Preparation method of high-purity cloxacillin sodium

Abstract

The invention discloses a preparation method of high-purity cloxacillin sodium, which comprises the following steps: carrying out condensation reaction on 6-aminopenicillanic acid and 3-o-chlorophenyl-5-methyl-4-isoxazole acyl chloride to obtain a cloxacillin sodium aqueous solution; the cloxacillin sodium aqueous solution passes through macroporous strong-basicity anion exchange resin, cloxacillin sodium is adsorbed on the resin, and is resolved by absolute ethyl alcohol to obtain high-purity cloxacillin sodium resolved solution, so that the high-purity cloxacillin sodium is obtained. According to the method, the condensation reaction of the 6-aminopenicillanic acid and the 3-o-chlorophenyl-5-methyl-4-isoxazole acyl chloride does not need to dissolve the 6-aminopenicillanic acid and ensures that the reaction is performed under an alkaline condition, so that the materials are subjected to a solid-liquid mixed system reaction, the dissolution and clarification processes are reduced, the reaction time is shortened, and the reaction efficiency is improved. The generation of impurities caused by decomposition of the 6-aminopenicillanic acid in the dissolving process is prevented; a high-purity cloxacillin sodium product is obtained by using macroporous strong-basicity anion exchange resin, the content of the cloxacillin sodium product is 96.0% or above, and the purity of the cloxacillin sodium product can reach 99.7% or above.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical technology, and in particular relates to a method for preparing high-purity cloxacillin sodium. Background Art

[0002] Cloxacillin sodium, i.e. (2S,5R,6R)-3,3-dimethyl-6-[5-methyl-3-(2-chlorophenyl)-4-isoxazolecarboxamido)-7-oxo-4-thia-1-azabicycloheptane-2-carboxylic acid sodium salt, has the following structural formula:

[0003]

[0004] Cloxacillin sodium is a white powder or crystalline powder with a slight odor, bitter taste, hygroscopicity, easy dissolution in water, dissolution in ethanol, and almost insoluble in ethyl acetate.

[0005] The core value of cloxacillin sodium lies in its strong antibacterial ability. As a member of the penicillin antibiotics, it mainly exerts its bactericidal effect by inhibiting the synthesis of bacterial cell walls. Unlike traditional penicillins, cloxacillin sodium has higher stability against penicillinase-producing bacteria, which means that it can maintain strong antibacterial activity even in the face of bacteria that can decompose penicillin. This feature gives cloxacillin sodium a unique advantage in treating infections caused by penicillinase-producing Staphylococci.

[0006] Cloxacillin sodium has a wide range of clinical applications, mainly for the treatment of various infections caused by sensitive bacteria. In the treatment of severe infections such as sepsis, endocarditis, and pneumonia, cloxacillin sodium can quickly penetrate the bacterial cell wall and destroy its internal structure, thereby achieving the purpose of sterilization. In addition, the drug is also suitable for the treatment of mixed infections caused by Streptococcus pyogenes or Pneumococcus and penicillin-resistant Staphylococcus, providing clinicians with more treatment options.

[0007] The synthesis of cloxacillin sodium is as follows: first, 6-aminopenicillanic acid is dispersed in water, sodium hydroxide solution is added to generate 6-aminopenicillanic acid sodium and dissolved in water to obtain 6-aminopenicillanic acid sodium solution; in another container, o-chlorobenzylisoxazolecarbonyl chloride is dissolved in an organic solvent to obtain o-chlorobenzylisoxazolecarbonyl chloride solution; the two solutions are mixed to cause condensation reaction, acidified and extracted to obtain cloxacillin acid extract; sodium isooctanoate, a salt-forming agent, is added to the cloxacillin acid extract, crystals are precipitated by stirring, and cloxacillin sodium crystals are obtained by filtering. The cloxacillin sodium obtained by this process has a low content, the solvent residue is difficult to remove, and the salt particles are uneven, resulting in uneven quality of the finished product.

[0008] A domestic report proposed a method for synthesizing cloxacillin sodium (Li Zhonghua, Synthesis of Cloxacillin Sodium, Journal of Shanxi University (Natural Science Edition), 25(3): 224-226, 2002): o-chlorobenzaldehyde is used as a raw material, and o-chlorobenzaldehyde is oximated with hydroxylamine hydrochloride to obtain o-chlorobenzaldehyde, which is chlorinated with chlorine in ethanol to obtain an ethanol solution of o-chlorobenzaldehyde chloride; this solution is esterified and hydrolyzed with ethyl acetoacetate in n-hexane to generate o-chlorobenzaldehyde isoxazole acid; o-chlorobenzaldehyde isoxazole acid is reacted with POCl3 to obtain o-chlorobenzaldehyde isoxazole carboxylic acid chloride; o-chlorobenzaldehyde isoxazole carboxylic acid chloride is obtained by reacting an acetone solution with an aqueous solution of sodium 6-aminopenicillanate, and then extracted, acidified, and salted with sodium isooctanoate to obtain cloxacillin sodium crystals with a content of 93.06% and a yield of 90.6%. The cloxacillin sodium obtained by this process has a low content and low purity.

[0009] According to market research data, the market size of cloxacillin sodium for injection is showing a trend of year-on-year growth, that is, the demand for high-purity cloxacillin sodium is growing. The increasing number of medical institutions further provides a strong guarantee for drug demand. It is expected that in the next few years, the market for cloxacillin sodium for injection will continue to maintain a steady growth trend. As a higher quality product, the market demand for high-purity cloxacillin sodium will also grow accordingly. Due to its better efficacy and lower side effects, high-purity cloxacillin sodium is more likely to be favored by medical institutions. Patients are paying more and more attention to the treatment effect and course of treatment, and at the same time have higher requirements for the safety and side effects of drugs, which makes high-purity cloxacillin sodium a more popular choice. Patients hope to obtain better treatment effects and reduce unnecessary risks by using high-purity drugs. At present, the competition in the market for cloxacillin sodium for injection is extremely fierce, and the main competitors include domestic and foreign pharmaceutical companies and imported drugs. In order to stand out from the competition, pharmaceutical companies continue to improve product quality and prove the safety and effectiveness of products through clinical data and professional certification. High-purity cloxacillin sodium, as a higher quality product, is more likely to gain an advantageous position in market competition and meet the needs of medical institutions and patients. Summary of the invention

[0010] Technical issues

[0011] Therefore, the present invention is made in view of the above problems. The purpose of the present invention is to provide a method for preparing high-purity cloxacillin sodium. The cloxacillin sodium crystals prepared by the method have high content, high purity and good stability.

[0012] Technical Solution

[0013] In order to achieve the above-mentioned purpose of the present invention, the technical scheme adopted by the present invention is as follows: in a reaction bottle, 6-aminopenicillanic acid (6-APA) and water are added for dispersion, and an ethyl acetate solution of 3-o-chlorophenyl-5-methyl-4-isoxazole acid chloride and a sodium hydroxide solution are simultaneously added dropwise thereto, and a condensation reaction is carried out under stirring. After the reaction, the mixture is allowed to stand for stratification, and a cloxacillin sodium aqueous solution is obtained in the lower layer; the cloxacillin sodium aqueous solution passes through a macroporous strongly basic anion exchange resin, and cloxacillin sodium is adsorbed on the resin, and is analyzed by anhydrous ethanol to obtain a high-purity cloxacillin sodium analytical solution, and then a high-purity cloxacillin sodium product is obtained.

[0014] According to the present invention, the preparation method of high-purity cloxacillin sodium provided by the present invention comprises the following steps:

[0015] Preparation of Cloxacillin Sodium Aqueous Solution

[0016] In a reaction flask, 6-aminopenicillanic acid (6-APA) and water are added for dispersion, and an ethyl acetate solution of 3-o-chlorophenyl-5-methyl-4-isoxazole acid chloride and a sodium hydroxide solution are simultaneously added dropwise at 3° C. to 10° C. to make the pH of the reaction solution 6.5 to 7.5; after the ethyl acetate solution of 3-o-chlorophenyl-5-methyl-4-isoxazole acid chloride is added dropwise, sodium hydroxide solution is continuously added dropwise as needed to adjust the pH of the reaction solution to 7.5 to 8.0, and the condensation reaction is continued; after the reaction is completed, the reaction is allowed to stand for stratification, and a cloxacillin sodium aqueous solution is obtained in the lower layer;

[0017] Preparation of high purity cloxacillin sodium

[0018] Passing the above-obtained cloxacillin sodium aqueous solution through a macroporous strong alkaline anion exchange resin column, cloxacillin sodium is adsorbed on the resin, and then desorbed by anhydrous ethanol to obtain a cloxacillin sodium desorbed solution;

[0019] The cloxacillin sodium analytical solution is decolorized by activated carbon and then concentrated under reduced pressure to a dry solid; the dry solid is dispersed with C1-C4 alkyl acetate, then crystallized at 0°C to 10°C, filtered, washed with acetone, and dried to obtain high-purity cloxacillin sodium.

[0020] Beneficial Effects

[0021] The technical advantages of the present invention are:

[0022] (1) Since 6-aminopenicillanic acid decomposes when it encounters alkali and is relatively stable to acid, in the preparation method of the high-purity cloxacillin sodium of the present invention, in the preparation of the cloxacillin sodium aqueous solution, it is not necessary to dissolve 6-aminopenicillanic acid (6-APA). It is sufficient to ensure that the reaction is carried out under alkaline conditions, so that the materials react in a solid-liquid mixed system, reduce the dissolution process, and prevent the generation of impurities caused by the decomposition of 6-aminopenicillanic acid during the dissolution process.

[0023] (2) In the preparation of high-purity cloxacillin sodium, the present invention uses a macroporous strong alkaline anion exchange resin, cloxacillin sodium is adsorbed on the resin, and is resolved by anhydrous ethanol to obtain a high-purity cloxacillin sodium resolved solution, and then obtains a high-purity cloxacillin sodium product, the content of which is above 96.0%, and the purity can reach above 99.7%. Compared with the existing method, after the condensation reaction, the steps of acidification and salt formation with sodium isooctanoate are reduced. DETAILED DESCRIPTION

[0024] Hereinafter, the preparation method of high-purity cloxacillin sodium of the present invention will be described in detail to facilitate the understanding of the present invention. However, the embodiments of the present invention may be modified in various different forms, and the scope of the present invention is not limited to the embodiments to be described below. The embodiments of the present invention are provided to make the present disclosure clear and complete, so as to fully explain the present invention to those of ordinary skill in the art.

[0025] According to an embodiment of the present invention, in the preparation of the aqueous solution of cloxacillin sodium, 6-aminopenicillanic acid (6-APA) and water are added to a reaction bottle for dispersion, and an ethyl acetate solution of 3-o-chlorophenyl-5-methyl-4-isoxazole acid chloride and a sodium hydroxide solution are simultaneously added thereto at 3°C ​​to 10°C, so that the pH value of the reaction solution is 6.5 to 7.5; after the ethyl acetate solution of 3-o-chlorophenyl-5-methyl-4-isoxazole acid chloride is added dropwise, sodium hydroxide solution is continuously added dropwise as needed to adjust the pH value of the reaction solution to 7.5 to 8.0, and the condensation reaction is continued; after the reaction is completed, the solution is allowed to stand for stratification, and the lower layer is obtained as the aqueous solution of cloxacillin sodium.

[0026] More specifically, 6-aminopenicillanic acid and water are added to a reaction bottle, wherein the water may be reverse osmosis water, and the amount of water used is 5 to 20 ml, and preferably 7 to 15 ml, for each gram of 6-aminopenicillanic acid. The temperature is maintained at 3°C ​​to 10°C, and the mixture is dispersed under stirring. An ethyl acetate solution of 3-o-chlorophenyl-5-methyl-4-isoxazole chloride and a sodium hydroxide solution are simultaneously added dropwise thereto, so that the pH value of the reaction solution is 6.5 to 7.5. After the addition of the ethyl acetate solution of 3-o-chlorophenyl-5-methyl-4-isoxazole chloride is completed, the sodium hydroxide solution is continuously added dropwise as needed to adjust the pH value of the reaction solution to 7.5 to 8.0, and the condensation reaction is continuously carried out for 20 to 60 minutes. Then, the stirring is stopped, and the mixture is allowed to stand for stratification, and a cloxacillin sodium aqueous solution is obtained in the lower layer, and an ethyl acetate solution is obtained in the upper layer, and the ethyl acetate solution can be recycled.

[0027] The sodium hydroxide solution used, i.e., the sodium hydroxide aqueous solution, can be, for example, a 10wt% to 15wt% sodium hydroxide solution; the ethyl acetate solution of 3-o-chlorophenyl-5-methyl-4-isoxazole chloride used can be a solution prepared with ethyl acetate as a solvent, and the amount of ethyl acetate used is 8 to 20 ml, and preferably 10 to 15 ml, per g of 3-o-chlorophenyl-5-methyl-4-isoxazole chloride.

[0028] In the preparation of the cloxacillin sodium aqueous solution, the molar ratio of 6-aminopenicillanic acid to 3-o-chlorophenyl-5-methyl-4-isoxazole chloride is 1:1-1.2.

[0029] In the preparation of the cloxacillin sodium aqueous solution, the condensation reaction of 6-aminopenicillanic acid and 3-o-chlorophenyl-5-methyl-4-isoxazole acid chloride does not require dissolution of 6-aminopenicillanic acid (6-APA), and it is sufficient to ensure that the reaction is carried out under alkaline conditions, so that the materials react in a solid-liquid mixed system, reduce the dissolution process, and prevent the generation of impurities caused by the decomposition of 6-aminopenicillanic acid during the dissolution process.

[0030] In the preparation of the high-purity cloxacillin sodium, the cloxacillin sodium aqueous solution obtained above is passed through a macroporous strong alkaline anion exchange resin column, cloxacillin sodium is adsorbed on the resin, and is analyzed by anhydrous ethanol to obtain a cloxacillin sodium analytical solution; the cloxacillin sodium analytical solution is decolorized by activated carbon and then concentrated to a dry solid under reduced pressure; the dry solid is dispersed with C1-C4 alkyl acetate, and then crystallized at 0°C to 10°C, filtered, washed with acetone, and dried to obtain high-purity cloxacillin sodium.

[0031] The macroporous strong basic anion exchange resin is a styrene-based macroporous strong basic anion exchange resin, and its functional group is -N + (CH3)3, -N + (CH3)2(CH2OH) or -N + (CH3)2(C2H4OH), pore size is 400-1250 microns. The macroporous strong base anion exchange resin can be commercially available, such as Zhengguang D201 SC macroporous strong base anion exchange resin, 201×7SC strong base anion exchange resin, D202 SC macroporous strong base type II anion exchange resin, 201×7FC strong base anion exchange resin, D201 FC macroporous strong base anion exchange resin, D202 FC macroporous strong base type II anion exchange resin (from Ningbo Zhengguang Resin Co., Ltd.).

[0032] Newly purchased macroporous strongly alkaline anion exchange resin needs to be activated before use, and the steps are as follows: (1) first rinse with purified water for 10-15 minutes; (2) soak in an alkaline solution such as sodium hydroxide solution for activation, then drain the alkaline solution and rinse with purified water until the pH value of the washed water is neutral; (3) soak in an acid solution such as hydrochloric acid for activation, then drain the acid solution and rinse with purified water until the pH value of the washed water is neutral; (4) repeat step (2); (5) repeat step (3); (6) repeat step (2), and the activation pretreatment of the new resin, i.e., tri-base and di-acid activation, is completed.

[0033] The macroporous strongly alkaline anion exchange resin can be regenerated after use. It can be regenerated by two-base and one-acid activation. The steps are as follows: (1) first rinse with purified water for 10-15 minutes; (2) soak in an alkaline solution such as sodium hydroxide solution for activation, then drain the alkaline solution and rinse with purified water until the pH value of the washing water is neutral; (3) soak in an acid solution such as hydrochloric acid for activation, then drain the acid solution and rinse with purified water until the pH value of the washing water is neutral; (4) repeat step (2) to complete the regeneration of the resin.

[0034] In the preparation of the high-purity cloxacillin sodium, the cloxacillin sodium aqueous solution obtained above is passed through a macroporous strong alkaline anion exchange resin column, cloxacillin sodium is adsorbed on the resin, and is analyzed by anhydrous ethanol to obtain a cloxacillin sodium analysis solution.

[0035] Specifically, the activated pre-treated macroporous strong basic anion exchange resin is filled into a resin column with a height-to-diameter ratio of 3 to 10, preferably a height-to-diameter ratio of 3 to 7, and the resin column is balanced with anhydrous ethanol so that the water content of the anhydrous ethanol in the column outlet effluent is ≤3.0wt%; at 3°C ​​to 10°C, the above-obtained cloxacillin sodium aqueous solution is passed through the macroporous strong basic anion exchange resin column at a rate of 0.5BV / h to 2BV / h, and cloxacillin sodium is adsorbed on the resin. When the cloxacillin sodium content in the column outlet effluent is 0.3wt% (HPLC analysis), the loading is stopped; then, anhydrous ethanol is used for analysis, and the analysis solution with a pH of 6.5 to 7.5 is collected to obtain a cloxacillin sodium analysis solution. According to HPLC analysis, the liquid phase purity of the analysis solution can be 99.7%.

[0036] Then, the cloxacillin sodium analytical solution is decolorized with activated carbon and concentrated under reduced pressure to a dry solid; the dry solid is dispersed with C1-C4 alkyl acetate, and then crystallized at 0°C to 10°C, filtered, washed with acetone, and dried to obtain high-purity cloxacillin sodium.

[0037] Specifically, activated carbon is added to the cloxacillin sodium analytical solution for decolorization, and the solution is filtered to obtain a decolorized cloxacillin sodium analytical solution; the decolorized cloxacillin sodium analytical solution is concentrated under reduced pressure to a dry solid under an external temperature of 25° C.-45° C.; as needed, anhydrous ethanol can be added to the dry solid once or twice, and the solution is concentrated under reduced pressure to a dry solid under an external temperature of 25° C.-45° C. to remove excess water from the dry solid (this is because cloxacillin sodium is very soluble in water, and anhydrous ethanol is used once or twice to remove excess water from the dry solid). The method comprises the following steps: first, distilling the dried solid to remove excess water to increase the yield of the product); then, at a temperature of 15°C-20°C, adding a C1-C4 alkyl acetate solvent dropwise to the dry solid for dispersion, wherein the C1-C4 alkyl acetate is such as methyl acetate, ethyl acetate or butyl acetate, and 2-10 ml of the C1-C4 alkyl acetate solvent is added per gram of the dry solid; then, cooling the dried solid to 0°C-10°C for crystal growth for 1-4 hours, filtering, washing with acetone and vacuum drying to obtain high-purity cloxacillin sodium.

[0038] The preparation method of high-purity cloxacillin sodium of the present invention is further described in detail below through examples, and the protection scope of the present invention is not limited to the following examples, which are listed only for illustrative purposes and are not intended to limit the present invention in any way.

[0039] Zhengguang D201 SC macroporous strong base anion exchange resin activation pretreatment steps are as follows:

[0040] (1) First rinse with purified water for 10-15 minutes;

[0041] (2) immersing and activating with 7 wt % sodium hydroxide solution, then draining the alkali solution and rinsing with purified water until the pH value of the effluent is neutral;

[0042] (3) immersing and activating with 7 wt % hydrochloric acid, then draining the acid solution and rinsing with purified water until the pH value of the effluent is neutral;

[0043] (4) Repeat step (2);

[0044] (5) Repeat step (3);

[0045] (6) Repeat step (2),

[0046] That is to complete the activation pretreatment of the new resin.

[0047] Example 1

[0048] Preparation of Cloxacillin Sodium Aqueous Solution

[0049] Weigh 60.5 g of 3-o-chlorophenyl-5-methyl-4-isoxazole acid chloride (0.236 mol) and 0.6 g of activated carbon, add 800 ml of ethyl acetate thereto, dissolve and decolorize to obtain a decolorized 3-o-chlorophenyl-5-methyl-4-isoxazole acid chloride solution;

[0050] Add 50g 6-aminopenicillanic acid (0.231mol) and 450ml reverse osmosis water into a reaction flask, stir, and cool to 3°C-5°C, add the above decolorized 3-o-chlorophenyl-5-methyl-4-isoxazole acid chloride solution dropwise into the reaction flask, and simultaneously add 12.5wt% sodium hydroxide solution dropwise to keep the pH of the reaction solution at 6.8-7.0; after the addition is completed, continue to add 12.5wt% sodium hydroxide solution dropwise to adjust the pH of the reaction solution to 7.5, keep the temperature at 3°C-5°C, and react for 30min; then, stop stirring, let stand to separate, and obtain 585ml of cloxacillin sodium aqueous solution in the lower layer, and ethyl acetate solution in the upper layer (the waste liquid can be recycled).

[0051] Preparation of high purity cloxacillin sodium

[0052] The activated pre-treated Zhengguang D201 SC macroporous strong basic anion exchange resin was filled into a resin column with a height-to-diameter ratio of 3, and the resin column was balanced with anhydrous ethanol so that the water content of the anhydrous ethanol in the column outlet effluent was ≤3.0wt%; at 3°C ​​to 5°C, the above-obtained cloxacillin sodium aqueous solution was passed through the macroporous strong basic anion exchange resin column at 0.5BV / h, and cloxacillin sodium was adsorbed on the resin; then, anhydrous ethanol was used for analysis, and the analysis solution with pH = 6.5 to 7.5 was collected to obtain 435ml of cloxacillin sodium analysis solution. After HPLC analysis, the liquid phase purity of the analysis solution was 99.7%.

[0053] 0.5 g of activated carbon was added to the cloxacillin sodium analytical solution for decolorization for 30 min, and the solution was filtered to obtain a decolorized cloxacillin sodium analytical solution; the decolorized cloxacillin sodium analytical solution was concentrated under reduced pressure to a dry solid under an external temperature of 25°C-45°C; 50 ml of anhydrous ethanol was added to the dry solid, and the solution was concentrated under reduced pressure to a dry solid under an external temperature of 25°C-45°C; 50 ml of anhydrous ethanol was added to the dry solid again, and the solution was concentrated under reduced pressure to a dry solid under an external temperature of 25°C-45°C; then, 300 ml of ethyl acetate was added dropwise to the dry solid at a temperature of 15°C-20°C for dispersion, and the addition time was 60 min; then, the solution was cooled to 0°C-5°C for crystal growth for 1-4 h, filtered, washed with acetone, and vacuum dried (vacuum degree of -0.085 MPa, temperature 65°C) for 4-8 hours to obtain 77.52 g of high-purity cloxacillin sodium.

[0054] The product yield was 155.04% (the weight of the prepared cloxacillin sodium / the weight of the raw material 6-aminopenicillanic acid×100%).

[0055] The prepared cloxacillin sodium was tested according to the detection method of cloxacillin sodium in Part 2 of the 2020 edition of the Pharmacopoeia of the People's Republic of China: the cloxacillin sodium content was 96.0%, the moisture was 4.20%, the impurity A was 0.011%, the impurity B was 0.013%, the impurity C was 0.001%, the impurity D was 0.015%, the impurity E was 0.11%, the maximum single impurity was 0.015%, the total impurity was 0.165%, the purity was 99.8%, and the product quality met the EP standards.

[0056] Example 2

[0057] Preparation of Cloxacillin Sodium Aqueous Solution

[0058] Weigh 60.5 g of 3-o-chlorophenyl-5-methyl-4-isoxazole acid chloride (0.236 mol) and 0.6 g of activated carbon, add 800 ml of ethyl acetate thereto, dissolve and decolorize to obtain a decolorized 3-o-chlorophenyl-5-methyl-4-isoxazole acid chloride solution;

[0059] Add 50g 6-aminopenicillanic acid (0.231mol) and 450ml reverse osmosis water into a reaction flask, stir, and cool to 3°C-5°C. Add the above decolorized 3-o-chlorophenyl-5-methyl-4-isoxazole acid chloride solution dropwise into the reaction flask, and simultaneously add 12.5wt% sodium hydroxide solution dropwise to keep the pH of the reaction solution at 6.8-7.0. After the addition is completed, continue to add 12.5wt% sodium hydroxide solution dropwise to adjust the pH of the reaction solution to 7.5, keep the temperature at 3°C-5°C, and react for 30min. Then, stop stirring, let stand to separate, and obtain 574ml of cloxacillin sodium aqueous solution in the lower layer, and ethyl acetate solution in the upper layer (the waste liquid can be recycled).

[0060] Preparation of high purity cloxacillin sodium

[0061] The activated pre-treated Zhengguang D202 SC macroporous strongly basic anion exchange resin was filled into a resin column with a height-to-diameter ratio of 5, and the resin column was balanced with anhydrous ethanol so that the water content of the anhydrous ethanol in the column outlet effluent was ≤3.0wt%; at 3°C ​​to 5°C, the above-obtained cloxacillin sodium aqueous solution was passed through the macroporous strongly basic anion exchange resin column at a rate of 1BV / h, and cloxacillin sodium was adsorbed on the resin; then, anhydrous ethanol was used for analysis, and the analysis solution with a pH of 6.5 to 7.5 was collected to obtain 415 ml of cloxacillin sodium analysis solution. After HPLC analysis, the liquid phase purity of the analysis solution was 99.73%.

[0062] 0.5 g of activated carbon was added to the cloxacillin sodium analytical solution for decolorization for 30 min, and the solution was filtered to obtain a decolorized cloxacillin sodium analytical solution; the decolorized cloxacillin sodium analytical solution was concentrated under reduced pressure to a dry solid under a controlled external temperature of 25°C-45°C; 50 ml of anhydrous ethanol was added to the dry solid, and the solution was concentrated under reduced pressure to a dry solid under an external temperature of 25°C-45°C; 50 ml of anhydrous ethanol was added to the dry solid again, and the solution was concentrated under reduced pressure to a dry solid under an external temperature of 25°C-45°C; then, 300 ml of butyl acetate was added dropwise to the dry solid at a temperature of 15°C-20°C for dispersion, and the addition time was 60 min; then, the solution was cooled to 0°C-5°C for crystal growth for 1-4 h, filtered, washed with acetone, and vacuum dried (vacuum degree of -0.085 MPa, temperature 65°C) for 4-8 hours to obtain 77.38 g of high-purity cloxacillin sodium.

[0063] The product yield was 154.76%.

[0064] The prepared cloxacillin sodium was tested according to the detection method of cloxacillin sodium in Part 2 of the 2020 edition of the Pharmacopoeia of the People's Republic of China: the cloxacillin sodium content was 95.9%, the moisture content was 4.10%, the impurity A was 0.012%, the impurity B was 0.011%, the impurity C was 0.001%, the impurity D was 0.014%, the impurity E was 0.12%, the maximum single impurity was 0.013%, the total impurity was 0.171%, the purity was 99.8%, and the product quality met the EP standards.

[0065] Example 3

[0066] Preparation of Cloxacillin Sodium Aqueous Solution

[0067] Weigh 60.5 g of 3-o-chlorophenyl-5-methyl-4-isoxazole acid chloride (0.236 mol) and 0.6 g of activated carbon, add 800 ml of ethyl acetate thereto, dissolve and decolorize to obtain a decolorized 3-o-chlorophenyl-5-methyl-4-isoxazole acid chloride solution;

[0068] Add 50g 6-aminopenicillanic acid (0.231mol) and 450ml reverse osmosis water into a reaction flask, stir, and cool to 3°C-5°C, add the above decolorized 3-o-chlorophenyl-5-methyl-4-isoxazole acid chloride solution dropwise into the reaction flask, and simultaneously add 12.5wt% sodium hydroxide solution dropwise to keep the pH of the reaction solution at 6.8-7.0; after the addition is completed, continue to add 12.5wt% sodium hydroxide solution dropwise to adjust the pH of the reaction solution to 7.5, keep the temperature at 3°C-5°C, and react for 30min; then, stop stirring, let stand to separate, and obtain 580ml of cloxacillin sodium aqueous solution in the lower layer, and ethyl acetate solution in the upper layer (the waste liquid can be recycled).

[0069] Preparation of high purity cloxacillin sodium

[0070] The activated pre-treated Zhengguang D201 SC macroporous strong basic anion exchange resin was filled into a resin column with a height-to-diameter ratio of 7, and the resin column was balanced with anhydrous ethanol so that the water content of the anhydrous ethanol in the column outlet effluent was ≤3.0wt%; at 3°C ​​to 5°C, the above-obtained cloxacillin sodium aqueous solution was passed through the macroporous strong basic anion exchange resin column at 2BV / h, and cloxacillin sodium was adsorbed on the resin; then, anhydrous ethanol was used for analysis, and the analysis solution with pH = 6.5 to 7.5 was collected to obtain 428ml of cloxacillin sodium analysis solution. After HPLC analysis, the liquid phase purity of the analysis solution was 99.65%.

[0071] 0.5 g of activated carbon was added to the cloxacillin sodium analytical solution for decolorization for 30 min, and the solution was filtered to obtain a decolorized cloxacillin sodium analytical solution; the decolorized cloxacillin sodium analytical solution was concentrated under reduced pressure to a dry solid under a controlled external temperature of 25°C-45°C; 50 ml of anhydrous ethanol was added to the dry solid, and the solution was concentrated under reduced pressure to a dry solid under an external temperature of 25°C-45°C; 50 ml of anhydrous ethanol was added to the dry solid again, and the solution was concentrated under reduced pressure to a dry solid under an external temperature of 25°C-45°C; then, 300 ml of methyl acetate was added dropwise to the dry solid at a temperature of 15°C-20°C for dispersion, and the addition time was 60 min; then, the solution was cooled to 0°C-5°C for crystal growth for 1-4 h, filtered, washed with acetone, and vacuum dried (vacuum degree of -0.085 MPa, temperature 65°C) for 4-8 hours to obtain 76.85 g of high-purity cloxacillin sodium.

[0072] The product yield was 153.7%.

[0073] The prepared cloxacillin sodium was tested according to the detection method of cloxacillin sodium in Part 2 of the 2020 edition of the Pharmacopoeia of the People's Republic of China: the cloxacillin sodium content was 96.1%, the moisture content was 4.09%, the impurity A was 0.013%, the impurity B was 0.015%, the impurity C was 0.003%, the impurity D was 0.012%, the impurity E was 0.14%, the maximum single impurity was 0.015%, the total impurity was 0.198%, the purity was 99.8%, and the product quality met the EP standards.

Claims

1. A method for preparing high-purity cloxacillin sodium, comprising the following steps: Preparation of Cloxacillin Sodium Aqueous Solution In a reaction flask, 6-aminopenicillanic acid (6-APA) and water are added for dispersion, and an ethyl acetate solution of 3-o-chlorophenyl-5-methyl-4-isoxazole acid chloride and a sodium hydroxide solution are simultaneously added dropwise at 3° C. to 10° C. to make the pH of the reaction solution 6.5 to 7.5; after the ethyl acetate solution of 3-o-chlorophenyl-5-methyl-4-isoxazole acid chloride is added dropwise, sodium hydroxide solution is continuously added dropwise as needed to adjust the pH of the reaction solution to 7.5 to 8.0, and the condensation reaction is continued; after the reaction is completed, the reaction is allowed to stand for stratification, and a cloxacillin sodium aqueous solution is obtained in the lower layer; Preparation of high purity cloxacillin sodium Passing the above-obtained cloxacillin sodium aqueous solution through a macroporous strong alkaline anion exchange resin column, cloxacillin sodium is adsorbed on the resin, and then desorbed by anhydrous ethanol to obtain a cloxacillin sodium desorbed solution; The cloxacillin sodium analytical solution is decolorized by activated carbon and then concentrated under reduced pressure to a dry solid; the dry solid is dispersed with C1-C4 alkyl acetate, then crystallized at 0°C to 10°C, filtered, washed with acetone, and dried to obtain high-purity cloxacillin sodium.

2. The method for preparing high-purity cloxacillin sodium according to claim 1, Its characteristic is that In the preparation of the cloxacillin sodium aqueous solution, 6-aminopenicillanic acid and water are added to a reaction bottle, wherein the water is reverse osmosis water, and the amount of water used is 5 to 20 ml for each gram of 6-aminopenicillanic acid, the temperature is maintained at 3° C. to 10° C., the mixture is dispersed under stirring, and an ethyl acetate solution of 3-o-chlorophenyl-5-methyl-4-isoxazole acid chloride and a sodium hydroxide solution are simultaneously added dropwise thereto, so that the pH value of the reaction solution is 6.5 to 7.5; after the ethyl acetate solution of 3-o-chlorophenyl-5-methyl-4-isoxazole acid chloride is added dropwise, the sodium hydroxide solution is continuously added dropwise as needed to adjust the pH value of the reaction solution to 7.5 to 8.0, and the condensation reaction is continuously carried out for 20 to 60 minutes; then, the stirring is stopped, the mixture is allowed to stand for stratification, and the cloxacillin sodium aqueous solution is obtained as the lower layer, and the upper layer is the ethyl acetate solution.

3. The method for preparing high-purity cloxacillin sodium according to claim 2, Its characteristics are: The ethyl acetate solution of 3-o-chlorophenyl-5-methyl-4-isoxazole acid chloride used is a solution prepared with ethyl acetate as a solvent. The amount of ethyl acetate used is 8 to 20 ml for each gram of 3-o-chlorophenyl-5-methyl-4-isoxazole acid chloride.

4. The method for preparing high-purity cloxacillin sodium according to claim 2, Its characteristics are: The molar ratio of 6-aminopenicillanic acid to 3-o-chlorophenyl-5-methyl-4-isoxazole chloride is 1:1-1.

2.

5. The method for preparing high-purity cloxacillin sodium according to claim 1, Its characteristic is that In the preparation of the high-purity cloxacillin sodium, the macroporous strong basic anion exchange resin is a styrene-based macroporous strong basic anion exchange resin, and its functional group is -N + (CH 3 ) 3 、-N + (CH 3 ) 2 (CH 2 OH) or -N + (CH 3 ) 2 (C 2 H 4 OH).

6. The method for preparing high-purity cloxacillin sodium according to claim 5, Its characteristics are: New macroporous strongly alkaline anion exchange resin needs to be activated before use, and the steps are as follows: (1) first rinse with purified water for 10-15 minutes; (2) soak in sodium hydroxide solution for activation, then drain the alkaline solution and rinse with purified water until the pH value of the washed water is neutral; (3) soak in hydrochloric acid for activation, then drain the acid solution and rinse with purified water until the pH value of the washed water is neutral; (4) repeat step (2); (5) repeat step (3); (6) repeat step (2), and the activation pretreatment of the new resin is completed.

7. The method for preparing high-purity cloxacillin sodium according to claim 5, Its characteristics are: The macroporous strongly alkaline anion exchange resin is regenerated after use in the following steps: (1) first rinse with purified water for 10-15 minutes; (2) soak in sodium hydroxide solution for activation, then drain the alkaline solution and rinse with purified water until the pH value of the washed water is neutral; (3) soak in hydrochloric acid for activation, then drain the acid solution and rinse with purified water until the pH value of the washed water is neutral; (4) repeat step (2) to complete the regeneration of the resin.

8. The method for preparing high-purity cloxacillin sodium according to claim 1, Its characteristic is that In the preparation of the high-purity cloxacillin sodium, a macroporous strongly basic anion exchange resin that has been activated and pretreated is filled into a resin column with a height-to-diameter ratio of 3 to 10, and the resin column is balanced with anhydrous ethanol so that the water content of the anhydrous ethanol in the column outlet effluent is ≤3.0wt%; at 3°C ​​to 10°C, the above-obtained cloxacillin sodium aqueous solution is passed through the macroporous strongly basic anion exchange resin column at a rate of 0.5BV / h to 2BV / h, and cloxacillin sodium is adsorbed on the resin; then, anhydrous ethanol is used for analysis, and an analysis solution with a pH of 6.5 to 7.5 is collected to obtain a cloxacillin sodium analysis solution.

9. The method for preparing high-purity cloxacillin sodium according to claim 1, Its characteristic is that In the preparation of the high-purity cloxacillin sodium, activated carbon is added to the cloxacillin sodium analytical solution for decolorization, and the solution is filtered to obtain a decolorized cloxacillin sodium analytical solution; the decolorized cloxacillin sodium analytical solution is concentrated under reduced pressure to a dry solid while controlling the external temperature at 25°C-45°C; as needed, anhydrous ethanol can be added to the dry solid once or twice, and the solution is concentrated under reduced pressure to a dry solid at an external temperature of 25°C-45°C to remove excess water from the dry solid.

10. The method for preparing high-purity cloxacillin sodium according to claim 1, Its characteristic is that In the preparation of the high-purity cloxacillin sodium, a C1-C4 alkyl acetate solvent is added dropwise to the dry solid at a temperature of 15°C-20°C for dispersion, wherein the C1-C4 alkyl acetate is methyl acetate, ethyl acetate or butyl acetate, and 2-10 ml of the C1-C4 alkyl acetate solvent is added per gram of dry solid; then the temperature is lowered to 0°C-10°C for crystal growth for 1-4 hours, and the high-purity cloxacillin sodium is obtained by filtration, washing with acetone and vacuum drying.

Images