 ℃, the reduced pressure distillation or the inert gas introduction is carried out, and the temperature is further preferably controlled to be 35-45 ℃.
In the preparation method, after the pH value reaches 8.0-9.5, the temperature of the inert gas is reduced and the inert gas is introduced at 0-5 ℃, and the stirring time is 1-3 hours.
Compared with the prior art, the invention has the beneficial effects that:
(1) by adopting the preparation method, the obtained sitafloxacin hydrate has high purity, the maximum impurity is less than or equal to 0.6 per mill, the content is high, the appearance is white, the long-term stability is good, and the sitafloxacin hydrate is convenient to store for a long time;
(2) the preparation method has the advantage of high product yield and is convenient for industrial application.
Drawings
FIG. 1 is an X-ray diffraction powder diffraction pattern of sitafloxacin 3/2 hydrate of the present invention;
FIG. 2 is a mass spectrum of sitafloxacin 3/2 hydrate;
FIG. 3 is a hydrogen spectrum of sitafloxacin 3/2 hydrate;
FIG. 4 is a carbon spectrum of sitafloxacin 3/2 hydrate;
fig. 5 is an infrared spectrum of sitafloxacin 3/2 hydrate.
Detailed Description
The general operational steps of the present invention include:
under the protection of inert gas, adding a sitafloxacin crude product, water, ethanol and ammonia water into a crystallization kettle in a ratio of 1: 2-5: 3-8: 1-4 (weight ratio), heating to 30-60 ℃, stirring for 20-60 minutes, dissolving and clearing, and performing heat filtration. Controlling the temperature in the kettle to be 30-50 ℃, and distilling the filtrate under reduced pressure or continuously introducing inert gas; keeping the volume in the kettle constant during distillation or gas introduction, and supplementing a fresh ethanol/water mixed solution when the volume change in the kettle exceeds +/-10%, wherein the material ratio in the mixed solution is controlled as follows: water is in a range of 10:1 to 1:10 (weight ratio); the temperature of the cooling device is required to be within the range of-20 to 15 ℃ to condensate the distilled ethanol/water mixed solution; and (3) introducing ammonia taken away by the introduced inert gas (the flow rate is 1-10 liters/hour) into the acidic solution, recovering the ammonia into ammonium salt, and introducing the inert gas into the next recrystallization reaction kettle. Distilling under reduced pressure or introducing inert gas into the crystallization kettle, wherein the pH value of the crystallization liquid in the kettle is 5.0-9.5 as the crystallization end point. And cooling the crystallization kettle to 0-5 ℃, and preserving heat for 2 hours. Centrifuging, washing with water, ethanol/water, and ethanol. And drying at 20-25 ℃ under reduced pressure to obtain the product, wherein the yield is 90-97%.
The concrete preparation method of the sitafloxacin crude product comprises the following steps:
trifluoroacetic acid (5.5L) was added to a reaction flask equipped with a mechanical stirring device and a thermometer, cooled to-5 ℃ with stirring, added with 7- [ (7S) -7-tert-butoxycarbonylamino-5-azaspiro [2,4] -hept-5-yl ] -8-chloro-6-fluoro-1- [ (1R,2S) -cis-2-fluoro-1-cyclopropyl ] -1, 4-dihydro-4-oxoquinoline-3-carboxylic acid (540g, 1.06mol) and anisole (110ml), slowly warmed to 0-5 ℃ and stirred for 30min (HPLC showed less than 0.5% residue of starting material). Concentrating under reduced pressure at 35 deg.C, adding dichloromethane (4.5L) into the residue, adding 0.5mol/L sodium hydroxide solution (about 150L) at 0-10 deg.C to adjust pH to 10-12, separating out water layer after the solid is completely dissolved, and extracting the organic layer with 0.1mol/L sodium hydroxide (1.5L × 2). The aqueous layers were combined, washed with dichloromethane (4L × 2), filtered, the filtrate was adjusted to pH 7 by the addition of 15% citric acid solution (about 4.8L) at 0-10 ℃, stirred at the same temperature for 30min, filtered, the filter cake was washed with water and dried at 40 ℃ under reduced pressure for 12h to give crude yellow solid (410 g).
The present invention is further described below with reference to examples to enable those skilled in the art to better understand the present invention. The examples are illustrative only and are not meant to limit the scope of the invention in any way.
Example 1
Adding 10g of sitafloxacin crude product (with HPLC purity of 99.4%), 35g of ethanol and 60g of water into a reaction kettle, slowly heating to 50-55 ℃, adding 28g of 28% ammonia water, dissolving, and performing constant-temperature filter pressing; introducing 3 liters of nitrogen flow into the filtrate per hour, starting a condenser to cool to 0-5 ℃, and neutralizing the tail gas by 50% sulfuric acid water solution to convert the tail gas into ammonium sulfate; and (3) cooling the crystallization kettle to 35-40 ℃, continuously introducing nitrogen into the reaction kettle, supplementing 20g of 15% water-ethanol mixed solvent, cooling to 0-5 ℃ when the pH of the crystallization kettle reaches 8-9, and continuously introducing nitrogen. Stirring for 2 hours at a constant temperature of 0-5 ℃, centrifuging, and drying to obtain 9.5g of sitafloxacin finished product, wherein the yield is 95%, the purity is 99.8%, and the X-diffraction powder diffraction spectrogram, the mass spectrum, the hydrogen spectrum, the carbon spectrum and the infrared spectrogram of the obtained sitafloxacin finished product are shown in figures 1-5.
Meanwhile, the stability test is carried out on the finished sitafloxacin hydrate product, the temperature is 25 ℃, the humidity is 60 +/-10%, and the long-term stability test result is shown in the following table:
example 2
Adding 10g of sitafloxacin crude product (with HPLC purity of 99.4%), 55g of ethanol and 30g of water into a reaction kettle, slowly heating to 50-55 ℃, adding 25g of 28% ammonia water for clearing, and then carrying out heat preservation and filter pressing; blowing nitrogen gas flow into the filtrate for 2 liters/hour, starting a condenser to cool to 0-5 ℃, and neutralizing tail gas by 50% sulfuric acid water solution to convert the tail gas into ammonium sulfate; continuously introducing nitrogen into a reaction kettle at the temperature of 45-50 ℃, and supplementing 30g of 25% water-ethanol mixed solvent; when the pH value of the crystallization kettle reaches 8-9, cooling to 0-5 ℃, and continuously introducing nitrogen. Stirring for 2 hours at a constant temperature of 0-5 ℃, centrifuging, and drying to obtain 9.6g of sitafloxacin finished product, wherein the yield is 96%, and the purity is 99.8%.
Example 3
Adding 10g of sitafloxacin crude product (with HPLC purity of 99.4%), 50g of ethanol and 25g of water into a reaction kettle, slowly heating to 50-55 ℃, adding 26g of 28% ammonia water for clearing, and then carrying out heat preservation and filter pressing; controlling the temperature in the kettle to be 35-40 ℃, distilling the filtrate under reduced pressure, and opening a condenser to cool to 0-5 ℃; in the process of reduced pressure distillation, 18 percent of aqueous ethanol solution is supplemented to keep the volume in the kettle constant; when the pH value in the crystallization kettle reaches 8-9, cooling to 0-5 ℃, and continuously introducing nitrogen. Stirring for 2 hours at a constant temperature of 0-5 ℃, centrifuging, and drying to obtain 9.4g of sitafloxacin finished product, wherein the yield is 94%, and the purity is 99.9%.
Example 4
Adding 10g of sitafloxacin crude product (with HPLC purity of 99.4%), 45g of ethanol and 25g of water into a reaction kettle, slowly heating to 50-55 ℃, adding 27g of 28% ammonia water for clearing, and then carrying out heat preservation and filter pressing; controlling the temperature in the kettle to be 35-40 ℃, distilling the filtrate under reduced pressure, and opening a condenser to cool to 0-5 ℃; in the process of reduced pressure distillation, 20 percent of aqueous ethanol solution is supplemented to keep the volume in the kettle constant; when the pH value in the crystallization kettle reaches 8-9, cooling to 0-5 ℃, and continuously introducing nitrogen. Stirring for 2 hours at a constant temperature of 0-5 ℃, centrifuging, and drying to obtain 9.7g of sitafloxacin finished product, wherein the yield is 97%, and the purity is 99.8%.
Comparative example 1
Adding 7.7g of crude crystals of 7- [ (7- (S) -amino-5-azaspiro [2,4] hept-5-yl ] -8-chloro-6-fluoro-1- [ (1R,2S) -2-fluorocyclopropyl ] -4-oxo-1, 4-dihydroquinoline-3-carboxylic acid into 45ml of ethanol, 37ml of water and 25ml of 28% ammonia water, heating to 45 ℃, stirring to dissolve, concentrating under reduced pressure (the vacuum degree is about 0.09MPa to 0.095MPa), distilling to about 37ml, stopping concentrating, cooling to room temperature, stirring for 30 minutes, filtering, washing and drying filter cakes to obtain pale yellow powder with the appearance of more than 0.05 percent, the yield of 85 percent and the HPLC purity of 99.7 percent.
Comparative example 2
Adding 1680ml of absolute ethyl alcohol/28% ammonia water (2:1, V/V) into 210g of sitafloxacin crude product, heating to 35-40 ℃, stirring for 1 hour until the mixture can not be dissolved, continuously heating to 50 ℃ for dissolving, adding activated carbon for decoloring, and filtering. And (2) adding 840ml of acetone into the filtrate at 35-40 ℃, cooling to 0-5 ℃ for 1 hour after adding, cooling (in the acetone adding process, the local supersaturation degree is high, the oil production phenomenon of the product is observed, oil drops are solidified to form a yellow coagulated product, the appearance and the purity of the product are influenced), filtering, and drying a filter cake at 40-45 ℃ to obtain sitafloxacin, wherein the maximum single impurity content is more than 0.05%, the yield is 75%, the HPLC purity is 99.8%, and the product appearance is uneven and is partially yellow.
The result of comparative example 2 shows that when the mixed solvent of absolute ethyl alcohol and ammonia water is directly adopted for dissolving, the crude sitafloxacin product is difficult to dissolve, the crystallization process is not easy to control by adopting the method, the yield of the obtained product is low, and the appearance of the product is not good.
Claims (10)
1. A preparation method of high-purity sitafloxacin 3/2 hydrate is characterized by comprising the following steps:
mixing the sitafloxacin crude product, water, a solvent and ammonia water, dissolving, filtering, then distilling the filtrate under reduced pressure or introducing inert gas for crystallization, and supplementing a fresh mixed solvent of the solvent and the water when the total volume change exceeds 5-15%; when the pH value is 8.0-9.5, cooling, introducing inert gas, and continuing crystallization; and after the crystallization end point is reached, carrying out post-treatment to obtain the high-purity sitafloxacin 3/2 hydrate.
2. The method for preparing high purity sitafloxacin 3/2 hydrate according to claim 1, wherein the solvent is ethanol.
3. The method for preparing high-purity sitafloxacin 3/2 hydrate according to claim 1 or 2, wherein the ratio of the crude sitafloxacin: solvent: water: the weight ratio of ammonia water is 1: (2-5): (3-8): (1-4).
4. The method for preparing high-purity sitafloxacin 3/2 hydrate according to claim 1 or 2, wherein the concentration of the ammonia water is 10-28%.
5. The method for preparing high-purity sitafloxacin 3/2 hydrate according to claim 1 or 2, wherein the temperature of mixing, dissolving and filtering is 30-60 ℃.
6. The preparation method of high-purity sitafloxacin 3/2 hydrate according to claim 1 or 2, wherein the inert gas is nitrogen or argon, and the feeding speed is 1-10L/h.
7. The method for preparing high-purity sitafloxacin 3/2 hydrate according to claim 1 or 2, wherein the temperature of reduced pressure distillation or inert gas introduction is 30-50 ℃.
8. The method for preparing high purity sitafloxacin 3/2 hydrate according to claim 1 or 2, wherein the supplemented solvent is ethanol;
in the mixed solvent, the weight ratio of water to ethanol is 10: 1-1: 10.
9. The preparation method of high-purity sitafloxacin 3/2 hydrate according to claim 8, wherein the weight ratio of water to ethanol in the supplemented mixed solvent is 6: 1-1: 6.
10. The preparation method of the high-purity sitafloxacin 3/2 hydrate according to claim 1 or 2, wherein the temperature of the inert gas is lowered to 0-5 ℃, and the stirring time is 1-3 hours.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111592708.7A CN114195761B (en) | 2021-12-23 | 2021-12-23 | Preparation method of high-purity sitafloxacin hydrate 3/2 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111592708.7A CN114195761B (en) | 2021-12-23 | 2021-12-23 | Preparation method of high-purity sitafloxacin hydrate 3/2 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN114195761A true CN114195761A (en) | 2022-03-18 |
| CN114195761B CN114195761B (en) | 2023-04-14 |
Family
ID=80656309
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202111592708.7A Active CN114195761B (en) | 2021-12-23 | 2021-12-23 | Preparation method of high-purity sitafloxacin hydrate 3/2 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114195761B (en) |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1246113A (en) * | 1997-02-05 | 2000-03-01 | 麦克公司 | Process for crystallization of reverse transcriptase inhibitor using anti-solvent |
| CN103508973A (en) * | 2012-06-25 | 2014-01-15 | 上海迪赛诺药业有限公司 | Efavirenz I type crystal preparation method |
| CN103524487A (en) * | 2013-09-29 | 2014-01-22 | 南京优科生物医药研究有限公司 | Sitafloxacin preparation method |
| CN105061395A (en) * | 2015-08-10 | 2015-11-18 | 江苏吴中医药集团有限公司 | Preparation method for sitafloxacin hydrate |
| CN105669646A (en) * | 2016-02-26 | 2016-06-15 | 济川药业集团有限公司 | Synthesis method of sitafloxacin hydrate |
| CN105906545A (en) * | 2016-05-06 | 2016-08-31 | 广州康瑞泰药业有限公司 | Preparation method for efficiently synthesizing Sitafloxacin midbody (7S)-5-azaspiro[2.4] heptanes-7-phenylbutane |
| CN106349218A (en) * | 2016-08-25 | 2017-01-25 | 山东齐都药业有限公司 | Method for preparing sitafloxacin |
-
2021
- 2021-12-23 CN CN202111592708.7A patent/CN114195761B/en active Active
Patent Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1246113A (en) * | 1997-02-05 | 2000-03-01 | 麦克公司 | Process for crystallization of reverse transcriptase inhibitor using anti-solvent |
| CN103508973A (en) * | 2012-06-25 | 2014-01-15 | 上海迪赛诺药业有限公司 | Efavirenz I type crystal preparation method |
| CN103524487A (en) * | 2013-09-29 | 2014-01-22 | 南京优科生物医药研究有限公司 | Sitafloxacin preparation method |
| CN105061395A (en) * | 2015-08-10 | 2015-11-18 | 江苏吴中医药集团有限公司 | Preparation method for sitafloxacin hydrate |
| CN107513053A (en) * | 2015-08-10 | 2017-12-26 | 江苏吴中医药集团有限公司 | A kind of preparation method of sitafloxacin hydrate |
| CN105669646A (en) * | 2016-02-26 | 2016-06-15 | 济川药业集团有限公司 | Synthesis method of sitafloxacin hydrate |
| CN105906545A (en) * | 2016-05-06 | 2016-08-31 | 广州康瑞泰药业有限公司 | Preparation method for efficiently synthesizing Sitafloxacin midbody (7S)-5-azaspiro[2.4] heptanes-7-phenylbutane |
| WO2017190609A1 (en) * | 2016-05-06 | 2017-11-09 | 广州康瑞泰药业有限公司 | Method for preparing efficiently synthetic sitafloxacin intermediate (7s)-5-azaspiro[2.4]heptane-7-yl tert-butyl carbamate |
| CN106349218A (en) * | 2016-08-25 | 2017-01-25 | 山东齐都药业有限公司 | Method for preparing sitafloxacin |
Also Published As
| Publication number | Publication date |
|---|---|
| CN114195761B (en) | 2023-04-14 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US6218574B1 (en) | Process for purifying long-chain dicarboxylic acid | |
| US8258327B2 (en) | Crystalline minocycline base and processes for its preparation | |
| CN108658858B (en) | Preparation and refining method of hydroxychloroquine and preparation method of sulfate thereof | |
| CN104230803B (en) | Preparation method of hydroxychloroquine sulfate | |
| KR100979216B1 (en) | Process for the manufacture of quinoline derivatives | |
| CN101941969B (en) | Preparation method of moxifloxacin hydrochloride | |
| CN106256824B (en) | Preparation method of high-purity delafloxacin meglumine salt | |
| CN1321121C (en) | Post processing method for preparing levo-ofloxacin | |
| CN103435632A (en) | Preparation method of cefuroxime axetil | |
| CN106831723B (en) | Improved refining method of delafloxacin | |
| CN114195761B (en) | Preparation method of high-purity sitafloxacin hydrate 3/2 | |
| CN104031043A (en) | Novel synthesis method of moxifloxacin hydrochloride | |
| CN106854179B (en) | Preparation method of dequalinium chloride and analogs thereof | |
| CN107488129A (en) | A kind of method that L valines are purified in the valine compound from L | |
| CN111978258B (en) | Method for preparing phenytoin sodium | |
| CN110878082B (en) | Gatifloxacin and its synthesis method | |
| CN112250621A (en) | Synthetic method of clodinafop-propargyl | |
| CN111848561A (en) | Method for purifying mycophenolic acid | |
| CN108101761B (en) | Preparation method of curcumin | |
| CA2068429C (en) | Process for the purification of 7-chloroquinoline-8-carboxylic acids | |
| CN108659004B (en) | Preparation method of oxiracetam isomer | |
| CN112694436B (en) | Method for synthesizing arecoline | |
| CN115594640A (en) | Refining method of dibenzoyl thiamine disulfide | |
| CN110172038B (en) | Process for preparing analgin magnesium by one-pot method | |
| CN109761801B (en) | Novel method for preparing ketovaline calcium |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |