Method for producing berberine, palmatine and jateorhizine hydrochloride based on herba fibraureae recisae

Abstract

The invention provides a method for producing berberine, palmatine and jateorhizine hydrochloride based on herba fibraureae recisae. According to the method, specific herba fibraureae recisae is taken as a raw material, and berberine hydrochloride is separated through crystallization and recrystallization after crushing, dilute acid temperature raising, temperature-controlled filtration clarification and membrane separation, then crystallization mother liquor is subjected to fractional crystallization and recrystallization, and palmatine hydrochloride is separated; and finally, separating through combined use of ion exchange resin and macroporous adsorption resin chromatography to obtain jatrorrhizine hydrochloride. According to the invention, three alkaloid monomers with high added value are prepared based on continuous production of herba fibraureae recisae containing berberine, palmatine and jatrorrhizine, and all the alkaloid monomers are heterocyclic compounds; the method can also solve the problems of environmental pollution caused by salt wastewater, difficult regeneration caused by alkaline browning and resin dyeing in the production process and improvement of the purity of the alkaloid monomer, and a production system capable of being industrially applied is formed.

Description

Technical Field

[0001] The invention relates to heterocyclic compounds, and in particular to a method for producing berberine, palmatine and jatrorrhizine hydrochloride based on Phellodendron chinense. Background Art

[0002] Yellow rattan Fibraurea recisa Pierre. , a plant of the Menispermaceae family, also known as Tianxianteng, Tuhuanglian, Jinsuoshi, and Ganghuanglian, etc. The medicinal part is the dried vine stems, which mostly grow in the moist and fertile tropical and subtropical dense forests at an altitude of 180~1000 m, and often climb tall vines. The vine stems of domestic yellow rattan mainly contain alkaloids: palmatine, jatrorrhizine, pseudoafricanine, and yellow rattan lactone, and contain jatrorrhizine A, jatrorrhizine B, sterols, etc.; palmatine and jatrorrhizine are the main alkaloid components of yellow rattan medicinal materials. Due to factors such as the price of medicinal materials and the cost of production and processing, there is a great contradiction between the value of the output of bamipine hydrochloride; therefore, yellow rattan is mainly used as a traditional Chinese medicinal material, and it is rarely used in large quantities as a raw material for extracting and preparing jatrorrhizine (bamipine). Since the berberine content in domestic Phellodendron chinense medicinal materials is very low and has no extraction value, there is only a relatively high content of bamipine and an appropriate amount of jatrorrhizine. Even when extracting and processing Phellodendron chinense, existing research mainly focuses on the extraction and purification of a single component of bamipine hydrochloride, and rarely prepares jatrorrhizine hydrochloride at the same time, and there is no report on the simultaneous preparation of berberine hydrochloride.

[0003] For example, the Chinese invention patent application with publication number CN101058575A discloses a method for extracting and refining palmatine hydrochloride, which comprises the following steps: (1) acid treatment: crush the Phellodendron chinense medicinal material, add 6 to 14 times the amount of dilute sulfuric acid aqueous solution, soak for 24 to 72 hours, and filter; (2) alkali treatment: adjust the pH of the filtrate to 7.0 to 14; (3) separation: add industrial sodium chloride according to the weight of 5 to 30% of the volume of the filtrate, stir to dissolve, let stand for 12 to 36 hours, siphon off the supernatant, and centrifuge the lower sediment to obtain crude palmatine hydrochloride; (4) alcohol treatment : The crude product is extracted with 8-20 times the amount of ethanol under reflux for 10-60 minutes and filtered while hot; (5) Concentration: Concentrate to 3-8 times the amount of crude alkali; (6) Acid treatment: Adjust the pH to 1-5 with acid, let stand, cool, precipitate yellow needle crystals, filter, and dry to obtain bamipine hydrochloride; (7) Water treatment: Heat and dissolve bamipine hydrochloride 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 is precipitated, let stand for 12-48 hours, siphon off the supernatant, filter the lower precipitate, and dry to obtain refined bamipine hydrochloride. Although the above patent application realizes the extraction of bamipine hydrochloride, it uses dilute sulfuric acid for immersion extraction at room temperature, which has a long production cycle; salting out under alkaline conditions is prone to browning, making the product color darker; sodium chloride is added according to the volume of the extract, and the amount of salt is large, which is easy to cause environmental pollution; more importantly, it only involves the preparation of a single ingredient of bamipine 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 Phellodendron chinense, so as to solve or at least alleviate the technical problem of how to simultaneously prepare berberine hydrochloride, palmatine hydrochloride and jatrorrhizine hydrochloride through Phellodendron chinense and achieve efficient production. Summary of the invention

[0005] The main purpose of the present invention is to provide a method for producing berberine, palmatine and jatrorrhizine hydrochloride based on Phellodendron chinense, aiming to solve the technical problem of how to simultaneously prepare berberine hydrochloride, palmatine hydrochloride and jatrorrhizine hydrochloride through Phellodendron chinense 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 Phellodendron chinense, comprising the steps of: S1, providing a powder derived from Phellodendron chinense and containing berberine, palmatine and jatrorrhizine; S2, extracting the powder to obtain an extract; S3, the extract is filtered, ultrafiltered and nanofiltered in sequence, and the membrane upstream liquid after nanofiltration is taken; S4, using alkaline solution to adjust the pH of the membrane upstream liquid to 6-8, after filtering, using hydrochloric acid solution to adjust the pH to 2-3, standing at 25-30°C and filtering, collecting the first wet precipitate and the first mother liquor; adding 60-65% ethanol solution to the first wet precipitate, heating and dissolving, standing and filtering, collecting the second wet precipitate and the second mother liquor; making the ethanol concentration in the second mother liquor reach 60-65%, standing and filtering, collecting the third wet precipitate and the third mother liquor; combining the first mother liquor and the third mother liquor to obtain berberine crystal 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, letting it stand and filtering, to obtain 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, letting it stand and filtering, collecting a fifth wet precipitate and a fifth mother liquor; making the ethanol concentration in the fifth mother liquor reach 60-65%, letting it stand and filtering, collecting a sixth wet precipitate and a 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 bamipine crystallization mother liquor to obtain a concentrated solution; feeding the concentrated solution into an anion exchange resin column, feeding the collected feed effluent into a macroporous adsorption resin column, and collecting the desorbed solution after desorption; concentrating the desorbed solution, adjusting the pH to 4-6 with a hydrochloric acid solution, and obtaining a combined resin refined solution containing jatrorrhizine hydrochloride.

[0007] Furthermore, in terms of weight percentage and in the form of hydrochloride, the content of berberine hydrochloride in the powder is 1.5-3%, the content of palmatine hydrochloride is 2-4.5%, and the content of jatrorrhizine hydrochloride is 0.4-1.0%.

[0008] Furthermore, in step S2, leaching is performed with a sulfuric acid solution containing an antioxidant protective agent; the concentration of the sulfuric acid solution is 0.2-0.7%, and the leaching temperature is 50-65° C.; the antioxidant protective agent includes vitamin C and ferrous sulfate, and the mass ratio of the vitamin C to the ferrous sulfate is 1-3:1; the mass percentage of the antioxidant protective agent and the powder is 1.0-4.0%.

[0009] Furthermore, in step S2, the number of leaching is three times; when performing the first leaching, the ratio of the sulfuric acid solution to the powder is controlled to be 5-7 mL: 1 g, the powder is leached in the sulfuric acid solution for 2-4 hours, and the first filtrate and the first filter residue are collected after filtering; when performing the second leaching, the ratio of the sulfuric acid solution to the powder is controlled to be 4-6 mL: 1 g, the first filter residue is leached in the sulfuric acid solution for 1-3 hours, and the second filtrate and the second filter residue are collected after filtering; when performing the third leaching, the ratio of the sulfuric acid solution to the powder is controlled to be 5-7 mL: 1 g, the second filter residue is leached in the sulfuric acid solution for 0.5-1.5 hours, and the third filtrate is collected after filtering; the first filtrate and the second filtrate are combined as the extract, and the third filtrate is used for leaching the next batch of the powder.

[0010] Furthermore, in step S3, the filtering process includes: controlling the temperature of the extract to be 60-65° C.; performing primary filtration and microfiltration on the extract in sequence to obtain a clear liquid; The ultrafiltration process includes: controlling the temperature of the clear liquid to 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 to collect the liquid downstream of the membrane; the maximum bearing temperature of the high-temperature ultrafiltration membrane is not less than 70°C, and the molecular weight cutoff of the high-temperature ultrafiltration membrane is 3-5KD; The nanofiltration process includes: controlling the temperature of the liquid downstream of the membrane to 60-65°C; passing the liquid downstream of the membrane through a high-temperature nanofiltration membrane, collecting the liquid upstream of the membrane, and the liquid upstream of the membrane is the membrane refined liquid; the maximum tolerable temperature of the high-temperature nanofiltration membrane is not less than 70°C, and the molecular weight cutoff of the high-temperature nanofiltration membrane is 150-300D.

[0011] Further, in the 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%.

[0012] Furthermore, in the step S5, the process of concentrating the berberine crystallization mother liquor comprises: concentrating the berberine crystallization mother liquor to 1 / 2 to 1 / 3 of the original volume; In the 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%.

[0013] Furthermore, in the step S6, the process of concentrating the bamipine crystallization mother liquor comprises: concentrating the bamipine crystallization mother liquor until there is no alcohol taste, and controlling the brix of the bamipine crystallization mother liquor to be 1-3 Brix; In the step S6, desorption is performed using an ethanol solution with a concentration of 40-45%; In the step S6, the process of concentrating the desorption liquid includes: concentrating the desorption liquid to 17-25 degrees Baume; The step S6 also includes: after the concentrated solution enters the anion exchange resin column, the column is washed with purified water, the washing column liquid is collected, the feed effluent and the washing column liquid are combined as an ion exchange resin decolorizing liquid, and they are jointly introduced into the macroporous adsorption resin column; after the ion exchange resin decolorizing liquid enters the macroporous adsorption resin column, before the desorption is performed, the column is washed with purified water.

[0014] 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.

[0015] 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; and the combined resin refined liquid containing jatrorrhizine hydrochloride is dried to obtain a jatrorrhizine hydrochloride product.

[0016] Compared with the prior art, the present invention has at least the following advantages: 1. The present invention can simultaneously separate and extract berberine hydrochloride, palmatine hydrochloride and jatrorrhizine hydrochloride from Phellodendron chinense; the present invention discovered a type of high-quality Phellodendron chinense imported from Laos, which not only has a certain content of palmatine hydrochloride and jatrorrhizine hydrochloride, but also contains 1.5-3% berberine hydrochloride; however, there is no report on the content of berberine hydrochloride in Phellodendron chinense in existing research, only the content of palmatine hydrochloride and jatrorrhizine is reported. The present invention is based on the improvement of specific Phellodendron chinense and the overall technical solution, and creatively realizes the simultaneous separation and extraction of berberine hydrochloride, palmatine hydrochloride and jatrorrhizine hydrochloride, and the yield and purity are both high.

[0017] 2. The present invention can continuously prepare berberine hydrochloride, bamipine and jatrorrhizine through industrial production, forming an industrializable technology system for extraction, separation and deep processing of Phellodendron chinense, solving the technical problem that traditional technology only focuses on bamipine hydrochloride (Phellodendron chinense) and rarely prepares jatrorrhizine hydrochloride at the same time. It is the first industrial production technology for simultaneously preparing three alkaloid monomer components from Phellodendron chinense, realizing the comprehensive utilization of resources and creating good economic and social benefits.

[0018] 3. The present invention can significantly shorten the extraction time, improve production efficiency and reduce equipment occupancy; the present invention uses dilute sulfuric acid at 50-65°C to extract, shortening the immersion extraction time of the traditional process from 24-72 hours to less than 10 hours.

[0019] 4. The present invention solves the problem of salt wastewater polluting the environment by using temperature-controlled special high-temperature resistant ultrafiltration membrane separation and nanofiltration membrane concentration and refining instead of salting out; at the same time, the temperature control is combined with the degree of concentration, standing time, crystallization and recrystallization, and step-by-step crystallization technology to successively separate berberine hydrochloride, bamipine and jatrorrhizine, thus solving the problem of difficulty in separating and purifying monomer alkaloids caused by salting out all alkaloids.

[0020] 5. The present invention avoids the loss of alkaloid adsorption caused by activated carbon decolorization by adding antioxidant protective agents in the extraction stage, temperature control and membrane separation, crystallization and recrystallization, step-by-step crystallization, and resin combination technology, while improving the product yield, preparing yellow berberine hydrochloride, bamipine hydrochloride and red-yellow jatrorrhizine hydrochloride, solving the problem of poor product color on the market.

[0021] 6. The present invention does not use organic solvents other than water and ethanol, does not use high-cost extraction and separation technologies such as aluminum oxide and silica gel chromatography, has fewer process steps, and improves the operability and safety of production. DETAILED DESCRIPTION

[0022] The technical solutions in the embodiments of the present invention are described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0023] Furthermore, the technical solutions between the various embodiments of the present invention may be combined with each other, but this must be based on the fact that they can be implemented by ordinary technicians in the field. When the combination of technical solutions is mutually contradictory or cannot be implemented, it should be deemed that such combination of technical solutions does not exist and is not within the scope of protection required by the present invention.

[0024] When numerical ranges are given in the embodiments, 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 are familiar to those skilled in the art and the description of the present invention, and any methods, equipment and materials of the prior art similar or equivalent to the methods, equipment and materials described in the embodiments of the present invention can also be used to implement the present invention.

[0025] The yellow rattan used in the present invention was purchased from Laos and harvested in late November. The purified water used was made by a pure water machine, and 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 ethanol is the volume concentration, all of which are prepared with water.

[0026] In the present invention, the contents of berberine hydrochloride, berberine (palmatine hydrochloride), and jatrorrhizine hydrochloride are determined separately by high performance liquid chromatography (HPLC) according to the 2020 edition of the Pharmacopoeia of the People's Republic of China under the items of "berberine hydrochloride", "berberine", and "berberine hydrochloride"; the above three alkaloids are determined simultaneously by high performance liquid chromatography (HPLC) according to the 2020 edition of the Pharmacopoeia of the People's Republic of China under the item of "Mahonlaomu". It should be made clear that although the jatropha in the present invention contains berberine, palmatine, and jatrorrhizine, the unified standard for determining the content in the 2020 edition of the Pharmacopoeia of the People's Republic of China is hydrochloride. Therefore, when expressing the substance content of berberine, palmatine, and jatrorrhizine in jatropha, the present invention is calculated in the form of hydrochloride; and after completing the production in the present invention, the substances obtained are berberine hydrochloride, palmatine hydrochloride, and jatrorrhizine hydrochloride.

[0027] The present invention accidentally discovered in the research that some Laotian yellow rattans have comparable contents of palmatine hydrochloride and jatrorrhizine hydrochloride compared with domestic yellow rattans, but Laotian yellow rattans also contain 1.5-3% berberine hydrochloride, and there is no literature so far reporting that yellow rattans contain such a high content of berberine hydrochloride. After actual analysis and testing, the content of berberine hydrochloride in Laotian imported yellow rattan medicinal materials is 2.37%, the content of palmatine hydrochloride is 2.21%, and the content of jatrorrhizine hydrochloride is 0.79%. This result overturns the cognition of yellow rattan medicinal materials. Since Laotian yellow rattan medicinal materials have higher contents of three alkaloids, the import price is the same as that of domestic products, so they have the highest cost performance. Considering the sustainability of extraction and processing, as well as the comprehensive utilization of medicinal resources, Laotian yellow rattan can not only be used as a conventional Chinese medicinal material, but also as a stable extraction raw material for large-scale production of three high-value-added products: berberine hydrochloride, bamipine hydrochloride and jatrorrhizine hydrochloride, thereby generating higher economic benefits and good social benefits.

[0028] The specific information of berberine hydrochloride, palmatine hydrochloride and jatrorrhizine hydrochloride is as follows: Berberine hydrochloride: Also known as berberine hydrochloride, it is a yellow crystalline powder with a very bitter taste. It is easily soluble in boiling water, dissolves in hot water, slightly soluble in cold water, and is almost insoluble in cold ethanol, chloroform and ether. It is mainly used as an antibacterial drug, and is mainly used clinically for intestinal infections and bacillary dysentery, etc. It has an anti-arrhythmic effect. Chinese name: berberine hydrochloride; English name: Berberine; CAS Number: 633-65-8; Molecular formula: C 20 H 18 ClNO4; Molecular weight: 372.82.

[0029] Palmatine hydrochloride: Also known as calendula, it is yellow needle-shaped crystals with a very 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. It is mainly used clinically for gynecological inflammation, bacillary dysentery, enteritis, respiratory and urinary tract infections, surgical infections, and conjunctivitis. Chinese name: Bamatin hydrochloride; English name: Palmatine; CAS Number: 3486-67-7; Molecular formula: C 21 H 22 ClNO4; Molecular weight: 387.86.

[0030] Jatrorrhizine hydrochloride: Also known as jatrorrhizine, it is a red-yellow needle-shaped crystal with a very bitter taste. It is soluble in water and ethanol. It has the effects of detoxification, sterilization, lowering blood sugar and positive inotropic effects. Chinese name: Jatrorrhizine hydrochloride; English name: Jatrorrhizine; CAS Number: 3621-38-3; Molecular formula: C 20 H 20 ClNO4; Molecular weight: 465.28.

[0031] It should be pointed out that the existing research mainly focuses on the extraction and purification of a single component of calendula, 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 the existing research are mainly dilute sulfuric acid, acetic acid and organic solvents. In comparison, the production cost of acid extraction is lower, but it takes a long time, is relatively easy to separate and purify, and is more suitable for industrial production; the existing research generally has salting out under alkaline conditions, which is easy to produce browning and deepen the color of the product; in the existing research, the amount of sodium chloride used for salting out is relatively large, which is easy to pollute the environment. In addition, some existing studies use macroporous adsorption resins for purification, but due to the lack of pretreatment, the macroporous adsorption resins are seriously polluted when stained, and the resin regeneration treatment is difficult; some existing studies use silica gel, alumina, and organic solvents such as n-butanol to prepare high-purity calendula and jatrorrhizine, which makes the preparation cost high and difficult to achieve in production; the existing research focuses on experimental technology as a whole, and there is still a certain distance from industrial production. Therefore, with the upgrading and improvement of technology, and the early simultaneous separation of berberine hydrochloride, bamipine hydrochloride and jatrorrhizine hydrochloride, it is necessary to establish a relatively complete industrial production and comprehensive utilization technology system for the extraction, separation and deep processing of Phellodendron chinense.

[0032] The present invention mainly realizes the efficient production of berberine hydrochloride, palmatine hydrochloride and jatrorrhizine hydrochloride through the following aspects: (1) obtaining high-quality Phellodendron chinense raw materials to realize sustainable production; (2) comprehensively utilizing Phellodendron chinense medicinal material resources to continuously prepare alkaloid monomer components with a higher content therein, thereby reducing production costs; (3) improving production efficiency, reducing equipment occupation, and changing the traditional process of long-term immersion extraction; (4) adding no or less salt as much as possible to reduce salt wastewater pollution to the environment; (5) improving product color, reducing the process steps that deepen the color during the production and processing process, or simplifying the decolorization step; (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.

[0033] The present invention provides a method for producing berberine, palmatine and jatrorrhizine hydrochloride based on Phellodendron chinense, the steps of which are: S1, broken: The dried stems of the medicinal material Phellodendron chinense are crushed into coarse powder of substantially the size of grains; that is, a powder of Phellodendron chinense (e.g., 500-1000 kg) is provided; the powder contains berberine, palmatine and jatrorrhizine. In terms of mass percentage and the form of hydrochloride, the content of berberine hydrochloride in the powder is 1.5-3%, the content of palmatine hydrochloride is 2-4.5%, and the content of jatrorrhizine hydrochloride is 0.4-1.0%.

[0034] S2, dilute acid warm extraction: The powder is leached with a sulfuric acid solution containing an antioxidant, and an extract is obtained after filtration; the concentration of the sulfuric acid solution is 0.2-0.7%, the leaching temperature is 50-65°C, and the total leaching time can be 5-8 hours. The antioxidant 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 (total amount added for leaching) and the powder is 1.0-4.0%; the stirring method during the leaching process of the present invention can be: stirring is started at intervals of 10 minutes or air pressure recoil is performed for 2 minutes.

[0035] In this step, the number of leachings can be three times; when performing the first leaching, the ratio of the sulfuric acid solution to the powder is controlled to be 5-7 mL: 1 g, the powder is leached in the sulfuric acid solution for 2-4 hours, and the first filtrate and the first filter residue are collected after filtering; when performing the second leaching, the ratio of the sulfuric acid solution to the powder is controlled to be 4-6 mL: 1 g, the first filter residue is leached in the sulfuric acid solution for 1-3 hours, and the second filtrate and the second filter residue are collected after filtering; the first filtrate and the second filtrate are combined as the extract.

[0036] In this step, the number of leaching can also be 3 times, and the third leaching is a set leaching, that is, the filtrate after the third leaching is used to leaching the next batch of the powder. When performing the third leaching, the ratio of the sulfuric acid solution to the powder is controlled to be 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 and the third filter residue are collected after filtering; and the third filtrate is used to leaching the next batch of the powder.

[0037] In the present invention, when the first extraction is carried out, the mass percentage of the antioxidant protective agent and the powder is 1.0-3.0%; when the second extraction is carried out, the mass percentage of the antioxidant protective agent and the powder is 0.5-1.0%; when the third extraction is carried out, the mass percentage of the antioxidant protective agent and the powder is 0.3-0.5%.

[0038] S3, temperature controlled filtration clarification and membrane separation: S31, controlling the temperature of the extract to be 60-65°C, filtering the extract to obtain a clear liquid; the process of filtering the extract includes: first filtering the extract, and then microfiltering the extract through a ceramic membrane with a pore size of 200-800nm; the specific operation may be: first three-legged bag centrifugation or plate and frame filtration, and then clarifying the filtrate through a ceramic membrane made of aluminum oxide or zirconium oxide with a pore size of 200-800nm.

[0039] In the present invention, when the liquid after the initial filtration is microfiltered through the ceramic membrane, when the volume of the upstream liquid is only 1 / 30 to 1 / 40 of the extract, hot water is added to the upstream liquid (the volume of the hot water is 1.5 to 2.5 times the volume of the residual liquid of the upstream liquid, and the temperature is 60 to 65°C) to dilute it, and continue to pass through the membrane; when the volume of the upstream liquid is only 1 / 30 to 1 / 40 of the extract again, hot water is added to the upstream liquid again (the volume of the hot water is 1.5 to 2.5 times the volume of the residual liquid of the upstream liquid, and the temperature is 60 to 65°C) to dilute it, and continue to pass through the membrane.

[0040] S32, controlling the temperature of the clear liquid to be 60-65°C, adjusting the pH of the clear liquid to be 1-5 with alkaline solution, and then passing the clear liquid through a high-temperature ultrafiltration membrane to collect the liquid downstream of the membrane; the maximum tolerable temperature of the high-temperature ultrafiltration membrane is not less than 70°C, and the molecular weight cutoff of the high-temperature ultrafiltration membrane is 3-5KD.

[0041] In the present invention, when the clear liquid passes through the high-temperature ultrafiltration membrane, when the volume of the upstream liquid is only 1 / 30 to 1 / 40 of the extract, hot water is added to the upstream liquid (the volume of the hot water is 1.5 to 2.5 times the volume of the residual liquid of the upstream liquid, and the temperature is 60 to 65° C.) to dilute it, and continue to pass through the membrane; when the volume of the upstream liquid is only 1 / 30 to 1 / 40 of the extract again, hot water is added to the upstream liquid again (the volume of the hot water is 1.5 to 2.5 times the volume of the residual liquid of the upstream liquid, and the temperature is 60 to 65° C.) to dilute it, and continue to pass through the membrane.

[0042] S33, controlling the temperature of the liquid downstream of the membrane to 60-65°C, passing the liquid downstream of the membrane through a high-temperature nanofiltration membrane, collecting the liquid upstream of the membrane, and using the liquid upstream of the membrane as a membrane refining liquid; the maximum temperature that the high-temperature nanofiltration membrane can withstand is not less than 70°C, and the molecular weight cutoff of the high-temperature nanofiltration membrane is 150-300D, specifically 200D.

[0043] As a further explanation, in this step, the high temperature ultrafiltration membrane and the high temperature nanofiltration membrane can withstand a maximum temperature of 70°C, and the alkali solution is a sodium hydroxide solution with a concentration of 1-3%.

[0044] S4, separation of berberine hydrochloride: S41, using alkaline solution to adjust the pH of the membrane refined liquid to 6-8 (specifically 7), and then filtering to obtain a filtered liquid; using hydrochloric acid solution to adjust the pH of the filtered liquid to 2-3, naturally cooling, and standing at 25-30°C for at least 48 hours or standing for 48-72 hours to allow the precipitate to fully precipitate; filtering after completion of standing, collecting the first wet precipitate and the first mother liquor.

[0045] S42, adding 60-65% ethanol solution to the first wet precipitate at a ratio of 1 g: 12-15 mL, and heating to 80° C.-90° C.; when the first wet precipitate is completely dissolved, cooling naturally, and standing at 5-25° C. for at least 20 h or 22-26 h; filtering after standing, collecting the second wet precipitate and the second mother liquor.

[0046] S43, concentrating the second mother liquor to 1 / 5 to 1 / 4 of the original volume, and the concentrating method can be vacuum concentration; then adding high-grade ethanol to the second mother liquor to make the ethanol concentration in the second mother liquor reach 60 to 65%; letting the second mother liquor stand at 5 to 25°C for at least 20 hours or for 22 to 26 hours, filtering after completion of the standing, and collecting the third wet precipitate and the third mother liquor.

[0047] S44, 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.

[0048] As a further explanation, in this step, the filtering method can be suction filtration or plate and frame filtration; the alkali solution uses a sodium hydroxide solution with a concentration of 1-3%; the concentration of the hydrochloric acid solution is 1-3%.

[0049] S5, separation of palmatine hydrochloride: S51, after concentrating the berberine crystallization mother liquor to 1 / 2-1 / 3 of the original volume (the Brix of the concentrate is usually 4-6 Brix at this time), let it stand at 5-25° C. for at least 48 h or 48-72 h to allow the precipitate to fully precipitate out, and the concentration method can be vacuum reduced pressure concentration; after completion of the standing, filter to obtain a fourth wet precipitate and a fourth mother liquor.

[0050] S52, adding an ethanol solution with a concentration of 60-65% to the fourth wet precipitate at a ratio of 1 g: 12-15 mL, and heating to 80°C-90°C; when the fourth wet precipitate is completely dissolved, naturally cool, and stand at 5-25°C for at least 20 hours or 22-26 hours; after standing, filter and collect the fifth wet precipitate and the fifth mother liquor.

[0051] S53, concentrating the fifth mother liquor to 1 / 5~1 / 4 of the original volume, and the concentrating method can be vacuum concentration; then adding high-grade ethanol to the fifth mother liquor to make the ethanol concentration in the fifth mother liquor reach 60~65%; letting the fifth mother liquor stand at 5~25°C for at least 20h or 22~26h, filtering after completion of standing, and collecting the sixth wet precipitate and the sixth mother liquor.

[0052] S54, combining the fourth mother liquor and the sixth mother liquor to obtain a bamipine crystallization mother liquor; combining the fifth wet precipitate and the sixth wet precipitate to obtain a wet precipitate containing bamipine hydrochloride.

[0053] As a further explanation, in this step, the filtering method can be suction filtration or plate and frame filtration.

[0054] S6, separation of jatrorrhizine hydrochloride by ion exchange resin and macroporous adsorption resin chromatography: S61, concentrating the bamipine crystallization mother liquor until it has no alcohol taste, and controlling the Brix of the bamipine crystallization mother liquor to be 1-3 Brix, to obtain a concentrated solution; specifically, vacuum-reducing the bamipine crystallization mother liquor to recover ethanol until it has no alcohol taste, and continuing to concentrate to 1-3 Brix, to obtain the concentrated solution.

[0055] S62, the concentrated solution is fed into an anion exchange resin at room temperature (e.g., 5-25°C), the feed effluent is collected, and the feed effluent is used as an ion exchange resin decolorant; as a preferred embodiment, after the concentrated solution is fed into the anion exchange resin column, a 3-5BV purification water washing column is used, 0-3BV of the washing column liquid is collected, and the feed effluent and the washing column liquid are combined as the ion exchange resin decolorant.

[0056] 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.

[0057] S63, the ion exchange resin decolorizing solution is introduced into a macroporous adsorption resin column, and then desorbed with an ethanol solution having a concentration of 40-45%, and the desorbed solution is collected; the desorbed solution is concentrated to 17-25 degrees Baume, and then the pH is adjusted to 4-6 with a hydrochloric acid solution to obtain a combined resin refined solution containing jatrorrhizine hydrochloride. As a preferred embodiment, after the ion exchange resin decolorizing solution is introduced into the macroporous adsorption resin column, before the desorption is performed, 2-4 BV of purified water is used to wash the column. 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%.

[0058] S7, Drying: 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 refined liquid containing jatrorrhizine hydrochloride is dried to obtain a jatrorrhizine hydrochloride product. Specifically, the wet precipitate containing berberine hydrochloride, the wet precipitate containing palmatine hydrochloride, and the combined resin refined liquid containing jatrorrhizine hydrochloride are vacuum dried or microwave vacuum dried at a temperature of 60°C to 65°C and a vacuum degree of ≧-0.085MPa to obtain bright yellow berberine hydrochloride and palmatine hydrochloride, and red-yellow jatrorrhizine hydrochloride, respectively; specifically, the berberine hydrochloride product and the palmatine hydrochloride product are yellow powders, and the jatrorrhizine hydrochloride product is a reddish-yellow powder with an orange-red tint.

[0059] 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 amount used will be too large, and if it is too high, it will cause waste and increase production costs, and cause obvious acid corrosion to the pipeline system.

[0060] In step S2 of the present invention, the leaching temperature is 50-65°C. The conventional process uses room temperature dilute acid leaching, 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 is significantly deepened, which is not conducive to product decolorization and purification, and damages the alkaloids, reducing the content of the extract, and the higher the temperature, the more obvious; the leaching temperature in the present invention can quickly extract the three alkaloid components, with stable content, short time, and high extraction efficiency.

[0061] In step S2 of the present invention, the antioxidant protective agent is a substance compounded with vitamin C and ferrous sulfate in a certain ratio, specifically vitamin C and ferrous sulfate in a mass ratio of 1 to 3:1. It should be noted that the addition of a specific antioxidant protective agent, especially a compound substance, can not only slow down the deepening of the color of the extract, but also keep the alkaloid component stable and not easily destroyed in a heating environment of 50 to 65°C, which is beneficial to decolorization and refining.

[0062] In step S3 of the present invention, the temperature is maintained at 60-65°C. At this temperature, the alkaloids of Phellodendron chinense, especially the sulfates of berberine, palmatine and jatrorrhizine, have a large solubility and are not easy to precipitate, which is conducive to membrane separation and purification. When the temperature is room temperature, the extract will become turbid and precipitate, and in severe cases, the membrane pores will be blocked and the equipment will be damaged. When the temperature is too high, it is not conducive to the stability of the content of the alkaloid components, and it also exceeds the maximum temperature that the special membrane can withstand, and the membrane separation technology cannot be used to purify the alkaloids.

[0063] In step S3 of the present invention, after the initial filtration, the extract is clarified by microfiltration through a ceramic membrane with a pore size of 200-800 nm; at 60-65° C., the precipitate in the extract can be removed by microfiltration through the ceramic membrane with the pore size to obtain a clear and transparent clear liquid without post-precipitation, which is beneficial to membrane separation and purification.

[0064] In step S3 of the present invention, the high-temperature ultrafiltration membrane can withstand a maximum temperature of 70°C, and the molecular weight cutoff is about 5KD. It is prepared by a unique high-temperature resistant membrane silk and paper membrane process. The membrane material of the high-temperature ultrafiltration membrane is PES or PVDF, and the model is UE series (such as UE005-8040H). It should be noted that only ultrafiltration membranes of special specifications can be used for preliminary purification of Phellodendron chinense alkaloids, because the maximum temperature that ordinary ultrafiltration membranes can withstand is 45°C, and under 45°C conditions, due to the difference in solubility of different alkaloid sulfates, when the ultrafiltration membrane runs to a smaller volume, alkaloids and other impurities will precipitate and block the membrane pores, which will not only damage the equipment and make the process impossible to proceed, but also reduce the product yield. In the present invention, the molecular weight cutoff is about 5KD, which can remove most impurities and pigments, and the Phellodendron chinense alkaloids can be completely passed through, thereby obtaining a higher purity of total Phellodendron chinense alkaloids.

[0065] In step S3 of the present invention, the high-temperature nanofiltration membrane can withstand a maximum temperature of 70°C, and the molecular weight cutoff is about 200D. The membrane material of the high-temperature nanofiltration membrane is PES, UF series (such as UF8040). It should be noted that only a specific type of nanofiltration membrane can concentrate the ultrafiltration membrane separation liquid of Phellodendron chinense alkaloids, because the maximum temperature that ordinary nanofiltration membranes can withstand is 45°C, and under 45°C conditions, due to the difference in the solubility of different alkaloid sulfates, during the nanofiltration membrane concentration process, alkaloids and other impurities will precipitate and block the membrane pores, which will not only damage the equipment and make the process impossible, but also reduce the product yield; the molecular weight cutoff is about 200D, which can completely intercept the Phellodendron chinense alkaloids; at 60~65°C, high-temperature resistant nanofiltration membrane concentration can replace traditional vacuum decompression concentration to obtain membrane refined liquid.

[0066] In step S4 of the present invention, berberine hydrochloride needs to be adjusted to a pH of 6 to 8 with dilute alkali before crystallization, filtered, and then adjusted to a pH of 2 to 3 with dilute hydrochloric acid. It should be noted that the solubility of the alkaloid sulfate of Phellodendron chinense is greater than that of the hydrochloride, and the solubility of berberine, palmatine and jatrorrhizine sulfate is not much different, which is not conducive to the crystallization of monomer alkaloids; and the solubility of the hydrochloride in cold and hot water is quite different, therefore, the hydrochloride is conducive to separation and purification, and the sulfate needs to be converted into the hydrochloride.

[0067] In step S4 of the present invention, the berberine hydrochloride crystallization condition is naturally cooled to 25-30°C, and kept warm for at least 48h or 48-72h; the recrystallization condition is 60-65% ethanol, 80-90°C heating to completely dissolve the precipitate, and after natural cooling, stand for at least 20h or 22-26h. It should be noted that after the aforementioned process is separated and concentrated with a high-temperature ultrafiltration membrane and a nanofiltration membrane, after naturally cooling to 25-30°C, the precipitation is allowed to stand for a sufficient time, and the berberine hydrochloride crystals are precipitated first, while only a small amount of bamipine hydrochloride is precipitated, and jatrorrhizine hydrochloride is not precipitated. The method of high-temperature membrane separation and temperature-controlled crystallization, due to the improvement of the purity and control temperature of the yellow rattan alkaloids, can not only replace salting out to completely precipitate berberine hydrochloride, but also obtain higher purity berberine hydrochloride crystals, avoiding the defects of salting out all alkaloids and increasing the difficulty of later purification and the pollution of the environment by a large amount of salt. As the crystallization temperature decreases, the amount of Bamipine hydrochloride crystallization increases, which is not conducive to the recrystallization and purification of berberine hydrochloride. Therefore, temperature control is very important. In the present invention, berberine hydrochloride with a purity of more than 97% can be obtained by recrystallization and fractional crystallization of 60-65% ethanol, while solving the practical problem that high ethanol is not easy to be recovered in industrial production due to the use of ethanol with a concentration of more than 80% in the traditional process, and is completely separated from a small amount of Bamipine hydrochloride precipitated in the crystallization stage.

[0068] In step S5 of the present invention, the condition for the crystallization of Bamipine hydrochloride is to concentrate the berberine hydrochloride crystallization mother liquor, and after natural cooling, stand for at least 48h or 48~72h; the condition for recrystallization is 60~65% ethanol, 80~90℃ heating to completely dissolve the precipitate, and naturally cool, and stand for at least 20h or 22~26h. It should be noted that after a certain volume and natural cooling, the precipitation is left to stand for enough time, and the crystallization of Bamipine hydrochloride is basically completely precipitated, and a small amount of berberine hydrochloride is precipitated together before, and jatrorrhizine hydrochloride is basically not precipitated. The results show that 60~65% ethanol recrystallization and fractional crystallization can obtain Bamipine hydrochloride with a purity of more than 95%, and solve the practical problem that the traditional process is not easy to recover high ethanol in industrial production due to the use of ethanol with a concentration of more than 80%, and separate from the small amount of berberine hydrochloride remaining in the mother liquor before.

[0069] In step S6 of the present invention, the anion exchange resin is a basic anion exchange resin, including gel-type and macroporous acrylic acid weak base anion resin, acrylic acid strong base and weak base anion resin, gel-type and macroporous styrene strong base anion resin, macroporous acrylic acid strong base anion resin, macroporous styrene weak base anion resin, preferably one of D900, D941, D316, D296, and D280. The crystallization mother liquor after separation of berberine hydrochloride and bamipine contains more pigments, and it is necessary to further separate the pigments and jatrorrhizine; there are literature reports on the use of cation exchange resin to purify alkaloids, and the cation resin has no adsorption on the pigment, but exchanges and adsorbs with jatrorrhizine hydrochloride and makes jatrorrhizine difficult to resolve, and the overall desorption rate is less than 20%, thereby causing a large amount of losses and cannot be used in production. The present invention adopts another method, firstly removing the pigment, that is, using anion exchange resin to exchange and adsorb the pigment, and the resin has no adsorption to jatrorrhizine hydrochloride, so that jatrorrhizine flows out from the anion resin column, thereby realizing the separation of jatrorrhizine and the pigment.

[0070] In step S6 of the present invention, the macroporous adsorption resin includes one of non-polar D101, LX-100B, LX-T28, weak polar AB-8, etc.; the desorption ethanol concentration is 40-45%. It should be noted that the macroporous adsorption resin of a certain specification has a strong adsorption to jatrorrhizine, but has a small adsorption to other impurities in the step-by-step crystallization mother liquor. After the high temperature membrane separation, crystallization, recrystallization and step-by-step crystallization separation of berberine hydrochloride and bamipine, and then the separation of pigments by anion exchange resin, some other impurities can be separated by a macroporous adsorption resin of a specific specification. When the ethanol concentration is high, the jatrorrhizine adsorbed on the resin and the impurities can be desorbed together, and the appropriate ethanol concentration, such as 40-45%, can be controlled to desorb only jatrorrhizine without desorbing most 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 performed first, if the macroporous adsorption resin is directly added, acid and alkali treatment is required after each batch of materials is added, which is difficult to apply to production; however, it has been verified through actual production that the present invention can use acid and alkali treatment once after treating 6 batches of materials, and during this period, it only needs to be treated with hot pure water before the next batch of materials can be added.

[0071] The present invention is based on Phellodendron chinense containing berberine hydrochloride, bamipine hydrochloride and jatrorrhizine hydrochloride, and continuously produces and prepares three high value-added products, thereby realizing comprehensive utilization of raw materials; temperature-controlled separation and crystallization are carried out through special high-temperature-resistant membranes, replacing salting out of acid-base solutions, thereby solving the problems of environmental pollution caused by salt wastewater, difficulty in regeneration due to alkaline browning and resin staining, and improving the purity of alkaloid monomers; jatrorrhizine hydrochloride is recovered from the mother liquor through the combination of resins; thus, an advanced and practical Phellodendron chinense extraction, separation and deep processing production technology system is formed.

[0072] The following are specific examples of the present invention: Example 1 A method for producing berberine, palmatine and jatrorrhizine hydrochloride based on Phellodendron chinense, the steps of which are: S1, broken: 800 kg of dried vine stems of Phellodendron chinense imported from Laos were taken and crushed into coarse powder basically the size of grains by a hammer mill; based on the weight proportion and the form of hydrochloride, the coarse powder of Phellodendron chinense contained 2.37% berberine hydrochloride, 2.21% bamipine hydrochloride and 0.79% jatrorrhizine hydrochloride.

[0073] S2, dilute acid warm extraction: The above coarse powder is put into 6m 3 Extract with dilute sulfuric acid in an enamel extraction tank.

[0074] In this embodiment, extraction is performed three times, and the third extraction is performed as a set; the extraction temperature is 58°C; the stirring mode during extraction is: stirring is started for 2 minutes at intervals of 10 minutes; during the three extractions, the amount of antioxidant added is 16.0kg, 6.5kg, and 3.0kg, respectively, and the antioxidant is composed of vitamin C and ferrous sulfate in a mass ratio of 2:1; during the three extractions, the extraction time is 3.0h, 2.0h, and 1.0h, respectively; the concentration of dilute sulfuric acid used is 0.3%; during the three extractions, the amount of dilute sulfuric acid added is 4800L, 4000L, and 4800L, respectively; filtration is performed after each extraction, and the filter residue enters the next extraction, and the filtrate obtained from the first two extractions is combined to obtain 7150L of extract.

[0075] S3, temperature controlled filtration clarification and membrane separation: S31, control and maintain the temperature of the extract at 63°C; first filter by plate and frame, and then clarify the filtrate through microfiltration of a ceramic membrane made of zirconium oxide and with a pore size of 500nm; when only 200L of the upstream liquid is left, add 400L of hot water at a temperature of 65°C to dilute the upstream liquid and continue to pass through the membrane; when only 200L of the upstream liquid is left again, add 400L of hot water at a temperature of 65°C to dilute the upstream liquid and continue to pass through the membrane; collect the liquid downstream of the membrane to obtain the clear liquid.

[0076] S32, control and maintain the temperature of the clear liquid at 63℃; adjust the pH value of the clear liquid to 3 with 2% sodium hydroxide solution, and then pass it through a high-temperature ultrafiltration membrane (membrane material PVDF, model UE005-8040H) that can withstand a maximum temperature of 70℃ and has a molecular weight cutoff of 5KD; when only 200L of the upstream liquid is left, add 400L of hot water at a temperature of 63℃ to dilute the upstream liquid and continue to pass through the membrane; when only 200L of the upstream liquid is left again, add 400L of hot water at a temperature of 63℃ to dilute the upstream liquid again and continue to pass through the membrane; collect the liquid downstream of the membrane, about 8300L.

[0077] S33, control and maintain the temperature of the downstream liquid of the membrane (derived from step S32) at 63°C; pass the downstream liquid of the membrane through a high-temperature nanofiltration membrane (material PES, model UF8040) that can withstand a maximum temperature of 70°C and has a molecular weight cutoff of 200D, collect the upstream liquid of the membrane, and obtain a membrane refined liquid, about 850L.

[0078] S4, separation of berberine hydrochloride: S41, adjust the pH value of membrane refined liquid to 7 with 2% sodium hydroxide solution, filter with plate and frame, and then adjust the pH value to 2 with 2% hydrochloric acid solution, cool naturally to 28℃ and keep warm for 65h (do it under static condition) to make the precipitate fully precipitate out, filter with plate and frame, collect wet precipitate and mother liquor separately, weigh and measure the volume, and get 43.10kg wet precipitate and 810L mother liquor.

[0079] S42, add 600 L of 64% ethanol, heat at 85°C and stir to completely dissolve the wet precipitate in step S41, cool naturally to room temperature (in this embodiment, the liquid temperature corresponding to room temperature is about 15°C), let stand for 24 hours, filter by plate and frame, collect the wet precipitate and mother liquor separately, weigh and measure the volume, and obtain 28.0 kg of wet precipitate and 570 L of mother liquor.

[0080] S43, vacuum-concentrate 570L of mother liquor in step S42 to 130L, add high-grade ethanol to adjust the ethanol concentration to 60%, naturally cool to room temperature, let stand for 24h, filter by plate and frame, collect wet precipitate and mother liquor separately, and obtain 6.9kg of wet precipitate and 150L of mother liquor.

[0081] S44, combining the mother liquors in step S41 and step S43 to obtain about 960 L of berberine crystallization mother liquor; combining the wet precipitates in step S42 and step S43 to obtain 34.9 kg of bright yellow wet precipitate containing berberine hydrochloride.

[0082] S5, separation of palmatine hydrochloride: S51, 960L of berberine crystallization mother liquor was concentrated to 350L by vacuum decompression, cooled naturally to room temperature, and allowed to stand for 72h to allow the precipitate to fully precipitate, and the wet precipitate and mother liquor were collected by plate and frame filtration, respectively, and weighed and measured to obtain 41.50kg of wet precipitate and 310L of mother liquor.

[0083] S52, add 550L of 64% ethanol, heat at 85°C and stir to completely dissolve the wet precipitate in step S51, cool naturally to room temperature, let stand for 24h, filter by plate and frame, collect the wet precipitate and mother liquor separately, and obtain 27.6kg of wet precipitate and 530L of mother liquor.

[0084] S53, vacuum-concentrate the 530L mother liquor in step S52 to 120L, add high-grade ethanol to adjust the ethanol concentration to 60%, naturally cool to room temperature, let stand for 24h, filter by plate and frame, collect the wet precipitate and mother liquor separately, and obtain 7.2kg wet precipitate and 140L mother liquor.

[0085] S54, combining the mother liquors in step S51 and step S53 to obtain 450 L of bamipine crystallization mother liquor; combining the wet precipitates in step S52 and step S53 to obtain 34.8 kg of bright yellow wet precipitate containing bamipine hydrochloride.

[0086] S6, separation of jatrorrhizine hydrochloride by ion exchange resin + macroporous adsorption resin chromatography: S61, vacuum decompress the mother liquor of bamipine crystallization to recover ethanol until there is no alcohol taste, add water to remove alcohol, and concentrate to 350L to obtain a concentrated solution (2.2Brix).

[0087] S62, the concentrated liquid is cooled to room temperature and fed into an anion exchange resin column loaded with 60 kg of model D900. After the feeding is completed, it is fed into a 250 L purified water washing column (4.17 BV). The feed effluent and 180 L of water washing column liquid (3 BV) are collected and combined to obtain an ion exchange resin decolorizing liquid.

[0088] S63, the ion exchange resin decolorizing liquid is fed into a non-polar macroporous adsorption resin column containing 250 kg of LX-T28, and then fed into a 750 L purified water washing column (3BV), and then desorbed with 900 L of 40% ethanol, the desorbed liquid is collected, and concentrated to 18 degrees Baume under vacuum, and the pH is adjusted to 4 with 2% hydrochloric acid solution to obtain a combined resin refined liquid containing jatrorrhizine hydrochloride.

[0089] S7, Drying: The wet precipitate containing berberine hydrochloride is dried to obtain a berberine hydrochloride product; the wet precipitate containing bamipine hydrochloride is dried to obtain a bamipine hydrochloride product; the combined resin refined liquid containing jatrorrhizine hydrochloride is dried to obtain a jatrorrhizine hydrochloride product; the drying method is: microwave vacuum drying, the temperature is 63°C, and the vacuum degree is ≧-0.085MPa.

[0090] In this embodiment, the mass of the berberine hydrochloride product is 16.40 kg, the mass of the palmatine hydrochloride product is 15.1 kg, and the mass of the jatrorrhizine hydrochloride product is 6.2 kg.

[0091] In the berberine hydrochloride product of this embodiment, the mass proportion of berberine hydrochloride is 97.61%; in the bamipine hydrochloride product of this embodiment, the mass proportion of bamipine hydrochloride is 95.86%; in the jatrorrhizine hydrochloride product of this embodiment, the mass proportion of jatrorrhizine hydrochloride is 81.20%.

[0092] In this embodiment, the berberine hydrochloride product and the palmatine hydrochloride product are yellow powders, and the jatrorrhizine hydrochloride product is a reddish yellow powder with an orange-red tint.

[0093] Comparative Example 1 Compared with Example 1, in this comparative example, only the extraction temperature in step S2 is adjusted to room temperature, and other conditions remain unchanged.

[0094] In this comparative example, the mass of the berberine hydrochloride product is 11.80 kg, the mass of the palmatine hydrochloride product is 11.02 kg, and the mass of the jatrorrhizine hydrochloride product is 4.33 kg; the results show that when extracted at room temperature for the same time as in Example 1, the yields of the three alkaloids are all less than 70%, and they cannot be fully extracted.

[0095] Comparative Example 2 Compared with Example 1, the antioxidant protective agent in step S2 was omitted in this comparative example, and other conditions remained unchanged.

[0096] In this comparative example, visual inspection of the products showed that the berberine hydrochloride product and the bamipine hydrochloride product were dark yellow in color and had poor gloss.

[0097] Comparative Example 3 Compared with Example 1, in this comparative example, only the control temperature of the extract in step S31 is adjusted to 45° C., and other conditions remain unchanged.

[0098] In this comparative example, after 30 minutes of operation, the flux of the ceramic membrane dropped from 1.5 T / h to 400 L / h, a significant decrease, and could not operate normally, requiring shutdown for cleaning, and the upstream liquid volume was greater than 500 L.

[0099] Comparative Example 4 Compared with Example 1, in this comparative example, only the control temperature of the clear liquid in step S32 is adjusted to 40° C., and other conditions remain unchanged.

[0100] In this comparative example, after the ultrafiltration membrane ran for 1 hour, the flux dropped from 1000L / h to 300L / h, a significant drop, and could not operate normally, requiring shutdown for cleaning, and the upstream liquid volume was greater than 1000L.

[0101] Comparative Example 5 Compared with Example 1, in this comparative example, only the control temperature of the membrane downstream liquid (derived from step S32) in step S33 is adjusted to 40° C., and other conditions remain unchanged.

[0102] In this comparative example, after the nanofiltration membrane ran for 40 minutes, the flux dropped from 1000L / h to 200L / h, a significant drop, and could not operate normally, requiring shutdown for cleaning, and the upstream liquid volume was greater than 3000L.

[0103] Comparative Example 6 Compared with Example 1, in this comparative example, only the insulation temperature in step S41 is adjusted from 28° C. to room temperature, and other conditions remain unchanged.

[0104] In this comparative example, the mass of the wet precipitate obtained in step S41 is 80.70 kg, and the mother liquor is 760 L, indicating that most of the palmatine hydrochloride and jatrorrhizine hydrochloride will precipitate simultaneously with berberine hydrochloride.

[0105] In this comparative example, the mass of the berberine hydrochloride product is 16.85 kg, and the mass proportion of berberine hydrochloride in the berberine hydrochloride product is only 94.10%, which does not meet the requirement of the 2020 edition of the Pharmacopoeia of the People's Republic of China that the content of berberine hydrochloride from the extraction source should not be less than 97%.

[0106] Comparative Example 7 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.

[0107] In this comparative example, the mass of the jatrorrhizine hydrochloride product is 4.05 kg, the mass of jatrorrhizine hydrochloride in the jatrorrhizine hydrochloride product accounts for 81.50%, and the color is reddish yellow, indicating that the activated carbon causes significant adsorption loss of jatrorrhizine hydrochloride.

[0108] Comparative Example 8 Compared with Example 1, this comparative example omits step S62 (i.e., the concentrated solution of the bamipine crystallization mother solution is directly fed into the non-polar macroporous adsorption resin column), and other conditions remain unchanged.

[0109] In this comparative example, the mass of the jatrorrhizine hydrochloride product is 6.85 kg, and the mass proportion of jatrorrhizine hydrochloride in the jatrorrhizine hydrochloride product is 73.50%; the color is yellowish and shiny, which is quite different from the reddish-yellow shiny color.

[0110] The above technical solutions of the present invention are only preferred embodiments of the present invention, and are not intended to limit the patent scope of the present invention. All equivalent structural changes made using the specification of the present invention under the technical concept of the present invention, or directly / indirectly applied in other related technical fields, are included in the patent protection scope of the present invention.

Claims

1. A method for producing berberine, palmatine and jatrorrhizine hydrochloride based on Phellodendron chinense, characterized in that: Includes steps: S1, providing a powder derived from Phellodendron chinense and containing berberine, palmatine and jatrorrhizine; S2, extracting the powder to obtain an extract; S3, the extract is filtered, ultrafiltered and nanofiltered in sequence, and the membrane upstream liquid is taken; S4, adjusting the pH of the membrane upstream liquid to 6-8 with an alkali solution, filtering, adjusting the pH to 2-3 with a hydrochloric acid solution, letting it stand and filtering, and 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, letting it stand and filtering, collecting a second wet precipitate and a second mother liquor; making the ethanol concentration in the second mother liquor reach 60-65%, letting it stand and filtering, collecting a third wet precipitate and a 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, letting it stand and filtering, to obtain 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, letting it stand and filtering, collecting a fifth wet precipitate and a fifth mother liquor; making the ethanol concentration in the fifth mother liquor reach 60-65%, letting it stand and filtering, collecting a sixth wet precipitate and a 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 bamipine crystallization mother liquor to obtain a concentrated solution; feeding the concentrated solution into an anion exchange resin column, feeding the collected feed effluent into a macroporous adsorption resin column, and collecting the desorbed solution after desorption; concentrating the desorbed solution, adjusting the pH to 4-6 with a hydrochloric acid solution, and obtaining a combined resin refined solution containing jatrorrhizine hydrochloride.

2. The method for producing berberine, palmatine and jatrorrhizine hydrochloride based on Phellodendron chinense according to claim 1, characterized in that: Calculated by weight percentage and in the form of hydrochloride, the content of berberine hydrochloride in the powder is 1.5-3%, the content of palmatine hydrochloride is 2-4.5%, and the content of jatrorrhizine hydrochloride is 0.4-1.0%.

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

4. The method for producing berberine, palmatine and jatrorrhizine hydrochloride based on Phellodendron chinense according to claim 3, characterized in that: In the step S2, the number of leaching is three times; when performing the first leaching, the ratio of the sulfuric acid solution to the powder is controlled to be 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 filtering; when performing the second leaching, the ratio of the sulfuric acid solution to the powder is controlled to be 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 filtering; when performing the third leaching, the ratio of the sulfuric acid solution to the powder is controlled to be 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 filtering; the first filtrate and the second filtrate are combined as the extract, and the third filtrate is used for leaching the next batch of the powder.

5. The method for producing berberine, palmatine and jatrorrhizine hydrochloride based on Phellodendron chinense according to claim 1, characterized in that: In step S3, the filtering process includes: controlling the temperature of the extract to be 60-65° C.; performing primary filtration and microfiltration on the extract in sequence to obtain a clear solution; The ultrafiltration process includes: controlling the temperature of the clear liquid to 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 to collect the liquid downstream of the membrane; the maximum bearing temperature of the high-temperature ultrafiltration membrane is not less than 70°C, and the molecular weight cutoff of the high-temperature ultrafiltration membrane is 3-5KD; The nanofiltration process includes: controlling the temperature of the liquid downstream of the membrane to 60-65°C; passing the liquid downstream of the membrane through a high-temperature nanofiltration membrane, collecting the liquid upstream of the membrane, and the liquid upstream of the membrane is the membrane refined liquid; the maximum tolerable temperature of the high-temperature nanofiltration membrane is not less than 70°C, and the molecular weight cutoff of the high-temperature nanofiltration membrane is 150-300D.

6. The method for producing berberine, palmatine and jatrorrhizine hydrochloride based on Phellodendron chinense according to claim 1, characterized in that: In the 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 Phellodendron chinense according to claim 1, characterized in that: In the step S5, the process of concentrating the berberine crystallization mother liquor comprises: concentrating the berberine crystallization mother liquor to 1 / 2 to 1 / 3 of the original volume; In the 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 Phellodendron chinense according to claim 1, characterized in that: In the step S6, the process of concentrating the bamipine crystallization mother liquor comprises: concentrating the bamipine crystallization mother liquor until there is no alcohol taste, and controlling the brix of the bamipine crystallization mother liquor to be 1-3 Brix; In the step S6, desorption is performed using an ethanol solution with a concentration of 40-45%; In the step S6, the process of concentrating the desorption liquid includes: concentrating the desorption liquid to 17-25 degrees Baume; The step S6 also includes: after the concentrated solution enters the anion exchange resin column, the column is washed with purified water, the washing column liquid is collected, the feed effluent and the washing column liquid are combined as an ion exchange resin decolorizing liquid, and they are jointly introduced into the macroporous adsorption resin column; after the ion exchange resin decolorizing liquid enters the macroporous adsorption resin column, before the desorption is performed, the column is washed with purified water.

9. The method for producing berberine, palmatine and jatrorrhizine hydrochloride based on Phellodendron chinense according to claim 1, characterized in that: 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.

10. The method for producing berberine, palmatine and jatrorrhizine hydrochloride based on Phellodendron chinense according to any one of claims 1 to 9, 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 combined resin refined liquid containing jatrorrhizine hydrochloride is dried to obtain a jatrorrhizine hydrochloride product.