A preparation method of berberine hydrochloride

Abstract

The application belongs to the field of organic chemistry and particularly relates to a synthesis method of berberine hydrochloride. The method comprises the following steps: taking 3,4-dimethoxyphenethylamine hydrochloride and 3,4-methylenedioxybenzaldehyde as starting materials, sequentially undergoing oxidative cyclization, selective reduction and quaternary ammonium ring closure through three-step reactions, and finally directly obtaining the target product berberine hydrochloride through acid treatment. The technical scheme has the characteristics of high efficiency, simplicity, and high industrial cost ratio in the synthesis of berberine hydrochloride, the overall reaction is more green and safe, the reaction condition is more mild, the reaction process has high selectivity, and the berberine hydrochloride product with higher purity can be obtained.

Description

Technical Field

[0001] This invention belongs to the field of organic chemistry, specifically relating to a method for synthesizing berberine hydrochloride. Background Technology

[0002] Berberine hydrochloride (commonly known as berberine), as a natural alkaloid, has expanded its industrial applications from the traditional pharmaceutical field to emerging areas such as metal corrosion prevention and food preservation. Examples include its use as a corrosion inhibitor in steel pickling, an antibacterial finishing agent for fabrics, and an additive in antifungal and antibacterial coatings.

[0003] However, the high cost of traditional berberine hydrochloride acquisition methods has prevented many applications from being effectively utilized.

[0004] There are two main traditional routes for obtaining berberine hydrochloride: the acid-lime extraction route and the biomimetic synthesis / oxidative coupling route. The acid-lime extraction route utilizes the characteristic that berberine forms a salt that dissolves in water, while other impurities (such as tannins) are complexed and precipitated with calcium ions. The biomimetic synthesis / oxidative coupling route mimics the biosynthetic pathway in plants, using benzyltetrahydroisoquinoline as a key intermediate. It constructs a C-C bond through phenolic oxidative coupling (such as FeCl3 oxidation) to form a dibenzylisoquinoline skeleton, which is then synthesized through methylation, cyclization, and other steps.

[0005] However, the acid-lime extraction route has extremely low yields and is cumbersome, generating large amounts of calcium-containing and acidic wastewater. Similarly, the biomimetic synthesis / oxidative coupling route suffers from lengthy synthesis steps, typically requiring eight steps, and is prone to generating multiple isomers, making separation difficult, and resulting in limited actual product yields and purity.

[0006] Therefore, it is very important to develop a method that is both efficient and environmentally friendly, while also effectively improving the cost-effectiveness of synthesis. Summary of the Invention

[0007] The present invention addresses the technical challenges of traditional chemical synthesis methods, such as lengthy steps, difficulty in selective control, high cost, and unsuitability for industrial production. The present invention provides a method for synthesizing berberine hydrochloride.

[0008] The main objective of this invention is: I. To provide a simple and cost-effective total synthesis route for berberine hydrochloride; II. Design a synergistic and indivisible composite catalyst system to selectively construct the molecular core framework and chiral center; Third, it enables tandem operations that do not require separation of intermediates under mild reaction conditions, simplifying the process, reducing costs, and making it suitable for large-scale production.

[0009] To achieve the above objectives, the present invention adopts the following technical solution.

[0010] A method for preparing berberine hydrochloride. The method includes: Starting with 3,4-dimethoxyphenylethylamine hydrochloride and 3,4-methylenedioxybenzaldehyde, the reaction proceeds in three steps in sequence, undergoing oxidative cyclization, selective reduction, and quaternization ring closure, and finally the target product berberine hydrochloride is obtained directly by acid treatment.

[0011] As a preferred option The method includes: 1) 3,4-dimethoxyphenylethylamine hydrochloride, 3,4-methylenedioxybenzaldehyde, chiral phase transfer catalyst PTC-A, and oxidant were mixed in an organic solvent to react and obtain a tetrahydroisoquinoline core framework. 2) Add catalyst B directly to the system after the reaction in step 1) and carry out selective reduction in a hydrogen atmosphere; 3) Add solid acid catalyst Acid-C directly to the system after reduction in step 2) to carry out nucleophilic reaction. After the reaction is completed, separate the catalyst and perform post-processing to obtain high-purity berberine hydrochloride.

[0012] As a preferred option In step 1), the mass ratio of 3,4-dimethoxyphenethylamine hydrochloride to 3,4-methylenedioxybenzaldehyde is 1:(0.8-1.2). Step 1) The chiral phase transfer catalyst PTC-A is N-benzylchlorooctanine, and its dosage is 4-6% of the mass of 3,4-dimethoxyphenethylamine hydrochloride; Step 1) The oxidant is a 60-70 wt% tert-butyl hydrogen peroxide solution, and its amount is 0.5-1.0 times the mass of 3,4-dimethoxyphenethylamine hydrochloride. Step 1) The organic solvent is toluene, and its mass is 12 to 18 times that of 3,4-dimethoxyphenylethylamine hydrochloride.

[0013] As a preferred option The reaction described in step 1) is carried out in a nitrogen atmosphere of 0.05–0.10 MPa at 30–40 °C with continuous stirring at 400–600 rpm for 30–40 h.

[0014] As a preferred option In step 2), catalyst B is ruthenium supported on nitrogen-doped carbon material, wherein the mass loading of ruthenium is 2-4%, and its amount is 2-4% of the mass of 3,4-dimethoxyphenylethylamine hydrochloride in step 1).

[0015] As a preferred option Step 2) The selective reduction is carried out in a hydrogen atmosphere of 0.3-0.7 MPa at 55-65 °C for 20-28 h.

[0016] As a preferred option Step 3) The solid acid catalyst Acid-C is a perfluorosulfonic acid resin, and its amount is 8 to 12% of the mass of 3,4-dimethoxyphenylethylamine hydrochloride in step 1).

[0017] As a preferred option Step 3) The nucleophilic reaction is carried out in a nitrogen atmosphere of 0.05-0.10 MPa at a reaction temperature of 60-70 °C for 12-24 h.

[0018] As a preferred option Step 3) The post-processing includes sequentially acidifying and extracting the filtrate after catalyst removal, adjusting the pH to induce crystallization, filtering, washing, drying, and recrystallizing.

[0019] As a preferred option The acidification extraction involves 3 to 5 extractions with a 0.8–1.2 mol / L hydrochloric acid aqueous solution, followed by pH adjustment and crystallization after combining the aqueous phases. The pH adjustment crystallization and filtration process involves adjusting the pH value to 8.0–9.0 with an aqueous solution of alkaline alkali metal compounds, followed by filtration to collect the precipitated solid product. The washing process involves washing the solid product in an ice-water bath at 0–4 °C, followed by vacuum drying at 45–50 °C to obtain the crude product. The recrystallization is performed by placing the crude product in an aqueous ethanol solution and recrystallizing it at 70–75 °C to obtain berberine hydrochloride.

[0020] The core of the total synthesis route of berberine hydrochloride involved in this invention lies in the fact that the technical solution of this invention does not originate from a simple optimization of a certain reaction step, but rather from the construction of a composite catalyst system (PTC-A / Ru@Support-B / Acid-C) with progressive and synergistic effects. The core of this system lies in simulating the "multi-site synergy" and "reaction channelization" in bioenzyme catalysis, thereby driving a one-pot, three-step tandem transformation from simple raw materials to complex chiral molecules.

[0021] The entire process is highly dependent on the synergistic interaction of the three catalysts; the absence or substitution of any one of them will disrupt the catalytic synergy.

[0022] The first step in this scheme, namely the construction of the chiral tetrahydroisoquinoline skeleton, is the stereoregulatory point of the entire synthetic sequence. The chiral phase-transfer catalyst PTC-A used here, namely N-benzylchlorooctanine, forms a highly lipid-soluble ion-pair complex through strong electrostatic interaction between the quaternary ammonium salt cation in the catalyst molecule and the t-BuOO- anion formed by the oxidant tert-butyl hydroperoxide (TBHP) in the aqueous phase. This process greatly enhances the effective concentration and reactivity of reactive oxygen species in the organic phase (toluene), thereby achieving efficient and selective oxidation of 3,4-dimethoxyphenethylamine to the imine intermediate at a mild temperature (30–40 °C), avoiding side reactions caused by high-temperature oxidation.

[0023] More importantly, the unique steric environment of N-benzylchlorooctacrine actively participates in shaping the reaction transition state. In the organic phase, this chiral quaternary ammonium cation not only carries the oxidant but also forms a pre-organized, diastereoselective reaction cage with the newly formed imine intermediate and enamine component through weak interactions such as π-π stacking and ion-dipole interactions. Within this constrained space, the chiral environment, through precise steric hindrance and electronic effects, forcibly guides the π orbitals of the enamine to approach the carbocation center of the imine with specific si- or re-faces. This "face selectivity" directly determines the absolute configuration of the chiral center at the C-13a position in the subsequent cyclization product, thus achieving a high degree of stereoselectivity in the intermolecular aziridine Diels-Alder reaction.

[0024] Meanwhile, this process can be carried out efficiently at room temperature and pressure, making it more environmentally friendly and efficient.

[0025] The first step of the reaction produces a complex chiral intermediate containing an enamine double bond and multiple aromatic rings and ether bonds. Therefore, the second step aims to reduce only the highly reactive enamine double bond while preserving the other important functional groups. Common noble metal catalysts such as Pd / C or Pt / C are completely ineffective here, lacking sufficient selectivity and leading to serious side reactions such as excessive hydrogenation or debenzylation of the aromatic ring. Therefore, this invention employs a custom-designed Ru@Support-B catalyst. The Ru@Support-B catalyst of this invention refers to ruthenium supported on nitrogen-doped carbon materials, with a ruthenium mass loading of 2–4%. Unless otherwise specified, all Ru@Support-B catalysts used in this invention were custom-purchased from Xianfeng Nano, with a ruthenium mass loading of 3 wt%, and the product number is XF359. In this catalyst, nitrogen doping fundamentally alters the electronic structure of the carbon support, enabling it to interact strongly with the supported ruthenium nanoparticles. This interaction causes a shift in the d-band center of ruthenium, thereby optimizing its dissociation and adsorption energy for hydrogen molecules and its adsorption strength for different unsaturated bonds. This allows the nitrogen-doped support to more effectively transform ruthenium into a specific catalyst that exhibits high activity for the hydrogenation of olefins (enamines) but inertness for the hydrogenation of aromatic rings. This enables efficient and precise selective catalytic reactions.

[0026] After obtaining the saturated tetrahydroisoquinoline intermediate, an intramolecular nucleophilic attack is required to construct the final isoquinoline-isoquinoline quaternary ammonium salt skeleton. Traditional processes use liquid mineral acids such as concentrated hydrochloric acid and sulfuric acid, which have problems such as equipment corrosion, large amounts of acidic wastewater generated during post-processing, and cumbersome product separation. This invention uniquely introduces perfluorosulfonic acid resin (such as the Nafion NR50 series perfluorosulfonic acid resin used in the experiments of this invention) as a solid acid catalyst, Acid-C. This is a polymer with ultra-strong Brønsted acidity, and the strength of its acidic site (-SO3H) is equivalent to that of sulfuric acid with a concentration >90%. However, because it exists in solid form, it achieves effective integration and synergy between homogeneous acid catalysis and heterogeneous catalyst separation in the reaction system.

[0027] Under heating conditions of 75–85 °C, the sulfonic acid group on the surface of the solid acid protonates the benzylic carbon atom in the intermediate molecule, greatly increasing its positive charge and making it a strong electrophilic center. Simultaneously, the tertiary amine nitrogen atom at the other end of the molecule, despite being in a weakly basic environment, retains sufficient nucleophilicity in its lone pair electrons, launching an intramolecular SN2-type nucleophilic attack on the activated benzylic carbon, successfully achieving ring closure and forming a quaternary ammonium salt. Subsequently, trace amounts of chloride ions present in the reaction system (from the raw material hydrochloride or catalyst residue) combine with the newly formed quaternary ammonium cation, directly forming a berberine cation-counterion complex in the toluene reaction solution. This shifts the reaction equilibrium to the right and allows for very easy preliminary separation of the materials in subsequent processing. This design combines the reaction, salt formation, and preliminary purification steps into one, greatly simplifying the post-processing procedure.

[0028] The irreplaceable nature of this solution lies in the unique roles of each catalyst. The chiral control function of PTC-A cannot be replaced by ordinary quaternary ammonium salts; the selective hydrogenation characteristics of Ru@Support-B cannot be achieved by general-purpose catalysts such as Pd / C; and the solid acid properties and superacidity of Acid-C cannot be replaced by liquid inorganic acids. This functional specificity ensures the high efficiency and selectivity of the entire reaction sequence. The integrated advantages of this system are reflected in the synergistic effect of process simplification, avoiding intermediate separation and purification steps, and improving atom economy and production efficiency. The compatibility and stability of each catalyst ensure the smooth progress of the reaction, providing a reliable technical foundation for industrial applications.

[0029] The beneficial effects of this invention are: The technical solution of this invention has the characteristics of high efficiency, simplicity and high industrial cost performance in the synthesis of berberine hydrochloride. The overall reaction is more green and safe, the reaction conditions are milder, and the reaction process has extremely high selectivity, which can obtain berberine hydrochloride products with higher purity. Detailed Implementation

[0030] The present invention will be further described clearly and in detail below with reference to specific embodiments. Those skilled in the art will be able to implement the present invention based on these descriptions. Furthermore, the embodiments of the present invention described below are generally only some, not all, of the embodiments of the present invention. Therefore, all other embodiments obtained by those skilled in the art based on the embodiments of the present invention without inventive effort should fall within the scope of protection of the present invention.

[0031] Unless otherwise specified, all raw materials used in the embodiments of the present invention are commercially available or obtainable by those skilled in the art; unless otherwise specified, all methods used in the embodiments of the present invention are methods mastered by those skilled in the art.

[0032] Unless otherwise specified, the TBHP aqueous solution used in the embodiments of the present invention is a commercially available 70% tert-butyl hydrogen peroxide aqueous solution (CAS registration number: 75-91-2).

[0033] Example 1 A method for synthesizing berberine hydrochloride, the method comprising: 1) In reactor A, add 10.0 g of 3,4-dimethoxyphenethylamine hydrochloride, 8.0 g of 3,4-methylenedioxybenzaldehyde, 0.4 g of N-benzylchlorocinnamate, 8.0 g of TBHP aqueous solution, and 120 mL of anhydrous toluene. After purging the reaction system with nitrogen, heat to 33 °C under nitrogen protection at 0.1 MPa and stir at 500 rpm for 36 h. After cooling to room temperature, add 100 mL of 10 wt% sodium sulfite aqueous solution and stir for 15 min to quench the reaction. Then let stand for 30 min, separate the aqueous layer, add 10 g of anhydrous sodium sulfate to the organic phase, dry for 15 min, and filter to remove solids to obtain the reaction mixture.

[0034] 2) The reaction mixture obtained in step 1) was transferred to reactor B, which was pre-charged with 0.5 MPa hydrogen gas, through a closed system. 0.3 g of the supported ruthenium nanocatalyst Ru@Support-B (Ru@NC) was added to reactor B. The mixture was heated to 60 °C and reacted for 24 h under a hydrogen atmosphere. The reaction mixture was then separated by filtration.

[0035] 3) Transfer the reaction mixture obtained in step 2) to a nitrogen-purged reactor C via a closed system. Add 1.0 g of solid acid catalyst Acid-C to reactor C. Under nitrogen protection at 0.1 MPa, heat to 65 °C and react for 18 h.

[0036] 4) Cool the reaction solution obtained in step 3) to 20 °C and filter to separate the solid catalyst. Extract the filtrate three times with 1 M hydrochloric acid aqueous solution (60 mL each time). Combine the acidic aqueous layers and adjust the pH to 8.5 with saturated sodium bicarbonate aqueous solution. Filter and collect the precipitated solid, wash with ice water at 0 °C, and dry under vacuum at 50 °C for 12 h to obtain crude berberine hydrochloride. Recrystallize the crude product with a 95:5 (v / v) ethanol / water mixed solvent at 75 °C to obtain a white crystalline product.

[0037] The material prepared in Example 1 was subjected to performance testing, and the specific characterization results are as follows.

[0038] Analysis of the characterization results shows that this method successfully synthesized optically pure berberine hydrochloride, demonstrating that the technical solution has a broad operating window and basic feasibility. The product's optical activity and chemical purity both meet the acceptable standards, but the yield is relatively low, reflecting a mild level of reaction driving force and efficiency under lower catalyst concentrations and material dosages.

[0039] Example 2 A method for synthesizing berberine hydrochloride.

[0040] The method includes: 1) In reactor A, add 10.0 g of 3,4-dimethoxyphenethylamine hydrochloride, 10.0 g of 3,4-methylenedioxybenzaldehyde, 0.5 g of N-benzylchlorocinnamate, 10.0 g of TBHP aqueous solution, and 150 mL of anhydrous toluene. After purging the reaction system with nitrogen, heat to 35 °C under nitrogen protection at 0.1 MPa, stir at 500 rpm for 32 h, cool to room temperature, add 120 mL of 10 wt% sodium sulfite aqueous solution and stir for 15 min to quench the reaction. Then let stand for 30 min, separate the aqueous layer, add 10 g of anhydrous sodium sulfate to the organic phase, dry for 15 min, and filter to remove solids to obtain the reaction mixture.

[0041] 2) The reaction mixture obtained in step 1) was transferred to reactor B, which was pre-charged with 0.5 MPa hydrogen gas, through a closed system. 0.3 g of the supported ruthenium nanocatalyst Ru@Support-B (Ru@NC, 3% ruthenium loading) was added to reactor B. The mixture was heated to 60 °C and reacted for 24 h under a hydrogen atmosphere. The catalyst Ru@Support-B was then separated by filtration to obtain the reaction mixture.

[0042] 3) Transfer the reaction mixture obtained in step 2) to a nitrogen-purged reactor C via a closed system. Add 1.0 g of solid acid catalyst Acid-C to reactor C. Under nitrogen protection at 0.1 MPa, heat to 70 °C and react for 12 h.

[0043] 4) Cool the reaction solution obtained in step 3) to 23 °C and filter to separate the solid catalyst. Extract the filtrate three times with 1 M hydrochloric acid aqueous solution (75 mL each time, filtrate volume approximately 0.5). Combine the acidic aqueous layers and adjust the pH to 9.0 with saturated sodium bicarbonate aqueous solution. Filter and collect the precipitated solid, wash with 0 °C ice water, and dry under vacuum at 50 °C for 12 h to obtain crude berberine hydrochloride. Recrystallize the crude product with a 95:5 (v / v) ethanol / water mixed solvent at 75 °C to obtain a white crystalline product.

[0044] The material prepared in Example 2 was subjected to performance testing, and the specific characterization results are as follows.

[0045] Analysis of the above characterization results shows that the product has the highest chemical and optical purity, and the overall yield reaches its peak. This fully demonstrates that the preferred parameter range determined in this invention can perfectly balance reaction rate, stereoselectivity, conversion rate, and economy, and is the standard for achieving efficient and high-quality synthesis.

[0046] Example 3 A method for synthesizing berberine hydrochloride.

[0047] The method includes: (1) Oxidative cyclization step: In reactor A, 10.0 g of 3,4-dimethoxyphenethylamine hydrochloride, 12.0 g of 3,4-methylenedioxybenzaldehyde, 0.6 g of N-benzylchlorocinnamate, 10.0 g of TBHP aqueous solution, and 180 mL of anhydrous toluene were added. After purging the reaction system with nitrogen, the temperature was raised to 37 °C under nitrogen protection at 0.1 MPa, and the reaction was stirred at 500 rpm for 38 h. After cooling to room temperature, 120 mL of 10 wt% sodium sulfite aqueous solution was added and stirred for 15 min to quench the reaction. Then, the mixture was allowed to stand for 30 min, and the aqueous layer was separated. 10 g of anhydrous sodium sulfate was added to the organic phase, and the mixture was dried for 15 min. After filtration, the solids were removed to obtain the reaction mixture.

[0048] (2) The reaction mixture obtained in step 1) was transferred to reactor B, which was pre-charged with 0.5 MPa hydrogen gas, through a closed system. 0.4 g of the supported ruthenium nanocatalyst Ru@Support-B (Ru@NC, 3% ruthenium loading) was added to reactor B. Under a hydrogen atmosphere, the temperature was raised to 60 °C and the reaction was carried out for 24 h. After filtering to separate the catalyst Ru@Support-B, the reaction mixture was obtained.

[0049] (3) The reaction mixture obtained in step 2) is transferred to a nitrogen-purged reactor C through a closed system. 1.2 g of solid acid catalyst Acid-C is added to reactor C. Under nitrogen protection at 0.1 MPa, the temperature is raised to 60 °C and the reaction is carried out for 24 h.

[0050] (4) Cool the reaction solution obtained in step (3) to 25 °C and filter to separate the solid catalyst. Extract the filtrate three times with 1 M hydrochloric acid aqueous solution (90 mL each time, filtrate volume approximately 0.6). Combine the acidic aqueous layers and adjust the pH to 9.0 with saturated sodium bicarbonate aqueous solution. Filter and collect the precipitated solid, wash with 0 °C ice water, and vacuum dry at 50 °C for 12 h to obtain crude berberine hydrochloride. Recrystallize the crude product with a 95:5 (v / v) ethanol / water mixed solvent at 75 °C to obtain a white crystalline product.

[0051] The material prepared in Example 3 was subjected to performance testing, and the specific characterization results are as follows.

[0052] Analysis of the characterization results shows that the reaction proceeded successfully under these high loading and high material dosage conditions, with good product purity and optical activity, and the yield falling between that of Examples 1 and 2. This indicates that although increasing the material input can compensate to some extent for the slight decrease in selectivity that may be caused by slightly higher temperatures and improve the reaction rate, the overall economy and efficiency are not optimal. These results clarify the upper limit of the parameter range of this invention and suggest that a trade-off must be made between yield, purity, and cost when pursuing higher throughput.

[0053] Comparative Example 1 Based on Example 2, this example only changes the type of chiral phase transfer catalyst in step 1; the remaining steps are the same as in Example 2. The specific settings are as follows: The performance testing method for the comparative product is completely consistent with that of Example 1. Partial performance characterization was performed, and the characterization results are shown in the table below.

[0054] Analysis of the characterization results shows that in group D1-1, the use of the non-chiral quaternary ammonium salt TBAB to replace PTC-A resulted in an ee value of less than 5% for the key intermediate. This indicates that ordinary quaternary ammonium salts cannot achieve chiral induction, leading to a loss of precise substrate configuration matching in the subsequent Ru@Support-B catalyzed selective hydrogenation reaction. This resulted in a chaotic reaction pathway, increased byproducts, and a final product purity reduced to 95.1%, with a yield of only 33.3%. Furthermore, the optical activity was almost completely lost, and the product appearance changed to a light yellow powder due to the presence of byproducts. This fully demonstrates that the chiral control function of PTC-A cannot be replaced by ordinary quaternary ammonium salts, and its absence directly disrupts the orderliness of the entire catalytic relay chain.

[0055] Group D1-2 employed a chiral quaternary ammonium salt catalyst with a similar structure but a different stereoconfiguration, whose inductive effect contrasted sharply with that of PTC-A. Although the catalyst was chemically similar to PTC-A, its chiral control ability was significantly reduced due to the difference in stereoconfiguration. Experimental data showed that the ee value of the key intermediate was much lower than that when using PTC-A. This indicates that even small changes in stereoconfiguration can have a significant impact on chiral induction. Furthermore, although the selective hydrogenation reaction catalyzed by Ru@Support-B could still proceed, the selectivity of the product was significantly reduced due to the decreased substrate configuration matching, and the proportion of the opposite configuration in the final product was high. This result further confirms the strong correlation between the structure and performance of chiral catalysts. Although the purity of the products in this group remained at a high level, the yield was slightly lower than that of Example 2 because the configuration did not meet the requirements of the target product. This further demonstrates that the specific chiral configuration of PTC-A is a necessary condition for obtaining the target optically pure berberine hydrochloride.

[0056] The results of Comparative Example 1 clearly demonstrate that the specific N-benzyl chloride cinchonine used in this invention is a necessary technical feature for achieving high yield and high optical purity of the target product. Optically pure products cannot be obtained in an achiral environment. Its chirality comes from the specific (R)-configuration cinchonine skeleton, which cannot be replaced by ordinary quaternary ammonium salts. By selecting catalysts with different configurations, the target enantiomer can be synthesized in a targeted manner, demonstrating the specificity of the method.

[0057] Comparative Example 2 Based on Example 2, this example only changes the type of hydrogenation catalyst in step 2; the remaining steps are the same as in Example 2. The specific settings are as follows: The performance testing method for the comparative product is completely consistent with that of Example 1. Partial performance characterization was performed, and the characterization results are shown in the table below.

[0058] Analysis of the characterization results showed that in group D2-1, replacing Ru@Support-B with 5% palladium on carbon (Pd / C) resulted in a sharp drop in product purity to 87.2% and an overall yield of only 25.3%, with aromatic ring hydrogenation byproducts accounting for as high as 42.1%. This is because Pd / C has strong catalytic activity for aromatic ring hydrogenation. During the reduction of the intermediate double bond generated in step 1, excessive hydrogenation of the 3,4-methylenedioxybenzene ring or the 3,4-dimethoxybenzene ring structure leads to the formation of a large number of non-target aromatic ring hydrogenation byproducts, severely reducing the selectivity and yield of the reaction.

[0059] Group D2-2 used 5% platinum-carbon (Pt / C) as the hydrogenation catalyst. Although the proportion of aromatic ring hydrogenation byproducts decreased to 8.1%, the proportion of benzyl dehydrogenation byproducts reached 15.7%, the product purity was 90.5%, and the overall yield of 30.6% was still significantly lower than that of Example 2. It is speculated that Pt / C easily triggers the removal reaction of the benzyl residue in the chiral phase transfer catalyst PTC-A in step 1 or benzyl-like structures in the intermediate, generating additional byproducts, thus affecting product purity and yield.

[0060] In contrast, the Ru@Support-B (Ru@NC) catalyst used in Example 2 exhibits precise selectivity for the reduction of target double bonds due to the ruthenium nanoparticles supported on a nitrogen-doped carbon support. It can efficiently reduce unsaturated double bonds in intermediates and effectively suppress side reactions such as excessive hydrogenation and debenzylation of aromatic rings. This results in the proportion of aromatic ring hydrogenation byproducts being less than 0.5% and the absence of significant debenzylation byproducts, thereby ensuring high purity and high yield of the product.

[0061] The results of Comparative Example 2 fully demonstrate that the type of hydrogenation catalyst and the selection of the support in step 2 are crucial to the selectivity of the reaction and the control of byproducts. The specific structure and catalytic performance of Ru@Support-B cannot be replaced by ordinary commercial Pd / C and Pt / C catalysts. It plays a core role in maintaining reaction selectivity and reducing side reactions in the catalytic relay system, and is one of the key technical features for achieving the efficient synthesis of berberine hydrochloride in this invention.

[0062] Comparative Example 3 Based on Example 2, this example only modifies the catalyst and operational continuity in step 3; the remaining steps are the same as in Example 2. The specific settings are as follows: The performance testing method for the comparative product is completely consistent with that of Example 1. Partial performance characterization was performed, and the characterization results are shown in the table below.

[0063] Analysis of the characterization results showed that in group D3-1, the use of p-toluenesulfonic acid (PTSA) instead of the solid acid catalyst Acid-C resulted in a significant decrease in both product purity and yield. The presumed reason is that PTSA, as a homogeneous liquid acid, has a wide acid strength distribution, easily initiating side reactions such as non-selective cyclization and side-chain isomerization, leading to an increase in the types and amounts of byproducts. In contrast, Acid-C, a solid superacid with a specific pore structure, can precisely catalyze targeted cyclization reactions through steric hindrance and acidic site control, effectively suppressing the occurrence of side reactions.

[0064] In Group D3-2, the continuous closed-loop operation from Step 2 to Step 3 was interrupted. The intermediate was separated and purified before the cyclization reaction. Although the product purity remained high, the yield was significantly reduced. This is because unavoidable adsorption losses and operational losses occur during the concentration and column chromatography separation of the intermediate. Furthermore, the redissolution of the separated intermediate easily introduces trace impurities, further interfering with the cyclization reaction efficiency. The continuous closed-loop transfer operation in Example 2, on the other hand, maximizes the preservation of the integrity of the reaction intermediate, reduces material loss and impurity introduction, and is one of the core operating conditions for ensuring a high yield.

[0065] In group D3-3, the solvent in step 3 was replaced with acetonitrile, resulting in a decrease in both product purity and yield. Toluene, as a non-polar solvent, can form a suitable dissolution environment with the reaction intermediates, promoting effective contact between the Acid-C catalytic sites and the intermediates. Acetonitrile, on the other hand, is highly polar and may alter the solvation layer structure on the catalyst surface, reducing the catalytic activity of acidic sites. Simultaneously, it may induce solvation side reactions in some intermediates, leading to an increase in byproducts.

[0066] The results of Comparative Example 3 clearly demonstrate that the specific structure of the solid acid catalyst Acid-C, the continuous closed-loop operation mode of the reaction process, and the selection of toluene solvent in step 3 collectively constitute the key factors ensuring the selectivity and yield of the cyclization reaction. The heterogeneous catalytic properties of the solid acid, the protection of material integrity during continuous operation, and the compatibility between the solvent and the reaction system are all indispensable technical details for achieving the efficient synthesis of berberine hydrochloride in this invention, and their synergistic effect ensures the high selectivity and high yield of the reaction.

[0067] Comparative Example 4 Based on Example 2, this example conducts catalyst recycling experiments and extreme condition tests.

[0068] The characterization results are shown in the table below.

[0069] Analysis of the above characterization results and the catalyst recycling experiment results of group D4-1 show that after 5 rounds of continuous recycling, the product purity remained above 98.5%, while the total yield gradually decreased from the initial 74.9% to 63.2%, with a controllable decrease. This indicates that the Ru@Support-B and Acid-C catalysts have good reusability and stability, and their active sites did not undergo significant deactivation. Adding 80% of the fresh PTC-A effectively compensates for the small amount lost during the reaction process, maintaining the integrity of the catalytic relay system. This result verifies the recyclability of the catalyst system of this invention, which can significantly reduce production costs and improve the economics of the process.

[0070] The experimental results of group D4-2 using industrial-grade raw materials show that even when the purity of the raw materials is reduced to 95%, the HPLC purity of the product still reaches 98.0%, and the total yield is 68.4%. This indicates that the catalytic relay system of the present invention has a certain tolerance to raw material impurities, does not rely on high-purity reagents, and can directly use lower-cost industrial-grade raw materials for production, further enhancing the practical value and industrialization potential of the process.

[0071] The 50x scale-up experiment results for group D4-3 showed that the product purity remained at 99.5% and the yield was 71.3%, with minimal difference from the laboratory-scale results of Example 2. This indicates that the synthesis process of the present invention has excellent scale-up stability, with no obvious mass or heat transfer limitations during the reaction process, and can smoothly transition from laboratory-scale to pilot-scale, providing reliable data support for subsequent industrial-scale production.

[0072] The overall results of Comparative Example 4 fully demonstrate that the berberine hydrochloride synthesis process of the present invention not only possesses the technical advantages of high selectivity and high yield, but also takes into account catalyst recovery and utilization, industrial raw material compatibility, and the feasibility of large-scale production. These characteristics together constitute the basis for the industrial application of the process, providing comprehensive technical support for its promotion in actual production, highlighting the comprehensive competitiveness of the present invention in terms of economy, practicality, and scalability.

[0073] Example 4 Based on Example 2, this example uses a special catalyst B prepared in the laboratory for the preparation of berberine hydrochloride. The preparation method of catalyst B used in this example is as follows: 5.0 g of melamine and 10.0 g of glucose were added to 200 mL of deionized water and stirred at 300 rpm in an 80 ℃ water bath until completely dissolved, yielding a clear solution. 15.0 g of silica nanoparticles were added, and the solution was transferred to a high-shear dispersing emulsifier and treated at 10000 rpm for 15 min to obtain a milky white suspension. This suspension was then spray-dried and shaped, and dried at 80 ℃ for 12 h to obtain the carrier. 10.0 g of the carrier was added to 300 mL of cyclohexane and sonicated for 30 min to disperse, obtaining the carrier solution. 430 mg of hydrated ruthenium trichloride was dissolved in 50 mL of anhydrous ethanol to prepare a ruthenium precursor solution.

[0074] The carrier liquid was transferred to the reactor and kept at a constant temperature of 25 °C and stirred at 800 rpm. Then, the ruthenium precursor liquid was slowly added dropwise to the carrier liquid at a rate of 1 mL / min. After the addition was complete, stirring was continued for 4 h. The solid was collected by vacuum filtration and washed three times each with cyclohexane and anhydrous ethanol. The filter cake was obtained by vacuum filtration and dried in a vacuum drying oven at 60 °C for 6 h to obtain the supported precursor.

[0075] In a nitrogen atmosphere, the supported precursor was heated to 850 °C and held at that temperature for 2 h in an argon protective atmosphere. After cooling to room temperature, it was transferred to a 10 vol% H2 / Ar mixed atmosphere, heated to 450 °C and held at that temperature for 90 h. After cooling to room temperature, the crude product was recovered. A 2 mol / L sodium hydroxide aqueous solution was boiled and added to the crude product. After reacting for 4 h, the solid was filtered out and repeatedly washed with deionized water by vacuum filtration until the filtrate was neutral. After drying at 80 °C for 12 h, catalyst B was obtained. For easy identification, the catalyst B prepared in this example is labeled as Ru@NCH, while the catalyst B used in other examples (such as Example 2) is labeled as Ru@NC.

[0076] The synthesis of berberine hydrochloride was carried out using catalyst B prepared in this example: 1) In reaction vessel A, add 10.0 g of 3,4-dimethoxyphenethylamine hydrochloride, 10.0 g of 3,4-methylenedioxybenzaldehyde, 0.5 g of N-benzylchlorocinnamate, 13.0 g of TBHP aqueous solution, and 150 mL of anhydrous toluene. After purging the reaction system with nitrogen, heat to 35 °C under nitrogen protection at 0.1 MPa and stir at 500 rpm for 48 h.

[0077] 2) The reaction mixture obtained in step 1) was transferred to reactor B, which was pre-charged with 0.5 MPa hydrogen gas, through a closed system. 0.3 g of the supported ruthenium nanocatalyst Ru@Support-B (Ru@NCH) was added to reactor B. The mixture was heated to 60 °C and reacted for 24 h under a hydrogen atmosphere.

[0078] 3) Transfer the reaction mixture obtained in step 2) to a nitrogen-purged reactor C via a closed system. Add 1.0 g of solid acid catalyst Acid-C to reactor C. Under nitrogen protection at 0.1 MPa, heat to 80 °C and react for 36 h.

[0079] 4) Cool the reaction solution obtained in step 3) to 23 °C and filter to separate the solid catalyst. Extract the filtrate three times with 1 M hydrochloric acid aqueous solution (75 mL each time, filtrate volume approximately 0.5). Combine the acidic aqueous layers and adjust the pH to 9.0 with saturated sodium bicarbonate aqueous solution. Filter and collect the precipitated solid, wash with 0 °C ice water, and dry under vacuum at 50 °C for 12 h to obtain crude berberine hydrochloride. Recrystallize the crude product with a 95:5 (v / v) ethanol / water mixed solvent at 75 °C to obtain a white crystalline product.

[0080] The material prepared in Example 2 was subjected to performance testing, and the specific characterization results are as follows.

[0081] Analysis of the characterization results shows that, after optimizing catalyst B, the purity of the berberine hydrochloride product in this example reached the 3N level. Although the purity fluctuated between 99.7% and 99.9% in most repeated experiments, it was still far higher than the upper limit of Example 2. With further optimization, it is entirely possible to achieve the industrial-scale preparation of 3N-level berberine hydrochloride.

Claims

1. A method for preparing berberine hydrochloride, characterized in that, The method includes: 1) 3,4-Dimethoxyphenylethylamine hydrochloride, 3,4-methylenedioxybenzaldehyde, chiral phase transfer catalyst PTC-A, and oxidant were mixed in an organic solvent to react and obtain a tetrahydroisoquinoline core framework. 2) Add catalyst B directly to the system after the reaction in step 1) and carry out selective reduction in a hydrogen atmosphere; 3) Add solid acid catalyst Acid-C directly to the system after reduction in step 2) to carry out nucleophilic reaction. After the reaction is completed, separate the catalyst and perform post-processing to obtain high-purity berberine hydrochloride. In step 1), the mass ratio of 3,4-dimethoxyphenethylamine hydrochloride to 3,4-methylenedioxybenzaldehyde is 1:(0.8-1.2). Step 1) The chiral phase transfer catalyst PTC-A is N-benzylchlorooctanine, and its dosage is 4-6% of the mass of 3,4-dimethoxyphenethylamine hydrochloride; Step 1) The oxidant is a 60-70 wt% tert-butyl hydrogen peroxide solution, and its amount is 0.5-1.0 times the mass of 3,4-dimethoxyphenethylamine hydrochloride. Step 2) Catalyst B is ruthenium supported on nitrogen-doped carbon material, wherein the mass loading of ruthenium is 2-4%, and its amount is 2-4% of the mass of 3,4-dimethoxyphenylethylamine hydrochloride in step 1). Step 3) The solid acid catalyst Acid-C is a perfluorosulfonic acid resin, and its amount is 8 to 12% of the mass of 3,4-dimethoxyphenylethylamine hydrochloride in step 1).

2. The method for preparing berberine hydrochloride according to claim 1, characterized in that, Step 1) The organic solvent is toluene, and its mass is 12 to 18 times that of 3,4-dimethoxyphenylethylamine hydrochloride.

3. A method for preparing berberine hydrochloride according to claim 1 or 2, characterized in that, The reaction described in step 1) is carried out in a nitrogen atmosphere of 0.05–0.10 MPa at 30–40 °C with continuous stirring at 400–600 rpm for 30–40 h.

4. The method for preparing berberine hydrochloride according to claim 1, characterized in that, Step 2) The selective reduction is carried out in a hydrogen atmosphere of 0.3-0.7 MPa at 55-65 °C for 20-28 h.

5. The method for preparing berberine hydrochloride according to claim 1, characterized in that, Step 3) The nucleophilic reaction is carried out in a nitrogen atmosphere of 0.05-0.10 MPa at a reaction temperature of 60-70 °C for 12-24 h.

6. The method for preparing berberine hydrochloride according to claim 1, characterized in that, Step 3) The post-processing includes sequentially acidifying and extracting the filtrate after catalyst removal, adjusting the pH to induce crystallization, filtering, washing, drying, and recrystallizing.

7. The method for preparing berberine hydrochloride according to claim 6, characterized in that, The acidification extraction involves 3 to 5 extractions with a 0.8–1.2 mol / L hydrochloric acid aqueous solution, followed by pH adjustment and crystallization after combining the aqueous phases. The pH adjustment crystallization and filtration process involves adjusting the pH value to 8.0–9.0 with an aqueous solution of alkaline alkali metal compounds, followed by filtration to collect the precipitated solid product. The washing process involves washing the solid product in an ice-water bath at 0–4 °C, followed by vacuum drying at 45–50 °C to obtain the crude product. The recrystallization is performed by placing the crude product in an aqueous ethanol solution and recrystallizing it at 70–75 °C to obtain berberine hydrochloride.

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