A synthetic method suitable for industrial production of berberine and berberine hydrochloride

Abstract

The application discloses a synthetic method suitable for industrial production of berberine and berberine hydrochloride, which comprises the following steps: adding berberine acetonitrile, o-veratraldehyde, an alcohol reaction solvent and a mixture of anhydrous copper sulfate-Pd / C in a reaction container in proportion, carrying out a reduction reaction by introducing hydrogen under the conditions of 50-70 DEG C and 0.3-0.8 MPa, removing the hydrogen after the system stops eating hydrogen, adding glyoxal, stirring and heating to 80-100 DEG C, reacting for 4-8 hours or more, cooling to room temperature, and then carrying out suction filtration to obtain a berberine methanol solution; the berberine methanol solution is subjected to post-treatment to obtain berberine or hydrogen chloride is introduced to obtain berberine hydrochloride by crystallization. The catalyst is matched by Pd / C and anhydrous copper sulfate, the temperature and pressure requirements in the reaction process are improved, the traditional high-temperature and high-pressure reaction is reduced to controllable reaction temperature and pressure, the reaction risk is greatly reduced, the catalyst can be recycled and reused, and the material cost and three-waste treatment are reduced.

Description

Technical Field

[0001] This invention relates to a method for synthesizing berberine and berberine hydrochloride, belonging to the field of compound preparation technology. Background Technology

[0002] Berberine, also known as berberine, is a chemical compound consisting of 5,6-dihydro-9,10-dimethoxybenzo[G]-1,3-dicyclobenzo[5,6-A]quinazine. Its molecular formula is C2. 20 H 18 NO4 + Molecular weight: 336.37, CAS number: 2086-83-1, Structural formula:

[0003] Key properties: Colored to yellow crystalline powder, soluble in chloroform, dichloromethane, ethyl acetate, DMSO, acetone, etc.

[0004] Earlier literature described a synthetic route for berberine using piperoethylamine and 3,4-dimethoxyphenylacetic acid as starting materials, involving the preparation of acyl chloride, condensation, dehydration cyclization, reduction, cyclization, and oxidation to obtain berberine. The synthetic route is as follows:

[0005]

[0006] This route requires a longer cyclization process and exhibits poor selectivity in the second cyclization reaction. Therefore, the overall yield is lower and the cost is higher.

[0007] In 1980, the State Pharmaceutical Administration published the "National Compendium of Raw Material Drug Processes," which reported a relatively mature synthesis process for berberine. The process route is as follows:

[0008]

[0009] This process uses piperine as a raw material, followed by dehydration condensation of piperine ethylamine and o-veratrol, and finally cyclization to obtain berberine. It is simpler and more efficient than earlier literature. Chinese patent CN1312250A also reports the same route.

[0010] In recent years, several new laboratory routes for the synthesis of berberine have been developed, but most of them require expensive catalysts or harsh reaction conditions for the synthesis of berberine, making industrialization difficult to achieve in the short term.

[0011] However, the current mainstream industrial production process still involves dehydrating and condensing piperoethylamine and o-veratrol to form a Schiff base, followed by reduction to obtain the condensate, and further cyclizing with glyoxal to obtain berberine. This process route has several main problems in industrial production:

[0012] 1. The reduction of pepper acetonitrile to pepper ethylamine requires a high-temperature and high-pressure reaction catalyzed by Raney nickel (100℃, 2MPa), which places high demands on equipment and poses significant safety risks.

[0013] 2. The Schiff base reduction process also requires Raney nickel catalysis for a high-temperature and high-pressure reaction (110℃, 3MPa), which poses a significant safety hazard.

[0014] 3. Raney nickel is highly susceptible to fire and explosion during storage, transportation, and use. Furthermore, the two reduction reactions of this product require a large amount of Raney nickel for catalytic reduction, which further increases the safety risks.

[0015] 4. In the process of reducing cyano to amino, piperoacetonitrile is first converted into the intermediate (IMPA) piperoethylene imine after reduction, and then further reduced to piperoethylamine. However, if liquid ammonia is not added to the reaction system, piperoethylene imine will condense to produce piperoethylamine hydrazine impurity (IMP B). Therefore, in the traditional process, a large amount of liquid ammonia needs to be added to suppress the generation of side reactions. However, the material properties of liquid ammonia mean that its storage and transportation require special equipment, and storing it in the factory area is highly dangerous.

[0016]

[0017] 5. After the Schiff base is reduced to the condensate, the glyoxal cyclization process requires the use of copper chloride or copper sulfate pentahydrate as a catalyst for cyclization. After cyclization, the copper salt of berberine precipitated in water needs to undergo a rather cumbersome copper removal process, such as slurrying ammonia water to form a copper ammonia complex and dissolving it in water for removal. The process is cumbersome and complicated.

[0018] In summary, the synthesis of berberine using this process places high demands on plant equipment, design, material transportation, and storage. Furthermore, it requires high temperatures and pressures during the reaction process, posing significant safety risks. In addition, the post-processing is cumbersome and causes substantial environmental pollution, which does not align with the current advocacy of green chemistry. Summary of the Invention

[0019] The technical problem to be solved by the present invention is to provide a method for preparing berberine and berberine hydrochloride. The method uses anhydrous copper sulfate and Pd / C as catalysts to achieve one-pot production, which improves the production capacity and yield as well as the safety of the reaction system, and avoids the risks in post-processing.

[0020] To address the above technical problems, this invention first discloses a synthesis method suitable for the industrial production of berberine. In a reaction vessel, piperine acetonitrile, o-veratrol, an alcoholic reaction solvent, and an anhydrous copper sulfate-Pd / C mixture as a catalyst are added in proportion. The reaction is carried out under conditions of 50–70°C and 0.3–0.8 MPa (preferably 0.3–0.5 MPa), with hydrogen gas introduced for reduction. After the system no longer absorbs hydrogen, the hydrogen gas is removed under vacuum. Glyoxal is added, and the mixture is stirred and heated to 80–100°C. The reaction is carried out for 4–8 hours, then cooled to room temperature (preferably 20–25°C), filtered, and a berberine methanol solution is obtained. Berberine is then obtained after post-treatment.

[0021] Furthermore, the alcohol reaction solvent is anhydrous methanol, ethanol, isopropanol, or n-propanol.

[0022] Furthermore, the molar ratio of pepper acetonitrile to o-veratrol is 1:0.9 to 1.1.

[0023] Furthermore, the molar ratio of pepper acetonitrile to glyoxal is 1:1.5 to 2.0.

[0024] Furthermore, in the catalyst, the weight ratio of Pd / C to anhydrous copper sulfate is 1:12.5 to 25.

[0025] Furthermore, the combined weight of anhydrous copper sulfate and Pd / C in the catalyst is 50% to 100% of the weight of pepper acetonitrile.

[0026] Furthermore, the palladium content in the Pd / C is 10% by weight, and the weight of Pd / C is 4% of the weight of pepper acetonitrile.

[0027] Furthermore, the catalyst is first prepared by uniformly mixing Pd / C and anhydrous copper sulfate in an alcohol solvent, with the weight ratio of Pd / C to the alcohol solvent being 1:20-50. This alcohol solvent is consistent with the alcohol reaction solvent.

[0028] Furthermore, the weight ratio of the pepper acetonitrile to the alcohol reaction solvent is 1:3 to 10.

[0029] The present invention also discloses a method for synthesizing berberine hydrochloride suitable for industrial production. In this method, hydrogen chloride gas is introduced into the berberine methanol solution obtained above. After the pH of the solution is less than 1, the introduction of hydrogen chloride gas is stopped, crystallization occurs, and berberine hydrochloride solid is obtained.

[0030] The complete reaction formula for the generation of berberine and berberine hydrochloride in this invention is as follows:

[0031]

[0032] This invention involves adding piperithione and o-veratrol together into a reaction vessel, using Pd / C and anhydrous copper sulfate as catalysts. This allows a portion of the piperithione to react to piperitimine and simultaneously begin a condensation reaction with o-veratrol to form a Schiff base, which is then further reduced to a condensate, thus achieving a one-pot reaction.

[0033] Specifically:

[0034] 1. The one-pot synthesis process of berberine and berberine hydrochloride from pepper acetonitrile can greatly improve equipment utilization. At the same time, since the reaction reduces the generation of by-product impurities, it does not require too many steps for solid crystallization to remove impurities, thereby improving the overall yield, comprehensively improving the corresponding production capacity and yield, and reducing the generation of waste.

[0035] 2. Using Pd / C and anhydrous copper sulfate as catalysts not only avoids the use of Raney nickel, thus reducing the risk of flammability and explosion of Raney nickel during the post-treatment process after hydrogenation reduction, but also greatly reduces the reaction temperature and reaction pressure, improving the safety of the reaction system.

[0036] 3. In the one-pot reaction, the use of high-risk raw materials such as liquid ammonia is avoided. o-Veratral reacts directly with the generated piperine ethylidene imine to form a reversible Schiff base. Anhydrous copper sulfate inhibits the reverse reaction, allowing the Schiff base to be directly reduced to a condensate, thus avoiding the formation of the byproduct piperine ethylidene hydrazine. The specific reaction equation is as follows:

[0037]

[0038] 4. After the hydrogenation condensation reaction is completed and filtered, the filtered catalyst Pd / C is washed with an alcohol solvent to remove the reaction residue. Then, a certain amount of anhydrous copper sulfate is added and stirred in an alcohol solvent to obtain a new catalyst system for the reaction catalysis, thereby greatly reducing the reaction cost.

[0039] 5. In this invention, after synthesizing berberine into a methanol solution in a one-pot process, berberine can be separated by concentration and crystallization, or the methanol solution of berberine can be directly filtered to remove palladium on carbon in the catalyst complex, and then berberine hydrochloride can be precipitated directly from methanol by forming hydrochloride, thus avoiding the formation of copper salts and reducing cumbersome post-processing.

[0040] In summary, this invention utilizes the synergistic effect of Pd / C and anhydrous copper sulfate catalysts to improve the temperature and pressure requirements of the reaction process. It reduces the high-temperature, high-pressure reactions in traditional industrial production to controllable temperature and pressure, significantly reducing reaction risks. Furthermore, catalyst recycling lowers material costs and simplifies waste treatment, aligning with the principles of green chemistry. The direct reduction of piperine acetonitrile to a condensate via the intermediate state of piperine ethyleneimine and o-veratrol significantly improves product quality and reduces byproduct impurities. Moreover, the one-pot synthesis of berberine from starting materials drastically reduces the required amount of reaction equipment, greatly improving efficiency and increasing the capacity and yield of limited production equipment. Attached Figure Description

[0041] Figure 1 This is the HPLC detection chromatogram of berberine hydrochloride obtained in Example 2 of the invention. Detailed Implementation

[0042] The present invention will be further explained below with reference to the embodiments. The following embodiments are for illustrative purposes only and are not intended to limit the scope of the invention.

[0043] Example 1: Palladium on carbon / anhydrous copper sulfate mixture (catalyst preparation)

[0044] Add 4g of palladium on carbon with a palladium content of 10wt%, 80g of anhydrous copper sulfate, and 100g of anhydrous methanol to a 500mL reaction flask, mix well, stir for 3 hours, and let stand until ready for use.

[0045] Example 2: Preparation of Berberine Hydrochloride

[0046] Add 500g anhydrous methanol, 100g piperine acetonitrile (0.62mol), 104.5g o-veratrol (0.63mol), and the entire batch (184g) of catalyst prepared in Example 1 to a 2000mL reactor. Close the reactor, purge the air three times with nitrogen at 0.4MPa, then purge the nitrogen three times with hydrogen at 0.4MPa, maintaining the pressure in the reactor at 0.3-0.4MPa. Heat to 60℃, maintain the temperature, and stir. After 3 hours of reaction, when the pressure in the system no longer changes, pump in 56.5g g(0.97mol) of glyoxal, heat to 85℃, and react for 4 hours. Cool down, extract the liquid, filter, and wash the filter residue (palladium on carbon) with 100mL of anhydrous methanol. The residue can be reused in the catalyst preparation of Example 1. The filtrate is a methanol solution of berberine, which can be concentrated and crystallized to obtain berberine.

[0047] After the filtrate was cooled to 10℃, hydrogen chloride gas was introduced until the pH of the reaction solution reached 0.5. Gas flow was then stopped, and the mixture was stirred to allow crystallization for 3 hours. The crystals were then filtered and dried at 65℃ to obtain 235 g of berberine hydrochloride, with a molar yield of 97.2% and a purity of 99% as determined by HPLC. The HPLC chromatogram is shown below. Figure 1 .

[0048] Multiple batches of experiments were conducted to test the feeding ratios of pepper acetonitrile, o-veratrol, and glyoxal. The experimental results are shown in Table 1.

[0049] Table 1: Experimental results of different feed ratios of pepper acetonitrile, o-veratrol, and glyoxal.

[0050]

Claims

1. A method for synthesizing berberine suitable for industrial production, characterized in that: Piperone acetonitrile, o-veratrol, an alcoholic reaction solvent, and anhydrous copper sulfate-Pd / C mixture as a catalyst were added to a reaction vessel in proportion. The reaction was carried out under the conditions of 50-70℃ and 0.3-0.8MPa, with hydrogen gas introduced to carry out the reduction reaction. After the system no longer absorbed hydrogen, the hydrogen gas in the system was removed by vacuum. Glyoxal was added and the temperature was raised to 80-100℃. The reaction was carried out for 4-8 hours, cooled to room temperature, and filtered to obtain a berberine methanol solution. Berberine was obtained after post-treatment.

2. The method for synthesizing berberine suitable for industrial production according to claim 1, characterized in that: The alcohol reaction solvent is anhydrous methanol, ethanol, isopropanol, or n-propanol.

3. The method for synthesizing berberine suitable for industrial production according to claim 1, characterized in that: The molar ratio of pepper acetonitrile to o-veratrol is 1:0.9-1.

1.

4. The method for synthesizing berberine suitable for industrial production according to claim 1, characterized in that: The molar ratio of pepper acetonitrile to glyoxal is 1:1.5 to 2.

0.

5. The method for synthesizing berberine suitable for industrial production according to claim 1, characterized in that: The weight ratio of Pd / C to anhydrous copper sulfate in the catalyst is 1:12.5-25.

6. The method for synthesizing berberine suitable for industrial production according to claim 1, characterized in that: The combined weight of anhydrous copper sulfate and Pd / C in the catalyst is 50% to 100% of the weight of pepper acetonitrile.

7. The method for synthesizing berberine suitable for industrial production according to claim 6, characterized in that: The Pd / C contains 10% palladium by weight, and the weight of Pd / C is 4% of the weight of pepper acetonitrile.

8. The method for synthesizing berberine suitable for industrial production according to claim 1, 6, or 7, characterized in that: The catalyst is prepared by first mixing Pd / C and anhydrous copper sulfate with an alcohol solvent, wherein the weight ratio of Pd / C to the alcohol solvent is 1:20-50.

9. The method for synthesizing berberine suitable for industrial production according to claim 1, characterized in that: The weight ratio of pepper acetonitrile to alcohol reaction solvent is 1:3 to 10.

10. A method for synthesizing berberine hydrochloride suitable for industrial production, characterized in that: The method involves passing hydrogen chloride gas into a berberine methanol solution obtained according to any one of claims 1-8. Once the pH of the solution is less than 1, the gas flow is stopped, and crystals are formed to obtain berberine hydrochloride solid.

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