A preparation method of pharmaceutical grade cetabularium chloride

Abstract

The invention relates to a preparation method of pharmaceutical-grade cetabularium chloride. The preparation method fully considers the practicality of large-scale production and has the characteristics of reasonable steps, high process stability, low energy consumption, etc. The related substances and alkyl impurities of the obtained cetabularium chloride are controlled at low levels, and the product is in the form of white granules. The overall quality of the product is superior to that of products prepared by conventional methods.

Description

[0001] This application is a divisional application of application number 202010298298.4, application date April 16, 2020, and invention name “A method for preparing pharmaceutical-grade cetabularium chloride”. Technical Field

[0002] The invention belongs to the field of drug synthesis, and in particular relates to a method for preparing pharmaceutical-grade cetabularium chloride. Background Art

[0003] Cetalkonium chloride (CAS number: 10328-34-4), also known as hexadecyldimethylbenzylammonium chloride, is one of the three quaternary ammonium salt components (dodecyldimethylbenzylammonium chloride, tetradecyldimethylbenzylammonium chloride, and hexadecyldimethylbenzylammonium chloride) that make up the surfactant and broad-spectrum antibacterial agent benzalkonium chloride. Cetalkonium chloride has a melting point of 50-60°C and is readily soluble in polar solvents such as water, methanol, and ethanol, but poorly soluble in non-polar solvents such as ethyl acetate and petroleum ether. Its physical properties manifest itself in its ability to alter the interfacial state of solution systems and its antibacterial properties. It is widely used as a surfactant and antibacterial agent in daily chemical products, cosmetics, and pharmaceuticals. Currently, the quality standard for cetalkonium chloride is not included in domestic or international pharmacopoeias. Instead, its quality standard often refers to that of benzalkonium chloride, a pharmaceutical excipient.

[0004]

[0005] Currently, the industrial preparation of cephalosporinium chloride mostly uses hexadecyldimethylamine and benzyl chloride as raw materials and is prepared by a condensation method.

[0006]

[0007] Chinese patent CN109553539A discloses a method for preparing cetyldimethylbenzylammonium chloride, which uses cetyldimethylamine and benzyl chloride as raw materials, ethanol, n-propanol, methanol, etc. as solvents, cools the mixture to ≤0°C after the condensation reaction, and stirs to precipitate a solid. The method has the characteristics of high total yield and high purity of the obtained product. However, due to the low melting point of cetyldimethylamine chloride, there is a risk of the product precipitating as an oily substance during the cooling and crystallization process. After the oily substance is precipitated, the product cannot be obtained in a solid form by cooling the system or changing the stirring rate. It can be seen that the process for preparing cetyldimethylamine chloride is not stable enough, and the preparation process involves a relatively low temperature crystallization step (≤0°C), which also makes the process energy consumption relatively large.

[0008] The document (Ternary Water in Oil Microemulsions Made of Cationic Surfactants, Water, and Aromatic Solvents.1. Water Solubility Studies, J. Phys. Chem., 1990, 94, 381-387) discloses a method for preparing hexadecyldimethylbenzyl ammonium chloride. The method uses hexadecyl bromide and N,N-dimethylbenzylamine as raw materials and ethanol as a reaction solvent. The crude product is prepared by condensation and ion exchange. The crude product needs to be recrystallized three times from ethyl acetate or ethyl acetate / ethanol or diethyl ether to obtain a qualified final product. The preparation process is relatively complicated.

[0009] The literature (Synthesis and properties of quaternary ammonium surfactants containing a methoxy benzyl substitute, RSC Adv., 2014, 4, 56918–56925) discloses a method for preparing a series of fatty alkyl dimethyl benzyl quaternary ammonium salts. After reflux reaction using isopropyl alcohol as a solvent, a crude product is directly obtained by rotary evaporation. This crude product is then recrystallized using a mixed solvent of ethyl acetate / petroleum ether / acetone. Three recrystallizations are required to obtain the final product, and the preparation process is far from optimal.

[0010] In summary, finding a method for preparing pharmaceutical-grade cephalosporinium chloride that is green, environmentally friendly, has low energy consumption, reasonable steps, high process stability, and is suitable for industrial large-scale production is a technical problem that has not yet been solved in the prior art. Summary of the Invention

[0011] The present invention aims to overcome the shortcomings of the prior art and provides a preparation method for pharmaceutical-grade cetabularium chloride. The preparation method fully considers the practicality of large-scale production and has the characteristics of reasonable steps, high process stability, low energy consumption, etc. The solvents used in the process are all three types of solvents listed in the "Technical Guidelines for the Study of Residual Solvents in Chemical Drugs" and the ICH "Guideline for Residual Solvents". The related substances and alkyl impurities of the obtained cetabularium chloride are controlled at low levels, and the product is in the form of white granules. The overall quality of the product is superior to that of products prepared by conventional methods.

[0012] The above-mentioned purpose of the present invention is achieved through the following technical solutions:

[0013] A preparation method of cetabularium chloride comprises a condensation reaction, after which the solvent is removed from the system after the condensation reaction is completed, acetone and / or butanone is added to the system, and the solvent is removed again to obtain a crude cetabularium chloride product. The amount of the acetone and / or butanone is such that the mass-to-volume ratio of the theoretical yield of cetabularium chloride to the amount of the acetone and / or butanone is 1:0.6-1.2 g / mL.

[0014] Specifically, the starting materials for the condensation reaction can be hexadecyldimethylamine and benzyl chloride, or hexadecyl chloride and N,N-dimethylbenzylamine. Specifically, the molar ratio of hexadecyldimethylamine / hexadecyl chloride to benzyl chloride / N,N-dimethylbenzylamine in the starting materials is 1:0.9-1.1. Preferably, the starting materials for the condensation reaction are hexadecyldimethylamine and benzyl chloride, and the molar ratio of hexadecyldimethylamine to benzyl chloride in the starting materials is 1:0.95-1.05.

[0015] The reaction formula of the condensation reaction is as follows:

[0016]

[0017] The condensation reaction step of the present invention has relatively low requirements for the solvent, and an organic solvent that can dissolve the substrate can generally achieve the reaction; specifically, the solvent used in the condensation reaction is preferably a mixture of one or more of ethanol, n-propanol, and isopropanol in any proportion, and the amount of the solvent used is such that the mass-to-volume ratio of the theoretical yield (mass) of cetaxel ammonium chloride to the amount (volume) of the solvent used is 1:1.5-2.5 g / mL.

[0018] The present invention has a choice regarding the type and amount of solvent used in the condensation reaction step. The use of too much solvent results in a low concentration of reactants, which affects the reaction rate and takes longer to remove the solvent. The use of too little solvent is prone to side reactions, affecting product quality.

[0019] More preferably, the solvent used in the condensation reaction is ethanol, and the mass-to-volume ratio of the amount (volume) of the solvent to the theoretical yield (mass) of cephalosporinium chloride is 1:1.8-2.2 g / mL.

[0020] The reaction temperature of the condensation reaction is 40° C. to reflux temperature, preferably 50° C. to reflux temperature; at this temperature, the reaction can be completed relatively quickly, and the reaction endpoint is: the reaction raw materials are completely consumed or substantially consumed, that is, the reaction is completed.

[0021] In the above-mentioned preparation method of cetabularium chloride, after removing the solvent, acetone and / or butanone are added to the system, and the step of removing the solvent again is one of the key technical features for achieving the technical purpose. Since cetabularium chloride has a low melting point, it is easy to include the solvent in the process of removing the solvent to form an oily substance. The solidification of the crude product in this step is more important in the preparation method. If an oily substance is formed, the product may be precipitated as an oily substance again in the subsequent recrystallization step, or even if a solid is precipitated, its yield is significantly reduced. This phenomenon is more obvious in large-scale production. The inventor accidentally discovered in process optimization that when removing the solvent, When acetone and / or butanone are subsequently added to the system, the crude product can be solidified during the process of removing the solvent again. The amount of acetone and / or butanone added is also selectable. Specifically, the addition of too much acetone and / or butanone results in an excessive amount of solvent, a longer time is required to remove the solvent, and the effect is not correspondingly enhanced. However, the addition of too little acetone and / or butanone fails to achieve the effect of immediately forming a solid crude product. When the mass-to-volume ratio of the amount of acetone and / or butanone added to the system to the theoretical yield of cephalosporin is 1:0.6-1.2 g / mL, the crude product can be solidified immediately.

[0022] Preferably, after removing the solvent, acetone is added to the system, and the mass volume ratio of the acetone to the theoretical yield of cephalosporin is 1:0.8-1.0 g / mL, at which time the best solidification effect of the crude product can be obtained.

[0023] Furthermore, the preparation method of the aforementioned cetabularium chloride further includes a recrystallization step. The description and preferred embodiments of the condensation reaction step in the preparation method are the same as those in the aforementioned content of the present invention. The preparation method is as follows:

[0024] A preparation method of cetabularium chloride, comprising:

[0025] (1) Condensation reaction;

[0026] (2) Recrystallization;

[0027] After the condensation reaction (1) is completed, the solvent is removed and acetone and / or butanone are added to the system, and the solvent is removed again to obtain a crude cephalosporinium chloride product, wherein the mass volume ratio of the amount of acetone and / or butanone to the theoretical yield of cephalosporinium chloride is 1:0.6-1.2 g / mL;

[0028] The selection of the recrystallization solvent in the (2) recrystallization step is another key technical feature of the present invention. Specifically, the recrystallization solvent used in the (2) recrystallization is a solvent system of a mixture of a poor solvent and a good solvent, wherein the volume ratio of the poor solvent to the good solvent is 1:0.05-0.10, the poor solvent is selected from any one of ethyl acetate, methyl acetate, propyl acetate, and isopropyl acetate, or a mixture of two or more thereof in any proportion, the good solvent is selected from any one of ethanol, n-propanol, and isopropanol, or a mixture of two or more thereof in any proportion, and the amount (volume) of the recrystallization solvent is proportional to the theoretical yield (mass) of cephalosporin. The mass volume ratio is 1:2.0~3.0g / mL. More specifically, the impurities of the medicinal cetabularium chloride of the present invention are divided into related substances (benzyl alcohol, benzaldehyde, benzyl chloride) and alkyl impurities (dodecyldimethylbenzylammonium chloride, tetradecyldimethylbenzylammonium chloride, octadecyldimethylbenzylammonium chloride). Benzalkonium chloride is a pharmaceutical excipient, and the quality control standards of domestic and foreign pharmacopoeias are relatively loose. The present invention refers to the provisions of domestic and foreign pharmacopoeias on benzalkonium chloride, combined with the relevant provisions of ICH on the quality of raw materials, the impurity content in the product, and strictly controls the quality control standards of cetabularium chloride, limiting the contents of related substances and alkyl impurities to less than 0.15%.

[0029] During the experiment, the inventors found that the use of a poor solvent is beneficial for removing related substances, especially ethyl acetate, while the use of a good solvent is beneficial for removing alkyl impurities, especially ethanol; but at the same time, the inventors also unexpectedly found that excessive use of a poor solvent easily causes the product to precipitate with a very small particle size, making the system slurry, which is not conducive to product filtration and optimization of product properties. The resulting product is a white powder with agglomeration, poor fluidity, and easy adhesion to the surface of the device, especially ethyl acetate. After comprehensive consideration of the impurity removal effect, process optimization, and product properties, the inventors found that when the volume ratio of the recrystallization solvent and the amount of the recrystallization solvent are within a specific range, the impurity removal effect of the recrystallization step is optimal, and the resulting product is uniform white particles with good fluidity; preferably, the poor solvent is ethyl acetate, the good solvent is ethanol, the volume ratio of the poor solvent to the good solvent is 1:0.07-0.08, and the mass volume ratio of the amount (volume) of the recrystallization solvent to the theoretical yield (mass) of cephalosporin is 1:2.2-2.6 g / mL.

[0030] The (2) recrystallization step complies with the common recrystallization operation steps in the art. Specifically, the (2) recrystallization step includes a step of slowly cooling the crude product after dissolving it. The cooling step can adopt a one-step cooling method or a step-by-step cooling method. The end point temperature can be room temperature or a temperature below room temperature. Preferably, when the cooling end point temperature is 10-20°C, the (2) recrystallization step can achieve the best combination of product yield and product purity.

[0031] A preferred implementation method of the present invention is as follows:

[0032] A preparation method of cetabularium chloride, comprising:

[0033] (1) Condensation reaction;

[0034] (2) Recrystallization;

[0035] The starting materials of the condensation reaction (1) are hexadecyldimethylamine and benzyl chloride, the molar ratio of hexadecyldimethylamine to benzyl chloride is 1:1, the solvent used in the condensation reaction is ethanol, and the mass-to-volume ratio of the amount (volume) of the solvent to the theoretical yield (mass) of cephalosporin is 1:2.1 g / mL;

[0036] After the condensation reaction (1) is completed, the solvent is removed and acetone is added to the system. The solvent is removed again to obtain a crude product of cephalosporin. The mass volume ratio of the amount of acetone to the theoretical yield of cephalosporin is 1:0.8 g / mL;

[0037] The recrystallization solvent used in the (2) recrystallization is a mixed solvent system of ethyl acetate and ethanol, wherein the volume ratio of the poor solvent to the good solvent is 1:0.08, and the mass-to-volume ratio of the amount (volume) of the recrystallization solvent to the theoretical yield (mass) of cephalosporin is 1:2.4 g / mL.

[0038] The preparation method of the present invention fully considers process feasibility and can prepare a high-quality cetabularium chloride product. Specifically, the process steps of the preparation method of the present invention are relatively simple, low temperature (≤0°C) can be avoided, and the solvents used in the reaction, post-treatment and purification steps are all three types of solvents listed in the "Technical Guidelines for the Study of Residual Solvents in Chemical Drugs" and the ICH "Guideline for Residual Solvents". They are environmentally friendly and have relatively wider control requirements for residual solvents. The prepared cetabularium chloride product has related substances stably controlled at less than 0.03%, alkyl impurities stably controlled at less than 0.15%, and is in the form of white uniform granules with a stable repose angle between 30° and 40°. It has good fluidity and high overall product quality.

[0039] A second object of the present invention is to provide a pharmaceutical preparation containing cetabularium chloride prepared by the aforementioned method. According to literature reports, when major ophthalmic preparation manufacturers at home and abroad use benzalkonium chloride as a preservative, its concentration range is mostly controlled between 0.005% and 0.02%. Cetabularium chloride, as one of the components of benzalkonium chloride, is generally controlled at a concentration range of 0.001% to 0.01% in preparation applications.

[0040] Low-concentration cethamidium chloride solution corresponds to a smaller amount of cethamidium chloride, which often requires precise weighing. Therefore, the quality of the cethamidium chloride product is particularly important. Based on the aforementioned preparation method of the present invention, the obtained cethamidium chloride has the advantages of high purity, good quality and fluidity, and is easy to achieve precise measurement. Specifically, this is reflected in the precise concentration of cethamidium chloride in the preparation, the content of related impurities generated by cethamidium chloride is low, and correspondingly, the preparation instability factors caused by cethamidium chloride are reduced.

[0041] Compared with the prior art, the present invention has the following advantages and beneficial effects:

[0042] 1. A method for preparing pharmaceutical-grade cetabularium chloride according to the present invention has the characteristics of reasonable steps, high process stability, low energy consumption, etc., the related substances and alkyl impurities of the obtained cetabularium chloride are controlled at a low level, and the product is in the form of white granules. The overall quality of the product is superior to that of products prepared by other methods;

[0043] 2. A preparation containing cetabularium chloride prepared by the aforementioned method according to the present invention has precise concentration, low content of cetabularium chloride-related impurities, and high preparation stability. BRIEF DESCRIPTION OF THE DRAWINGS

[0044] Figure 1 This is a photo of the product obtained in Comparative Example 2;

[0045] Figure 2 This is a photo of the product obtained in Comparative Example 5;

[0046] Figure 3 This is a photo of the product obtained in Example 9;

[0047] Figure 4 This is a photo of the product obtained in Comparative Example 6. DETAILED DESCRIPTION

[0048] The present invention will be described in further detail below with reference to the embodiments and drawings, but the embodiments of the present invention are not limited thereto.

[0049]

[0050] Example 1

[0051] Dissolve 288.7 g (1.072 mol) of hexadecyldimethylamine in 900 mL of ethanol, add 135.1 g (1.072 mol) of benzyl chloride while stirring, raise the temperature to 55-65 ° C, stir and react for 4 hours, evaporate the ethanol to obtain a white oil, add 350 mL of acetone to the reaction vessel, and concentrate to dryness to obtain a white solid.

[0052] Example 2

[0053] Dissolve 288.7 g (1.072 mol) of hexadecyldimethylamine in 800 mL of n-propanol, add 141.1 g (1.12 mol) of benzyl chloride while stirring, raise the temperature to 55-65 ° C, stir and react for 4 hours, evaporate the n-propanol to obtain a white oil, add 400 mL of acetone to the reaction vessel, and concentrate to dryness to obtain a white solid.

[0054] Example 3

[0055] Dissolve 296.2 g (1.1 mol) of hexadecyldimethylamine in 900 mL of isopropanol, add 135.1 g (1.072 mol) of benzyl chloride while stirring, raise the temperature to 55-65 ° C, stir and react for 4 hours, evaporate the isopropanol to obtain a white oil, add 350 mL of butanone to the reaction vessel, and concentrate to dryness to obtain a white solid.

[0056] Examples 4-9 and Comparative Examples 1-4

[0057] Using the same charging ratio and reaction steps as in Example 1, the charging amount was reduced by 10 times, and the type and amount of solvent added after the condensation reaction was spin-dried were studied:

[0058] Example Solvent type Dosage (mL) result Example 4 acetone 50 White solid Example 5 acetone 45 White solid Example 6 acetone 40 White solid Example 7 acetone 30 White solid Example 8 acetone 25 White solid* Comparative Example 1 acetone 55 White solid Comparative Example 2 acetone 20 Oily liquid Comparative Example 3 ethanol 35 Oily liquid Comparative Example 4 Ethyl acetate 35 Oily liquid

[0059] *The crude product obtained in this example was barely a white solid, and the residual solvent was significantly higher than that in Examples 4-7.

[0060] It can be seen that after the condensation reaction is completed and the system is spin-dried, acetone and butanone are added. When the mass volume ratio of the solvent dosage to the theoretical yield of cephalosporinium chloride is higher than 0.6 g / mL, the crude product can be formed into a solid at one time, while too little solvent dosage (such as Comparative Example 2) cannot achieve the effect of solidifying the crude product (such as Figure 1 As shown), excessive solvent usage causes the crude solid to precipitate when the solvent is not completely dried (as in Comparative Example 1);

[0061] Under the same conditions, ethyl acetate and ethanol could not achieve the purpose of solidifying the crude product;

[0062] In summary, after the condensation reaction is completed and the mixture is spin-dried, acetone and / or butanone is added to the system. When the mass-volume ratio of the solvent dosage to the theoretical yield of cephalosporin chloride is 0.6-1.2 g / mL, the crude product can be formed into a solid at one time; when the mass-volume ratio of the solvent dosage to the theoretical yield of cephalosporin chloride is 0.8-1.0 g / mL, the obtained crude product has lower solvent residue and better quality.

[0063] Comparative Example 5

[0064] The experiment was carried out according to the method of Example 3 of patent CN109553539A. 60g (0.223mol) of hexadecyldimethylamine, 28g (0.223mol) of benzyl chloride and 230mL of ethanol were added to the reactor and stirred at 40°C for 6h. Then the temperature was lowered to -5°C. Repeated experiments found that the reaction had a certain probability of precipitating an oily substance during the repeated process (such as Figure 2 and becomes more obvious when the feed amount increases.

[0065] Example 9

[0066] 1000 mL of ethyl acetate-ethanol mixed solution (V 乙酸乙酯 :V 乙醇 =1:0.08) was added to the crude solid obtained in Example 1, heated until dissolved, slowly cooled to 20°C, filtered, and dried at 40°C under reduced pressure to obtain 380.0 g of a white solid (yield: 89.7%).

[0067] The product was tested and the content was 99.5%, other alkyl components were 0.10%, and related substances (benzyl alcohol, benzaldehyde, benzyl chloride) were not detected. The product was white fine particles (such as Figure 3 As shown in the figure, the powder repose angle is 33°, which shows that the product has the characteristics of high purity, good fluidity, etc. and is of high quality.

[0068] Example 10

[0069] 1000 mL of ethyl acetate-isopropanol mixed solution (V 乙酸乙酯 :V 异丙醇 =1:0.08) was added to the crude solid obtained in Example 2, heated until dissolved, slowly cooled to 20°C, filtered, and dried under reduced pressure to obtain 368.5 g of a white solid (yield: 87.1%).

[0070] The product obtained by testing showed a content of 99.3%, other alkyl components of 0.13%, and no related substances (benzyl alcohol, benzaldehyde, benzyl chloride) were detected. The product was white fine particles with a powder repose angle of 36°. It can be seen that the product has the characteristics of high purity, good fluidity, etc., and is of high quality.

[0071] Example 11

[0072] 1000mL of isopropyl acetate-n-propanol mixed solution (V 乙酸异丙酯 :V 正丙醇 =1:0.09) was added to the crude solid obtained in Example 3, heated until dissolved, slowly cooled to 10°C, filtered, and dried at 40°C under reduced pressure to obtain 380.5 g of a white solid (yield: 87.3%).

[0073] The product obtained by testing showed a content of 99.2%, other alkyl components of 0.13%, and related substances (benzyl alcohol, benzaldehyde, benzyl chloride) of 0.01%. It is white fine particles with a powder repose angle of 38°. It can be seen that the product has the characteristics of high purity, good fluidity, etc., and is of high quality.

[0074] Comparative Example 6

[0075] 1200 mL of ethyl acetate solution was added to the crude solid obtained by the method of Example 1, heated until dissolved, slowly cooled to 20°C, filtered, and dried at 40°C under reduced pressure to obtain 394.8 g of white solid powder (yield: 93.2%).

[0076] The obtained product was tested, and the content was 98.7%, other alkyl components were 0.35%, and related substances (benzyl alcohol, benzaldehyde, benzyl chloride) were not detected. Although the product yield was improved, its purity was relatively low, and other alkyl components were also at a high value. In addition, during its recrystallization process, the precipitated product was relatively fine, making the system slurry-like, and the filtration time was long. After filtration, the obtained product was in the form of a white powder with poor fluidity and was accompanied by agglomeration (such as Figure 4 As shown in the figure, the angle of repose of the powder is 47°, which shows that the quality of the obtained product is not as good as that of the product obtained by using a mixed solvent.

[0077] Examples 12-17 Comparative Examples 7-10

[0078] The same feed ratio and reaction steps as in Example 1 were used, but the feed amount was reduced by half. After obtaining a crude solid product, the effects of the recrystallization solvent system and solvent dosage on product quality were studied:

[0079]

[0080] The experimental results show that the composition and amount of the solvent used in recrystallization affect product quality and yield. Specifically, when the volume ratio of ethyl acetate (poor solvent) to ethanol (good solvent) is between 1:0.05-0.10, and the ratio of theoretical product mass to solvent usage is between 1:2.0-3.0, the resulting product is of high quality and has a high yield, as demonstrated by a product purity of ≥99.0%, other alkyl impurities less than 0.15%, and related impurities less than 0.03% or even undetectable.

[0081] In contrast, the comparative examples have a product quality inferior to that of the product obtained by the method of the present invention because at least one of the composition and amount of the solvent used for recrystallization does not fall within the scope of protection of the present invention. Specifically:

[0082] In Comparative Example 8, too much ethanol was used in the recrystallization solvent, resulting in a low product yield and a high content of related substances in the obtained product;

[0083] In Comparative Example 9, the amount of ethanol in the recrystallization solvent was too little, resulting in a higher composition of other alkyl groups in the product. In addition, the fluidity of the product was not as good as that of the products obtained by other methods in the examples.

[0084] Comparative Example 10: The amount of recrystallization solvent used was too small, which affected the purity of the product and also caused a high impurity content.

[0085] In Comparative Example 11, the amount of recrystallization solvent used was too much. Although the product quality was the same as that of the examples, the product yield was significantly lower than that of the other examples.

[0086] Based on all the above embodiments, it can be seen that the preparation method of pharmaceutical-grade cetabularium chloride of the present invention achieves a significant improvement in product quality by optimizing the post-treatment method of the condensation reaction and the recrystallization solvent in the refining process. The steps of the entire preparation process are reasonably set, and the solvents used in the process are all the three types of solvents listed in the "Technical Guidelines for the Study of Residual Solvents in Chemical Drugs" and the ICH "Guideline for Residual Solvents". The conditions required for the process are mild and do not involve excessively high or low temperatures, and have a high process level.

[0087] The above embodiments are preferred implementation modes of the present invention, but the implementation modes of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications that do not deviate from the spirit and principles of the present invention should be considered as equivalent replacement methods and are included in the scope of protection of the present invention.

Claims

1. A method for preparing cetabularium chloride, comprising: (1) Condensation reaction; the starting materials are hexadecyldimethylamine and benzyl chloride, or hexadecyl chloride and N,N-dimethylbenzylamine; (2) Recrystallization; After the condensation reaction (1) is completed, the solvent is removed and acetone and / or butanone are added to the system, and the solvent is removed again to obtain a crude cephalosporinium chloride product, wherein the mass volume ratio of the amount of acetone and / or butanone to the theoretical yield of cephalosporinium chloride is 1: 0.6-1.2 g / mL; The recrystallization solvent is a mixed solvent system of a poor solvent and a good solvent, wherein the volume ratio of the poor solvent to the good solvent is 1: 0.05-0.10, and the mass volume ratio of the recrystallization solvent volume to the mass of cephalosporin is 1: 2.0-3.0 g / mL; The poor solvent is selected from any one of ethyl acetate, methyl acetate, propyl acetate, and isopropyl acetate, or a mixture of two or more thereof in any proportion; the good solvent is selected from any one of ethanol, n-propanol, and isopropanol, or a mixture of two or more thereof in any proportion.

2. The preparation method according to claim 1, wherein The molar ratio of hexadecyldimethylamine to benzyl chloride in the starting materials is 1: 0.9-1.1; the molar ratio of hexadecyl chloride to N,N-dimethylbenzylamine is 1: 0.9-1.

1.

3. The preparation method according to claim 1, wherein The molar ratio of hexadecyldimethylamine to benzyl chloride in the starting material is 1: 0.95-1.

05.

4. The preparation method according to claim 1, characterized in that The poor solvent is ethyl acetate.

5. The preparation method according to claim 1, characterized in that The good solvent is ethanol.

6. The preparation method according to claim 1, wherein The volume ratio of the poor solvent to the good solvent is 1: 0.07-0.

08.

7. The preparation method according to claim 1, wherein The mass volume ratio of the recrystallization solvent volume to the mass of cephalosporin is 1: 2.2-2.6 g / mL.

8. A method for preparing cetabularium chloride, comprising: (1) Condensation reaction; the starting materials are hexadecyldimethylamine and benzyl chloride, or hexadecyl chloride and N,N-dimethylbenzylamine; (2) Recrystallization; After the condensation reaction (1) is completed, the solvent is removed and acetone and / or butanone are added to the system, and the solvent is removed again to obtain a crude cephalosporinium chloride product, wherein the mass volume ratio of the amount of acetone and / or butanone to the theoretical yield of cephalosporinium chloride is 1: 0.6-1.2 g / mL; The recrystallization solvent is a mixed solvent system of ethyl acetate and ethanol, wherein the volume ratio of ethyl acetate to ethanol is 1:0.07-0.08, and the mass volume ratio of the recrystallization solvent volume to the mass of cephalosporin is 1:2.2-2.6 g / mL.

9. The preparation method according to claim 8, wherein The volume ratio of the ethyl acetate to the ethanol is 1:0.08, and the mass volume ratio of the recrystallization solvent volume to the mass of cephalosporin is 1:2.4 g / mL.

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