CN114195761B - Preparation method of high-purity sitafloxacin hydrate 3/2 - Google Patents
Preparation method of high-purity sitafloxacin hydrate 3/2 Download PDFInfo
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- CN114195761B CN114195761B CN202111592708.7A CN202111592708A CN114195761B CN 114195761 B CN114195761 B CN 114195761B CN 202111592708 A CN202111592708 A CN 202111592708A CN 114195761 B CN114195761 B CN 114195761B
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Abstract
The invention discloses a preparation method of high-purity sitafloxacin hydrate 3/2, which comprises the following steps: mixing a sitafloxacin crude product, water, a solvent and ammonia water, dissolving, filtering, then carrying out reduced pressure distillation on the filtrate 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 and introducing inert gas for continuous crystallization; and after reaching the crystallization end point, 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 a quinolone antibacterial agent developed by the first three co-company, 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 strong antibacterial activity on gram-positive bacteria, anaerobic bacteria, mycoplasma, chlamydia and the like, and also has good bactericidal effect 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, hydrous 1/2 hydrates, 1 hydrates, 3/2 hydrates, and five crystal forms in total are reported in the literature [ International Journal of pharmaceuticals (2012) 422,1-8 ]. The crystal form used by the clinical medicine is 3/2 hydrate. It is also described that the three crystalline forms of the hydrous compound can be converted into the alpha, 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 the 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 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 amplification production is poor.
Chinese patent application publication No. CN 103524887A 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: 1, sitafloxacin is not easy to dissolve, the concentration of the used ammonia water is high, and 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 methods reported in the prior patents and literatures for preparing sitafloxacin hydrate 3/2 generally have 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 hydrate 3/2, which is high in yield, high in purity of the obtained product, less in impurity and convenient to repeat.
A preparation method of high-purity sitafloxacin hydrate 3/2 comprises the following steps:
mixing the crude sitafloxacin hydrate, water, a solvent and ammonia water, dissolving, filtering, then distilling the filtrate under reduced pressure or introducing inert gas, supplementing the mixed solvent of fresh solvent and water for crystallization when the volume change in the kettle exceeds 5-15%, cooling and introducing inert gas for continuous crystallization when the pH value is 8.0-9.5, and performing post-treatment to obtain the high-purity sitafloxacin hydrate 3/2 after the crystallization end point is reached.
According to the method, a new crystallization method of sitafloxacin hydrate 3/2 is explored through accumulation of a large amount of experimental data, a certain amount of water is additionally supplemented as a solvent besides a crystallization solvent and ammonia water, then ammonia gas in a system is expelled 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 precipitated, and the obtained product is high in purity, few in impurities and white-like 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 to 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 usually 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 of the invention, 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 addition temperature of the aqueous ammonia is generally from 30 to 60 ℃ and preferably from 40 to 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 solvent in the fresh mixed solvent is between 10. 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 present invention, before the pH value reaches 8.0 to 9.5, the temperature in the crystallization vessel is controlled to 30 to 50 ℃ and the distillation under reduced pressure or the introduction of an inert gas is carried out, and more preferably, the temperature is controlled to 35 to 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 has high purity, the maximum impurity is less than or equal to 0.6 per thousand, the content is high, the appearance is white, the long-term stability is good, and the long-term storage is convenient;
(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;
FIG. 2 is a mass spectrum of sitafloxacin 3/2 hydrate;
FIG. 3 is a hydrogen spectrum of sitafloxacin hydrate 3/2;
FIG. 4 is a carbon spectrum of sitafloxacin 3/2 hydrate;
FIG. 5 is an infrared spectrum of sitafloxacin hydrate 3/2.
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 1-5: 3-8, heating to 30-60 ℃, stirring for 20-60 minutes, dissolving and cleaning, and carrying out hot filtration. Controlling the temperature in the kettle at 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 =10 (weight ratio); the temperature of the cooling device is required to be within the range of minus 20 ℃ to 15 ℃ to condensate the distilled ethanol/water mixed solution; the ammonia taken away by the introduced inert gas (the flow rate is 1-10 liters per hour) is introduced into the acid solution and recycled into ammonium salt, and the inert gas is introduced into the next recrystallization reaction kettle. Vacuum distilling or introducing inert gas into the crystallization kettle, and taking the pH value of the crystallization liquid in the kettle between 5.0 and 9.5 as the crystallization end point. The temperature of the crystallization kettle is reduced to 0-5 ℃, and the temperature is kept for 2 hours. Centrifuging, washing with water, ethanol/water, and ethanol. The product is obtained by drying under reduced pressure at the temperature of 20-25 ℃, and 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 (110 ml), slowly warmed to 0 to 5 ℃ and reacted for 30min with stirring (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 = 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 adding 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 under reduced pressure at 40 ℃ 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 nitrogen flow into the filtrate for 3 liters/hour, starting a condenser to cool to 0-5 ℃, and neutralizing the tail gas by 50% sulfuric acid aqueous 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, adding 20g 15% of water-ethanol mixed solvent, cooling to 0-5 ℃ when the pH value of the crystallization kettle reaches 8-9, and continuously introducing nitrogen. Stirring for 2 hours at a constant temperature of 0-5 ℃, centrifuging, 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, dissolving, and then carrying out heat preservation and filter pressing; blowing nitrogen flow 2L/h into the filtrate, starting a condenser to cool to 0-5 ℃, and neutralizing the tail gas by 50% sulfuric acid aqueous solution to convert the tail gas into ammonium sulfate; continuously introducing nitrogen into the reaction kettle at the temperature of between 45 and 50 ℃, and supplementing 30g of 25 percent of water-ethanol mixed solvent; when the pH value of the crystallization kettle reaches 8-9, the temperature is reduced to 0-5 ℃, and nitrogen is continuously introduced. Stirring for 2 hours at the constant temperature of 0-5 ℃, centrifuging and drying to obtain 9.6g of sitafloxacin finished product, wherein the yield is 96 percent and the purity is 99.8 percent.
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, dissolving, 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, the temperature is reduced to 0-5 ℃, and nitrogen is continuously introduced. Stirring for 2 hours at the constant temperature of 0-5 ℃, centrifuging and drying to obtain 9.4g of sitafloxacin finished product, wherein the yield is 94 percent and the purity is 99.9 percent.
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, dissolving, 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, the temperature is reduced to 0-5 ℃, and nitrogen is continuously introduced. Stirring for 2 hours at the constant temperature of 0-5 ℃, centrifuging and drying to obtain 9.7g of sitafloxacin finished product with the yield of 97 percent and the purity of 99.8 percent.
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 0.095 MPa), distilling to about 37ml, stopping concentrating, cooling to room temperature, stirring for 30 minutes, filtering, washing and drying filter cakes to obtain a product, namely pale yellow powder with the appearance, the maximum single impurity content of more than 0.05%, the yield of 85% and the HPLC purity of 99.7%.
Comparative example 2
Adding 1680ml of absolute ethyl alcohol/28% ammonia water (2, V/V) into 210g of sitafloxacin crude product, heating to 35-40 ℃, stirring for 1 hour to ensure that the sitafloxacin crude product cannot be dissolved clearly, continuously heating to 50 ℃ to dissolve clearly, adding activated carbon to decolor, and filtering. Adding 840ml of acetone into the filtrate at 35-40 ℃, cooling to 0-5 ℃ after adding, cooling for 1 hour (in the acetone adding process, the local supersaturation degree is large, 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 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 used for dissolving, the crude sitafloxacin product is difficult to dissolve, the crystallization process is difficult to control by adopting the method, the yield of the obtained product is low, and the appearance of the product is poor.
Claims (6)
1. A preparation method of high-purity sitafloxacin hydrate 3/2 is characterized by comprising the following steps:
mixing a sitafloxacin crude product, water, a solvent and ammonia water, dissolving, filtering, then carrying out reduced pressure distillation on the filtrate 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 and introducing inert gas for continuous crystallization; after the crystallization end point is reached, post-treating to obtain the high-purity sitafloxacin hydrate 3/2;
the solvent is ethanol;
the supplemented solvent is ethanol;
in the mixed solvent, the weight ratio of water to ethanol is 10;
the crude product of sitafloxacin: solvent: water: the weight ratio of ammonia water is 1: (2-5): (3-8): (1-4);
the temperature of mixing, dissolving and filtering is 30-60 ℃.
2. The method for preparing high-purity sitafloxacin 3/2 hydrate as claimed in claim 1, wherein the concentration of the ammonia water is 10-28%.
3. The method for preparing high-purity sitafloxacin 3/2 hydrate according to claim 1, wherein the inert gas is nitrogen or argon, and the feeding speed is 1-10 liters/hour.
4. The method for preparing high purity sitafloxacin 3/2 hydrate as claimed in claim 1 or 2, wherein the temperature of the reduced pressure distillation or the inert gas introduction is 30-50 ℃.
5. The method for preparing high-purity sitafloxacin 3/2 hydrate according to claim 1, wherein the weight ratio of the added mixed solvent to the water to the ethanol is 6.
6. The method for preparing high-purity sitafloxacin 3/2 hydrate as claimed in claim 1, wherein the temperature of the inert gas is lowered to 0-5 ℃, and the stirring time is 1-3 hours.
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