Synthesis process of benzalkonium bromide

Abstract

The invention relates to the technical field of medicines, and discloses a benzalkonium bromide synthesis process, which comprises: S1, blending bromododecane and water, and heating to a first temperature; s2, slowly adding dimethyl benzylamine, and heating to a second temperature; s3, after the reaction is finished, adding a crystallization solvent, stirring, crystallizing, centrifuging and drying to obtain a finished product. By adopting the synthesis process provided by the invention, the problems that the content of impurities in the product is high and the product is finally solid or colloid in the existing synthesis process of benzalkonium bromide can be solved. The benzalkonium bromide synthesized by the method has the advantages of stable product crystalline state and high purity.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and more specifically, to a synthesis process for benzalkonium bromide. Background Technology

[0002] Benzalkonium bromide is a yellowish-white waxy solid or gel. It is readily soluble in water or ethanol, has an aromatic odor, and a very bitter taste. Benzalkonium bromide is a common cationic surfactant bactericide on the market, widely used in medical and industrial disinfection fields. The disinfection mechanism of benzalkonium bromide is that its cations interact with the negatively charged substances on the bacterial cell membrane, causing changes in cell membrane permeability. By altering the permeability of the bacterial cell membrane, it inhibits bacterial growth and metabolism, thereby achieving a bactericidal effect.

[0003] The current synthesis of benzalkonium bromide is obtained by directly reacting bromododecane and dimethylbenzylamine. The reaction process is exothermic and has high viscosity. The raw materials will partially decompose, resulting in a high impurity content in the product. The purity of the product is basically maintained at around 94%-96%. The final product is a solid or colloidal substance, which is difficult to use. Summary of the Invention

[0004] The technical problem solved by this invention:

[0005] This is intended to address the problems of excessive exothermic reaction and high viscosity during the synthesis of benzalkonium bromide, which leads to incomplete reaction, partial decomposition of raw materials, and consequently, high impurity content in the final product, resulting in a solid or colloidal final product.

[0006] The technical solution adopted in this invention is as follows:

[0007] To address the aforementioned technical problems, the present invention aims to provide a synthesis process for benzalkonium bromide. The specific details are as follows:

[0008] A process for synthesizing benzalkonium bromide includes the following steps:

[0009] S1 mixes bromododecane with water and then heats it to the first temperature;

[0010] S2 is slowly added to dimethylbenzylamine, and the temperature is raised to the second temperature.

[0011] After the S3 reaction is complete, a crystallization solvent is added, and the product is obtained by stirring, crystallizing, centrifuging, and drying.

[0012] According to some preferred embodiments, the molar ratio of bromododecane, dimethylbenzylamine, and water is 1:0.8-1.2:0.5-2, and the preferred ratio is 1:1-1.1:0.9-1.1.

[0013] According to some preferred embodiments, in S1, the first temperature is 60-90°C.

[0014] According to some preferred embodiments, in S2, the second temperature is 90-120°C and the reaction time is 3-6 hours.

[0015] According to some preferred embodiments, in S3, the crystallization solvent includes methyl acetate, ethyl acetate, n-heptane, petroleum ether, etc., and the amount of solvent added is 1 to 5 times the total mass of the raw materials.

[0016] According to some preferred embodiments, in S3, crystallization treatment is performed at -10°C to 15°C.

[0017] According to some preferred embodiments, in S3, seed crystals are added at 15°C to assist crystallization. Around 15°C is the freezing point of benzalkonium bromide, which produces solid crystals. Adding seed crystals at the critical crystallization temperature provides nuclei for crystallization, allowing the precipitated product to be quickly adsorbed onto the nuclei, thereby accelerating the product precipitation rate and increasing the solid particle size.

[0018] The technical mechanism and beneficial effects of this invention are as follows:

[0019] (1) In this invention, water is added during the reaction to ensure that the reaction system is uniform and the conversion rate is higher. Benzalkonium bromide requires water of crystallization to form a stable crystalline solid form.

[0020] (2) In this invention, solvent dissolution crystallization is used to ensure that the crystallization state of the product is uniform and stable, and to wash away impurities and by-products of the adsorption reaction, thereby achieving the effect of crystallization purification.

[0021] (3) In this invention, adding seed crystals during crystallization can, firstly, increase the crystallization point of the product and control the crystallization temperature of the product; secondly, provide crystal nuclei for the crystallized body, making the crystallized particles of the product larger, making the post-processing faster and preventing redissolution, and making the drying process easier. Attached Figure Description

[0022] Figure 1 This is a photograph of the product prepared in Comparative Example 1.

[0023] Figure 2 Here is a picture of the product prepared in Comparative Example 2;

[0024] Figure 3 A photograph of the product prepared in Example 4;

[0025] Figure 4 This is a picture of the product prepared in Comparative Example 4. Detailed Implementation

[0026] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Where specific conditions are not specified in the embodiments, conventional conditions or conditions recommended by the manufacturer shall apply. Reagents or instruments whose manufacturers are not specified are all conventional products that can be purchased commercially.

[0027] Example 1

[0028] This embodiment provides a synthesis process for benzalkonium bromide, wherein the molar ratio of each component of the raw materials is limited to 1:1.2:0.9 for dodecane bromo, dimethyl benzylamine and water.

[0029] The specific implementation steps are as follows:

[0030] S1 involves mixing bromododecane with water and then heating the mixture to 60°C.

[0031] S2 is slowly added to dimethylbenzylamine, the temperature is raised to 90°C, and the reaction time is 6 hours.

[0032] After the S3 reaction is complete, ethyl acetate is added. The amount of ethyl acetate added is 1.5 times the total amount of the raw materials (bromododecane, dimethylbenzylamine and water). After complete dissolution, the mixture is cooled to crystallize, and seed crystals are added at 15°C.

[0033] Example 2

[0034] This embodiment provides a synthesis process for benzalkonium bromide, wherein the molar ratio of each component of the raw materials is limited to 1:1.1:0.95 for dodecane bromo, dimethyl benzylamine and water.

[0035] The specific implementation steps are as follows:

[0036] S1 mixes bromododecane with water and then heats it to 70°C;

[0037] S2 is slowly added to dimethylbenzylamine, the temperature is raised to 90°C, and the reaction time is 6 hours.

[0038] After the S3 reaction is complete, ethyl acetate is added. The amount of ethyl acetate added is 1.5 times the total amount of the raw materials (bromododecane, dimethylbenzylamine and water). After complete dissolution, the mixture is cooled to crystallize, and seed crystals are added at 15°C.

[0039] Example 3

[0040] This embodiment provides a synthesis process for benzalkonium bromide, wherein the molar ratio of each component of the raw materials is limited to 1:1.05:0.95 for dodecane bromo, dimethyl benzylamine and water.

[0041] The specific implementation steps are as follows:

[0042] S1 involves mixing bromododecane with water and then heating the mixture to 80°C.

[0043] S2 is slowly added to dimethylbenzylamine, the temperature is raised to 90°C, and the reaction time is 6 hours.

[0044] After the S3 reaction is complete, ethyl acetate is added. The amount of ethyl acetate added is twice the total amount of the raw materials (bromododecane, dimethylbenzylamine and water). After complete dissolution, the mixture is cooled to crystallize, and seed crystals are added at 15°C.

[0045] Example 4

[0046] This embodiment provides a synthesis process for benzalkonium bromide, wherein the molar ratio of each component of the raw materials is limited to 1:1.05:1.05 for dodecane bromo, dimethyl benzylamine and water.

[0047] The specific implementation steps are as follows:

[0048] S1 involves mixing bromododecane with water and then heating the mixture to 80°C.

[0049] S2 is slowly added to dimethylbenzylamine, the temperature is raised to 100℃, and the reaction time is 5 hours.

[0050] After the S3 reaction is complete, ethyl acetate is added. The amount of ethyl acetate added is three times the total amount of the raw materials (bromododecane, dimethylbenzylamine and water). After complete dissolution, the mixture is cooled to crystallize, and seed crystals are added at 15°C.

[0051] Example 5

[0052] This embodiment provides a synthesis process for benzalkonium bromide, wherein the molar ratio of each component of the raw materials is limited to 1:1.05:1.05 for dodecane bromo, dimethyl benzylamine and water.

[0053] The specific implementation steps are as follows:

[0054] S1 involves mixing bromododecane with water and then heating the mixture to 80°C.

[0055] S2 is slowly added to dimethylbenzylamine, the temperature is raised to 100℃, and the reaction time is 4 hours.

[0056] After the S3 reaction is complete, ethyl acetate is added. The amount of ethyl acetate added is three times the total amount of the raw materials (bromododecane, dimethylbenzylamine and water). After complete dissolution, the mixture is cooled to crystallize, and seed crystals are added at 15°C.

[0057] Comparative Example

[0058] Comparative Example 1

[0059] This comparative example provides a synthesis process for benzalkonium bromide, wherein the molar ratio of each component of the raw materials is limited to 1:1.05:1.05 for dodecane bromo, dimethyl benzylamine and water.

[0060] The specific implementation steps are as follows:

[0061] S1 involves mixing bromododecane with water and then heating the mixture to 80°C.

[0062] S2 is slowly added to dimethylbenzylamine, the temperature is raised to 100℃, and the reaction time is 5 hours.

[0063] After the S3 reaction is complete, the product is cooled down and collected; the product is a gel-like liquid.

[0064] Comparative Example 2

[0065] This comparative example provides a synthesis process for benzalkonium bromide, wherein the molar ratio of each component of the raw materials is limited to 1:1.05 for dodecane bromo and dimethyl benzylamine.

[0066] The specific implementation steps are as follows:

[0067] S1 heats bromododecane to 80°C;

[0068] S2 is slowly added to dimethylbenzylamine, the temperature is raised to 100℃, and the reaction time is 5 hours.

[0069] After the S3 reaction is complete, ethyl acetate is added, with a mass three times that of the total raw materials (bromododecane and dimethylbenzylamine). After complete dissolution, the mixture is cooled to crystallize. Seed crystals are added at 15°C. The product precipitates as a paste and cannot be further dried.

[0070] Comparative Example 3

[0071] This comparative example provides a synthesis process for benzalkonium bromide, wherein the molar ratio of each component of the raw materials is limited to 1:1.05:1.05 for dodecane bromo, dimethyl benzylamine and water.

[0072] The specific implementation steps are as follows:

[0073] S1 heats bromododecane to 80°C;

[0074] S2 is slowly added to dimethylbenzylamine, the temperature is raised to 100℃, and the reaction time is 5 hours.

[0075] After the S3 reaction is complete, water and ethyl acetate are added. The mass of ethyl acetate is three times the total mass of the raw materials (bromododecane, dimethylbenzylamine, and water). After complete dissolution, the mixture is cooled to crystallize. Seed crystals are added at 15°C, and the product precipitates crystals, but the yield is low.

[0076] Comparative Example 4

[0077] This comparative example provides a synthesis process for benzalkonium bromide, wherein the molar ratio of each component of the raw materials is limited to 1:1.05:1.05 for dodecane bromo, dimethyl benzylamine and water.

[0078] The specific implementation steps are as follows:

[0079] S1 heats bromododecane to 80°C;

[0080] S2 is slowly added to dimethylbenzylamine, the temperature is raised to 100℃, and the reaction time is 5 hours.

[0081] After the S3 reaction is complete, ethyl acetate is added. The mass of ethyl acetate is three times the total mass of the raw materials (bromododecane, dimethylbenzylamine, and water). After complete dissolution, the mixture is cooled to crystallize.

[0082] Test case

[0083] The products obtained in Examples 1-5 and Comparative Examples 1-4 were used as samples for testing. The detection methods were based on the *Pharmacopoeia of the People's Republic of China (2020 Edition)* and *QB / T 2852-2007 Dialkyl (C14-C18) Dimethyl Ammonium Halides*. The test results are shown in Table 1. In Table 1, purity is calculated based on anhydrous content, i.e.: Purity = Content / (100% - Moisture Content). The content range specified in the *Pharmacopoeia* is 95-105%.

[0084] See the physical image of the product prepared in Comparative Example 1. Figure 1 (The difference between Comparative Example 1 and Example 4 is that Comparative Example 1 was not subjected to crystallization treatment.) A physical image of the product prepared in Comparative Example 2 can be found below. Figure 2 The actual product obtained in Example 4 is shown in the image below. Figure 3 The physical image of the product prepared in Comparative Example 4 is shown below. Figure 4 .

[0085] Table 1 Product Testing Indicators

[0086] sample Free amine residue % Bromate residue % purity% Yield % Example 1 0.66 0.28 99.47 79.40 Example 2 0.58 0.12 99.36 87.23 Example 3 0.54 0.10 99.92 90.64 Example 4 0.44 0.02 100.20 95.35 Example 5 0.56 0.07 100.00 94.33 Comparative Example 1 0.86 0.55 98.69 98.00 Comparative Example 2 - - - - Comparative Example 3 0.57 0.12 99.36 56.31 Comparative Example 4 0.55 0.05 100.05 93.71

[0087] Note: - indicates that it cannot be detected.

[0088] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A process for synthesizing benzalkonium bromide, characterized in that, Includes the following steps: S1 mixes bromododecane with water and then heats it to the first temperature; S2 is slowly added to dimethylbenzylamine, and the temperature is raised to the second temperature. After the S3 reaction is complete, a crystallization solvent is added, and the product is obtained by stirring, crystallizing, centrifuging, and drying.

2. The synthesis process of benzalkonium bromide according to claim 1, characterized in that, The molar ratio of bromododecane, dimethylbenzylamine, and water is 1:0.8–1.2:0.5–2.

3. The synthesis process of benzalkonium bromide according to claim 2, characterized in that, The molar ratio of bromododecane, dimethylbenzylamine, and water is 1:1 to 1.1:0.9 to 1.

1.

4. The synthesis process of benzalkonium bromide according to claim 1, characterized in that, In S1, the first temperature is 60–90℃.

5. The synthesis process of benzalkonium bromide according to claim 1, characterized in that, In S2, the second temperature is 90–120℃, and the reaction time is 3–6 hours.

6. The synthesis process of benzalkonium bromide according to claim 5, characterized in that, In S2, the second temperature is 100℃ and the reaction time is 5h.

7. The synthesis process of benzalkonium bromide according to any one of claims 1 to 6, characterized in that, In S3, the crystallization solvent includes at least one of methyl acetate, ethyl acetate, n-heptane, and petroleum ether, and the mass of the solvent is 1 to 5 times the total mass of the raw materials; the total mass of the raw materials is the total amount of bromododecane, water, and dimethylbenzylamine.

8. The synthesis process of benzalkonium bromide according to claim 7, characterized in that, In S3, crystallization treatment is carried out at -10℃ to 15℃.

9. The synthesis process of benzalkonium bromide according to claim 7, characterized in that, In S3, seed crystals are added at 15℃ to assist crystallization.

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