阅读说明：本技术 一种药用级西他氯铵的制备方法 (Preparation method of medicinal-grade sitaglinium chloride ) 是由 张振锋 谭珍友 罗明亮 张兰 于 2020-04-16 设计创作，主要内容包括：本发明涉及一种药用级西他氯铵的制备方法,该制备方法充分考虑规模化生产的实际,具有步骤合理、工艺稳定性高、能耗较低等特点,所得西他氯铵的有关物质及烷基杂质均控制在较低水平,且产品呈白色颗粒状,产品综合品质优于常规方法制得的产品。(The invention relates to a preparation method of medicinal grade sitaglinium chloride, which fully considers the reality of large-scale production and has the characteristics of reasonable steps, high process stability, lower energy consumption and the like.)

1. The preparation method of the sitaxenium chloride comprises a condensation reaction, and is characterized in that a solvent is removed after the condensation reaction is completed, a second solvent, namely acetone and/or butanone, is added into a system, and a crude sitaxenium chloride product is obtained after the second solvent is removed, wherein the dosage of the acetone and/or butanone is as follows: the mass-volume ratio of the theoretical yield of the sitafloxacin chloride to the dosage of the acetone and/or the butanone is 1: 0.6-1.2 g/mL; the starting materials for the condensation reaction are hexadecyldimethylamine and chlorobenzyl, or hexadecyl chloride and N, N-dimethylbenzylamine.

2. The method for preparing sitaglinium chloride as claimed in claim 1, wherein 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: 0.9-1.1.

3. The method for preparing sitaglinium chloride according to claim 2, wherein the molar ratio of hexadecyldimethylamine to benzyl chloride in the starting material is 1: 0.95-1.05.

4. A method for preparing sitaxonium chloride according to any one of claims 1-3, wherein the solvent used in the condensation reaction is a mixture of one or more of ethanol, n-propanol and isopropanol in any proportion, and the solvent is used in the following amounts: the mass-volume ratio of the theoretical yield of the sitafloxacin chloride to the dosage of the solvent is 1: 1.5-2.5 g/mL.

5. A method for preparing sitaxonium chloride according to any one of claims 1-4, wherein the solvent used in the condensation reaction is ethanol, and the solvent is used in the following amounts: the mass-volume ratio of the theoretical yield of the sitafloxacin chloride to the dosage of the solvent is 1: 1.8-2.2 g/mL.

6. A process for the preparation of cetearonium chloride according to any of claims 1-5 wherein the condensation reaction is carried out at a temperature of from 40 ℃ to reflux temperature, preferably from 50 ℃ to reflux temperature.

7. A process for the preparation of cetearonium chloride as claimed in any of claims 1-6 wherein the solvent is removed after the condensation reaction and acetone is added to the system in the following amounts: the mass-volume ratio of the theoretical yield of the sitafloxacin chloride to the dosage of the acetone is 1: 0.8-1.0 g/mL.

8. A process for the preparation of cetearonium chloride according to any one of claims 1-7 comprising:

(1) condensation reaction;

(2) recrystallizing;

the recrystallization solvent used in the step (2) is a solvent system formed by mixing 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 a mixture obtained by mixing any one or more than two of ethyl acetate, methyl acetate, propyl acetate and isopropyl acetate in any proportion, the good solvent is selected from a mixture obtained by mixing any one or more than two of ethanol, n-propanol and isopropanol in any proportion, and the mass-volume ratio of the usage amount of the recrystallization solvent to the theoretical yield of the sitaxenium chloride is 1:2.0-3.0 g/mL.

9. The preparation method of sitaxenium chloride according to claim 8, wherein the recrystallization solvent used in step (2) is a mixed solvent system of ethyl acetate and ethanol, the volume ratio of ethyl acetate to ethanol is 1: 0.07-0.08, and the mass-to-volume ratio of the amount of the recrystallization solvent to the theoretical yield of the sitaxenium chloride is 1: 2.2-2.6 g/mL.

10. A pharmaceutical formulation comprising sitaxonium chloride, wherein the pharmaceutical formulation comprises the sitaxonium chloride produced by the method of any one of claims 1-9.

Technical Field

The invention belongs to the field of drug synthesis, and particularly relates to a preparation method of medicinal-grade sitaglinium chloride.

Background

Sitaxonium Chloride (Cetalkonium Chloride), also known as cetyldimethylbenzylammonium Chloride, CAS number: 10328-34-4, which is one of three quaternary ammonium salt components (dodecyl dimethyl benzyl ammonium chloride, tetradecyl dimethyl benzyl ammonium chloride and hexadecyl dimethyl benzyl ammonium chloride) for composing surfactant and broad spectrum bacteriostat benzalkonium chloride. The melting point of the sitafloxacin chloride is 50-60 ℃, the sitafloxacin chloride is easily soluble in polar solvents such as water, methanol, ethanol and the like and is hardly soluble in non-polar solvents such as ethyl acetate, petroleum ether and the like, the sitafloxacin chloride has the effect of changing the interface state of a solution system on the physical property, has the bacteriostatic action, and is widely applied to the fields of daily chemical products, cosmetics, medical products and the like as a surfactant and a bacteriostatic agent; at present, the quality standard of the sitaglinium chloride is not recorded in pharmacopoeia at home and abroad, and the quality standard of the sitaglinium chloride is mainly referred to the quality standard of benzalkonium chloride (as a (medicinal) auxiliary material).

Currently, the industrial preparation of the sitafloxacin chloride is mainly prepared by taking hexadecyl dimethylamine and benzyl chloride as raw materials and adopting a condensation method.

Chinese patent CN109553539A discloses a preparation method of hexadecyl dimethyl benzyl ammonium chloride, which takes hexadecyl dimethyl amine and benzyl chloride as raw materials, adopts ethanol, n-propanol, methanol and the like as solvents, and is stirred to separate out solids after cooling to be less than or equal to 0 ℃ after condensation reaction is completed.

The literature (Ternary Water in Oil microorganisms Made of Cationic Surfactants, Water, and Aromatic solutions.1. Water solutions Studies, J.Phys.chem.,1990,94,381-387) discloses a method for preparing hexadecyl dimethyl benzyl ammonium chloride, which uses hexadecyl bromide and N, N-dimethyl benzyl amine as raw materials, uses ethanol as a reaction solvent, and prepares a crude product by condensation and ion exchange methods, wherein the crude product needs to be recrystallized for three times by ethyl acetate or ethyl acetate/ethanol or ether to obtain a final product meeting the requirements, and the preparation process is relatively complicated.

The literature (Synthesis and Properties of quaternary ammonium surfactants contacting a method of fatty alkyl benzyl quaternary ammonium salt, RSC adv, 2014,4, 56918-.

In conclusion, the method for preparing the medicinal grade sitaglinium chloride, which is green and environment-friendly, has low energy consumption, reasonable steps and high process stability and is suitable for industrial large-scale production, is a technical problem which is not solved in the prior art.

Disclosure of Invention

The invention aims to overcome the defects of the prior art and provides a preparation method of medicinal-grade sitaxenium chloride, which fully considers the reality of large-scale production and has the characteristics of reasonable steps, high process stability, low energy consumption and the like, Solvents adopted by the process are three Solvents listed in technical guide principles of chemical drug Residual solvent research and ICH Guideline for Residual Solvents, the related substances and alkyl impurities of the obtained sitaxenium chloride are controlled at lower levels, the product is white granular, and the comprehensive quality of the product is superior to that of the product prepared by the conventional method.

The above object of the present invention is achieved by the following technical solutions:

a preparation method of sitaxonium chloride comprises a condensation reaction, acetone and/or butanone is added into a system after a solvent is removed after the condensation reaction is completed, and a crude product of the sitaxonium chloride is obtained after the solvent is removed again, wherein the dosage of the acetone and/or the butanone is as follows: the mass-volume ratio of the theoretical yield of the sitafloxacin chloride to the dosage of the acetone and/or the butanone is 1: 0.6-1.2 g/mL.

Specifically, the starting materials for the condensation reaction may be hexadecyldimethylamine and chlorobenzyl, or hexadecyl chloride and N, N-dimethylbenzylamine, specifically, the molar ratio of hexadecyldimethylamine/hexadecyl chloride to chlorobenzyl/N, N-dimethylbenzylamine in the starting materials is 1: 0.9-1.1, preferably, the starting materials for the condensation reaction are hexadecyldimethylamine and chlorobenzyl, and the molar ratio of hexadecyldimethylamine to chlorobenzyl in the starting materials is 1: 0.95-1.05.

The reaction formula of the condensation reaction is as follows:

the condensation reaction step of the invention has relatively low requirements on the solvent, and the organic solvent which can dissolve the substrate can usually realize the reaction; specifically, the solvent used in the condensation reaction is preferably a mixture obtained by mixing one or more of ethanol, n-propanol and isopropanol in any proportion, and the amount of the solvent is as follows: the mass-volume ratio of the theoretical yield (mass) of the sitafloxacin chloride to the dosage (volume) of the solvent is 1: 1.5-2.5 g/mL.

The invention has the advantages that the selection of the type and the dosage of the solvent in the condensation reaction step exists, the use of excessive solvent ensures that the concentration of the reactant is lower, on one hand, the reaction rate is influenced, on the other hand, the time for removing the solvent is longer, and the use of too little solvent is easy to generate side reaction and influence the product quality.

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

The reaction temperature of the condensation reaction is from 40 ℃ to reflux temperature, preferably from 50 ℃ to reflux temperature; at the temperature, the reaction can be completed quickly, and the reaction end point is as follows: and (4) finishing the reaction when the reaction raw materials are completely or basically consumed.

In the preparation method of the sitaxonium chloride, the step of adding acetone and/or butanone to the system after removing the solvent and removing the solvent again is one of the key technical characteristics for realizing the technical purpose, because the melting point of the sitaxonium chloride is lower, the solvent is easy to be included in the process of removing the solvent to form oily substances, the solidification of a crude product in the step is important in the preparation method, if the oily substances are formed, the product is separated out in the oily substances again in the subsequent recrystallization step, or even if the solid is separated out, the yield is also obviously reduced, and the phenomenon is more obvious in large-scale production; the inventor accidentally finds out in process optimization that when acetone and/or butanone is added into a system after solvent is removed, the crude product can form solid in the process of removing the solvent again, the amount of the added acetone and/or butanone is also selected, specifically, the addition of too much acetone and/or butanone leads to the use of too much solvent, the time for removing the solvent is longer, and the effect is not correspondingly enhanced, while the addition of too little acetone and/or butanone cannot realize the effect of forming solid even if the crude product is added once, and when the mass-to-volume ratio of the amount of the added acetone and/or butanone to the theoretical yield of the sitafloxacin chloride is 1: 0.6-1.2g/mL, the effect of forming solid even if the crude product is added once can be realized.

Preferably, acetone is added into the system after the solvent is removed, and the mass-volume ratio of the acetone dosage to the theoretical yield of the sitafloxacin chloride is 1: 0.8-1.0g/mL, so that the optimal crude product curing effect can be obtained.

Further, the above-mentioned preparation method of sitaxonium chloride further comprises a recrystallization step, and the description and preferred cases of the condensation reaction steps in the preparation method are the same as those described above in the present invention, and the preparation method is as follows:

a method of making sitaxonium chloride, the method comprising:

(1) condensation reaction;

(2) recrystallizing;

after the condensation reaction in the step (1) is finished, removing the solvent, adding acetone and/or butanone into the system, and removing the solvent again to obtain a crude product of the sitafloxacin chloride, wherein the mass-to-volume ratio of the dosage of the acetone and/or butanone to the theoretical yield of the sitafloxacin chloride is 1: 0.6-1.2 g/mL;

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 step 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 to 0.10, the poor solvent is selected from a mixture of any one or more of ethyl acetate, methyl acetate, propyl acetate and isopropyl acetate in any proportion, the good solvent is selected from a mixture of any one or more of ethanol, n-propanol and isopropanol in any proportion, the mass-to-volume ratio of the dosage (volume) of the recrystallization solvent to the theoretical yield (mass) of the sitafloxacin chloride is 1:2.0 to 3.0g/mL, and more specifically, the impurities of the pharmaceutical sitafloxacin chloride are classified into related substances (benzyl alcohol, or mixtures of the pharmaceutical sitafloxacin chloride in any proportion, Benzaldehyde and benzyl chloride) and alkyl impurities (dodecyl dimethyl benzyl ammonium chloride, tetradecyl dimethyl benzyl ammonium chloride and octadecyl dimethyl benzyl ammonium chloride), benzalkonium chloride is used as a pharmaceutic adjuvant, the requirements of domestic and foreign pharmacopoeia on the quality control standard of benzalkonium chloride are relatively loose, the invention refers to the stipulation of domestic and foreign pharmacopoeia on benzalkonium chloride, the quality control standard of the sitafloxacin chloride is strictly controlled by combining the impurity content in the relevant stipulation product of ICH on the quality of the raw material medicine, and the content of the relevant substances and the alkyl impurities is limited to be lower than 0.15 percent.

The inventor finds in the experimental process that the use of a poor solvent is beneficial to removing related substances, particularly the use of ethyl acetate is obvious, while the use of a good solvent is beneficial to removing alkyl impurities, particularly the use of ethanol; the inventor also unexpectedly discovers that excessive use of the poor solvent is easy to separate out the product with a very small particle size, so that a system is in a slurry state, the product filtration and the optimization of product properties are not facilitated, the obtained product is in a white powder state, the caking phenomenon exists, the fluidity is poor, the product is easy to adhere to the surface of an appliance, and the ethyl acetate is particularly obvious; 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-to-volume ratio of the dosage (volume) of the recrystallization solvent to the theoretical yield (mass) of the sitafloxacin chloride is 1: 2.2-2.6 g/mL.

The (2) recrystallization step follows a recrystallization operation step which is common in the field, and particularly, the (2) recrystallization step comprises a step of slowly cooling the crude product after the crude product is dissolved, the cooling step can adopt a one-step cooling method or a step-by-step cooling method, the end temperature of the cooling step can be room temperature or a temperature lower than the room temperature, and preferably, when the cooling end temperature is 10-20 ℃, the (2) recrystallization step can achieve the optimal combination of the product yield and the product purity.

A preferred method of carrying out the invention is as follows:

a method of making sitaxonium chloride, the method comprising:

(1) condensation reaction;

(2) recrystallizing;

the starting materials of the condensation reaction (1) are hexadecyl dimethylamine and benzyl chloride, the molar ratio of the hexadecyl dimethylamine to the benzyl chloride is 1:1, the solvent used in the condensation reaction is ethanol, and the mass-to-volume ratio of the dosage (volume) of the solvent to the theoretical yield (mass) of the sitafloxacin chloride is 1:2.1 g/mL;

after the condensation reaction in the step (1) is finished, removing the solvent, adding acetone into the system, and removing the solvent again to obtain a crude product of the sitafloxacin chloride, wherein the mass-volume ratio of the acetone dosage to the theoretical yield of the sitafloxacin chloride is 1:0.8 g/mL;

the recrystallization solvent used in the recrystallization (2) is a solvent system formed by mixing 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 dosage (volume) of the recrystallization solvent to the theoretical yield (mass) of the sitafloxacin chloride is 1:2.4 g/mL.

The preparation method provided by the invention fully considers the process feasibility, and can be used for preparing a high-quality sitaglinium chloride product, and particularly, the preparation method provided by the invention has relatively simple process steps, can be used for preparing the sitaglinium chloride product without adopting low temperature (less than or equal to 0 ℃), and adopts Solvents in the reaction, post-treatment and refining steps, which are all three Solvents listed in technical guide principle of chemical drug residue solvent research and ICH Guideline for Residual Solvents, is environment-friendly and has relatively wider control requirements on solvent residues, and the prepared sitaglinium chloride product has the advantages that the related substances are stably controlled below 0.03%, the alkyl impurities are stably controlled below 0.15%, the product is white, uniform and granular, the angle of repose is stable between 30-40 degrees, the product has good fluidity, and the comprehensive quality of the product is high.

The second purpose of the invention is to provide a medicinal preparation containing the sitafloxacin chloride prepared by the method. According to the literature report, when benzalkonium chloride is selected as a preservative by various major eye preparation manufacturers at home and abroad, the concentration range is controlled to be between 0.005 and 0.02 percent, while the concentration range of the cetylpyridinium chloride is controlled to be between 0.001 and 0.01 percent in the preparation application as one of the benzalkonium chloride components.

The low-concentration sitaxonium chloride solution corresponds to less dosage of the sitaxonium chloride and needs to be accurately weighed, so that the quality of the sitaxonium chloride product is particularly important.

Compared with the prior art, the invention has the following advantages and beneficial effects:

1. according to the preparation method of the medicinal grade sitaglinium chloride, the preparation method has the characteristics of reasonable steps, high process stability, low energy consumption and the like, related substances and alkyl impurities of the obtained sitaglinium chloride are controlled at a low level, the product is white granular, and the comprehensive quality of the product is superior to that of the products prepared by other methods;

2. the preparation containing the sitaglinium chloride prepared by the method has accurate concentration, low content of impurities related to the sitaglinium chloride and high stability.

Drawings

FIG. 1 is a photograph of a product obtained in comparative example 2;

FIG. 2 is a photograph of a product obtained in comparative example 5;

FIG. 3 is a photograph of the product obtained in example 9;

FIG. 4 is a photograph of a product obtained in comparative example 6.

Detailed Description

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

Example 1

288.7g (1.072mol) hexadecyl dimethylamine is dissolved in 900mL ethanol, 135.1g (1.072mol) benzyl chloride is added under stirring, the temperature is raised to 55-65 ℃, the reaction is stirred for 4 hours, the ethanol is distilled off to obtain white oily matter, 350mL acetone is added into a reaction vessel, and the white solid is obtained after concentration and drying.

Example 2

288.7g (1.072mol) hexadecyldimethylamine is dissolved in 800mL of n-propanol, 141.1g (1.12mol) benzyl chloride is added under stirring, the temperature is raised to 55-65 ℃, the reaction is stirred for 4 hours, the n-propanol is evaporated to obtain white oily matter, 400mL of acetone is added into a reaction vessel, and the white oily matter is obtained by concentration and drying.

Example 3

296.2g (1.1mol) of hexadecyldimethylamine is dissolved in 900mL of isopropanol, 135.1g (1.072mol) of benzyl chloride is added under stirring, the temperature is raised to 55-65 ℃, the reaction is stirred for 4 hours, the isopropanol is distilled off to obtain white oily matter, 350mL of butanone is added into a reaction vessel, and the white oily matter is obtained by concentration and drying.

Examples 4 to 9 and comparative examples 1 to 4

The same charge ratio and reaction steps as those of example 1 were adopted, the charge amount was reduced by 10 times, and the types and amounts of the solvents added after the spin-drying of the condensation reaction were investigated:

examples	Kind of solvent	Dosage (mL)	Results
				Example 4	Acetone (II)	50	White solid
Example 5	Acetone (II)	45	White solid
				Example 6	Acetone (II)	40	White solid
Example 7	Acetone (II)	30	White solid
				Example 8	Acetone (II)	25	White solid
Comparative example 1	Acetone (II)	55	White solid
				Comparative example 2	Acetone (II)	20	Oily liquid
Comparative example 3	Ethanol	35	Oily liquid
				Comparative example 4	Ethyl acetate	35	Oily liquid

The crude product obtained in this example was a barely white solid, which was visually observed to have significantly higher solvent residue than examples 4-7.

It can be seen that acetone and butanone are added into the system after the condensation reaction is finished and the crude product can be formed into a solid at one time when the mass-to-volume ratio of the solvent dosage to the theoretical yield of the sitafloxacin chloride is higher than 0.6g/mL, while too little solvent dosage (as in comparative example 2) cannot achieve the effect of solidifying the crude product (as shown in fig. 1), and too much solvent dosage causes the crude product solid to be separated out when the solvent is not completely dried (as in comparative example 1);

under the same condition, the ethyl acetate and the ethanol can not realize the purpose of solidifying the crude product;

in conclusion, after the condensation reaction is finished and the rotary drying is finished, acetone and/or butanone is added into the system, and when the mass volume ratio of the solvent dosage to the theoretical yield of the sitafloxacin chloride is 0.6-1.2g/mL, the crude product can be formed into solid at one time; when the mass-to-volume ratio of the solvent dosage to the theoretical yield of the sitafloxacin chloride is 0.8-1.0g/mL, the obtained crude product has lower solvent residue and better quality.

Comparative example 5

The experiment was carried out according to the method of example 3 of patent CN 109553539A. 60g (0.223mol) of hexadecyldimethylamine, 28g (0.223mol) of benzyl chloride and 230mL of ethanol were added to the reactor and stirred at 40 ℃ for 6 h. Then the temperature is reduced to-5 ℃. Repeated experiments show that the reaction is separated out as oil with a certain probability in the repeated process (as shown in figure 2), and the feeding amount is more obvious when being increased.

Example 9

1000mL of an ethyl acetate-ethanol mixed solution (V)_{Ethyl acetate}:V_Ethanol1:0.08) the crude solid obtained in example 1 was added, heated to a clear solution, slowly cooled to 20 ℃, filtered and dried under reduced pressure at 40 ℃ to give 380.0g of a white solid (yield: 89.7%).

The content of the obtained product is 99.5 percent through detection, the content of other alkyl groups is 0.10 percent, related substances (benzyl alcohol, benzaldehyde and benzyl chloride) are not detected, the product is white fine particles (as shown in figure 3), the powder body angle of repose is 33 degrees, and the product has the characteristics of high purity, good fluidity and the like and has high quality.

Example 10

1000mL of an ethyl acetate-isopropyl alcohol mixed solution (V)_{Ethyl acetate}:V_{Isopropanol (I-propanol)}1:0.08) was added the crude solid obtained in example 2, heated to a clear solution, slowly cooled to 20 deg.cAfter filtration and drying under reduced pressure, 368.5g of a white solid was obtained (yield: 87.1%).

The content of the obtained product is 99.3 percent through detection, the content of other alkyl groups is 0.13 percent, related substances (benzyl alcohol, benzaldehyde and benzyl chloride) are not detected, the product is white fine particles, the powder body angle of repose is 36 degrees, and the obtained product has the characteristics of high purity, good fluidity and the like and has high quality.

Example 11

1000mL of isopropyl acetate-n-propanol mixed solution (V)_{Acetic acid isopropyl ester}:V_N-propanol1:0.09) was added to the crude solid obtained in example 3, heated to a clear solution, slowly cooled to 10 ℃, filtered, and dried under reduced pressure at 40 ℃ to give 380.5g of a white solid (yield: 87.3%).

The content of the obtained product is 99.2 percent through detection, the content of other alkyl groups is 0.13 percent, the content of related substances (benzyl alcohol, benzaldehyde and benzyl chloride) is 0.01 percent, the product is white fine particles, the powder body angle of repose is 38 degrees, and the product has the characteristics of high purity, good fluidity and the like and has high quality.

Comparative example 6

1200mL of ethyl acetate solution was added to the crude solid obtained in example 1, heated to a clear solution, slowly cooled to 20 deg.C, filtered, and dried under reduced pressure at 40 deg.C to give 394.8g of white solid powder (yield: 93.2%).

The content of the obtained product is 98.7 percent, other alkyl groups form 0.35 percent, and related substances (benzyl alcohol, benzaldehyde and benzyl chloride) are not detected. Despite the improved product yield, the purity is relatively low and other alkyl compositions are at higher values. In addition, in the recrystallization process, the precipitated product is fine, so that the system is in a slurry state, the filtration time is long, the obtained product after filtration is in a white powder state, the fluidity is poor, the agglomeration phenomenon is accompanied (as shown in fig. 4), the powder repose angle is 47 degrees, and the obtained product is inferior to the product obtained by using the mixed solvent.

Examples 12-17 comparative examples 7-10

The same charge ratio and reaction steps as those in example 1 were adopted to reduce the charge amount by 1 time, and after a solid crude product was obtained, the influence of the recrystallization solvent system and the amount of solvent on the product quality was studied:

from the experimental results, it can be seen that the composition and amount of the solvent used for recrystallization have an influence on the quality and yield of the product. Specifically, when the volume ratio of ethyl acetate (poor solvent) to ethanol (good solvent) is 1:0.05-0.10, and the ratio of theoretical product mass to solvent amount is 1:2.0-3.0, the obtained product has high quality and high yield, which means that the product purity is more than or equal to 99.0%, and other alkyl group composition impurities are less than 0.15%, and related impurities are less than 0.03%, even are not detected.

In contrast to the comparative examples, the quality of the product is inferior to that obtained by the process of the present invention, since at least one of the composition and the amount of the solvent used for recrystallization does not fall within the scope of the present invention. Specifically, the method comprises the following steps:

in comparative example 8, the use of too much ethanol in the recrystallization solvent results in lower product yield and higher content of related substances in the obtained product;

in comparative example 9, too little ethanol is contained in the recrystallization solvent, which results in higher composition of other alkyl groups in the product, and the product fluidity is inferior to that of the product obtained by other methods in the examples;

in comparative example 10, the amount of the recrystallization solvent used is too small, so that the product purity is affected and the impurity content is too high;

comparative example 11 the recrystallization solvent was used in an excessive amount, and although the product quality was not inferior to that of the examples, the product yield was significantly lower than that of the remaining examples.

By combining all the embodiments, the preparation method of the medicinal-grade sitaxenium chloride provided by the invention realizes the remarkable improvement of the product quality by optimizing the post-treatment method including the condensation reaction and the recrystallization solvent in the refining process, the steps of the whole preparation process are reasonably set, the Solvents adopted by the process are all three Solvents listed in technical guidance principle of chemical drug Residual solvent research and ICH Guideline for Residual Solvents, the conditions required by the process are mild, excessive or excessive temperature is not involved, and the process level is higher.

The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.