CN114195761B - A kind of preparation method of high-purity sitafloxacin 3/2 hydrate - Google Patents

Abstract

The invention discloses a preparation method of high-purity sitafloxacin 3/2 hydrate, which comprises the following steps: mixing crude sitafloxacin, water, solvent and ammonia water, dissolving, filtering, and then distilling the filtrate under reduced pressure Or feed inert gas for crystallization, when the total volume change exceeds 5-15%, add a fresh mixed solution of solvent and water; when the pH is 8.0-9.5, cool down and feed inert gas to continue crystallization; after reaching the end point of crystallization, Post-treatment to obtain the high-purity sitafloxacin 3/2 hydrate. The sitafloxacin obtained by the preparation method has high purity, maximum impurity ≤ 0.6‰, high content, off-white appearance and good long-term stability.

Description

A kind of preparation method of high-purity sitafloxacin 3/2 hydrate

technical field

The invention belongs to the field of chemical pharmacy, and in particular relates to a preparation method of high-purity sitafloxacin 3/2 hydrate.

Background technique

Sitafloxacin hydrate is a quinolone antibacterial drug developed by Daiichi Sankyo Co., Ltd., and its 3/2 hydrate is used clinically. Sitafloxacin is a new type of oral antibacterial drug with broad-spectrum antibacterial effect. It not only has antibacterial activity against Gram-negative bacteria, but also has strong antibacterial activity against Gram-positive bacteria, anaerobic bacteria, mycoplasma, chlamydia, etc. , It also has a good bactericidal effect on many common clinical fluoroquinolone-resistant strains.

Sitafloxacin chemical name: 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. It is reported in the literature [International Journal of Pharmaceuticals (2012) 422,1–8] that it is anhydrous α, β, water-containing 1/2 hydrate, 1 hydrate, 3/ 2 hydrates, a total of five crystal forms. The crystal form used in clinical medicine is 3/2 hydrate. This article also introduced that three crystal forms of hydrated compounds can be transformed into α and β forms by heat treatment.

The original research patent CN1106006 discloses the preparation methods and parameter ranges of five crystal forms of sitafloxacin, in which the 3/2 hydrate is obtained by recrystallization from ammonia water and aqueous ethanol solvent. Among them, the preparation method of 3/2 hydrate is as follows: the crude product is dissolved in the mixed solvent of ethanol, water and ammonia water, after activated carbon is decolorized, about half of the solvent is evaporated under reduced pressure, then cooled to room temperature, and vacuum-dried to obtain 3/2 hydrate Hydrate. The problem that this technology exists is that the impurity of the product obtained by recrystallization is high, the purity is poor, and appearance color is deep, turns yellow, and solvent residue is high.

Patent CN105566287 discloses a method for preparing sitafloxacin 3/2 hydrate by recrystallization under the condition of acetic acid system. The product yield of recrystallization in this process is only 86%, and the product stability is poor under acidic conditions during scale-up production .

The Chinese patent application whose publication number is CN 103524887 A discloses a preparation method of sitafloxacin, and discloses a refining method of sitafloxacin. The refining method uses ethanol and ammonia water to dissolve sitafloxacin, and then adds acetone Crystals are precipitated; however, when the inventor repeats the process, he finds that sitafloxacin is not easy to dissolve when ethanol: ammonia water=2:1, and the concentration of ammonia water used is large, resulting in an increase in impurities; simultaneously, the process will be accompanied by oily condensation during crystallization solidification of the product, resulting in uneven and local yellowish appearance of the product; strong ammonia smell during centrifugal suction filtration, which affects the working environment in the crystallization area; poor stability and easy discoloration of the product; The purity of sitafloxacin is increased from about 99.4% to about 99.7%, the yield is only 75%, and the refining efficiency is not high.

To sum up, the recrystallization method reported in existing patents and literatures to prepare sitafloxacin 3/2 hydrate generally has the following problems: the obtained product has many impurities, large single impurities, large repeatability differences between batches, and appearance color deep flaws.

Contents of the invention

The invention provides a preparation method of high-purity sitafloxacin 3/2 hydrate. The preparation method has high yield, and the obtained product has high purity, less impurities and is easy to repeat.

A preparation method of high-purity sitafloxacin 3/2 hydrate, comprising the following steps:

Mix the crude sitafloxacin, water, solvent and ammonia water, dissolve and filter, then distill the filtrate under reduced pressure or pass inert gas, when the volume change in the kettle exceeds 5-15%, add fresh solvent and water The mixed solvent is used for crystallization. When the pH is 8.0-9.5, the temperature is lowered and inert gas is introduced to continue the crystallization. After reaching the crystallization end point, post-treatment is performed to obtain the high-purity sitafloxacin 3/2 hydrate.

The present invention explores a new crystallization method of sitafloxacin 3/2 hydrate through the accumulation of a large amount of experimental data. In addition to adding crystallization solvent and ammonia water, the crystallization method also supplements a certain amount of water as a solvent, and then The ammonia gas in the system is driven out by vacuum distillation or the way of feeding inert gas, and when the specified pH value is reached, the method of feeding inert gas is continued to continue crystallization, so that sitafloxacin crystals can be precipitated stably, and the obtained The product has high purity, less impurities and off-white appearance.

In the preparation method of the present invention, the solvent used is obtained through a large number of experiments. The solvents used in the experiment process are water, ammonia water, methanol, ethanol, isopropanol, n-butanol, acetonitrile, dichloromethane, ethyl acetate, acetone, toluene, tetrahydrofuran or a mixture of two, the solvent used Most preferred is ethanol.

As preferably, when mixing at the initial stage, the ratio range of sitafloxacin crude product to solvent, water and ammonia water is: the weight ratio of sitafloxacin crude product, solvent, water and 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 crude sitafloxacin, thereby ensuring the smooth progress of subsequent crystallization.

The inert gas introduced in the present invention is argon, nitrogen, etc., and nitrogen is usually used. The flow rate can be controlled at 1-10 liters/hour according to the size of the feeding amount. The inert gas can be recycled after being treated and absorbed by an acid, which is usually an aqueous solution of hydrochloric acid, sulfuric acid, acetic acid, phosphoric acid or nitric acid, etc.

In the preparation method of the present invention, the concentration of the ammonia water used is 10-28%, and the preferred use range is that the concentration of the ammonia water is between 20-28%. The temperature for adding ammonia water is usually 30-60°C, preferably 40-60°C.

When the volume in the control tank of the present invention is continuously distilled under reduced pressure or passed through inert gas for recrystallization, fresh mixed solution of solvent and water is added to keep the volume in the crystallization tank constant. The weight ratio of water and solvent in the added fresh mixed solvent is 10:1-1:10, more preferably controlled at 6:1-1:6. The weight or volume of the added mixed solvent is based on the constant ±10% of the volume in the control kettle.

In the preparation method of the present invention, before the pH value reaches 8.0-9.5, the temperature in the crystallization tank is controlled at 30-50°C, vacuum distillation or inert gas is introduced, more preferably controlled at 35-45°C.

In the preparation method of the present invention, after the pH value reaches 8.0-9.5, the temperature for cooling and feeding inert gas is 0-5° C., and the stirring time is 1-3 hours.

Compared with the prior art, the beneficial effects of the present invention are reflected in:

(1) By adopting the preparation method of the present invention, the obtained sitafloxacin has high purity, maximum impurity≤0.6‰, high content, off-white appearance, good long-term stability, and is convenient for long-term storage;

(2) Adopting the preparation method of the present invention has the advantage of high product yield and is convenient for industrial application.

Description of drawings

Fig. 1 is the X-ray diffraction powder diffraction spectrogram of sitafloxacin 3/2 hydrate of the present invention;

Fig. 2 is the mass spectrum of sitafloxacin 3/2 hydrate;

Fig. 3 is the hydrogen spectrum of sitafloxacin 3/2 hydrate;

Fig. 4 is the carbon spectrum of sitafloxacin 3/2 hydrate;

Figure 5 is the infrared spectrum of sitafloxacin 3/2 hydrate.

Detailed ways

General operating steps of the present invention include:

Under the protection of inert gas, add sitafloxacin crude product, water, ethanol, and ammonia water into the crystallization kettle in a ratio of 1:2～5:3～8:1～4 (weight ratio), and heat up to 30～60°C. Stir for 20-60 minutes to dissolve, and filter hot. Control the temperature in the kettle at 30-50°C, distill the filtrate under reduced pressure or continuously feed inert gas; keep the volume in the kettle constant when distilling or feeding gas, and add fresh when the volume change in the kettle exceeds ±10%. Ethanol/water mixed solution, the ratio of materials in the mixed solution is controlled within the range of ethanol:water=10:1～1:10 (weight ratio); The water mixed solution is condensed; the ammonia that is taken away by the inert gas (flow rate 1-10 liters/hour) is passed into the acidic solution, and recovered into ammonium salt, and the inert gas is passed into the next recrystallization reactor. Distill under reduced pressure or pass inert gas into the crystallization tank, and the pH of the crystallization liquid in the tank is in the range of 5.0 to 9.5 as the crystallization end point. The temperature of the crystallization kettle was lowered to 0-5°C, and the temperature was kept for 2 hours. Centrifuge, wash with water, ethanol/water, ethanol. Dry at 20-25°C under reduced pressure to obtain the product with a yield of 90-97%.

The specific preparation method of the sitafloxacin crude product used is as follows:

Add trifluoroacetic acid (5.5 L) into a reaction flask equipped with a mechanical stirring device and a thermometer, cool to -5°C under stirring, add 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) were slowly warmed up to 0-5°C, and stirred for 30min (HPLC showed that the remaining raw material was less than 0.5%). Concentrate under reduced pressure at 35°C, add dichloromethane (4.5L) to the residue, add 0.5mol/L sodium hydroxide solution (about 150L) at 0-10°C to adjust to pH = 10-12, separate the water after all the solids are dissolved layer, and the organic layer was extracted with 0.1mol/L sodium hydroxide (1.5L×2). Combine the aqueous layers, wash with dichloromethane (4L×2), filter, add 15% citric acid solution (about 4.8L) to the filtrate at 0-10°C to adjust to pH = 7, stir at the same temperature for 30min, suction filter, filter The cake was washed with water and dried under reduced pressure at 40° C. for 12 hours to obtain a crude yellow solid (410 g).

The present invention will be further described below in conjunction with the examples, so that those skilled in the art can better understand the present invention. The examples are illustrative only and are in no way meant to limit the scope of the invention in any way.

Example 1

Add 10 g of sitafloxacin crude product (HPLC purity 99.4%), 35 g of ethanol, and 60 g of water in the reaction kettle, slowly heat up to 50-55° C., add 28 g of 28% ammonia water to dissolve, and press filter at a constant temperature; liter/hour, open the condenser and cool down to 0-5°C, the tail gas is neutralized by 50% sulfuric acid aqueous solution and converted into ammonium sulfate; Water and ethanol mixed solvent, when the pH of the crystallization tank reaches 8-9, cool down to 0-5°C, and continue to feed nitrogen. Stir at 0-5°C for 2 hours at a constant temperature, centrifuge, and dry to obtain 9.5 g of sitafloxacin finished product, with a yield of 95% and a purity of 99.8%. The X-ray powder diffraction spectrum, mass spectrum, and hydrogen Spectrum, carbon spectrum and infrared spectrum are shown in Figures 1-5.

At the same time, a stability test was carried out on the finished sitafloxacin product. The results of the long-term stability test at 25°C and a humidity of 60±10% are shown in the table below:

Example 2

Add 10 g of sitafloxacin crude product (HPLC purity 99.4%), 55 g of ethanol, and 30 g of water in the reaction kettle, slowly heat up to 50-55° C., add 25 g of 28% ammonia water to dissolve, then heat-preserve and press filter; liter/hour, open the condenser and cool down to 0-5°C, the tail gas is neutralized by 50% sulfuric acid aqueous solution and converted into ammonium sulfate; nitrogen is continuously fed into the reaction kettle at 45-50°C and 30g of 25% water-ethanol mixed solvent is added; When the pH of the crystallization tank reaches 8-9, lower the temperature to 0-5°C, and continue feeding nitrogen. Stir at 0-5°C for 2 hours at a constant temperature, centrifuge, and dry to obtain 9.6 g of finished sitafloxacin, with a yield of 96% and a purity of 99.8%.

Example 3

Add 10 g of sitafloxacin crude product (HPLC purity 99.4%), 50 g of ethanol, and 25 g of water into the reaction kettle, slowly heat up to 50-55° C., add 26 g of 28% ammonia water to dissolve it, and then heat-preserve and press filter; control the temperature in the kettle to 35 Distill the filtrate under reduced pressure at ~40°C, open the condenser and cool down to 0~5°C; during the vacuum distillation process, add 18% water-ethanol solution to keep the volume in the kettle constant; when the pH in the crystallization kettle reaches 8~9 , lower the temperature to 0-5°C, and continue to feed nitrogen. Stir at a constant temperature at 0-5°C for 2 hours, centrifuge, and dry to obtain 9.4 g of finished sitafloxacin, with a yield of 94% and a purity of 99.9%.

Example 4

Add 10 g of sitafloxacin crude product (HPLC purity 99.4%), 45 g of ethanol, and 25 g of water into the reaction kettle, slowly heat up to 50-55° C., add 27 g of 28% ammonia water to dissolve, then heat-preserve and press filter; control the temperature in the kettle to 35 Distill the filtrate under reduced pressure at ~40°C, open the condenser and cool down to 0~5°C; during the vacuum distillation process, add 20% water-ethanol solution to keep the volume in the kettle constant; when the pH in the crystallization kettle reaches 8~9 , lower the temperature to 0-5°C, and continue to feed nitrogen. Stir at a constant temperature at 0-5°C for 2 hours, centrifuge, and dry to obtain 9.7 g of finished sitafloxacin, with a yield of 97% and a purity of 99.8%.

Comparative example 1

7-[(7-(S)-amino-5-azaspiro[2,4]hept-5-yl]-8-chloro-6-fluoro-1-[(1R,2S)-2-fluoro Cyclopropyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid crystalline crude 7.7g was added to 45ml of ethanol, 37ml of water, 25ml of 28% ammonia water, heated to 45°C, stirred Dissolve, concentrate under reduced pressure (vacuum degree is about 0.09MPa～0.095Mpa), distill to about 37ml, stop concentrating, cool down to room temperature, stir for 30 minutes, filter, wash and dry the filter cake to obtain the product. The appearance is light yellow powder, the largest single Impurities > 0.05%, yield 85%, HPLC purity 99.7%.

Comparative example 2

Add 1680ml of absolute ethanol/28% ammonia water (2:1, V/V) to 210g of sitafloxacin crude product, heat up to 35-40°C, stir for 1 hour to dissolve, continue to heat up to 50°C to dissolve, Add activated carbon for decolorization and filter. 35～40℃, add 840ml acetone to the filtrate, after the addition, cool down to 0～5℃ and cool for 1 hour (during the process of adding acetone, the local supersaturation degree is high, it is observed that the product produces oil, and the oil droplets solidify to form a yellow condensed product , affect the appearance and purity of the product), filter, and dry the filter cake at 40-45° C. to obtain sitafloxacin, the maximum single impurity > 0.05%, the yield is 75%, the HPLC purity is 99.8%, and the product appearance is uneven and partially partial yellow.

The results of comparative example 2 show that when the mixed solvent of absolute ethanol and ammonia water is directly used for dissolving, the sitafloxacin crude product is difficult to dissolve, and the crystallization process is not easy to control by this method, and the product yield obtained is low, and the product appearance not good.

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.

Images