Production process of low-residue medicinal benzalkonium chloride
阅读说明：本技术 一种低残留药用苯扎氯铵生产工艺 (Production process of low-residue medicinal benzalkonium chloride ) 是由 夏建俊 徐慧 顾宇峰 朱静燕 张波 陆慧红 于 2021-09-24 设计创作，主要内容包括：本申请属于阳离子表面活性剂合成技术领域,涉及一种低残留药用苯扎氯铵生产工艺,包括如下步骤：向装有30-60℃混合烷基叔胺的反应釜分若干次加入氯化苄并逐次进行控温降温以调节反应温度；控制温度在70-100℃后进行保温反应；保温反应后向反应釜中中加入处理剂并通入氮气,经水解脱水或反应处理脱盐得到高质量苯扎氯铵产品。本发明通过加水水解并协同蒸发或加处理剂反应处理的方式解决了目前苯扎氯铵中高氯化苄残留的问题,产品具有混合碳链,从而提高了苯扎氯铵的灭菌抑菌性能,满足市场需要。(The application belongs to the technical field of cationic surfactant synthesis, and relates to a production process of low-residue medicinal benzalkonium chloride, which comprises the following steps: adding benzyl chloride into a reaction kettle filled with mixed alkyl tertiary amine at the temperature of 30-60 ℃ for several times, and gradually controlling the temperature and reducing the temperature to adjust the reaction temperature; controlling the temperature to be 70-100 ℃ and then carrying out heat preservation reaction; and after the heat preservation reaction, adding a treating agent into the reaction kettle, introducing nitrogen, and performing hydrolysis dehydration or reaction treatment for desalination to obtain a high-quality benzalkonium chloride product. The invention solves the problem of high benzyl chloride residue in benzalkonium chloride at present by adding water for hydrolysis and cooperating with evaporation or adding a treating agent for reaction treatment, and the product has a mixed carbon chain, thereby improving the sterilization and bacteriostasis performance of benzalkonium chloride and meeting the market demand.)
1. A production process of low-residue medicinal benzalkonium chloride is characterized by comprising the following steps:
1) adding benzyl chloride into a reaction kettle (1) filled with mixed alkyl tertiary amine at 30-60 ℃ for several times, and gradually controlling the temperature and reducing the temperature to adjust the reaction temperature;
2) controlling the temperature to be 70-100 ℃ and then carrying out heat preservation reaction;
3) and (3) after the heat preservation reaction, adding a treating agent into the reaction kettle (1), introducing nitrogen, and dehydrating or desalting to obtain a high-quality benzalkonium chloride product.
2. The process for producing low residue pharmaceutical benzalkonium chloride as claimed in claim 1, wherein: the mixed alkyl tertiary amine comprises dodecyl dimethyl mixed tertiary amine and tetradecyl dimethyl mixed tertiary amine with the content of more than 70 percent, wherein the content of the dodecyl dimethyl mixed tertiary amine is more than 40 percent, and the content of the tetradecyl dimethyl mixed tertiary amine is more than 20 percent.
3. The process for producing low residue pharmaceutical benzalkonium chloride as claimed in claim 1, wherein: in the step 1), adding benzyl chloride into the mixed alkyl tertiary amine for three times;
adding benzyl chloride accounting for 20-80% of the total amount of the benzyl chloride into the mixed alkyl tertiary amine for the first time, and then, controlling the temperature to reduce the temperature to ensure that the reaction temperature does not exceed 80 ℃, and slowly reducing the temperature to 70 ℃;
secondly, adding benzyl chloride accounting for 10-50% of the total dosage of the benzyl chloride into the mixed alkyl tertiary amine, and then, controlling the temperature and reducing the temperature to ensure that the reaction temperature does not exceed 90 ℃, and slowly reducing the temperature to 70 ℃;
and adding the rest benzyl chloride into the mixed alkyl tertiary amine for the third time, then controlling the temperature and reducing the temperature to ensure that the reaction temperature does not exceed 120 ℃, and slowly reducing the temperature to 70-100 ℃ for heat preservation reaction for 2-6 hours.
4. The process for producing low residue pharmaceutical benzalkonium chloride as claimed in claim 1, wherein: the treating agent is deionized water, deionized water is added into the reaction kettle (1) after the heat preservation reaction in the step 3), nitrogen is introduced, and the high-quality benzalkonium chloride product is obtained after 3-8 hours of reduced pressure dehydration.
5. The process for producing low residue pharmaceutical benzalkonium chloride as claimed in claim 1, wherein: the treating agent is an alkaline solution, the alkaline solution is added into the reaction kettle (1) after the heat preservation reaction in the step 3) until the pH value of the reaction system is 8-13, nitrogen is introduced, the reaction is carried out for 3-8 hours at 70-100 ℃, and a high-quality benzalkonium chloride product is obtained by desalting in a filtering mode.
6. The process for producing low residue pharmaceutical benzalkonium chloride as claimed in claim 5, wherein: the alkaline solution is NaOH solution or Na solution2CO3Solution, NaHCO3Solution, KOH solution, K2CO3Solution or KHCO3A solution, the concentration of the alkaline solution being 2-50 wt%.
7. The process for producing low residue pharmaceutical benzalkonium chloride as claimed in claim 4, wherein: in the step 3), the treating agent is continuously introduced from the bottom of the reaction kettle (1), and the content of the treating agent in the reaction kettle (1) is kept to be 8-12 wt% in the process of pressure reduction and dehydration.
8. The process for producing low residue pharmaceutical benzalkonium chloride as claimed in claim 4, wherein: in the step 3), the pressure of the reduced pressure dehydration is controlled at-0.05 MPa, and the reaction temperature in the reduced pressure dehydration process is 100-105 ℃.
9. The process for producing low residue pharmaceutical benzalkonium chloride as claimed in claim 1, wherein: carry out the production of high quality benzalkonium chloride product through benzalkonium chloride synthesizer, benzalkonium chloride synthesizer includes reation kettle (1), charge-in pipeline (8) that are used for letting in mixed alkyl tertiary amine and benzyl chloride are connected in reation kettle (1), the outside of this reation kettle (1) is equipped with presss from both sides cover (2), hot medium passageway (3) and cold medium passageway (4) are connected respectively in this cover (2), treating agent pipeline (5) that are used for letting in the treating agent and nitrogen gas pipeline (6) that are used for letting in nitrogen gas are connected to the bottom of reation kettle (1), connect dewatering device (7) on reation kettle (1).
10. The process for producing low residue pharmaceutical benzalkonium chloride as claimed in claim 9, wherein: the dehydration device (7) comprises a condenser (7a), a receiving groove (7b) and a vacuum pump (7c) which are sequentially connected along the top of the reaction kettle (1).
Technical Field
The invention belongs to the technical field of synthesis of cationic surfactants, relates to a method for synthesizing benzalkonium chloride, and particularly relates to a production process of low-residue medicinal benzalkonium chloride.
Background
At present, the national standard executed by medicinal benzalkonium chloride in China refers to the quality standard of the 2015 edition of Chinese pharmacopoeia, and the composition of a carbon chain and the content of benzyl chloride are not specified clearly. The carbon chain composition is related to the sterilization and bacteriostasis performance of the product and the irritation to human bodies, and has related requirements in European and American pharmacopoeias. In addition, benzyl chloride, benzaldehyde and benzyl alcohol residues influence the irritation and toxicity of downstream products to human bodies, particularly benzyl chloride is used as a raw material for synthesizing benzalkonium chloride, is colorless or yellowish transparent liquid, belongs to a carcinogen, has an irritant odor and has a strong irritation effect on eyes, particularly corneas. The benzalkonium chloride products on the domestic market generally have the characteristic of high benzyl chloride residue, downstream preparation production enterprises urgently hope to improve the quality of the benzalkonium chloride products, and under the background, a production method of benzalkonium chloride with low impurity residue is urgently needed.
The Chinese patent application with publication number CN106956717A discloses a synthesis process of benzalkonium chloride monomer, which is mainly characterized in that thiourea is added in the synthesis process to promote the reaction, and the benzalkonium chloride monomer with high quality is obtained by purifying the mixture by a filtering, crystallizing and drying method in the post-treatment. The method adopts tertiary amine with single carbon chain, and can not reach the standard specified in European and American pharmacopoeias. In addition, crystallization with solvents requires a large investment in equipment and introduces other impurities.
The Chinese patent application with publication number CN104151172A discloses a production method of refined benzalkonium chloride, which is mainly to distill and purify raw materials of dodecyl dimethylamine and benzyl chloride, and the residue of the benzyl chloride does not have a relevant treatment method and can not reach the standard specified in European and American pharmacopoeias.
The Chinese patent application with publication number CN106916071A discloses a method for synthesizing a benzalkonium chloride mixture, which adopts metal or nonmetal halide as an additive, improves the conversion rate of reactants by dropwise adding benzyl chloride, and obtains a product by performing suction filtration, washing and recrystallization on a mixed system. The technical scheme has the advantages of complex steps, high equipment cost required to be input, low production efficiency and long production period.
Disclosure of Invention
The application aims to solve the problems and provides a production process of low-residue medicinal benzalkonium chloride;
in order to achieve the purpose, the invention adopts the following technical scheme:
the application creatively provides a production process of low-residue medicinal benzalkonium chloride, which comprises the following steps:
1) adding benzyl chloride into a reaction kettle filled with mixed alkyl tertiary amine at the temperature of 30-60 ℃ for several times, and gradually controlling the temperature and reducing the temperature to adjust the reaction temperature;
2) controlling the temperature to be 70-100 ℃ and then carrying out heat preservation reaction;
3) and (3) after the heat preservation reaction, adding a treating agent into the reaction kettle, introducing nitrogen, and dehydrating or desalting to obtain a high-quality benzalkonium chloride product.
In the production process of the low-residue medicinal benzalkonium chloride, the adding modes of the treating agent in the step 3) are divided into two modes.
Firstly, adding a treating agent into a reaction kettle for several times;
and secondly, continuously introducing the treating agent from the bottom of the reaction kettle.
In the production process of the low-residue medicinal benzalkonium chloride, the mixed alkyl tertiary amine comprises dodecatetradecyldimethyl mixed tertiary amine.
The dodecatetradecyl dimethyl mixed tertiary amine, namely the dodecatetradecyl dimethyl tertiary amine, which is English name NoKe DMA1214, has two carbon chain structures of C12 and C14, solves the problem of single carbon chain of benzalkonium chloride, and thus produces a product meeting the requirements of European and American pharmacopoeias.
In the production process of the low-residue medicinal benzalkonium chloride, the mixed alkyl tertiary amine contains dodecyl dimethyl mixed tertiary amine and tetradecyl dimethyl mixed tertiary amine with the content of more than 70 percent, wherein the content of the dodecyl dimethyl mixed tertiary amine is more than 40 percent, and the content of the tetradecyl dimethyl mixed tertiary amine is more than 20 percent.
In the production process of the low-residue medicinal benzalkonium chloride, the weight ratio of the total dosage of the mixed alkyl tertiary amine and the benzyl chloride is 1.5-2: 1.
Preferably, the weight ratio of the total amount of mixed alkyl tertiary amine and benzyl chloride used is 1.7: 1.
In the production process of the low-residue medicinal benzalkonium chloride, in the step 1), the temperature control and temperature reduction is carried out in the reaction kettle once after the benzyl chloride is added every time, and the upper temperature control limit in the temperature control and temperature reduction process every time is higher than that in the previous temperature control and temperature reduction process.
In the production process of the low-residue medicinal benzalkonium chloride, benzyl chloride is added into the mixed alkyl tertiary amine for three times in the step 1);
adding benzyl chloride accounting for 20-80% of the total amount of the benzyl chloride into the mixed alkyl tertiary amine for the first time, and then, controlling the temperature to reduce the temperature to ensure that the reaction temperature does not exceed 80 ℃, and slowly reducing the temperature to 70 ℃;
secondly, adding benzyl chloride accounting for 10-50% of the total dosage of the benzyl chloride into the mixed alkyl tertiary amine, and then, controlling the temperature and reducing the temperature to ensure that the reaction temperature does not exceed 90 ℃, and slowly reducing the temperature to 70 ℃;
and adding the rest benzyl chloride into the mixed alkyl tertiary amine for the third time, then controlling the temperature and reducing the temperature to ensure that the reaction temperature does not exceed 120 ℃, and slowly reducing the temperature to 70-100 ℃ for heat preservation reaction for 2-6 hours.
In the production process of the low-residue medicinal benzalkonium chloride, the treating agent is deionized water or alkaline solution, the treating agent is different in dosage, and the modes of removing the residues of the treating agent are different.
When the treating agent is deionized water, adding the deionized water into the reaction kettle after the heat preservation reaction, introducing nitrogen from the bottom of the reaction kettle, and dehydrating under reduced pressure for 3-8 hours, wherein the pressure of the dehydration under reduced pressure is controlled at-0.05 MPa, and the reaction temperature in the process of the dehydration under reduced pressure is 100 plus 105 ℃.
Preferably, deionized water is continuously introduced from the bottom of the reaction kettle, and the water content in the reaction kettle is kept between 8 and 12 weight percent in the decompression dehydration process.
When the treating agent is an alkaline solution, adding the alkaline solution into a reaction kettle after heat preservation reaction until the pH value of a reaction system is 8-13, introducing nitrogen, reacting at 70-100 ℃ for 3-8 hours, removing benzyl chloride, generating sodium chloride through reaction, forming crystals in the product and precipitating at the bottom of the reaction kettle, discharging a small amount of benzalkonium chloride containing sodium chloride crystals from the bottom of the reaction kettle after the reaction is finished, and desalting to obtain a high-quality benzalkonium chloride product, or desalting the product by adopting a pressurizing, normal-pressure or reduced-pressure filtering mode.
The alkaline solution is NaOH solution or Na2CO3Solution, NaHCO3Solution, KOH solution, K2CO3Solution or KHCO3The concentration of the solution, the alkaline solution is 2-50 wt%.
The production process of the low-residue medical benzalkonium chloride is realized by benzalkonium chloride synthesis equipment, the benzalkonium chloride synthesis equipment comprises a reaction kettle, the reaction kettle is connected with a feeding pipeline for introducing mixed alkyl tertiary amine and benzyl chloride, the outer side of the reaction kettle is provided with a jacket, the jacket is respectively connected with a hot medium channel for introducing steam and a cold medium channel for introducing cooling water, the bottom of the reaction kettle is connected with a treating agent pipeline for introducing deionized water and a nitrogen pipeline for introducing nitrogen, and the reaction kettle is connected with a dewatering device.
In the production process of the low-residue medicinal benzalkonium chloride, the dehydration device comprises a condenser, a receiving tank and a vacuum pump which are sequentially connected along the top of the reaction kettle.
Compared with the prior art, the invention has the advantages that:
the invention solves the problem of high benzyl chloride residue in benzalkonium chloride at present by adding water and cooperatively evaporating, and the product has mixed carbon chains, thereby improving the sterilization and bacteriostasis performance of benzalkonium chloride, filling the vacancy of benzalkonium chloride performance and low residue in domestic market, and meeting the market demand.
The synthesized benzalkonium chloride is treated by two different treating agents, so that a product with high active matter content and low benzyl chloride residue can be obtained, the two treating methods are simple and effective, and other impurities cannot be introduced into the product.
The residual benzyl chloride content in the product can be controlled below 0.05% by adopting a reduced pressure distillation mode of adding distilled water and a treatment mode of adjusting the pH value to 8-13 by using alkali liquor.
In addition, the invention controls the reaction temperature to reduce the volatilization of benzyl chloride and improve the reaction efficiency by feeding materials in several times and controlling the temperature gradually, thereby improving the conversion rate of benzyl chloride.
The method is directly operated on the basis of the synthesis reaction equipment, and does not need the investment of other equipment, thereby greatly reducing the production cost and improving the production efficiency.
Drawings
FIG. 1 is a process flow diagram provided herein.
In the figure, a reaction vessel 1, a jacket 2, a heat medium channel 3, a cold medium channel 4, a treating agent pipeline 5, a nitrogen pipeline 6, a dehydration device 7, a condenser 7a, a receiving tank 7b, a vacuum pump 7c and a feeding pipeline 8 are arranged.
Detailed Description
Further illustrated by the following specific examples;
example 1
As shown in figure 1, benzalkonium chloride synthesis equipment comprises a reaction kettle 1, wherein the reaction kettle 1 is connected with a feeding pipeline 8 for introducing mixed alkyl tertiary amine and benzyl chloride, the outer side of the reaction kettle 1 is provided with a jacket 2, the jacket 2 is respectively connected with a hot medium channel 3 and a cold medium channel 4, the bottom of the reaction kettle 1 is connected with a treating agent pipeline 5 for introducing deionized water and a nitrogen pipeline 6 for introducing nitrogen, and the reaction kettle 1 is connected with a dehydration device 7. The dehydration device 7 comprises a condenser 7a, a receiving tank 7b and a vacuum pump 7c which are connected in sequence along the top of the reaction kettle 1.
Based on the benzalkonium chloride synthesis equipment, the production process of the low-residue medicinal benzalkonium chloride comprises the following steps:
s1 adding 2240g of dodecatetradecyl dimethyl mixed tertiary amine into a reaction kettle 1, introducing steam into a heat medium channel 3 of a jacket 2 to raise the temperature of the reaction kettle 1 to 50 ℃, adding 657g of benzyl chloride into the reaction kettle 1 for the first time, slowly raising the temperature after the reaction is started, introducing cooling water into a cold medium channel 4 of the jacket 2, controlling the reaction temperature to be not more than 80 ℃, and slowly lowering the temperature to 70 ℃. 262.8g of benzyl chloride is added into the reaction kettle 1 for the second time, the temperature is slowly increased after the reaction is started, cooling water is introduced into a cold medium channel 4 of a jacket 2, the reaction temperature is controlled not to exceed 90 ℃, and the temperature is slowly reduced to 70 ℃. 394.2g of benzyl chloride is added into the reaction kettle 1 for the third time, the temperature is slowly increased after the reaction is started, cooling water is introduced into the cold medium channel 4 of the jacket 2, the reaction temperature is controlled not to exceed 120 ℃, and the temperature is slowly reduced to 90 ℃.
S2 was kept at 90 ℃ and the reaction was incubated for 6 h.
S3, after reacting for 6 hours with heat preservation, 333g of deionized water is introduced into the reaction kettle 1, stirring is carried out for 5 minutes, nitrogen is introduced from a nitrogen pipeline 6 at the bottom of the reaction kettle 1, meanwhile, a vacuum pump 7c is started, so that water is collected into a receiving tank 7b through a condenser 7a, the pressure in the reaction kettle 1 is controlled to be-0.05 MPa, the temperature of the kettle is raised to 100 ℃, and dehydration is continuously carried out for 2 hours. After 2h, an additional 333g of deionized water was added and the dehydration continued for 2 h. And finally, adding 333g of deionized water into the reaction kettle 1, and continuously dehydrating for 3 hours to obtain a high-quality benzalkonium chloride product.
Example 2
This embodiment is substantially the same as embodiment 1 except that:
s3, after reacting for 6 hours with heat preservation, 333g of deionized water is introduced into the reaction kettle 1, nitrogen is introduced from a nitrogen pipeline 6 at the bottom of the reaction kettle 1, meanwhile, a vacuum pump 7c is started, so that water is collected into a receiving tank 7b through a condenser 7a, the pressure in the reaction kettle 1 is controlled to be-0.05 MPa, and the temperature of the kettle is raised to 100 ℃. And (3) starting continuous dehydration, continuously introducing deionized water from the treating agent pipeline 5, controlling the evaporated moisture to be basically the same as the moisture entering the reaction kettle 1, controlling the moisture content in the reaction kettle 1 to be 10 wt% all the time, and continuously dehydrating for 5 hours to obtain the benzalkonium chloride product with high quality.
Example 3
Based on the benzalkonium chloride synthesis equipment in embodiment 1, the production process of the low-residue medicinal benzalkonium chloride comprises the following steps:
s1 adding 2240g of dodecatetradecyl dimethyl mixed tertiary amine into a reaction kettle 1, introducing steam into a heat medium channel 3 of a jacket 2 to raise the temperature of the reaction kettle 1 to 40 ℃, adding 383.4g of benzyl chloride into the reaction kettle 1 for the first time, waiting for the reaction to start, slowly raising the temperature, introducing cooling water into a cold medium channel 4 of the jacket 2, controlling the reaction temperature not to exceed 80 ℃, and slowly lowering the temperature to 70 ℃. 511.2g of benzyl chloride is added into the reaction kettle 1 for the second time, the temperature is slowly increased after the reaction is started, cooling water is introduced into the cold medium channel 4 of the jacket 2, the reaction temperature is controlled not to exceed 90 ℃, and the temperature is slowly reduced to 70 ℃. 383.4g of benzyl chloride is added into the reaction kettle 1 for the third time, the temperature is slowly increased after the reaction is started, cooling water is introduced into a cold medium channel 4 of the jacket 2, the reaction temperature is controlled not to exceed 120 ℃, and the temperature is slowly reduced to 90 ℃.
S2 was kept at 90 ℃ and the reaction was incubated for 6 h.
S3, after reacting for 6 hours under heat preservation, introducing 10% NaOH solution into the reaction kettle 1 to adjust the pH value of the reaction system to 9-9.5, introducing nitrogen from a nitrogen pipeline 6 at the bottom of the reaction kettle 1, keeping stirring for 4 hours, and filtering the product by adopting a pressure filtration mode after the reaction is finished, thus obtaining the benzalkonium chloride product with high quality.
Example 4
Based on the benzalkonium chloride synthesis equipment in embodiment 1, the production process of the low-residue medicinal benzalkonium chloride comprises the following steps:
s1 adding 2240g of dodecatetradecyl dimethyl mixed tertiary amine into a reaction kettle 1, introducing steam into a heat medium channel 3 of a jacket 2 to raise the temperature of the reaction kettle 1 to 40 ℃, adding 511.4g of benzyl chloride into the reaction kettle 1 for the first time, slowly raising the temperature after the reaction is started, introducing cooling water into a cold medium channel 4 of the jacket 2, controlling the reaction temperature not to exceed 80 ℃, and slowly lowering the temperature to 70 ℃. 511.2g of benzyl chloride is added into the reaction kettle 1 for the second time, the temperature is slowly increased after the reaction is started, cooling water is introduced into the cold medium channel 4 of the jacket 2, the reaction temperature is controlled not to exceed 90 ℃, and the temperature is slowly reduced to 70 ℃. 255.4g of benzyl chloride is added into the reaction kettle 1 for the third time, the temperature is slowly increased after the reaction is started, cooling water is introduced into the cold medium channel 4 of the jacket 2, the reaction temperature is controlled not to exceed 120 ℃, and the temperature is slowly reduced to 90 ℃.
S2 was kept at 90 ℃ and the reaction was incubated for 6 h.
S3, after reacting for 6 hours under heat preservation, introducing 10% NaOH solution into the reaction kettle 1 to adjust the pH value of the reaction system to 10-11, introducing nitrogen from a nitrogen pipeline 6 at the bottom of the reaction kettle 1, keeping stirring for 8 hours, and filtering the product in a pressure filtration mode after the reaction is finished to obtain the benzalkonium chloride product with high quality.
Comparative example 1
This comparative example is the same as example 2 except that the treatment of step S3 was not performed.
Comparative example 2
This comparative example is substantially the same as comparative example 1 except that:
and S3, after the reaction is carried out for 6 hours under the condition of heat preservation, the benzalkonium chloride is filtered, washed for three times and recrystallized by ethyl acetate to obtain the benzalkonium chloride product.
Benzalkonium chloride products were prepared in the manner of examples 1, 2 and comparative examples 1, 2, and tested for actives and residual benzyl chloride content, as shown in table 1 below:
TABLE 1
Active substance%
Residual benzyl chloride%
Example 1
98.57
0.043
Example 2
98.62
0.035
Example 3
99.23
0.017
Example 4
98.82
0.003
Comparative example 1
97.57
1.06
Comparative example 2
97.89
0.86
The result shows that the benzalkonium chloride product synthesized by the method has higher active matter content, better sterilization effect and low benzyl chloride residue content, meets higher standards, and reduces the irritation and toxicity of benzalkonium chloride.
The specific embodiments described herein are merely illustrative of the spirit of the invention. Various modifications or additions may be made to the described embodiments or alternatives may be employed by those skilled in the art without departing from the spirit or ambit of the invention as defined in the appended claims.
Although the terms reaction vessel, jacket, hot media path, cold media path, treating agent line, nitrogen line, dehydration engine, condenser, sump, vacuum pump, feed line, etc. are used more herein. These terms are used merely to more conveniently describe and explain the nature of the present invention and they are to be interpreted as any additional limitation which is not in accordance with the spirit of the present invention.
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