CN117384050A - Preparation method of pharmaceutical grade benzethonium chloride - Google Patents

Abstract

The invention discloses a preparation method of medical grade benzethonium chloride, which adopts salt of aryl polyoxyalkyl chloride and dimethylamine to carry out C-N coupling reaction, and realizes amination reaction mildly at normal pressure by introducing palladium catalyst or catalyst of iodized salt and polyethylene glycol; removing harmful impurities after molecular distillation treatment to obtain a compound 3; then the compound 3 and benzyl chloride are subjected to quaternization reaction in a solvent, and a benzethonium chloride product meeting the standard of raw materials can be obtained. The invention improves the product quality in terms of purity, impurities, residual solvent, chromaticity and the like, controls the product index more strictly, leads the standards of domestic and foreign peers and customers, and is superior to the USP36 standard and the EP10.0 standard.

Description

A kind of preparation method of pharmaceutical grade benzethonium chloride

Technical field

The invention relates to a preparation method of pharmaceutical grade benzethonium chloride and belongs to the field of medical technology.

Background technique

Benzethonium chloride, also known as benzyldimethyl[2-[2-[4-(1,1,3,3-tetramethylbutyl)phenoxy]ethoxy]ethyl [Basic] ammonium chloride, CAS registration number is 121-54-0. It is a flaky crystal with a melting point of 164-166°C. It is easily soluble in water to form a foamy soapy water-like solution, and is soluble in ethanol, acetone and chloroform.

The chemical structural formula of benzethonium chloride is as follows:

Benzethonium chloride also has important applications in the field of medicine and health as a bactericidal and antibacterial agent. For example, it has been widely used in Western countries as an antibacterial component of eye drops or as an antibacterial component of injections. This product is included in the FDA "Inactive Ingredients Guide" (intramuscular injection preparations, intravenous injection preparations, ophthalmic preparations and otic preparations).

In the field of heparin sodium, the annual demand for this product reaches 500 tons. It is mainly used for purifying heparin sodium or for the production of low molecular weight heparin sodium and enoxaparin. As a key starting material for the synthesis of enoxaparin, it is used to prevent severe Venous thrombosis and pulmonary embolism, treatment of existing venous thrombosis, prevention of thrombus formation in extracorporeal circulation during hemodialysis, treatment of unstable angina and non-Q wave myocardial infarction. Benzethonium chloride can also be used as a wetting agent, solubilizer and external disinfectant. In cosmetics such as deodorants, solutions of benzethonium chloride with a concentration greater than 0.5% w/v can also be used as antibacterial agents.

The synthesis routes of benzethonium chloride in the prior art include the following:

Beijing Sangpu Biochemical Co., Ltd. disclosed the following technical solution in U.S. Patent US2014187819 (A1): 1) phenol and dihalogenated polyalkylene ether react under the action of a phase transfer catalyst to obtain arylpolyoxyalkyl halide; 2) Aryl polyoxyalkyl halides react with amination reagents under the action of phase transfer catalysts to obtain aryl polyoxyalkyl amines; 3) Aryl polyoxyalkyl amines react with alkylating reagents to obtain aryl polyoxyalkyl halides. Oxyalkyl quaternary ammonium compounds.

The reaction equation of this technical route is as follows:

In the above technical solution, a large amount of phase transfer catalyst benzyltriethylammonium chloride is used, the reaction temperature is about 160°C, and the reaction pressure reaches about 8-10 kg. The equipment requirements are relatively stringent and are not conducive to the expansion of the production workshop.

Clariant Manufacturing (Germany) Co., Ltd. disclosed the quaternization reaction of arylpolyoxyalkyl halides and dimethylbenzylamine in US patent US2003114533 (A1). Although the invention claims to simplify the preparation process, the actual application It also involves the preparation of the raw material arylpolyoxyalkyl halide, and the collection and purification operation of the product quaternary ammonium substances is too complicated. Since the halogen activity of arylpolyoxyalkyl halides is also very low, the reaction with benzyldimethylamine has problems such as high temperature and long reaction time, and the temperature and pressure resistance of the reaction equipment. The most important thing is that high-temperature reaction results in poor product quality and is not the best commercial production route. The reaction formula of this technical path is as follows:

Chinese patent CN113372227(A) and patent CN109651177(A) respectively disclose a preparation method of benzethonium chloride, which involves adding dichloroethane to p-teroctylphenol for a one-step reaction, and then mixing dimethylethanolamine for a second step. A three-step reaction, and finally benzyl chloride is added to perform a three-step reaction to obtain the product. The reaction equation is as follows:

However, the reaction temperature in this preparation method is also relatively high, and there are hidden dangers in high temperature and high pressure environments. Benzethonium chloride is a quaternary ammonium compound. It is used as an antibacterial agent in pharmaceutical preparations. It can be used as an antibacterial agent for injections, eye preparations and otic preparations. Therefore, the synthesis of benzethonium chloride should try not to involve the use of substances that are known to be carcinogenic and 1,2-dichloroethane is a type of solvent that is harmful to people and the environment, so this route is not suitable for production.

Indian Dismant disclosed in its patent EP1892235(A) a method using 4-tert-octylphenol, chloroethanol and (β-chloroethyl)dimethylamine as raw materials, which was synthesized in three steps, all under normal pressure. reaction. The reaction equation is as follows:

2-Dimethylaminoethyl chloride hydrochloride has a genotoxicity warning structure of a halogenated hydrocarbon. This type of impurity needs to be controlled, which affects the safety of benzethonium chloride products. Chlorohydrin is a highly toxic drug. According to relevant laws, regulations and policies of China, the production, sale, use or possession of this product is prohibited. Therefore, the patented method is not suitable for commercial production.

To sum up, the current production process requires high temperature and pressure, which has hidden dangers for production safety. It is necessary to improve the process and reduce the harsh conditions of the reaction, so as to obtain high-quality pharmaceutical-grade benzethonium chloride products.

Contents of the invention

In order to overcome the above technical problems, the present invention provides a preparation method of pharmaceutical grade benzethonium chloride, and the reaction process is as follows:

S1:

, in the formula, HX is hydrochloric acid, hydrobromic acid, sulfuric acid or hydriodic acid;

S2：

In view of the shortcomings of existing synthesis methods, the source and theoretical basis of the innovative technical method of the present invention will be described in detail below.

S1:

At present, domestic and foreign production generally adopt the technical solution in US patent US2014187819 (A1). Arylpolyoxyalkyl halides react with amination reagents under the action of a phase transfer catalyst to obtain arylpolyoxyalkyl aminations. Even if a large amount of The patented phase transfer catalyst uses a reaction temperature of about 160°C and a reaction pressure of about 8-10 kg.

Clariant Manufacturing (Germany) Company's U.S. patent US2003114533 (A1) uses a quaternization reaction of arylpolyoxyalkyl halides and dimethylbenzylamine. The reaction temperature is 120°C and the reaction pressure is about 2 kg. The patent was obtained The quality of the quaternary ammonium substances in the products is poor and requires overly complex purification operations to achieve qualified products.

Due to the low reactivity of the chlorine atoms of arylpolyoxyalkyl halides, almost all manufacturers currently use dimethylamine aqueous solutions for amination reactions. As a result, the current production process requires high temperature and pressure, which has hidden dangers for production safety. , it is necessary to improve the process and reduce the harsh conditions of the reaction, which is a key technical problem to be solved by the present invention.

From the theory of organic synthesis, a catalyst system containing potassium iodide, sodium iodide and polyethylene glycol is used to carry out a nucleophilic substitution reaction of chlorine replacement. The chloride ion is replaced by iodide ion. The leaving ability of iodide ion is much greater than that of chloride ion. After the iodide ions are detached, they can be recycled to the remaining reaction system, thereby greatly increasing the reaction speed and lowering the reaction temperature.

In addition, the Buchwald-Hartwig coupling reaction is an important method for the synthesis of aromatic amines. This reaction is a cross-coupling reaction between amines and aromatic halides under palladium catalysis and the presence of a base, producing C-N bonds and generating the N-aryl group of the amine. chemical products.

Correspondingly, the present invention uses the salt of aryl polyoxyalkyl chloride and dimethylamine to carry out C-N coupling reaction. By introducing a palladium catalyst or a catalyst of iodide salt and polyethylene glycol, the amination reaction can be realized mildly under normal pressure. , thereby forming the preparation method of step 1 of the present invention.

S2:

Since benzethonium chloride is used for mucous membrane disinfection and anti-mold in eye drops and powder products, it must be extremely low-irritating and contains harmful impurities, such as residual solvents, benzyl chloride, and β, β'-dichlorodiethyl ether, etc. , in the existing technology, the residual amount in the product is not effectively controlled, causing the product to fail to meet pharmaceutical grade quality requirements.

According to the ICHQ3 guidelines of the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use, the quality specifications of benzethonium chloride from most manufacturers do not meet pharmaceutical grade requirements.

For example: The product indicators of a domestic company are as follows, but according to the guiding principles of API ICHQ3, the indicators lack control standards for harmful impurity limits.

The currently reported purification method for p-tert-octylphenoxyethoxyethyldimethylamine is through vacuum distillation. However, during the distillation process, the product will be degraded due to being at high temperature for a long time. Polymerization not only reduces the yield, but may also produce impurities in the product and cause the product to be unqualified.

The research of the present invention has found that the p-tert-octylphenoxyethoxyethyldimethylamine prepared in the first step is subjected to molecular distillation treatment to remove harmful impurities, and then is quaternized with benzyl chloride in a solvent at medium and low temperatures. Ammonization reaction, thus forming the current industry-leading step 2 preparation process.

At the same time, the present invention draws on the product indicators of domestic and foreign counterparts and formulates enterprise standards for benzethonium chloride products with manufacturing characteristics based on the guiding principles of ICHQ3, which are superior to the United States Pharmacopoeia USP36 standard and the European Pharmacopoeia EP10.0 standard.

The beneficial results are that the present invention improves product quality in terms of purity, impurities, residual solvents, and color, and controls product indicators more strictly, leading domestic and foreign counterparts and customer standards.

The preparation method of the above-mentioned pharmaceutical grade benzethonium chloride includes the following steps:

S1-1: Preparation of compound 3

Into the reaction kettle, add p-tert-octylphenoxyethoxyethyl chloride 2, dimethylamine salt and catalyst under nitrogen protection, heat up the reaction, keep for 2-5h, HPLC detection control: control p-tert-octylbenzene When the residual amount of oxyethoxyethyl chloride 2 is ≤3.0%, the reaction ends; after the reaction is stirred and the reaction is completed, the temperature is lowered to below 35°C, ethyl acetate is added, and the reaction solution is allowed to stand and separated to obtain an organic layer.

Further, the dimethylamine salt in step S1-1 is dimethylamine hydrochloride, dimethylamine hydrobromide, dimethylamine sulfate and dimethylamino hydroiodide, preferably dimethylamine hydroiodide. Methylamine hydrochloride.

Further, the catalyst in step S1-1 is a catalyst containing at least one of lithium chloride, lithium bromide, potassium bromide, sodium bromide, cuprous bromide, sodium iodide, potassium iodide, cuprous iodide and palladium catalyst ; Preferred are sodium iodide and palladium catalysts.

Further, the palladium catalyst is Pd(OAc) ₂ , Pd2(dba) ₃ , PdCl ₂ (dppf), PdCl ₂ (PPh3) ₂ , PdCl ₂ (PCy) ₂ , PdCl ₂ , PdCl ₂ (CH ₃ CN) ₂ , etc.; preferably PdCl ₂ (dppf).

S1-2: Crude product purification

The organic layer is decompressed using an oil pump. The vacuum degree of the distillation system is controlled to 0.01-1.0 mbar. The oil bath temperature is 160-180°C. The film scraper speed is 200-300 rpm. Continuous sampling is performed. Control the sampling speed. Molecular distillation gave compound 3.

Further, the distillation method in step S1-2 is vacuum distillation, high vacuum distillation, and molecular distillation; preferably, molecular distillation is used.

Further, the absolute pressure when using molecular distillation in step S1-2 is 0.005MPa-0.01MPa.

S2-1: Preparation of compound 1

Pre-treatment of compound 3: Add compound 3 and solvent into the reaction kettle under nitrogen protection, stir and raise the temperature to between 30-50°C, add activated carbon to decolorize for the time specified in the process, and pass through a precision filter press with a pore size less than 45 microns. Press filtration to step S2-2 for reaction.

Further, the solvent in step S2-1 is ethyl acetate, isopropyl acetate, acetonitrile, acetone or methyl isobutyl ketone; preferably, it is ethyl acetate.

S2-2: Preparation of compound 1

Into the reaction kettle, add the compound 3 solution treated in step S2-1 under nitrogen protection, then pump benzyl chloride through a precision filter, stir and raise the temperature to 40-60°C for reaction, and maintain the reaction until the specified time of the process. No need Sampling is controlled and the reaction is completed. The reaction solution was filtered, and the obtained solid was stirred and washed with ethyl acetate. The obtained white solid was dried under reduced pressure to obtain compound 1.

Further, the reaction temperature in step S2-2 is 20-150°C; preferably 40-60°C.

Beneficial effects of the present invention:

1. The salts of the corresponding arylpolyoxyalkyl chlorides and dimethylamines of the present invention carry out C-N coupling reactions. By introducing palladium catalysts or catalysts of iodide salts and polyethylene glycol, the amination reaction can be achieved mildly under normal pressure. ; After molecular distillation treatment, harmful impurities are removed to obtain p-tert-octylphenoxyethoxyethyldimethylamine; and then quaternization reaction is performed with benzyl chloride in a solvent to obtain API that meets the API standards. Benzethonium Chloride Products.

2. Based on the product indicators of domestic and foreign counterparts, the present invention formulated relevant enterprise standards for benzethonium chloride products, which are superior to the United States Pharmacopoeia USP36 standard and the European Pharmacopoeia EP10.0 standard.

Description of the drawings

Figure 1 is an HPLC spectrum of purity detection of S2 compound 1 in Example 1.

Detailed ways

The following examples will help researchers understand the key points of the preparation technology of the present invention, but they cannot limit the content of the present invention.

Example 1

This embodiment provides a preparation method of pharmaceutical grade benzethonium chloride, which includes the following steps:

S1: Synthesis of Compound 3

Into the reaction kettle, add 48.0g p-tert-octylphenoxyethoxyethyl chloride 2, 88.0g dimethylamine hydrochloride, 2.5g sodium iodide and 0.05g PdCl2 (dppf) under nitrogen protection, and heat to React at 70-80°C for 5 hours. When the residual amount of p-tert-octylphenoxyethoxyethyl chloride 2 is controlled to be ≤3.0%, the reaction ends; after stirring the reactants and completing the reaction, cool down to below 35°C and add 50.0g ethyl acetate, the reaction solution is allowed to stand and stratified to obtain an organic layer; the organic layer is decompressed using an oil pump, the vacuum degree of the distillation system is controlled to 0.01-1.0mbar, the oil bath temperature is 160-180°C, and the rotation speed of the film scraper is 200 -300 rpm, the material injection speed is 5-10mL/min, and 42.4g of colorless transparent liquid compound 3 is obtained by molecular distillation, with a yield of 86.0%, a GC purity of 99.52%, and unknown impurities less than 0.3%.

S2: Synthesis of Compound 1

S2-1: Pre-treatment of compound 3

Into the reaction kettle, add 300.0g p-tert-octylphenoxyethoxyethyldimethylamine 3 and 900.0g ethyl acetate under nitrogen protection, stir and raise the temperature to between 30-50°C, add 20.0g needle 767 The carbon is decolorized and adsorbed to the time specified in the process, passed through a precision filter press with a pore size less than 45 microns, and filtered to step S2-2 for reaction.

S2-2: Add the p-tert-octylphenoxyethoxyethyldimethylamine 3 solution of S2-1 into the reaction kettle under nitrogen protection, then pump 121.0g of benzyl chloride through the precision filter, stir and raise the temperature React between 40-60℃. Keep the reaction until the time specified in the process, without the need for sampling and control, and end the reaction. Cool the reaction solution to 10-20°C and filter. Add 300.0g of ethyl acetate to the resulting solid, stir and wash. The resulting solid is vacuum dried at -0.098MPa and 35°C. The filter cake is then pulverized to obtain benzyl ethyl acetate. Ammonium Chloride Products. 365.9g of compound 1 was obtained, with a yield of 87.5% and an HPLC purity of 99.9% (as shown in Figure 1). Each impurity was less than 0.05%. After full inspection, it complied with the internal quality control indicators of benzethonium chloride.

On the basis of keeping other substances unchanged, changing different dimethylamine salts, the data listed in Table 1 below are obtained:

Experiment number dimethylamino acid salt S1 product yield (%) Product purity of step S1 (%) 1 dimethylamine sulfate 83.5 97.8 2 dimethylaminohydriodate 84.2 98.2 3 Dimethylamine hydrobromide 82.6 98.5

On the basis of keeping other substances unchanged, changing the catalyst, the data listed in Table 2 below are obtained:

Selection of product purification method in step S1:

On the basis that other substances remained unchanged, the inventor compared different distillation methods and obtained the data listed in Table 3 below:

Example 2

This embodiment provides a preparation method of pharmaceutical grade benzethonium chloride, which includes the following steps:

S1: Synthesis of Compound 3

Into the reaction kettle, add 240.0Kg p-tert-octylphenoxyethoxyethyl chloride 2, 220Kg dimethylamine hydrochloride, 1.5Kg sodium iodide and 0.05Kg PdCl2 (dppf) under nitrogen protection, and heat to 70 React at -80°C for 5 hours. When the residual amount of p-tert-octylphenoxyethoxyethyl chloride 2 is controlled to be ≤3.0%, the reaction ends. After the reactants are stirred and the reaction is completed, cool down to below 35°C and add 100.0 Kg of ethyl acetate, the reaction solution is allowed to stand and stratified to obtain an organic layer; the organic layer is decompressed using an oil pump, the vacuum degree of the distillation system is controlled to 0.01-1.0mbar, the oil bath temperature is 160-180°C, and the film scraper speed is 200-200 300 rpm, material injection speed 50-60L/h, molecular distillation to obtain 213.5Kg colorless transparent liquid compound 3, yield 86.37%, GC purity 98.62%, unknown impurities less than 0.3%.

S2: Synthesis of Compound 1

S2-1: Decolorization and adsorption treatment of compound 3

Into the reaction kettle, add 150Kg p-tert-octylphenoxyethoxyethyldimethylamine 3 and 600.0Kg ethyl acetate under nitrogen protection, stir and raise the temperature to between 30-50°C, add 20.0Kg needle type 767 The injection activated carbon is decolorized and adsorbed for the time specified in the process, passed through a precision filter press with a pore size less than 45 microns, and filtered to step S2-2 for reaction.

S2-2: Add the p-tert-octylphenoxyethoxyethyldimethylamine 3 solution of S2-1 into the reaction kettle under nitrogen protection, then pump 121.0Kg of benzyl chloride through the precision filter, stir and raise the temperature React between 40-60℃. Keep the reaction until the time specified in the process, without the need for sampling and control, and end the reaction. Cool the reaction solution to 10-20°C and filter. Add 300.0Kg of ethyl acetate to the resulting solid, stir and wash. The resulting solid is vacuum dried at -0.098MPa and 45°C. The filter cake is then crushed to obtain benzyl ethyl acetate. Ammonium Chloride Products. 187.8Kg of compound 1 was obtained, with a yield of 89.8%, an HPLC purity of 99.9%, and individual impurities less than 0.03%. After full inspection, it complied with the internal quality control indicators of benzethonium chloride.

Comparative example 1

This comparative example repeats Example 1 of US Patent US2014187819 (A1) of Beijing Samp Biochemical Co., Ltd.

In a 1L sealed reaction kettle, add 144.6g p-tert-octylphenoxyethoxyethyl chloride, 11.4g benzyltriethylammonium chloride, and 135.3g 33% dimethylamine aqueous solution, seal it and raise the temperature to The reaction was stirred for 8 hours at 160°C, and the conversion rate to tert-octylphenoxyethoxyethyl chloride was 100% through gas phase detection. At the end of the reaction, the material was allowed to stand and separated to remove the aqueous phase, and 136.2g of the organic phase was collected.

Add 136.2g of p-tert-octylphenoxyethoxyethyldimethylamine obtained above into a 1L four-neck reaction bottle, add 100.2g methyl isobutyl ketone and 126.6g benzyl chloride in sequence, and heat to Reflux, react for 2 hours, slowly add 168.2g of cyclohexane, cool down for crystallization, collect 156.3g of solid, vacuum dry the filter cake at -0.098MPa, 35°C, and then crush the filter cake to obtain the benzethonium chloride product. Finally, 142.6g of light yellow product was obtained, with a two-step total yield of 68.9% and a purity of 97.60%. The melting point of the product was 156.5-157.7°C. The product did not meet the indicators of the United States Pharmacopoeia.

The above data confirm that the yield and content of existing synthesis technology are very low and fail to meet the requirements of the pharmacopoeia.

The present invention is not limited to the above embodiments. On the basis of the technical solutions disclosed in the present invention, those skilled in the art can make some substitutions and modifications to some of the technical features without any creative work based on the disclosed technical content. Modifications, these substitutions and modifications are within the protection scope of the present invention.

Claims (9)

1. A preparation method of pharmaceutical grade benzethonium chloride, characterized in that the reaction formula is as follows: S1: S2： The preparation method includes the following steps: S1: Preparation of compound 3 Into the reaction kettle, add p-tert-octylphenoxyethoxyethyl chloride 2, dimethylamine salt and catalyst under nitrogen protection, and heat up the reaction; after the reactants are stirred and the reaction is completed, leave to stand and separate to form an organic layer. , use an oil pump to reduce pressure, and obtain compound 3 through molecular distillation; S2: Preparation of Compound 1 Add compound 3 and solvent into the reaction kettle under nitrogen protection, perform decolorization and adsorption, and filter through a precision filter press into the quaternary ammonium salt reaction kettle; Into the quaternary ammonium salt reaction kettle, pump benzyl chloride through a precision filter under nitrogen protection, stir and heat up for reaction. After the reactants are stirred and the reaction is completed, the solid obtained by filtering the reaction solution is added to ethyl acetate for stirring and washing, and the solid obtained is dried under reduced pressure to obtain compound 1. 2. a kind of preparation method of pharmaceutical grade benzethonium chloride according to claim 1, is characterized in that, specifically comprises: S1-1: Preparation of compound 3 Into the reaction kettle, add p-tert-octylphenoxyethoxyethyl chloride 2, dimethylamine salt and catalyst under nitrogen protection, heat up the reaction, keep for 2-5h, and control p-tert-octylphenoxyethoxyethyl chloride 2, dimethylamine salt and catalyst When the residual amount of ethyl chloride 2 is ≤3.0%, the reaction ends; after the reaction is stirred and the reaction is completed, the temperature is lowered to below 35°C, ethyl acetate is added, and the reaction solution is allowed to stand for layering to obtain an organic layer; S1-2: Crude distillation and purification The organic layer is decompressed using an oil pump. The vacuum degree of the distillation system is controlled to 0.01-1.0 mbar. The oil bath temperature is 160-180°C. The film scraper speed is 200-300 rpm. The feed is continuously fed for molecular distillation to obtain compound 3; S2-1: Preparation of compound 1 Pre-treatment of compound 3: Add compound 3 and solvent into the reaction kettle under nitrogen protection, stir and raise the temperature to between 30-50°C, add activated carbon to decolorize for the time specified in the process, and pass through a precision filter press with a pore size less than 45 microns. Press filtration to step S2-2 for reaction. S2-2: Preparation of compound 1 Into the reaction kettle, add S2-1's p-tert-octylphenoxyethoxyethyldimethylamine 3 solution under nitrogen protection, then pump benzyl chloride through a precision filter, stir and heat to react. Keep the reaction until the time specified in the process, no need to take samples for in-process control, and end the reaction. The reaction solution was filtered, and the obtained solid was added to ethyl acetate, stirred and washed, and the obtained solid was dried under reduced pressure to obtain compound 1. 3. The preparation method of a kind of pharmaceutical grade benzethonium chloride according to claim 2, characterized in that, in the formula in step S1-1, the dimethylamine salt is dimethylamine hydrochloride, dimethylamine hydrochloride, Methylamine hydrobromide, dimethylamine sulfate, dimethylamine hydroiodide, preferably dimethylamine hydrochloride. 4. the preparation method of a kind of pharmaceutical grade benzethonium chloride according to claim 2, is characterized in that, the catalyst in described step S1-1 is to comprise lithium chloride, lithium bromide, potassium bromide, sodium bromide, At least one of cuprous bromide, sodium iodide, potassium iodide, cuprous iodide and palladium catalyst, preferably sodium iodide and palladium catalyst. 5. The preparation method of a kind of pharmaceutical grade benzethonium chloride according to claim 4, characterized in that the palladium catalyst used in step S1-1 includes Pd(OAc) ₂ , Pd ₂ (dba) ₃ , PdCl ₂ (dppf), PdCl ₂ (PPh3) ₂ , PdCl ₂ (PCy) ₂ , PdCl ₂ and PdCl ₂ (CH ₃ CN) ₂ , preferably PdCl ₂ (dppf). 6. The preparation method of a kind of pharmaceutical grade benzethonium chloride according to claim 2, characterized in that the distillation mode in step S1-2 is vacuum distillation, high vacuum distillation or molecular distillation, preferably molecular distillation . 7. The preparation method of pharmaceutical grade benzethonium chloride according to claim 6, characterized in that the absolute pressure during molecular distillation is 0.005MPa-0.01MPa. 8. The preparation method of a kind of pharmaceutical grade benzethonium chloride according to claim 2, characterized in that the solvent in step S2-1 is ethyl acetate, isopropyl acetate, acetonitrile, acetone or methyl isobutyl Ketone, preferably ethyl acetate. 9. The preparation method of pharmaceutical grade benzethonium chloride according to claim 8, characterized in that the reaction temperature in step S2-2 is 20-150°C, preferably 40-60°C.