A method for producing berberine using recycled formic acid
By preparing a dehydrating agent by loading POCl3 onto activated and modified diatomaceous earth, the problems of high energy consumption, high impurities, and low yield in the formic acid recovery process were solved, achieving high-purity and high-yield production of berberine, reducing production costs and improving safety.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- WEIFANG HAIXIN PHARM CO LTD
- Filing Date
- 2026-05-09
- Publication Date
- 2026-06-05
AI Technical Summary
The existing formic acid recovery process is energy-intensive, dangerous, has high impurities, and low yield, resulting in high production costs and substandard purity of berberine.
Activated modified diatomaceous earth was used as a dehydrating agent. Phosphorus oxychloride (POCl3) was loaded through chemical bonding and treated with aluminum chloride and 8-hydroxyquinoline to prepare a dehydrating agent for the purification and recovery of formic acid. Subsequently, berberine was prepared by cyclization reaction under conditions without high temperature and high pressure.
It achieves high purity (99.843%~99.876%) and high yield (92.6%~93.2%) of berberine, reduces solvent consumption, avoids high temperature and high pressure equipment, and improves production safety.
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Figure CN122145455A_ABST
Abstract
Description
Technical Field
[0001] This invention discloses a method for producing berberine using recycled formic acid, belonging to the field of pharmaceutical and chemical raw material preparation technology. Background Technology
[0002] Berberine (berberine hydrochloride) is a widely used antibacterial drug in clinical practice, traditionally used for intestinal infections. Modern research has found that it also has multiple effects such as regulating metabolism and anti-inflammation. Its core industrial synthesis route generally starts with catechol as the starting material, followed by a cyclization reaction to obtain a piperon ring, a chlorocyanidation reaction to obtain piperone acetonitrile, condensation, catalysis, and hydrogenation to obtain the condensate hydrochloride. Then, using anhydrous formic acid as the reaction solvent and proton donor, and copper sulfate as the catalyst, it undergoes a cyclization reaction with glyoxal, followed by alkalization and salt formation to obtain berberine hydrochloride.
[0003] In the aforementioned cyclization reaction, formic acid only serves as a solvent and proton donor, not participating in the main reaction. After the reaction, the mother liquor contains a large amount of unconsumed formic acid. Directly discharging this formic acid-containing mother liquor would not only cause serious water pollution and environmental risks but also lead to persistently high raw material consumption and significantly increased production costs. Therefore, the recovery, purification, and recycling of formic acid is an unavoidable step in the clean production of berberine and a key research direction for achieving cost reduction, efficiency improvement, and green production.
[0004] The prior art disclosed in CN106543171A is a process for synthesizing berberine. This process uses catechol and dichloromethane as raw materials to synthesize piperine, which is then converted to piperaldehyde via ViLsmeiar formylation. Piperaldehyde is nitrated via a Henry reaction to generate β-nitro-3,4-dioxomethylenestyrene. β-nitro-3,4-dioxomethylenestyrene is reduced by Clemsen to generate piperidine. Piperidine is condensed with 2,3-dimethoxybenzaldehyde and then reduced to generate N-2,3-dimethoxybenzylpiperidine hydrochloride. N-2,3-dimethoxybenzylpiperidine hydrochloride is cyclized in the presence of glyoxal, formic acid, and copper sulfate to form berberine hydrochloride. However, this method has a long production process, with a β-nitro-3,4-dioxomethylenestyrene yield of only 91% and a piperidine hydrochloride yield of only 54%. It also suffers from significant raw material losses and does not involve formic acid recovery, resulting in high solvent consumption.
[0005] Prior art, disclosed in CN101596371A, is an apparatus and method for purifying formic acid solution using intermittent azeotropic distillation. This method employs pressurized distillation, controlling the pressure at 4 atm, and can achieve a high concentration of formic acid solution (80-85%) in the reboiler. Although pressurized distillation can weaken the azeotropic effect, it involves large equipment investment, high energy consumption, and high-temperature, high-pressure distillation conditions, posing significant safety risks. Furthermore, the formic acid in this method has a high water content, making it unsuitable for direct use as a solvent in the production of berberine.
[0006] In addition, existing technologies commonly use anhydrous sodium sulfate, anhydrous magnesium sulfate, and anhydrous calcium chloride as formic acid desiccants, but these methods have certain drawbacks. Anhydrous sodium sulfate and anhydrous magnesium sulfate tend to clump and clog equipment after absorbing water, and their equilibrium dehydration limit is approximately 1-2%, making them more suitable for preliminary pre-dehydration. Anhydrous calcium chloride, on the other hand, will dissolve calcium... 2+ The cyclohexane content competes with the copper catalyst in the cyclization reaction for active sites, leading to decreased catalytic efficiency and high impurities and low yield of the prepared berberine. The berberine cyclization reaction is highly sensitive to the moisture content of formic acid. Industry production practices and related research show that when the moisture content of formic acid exceeds 0.3%, it significantly inhibits the forward cyclization reaction, resulting in decreased raw material conversion rate, increased formation of byproducts or intermediates, and ultimately, substandard purity and reduced yield of the final berberine product.
[0007] In summary, existing technologies for producing berberine from recycled formic acid still suffer from technical problems such as high energy consumption, high risk, high impurities, and low yield. Summary of the Invention
[0008] To address the aforementioned problems in the existing technology, this invention provides a method for producing berberine using recycled formic acid, with the following objectives: the formic acid has a moisture content of <0.3%, the prepared berberine has high purity and high yield, and the production process is safe and does not require high-temperature and high-pressure equipment.
[0009] To achieve the above objectives, the following technical solution is adopted: This invention provides a method for producing berberine using recovered formic acid, comprising the following steps: Step 1: Prepare the dehydrating agent Diatomaceous earth powder was added to a dilute hydrochloric acid solution, heated to remove impurities, and filtered to retain the solid. The solid and aluminum chloride were dispersed in a dilute hydrochloric acid solution, kept warm and stirred for 1-2 hours, and then filtered. The filter cake was washed to obtain pretreated diatomaceous earth. The pretreated diatomaceous earth and 8-hydroxyquinoline were added to a sodium hydroxide solution and stirred to react. After filtration, the filter cake was acid washed, dried, and calcined to activate it to obtain activated modified diatomaceous earth. Under nitrogen protection, the activated modified diatomaceous earth was added to anhydrous toluene, heated and stirred, and phosphorus oxychloride (POCl3) was added dropwise. After the addition was complete, the solid was filtered to retain the solid. After rinsing and vacuum drying, a dehydrating agent was obtained and sealed for later use.
[0010] The heating and impurity removal process involves controlling the temperature at 55-60℃ and the impurity removal time at 2-3 hours. The amount of dilute hydrochloric acid solution used during the heating and impurity removal process is 4-5 times the mass of the diatomaceous earth powder. The mass concentration of the dilute hydrochloric acid solution is 5%-8%.
[0011] The heat preservation and stirring process involves maintaining a temperature of 55-60℃ and controlling the pH value of the system at 4.5-6.0. The amount of dilute hydrochloric acid solution used during the heat preservation and stirring process is 2-3 times the mass of the diatomaceous earth powder.
[0012] The mass concentration of the dilute hydrochloric acid solution is 5% to 8%.
[0013] The mass ratio of diatomaceous earth powder to aluminum chloride is 1:(0.01~0.03).
[0014] The diatomaceous earth powder has the following composition: SiO2 content ≥ 93%, Fe2O3 < 0.5%.
[0015] The sodium hydroxide solution has a mass concentration of 8%.
[0016] The mass ratio of the pretreated diatomaceous earth, 8-hydroxyquinoline, and sodium hydroxide solution is 1:(0.01~0.02):(3~5).
[0017] The stirring reaction is carried out at a temperature of 50-60°C for 1-2 hours.
[0018] The acid washing process involves stirring and dispersing the filter cake in a dilute hydrochloric acid solution for 0.5 to 1 hour, filtering to retain the filter cake, and rinsing with water until neutral. The mass concentration of the dilute hydrochloric acid solution is 5% to 8%, and the amount of dilute hydrochloric acid solution used is 2 to 3 times the mass of the filter cake.
[0019] The calcination activation process involves calcination at a temperature of 250-270°C for 1-2 hours.
[0020] The mass ratio of the activated modified diatomaceous earth, anhydrous toluene, and phosphorus oxychloride is 1:(2.5~4):(0.6~0.7).
[0021] The heating and stirring process involves controlling the temperature at 80~88℃.
[0022] The addition of phosphorus oxychloride: The dropping rate of phosphorus oxychloride is 0.005~0.01 mL / min per gram of activated modified diatomaceous earth.
[0023] The rinsing process uses n-hexane as the washing solution.
[0024] Step 2: Refining crude formic acid Anhydrous sodium sulfate is added to crude formic acid for pre-dehydration, the precipitate is filtered off, a dehydrating agent is added, and water is removed by slow stirring to obtain purified and recovered formic acid.
[0025] The crude formic acid is obtained by distillation of berberine cyclization mother liquor, with a moisture content of 12-15%.
[0026] The mass ratio of crude formic acid, anhydrous sodium sulfate, and dehydrating agent is 50:(4~5):(10~14).
[0027] Step 3, Cycling reaction Copper chloride, purified and recovered formic acid, and N-2,3-dimethoxybenzylpiperidine hydrochloride were added to the reactor, stirred and heated, and 40% glyoxal was slowly added dropwise. After the addition was completed, the reactor was kept at the temperature for 3-4 hours to complete the cyclization reaction.
[0028] The molar ratio of N-2,3-dimethoxybenzylpiperidine hydrochloride, glyoxal, and copper chloride is 1:(1.6~1.8):(1.95~2.12).
[0029] The amount of formic acid used in the refining and recovery process is 8 to 10 times the mass of N-2,3-dimethoxybenzylpiperidine hydrochloride.
[0030] The stirring and heating process involves controlling the temperature at 100~105℃.
[0031] The slow dripping method involves controlling the dripping time to 0.5~1h.
[0032] The heat-insulating ring is controlled at a temperature of 100~105℃.
[0033] Step 4, Post-processing The reaction solution was cooled and filtered to remove the cyclization mother liquor, retaining the solid to obtain filter cake 1. Filter cake 1 was washed and added to water, the alkalinity was adjusted and the temperature was raised, and the precipitate was removed by filtration, retaining the filtrate. The filtrate was acidified, cooled and crystallized, and the solid was filtered to obtain filter cake 2. Filter cake 2 was rinsed and dried to obtain the berberine product.
[0034] The cooling and temperature reduction process involves controlling the temperature to be between 20 and 30°C.
[0035] The alkali adjustment and temperature increase are controlled at 80~95℃ and the pH value is controlled at 8~9.
[0036] The acid adjustment involves controlling the pH value to 1-2.
[0037] The cooling crystallization process involves controlling the temperature at 15~25℃.
[0038] The beneficial effects of this invention are as follows: The berberine product prepared by this invention has a purity of 99.843%~99.876% and a yield of 92.6%~93.2%. This achieves the invention's objective of preparing berberine with high purity and high yield while ensuring a safe production process, effectively reducing solvent consumption. Formic acid treated with the dehydrating agent of this invention has a moisture content of 0.18%~0.23%, with no impurities introduced, fully meeting the requirements for application in production.
[0039] In the preparation of the dehydrating agent, the diatomaceous earth used in this invention was activated and modified. Aluminum chloride and Al were added during the pretreatment stage. 3+Doping diatomaceous earth surfaces through ion exchange and coordination can introduce new active aluminum hydroxyl groups (Al-OH), increasing the sites that can bond to POCl3; Al 3+ As a Lewis acid center, it can polarize adjacent silanol groups and activate the electrophilic P center of POCl3 through coordination, making POCl3 easier to load onto the diatomaceous earth surface. The addition of 8-hydroxyquinoline during the activation stage allows its phenoloxy anion and nitrogen on the quinoline ring to act as hydrogen bond acceptors, forming hydrogen bonds with the silanol groups on the diatomaceous earth surface. This disrupts the self-hydrogen bonds between silanol groups, promoting more hydroxyl exposure, increasing the effective hydroxyl density, and improving the uniformity of the bonding reaction. It can also complex with substances such as Fe. 3+ Trace amounts of metallic impurities are present. The combined use of these two materials provides an optimized modified diatomaceous earth surface for efficient POCl3 loading.
[0040] The dehydrating agent of this invention uses phosphorus oxychloride (POCl3) as the active ingredient for dehydration. It is prepared by loading phosphorus oxychloride onto activated and modified diatomaceous earth. POCl3 is chemically bonded to the activated and modified diatomaceous earth, and its structure can be represented as "diatomaceous earth-O-POCl2". When used for dehydration, the following reaction occurs: -O-POCl2+ 2H2O → -O-PO(OH)2+ 2HCl↑. The chemical reaction is more effective than physical adsorption for removing water. The phosphate groups generated in the reaction remain covalently bonded to the modified diatomaceous earth surface. The entire reaction process involves the transformation of surface functional groups without the breaking of PO bonds. Therefore, no phosphorus compounds will dissolve into the formic acid. The generated HCl gas is purged from the formic acid solution by a nitrogen bubbling gas stream, ensuring the purity of the formic acid and avoiding the risk of introducing new impurities. Attached Figure Description
[0041] Figure 1 This is the liquid phase detection spectrum of Example 1 of the present invention.
[0042] Figure 2 This is the liquid phase detection spectrum of Example 2 of the present invention.
[0043] Figure 3 This is the liquid phase detection spectrum of Example 3 of the present invention.
[0044] Figure 4 This is the liquid phase detection spectrum of Comparative Example 1 of the present invention. Detailed Implementation
[0045] To make the objectives, technical solutions, and advantages of the present invention clearer, the embodiments of the present invention will be described in further detail below. It should be understood that the specific embodiments described herein are for illustrative and explanatory purposes only and are not intended to limit the scope of the invention.
[0046] Example 1: Berberine produced using recycled formic acid A method for producing berberine using recycled formic acid includes the following steps: Step 1: Prepare the dehydrating agent 400g of diatomaceous earth powder was added to 1600g of a 5% (w / w) dilute hydrochloric acid solution. The mixture was heated to 60℃ and kept at this temperature for 2 hours to remove impurities. The mixture was then filtered, and the filter cake was washed three times with deionized water. The washed filter cake was dispersed in 200g of dilute hydrochloric acid solution, and 4g of aluminum chloride was added. The mixture was heated to 60℃, and the pH of the system was adjusted to 6.0. The mixture was kept at this temperature and stirred for 1 hour. The mixture was then filtered, and the filter cake was washed with deionized water until the washing liquid was neutral. The mixture was then dried to obtain pretreated diatomaceous earth.
[0047] 300g of pretreated diatomaceous earth was added to 1500g of 8% sodium hydroxide solution, and 6g of 8-hydroxyquinoline was added as a hydroxyl activation aid. The mixture was stirred at 50℃ for 2 hours, and filtered to obtain filter cake 1. Filter cake 1 was washed with deionized water until the washing liquid was neutral. Filter cake 1 was then acid-washed with a 5% dilute hydrochloric acid solution, with the amount of dilute hydrochloric acid solution being 3 times the mass of filter cake 1. The mixture was stirred and dispersed for 0.5 hours, and filtered to obtain filter cake 2. Filter cake 2 was rinsed with water until neutral, dried in a forced-air oven at 120℃ for 3 hours, and then calcined in a muffle furnace at 250℃ for 2 hours to activate it. After cooling to room temperature, activated modified diatomaceous earth was obtained.
[0048] Under nitrogen protection, 200g of activated modified diatomaceous earth was added to the reactor, followed by 500g of anhydrous toluene and stirring to disperse the mixture. The temperature was raised to 80℃, and 120g of phosphorus oxychloride was slowly added dropwise at a rate of 0.005mL / min per gram of activated modified diatomaceous earth. During the dropwise addition, nitrogen gas was bubbled into the reaction solution to purge the tail gas, which was then introduced into an alkali absorption device. After the dropwise addition was complete, the mixture was kept at this temperature for 0.5h, and then filtered under nitrogen protection to retain the solid. The filter cake was washed twice with anhydrous n-hexane and transferred to a vacuum drying oven. The oven was dried at 40℃ and <-0.09MPa for 4h to obtain a dehydrating agent, which was then sealed and stored.
[0049] Step 2: Refining crude formic acid Take 500g of crude formic acid, add 40g of anhydrous sodium sulfate and stir for 2 hours for pre-dehydration. After filtering out the sodium sulfate precipitate, add 110g of dehydrating agent. Control the stirring speed at 20r / min and stir slowly for 2 hours to remove water. During stirring, bubbling nitrogen gas is introduced into the formic acid to purge the tail gas. The purged tail gas enters the alkali absorption device, and the nitrogen bubbling rate is 2L / min. After stirring is completed, filter out the dehydrating agent to obtain purified recovered formic acid.
[0050] The tested purified formic acid had a water content of 0.22% and a chromatographic purity of 99.95%.
[0051] Step 3, Cycling reaction Copper chloride, purified and recovered formic acid, and N-2,3-dimethoxybenzylpiperidine hydrochloride were added sequentially to a 250ml four-necked flask. The mixture was stirred and heated to 100℃, and 40% glyoxal was slowly added dropwise over a period of 1 hour. After the addition was complete, the mixture was kept at 105℃ for 3 hours to allow the cyclization reaction to proceed.
[0052] In this step, the amount of N-2,3-dimethoxybenzylpiperidine hydrochloride used is 11.9 g, which corresponds to 0.0338 mol, denoted as 1.0 eq; the amount of 40% glyoxal used is 7.85 g, of which the amount of pure glyoxal is 0.0541 mol, denoted as 1.6 eq; and the amount of anhydrous copper chloride used is 8.88 g, which corresponds to 0.066 mol, denoted as 1.95 eq.
[0053] In this step, the amount of formic acid used for purification and recovery is 8 times the mass of N-2,3-dimethoxybenzylpiperidine hydrochloride.
[0054] Step 4, Post-processing The reaction solution was cooled to 30°C. After solid precipitation, the cyclization mother liquor was removed by vacuum filtration, and the filter cake was retained. The filter cake was rinsed with 30 ml of primary reverse osmosis water. The filter cake was then placed in a 500 ml jacketed bottle, 300 ml of primary reverse osmosis water was added, and calcium oxide was added to adjust the pH to 8. The temperature was raised to 80°C to precipitate copper ions. The precipitate was removed by filtration, and the filtrate was obtained. The pH of the filtrate was adjusted to 1 with concentrated hydrochloric acid, and the temperature was lowered to 20°C. After crystallization, the filtrate was filtered, and the filter cake was rinsed with 30 ml of primary reverse osmosis water. The filter cake was then dried to obtain the berberine product.
[0055] Example 2: Berberine produced using recycled formic acid A method for producing berberine using recycled formic acid includes the following steps: Step 1: Prepare the dehydrating agent 400g of diatomaceous earth powder was added to 500g of 8% hydrochloric acid solution, heated to 55℃, and kept at this temperature for 3 hours to remove impurities. The mixture was then filtered, and the filter cake was washed three times with deionized water. The washed filter cake was dispersed in 300g of dilute hydrochloric acid solution, and 12g of aluminum chloride was added. The mixture was heated to 55℃, and the pH of the system was adjusted to 5.5. The mixture was kept at this temperature and stirred for 2 hours, then filtered. The filter cake was washed with deionized water until the washing liquid was neutral, and then dried to obtain pretreated diatomaceous earth.
[0056] 300g of pretreated diatomaceous earth was added to 900g of 8% sodium hydroxide solution, and 3g of 8-hydroxyquinoline was added as a hydroxyl activation aid. The mixture was stirred at 60℃ for 1 hour, and filtered to obtain filter cake 1. Filter cake 1 was washed with deionized water until the washing liquid was neutral. Filter cake 1 was then acid-washed with 8% dilute hydrochloric acid solution (the amount of dilute hydrochloric acid solution was twice the mass of filter cake 1), stirred and dispersed for 1 hour, and filtered to obtain filter cake 2. Filter cake 2 was rinsed with water until neutral, dried in a forced-air oven at 120℃ for 3 hours, and then calcined in a muffle furnace at 270℃ for 1 hour to activate it. After cooling to room temperature, activated modified diatomaceous earth was obtained.
[0057] Under nitrogen protection, 200g of activated modified diatomaceous earth was added to the reactor, followed by 800g of anhydrous toluene and stirring to disperse the mixture. The temperature was raised to 88℃, and 140g of phosphorus oxychloride (POCl3) was slowly added dropwise at a rate of 0.01mL / min per gram of activated modified diatomaceous earth. During the dropwise addition, nitrogen gas was bubbled into the reaction solution to purge the tail gas, which was then introduced into an alkali absorption device. After the dropwise addition was complete, the mixture was kept at this temperature for 0.5h, and then filtered under nitrogen protection to retain the solid. The filter cake was washed twice with anhydrous n-hexane and transferred to a vacuum drying oven. It was dried for 4h at a controlled temperature of 40℃ and a pressure < -0.09MPa to obtain a dehydrating agent, which was then sealed and stored.
[0058] Step 2: Refining crude formic acid Take 500g of crude formic acid, add 50g of anhydrous sodium sulfate and stir for 1 hour for pre-dehydration. After filtering out the sodium sulfate precipitate, add 140g of dehydrating agent. Control the stirring speed at 30r / min and stir slowly to remove water for 1 hour. During stirring, bubbling nitrogen gas is introduced into the formic acid for tail gas purging. The purged tail gas enters the alkali absorption device, and the nitrogen bubbling rate is 2L / min. After stirring, filter out the dehydrating agent to obtain purified recovered formic acid.
[0059] The tested purified formic acid had a water content of 0.22% and a chromatographic purity of 99.95%.
[0060] Step 3, Cycling reaction Copper chloride, purified and recovered formic acid, and N-2,3-dimethoxybenzylpiperidine hydrochloride were added sequentially to a 250ml four-necked flask. The mixture was stirred and heated to 105℃, and 40% glyoxal was slowly added dropwise over a period of 0.5 hours. After the addition was complete, the mixture was kept at 100℃ for 4 hours to allow the cyclization reaction to proceed.
[0061] In this step, the amount of N-2,3-dimethoxybenzylpiperidine hydrochloride used is 11.9 g, which corresponds to 0.0338 mol, denoted as 1.0 eq; the amount of 40% glyoxal used is 8.84 g, of which the amount of pure glyoxal is 0.0609 mol, denoted as 1.8 eq; and the amount of anhydrous copper chloride used is 9.65 g, which corresponds to 0.0718 mol, denoted as 2.12 eq.
[0062] In this step, the amount of formic acid used for purification and recovery is 10 times the mass of N-2,3-dimethoxybenzylpiperidine hydrochloride.
[0063] Step 4, Post-processing The reaction solution was cooled to 20°C. After solid precipitation, the cyclization mother liquor was removed by suction filtration, and the filter cake was retained. The filter cake was rinsed with 30 ml of primary reverse osmosis water. The filter cake was then placed in a 500 ml jacketed bottle, 300 ml of primary reverse osmosis water was added, and calcium oxide was added to adjust the pH to 9. The temperature was raised to 90°C to precipitate copper ions. The precipitate was removed by filtration, and the filtrate was obtained. The pH of the filtrate was adjusted to 1 with concentrated hydrochloric acid, and the temperature was lowered to 25°C. After crystallization, the filtrate was filtered, and the filter cake was rinsed with 30 ml of primary reverse osmosis water. The filter cake was then dried to obtain the berberine product.
[0064] Example 3: Berberine produced using recycled formic acid A method for producing berberine using recycled formic acid includes the following steps: Step 1: Prepare the dehydrating agent 400g of diatomaceous earth powder was added to 2000g of a 5% (w / w) dilute hydrochloric acid solution, heated to 60℃, and kept at this temperature for 3 hours to remove impurities. The mixture was then filtered, and the filter cake was washed three times with deionized water. The washed filter cake was dispersed in 300g of dilute hydrochloric acid solution, and 8g of aluminum chloride was added. The mixture was heated to 60℃, and the pH of the system was adjusted to 4.5. The mixture was kept at this temperature and stirred for 2 hours, then filtered. The filter cake was washed with deionized water until the washing liquid was neutral, and then dried to obtain pretreated diatomaceous earth.
[0065] 300g of pretreated diatomaceous earth was added to 1200g of 8% sodium hydroxide solution, and 6g of 8-hydroxyquinoline was added as a hydroxyl activation aid. The mixture was stirred at 50℃ for 2 hours, and filtered to obtain filter cake 1. Filter cake 1 was washed with deionized water until the washing liquid was neutral. Filter cake 1 was then acid-washed with a 5% dilute hydrochloric acid solution (the amount of hydrochloric acid solution was twice the mass of filter cake 1), stirred and dispersed for 1 hour, and filtered to obtain filter cake 2. Filter cake 2 was rinsed with water until neutral, dried in a forced-air oven at 120℃ for 3 hours, and then calcined in a muffle furnace at 270℃ for 1.5 hours for activation. After cooling to room temperature, activated modified diatomaceous earth was obtained and sealed for later use.
[0066] Under nitrogen protection, 200g of activated modified diatomaceous earth was added to the reactor, followed by 600g of anhydrous toluene and stirred to disperse. The temperature was raised to 85℃, and 120g of phosphorus oxychloride (POCl3) was slowly added dropwise at a rate of 0.008mL / min per gram of activated modified diatomaceous earth. During the dropwise addition, nitrogen gas was bubbled into the reaction solution to purge the tail gas, which was then introduced into an alkali absorption device. After the dropwise addition was complete, the mixture was kept at this temperature for 1 hour. Under nitrogen protection, the mixture was filtered to retain the solid. The filter cake was washed twice with anhydrous n-hexane and then transferred to a vacuum drying oven. The oven was dried at 40℃ and a pressure < -0.09MPa for 4 hours to obtain a dehydrating agent, which was then sealed and stored.
[0067] Step 2: Refining crude formic acid Take 500g of crude formic acid, add 50g of anhydrous sodium sulfate and stir for 1 hour for pre-dehydration. After filtering out the sodium sulfate precipitate, add 130g of dehydrating agent. Control the stirring speed at 30r / min and stir slowly for 2 hours to remove water. During stirring, bubbling nitrogen gas is introduced into the formic acid to purge the tail gas. The purged tail gas enters the alkali absorption device, and the nitrogen bubbling rate is 2L / min. After stirring is completed, filter out the dehydrating agent to obtain purified recovered formic acid.
[0068] The tested purified formic acid had a water content of 0.22% and a chromatographic purity of 99.95%.
[0069] Step 3, Cycling reaction Copper chloride, purified and recovered formic acid, and N-2,3-dimethoxybenzylpiperidine hydrochloride were added sequentially to a 250ml four-necked flask. The mixture was stirred and heated to 105℃, and 40% glyoxal was slowly added dropwise over a period of 0.5 hours. After the addition was complete, the mixture was kept at 105℃ for 3 hours to allow the cyclization reaction to proceed.
[0070] In this step, the amount of N-2,3-dimethoxybenzylpiperidine hydrochloride used is 11.9 g, which corresponds to 0.0338 mol, denoted as 1.0 eq; the amount of 40% glyoxal used is 8.35 g, of which the amount of pure glyoxal is 0.0575 mol, denoted as 1.7 eq; and the amount of anhydrous copper chloride used is 9.28 g, which corresponds to 0.069 mol, denoted as 2.04 eq.
[0071] In this step, the amount of formic acid used for purification and recovery is 10 times the mass of N-2,3-dimethoxybenzylpiperidine hydrochloride.
[0072] Step 4, Post-processing The reaction solution was cooled to 30°C. After solid precipitation, the cyclization mother liquor was removed by suction filtration, and the filter cake was retained. The filter cake was rinsed with 30 ml of primary reverse osmosis water. The filter cake was then placed in a 500 ml jacketed bottle, 300 ml of primary reverse osmosis water was added, and calcium oxide was added to adjust the pH to 9. The temperature was raised to 95°C to precipitate copper ions. The precipitate was removed by filtration, and the filtrate was obtained. The pH of the filtrate was adjusted to 2 with concentrated hydrochloric acid, and the temperature was lowered to 15°C. After crystallization, the filtrate was filtered, and the filter cake was rinsed with 30 ml of primary reverse osmosis water. The filter cake was then dried to obtain the berberine product.
[0073] Comparative Example 1 Step 1: Refining crude formic acid Take 500g of crude formic acid, add 100g of anhydrous sodium sulfate and stir for 3 hours to dehydrate. After filtering out the sodium sulfate precipitate, the recovered formic acid is obtained.
[0074] Step 2, Cycling reaction Copper chloride, purified and recovered formic acid, and N-2,3-dimethoxybenzylpiperidine hydrochloride were added sequentially to a 250ml four-necked flask. The mixture was stirred and heated to 105℃, and 40% glyoxal was slowly added dropwise over a period of 0.5 hours. After the addition was complete, the mixture was kept at 105℃ for 3 hours to allow the cyclization reaction to proceed.
[0075] In this step, the amount of N-2,3-dimethoxybenzylpiperidine hydrochloride used is 11.9 g, which corresponds to 0.0338 mol, denoted as 1.0 eq; the amount of 40% glyoxal used is 8.35 g, of which the amount of pure glyoxal is 0.0575 mol, denoted as 1.7 eq; and the amount of anhydrous copper chloride used is 9.28 g, which corresponds to 0.069 mol, denoted as 2.04 eq.
[0076] In this step, the amount of formic acid used for purification and recovery is 10 times the mass of N-2,3-dimethoxybenzylpiperidine hydrochloride.
[0077] Step 3, Post-processing The reaction solution was cooled to 30°C. After solid precipitation, the cyclization mother liquor was removed by suction filtration, and the filter cake was retained. The filter cake was rinsed with 30 ml of primary reverse osmosis water. The filter cake was then placed in a 500 ml jacketed bottle, 300 ml of primary reverse osmosis water was added, and calcium oxide was added to adjust the pH to 9. The temperature was raised to 95°C to precipitate copper ions. The precipitate was removed by filtration, and the filtrate was obtained. The pH of the filtrate was adjusted to 2 with concentrated hydrochloric acid, and the temperature was lowered to 15°C. After crystallization, the filtrate was filtered, and the filter cake was rinsed with 30 ml of primary reverse osmosis water. The filter cake was then dried to obtain the berberine product.
[0078] Performance testing The moisture content of the formic acid used in Examples 1-3 and Comparative Example 1 was tested; the yield and chromatographic purity of the berberine prepared in Examples 1-3 and Comparative Example 1 were tested. The results of each performance test are shown in Table 1.
[0079] Formic acid moisture content: Tested using a Karl Fischer moisture analyzer and volumetric method.
[0080] Berberine product purity: tested and analyzed using high performance liquid chromatography.
[0081] Berberine yield: The yield was calculated based on N-2,3-dimethoxybenzylpiperidine hydrochloride. Let m1 be the mass of the prepared berberine product, and m0 be the mass of N-2,3-dimethoxybenzylpiperidine hydrochloride consumed as raw material. Yield = [(m1 / 371.82) / (m0 / 351.83)] × 100%.
[0082] Table 1 Performance Test Results As shown in Table 1, the berberine prepared by this invention has a purity of 99.843%~99.876% and a yield of 92.6%~93.2%. The purified formic acid treated with the dehydrating agent of this invention has a moisture content of 0.18%~0.23%, and the dehydration process introduces no impurities, fully meeting the requirements for reuse.
[0083] Obviously, there are many other specific implementation methods that can be varied under the concept of this invention. It should be stated here that any changes made under the inventive concept of this invention will fall within the protection scope of this invention.
Claims
1. A method for producing berberine using recovered formic acid, characterized in that: Includes the following steps: Step 1: Add diatomaceous earth powder to dilute hydrochloric acid solution, heat to remove impurities, filter and retain the solid; The solid and aluminum chloride were dispersed in a dilute hydrochloric acid solution, kept warm and stirred for 1-2 hours, and then filtered to obtain pretreated diatomaceous earth. Pretreated diatomaceous earth and 8-hydroxyquinoline were added to sodium hydroxide solution and stirred to react. After filtration, the filter cake was acid washed, dried, and calcined to activate it, thus obtaining activated modified diatomaceous earth. Under nitrogen protection, activated modified diatomaceous earth was added to anhydrous toluene, heated and stirred, and phosphorus oxychloride was added dropwise. After the addition was complete, the solid was filtered and retained. After rinsing and vacuum drying, the dehydrating agent was obtained. The mass ratio of diatomaceous earth powder to aluminum chloride is 1:(0.01~0.03). The mass ratio of the pretreated diatomaceous earth, 8-hydroxyquinoline, and sodium hydroxide solution is 1:(0.01~0.02):(3~5). The calcination activation is carried out at a temperature of 250-270℃ for 1-2 hours. The mass ratio of the activated modified diatomaceous earth, anhydrous toluene, and phosphorus oxychloride is 1:(2.5~4):(0.6~0.7). Step 2: Add anhydrous sodium sulfate to crude formic acid for pre-dehydration, filter out the precipitate, add a dehydrating agent, stir slowly to remove water, and obtain purified recovered formic acid; Step 3: Add copper chloride, purified and recovered formic acid, and N-2,3-dimethoxybenzylpiperidine hydrochloride to the reactor, stir and heat, slowly add 40% glyoxal, and after the addition is complete, keep the temperature and cyclization reaction for 3-4 hours. Step 4: Cool the reaction solution to remove the cyclization mother liquor by suction filtration, and retain the solid to obtain filter cake 1. Wash filter cake 1 and add it to water, adjust the alkali and raise the temperature, filter to remove the precipitate and retain the filtrate; adjust the acidity of the filtrate, cool and crystallize, filter to retain the solid to obtain filter cake 2, rinse and dry filter cake 2 to obtain berberine.
2. The method for producing berberine using recovered formic acid according to claim 1, characterized in that: Step 1, heating to remove impurities: control the temperature at 55~60℃ and the removal time at 2~3h; during the heating to remove impurities, the amount of dilute hydrochloric acid solution used is 4~5 times the mass of diatomaceous earth powder, and the mass concentration of the dilute hydrochloric acid solution is 5%~8%.
3. The method for producing berberine using recovered formic acid according to claim 1, characterized in that: The heat preservation and stirring process described in step 1 involves maintaining a heat preservation temperature of 55-60°C and controlling the pH value of the system at 4.5-6.0 during the heat preservation and stirring process. The amount of dilute hydrochloric acid solution used during the heat preservation and stirring process is 2-3 times the mass of the diatomaceous earth powder, and the mass concentration of the dilute hydrochloric acid solution is 5%-8%.
4. The method for producing berberine using recovered formic acid according to claim 1, characterized in that: The stirring reaction described in step 1: the reaction temperature is 50~60℃, and the reaction time is 1~2h; the acid washing: the amount of dilute hydrochloric acid solution used is 2~3 times the mass of the filter cake, and the mass concentration of the dilute hydrochloric acid solution is 5%~8%.
5. The method for producing berberine using recovered formic acid according to claim 1, characterized in that: The addition of phosphorus oxychloride in step 1: the dropping rate of phosphorus oxychloride is 0.005~0.01 mL / min per gram of activated modified diatomaceous earth; the rinsing: the washing solution is n-hexane.
6. The method for producing berberine using recovered formic acid according to claim 1, characterized in that: The mass ratio of crude formic acid, anhydrous sodium sulfate, and dehydrating agent in step 2 is 50:(4~5):(10~14).
7. The method for producing berberine using recovered formic acid according to claim 1, characterized in that: The molar ratio of N-2,3-dimethoxybenzylpiperidine hydrochloride, glyoxal, and copper chloride in step 3 is 1:(1.6~1.8):(1.95~2.12).
8. The method for producing berberine using recovered formic acid according to claim 1, characterized in that: The amount of formic acid used in step 3 is 8 to 10 times the mass of N-2,3-dimethoxybenzylpiperidine hydrochloride; the stirring and heating is controlled at 100 to 105°C; the slow dripping is controlled at a dripping time of 0.5 to 1 hour; and the heat preservation and cyclization are controlled at 100 to 105°C.
9. A method for producing berberine using recovered formic acid according to claim 1, characterized in that: Step 4 cooling and temperature reduction: control the temperature at 20~30℃; Alkali adjustment and temperature increase: control the temperature at 80~95℃ and control the pH value at 8~9.
10. A method for producing berberine using recovered formic acid according to claim 1, characterized in that: Step 4 involves adjusting the pH to 1-2; the cooling crystallization involves controlling the temperature to 15-25℃.