Method for efficiently synthesizing berberine hydrochloride by adopting solid resin catalyst

Abstract

The invention discloses a method for efficiently synthesizing berberine hydrochloride by adopting a solid resin catalyst, and belongs to the field of medical chemical synthesis. The berberine hydrochloride can be efficiently synthesized by optimizing reaction steps and reaction conditions and adopting a solid resin catalyst for catalytic reaction. The method has relatively high reaction yield and product purity, and the catalyst can be repeatedly used, so that the environmental pollution and the production cost are effectively reduced.

Description

Technical Field

[0001] The invention relates to the field of pharmaceutical chemical synthesis, in particular to a method for efficiently synthesizing berberine hydrochloride by using a solid resin catalyst. Background Art

[0002] Berberine hydrochloride is a natural alkaloid widely used in medicine, health products, cosmetics and traditional Chinese medicine preparations. Its main functions include antibacterial, anti-inflammatory, hypoglycemic, hypolipidemic, anti-cancer and other biological activities, so it has attracted extensive attention from researchers at home and abroad. As an important bioactive ingredient, berberine hydrochloride is mainly extracted from plants, such as traditional Chinese medicinal plants such as Coptis chinensis and Phellodendron chinense, but its extraction process is usually costly and has limited output.

[0003] Traditional methods for synthesizing berberine hydrochloride mostly rely on a combination of chemical synthesis and biosynthesis. Chemical synthesis methods involve converting raw materials into berberine hydrochloride through some complex multi-step reactions, but most methods have the following problems: Low efficiency and long reaction time: Traditional chemical synthesis methods usually require long reaction times and more complicated reaction steps, resulting in low raw material conversion rates and low production efficiency. For example, some synthesis processes require the use of chemical reagents such as strong acids and bases, and the reaction temperature is high and the reaction time is long, which increases production costs and may burden the environment.

[0004] Poor catalyst selectivity: Liquid acid catalysts or toxic catalysts are often used in traditional methods, resulting in poor product selectivity, many by-products, and difficulty in recovery, which increases environmental pollution and post-processing costs.

[0005] Catalysts cannot be reused: Some catalysts are consumed or deactivated during the reaction, making them non-reusable, increasing production costs. In addition, some catalysts are highly polluting to the environment and need to be properly disposed of after use.

[0006] Treatment of solvents and by-products: Traditional reaction systems usually involve organic solvents and complex reaction conditions. A large amount of by-products may be produced during the reaction, requiring additional separation and treatment steps, which increases the difficulty of product purity and cost control.

[0007] In order to overcome the above problems, in recent years, researchers have tried to improve the synthesis efficiency and environmental friendliness of berberine hydrochloride by optimizing reaction conditions, improving catalyst systems, and developing green solvents. However, although there are some improved synthesis methods, there are still problems such as long reaction time, high cost, and non-reusable catalysts. Therefore, it is urgent to develop a new, efficient, economical and environmentally friendly synthesis method for berberine hydrochloride. Summary of the invention

[0008] In order to overcome at least one of the technical problems in the above-mentioned background technology, the present invention proposes a novel, efficient, economical and environmentally friendly method for synthesizing berberine hydrochloride. By using a solid resin catalyst and optimizing the reaction conditions, the reaction efficiency can be significantly improved, the process flow can be simplified, and the production cost can be reduced. The catalyst can be reused and has a wide range of application prospects.

[0009] To achieve the above object, the technical solution adopted by the present invention is as follows: A method for efficiently synthesizing berberine hydrochloride using a solid resin catalyst comprises the following steps: Step 1: Add 10-15 parts of 5-halogenated o-veratraldehyde, 5-30 parts of piperonyl ethylamine and a reaction solvent into a reactor according to weight parts, then add a dehydrating agent, start the reaction, the reaction temperature is 20° C. to 80° C., the reaction time is 4 to 8 hours, and N-[2-(3,4-dioxyphenyl-5-yl)ethyl]-1-(5-halogenated-2,3-dimethoxybenzyl)methanimine is prepared; wherein the 5-halogenated o-veratraldehyde is selected from one of 5-bromo-o-veratraldehyde, 5-chloro-o-veratraldehyde, 5-iodo-o-veratraldehyde and 5-fluoro-o-veratraldehyde; Step 2: subjecting the N-[2-(3,4-dioxyphenyl-5-yl)ethyl]-1-(5-halogenated-2,3-dimethoxybenzyl)methylamine prepared in step 1 to a reduction reaction with a borohydride reducing agent in a reaction solvent at a reaction temperature of 0° C. to 50° C. for a reaction time of 2 to 5 hours to obtain 2-(3,4-dioxyphenyl)-N-(5-halogenated-2,3-dimethoxybenzyl)ethylamine; Step 3: reacting the 2-(3,4-dioxyphenyl)-N-(5-halogenated-2,3-dimethoxybenzyl)ethylamine prepared in step 2 with ether hydrochloride in a reaction solvent at a reaction temperature of 10° C. to 50° C. for 1 to 3 hours to prepare 2-(3,4-dioxyphenyl)-N-(5-halogenated-2,3-dimethoxybenzyl)ethylamine hydrochloride; Step 4: 2-(3,4-dioxyphenyl)-N-(5-halogen-2,3-dimethoxybenzyl)ethylamine hydrochloride is subjected to a ring-closing reaction with glyoxal in an organic acid solvent to prepare a 12-halogenated berberine derivative, and a metal inorganic salt and an inorganic proton acid are added to participate in the reaction; wherein the mass ratio of 2-(3,4-dioxyphenyl)-N-(5-halogen-2,3-dimethoxybenzyl)ethylamine hydrochloride to glyoxal is is 1: (1.2-2), the mass of the metal inorganic salt is 1-2% of the mass of 2-(3,4-dioxyphenyl)-N-(5-halogeno-2,3-dimethoxybenzyl)ethylamine hydrochloride, the mass of the inorganic protonic acid is 1-3 times the mass of 2-(3,4-dioxyphenyl)-N-(5-halogeno-2,3-dimethoxybenzyl)ethylamine hydrochloride, the reaction temperature is 50°C-100°C, and the reaction time is 8-12 hours; Step 5: Mix the 12-halogenated berberine derivative with dilute hydrochloric acid, add a solid resin catalyst, heat to 80°C to 120°C, and perform a hydrolysis reaction in an acidic environment to obtain berberine. After hydrolysis, add hydrochloric acid to convert berberine into berberine hydrochloride, and separate the berberine hydrochloride by concentration and precipitation methods; Step 6: Filter, wash, dry and purify the obtained berberine hydrochloride to obtain berberine hydrochloride with high purity.

[0010] Preferably, the reaction solvent in step 1, step 2 and step 3 is selected from at least one of diethyl ether, tetrahydrofuran, methanol and ethanol.

[0011] Preferably, in step 1, the dehydrating agent is selected from at least one of anhydrous sodium sulfate, anhydrous sodium chloride and anhydrous calcium chloride, and the mass of the added dehydrating agent is 0.5-2% of the total mass of the reactants.

[0012] Preferably, in step 2, the molar ratio of the borohydride reducing agent to N-[2-(3,4-dioxyphenyl-5-yl)ethyl]-1-(5-halo-2,3-dimethoxybenzyl)methanimine is 1:(1-2), and the borohydride is selected from at least one of sodium cyanoborohydride, sodium chloride borohydride, and sodium dichloroborohydride.

[0013] Preferably, the mass of ether hydrochloride in step 3 is 2 to 3 times the mass of 2-(3,4-dioxyphenyl)-N-(5-halo-2,3-dimethoxybenzyl)ethylamine.

[0014] Preferably, the inorganic protonic acid in step 4 is selected from at least one of concentrated hydrochloric acid, concentrated sulfuric acid, phosphoric acid or nitric acid.

[0015] Preferably, the metal inorganic salt in step 4 is selected from at least one of anhydrous copper sulfate, anhydrous copper chloride, anhydrous ferric sulfate or anhydrous ferric chloride.

[0016] Preferably, the organic acid solvent in step 4 is selected from formic acid or acetic acid.

[0017] Preferably, in step 5, the amount of the solid resin catalyst added is 5-10wt% of the mass of the 12-halogenated berberine derivative, and the solid resin catalyst is a plasma-modified macroporous strongly acidic cation exchange resin. The macroporous strongly acidic cation exchange resin is added to the reaction chamber, and the plasma gas is NH3, dichloroallyl phosphine vapor, and 3-thiophenylboric acid vapor. The macroporous strongly acidic cation exchange resin is plasma-treated in a volume ratio of (1-1.2): (0.2-0.5): (0.03-0.06); after the treatment, the modified macroporous strongly acidic cation exchange resin is taken out to obtain a solid resin catalyst; the solid resin catalyst is placed in an exchange column for transformation treatment before use, and 2-4 times the volume of 10-20% hydrochloric acid is passed through the exchange column from top to bottom for 2-3 hours to obtain a hydrogen-type resin; The conditions of the plasma treatment are: power 100-300W, gas pressure 10-100Pa, frequency 13.56MHz, and treatment time 10-30 minutes; The macroporous strongly acidic cation exchange resin is selected from at least one of D001 resin, D008 resin and NKC-9 resin, and the factory type is sodium-based resin.

[0018] Preferably, during the refining in step 6, 6 times the amount of water is used for boiling, lime milk is added to adjust the pH to 8.5-9.5, and after filtering, the pH is adjusted to 2-2.5 and precipitated to obtain berberine hydrochloride precipitate, which is then filtered, washed with water and dried.

[0019] Solid resin catalyst preparation mechanism: Introduction of amino groups: In a plasma environment, NH3 gas is excited to produce highly active nitrogen, hydrogen and other free radicals. These free radicals react with the active sites on the surface of NKC-9 resin to introduce amino groups (-NH2) into the polymer chain of the resin.

[0020] Amino-olefin addition reaction: The resin with the amino group introduced undergoes an amino-olefin addition reaction with allylphosphine dichloride, connecting the allylphosphine group to the resin surface through a covalent bond, thereby changing the surface properties and chemical structure of the resin and improving its catalytic performance and selectivity.

[0021] Synergistic effect: 3-Thiophenylboronic acid further adjusts the electron cloud distribution and acidity and alkalinity of the resin surface, optimizes the catalytic active sites of the resin, and thus enhances the catalytic ability of the resin for specific reactions.

[0022] Technical effect of catalyzing the reaction of 12-halogenated berberine derivatives with dilute hydrochloric acid: Improve reaction rate: The modified resin provides more acidic active sites and a suitable reaction microenvironment, which can effectively reduce the activation energy of the hydrolysis reaction of 12-haloberberine derivatives, significantly increase the reaction rate, and shorten the reaction time.

[0023] Enhanced selectivity: The specific groups introduced by modification can interact specifically with reactants and products, thereby improving the selectivity of the reaction, reducing the occurrence of side reactions, and making the reaction more inclined to produce berberine hydrochloride.

[0024] Improved stability: The modified resin structure is more stable and is not easy to swell, break or lose active groups in the acidic reaction system. It can maintain high catalytic activity and selectivity after multiple uses, reducing the cost of the catalyst.

[0025] Easy to separate and recycle: As a solid catalyst, the modified NKC-9 resin is easy and convenient to separate from the reaction solution, and can be quickly separated by filtration or centrifugation, which is convenient for subsequent product purification and catalyst reuse. DETAILED DESCRIPTION

[0026] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0027] The experimental methods in the following examples without specifying specific conditions are generally carried out under conventional conditions, and the raw materials and reagents used are conventional commercially available products unless otherwise specified.

[0028] Test method: For the following examples and comparative examples, the start and end time of the reaction were recorded to determine the yield and purity of the product. After the reaction was completed, the purity of berberine hydrochloride was analyzed by high performance liquid chromatography (HPLC).

[0029] Example 1: A method for efficiently synthesizing berberine hydrochloride using a solid resin catalyst, comprising the following steps: Step 1: Add 120g of 5-bromo-o-veratraldehyde, 200g of piperidine and ethanol as reaction solvents into a reactor, and then add anhydrous sodium sulfate as a dehydrating agent, the mass of the dehydrating agent is 1% of the total mass of the reactants, and react at 60°C for 6 hours to obtain N-[2-(3,4-dioxyphenyl-5-yl)ethyl]-1-(5-bromo-2,3-dimethoxybenzyl)methanimine; Step 2: The product obtained in step 1 is subjected to reduction reaction with sodium cyanoborohydride in tetrahydrofuran solvent, the molar ratio of sodium cyanoborohydride to N-[2-(3,4-diylidenephenyl-5-yl)ethyl]-1-(5-bromo-2,3-dimethoxybenzyl)methanimine is 1:1.5, and the reaction is carried out at 30° C. for 4 hours to obtain 2-(3,4-diylidenephenyl)-N-(5-bromo-2,3-dimethoxybenzyl)ethylamine; Step 3: reacting the product obtained in step 2 with ether hydrochloride having a mass 2.5 times that of 2-(3,4-dioxyphenyl)-N-(5-bromo-2,3-dimethoxybenzyl)ethylamine in a methanol solvent at a reaction temperature of 30° C. for a reaction time of 2 hours to obtain 2-(3,4-dioxyphenyl)-N-(5-bromo-2,3-dimethoxybenzyl)ethylamine hydrochloride; Step 4: The 2-(3,4-dioxyphenyl)-N-(5-bromo-2,3-dimethoxybenzyl)ethylamine hydrochloride prepared in the previous step was subjected to a ring-closing reaction with glyoxal in an acetic acid solvent to prepare a 12-haloberberine derivative. The mass ratio of 2-(3,4-dioxyphenyl)-N-(5-bromo-2,3-dimethoxybenzyl)ethylamine hydrochloride to glyoxal was 1:1.5. Anhydrous copper sulfate was added as a gold It is an inorganic salt, and its mass is 1.5% of the mass of 2-(3,4-dioxyphenyl)-N-(5-bromo-2,3-dimethoxybenzyl)ethylamine hydrochloride. At the same time, concentrated hydrochloric acid is added as an inorganic protonic acid, and its mass is twice the mass of 2-(3,4-dioxyphenyl)-N-(5-bromo-2,3-dimethoxybenzyl)ethylamine hydrochloride. The reaction is carried out at 90°C for 10 hours to obtain a 12-halogenated berberine derivative; Step 5: Mix the 12-halogenated berberine derivative with dilute hydrochloric acid, add a solid resin catalyst of 5 wt% of the mass of the 12-halogenated berberine derivative, heat to 100°C, and perform a hydrolysis reaction in an acidic environment. After hydrolysis, add hydrochloric acid to convert berberine into berberine hydrochloride, and separate it by concentration and precipitation methods.

[0030] The preparation method of the solid resin catalyst comprises: using a plasma-modified macroporous strongly acidic cation exchange resin as a solid resin catalyst, specifically, adding D001 resin into a reaction chamber, and plasma treatment is performed using NH3, dichloroallylphosphine vapor and 3-thiophenylboric acid vapor in a volume ratio of 1:0.3:0.04, and the treatment conditions are power 200W, air pressure 50Pa, frequency 13.56MHz, and treatment time 20 minutes. After the treatment, the modified D001 resin is taken out to obtain a solid resin catalyst. Before use, the catalyst is placed in an exchange column for transformation treatment, and 3 times the volume of 15% by mass hydrochloric acid is used to flow through the exchange column from top to bottom. The treatment time is 2.5 hours to obtain a hydrogen-type resin for subsequent berberine hydrochloride synthesis reaction; Step 6: Filter, wash, dry and purify the obtained berberine hydrochloride. During the purification, use 6 times the amount of water to boil, add lime milk to adjust the pH to 9, filter and adjust the pH to 2.5 and precipitate to obtain berberine hydrochloride precipitate. After filtering, wash and dry the precipitate.

[0031] The product yield in this example was 92.2% and the purity by HPLC analysis was 99.72%.

[0032] Example 2: A method for efficiently synthesizing berberine hydrochloride using a solid resin catalyst, comprising the following steps: Step 1: Add 100g of 5-chloro-o-veratraldehyde, 150g of piperonyl ethylamine and diethyl ether as reaction solvents into a reactor, and then add anhydrous calcium chloride as a dehydrating agent, the mass of the dehydrating agent is 0.8% of the total mass of the reactants, and react at 40°C for 8 hours; Step 2: The product obtained in step 1 is subjected to reduction reaction with sodium borohydride chloride in a methanol solvent, wherein the molar ratio of sodium borohydride chloride to N-[2-(3,4-dioxyphenyl-5-yl)ethyl]-1-(5-chloro-2,3-dimethoxybenzyl)methanimine is 1:1, and the reaction is carried out at 20° C. for 5 hours to obtain 2-(3,4-dioxyphenyl)-N-(5-chloro-2,3-dimethoxybenzyl)ethylamine; Step 3: reacting the product obtained in step 2 with ether hydrochloride having a mass twice that of 2-(3,4-dioxyphenyl)-N-(5-chloro-2,3-dimethoxybenzyl)ethylamine in an ethanol solvent at a reaction temperature of 20° C. for a reaction time of 3 hours to obtain 2-(3,4-dioxyphenyl)-N-(5-chloro-2,3-dimethoxybenzyl)ethylamine hydrochloride; Step 4: The 2-(3,4-dioxyphenyl)-N-(5-chloro-2,3-dimethoxybenzyl)ethylamine hydrochloride prepared in the previous step is subjected to a ring-closing reaction with glyoxal in a formic acid solvent to prepare a 12-haloberberine derivative, the mass ratio of 2-(3,4-dioxyphenyl)-N-(5-chloro-2,3-dimethoxybenzyl)ethylamine hydrochloride to glyoxal is 1:2, anhydrous cupric chloride is added as a metal inorganic salt, the mass of which is 2% of the mass of ethylamine hydrochloride, and concentrated sulfuric acid is added as an inorganic protonic acid, the mass of which is 3 times the mass of ethylamine hydrochloride, and the reaction is carried out at 80°C for 12 hours; Step 5: Mix the 12-halogenated berberine derivative with dilute hydrochloric acid, add a solid resin catalyst of 6.5 wt% of the mass of the 12-halogenated berberine derivative, heat to 80° C., and perform a hydrolysis reaction; The preparation method of the solid resin catalyst is as follows: the NKC-9 resin is prepared by plasma modification, the NKC-9 resin is placed in a reaction chamber, and plasma treatment is performed using NH3, dichloroallylphosphine vapor and 3-thiophenylboric acid vapor in a volume ratio of 1.2:0.4:0.06. The treatment conditions are set to 150W power, 30Pa air pressure, 13.56MHz frequency, and the treatment time is 15 minutes. After the modification is completed, the NKC-9 resin is taken out to obtain the desired solid resin catalyst. Before the catalyst is used, it is transformed through an exchange column, and a 2.5-fold volume of a 18% hydrochloric acid solution is used to flow through the exchange column from top to bottom for 2 hours. After being converted into a hydrogen-type resin, it is used for catalytic reactions; Step 6: Filter, wash, dry and purify the obtained berberine hydrochloride. During the purification, use 6 times the amount of water to boil, add lime milk to adjust the pH to 8.5, filter and adjust the pH to 2 and precipitate to obtain berberine hydrochloride precipitate. After filtering, wash and dry the precipitate.

[0033] The yield of the product in this example was 92.8%, and the purity by HPLC analysis was 99.77%.

[0034] Example 3: A method for efficiently synthesizing berberine hydrochloride using a solid resin catalyst, comprising the following steps: Step 1: 150 g of 5-iodo-o-veratraldehyde, 300 g of piperonyl ethylamine and tetrahydrofuran were added into a reactor as a reaction solvent, and a mixture of anhydrous sodium sulfate and anhydrous calcium chloride was added as a dehydrating agent, the mass of the dehydrating agent being 1.2% of the total mass of the reactants, and the reaction was carried out at 80° C. for 4 hours.

[0035] Step 2: The product obtained in step 1 is subjected to reduction reaction with sodium dichloroborohydride in a diethyl ether solvent, the molar ratio of sodium dichloroborohydride to N-[2-(3,4-dioxyphenyl-5-yl)ethyl]-1-(5-iodo-2,3-dimethoxybenzyl)methanimine is 1:2, and the reaction is carried out at 50° C. for 2 hours to obtain 2-(3,4-dioxyphenyl)-N-(5-iodo-2,3-dimethoxybenzyl)ethylamine; Step 3: reacting the product obtained in step 2 with ether hydrochloride having a mass three times that of 2-(3,4-dioxyphenyl)-N-(5-iodo-2,3-dimethoxybenzyl)ethylamine in a tetrahydrofuran solvent at a reaction temperature of 50° C. for a reaction time of 1 hour to obtain 2-(3,4-dioxyphenyl)-N-(5-iodo-2,3-dimethoxybenzyl)ethylamine hydrochloride; Step 4: The 2-(3,4-dioxyphenyl)-N-(5-iodo-2,3-dimethoxybenzyl)ethylamine hydrochloride prepared in the previous step is subjected to a ring-closing reaction with glyoxal in an acetic acid solvent to prepare a 12-haloberberine derivative, the mass ratio of 2-(3,4-dioxyphenyl)-N-(5-iodo-2,3-dimethoxybenzyl)ethylamine hydrochloride to glyoxal is 1:1.8, anhydrous ferric sulfate is added as a metal inorganic salt, the mass of which is 1% of the mass of ethylamine hydrochloride, and phosphoric acid is added as an inorganic proton acid, the mass of which is 1.5 times the mass of ethylamine hydrochloride, and the reaction is carried out at 100°C for 8 hours; Step 5: Mix the 12-halogenated berberine derivative with dilute hydrochloric acid, add a solid resin catalyst of 8 wt% of the mass of the 12-halogenated berberine derivative, heat to 120° C., and perform a hydrolysis reaction; The preparation method of the solid resin catalyst is as follows: using plasma-modified D008 resin as a catalyst, placing the D008 resin in a reaction chamber, and using NH3, dichloroallylphosphine vapor and 3-thiophenylboric acid vapor with a volume ratio of 1.1:0.25:0.05 for plasma treatment, the treatment conditions are power 300W, air pressure 100Pa, frequency 13.56MHz, and treatment time is 10 minutes. After the modified D008 resin is taken out, it is a solid resin catalyst. Before use, put it into an exchange column, and let 2 times the volume of 20% hydrochloric acid solution flow through the exchange column from top to bottom. The transformation treatment time is 3 hours, and it is converted into a hydrogen-type resin for standby use; Step 6: Filter, wash, dry and purify the obtained berberine hydrochloride. During the purification, use 6 times the amount of water to boil, add lime milk to adjust the pH to 9.5, filter and adjust the pH to 2.2 and precipitate to obtain berberine hydrochloride precipitate. After filtering, wash and dry the precipitate.

[0036] The product yield in this example was 93.1% and the purity by HPLC analysis was 99.82%.

[0037] Example 4: A method for efficiently synthesizing berberine hydrochloride using a solid resin catalyst, comprising the following steps: Step 1: 130 g of 5-fluoro-o-veratraldehyde, 250 g of piperidine and methanol were added into a reactor as a reaction solvent, and anhydrous sodium chloride was added as a dehydrating agent, the mass of the dehydrating agent was 1.5% of the total mass of the reactants, and the reaction was carried out at 20° C. for 7 hours.

[0038] Step 2: The product obtained in step 1 is subjected to a reduction reaction with a mixture of sodium cyanoborohydride and sodium dichloroborohydride in a tetrahydrofuran solvent, the molar ratio of sodium cyanoborohydride to N-[2-(3,4-diylideneoxyphenyl-5-yl)ethyl]-1-(5-fluoro-2,3-dimethoxybenzyl)methanimine is 1:1.3, and the reaction is carried out at 0° C. for 3 hours to obtain 2-(3,4-diylideneoxyphenyl)-N-(5-fluoro-2,3-dimethoxybenzyl)ethylamine; Step 3: reacting the product obtained in step 2 with ethereal hydrochloride having a mass 2.2 times that of 2-(3,4-dioxyphenyl)-N-(5-fluoro-2,3-dimethoxybenzyl)ethylamine in a diethyl ether solvent at a reaction temperature of 40° C. for a reaction time of 2.5 hours to obtain 2-(3,4-dioxyphenyl)-N-(5-fluoro-2,3-dimethoxybenzyl)ethylamine hydrochloride; Step 4: The 2-(3,4-dioxyphenyl)-N-(5-fluoro-2,3-dimethoxybenzyl)ethylamine hydrochloride prepared in the previous step is subjected to a ring-closing reaction with glyoxal in a formic acid solvent to prepare a 12-haloberberine derivative, the mass ratio of ethylamine hydrochloride to glyoxal is 1:1.2, anhydrous ferric chloride is added as a metal inorganic salt, the mass of which is 1.8% of the mass of ethylamine hydrochloride, and nitric acid is added as an inorganic protonic acid, the mass of which is 2.5 times the mass of ethylamine hydrochloride, and the reaction is carried out at 70°C for 11 hours; Step 5: Mix the 12-halogenated berberine derivative with dilute hydrochloric acid, add a solid resin catalyst of 10 wt% of the mass of the 12-halogenated berberine derivative, heat to 90° C., and perform a hydrolysis reaction; The preparation method of the solid resin catalyst comprises the following steps: using a plasma-modified D001 and NKC-9 resin mixture (mass ratio 1:1) as a solid resin catalyst, placing the mixed resin in a reaction chamber, and using NH3, dichloroallylphosphine vapor and 3-thiophenylboric acid vapor in a volume ratio of 1:0.2:0.03 for plasma treatment, wherein the treatment conditions are power 100W, air pressure 10Pa, frequency 13.56MHz, and treatment time 30 minutes. After the modified mixed resin is taken out, it is the desired solid resin catalyst. Before use, it is placed in an exchange column, and 4 times the volume of a 10% by mass hydrochloric acid solution flows through the exchange column from top to bottom. The transformation treatment time is 2 hours, and the resin is converted into a hydrogen-type resin for catalytic synthesis of berberine hydrochloride. Step 6: Filter, wash, dry and purify the obtained berberine hydrochloride. During the purification, use 6 times the amount of water to boil, add lime milk to adjust the pH to 9, filter and adjust the pH to 2.3 and precipitate to obtain berberine hydrochloride precipitate. After filtering, wash and dry the precipitate.

[0039] The product yield in this example was 93.2% and the purity by HPLC analysis was 99.84%.

[0040] Comparative Example 1: The difference from Example 1 is that during the plasma treatment of the solid resin catalyst in the reaction chamber, allylphosphine dichloride vapor is not used, and the rest is the same as Example 1.

[0041] The yield of the product in this example was 91.5%, and the purity by HPLC analysis was 99.56%.

[0042] Comparative Example 2: The difference from Example 1 is that during the plasma treatment of the solid resin catalyst in the reaction chamber, 3-thiophenylboric acid vapor is not used as the vapor, and the rest is the same as Example 1.

[0043] The product yield in this example was 92.0%, and the HPLC analysis purity was 99.68%.

[0044] Through the above tests and comparisons, the technical effect of the present invention of efficiently synthesizing berberine hydrochloride using a solid resin catalyst was verified.

[0045] Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and spirit of the present invention, and that the scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A method for efficiently synthesizing berberine hydrochloride using a solid resin catalyst, characterized in that: The following steps are involved: Step 1: Add 10-15 parts of 5-halogenated o-veratraldehyde, 5-30 parts of piperonyl ethylamine and a reaction solvent into a reactor according to weight parts, then add a dehydrating agent, start the reaction, the reaction temperature is 20° C. to 80° C., the reaction time is 4 to 8 hours, and N-[2-(3,4-dioxyphenyl-5-yl)ethyl]-1-(5-halogenated-2,3-dimethoxybenzyl)methanimine is prepared; wherein the 5-halogenated o-veratraldehyde is selected from one of 5-bromo-o-veratraldehyde, 5-chloro-o-veratraldehyde, 5-iodo-o-veratraldehyde and 5-fluoro-o-veratraldehyde; Step 2: subjecting the N-[2-(3,4-dioxyphenyl-5-yl)ethyl]-1-(5-halogenated-2,3-dimethoxybenzyl)methylamine prepared in step 1 to a reduction reaction with a borohydride reducing agent in a reaction solvent at a reaction temperature of 0° C. to 50° C. for a reaction time of 2 to 5 hours to obtain 2-(3,4-dioxyphenyl)-N-(5-halogenated-2,3-dimethoxybenzyl)ethylamine; Step 3: reacting the 2-(3,4-dioxyphenyl)-N-(5-halogenated-2,3-dimethoxybenzyl)ethylamine prepared in step 2 with ether hydrochloride in a reaction solvent at a reaction temperature of 10° C. to 50° C. for 1 to 3 hours to prepare 2-(3,4-dioxyphenyl)-N-(5-halogenated-2,3-dimethoxybenzyl)ethylamine hydrochloride; Step 4: 2-(3,4-dioxyphenyl)-N-(5-halogen-2,3-dimethoxybenzyl)ethylamine hydrochloride is subjected to a ring-closing reaction with glyoxal in an organic acid solvent to prepare a 12-halogenated berberine derivative, and a metal inorganic salt and an inorganic proton acid are added to participate in the reaction; wherein the mass ratio of 2-(3,4-dioxyphenyl)-N-(5-bromo-2,3-dimethoxybenzyl)ethylamine hydrochloride to glyoxal is 1: (1.2-2), the mass of the metal inorganic salt is 1-2% of the mass of 2-(3,4-dioxyphenyl)-N-(5-halogeno-2,3-dimethoxybenzyl)ethylamine hydrochloride, the mass of the inorganic protonic acid is 1-3 times the mass of 2-(3,4-dioxyphenyl)-N-(5-halogeno-2,3-dimethoxybenzyl)ethylamine hydrochloride, the reaction temperature is 50°C-100°C, and the reaction time is 8-12 hours; Step 5: Mix the 12-halogenated berberine derivative with dilute hydrochloric acid, add a solid resin catalyst, heat to 80°C to 120°C, and perform a hydrolysis reaction in an acidic environment to obtain berberine. After hydrolysis, add hydrochloric acid and separate the berberine hydrochloride by concentration and precipitation methods; Step 6: Filter, wash, dry and purify the obtained berberine hydrochloride to obtain berberine hydrochloride with high purity.

2. The method for efficiently synthesizing berberine hydrochloride using a solid resin catalyst according to claim 1, characterized in that: The reaction solvent in step 1, step 2 and step 3 is selected from at least one of diethyl ether, tetrahydrofuran, methanol and ethanol.

3. The method for efficiently synthesizing berberine hydrochloride using a solid resin catalyst according to claim 1, characterized in that: In step 1, the dehydrating agent is selected from at least one of anhydrous sodium sulfate, anhydrous sodium chloride and anhydrous calcium chloride, and the mass of the added dehydrating agent is 0.5-2% of the total mass of the reactants.

4. The method for efficiently synthesizing berberine hydrochloride using a solid resin catalyst according to claim 1, characterized in that: In step 2, the molar ratio of the borohydride reducing agent to N-[2-(3,4-dioxyphenyl-5-yl)ethyl]-1-(5-halogenated-2,3-dimethoxybenzyl)methanimine is 1:(1-2), and the borohydride is selected from at least one of sodium cyanoborohydride, sodium chloride borohydride, and sodium dichloroborohydride.

5. The method for efficiently synthesizing berberine hydrochloride using a solid resin catalyst according to claim 1, characterized in that: The mass of the hydrochloric acid ether in the step 3 is 2 to 3 times the mass of 2-(3,4-dioxyphenyl)-N-(5-halogenated-2,3-dimethoxybenzyl)ethylamine.

6. The method for efficiently synthesizing berberine hydrochloride using a solid resin catalyst according to claim 1, characterized in that: In step 4, the inorganic protonic acid is selected from at least one of concentrated hydrochloric acid, concentrated sulfuric acid, phosphoric acid or nitric acid.

7. The method for efficiently synthesizing berberine hydrochloride using a solid resin catalyst according to claim 1, characterized in that: In step 4, the metal inorganic salt is selected from at least one of anhydrous copper sulfate, anhydrous copper chloride, anhydrous ferric sulfate or anhydrous ferric chloride.

8. The method for efficiently synthesizing berberine hydrochloride using a solid resin catalyst according to claim 1, characterized in that: In step 4, the organic acid solvent is selected from formic acid or acetic acid.

9. The method for efficiently synthesizing berberine hydrochloride using a solid resin catalyst according to claim 1, characterized in that: The amount of solid resin catalyst added in step 5 is 5-10wt% of the mass of 12-halogenated berberine derivative, and the solid resin catalyst is a plasma-modified macroporous strongly acidic cation exchange resin; the preparation method of the solid resin catalyst is: adding a macroporous strongly acidic cation exchange resin into a reaction chamber, using plasma gas of NH3, dichloroallylphosphine vapor, and 3-thiophenylboric acid vapor, and plasma-treating the macroporous strongly acidic cation exchange resin in a volume ratio of (1-1.2): (0.2-0.5): (0.03-0.06) to obtain the obtained resin; after the treatment, taking out the modified macroporous strongly acidic cation exchange resin to obtain a solid resin catalyst; before use, the solid resin catalyst is placed in an exchange column for transformation treatment, and 2-4 times the volume of hydrochloric acid with a mass percentage of 10-20% is used to flow through the exchange column from top to bottom for 2-3 hours to obtain a hydrogen-type resin; The conditions of the plasma treatment are: power 100-300W, gas pressure 10-100Pa, frequency 13.56MHz, and treatment time 10-30 minutes; The macroporous strongly acidic cation exchange resin is selected from at least one of D001 resin, D008 resin and NKC-9 resin, and the factory type is sodium-based resin.

10. The method for efficiently synthesizing berberine hydrochloride using a solid resin catalyst according to claim 1, characterized in that: During the purification in step 6, 6 times the amount of water is used for boiling, lime milk is added to adjust the pH to 8.5-9.5, and after filtering, the pH is adjusted to 2-2.5 and precipitated to obtain berberine hydrochloride precipitate, which is then filtered, washed with water and dried.