A method for producing berberine, palmatine and jatrorrhizine hydrochloride based on Fibraurea recisa

Abstract

The present invention provides a method for producing berberine, palmatine and jatrorrhizine hydrochloride based on Fibraurea recisa Pierre; the present invention uses specific Fibraurea recisa Pierre as raw material, after crushing, warming extraction with dilute acid, temperature-controlled filtration for clarification and membrane separation, berberine hydrochloride is separated by crystallization and recrystallization: then the crystallization mother liquor is subjected to fractional crystallization and recrystallization to separate palmatine hydrochloride; finally, jatrorrhizine hydrochloride is separated by the combined use of ion exchange resin and macroporous adsorption resin chromatography. The present invention continuously produces three high-value-added alkaloid monomers based on Fibraurea recisa Pierre containing berberine, palmatine and jatrorrhizine, all of which are heterocyclic compounds; the present invention can also solve the problems of environmental pollution by salt wastewater, alkaline browning, difficult regeneration caused by resin staining during the production process, and improve the purity of alkaloid monomers, forming a production system that can be applied industrially.

Description

Technical Field

[0001] The present invention relates to heterocyclic compounds, and particularly to a method for producing berberine, palmatine and jatrorrhizine hydrochloride based on Fibraurea recisa Pierre. Background Art

[0002] Fibraurea recisa Pierre Fibraurea recisa Pierre. , a plant of the family Menispermaceae, also known as Aristolochia contorta Bge., Cortex Phellodendri Chinensis, Golden Lock Key, Caulis Fibraureae Recisae, etc. The medicinal part is the dried caulis. It mostly grows in the humid and fertile tropical and subtropical dense forests at an altitude of 180-1000 m and often climbs on tall lianas. The caulis of domestic Fibraurea recisa Pierre mainly contains alkaloids: palmatine, jatrorrhizine, pseudo-columbamine, and fibrauretin, and also contains fibrauretin A, fibrauretin B, sterols, etc.; palmatine and jatrorrhizine are the main alkaloid components of Fibraurea recisa Pierre medicinal materials. Due to factors such as the price of medicinal materials and the production and processing costs, there is a great contradiction with the value of producing palmatine hydrochloride; therefore, Fibraurea recisa Pierre is mainly used as a traditional Chinese medicine and rarely used as a raw material for extracting and preparing fibrauretin (palmatine) in batches. Since the content of berberine in domestic Fibraurea recisa Pierre medicinal materials is very low and has no extraction value, only palmatine with a high content and an appropriate amount of jatrorrhizine, even in the existing research on extracting and processing Fibraurea recisa Pierre, it mainly focuses on the extraction and purification of a single component of palmatine hydrochloride, rarely prepares jatrorrhizine hydrochloride at the same time, and there is no report on preparing berberine hydrochloride at the same time.

[0003] For example, a Chinese invention patent application with the publication number CN101058575A discloses a method for extracting and refining palmatine hydrochloride. The steps taken are as follows: (1) Acid treatment: Grind the fibraureae caulis medicinal materials, add 6 - 14 times the amount of dilute sulfuric acid aqueous solution, soak for 24 - 72 hours, and filter; (2) Alkali treatment: Adjust the pH of the filtrate to 7.0 - 14 with alkali; (3) Separation: Add industrial sodium chloride according to 5 - 30% of the weight of the filtrate volume, stir to dissolve, let stand for 12 - 36 hours, siphon off the supernatant and discard it, and centrifuge the lower precipitate to obtain the crude palmatine hydrochloride; (4) Alcohol treatment: Reflux and extract the crude product with 8 - 20 times the amount of ethanol for 10 - 60 minutes, and filter while it is hot; (5) Concentration: Concentrate to 3 - 8 times that of the crude alkali; (6) Acid treatment: Adjust the pH to 1 - 5 with acid, let stand, cool, precipitate yellow needle crystals, filter by suction, and dry to obtain palmatine hydrochloride; (7) Water treatment: Dissolve palmatine hydrochloride by heating with 20 - 60 times the amount of water; (8) Alkali treatment: Adjust the pH to 7.0 - 14 with alkali and filter; (9) Separation: Add sodium chloride, precipitate will form, let stand for 12 - 48 hours, siphon off the supernatant and discard it, filter the lower precipitate, and dry to obtain the refined palmatine hydrochloride. Although the above patent application realizes the extraction of palmatine hydrochloride, it uses dilute sulfuric acid for impregnation extraction at room temperature, resulting in a longer production cycle; salting out under alkaline conditions is prone to browning, deepening the color of the product; adding sodium chloride according to the volume of the extraction liquid requires a large amount of salt, which is likely to cause environmental pollution; more importantly, it only involves the preparation of a single component of palmatine hydrochloride and does not involve the simultaneous preparation of berberine hydrochloride and jatrorrhizine hydrochloride.

[0004] In view of this, it is necessary to provide a method for producing berberine, palmatine, and jatrorrhizine hydrochloride based on fibraureae caulis to solve or at least alleviate the technical problem of how to simultaneously prepare berberine hydrochloride, palmatine hydrochloride, and jatrorrhizine hydrochloride from fibraureae caulis and achieve efficient production. Summary of the Invention

[0005] The main object of the present invention is to provide a method for producing berberine, palmatine, and jatrorrhizine hydrochloride based on fibraureae caulis, aiming to solve the technical problem of how to simultaneously prepare berberine hydrochloride, palmatine hydrochloride, and jatrorrhizine hydrochloride from fibraureae caulis and achieve efficient production.

[0006] To achieve the above object, the present invention provides a method for producing berberine, palmatine, and jatrorrhizine hydrochloride based on fibraureae caulis, including the steps:

[0007] S1, providing a powder derived from fibraureae caulis and containing berberine, palmatine, and jatrorrhizine;

[0008] S2, subjecting the powder to leaching to obtain an extraction liquid;

[0009] S3, sequentially filtering, ultrafiltering, and nanofiltrating the extraction liquid, and taking the upstream liquid of the membrane after nanofiltration;

[0010] S4. Adjust the pH of the upstream solution of the membrane to 6 - 8 with an alkaline solution. After filtration, adjust the pH to 2 - 3 with a hydrochloric acid solution, let it stand at 25 - 30 °C and then filter to collect the first wet precipitate and the first mother liquor. Add an ethanol solution with a concentration of 60 - 65% to the first wet precipitate, heat to dissolve, let it stand and then filter to collect the second wet precipitate and the second mother liquor. Adjust the ethanol concentration in the second mother liquor to 60 - 65%, let it stand and then filter to collect the third wet precipitate and the third mother liquor. The first mother liquor and the third mother liquor are combined to obtain the berberine crystallization mother liquor. The second wet precipitate and the third wet precipitate are combined to obtain the wet precipitate containing berberine hydrochloride.

[0011] S5. Concentrate the berberine crystallization mother liquor, let it stand and then filter to obtain the fourth wet precipitate and the fourth mother liquor. Add an ethanol solution with a concentration of 60 - 65% to the fourth wet precipitate, heat to dissolve, let it stand and then filter to collect the fifth wet precipitate and the fifth mother liquor. Adjust the ethanol concentration in the fifth mother liquor to 60 - 65%, let it stand and then filter to collect the sixth wet precipitate and the sixth mother liquor. The fourth mother liquor and the sixth mother liquor are combined to obtain the palmatine crystallization mother liquor. The fifth wet precipitate and the sixth wet precipitate are combined to obtain the wet precipitate containing palmatine hydrochloride.

[0012] S6. Concentrate the palmatine crystallization mother liquor to obtain a concentrated solution. Pass the concentrated solution through an anion exchange resin column, pass the collected feed effluent through a macroporous adsorption resin column, collect the eluate after desorption. Concentrate the eluate and adjust the pH to 4 - 6 with a hydrochloric acid solution to obtain the refined solution of combined resin containing jatrorrhizine hydrochloride.

[0013] Furthermore, in the form of mass percentage and hydrochloride, in the powder material, the content of berberine hydrochloride is 1.5 - 3%, the content of palmatine hydrochloride is 2 - 4.5%, and the content of jatrorrhizine hydrochloride is 0.4 - 1.0%.

[0014] Furthermore, in step S2, leaching is carried out with a sulfuric acid solution containing an antioxidant protector. The concentration of the sulfuric acid solution is 0.2 - 0.7%, the leaching temperature is 50 - 65 °C. The antioxidant protector includes vitamin C and ferrous sulfate, and the mass ratio of vitamin C to ferrous sulfate is 1 - 3:1. The mass percentage of the antioxidant protector to the powder material is 1.0 - 4.0%.

[0015] Further, in the step S2, the number of leaching times is three. When performing the first leaching, control the ratio of the sulfuric acid solution to the powder material as 5 - 7 mL: 1 g, leach the powder material in the sulfuric acid solution for 2 - 4 h, filter and collect the first filtrate and the first filter residue. When performing the second leaching, control the ratio of the sulfuric acid solution to the powder material as 4 - 6 mL: 1 g, leach the first filter residue in the sulfuric acid solution for 1 - 3 h, filter and collect the second filtrate and the second filter residue. When performing the third leaching, control the ratio of the sulfuric acid solution to the powder material as 5 - 7 mL: 1 g, leach the second filter residue in the sulfuric acid solution for 0.5 - 1.5 h, filter and collect the third filtrate. Combine the first filtrate and the second filtrate as the extraction solution, and use the third filtrate for leaching the powder material in the next batch.

[0016] Further, in the step S3, the filtration process includes: controlling the temperature of the extraction solution as 60 - 65 °C; subjecting the extraction solution to primary filtration and microfiltration in sequence to obtain a clear solution.

[0017] The ultrafiltration process includes: controlling the temperature of the clear solution as 60 - 65 °C; adjusting the pH of the clear solution to 1 - 5 with an alkali solution, and then passing the clear solution through a high-temperature ultrafiltration membrane to collect the downstream solution of the membrane. The maximum temperature that the high-temperature ultrafiltration membrane can withstand is not lower than 70 °C, and the cut-off molecular weight of the high-temperature ultrafiltration membrane is 3 - 5 KD.

[0018] The nanofiltration process includes: controlling the temperature of the downstream solution of the membrane as 60 - 65 °C; passing the downstream solution of the membrane through a high-temperature nanofiltration membrane to collect the upstream solution of the membrane, and the upstream solution of the membrane is the membrane-refined solution. The maximum temperature that the high-temperature nanofiltration membrane can withstand is not lower than 70 °C, and the cut-off molecular weight of the high-temperature nanofiltration membrane is 150 - 300 D.

[0019] Further, in the step S4, add an ethanol solution with a concentration of 60 - 65% to the first wet precipitate at a ratio of 1 g: 12 - 15 mL.

[0020] In the step S4, the process of making the ethanol concentration in the second mother liquor reach 60 - 65% includes: concentrating the second mother liquor to 1 / 5 - 1 / 4 of the original volume, and then adding ethanol to the second mother liquor to make the ethanol concentration in the second mother liquor reach 60 - 65%.

[0021] Further, in the step S5, the process of concentrating the berberine crystallization mother liquor includes: concentrating the berberine crystallization mother liquor to 1 / 2 - 1 / 3 of the original volume.

[0022] In the step S5, add an ethanol solution with a concentration of 60 - 65% to the fourth wet precipitate at a ratio of 1 g: 12 - 15 mL.

[0023] In step S5, the process of making the ethanol concentration in the fifth mother liquor reach 60-65% includes: concentrating the fifth mother liquor to 1 / 5-1 / 4 of the original volume, and then adding ethanol to the fifth mother liquor to make the ethanol concentration in the fifth mother liquor reach 60-65%.

[0024] Furthermore, in step S6, the process of concentrating the palmatine crystallization mother liquor includes: concentrating the palmatine crystallization mother liquor until there is no alcohol smell, and controlling the Brix of the palmatine crystallization mother liquor to be 1-3 Brix;

[0025] In step S6, desorption is carried out with an ethanol solution having a concentration of 40-45%;

[0026] In step S6, the process of concentrating the desorbed solution includes: concentrating the desorbed solution to 17-25 Baume degrees;

[0027] Step S6 further includes: after the concentrated solution enters the anion exchange resin column, washing the column with purified water, collecting the washing solution of the column, combining the feed effluent and the washing solution of the column as the ion exchange resin decolorizing solution, and jointly entering the macroporous adsorption resin column; after the ion exchange resin decolorizing solution enters the macroporous adsorption resin column, before carrying out the desorption, washing the column with purified water.

[0028] Furthermore, the anion exchange resin column includes a basic anion exchange resin, and the basic anion exchange resin includes one of a gel-type acrylic strong base anion resin, a gel-type acrylic weak base anion resin, a gel-type styrene strong base anion resin, a gel-type styrene weak base anion resin, a macroporous acrylic strong base anion resin, a macroporous acrylic weak base anion resin, a macroporous styrene strong base anion resin, and a macroporous styrene weak base anion resin; the macroporous adsorption resin column includes one of a non-polar macroporous adsorption resin and a weakly polar macroporous adsorption resin.

[0029] Furthermore, the wet precipitate containing berberine hydrochloride is dried to obtain a berberine hydrochloride product; the wet precipitate containing palmatine hydrochloride is dried to obtain a palmatine hydrochloride product; the combined resin refining solution containing jatrorrhizine hydrochloride is dried to obtain a jatrorrhizine hydrochloride product.

[0030] Compared with the prior art, the present invention has at least the following advantages:

[0031] 1. The present invention can simultaneously extract and isolate berberine hydrochloride, palmatine hydrochloride, and jatrorrhizine hydrochloride from Fibraurea recisa Pierre; the present invention has discovered a high-quality type of Fibraurea recisa Pierre imported from Laos, which not only contains a certain amount of palmatine hydrochloride and jatrorrhizine hydrochloride, but also contains 1.5 - 3% of berberine hydrochloride; in existing research, there has been no report on the content of berberine hydrochloride in Fibraurea recisa Pierre, only reports on the contents of palmatine hydrochloride and jatrorrhizine. Based on the improvement of specific Fibraurea recisa Pierre and the overall technical solution, the present invention creatively realizes the simultaneous extraction and isolation of berberine hydrochloride, palmatine hydrochloride, and jatrorrhizine hydrochloride, and both the yield and purity are relatively high.

[0032] 2. The present invention can continuously produce berberine hydrochloride, palmatine, and jatrorrhizine industrially, forming an industrialized production technology system for the extraction, separation, and intensive processing of Fibraurea recisa Pierre, solving the technical problem that traditional technologies only focus on palmatine hydrochloride (fibrauretin) and rarely prepare jatrorrhizine hydrochloride simultaneously, and pioneering an industrial production technology for simultaneously preparing three alkaloid monomer components from Fibraurea recisa Pierre, realizing the comprehensive utilization of resources and creating good economic and social benefits.

[0033] 3. The present invention can significantly shorten the extraction time, improve production efficiency, and reduce equipment occupation; the present invention extracts with dilute sulfuric acid at 50 - 65°C, shortening the impregnation extraction time of the traditional process from 24 - 72 hours to within 10 hours.

[0034] 4. The present invention uses temperature-controlled special high-temperature ultrafiltration membrane separation and nanofiltration membrane concentration and refinement to replace salting-out, solving the problem of environmental pollution caused by salt wastewater; at the same time, by combining temperature control with the degree of concentration, standing time, crystallization and recrystallization, and stepwise crystallization techniques, berberine hydrochloride, palmatine, and jatrorrhizine are separated in sequence, solving the problem that it is difficult to separate and purify monomer alkaloids caused by all alkaloids precipitating out during salting-out.

[0035] 5. The present invention adds antioxidant protectants during the extraction stage, combines temperature control and membrane separation, crystallization and recrystallization, and stepwise crystallization, and resin combination technology, avoiding the adsorption loss of alkaloids caused by using activated carbon for decolorization. While increasing the product yield, yellow berberine hydrochloride, palmatine hydrochloride, and red-yellow jatrorrhizine hydrochloride are prepared, solving the problem of poor product color in the market.

[0036] 6. The present invention does not use organic solvents other than water and ethanol, and does not use high-cost extraction and separation technologies such as alumina and silica gel chromatography. The process steps are few, improving the operability and safety of production. Detailed implementation manners

[0037] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts belong to the scope of protection of the present invention.

[0038] Moreover, the technical solutions between various embodiments of the present invention can be combined with each other, but it must be based on the ability of those of ordinary skill in the art to implement. When the combination of technical solutions results in contradictions or cannot be implemented, it should be considered that such a combination of technical solutions does not exist and is not within the scope of protection required by the present invention.

[0039] When the embodiments give a numerical range, it should be understood that unless otherwise specified in the present invention, both endpoints of each numerical range and any value between the two endpoints can be selected. Unless otherwise defined, all technical and scientific terms used in the present invention, based on the understanding of those skilled in the art of the prior art and the description of the present invention, any method, device, and material similar to or equivalent to the methods, devices, and materials described in the embodiments of the present invention can also be used to implement the present invention.

[0040] The Fibraurea recisa Pierre used in the present invention was purchased from Laos, and the harvesting time was late November. The purified water used was prepared by a pure water machine. The ethanol, ion exchange resin, and macroporous adsorption resin used were obtained through conventional commercial channels unless otherwise specified. In the present invention, the concentration of the sulfuric acid solution is the volume concentration, the concentration of the hydrochloric acid solution is the volume concentration, the concentration of the sodium hydroxide solution is the mass concentration, and the concentration of the ethanol is the volume concentration, and all are prepared with water.

[0041] In the present invention, the contents of berberine hydrochloride, palmatine hydrochloride (fibrauretin), and jatrorrhizine hydrochloride are separately determined according to the high performance liquid chromatography (HPLC) method under the items of "berberine hydrochloride", "fibrauretin", and "berberine hydrochloride" in the Chinese Pharmacopoeia 2020 Edition; the simultaneous determination of the above 3 alkaloids at one time refers to the high performance liquid chromatography (HPLC) method under the item of "Mahonia bealei (Fort.) Carr." in the Chinese Pharmacopoeia 2020 Edition. It should be clear that although the Fibraurea recisa Pierre in the present invention contains berberine, palmatine, and jatrorrhizine, the unified standard for determining the content in the Chinese Pharmacopoeia 2020 Edition is hydrochloride. Therefore, when expressing the substance contents of berberine, palmatine, and jatrorrhizine in Fibraurea recisa Pierre in the present invention, they are calculated in the form of hydrochloride; and after the production in the present invention, the obtained substances are berberine hydrochloride, palmatine hydrochloride, and jatrorrhizine hydrochloride.

[0042] It was accidentally discovered during the research of the present invention that compared with domestic Fibraurea recisa Pierre, certain Fibraurea recisa Pierre from Laos has comparable contents of palmatine hydrochloride and jatrorrhizine hydrochloride, but the Fibraurea recisa Pierre produced in Laos also contains 1.5 - 3% of berberine hydrochloride. There is no report in the current literature that Fibraurea recisa Pierre contains such a high content of berberine hydrochloride. Through actual analysis and testing, the content of berberine hydrochloride in the imported Fibraurea recisa Pierre from Laos is 2.37%, the content of palmatine hydrochloride is 2.21%, and the content of jatrorrhizine hydrochloride is 0.79%. This result has overturned the understanding of Fibraurea recisa Pierre medicinal materials. Due to the relatively high content of 3 alkaloids in the Fibraurea recisa Pierre medicinal materials from Laos and the imported price being the same as that of domestic ones, it has the highest cost performance. Considering the sustainability of extraction and processing and the comprehensive utilization of medicinal material resources, Fibraurea recisa Pierre from Laos can not only be used as a conventional Chinese medicinal material, but also as a stable extraction raw material to mass-produce and prepare 3 products with high added value, namely berberine hydrochloride, palmatine hydrochloride, and jatrorrhizine hydrochloride, thus generating relatively high economic benefits and good social benefits.

[0043] The specific information of berberine hydrochloride, palmatine hydrochloride, and jatrorrhizine hydrochloride is as follows:

[0044] Berberine hydrochloride: Also known as berberine hydrochloride, it is a yellow crystalline powder with an extremely bitter taste. It is easily soluble in boiling water, soluble in hot water, slightly soluble in cold water, and almost insoluble in cold ethanol, chloroform, and ether; it is mainly used as an antibacterial drug and is clinically mainly used for intestinal infections and bacillary dysentery, etc., and has the effect of anti-arrhythmia;

[0045] Chinese name: Berberine hydrochloride;

[0046] English name: Berberine;

[0047] CAS Number: 633 - 65 - 8;

[0048] Molecular formula: C 20 H 18 ClNO4;

[0049] Molecular weight: 372.82.

[0050] Palmatine hydrochloride: Also known as fibrauretin, it is a yellow needle-like crystal with an extremely bitter taste. It is easily soluble in hot water, slightly soluble in water, slightly soluble in ethanol and chloroform, and almost insoluble in ether; it is mainly used as an antibacterial and antiviral drug and is clinically mainly used for gynecological inflammation, bacillary dysentery, enteritis, respiratory and urinary tract infections, surgical infections, and ophthalmic conjunctivitis;

[0051] Chinese name: Palmatine hydrochloride;

[0052] English name: Palmatine;

[0053] CAS Number: 3486 - 67 - 7;

[0054] Molecular formula: C 21 H 22 ClNO4;

[0055] Molecular weight: 387.86.

[0056] Jatrorrhizine hydrochloride: Also known as jatrorrhizine, it is a red-yellow needle crystal, extremely bitter in taste, soluble in water and ethanol; it has the effects of detoxification, sterilization, hypoglycemic and positive inotropic effects;

[0057] Chinese name: Jatrorrhizine hydrochloride;

[0058] English name: Jatrorrhizine;

[0059] CAS Number: 3621-38-3;

[0060] Molecular formula: C 20 H 20 ClNO4;

[0061] Molecular weight: 465.28.

[0062] It should be noted that existing research mainly focuses on the extraction and purification of berberine single component, and there are very few reports on the simultaneous preparation of jatrorrhizine hydrochloride, and there is no report on the simultaneous preparation of berberine hydrochloride; the extraction solvents in existing research mainly include dilute sulfuric acid, acetic acid and organic solvents. In comparison, the production cost of acid extraction is relatively low, but the time consumption is long, and it is relatively easy to separate and purify, which is more suitable for industrial production; existing research generally has salting out under alkaline conditions, which is prone to browning and deepens the color of the product; in existing research, the dosage of sodium chloride salting out is relatively large, which is easy to pollute the environment. In addition, some existing research uses macroporous adsorption resin for purification, but due to the lack of pretreatment, the macroporous adsorption resin is seriously polluted by dyeing, and the resin regeneration treatment is difficult; some existing research uses silica gel, alumina, and organic solvents such as n-butanol to prepare high-purity berberine and jatrorrhizine, resulting in high preparation costs and being difficult to achieve in production; existing research as a whole focuses on experimental techniques, and there is still a certain distance from industrial production. Therefore, with the upgrading and improvement of technology, and based on the simultaneous separation and extraction of berberine hydrochloride, palmatine hydrochloride and jatrorrhizine hydrochloride, it is necessary to establish a relatively complete industrial production comprehensive utilization technology system for the extraction, separation and intensive processing of fibraurea recisa pierre.

[0063] The present invention mainly realizes the efficient production of berberine hydrochloride, palmatine hydrochloride, and jatrorrhizine hydrochloride through the following aspects: (1) obtaining high-quality Fibraureae Recisae raw materials to achieve sustainable production; (2) comprehensively utilizing the Fibraureae Recisae medicinal material resources to continuously prepare the alkaloid monomer components with relatively high contents therein, reducing production costs; (3) improving production efficiency, reducing equipment occupation, and changing the traditional long-time maceration extraction process; (4) adding as little salt as possible or no salt to reduce the pollution of salt wastewater to the environment; (5) improving the product color and reducing the process steps that deepen the color during the production and processing process, or simplifying the decolorization steps; (6) preparing berberine hydrochloride and palmatine alkaloid monomer components with a content of more than 90%, and jatrorrhizine hydrochloride with a content of more than 80%, avoiding the use of organic solvents other than ethanol, and improving the operability and safety of production.

[0064] The present invention provides a method for producing berberine, palmatine, and jatrorrhizine hydrochloride based on Fibraureae Recisae, and the steps are as follows:

[0065] S1, Crushing:

[0066] Crush the dry vine stems of the Fibraureae Recisae medicinal materials into coarse powder basically the size of grains; that is, provide the powder of Fibraureae Recisae (such as 500 - 1000 kg); the powder contains berberine, palmatine, and jatrorrhizine. In terms of mass ratio and the form of hydrochloride, in the powder, the content of berberine hydrochloride is 1.5 - 3%, the content of palmatine hydrochloride is 2 - 4.5%, and the content of jatrorrhizine hydrochloride is 0.4 - 1.0%.

[0067] S2, Dilute acid warm extraction:

[0068] Use a sulfuric acid solution containing an antioxidant protector to extract the powder, and obtain an extract after filtration; the concentration of the sulfuric acid solution is 0.2 - 0.7%, the temperature of the extraction is 50 - 65 °C, and the total duration of the extraction can be 5 - 8 h. The antioxidant protector includes vitamin C and ferrous sulfate, and the mass ratio of vitamin C to ferrous sulfate is 1 - 3:1; the mass percentage of the antioxidant protector (total addition amount during extraction) to the powder is 1.0 - 4.0%; the stirring method in the extraction process of the present invention can be: start stirring every 10 min or perform air pressure backwashing for 2 min.

[0069] In this step, the number of extraction times can be three; when performing the first extraction, control the ratio of the sulfuric acid solution to the powder to be 5 - 7 mL:1 g, extract the powder in the sulfuric acid solution for 2 - 4 h, and collect the first filtrate and the first filter residue after filtration; when performing the second extraction, control the ratio of the sulfuric acid solution to the powder to be 4 - 6 mL:1 g, extract the first filter residue in the sulfuric acid solution for 1 - 3 h, and collect the second filtrate and the second filter residue after filtration; merge the first filtrate and the second filtrate as the extract.

[0070] In this step, the number of leaching times can also be 3 times. The third leaching is a nested leaching, that is, the filtrate after the third leaching is used for leaching the next batch of the powder material. When performing the third leaching, control the ratio of the sulfuric acid solution to the powder material to be 5 - 7 mL:1 g, leach the second filter residue in the sulfuric acid solution for 0.5 - 1.5 h, and collect the third filtrate and the third filter residue after filtration; and use the third filtrate for leaching the next batch of the powder material.

[0071] In the present invention, when performing the first leaching, the mass percentage of the antioxidant protector to the powder material is 1.0 - 3.0%; when performing the second leaching, the mass percentage of the antioxidant protector to the powder material is 0.5 - 1.0%; when performing the third leaching, the mass percentage of the antioxidant protector to the powder material is 0.3 - 0.5%.

[0072] S3, Temperature-controlled Filtration Clarification and Membrane Separation:

[0073] S31, Control the temperature of the extract to be 60 - 65 °C, filter the extract to obtain a clear liquid; the process of filtering the extract includes: first performing primary filtration on the extract, and then performing microfiltration through a ceramic membrane with a pore size of 200 - 800 nm; the specific operation can be: first performing centrifugation with a three-foot cloth bag or plate-frame filtration, and then clarifying the filtrate through a ceramic membrane made of alumina or zirconia with a pore size of 200 - 800 nm.

[0074] In the present invention, when performing microfiltration of the liquid after primary filtration through the ceramic membrane, when the volume of the upstream liquid only remains 1 / 30 - 1 / 40 of the extract, add hot water (the volume of the hot water is 1.5 - 2.5 times the remaining volume of the upstream liquid, and the temperature is 60 - 65 °C) to dilute the upstream liquid, and continue to pass through the membrane; when the volume of the upstream liquid only remains 1 / 30 - 1 / 40 of the extract again, add hot water (the volume of the hot water is 1.5 - 2.5 times the remaining volume of the upstream liquid, and the temperature is 60 - 65 °C) to dilute the upstream liquid again, and continue to pass through the membrane.

[0075] S32, Control the temperature of the clear liquid to be 60 - 65 °C, adjust the pH of the clear liquid to 1 - 5 using an alkali solution, and then pass the clear liquid through a high-temperature ultrafiltration membrane, and collect the downstream liquid of the membrane; the maximum temperature that the high-temperature ultrafiltration membrane can withstand is not lower than 70 °C, and the cut-off molecular weight of the high-temperature ultrafiltration membrane is 3 - 5 KD.

[0076] In the present invention, when passing the clear liquid through the high-temperature ultrafiltration membrane, when the volume of the upstream liquid remains only 1 / 30 to 1 / 40 of the extraction liquid, hot water (the volume of the hot water is 1.5 to 2.5 times that of the remaining upstream liquid, and the temperature is 60 to 65 °C) is added to the upstream liquid for dilution, and then continue to pass through the membrane; when the volume of the upstream liquid remains only 1 / 30 to 1 / 40 of the extraction liquid again, hot water (the volume of the hot water is 1.5 to 2.5 times that of the remaining upstream liquid, and the temperature is 60 to 65 °C) is added to the upstream liquid for dilution again, and then continue to pass through the membrane.

[0077] S33, control the temperature of the downstream liquid of the membrane to be 60 to 65 °C, pass the downstream liquid of the membrane through the high-temperature nanofiltration membrane, collect the upstream liquid of the membrane, and use the upstream liquid of the membrane as the membrane-refined liquid; the maximum temperature that the high-temperature nanofiltration membrane can withstand is not lower than 70 °C, the cut-off molecular weight of the high-temperature nanofiltration membrane is 150 to 300 D, specifically 200 D.

[0078] As a further illustration, in this step, the maximum temperature that the high-temperature ultrafiltration membrane and the high-temperature nanofiltration membrane can withstand is 70 °C, and the alkali solution is a sodium hydroxide solution with a concentration of 1 to 3%.

[0079] S4, separate berberine hydrochloride:

[0080] S41, adjust the pH of the membrane-refined liquid to 6 to 8 (specifically 7) with an alkali solution, then filter to obtain the filtered liquid; adjust the pH of the filtered liquid to 2 to 3 with a hydrochloric acid solution, naturally cool, and stand at 25 to 30 °C for at least 48 h or stand for 48 to 72 h to fully precipitate the precipitate; after standing, filter to collect the first wet precipitate and the first mother liquor.

[0081] S42, add an ethanol solution with a concentration of 60 to 65% to the first wet precipitate at a ratio of 1 g: 12 to 15 mL, and heat to 80 °C to 90 °C; when the first wet precipitate is completely dissolved, naturally cool, and stand at 5 to 25 °C for at least 20 h or stand for 22 to 26 h; after standing, filter to collect the second wet precipitate and the second mother liquor.

[0082] S43, concentrate the second mother liquor to 1 / 5 to 1 / 4 of the original volume, and the concentration method can be vacuum decompression concentration; then add high-proof ethanol to the second mother liquor to make the ethanol concentration in the second mother liquor reach 60 to 65%; stand the second mother liquor at 5 to 25 °C for at least 20 h or stand for 22 to 26 h, and after standing, filter to collect the third wet precipitate and the third mother liquor.

[0083] S44, combine the first mother liquor and the third mother liquor to obtain the berberine crystallization mother liquor; combine the second wet precipitate and the third wet precipitate to obtain the wet precipitate containing berberine hydrochloride.

[0084] As a further illustration, in this step, the filtration method can be suction filtration or plate and frame filtration; the lye is a sodium hydroxide solution with a concentration of 1-3%; the concentration of the hydrochloric acid solution is 1-3%.

[0085] S5. Separate palmatine hydrochloride:

[0086] S51. Concentrate the berberine crystallization mother liquor to 1 / 2-1 / 3 of the original volume (at this time, the Brix of the concentrated solution is usually 4-6 Brix), and let it stand at 5-25°C for at least 48 h or 48-72 h to fully precipitate the sediment. The concentration method can be vacuum concentration; after standing, filter to obtain the fourth wet sediment and the fourth mother liquor.

[0087] S52. Add an ethanol solution with a concentration of 60-65% to the fourth wet sediment at a ratio of 1 g:12-15 mL, and heat to 80°C-90°C; when the fourth wet sediment is completely dissolved, cool naturally and let it stand at 5-25°C for at least 20 h or 22-26 h; after standing, filter to collect the fifth wet sediment and the fifth mother liquor.

[0088] S53. Concentrate the fifth mother liquor to 1 / 5-1 / 4 of the original volume. The concentration method can be vacuum concentration; then add high-proof ethanol to the fifth mother liquor to make the ethanol concentration in the fifth mother liquor reach 60-65%; let the fifth mother liquor stand at 5-25°C for at least 20 h or 22-26 h, and after standing, filter to collect the sixth wet sediment and the sixth mother liquor.

[0089] S54. Combine the fourth mother liquor and the sixth mother liquor to obtain the palmatine crystallization mother liquor; combine the fifth wet sediment and the sixth wet sediment to obtain the wet sediment containing palmatine hydrochloride.

[0090] As a further illustration, in this step, the filtration method can be suction filtration or plate and frame filtration.

[0091] S6. Use ion exchange resin and macroporous adsorption resin chromatography in combination to separate jatrorrhizine hydrochloride:

[0092] S61. Concentrate the palmatine crystallization mother liquor until it has no alcohol smell and control the Brix of the palmatine crystallization mother liquor to 1-3 Brix to obtain the concentrated solution; specifically, vacuum-concentrate the palmatine crystallization mother liquor to recover ethanol until it has no alcohol smell, and continue to concentrate to 1-3 Brix to obtain the concentrated solution.

[0093] S62. Feed the concentrated solution into an anion exchange resin column at room temperature (such as 5 - 25 °C), collect the feed effluent, and use the feed effluent as the decolorized solution of the ion exchange resin. As a preferred embodiment, after feeding the concentrated solution into the anion exchange resin column, the column can be washed with 3 - 5 BV of purified water, and the 0 - 3 BV of the column wash solution is collected. The feed effluent and the column wash solution are combined as the decolorized solution of the ion exchange resin.

[0094] In the present invention, the resin in the anion exchange resin column includes or is a basic anion exchange resin, and the basic anion exchange resin includes one of a gel - type acrylic strong - base anion resin, a gel - type acrylic weak - base anion resin, a gel - type styrene strong - base anion resin, a gel - type styrene weak - base anion resin, a macroporous acrylic strong - base anion resin, a macroporous acrylic weak - base anion resin, a macroporous styrene strong - base anion resin, and a macroporous styrene weak - base anion resin.

[0095] S63. Feed the decolorized solution of the ion exchange resin into a macroporous adsorption resin column, then desorb with an ethanol solution with a concentration of 40 - 45%, and collect the desorbed solution. Concentrate the desorbed solution to 17 - 25 Baumé, and then adjust the pH to 4 - 6 with a hydrochloric acid solution to obtain a refined solution of combined resin containing jatrorrhizine hydrochloride. As a preferred embodiment, after feeding the decolorized solution of the ion exchange resin into the macroporous adsorption resin column and before desorption, the column can be washed with 2 - 4 BV of purified water. In the present invention, the resin in the macroporous adsorption resin column includes or is one of a non - polar macroporous adsorption resin and a weakly polar macroporous adsorption resin. In this step, the concentration of the hydrochloric acid solution is 1 - 3%.

[0096] S7. Drying:

[0097] Dry the wet precipitate containing berberine hydrochloride to obtain a berberine hydrochloride product; dry the wet precipitate containing palmatine hydrochloride to obtain a palmatine hydrochloride product; dry the refined solution of combined resin containing jatrorrhizine hydrochloride to obtain a jatrorrhizine hydrochloride product. Specifically, vacuum - dry or microwave - vacuum - dry the wet precipitate containing berberine hydrochloride, the wet precipitate containing palmatine hydrochloride, and the refined solution of combined resin containing jatrorrhizine hydrochloride at a temperature of 60 °C - 65 °C and a vacuum degree of ≥ - 0.085 MPa to obtain bright - yellow berberine hydrochloride and palmatine hydrochloride, and red - yellow jatrorrhizine hydrochloride. Specifically, the berberine hydrochloride product and the palmatine hydrochloride product are yellow powders, and the jatrorrhizine hydrochloride product is a red - yellow powder and is orange - red.

[0098] In step S2 of the present invention, the concentration of the sulfuric acid solution is 0.2 - 0.7%. If it is too low, the dosage is too large; if it is too high, it will cause waste and increase production costs, and there will be obvious acid corrosion to the pipeline system.

[0099] In step S2 of the present invention, the extraction temperature is 50 - 65°C. In the traditional process, room-temperature dilute acid extraction is used, which takes 24 - 72 hours, has a long production cycle, seriously occupies equipment, and has low efficiency. When the temperature exceeds 75°C, the color of the acid extract significantly deepens, which is not conducive to product decolorization and purification, and also damages the alkaloids, reducing the content of the extract, and the higher the temperature, the more obvious it is. The extraction temperature in the present invention can quickly extract the three alkaloid components, with stable content, short time, and high extraction efficiency.

[0100] In step S2 of the present invention, the antioxidant protector is a substance obtained by compounding vitamin C and ferrous sulfate in a certain proportion, specifically, vitamin C and ferrous sulfate are combined in a mass ratio of 1 - 3:1. It should be noted that adding a specific antioxidant protector, especially a compound substance, can not only slow down the deepening of the extract color, but also keep the alkaloid components stable and not easily damaged in a heating environment of 50 - 65°C, which is conducive to decolorization and refining.

[0101] In step S3 of the present invention, the temperature is maintained at 60 - 65°C. At this temperature, the sulfates of fibrauretin alkaloids, especially berberine, palmatine, and jatrorrhizine, have a large solubility and are not easily precipitated, which is conducive to membrane separation and purification. When the temperature is at room temperature, the extract will become turbid and have post-precipitation, and in severe cases, it will block the membrane pores and damage the equipment. When the temperature is too high, it is not conducive to the stable content of the alkaloid components, and it also exceeds the maximum temperature that a special membrane can withstand, so the membrane separation technology cannot be used to purify the alkaloids.

[0102] In step S3 of the present invention, after primary filtration, microfiltration clarification is carried out through a ceramic membrane with a pore size of 200 - 800 nm; at 60 - 65°C, through microfiltration clarification with this pore size ceramic membrane, the precipitate in the extract can be removed to obtain a clear and transparent supernatant without post-precipitation, which is conducive to membrane separation and purification.

[0103] In step S3 of the present invention, the highest temperature that the high-temperature ultrafiltration membrane can withstand can reach 70°C, and the cut-off molecular weight is about 5KD. It is prepared by using a unique high-temperature resistant membrane filament and paper membrane process. The membrane material of the high-temperature ultrafiltration membrane is PES or PVDF, and the model is the UE series (such as UE005 - 8040H). It should be noted that only special specifications of ultrafiltration membranes can preliminarily purify fibrauretin alkaloids. Because the highest temperature that a common ultrafiltration membrane can withstand is 45°C, and at 45°C, due to the solubility differences of different alkaloid sulfates, when the ultrafiltration membrane operates to a smaller volume, alkaloids and other impurities will precipitate and block the membrane pores, which not only damages the equipment and makes the process impossible to proceed, but also reduces the product yield. In the present invention, with a cut-off molecular weight of about 5KD, most impurities and pigments can be removed, while fibrauretin alkaloids can completely pass through, thus obtaining a higher purity of total fibrauretin alkaloids.

[0104] In step S3 of the present invention, the high-temperature nanofiltration membrane can withstand a maximum temperature of up to 70 °C, and the molecular weight cut-off is about 200 D. The membrane material of the high-temperature nanofiltration membrane is PES, UF series (such as UF8040). It should be noted that only specific types of nanofiltration membranes can concentrate the ultrafiltration membrane separation liquid of fibrauretin alkaloids. Because the maximum temperature that ordinary nanofiltration membranes can withstand is 45 °C, and at 45 °C, due to the solubility differences of different alkaloid sulfates, alkaloids and other impurities will precipitate and block the membrane pores during the nanofiltration membrane concentration process, which will not only damage the equipment and make the process impossible to proceed, but also reduce the product yield; with a molecular weight cut-off of about 200 D, fibrauretin alkaloids can be completely retained; at 60-65 °C, high-temperature nanofiltration membrane concentration can replace traditional vacuum decompression concentration, thereby obtaining a membrane-refined liquid.

[0105] In step S4 of the present invention, before the berberine hydrochloride crystallizes, the pH of the membrane-refined liquid needs to be adjusted to 6-8 with dilute alkali, filtered, and then the pH is adjusted to 2-3 with dilute hydrochloric acid. It should be noted that the solubility of fibrauretin alkaloid sulfate is greater than that of hydrochloride, and the solubility differences of sulfate of berberine, palmatine and jatrorrhizine are not significant, which is not conducive to the crystallization and precipitation of monomeric alkaloids; while the solubility of hydrochloride in cold and hot water has a large difference. Therefore, hydrochloride is beneficial to separation and purification, and the sulfate needs to be converted into hydrochloride.

[0106] In step S4 of the present invention, the crystallization conditions of berberine hydrochloride are to naturally cool to 25-30 °C and keep warm for at least 48 h or 48-72 h; the recrystallization conditions are 60-65% ethanol, heating at 80-90 °C to completely dissolve the precipitate, and after natural cooling, standing for at least 20 h or 22-26 h. It should be noted that after separation and concentration with high-temperature ultrafiltration membranes and nanofiltration membranes in the above-mentioned process, after naturally cooling to 25-30 °C and standing and precipitating for enough time, berberine hydrochloride crystallizes first, while only a small amount of palmatine hydrochloride precipitates, and jatrorrhizine hydrochloride does not precipitate. The method of high-temperature membrane separation and temperature-controlled crystallization, due to improving the purity of fibrauretin alkaloids and controlling the temperature, can not only replace salting-out to completely precipitate berberine hydrochloride, but also obtain high-purity berberine hydrochloride crystals, avoiding the defects that salting-out precipitates all alkaloids and increases the difficulty of later purification and the large amount of salt pollutes the environment. As the crystallization temperature decreases, the precipitation amount of palmatine hydrochloride increases, which is instead not conducive to the recrystallization and purification of berberine hydrochloride. Therefore, temperature control is very important. In the present invention, recrystallization with 60-65% ethanol and stepwise crystallization can obtain berberine hydrochloride with a purity of more than 97%, and at the same time solve the practical problem that traditional processes are not easy to recover highly concentrated ethanol due to the use of ethanol with a concentration of more than 80%, and are completely separated from the small amount of palmatine hydrochloride precipitated in the crystallization stage.

[0107] In step S5 of the present invention, the crystallization conditions of palmatine hydrochloride are to concentrate the crystallization mother liquor of berberine hydrochloride, and after natural cooling, let it stand for at least 48 h or 48 - 72 h; the recrystallization conditions are 60 - 65% ethanol, heat to dissolve the precipitate completely at 80 - 90 °C, cool naturally, and let it stand for at least 20 h or 22 - 26 h. It should be noted that after natural cooling with a certain volume, let the precipitate stand for a sufficient time, and the crystallization of palmatine hydrochloride is basically complete. A small amount of berberine hydrochloride is also precipitated before, while jatrorrhizine hydrochloride hardly precipitates. The results show that recrystallization with 60 - 65% ethanol and fractional crystallization can obtain palmatine hydrochloride with a purity of more than 95%. At the same time, it solves the practical problem that it is not easy to recover highly concentrated ethanol in industrial production due to the use of ethanol with a concentration of more than 80% in the traditional process, and separates it from a small amount of berberine hydrochloride remaining in the previous mother liquor.

[0108] In step S6 of the present invention, the anion exchange resin is an alkaline anion exchange resin, including gel - type and macroporous acrylic weak - base anion resins, acrylic - type strong and weak - base anion resins, gel - type and macroporous styrene - type strong - base anion resins, macroporous acrylic strong - base anion resins, macroporous styrene - type weak - base anion resins, and the preferred model is one of D900, D941, D316, D296, D280. The crystallization mother liquor separated from berberine hydrochloride and palmatine contains more pigments and needs to further separate pigments and jatrorrhizine. There are literature reports on purifying alkaloids with cation exchange resins. Cation resins have no adsorption of pigments, but they exchange and adsorb jatrorrhizine hydrochloride and make it difficult to desorb. The overall desorption rate is less than 20%, resulting in a large amount of loss and making it impossible to use in production. The present invention uses a different method. First, remove the pigments, that is, use anion exchange resin to exchange and adsorb pigments. This resin has no adsorption of jatrorrhizine hydrochloride, so that jatrorrhizine flows out from the anion resin column, thus realizing the separation of jatrorrhizine and pigments.

[0109] In step S6 of the present invention, the macroporous adsorption resin includes one of non-polar D101, LX-100B, and LX-T28, weakly polar AB-8, etc.; the desorption ethanol concentration is 40-45%. It should be noted that a macroporous adsorption resin of a certain specification and model has a strong adsorption capacity for jatrorrhizine, while having a relatively small adsorption for other impurities in the fractional crystallization mother liquor. After high-temperature membrane separation, crystallization, recrystallization, and fractional crystallization to separate berberine hydrochloride and palmatine in the early stage, and on the basis of separating pigments by anion exchange resin, some other impurities can be separated by a macroporous adsorption resin of a specific specification and model. When the ethanol concentration is relatively high, the jatrorrhizine and impurities adsorbed on the resin can be desorbed together, while controlling an appropriate ethanol concentration, such as 40-45%, can desorb only jatrorrhizine without desorbing most of the impurities, thereby preparing jatrorrhizine with a purity of more than 80%. In addition, in the present invention, if membrane separation and subsequent anion exchange resin decolorization are not carried out first, and directly entering the macroporous adsorption resin, acid-base treatment is required after each batch of materials is fed, which is difficult to apply in production; while verified by actual production, the present invention only needs to be treated with acid-base once after processing 6 batches of materials, and only hot pure water treatment is required during this period to feed the next batch of materials.

[0110] Based on fibraurea recisa pierre containing berberine hydrochloride, palmatine hydrochloride, and jatrorrhizine hydrochloride, the present invention continuously produces and prepares 3 high-value-added products, realizing the comprehensive utilization of raw materials; through special high-temperature resistant membrane temperature-controlled separation and crystallization, replacing salting-out with acid-base solutions, solving the problems of environmental pollution caused by salt wastewater, alkaline browning, difficult regeneration caused by resin staining, and improving the purity of alkaloid monomers; recovering jatrorrhizine hydrochloride from the mother liquor through resin combination; forming an advanced and practical production technology system for the extraction, separation, and intensive processing of fibraurea recisa pierre.

[0111] The following are specific examples of the present invention:

[0112] Example 1

[0113] A method for producing berberine, palmatine, and jatrorrhizine hydrochloride based on fibraurea recisa pierre, the steps of which are as follows:

[0114] S1, Crushing:

[0115] Take 800 kg of dry rattan stems of fibraurea recisa pierre imported from Laos and crush them into coarse powder basically the size of grains with a hammer mill; calculated by mass ratio and in the form of hydrochloride, in the coarse powder of fibraurea recisa pierre, the content of berberine hydrochloride is 2.37%, the content of palmatine hydrochloride is 2.21%, and the content of jatrorrhizine hydrochloride is 0.79%.

[0116] S2, Dilute acid warm extraction:

[0117] Put the above-mentioned coarse powder into a 6m 3 enamel extraction tank and extract with dilute sulfuric acid.

[0118] This example is extracted 3 times, with the third extraction being a nested extraction; the extraction temperature is 58°C; the stirring method during extraction is: stir for 2 minutes every 10 minutes; during the three extractions, the addition amounts of the antioxidant protectant are 16.0 kg, 6.5 kg, and 3.0 kg respectively, and the antioxidant protectant is composed of vitamin C and ferrous sulfate in a mass ratio of 2:1; during the three extractions, the extraction times are 3.0 h, 2.0 h, and 1.0 h respectively; the concentration of the dilute sulfuric acid used is 0.3%; during the three extractions, the addition amounts of the dilute sulfuric acid are 4800 L, 4000 L, and 4800 L respectively; after each extraction, filtration is carried out, and the filter residue enters the next extraction. The filtrates obtained from the first two extractions are combined to obtain 7150 L of the extract.

[0119] S3, Temperature Control, Filtration, Clarification and Membrane Separation:

[0120] S31, Control and maintain the temperature of the extract at 63°C; first, perform plate-and-frame filtration, and then clarify the filtrate through a ceramic membrane with a zirconia material and a pore size of 500 nm; when there is only 200 L of the upstream liquid left, add 400 L of hot water at 65°C to dilute the upstream liquid and continue membrane filtration; when there is again only 200 L of the upstream liquid left, add another 400 L of hot water at 65°C to dilute the upstream liquid and continue membrane filtration; collect the liquid downstream of the membrane to obtain the clear liquid.

[0121] S32, Control and maintain the temperature of the clear liquid at 63°C; adjust the pH of the clear liquid to 3 with a 2% sodium hydroxide solution, and then pass it through a high-temperature ultrafiltration membrane that can withstand a maximum temperature of 70°C and has a molecular weight cut-off of 5 KD (membrane material PVDF, model UE005-8040H); when there is only 200 L of the upstream liquid left, add 400 L of hot water at 63°C to dilute the upstream liquid and continue membrane filtration; when there is again only 200 L of the upstream liquid left, add another 400 L of hot water at 63°C to dilute the upstream liquid and continue membrane filtration; collect the liquid downstream of the membrane, approximately 8300 L.

[0122] S33, Control and maintain the temperature of the liquid downstream of the membrane (from step S32) at 63°C; pass the liquid downstream of the membrane through a high-temperature nanofiltration membrane that can withstand a maximum temperature of 70°C and has a molecular weight cut-off of 200 D (material PES, model UF8040), and collect the liquid upstream of the membrane to obtain the refined membrane liquid, approximately 850 L.

[0123] S4, Separate Berberine Hydrochloride:

[0124] S41, Adjust the pH of the refined membrane liquid to 7 with a 2% sodium hydroxide solution, perform plate-and-frame filtration, then adjust the pH to 2 with a 2% hydrochloric acid solution, naturally cool to 28°C and keep warm for 65 h (under static conditions) to fully precipitate, perform plate-and-frame filtration, and separately collect the wet precipitate and the mother liquor, weigh and measure the volume to obtain 43.10 kg of the wet precipitate and 810 L of the mother liquor.

[0125] S42. Add 600 L of ethanol with a concentration of 64%, heat and stir at 85 °C to completely dissolve the wet precipitate in step S41, naturally cool to room temperature (in this example, the liquid temperature corresponding to room temperature is about 15 °C), stand for 24 h, filter with a plate and frame, collect the wet precipitate and the mother liquor respectively, weigh and measure the volume, obtaining 28.0 kg of wet precipitate and 570 L of mother liquor.

[0126] S43. Vacuum-concentrate the 570 L of mother liquor in step S42 to 130 L, add high-grade ethanol to adjust the ethanol concentration to 60%, naturally cool to room temperature, stand for 24 h, filter with a plate and frame, collect the wet precipitate and the mother liquor respectively, obtaining 6.9 kg of wet precipitate and 150 L of mother liquor.

[0127] S44. Combine the mother liquors in steps S41 and S43 to obtain about 960 L of berberine crystallization mother liquor; combine the wet precipitates in steps S42 and S43 to obtain 34.9 kg of bright yellow wet precipitate containing berberine hydrochloride.

[0128] S5. Separate palmatine hydrochloride:

[0129] S51. Vacuum-concentrate the 960 L of berberine crystallization mother liquor to 350 L, naturally cool to room temperature, stand for 72 h to fully precipitate the crystals, filter with a plate and frame, collect the wet precipitate and the mother liquor respectively, weigh and measure the volume, obtaining 41.50 kg of wet precipitate and 310 L of mother liquor.

[0130] S52. Add 550 L of ethanol with a concentration of 64%, heat and stir at 85 °C to completely dissolve the wet precipitate in step S51, naturally cool to room temperature, stand for 24 h, filter with a plate and frame, collect the wet precipitate and the mother liquor respectively, obtaining 27.6 kg of wet precipitate and 530 L of mother liquor.

[0131] S53. Vacuum-concentrate the 530 L of mother liquor in step S52 to 120 L, add high-grade ethanol to adjust the ethanol concentration to 60%, naturally cool to room temperature, stand for 24 h, filter with a plate and frame, collect the wet precipitate and the mother liquor respectively, obtaining 7.2 kg of wet precipitate and 140 L of mother liquor.

[0132] S54. Combine the mother liquors in steps S51 and S53 to obtain 450 L of palmatine crystallization mother liquor; combine the wet precipitates in steps S52 and S53 to obtain 34.8 kg of bright yellow wet precipitate containing palmatine hydrochloride.

[0133] S6. Separate jatrorrhizine hydrochloride by combining ion exchange resin and macroporous adsorption resin chromatography:

[0134] S61. Vacuum-recover ethanol from the palmatine crystallization mother liquor until there is no alcohol smell, add water to remove alcohol, and concentrate to 350 L to obtain a concentrated solution (2.2 Brix).

[0135] S62. The concentrated solution was cooled to room temperature and fed into an anion exchange resin column of model D900 with a capacity of 60 kg. After feeding, 250 L of purified water was used to wash the column (4.17 BV). The feed effluent and 180 L of column wash liquor (3 BV) were collected and combined to obtain the ion exchange resin decolorized solution.

[0136] S63. The ion exchange resin decolorized solution was fed into a non-polar macroporous adsorption resin column of model LX-T28 with a capacity of 250 kg. After feeding, 750 L of purified water was used to wash the column (3 BV). Then, it was desorbed with 900 L of ethanol with a concentration of 40%. The desorbed solution was collected and concentrated under vacuum to 18 Baume degrees, and the pH was adjusted to 4 with a 2% hydrochloric acid solution to obtain the refined combined resin solution containing jatrorrhizine hydrochloride.

[0137] S7. Drying:

[0138] The wet precipitate containing berberine hydrochloride was dried to obtain the berberine hydrochloride product; the wet precipitate containing palmatine hydrochloride was dried to obtain the palmatine hydrochloride product; the refined combined resin solution containing jatrorrhizine hydrochloride was dried to obtain the jatrorrhizine hydrochloride product. The drying method was: microwave vacuum drying, at a temperature of 63 °C and a vacuum degree of ≥ -0.085 MPa.

[0139] In this example, the mass of the berberine hydrochloride product was 16.40 kg, the mass of the palmatine hydrochloride product was 15.1 kg, and the mass of the jatrorrhizine hydrochloride product was 6.2 kg.

[0140] In the berberine hydrochloride product of this example, the mass ratio of berberine hydrochloride was 97.61%; in the palmatine hydrochloride product of this example, the mass ratio of palmatine hydrochloride was 95.86%; in the jatrorrhizine hydrochloride product of this example, the mass ratio of jatrorrhizine hydrochloride was 81.20%.

[0141] In this example, the berberine hydrochloride product and the palmatine hydrochloride product were yellow powders, and the jatrorrhizine hydrochloride product was a red-yellow powder and inclined to orange-red.

[0142] Comparative Example 1

[0143] Compared with Example 1, in this comparative example, only the extraction temperature in step S2 was adjusted to room temperature, and other conditions remained unchanged.

[0144] In this comparative example, the mass of the berberine hydrochloride product was 11.80 kg, the mass of the palmatine hydrochloride product was 11.02 kg, and the mass of the jatrorrhizine hydrochloride product was 4.33 kg; the results showed that: when extracting for the same time as in Example 1 at room temperature, the yields of the three alkaloids were all less than 70%, and sufficient extraction could not be carried out.

[0145] Comparative Example 2

[0146] In this comparative example, compared with Example 1, the antioxidant in step S2 was omitted, and other conditions remained unchanged.

[0147] In this comparative example, the products were visually inspected. The colors of the berberine hydrochloride product and palmatine hydrochloride product were dark yellow and had poor luster.

[0148] Comparative Example 3

[0149] In this comparative example, compared with Example 1, only the controlled temperature of the extract in step S31 was adjusted to 45 °C, and other conditions remained unchanged.

[0150] In this comparative example, after the ceramic membrane ran for 30 min, the flux decreased from 1.5 T / h to 400 L / h, showing a significant decrease. It could not operate normally and needed to be shut down for cleaning, and the upstream liquid volume was greater than 500 L.

[0151] Comparative Example 4

[0152] In this comparative example, compared with Example 1, only the controlled temperature of the clear liquid in step S32 was adjusted to 40 °C, and other conditions remained unchanged.

[0153] In this comparative example, after the ultrafiltration membrane ran for 1 h, the flux decreased from 1000 L / h to 300 L / h, showing a significant decrease. It could not operate normally and needed to be shut down for cleaning, and the upstream liquid volume was greater than 1000 L.

[0154] Comparative Example 5

[0155] In this comparative example, compared with Example 1, only the controlled temperature of the liquid downstream of the membrane (from step S32) in step S33 was adjusted to 40 °C, and other conditions remained unchanged.

[0156] In this comparative example, after the nanofiltration membrane ran for 40 min, the flux decreased from 1000 L / h to 200 L / h, showing a significant decrease. It could not operate normally and needed to be shut down for cleaning, and the upstream liquid volume was greater than 3000 L.

[0157] Comparative Example 6

[0158] In this comparative example, compared with Example 1, only the holding temperature in step S41 was adjusted from 28 °C to room temperature, and other conditions remained unchanged.

[0159] In this comparative example, the mass of the wet precipitate obtained in step S41 was 80.70 kg, and the mother liquor was 760 L, indicating that most of the palmatine hydrochloride and jatrorrhizine hydrochloride would precipitate simultaneously with berberine hydrochloride.

[0160] In this comparative example, the mass of the berberine hydrochloride product is 16.85 kg, and the mass fraction of berberine hydrochloride in the berberine hydrochloride product is only 94.10%, which does not meet the requirement that the content of berberine hydrochloride from the extraction source shall not be less than 97% as specified in the Chinese Pharmacopoeia (2020 Edition).

[0161] Comparative Example 7

[0162] Compared with Example 1, in this comparative example, only the anion exchange resin column in Step S62 is adjusted to a granular activated carbon column, and other conditions remain unchanged.

[0163] In this comparative example, the mass of the jatrorrhizine hydrochloride product is 4.05 kg, and the mass fraction of jatrorrhizine hydrochloride in the jatrorrhizine hydrochloride product is 81.50%, and the color is red-yellow; it indicates that the activated carbon causes significant adsorption loss of jatrorrhizine hydrochloride.

[0164] Comparative Example 8

[0165] Compared with Example 1, in this comparative example, Step S62 is omitted (i.e., the concentrated solution of the palmatine crystallization mother liquor directly enters the non-polar macroporous adsorption resin column), and other conditions remain unchanged.

[0166] In this comparative example, the mass of the jatrorrhizine hydrochloride product is 6.85 kg, and the mass fraction of jatrorrhizine hydrochloride in the jatrorrhizine hydrochloride product is 73.50%; the color is yellowish and shiny, which is quite different from the red-yellow and shiny color.

[0167] In the above technical solutions of the present invention, the above are only the preferred embodiments of the present invention, and thus do not limit the patent scope of the present invention. Any equivalent structural transformation made using the description of the present invention under the technical concept of the present invention, or any direct / indirect application in other related technical fields is included in the patent protection scope of the present invention.

Claims

1. A method for producing berberine, palmatine and jatrorrhizine hydrochloride based on Fibraurea recisa Pierre, characterized in that, Including the steps: S1, providing a powder derived from Fibraurea recisa Pierre and containing berberine, palmatine and jatrorrhizine; S2, subjecting the powder to extraction to obtain an extract; S3, sequentially filtering, ultrafiltering and nanofiltrating the extract, and taking the upstream liquid of the membrane; The process of filtration includes: controlling the temperature of the extract at 60 - 65 °C; sequentially subjecting the extract to primary filtration and microfiltration to obtain a clear liquid; The process of ultrafiltration includes: controlling the temperature of the clear liquid at 60 - 65 °C; adjusting the pH of the clear liquid to 1 - 5 with an alkali solution, and then passing the clear liquid through a high-temperature ultrafiltration membrane, and collecting the downstream liquid of the membrane; the highest temperature that the high-temperature ultrafiltration membrane can withstand is not lower than 70 °C, and the molecular weight cut-off of the high-temperature ultrafiltration membrane is 3 - 5 KD; S4, adjusting the pH of the upstream liquid of the membrane to 6 - 8 with an alkali solution, filtering, then adjusting the pH to 2 - 3 with a hydrochloric acid solution, standing and then filtering, collecting the first wet precipitate and the first mother liquor; adding an ethanol solution with a concentration of 60 - 65% to the first wet precipitate, heating and dissolving, standing and then filtering, collecting the second wet precipitate and the second mother liquor; adjusting the ethanol concentration in the second mother liquor to 60 - 65%, standing and then filtering, collecting the third wet precipitate and the third mother liquor; combining the first mother liquor and the third mother liquor to obtain a berberine crystallization mother liquor; combining the second wet precipitate and the third wet precipitate to obtain a wet precipitate containing berberine hydrochloride; S5, concentrating the berberine crystallization mother liquor, standing and then filtering, obtaining a fourth wet precipitate and a fourth mother liquor; adding an ethanol solution with a concentration of 60 - 65% to the fourth wet precipitate, heating and dissolving, standing and then filtering, collecting the fifth wet precipitate and the fifth mother liquor; adjusting the ethanol concentration in the fifth mother liquor to 60 - 65%, standing and then filtering, collecting the sixth wet precipitate and the sixth mother liquor; combining the fourth mother liquor and the sixth mother liquor to obtain a palmatine crystallization mother liquor; combining the fifth wet precipitate and the sixth wet precipitate to obtain a wet precipitate containing palmatine hydrochloride; S6, concentrating the palmatine crystallization mother liquor to obtain a concentrated solution; passing the concentrated solution through an anion exchange resin column, passing the collected feed effluent through a macroporous adsorption resin column, desorbing and then collecting the desorbing solution; concentrating the desorbing solution, and adjusting the pH to 4 - 6 with a hydrochloric acid solution to obtain a combined resin refined solution containing jatrorrhizine hydrochloride; In step S6, the process of concentrating the palmatine crystallization mother liquor includes: concentrating the palmatine crystallization mother liquor until there is no alcohol smell, and controlling the Brix of the palmatine crystallization mother liquor at 1 - 3 Brix; In step S6, desorbing with an ethanol solution with a concentration of 40 - 45%; In step S6, the process of concentrating the desorbing solution includes: concentrating the desorbing solution to 17 - 25 degrees Baume; Step S6 further includes: after passing the concentrated solution through the anion exchange resin column, washing the column with purified water, collecting the column washing liquid, combining the feed effluent and the column washing liquid as an ion exchange resin decolorizing liquid, and jointly passing them through the macroporous adsorption resin column; after passing the ion exchange resin decolorizing liquid through the macroporous adsorption resin column, washing the column with purified water before desorbing.

2. The method for producing berberine, palmatine and jatrorrhizine hydrochloride based on fibraurea recisa pierre as claimed in claim 1, wherein, In the powder, the content of berberine hydrochloride is 1.5 - 3% and the content of palmatine hydrochloride is 2 - 4.5% and the content of jatrorrhizine hydrochloride is 0.4 - 1.0% in terms of mass ratio and hydrochloride form.

3. The method for producing berberine, palmatine and jatrorrhizine hydrochloride based on fibraurea recisa pierre according to claim 1, wherein, In step S2, leaching is performed with a sulfuric acid solution containing an antioxidant protector; the concentration of the sulfuric acid solution is 0.2 - 0.7%, and the leaching temperature is 50 - 65°C; the antioxidant protector includes vitamin C and ferrous sulfate, and the mass ratio of vitamin C to ferrous sulfate is 1 - 3:1; the mass percentage of the antioxidant protector to the powder is 1.0 - 4.0%.

4. The method for producing berberine, palmatine and jatrorrhizine hydrochloride based on fibraurea recisa pierre according to claim 3, characterized in that, In step S2, the number of leaching times is three; in the first leaching, the ratio of the sulfuric acid solution to the powder is controlled at 5 - 7 mL:1 g, the powder is leached in the sulfuric acid solution for 2 - 4 h, and the first filtrate and the first filter residue are collected after filtration; in the second leaching, the ratio of the sulfuric acid solution to the powder is controlled at 4 - 6 mL:1 g, the first filter residue is leached in the sulfuric acid solution for 1 - 3 h, and the second filtrate and the second filter residue are collected after filtration; in the third leaching, the ratio of the sulfuric acid solution to the powder is controlled at 5 - 7 mL:1 g, the second filter residue is leached in the sulfuric acid solution for 0.5 - 1.5 h, and the third filtrate is collected after filtration; the first filtrate and the second filtrate are combined as the extract, and the third filtrate is used for leaching the powder in the next batch.

5. The method for producing berberine, palmatine and jatrorrhizine hydrochloride based on fibraurea recisa pierre according to claim 1, characterized in that, In step S3, the nanofiltration process includes: controlling the temperature of the downstream liquid of the membrane at 60 - 65°C; passing the downstream liquid of the membrane through a high-temperature nanofiltration membrane, and collecting the upstream liquid of the membrane, and the upstream liquid of the membrane is the membrane-refined liquid; the maximum temperature that the high-temperature nanofiltration membrane can withstand is not lower than 70°C, and the cut-off molecular weight of the high-temperature nanofiltration membrane is 150 - 300 D.

6. The method for producing berberine, palmatine and jatrorrhizine hydrochloride based on fibraurea recisa pierre according to claim 1, wherein In step S4, an ethanol solution with a concentration of 60 - 65% is added to the first wet precipitate at a ratio of 1 g:12 - 15 mL. In step S4, the process of making the ethanol concentration in the second mother liquor reach 60 - 65% includes: concentrating the second mother liquor to 1 / 5 - 1 / 4 of the original volume, and then adding ethanol to the second mother liquor to make the ethanol concentration in the second mother liquor reach 60 - 65%.

7. The method for producing berberine, palmatine and jatrorrhizine hydrochloride based on fibraurea recisa pierre according to claim 1, wherein, In step S5, the process of concentrating the berberine crystallization mother liquor includes: concentrating the berberine crystallization mother liquor to 1 / 2 - 1 / 3 of the original volume. In step S5, an ethanol solution with a concentration of 60 - 65% is added to the fourth wet precipitate at a ratio of 1 g:12 - 15 mL. In step S5, the process of making the ethanol concentration in the fifth mother liquor reach 60 - 65% includes: concentrating the fifth mother liquor to 1 / 5 - 1 / 4 of the original volume, and then adding ethanol to the fifth mother liquor to make the ethanol concentration in the fifth mother liquor reach 60 - 65%.

8. The method for producing berberine, palmatine and jatrorrhizine hydrochloride based on Fibraurea recisa Pierre according to claim 1, characterized in that, The anion exchange resin column is filled with a basic anion exchange resin, which is one of a gel-type acrylic strong-base anion resin, a gel-type acrylic weak-base anion resin, a gel-type styrene strong-base anion resin, a gel-type styrene weak-base anion resin, a macroporous acrylic strong-base anion resin, a macroporous acrylic weak-base anion resin, a macroporous styrene strong-base anion resin, and a macroporous styrene weak-base anion resin; the macroporous adsorption resin column is filled with one of a non-polar macroporous adsorption resin and a weakly polar macroporous adsorption resin.

9. The method for producing berberine, palmatine, and jatrorrhizine hydrochloride based on fibraurea recisa pierre as claimed in any one of claims 1-8, characterized in that, The wet precipitate containing berberine hydrochloride is dried to obtain a berberine hydrochloride product; the wet precipitate containing palmatine hydrochloride is dried to obtain a palmatine hydrochloride product; the refined liquid of the combined resin containing jatrorrhizine hydrochloride is dried to obtain a jatrorrhizine hydrochloride product.