A method for electrochemically preparing a berberine reduction product

Abstract

The application discloses a method for electrochemically preparing berberine reduction products, and the method comprises the following steps: performing electrochemical reaction on a mixed electrolyte in an electrolysis reactor provided with an anode plate and a cathode plate; the mixed electrolyte comprises a first organic solvent, an electrolyte and free berberine; the concentration of the free berberine dissolved in the organic solvent is 0.1-10.0 mol / L, and the molar mass of the electrolyte is 20-100% of the molar mass of the free berberine; and the berberine reduction products are dihydroberberine and / or tetrahydroberberine. The method is simple to operate, avoids the use of noble metal catalysts, and has the advantages of high product yield, good purity, few by-products, and recyclable solvent and filtrate.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of chemical synthesis, and provides a method for preparing a berberine reduction product by reducing berberine through an electrochemical method. BACKGROUND

[0002] Berberine (CAS: 2086-83-1), also known as Coptis, is an isoquinoline quaternary alkaloid (5,6-dihydrobenzoquinolizine derivative) derived from various medicinal plants, such as Coptis teeta, Coptis chinensis, and Coptis deltoidea. Berberine has been used in traditional Chinese medicine for a long time to treat gastrointestinal diseases caused by bacterial infections. In addition, studies have shown that berberine also has anti-tumor, anti-infective, anti-oxidative, hypoglycemic, and hypolipidemic pharmacological effects. Berberine reduction products such as dihydroberberine (CAS: 483-15-8) and tetrahydroberberine (CAS: 522-97-4) have been reported.

[0003] Dihydroberberine is a natural plant alkaloid with strong anti-diabetic effects and has been proven to have a healthy weight loss effect, even better than anti-diabetic drugs such as metformin in controlled study trials. In addition, dihydroberberine also has a lipid-regulating mechanism mediated by hepatocyte nuclear factor-4α (HNF-4α) and achieved through the regulation of the MicroRNA 122 (miR122) pathway. This mechanism of action is related to the inhibition of relevant signaling pathways, particularly the inhibition of inflammatory responses. The application of dihydroberberine in clinical treatment, including its excellent performance in anti-diabetes and weight loss, plays an important role in the prevention and treatment of cardiovascular diseases, and also includes anti-inflammatory, anti-atherosclerotic, hypolipidemic, anti-tumor activity, anti-myocardial ischemia, and anti-arrhythmic effects. In addition, studies have also found that dihydroberberine plays an important role in anti-aging, particularly in reducing or preventing skin aging, cellular aging, or photoaging. The bioavailability of dihydroberberine is 5 times higher than that of ordinary berberine. Human studies have shown that 200 mg of dihydroberberine causes a 22-fold increase in berberine serum concentration compared to 500 mg of berberine, and significantly improves insulin signaling and glucose handling, with significant pharmacokinetic advantages.

[0004] Tetrahydroberberine (THB) is derived from the rhizome of the poppy family plant Corydalis, and belongs to tetrahydroisoquinoline alkaloids, which can also be hydrogenated from berberine. Compared with berberine, tetrahydroberberine also has a variety of significant biological activities. Current research has found that tetrahydroberberine has anti-hypertensive, anti-arrhythmic, anti-fibrillation, anti-acute myocardial infarction, and treatment and protection effects on ischemia-reperfusion injury. Studies have also reported that tetrahydroberberine has antioxidant and gastrointestinal function regulating effects.

[0005] Patent document CN108997332A discloses a preparation method of dihydroberberine, which comprises dissolving berberine in a certain solvent and carrying out catalytic transfer hydrogenation reaction with a hydrogen donor to obtain the reduced product dihydroberberine. The method needs to use a noble metal catalyst, which is high in cost, difficult to recover, and the residual noble metal may affect the product quality.

[0006] Although there are many research reports on the synthesis method of dihydroberberine / tetrahydroberberine in recent years, the main limitation is the traditional chemical synthesis method. Therefore, it is of great significance to develop a new preparation method of reduced product (dihydroberberine and / or tetrahydroberberine) which is low in cost, mild in reaction condition, easy to operate, simple in post-treatment, environment-friendly and high in yield. SUMMARY

[0007] In view of the deficiencies in the prior art, the first aspect of the present application provides a method for electrochemically preparing a reduced product of berberine.

[0008] In the first aspect, the present application provides a method for electrochemically preparing a reduced product of berberine, characterized in that an electrochemical reaction is carried out by applying electricity to a mixed electrolyte in an electrolytic reactor provided with an anode and a cathode plate.

[0009] The material of the anode is metal Mg, Al, Zn, Pt, or an alloy or plating layer containing at least two or more of Mg, Al, Zn and Pt, and the material of the cathode is metal Pt, Ni, Cu, Ag, Au, Pb, or an alloy or plating layer containing at least two or more of Pt, Ni, Cu, Ag, Au and Pb.

[0010] The mixed electrolyte contains a first organic solvent, an electrolyte and free berberine (compound 3); the first organic solvent is selected from one or more of methanol, ethanol, propanol, toluene, acetonitrile, N,N-dimethylformamide and dimethyl sulfoxide; the electrolyte is selected from one or more of sodium methoxide, sodium ethoxide, sodium hydroxide and potassium tert-butoxide; in the mixed electrolyte, the concentration of free berberine dissolved in the organic solvent is 0.1-10.0 mol / L, and the molar amount of the electrolyte is 20-100% of the molar amount of free berberine.

[0011] When electricity is applied, the current density is maintained at 1200-1800 A / m 2 , and the electrolytic potential is 1.5-3.0 V.

[0012] In the electrochemical reaction, the reaction temperature is 0-80℃, and the reaction pressure is 0.5-5 MPa.

[0013] The reduced product of berberine is dihydroberberine and / or tetrahydroberberine.

[0014] In some embodiments, the material of the anode is metal Mg or Al.

[0015] Preferably, in some embodiments, the material of the anode is metal Mg.

[0016] Preferably, in some embodiments, the material of the anode is metal Al.

[0017] In some embodiments, the material of the cathode is metal Ag or Pt.

[0018] Preferably, in some embodiments, the material of the cathode is metal Ag.

[0019] Preferably, in some embodiments, the material of the cathode is metal Pt.

[0020] In some embodiments, the first organic solvent is methanol or ethanol.

[0021] Preferably, in some embodiments, the first organic solvent is methanol.

[0022] Preferably, in some embodiments, the first organic solvent is ethanol.

[0023] In some embodiments, the electrolyte is sodium methoxide or sodium ethoxide.

[0024] Preferably, in some embodiments, the electrolyte is sodium methoxide.

[0025] Preferably, in some embodiments, the electrolyte is sodium ethoxide.

[0026] In some embodiments, the first organic solvent is methanol and the electrolyte is sodium methoxide.

[0027] In other embodiments, the first organic solvent is ethanol and the electrolyte is sodium ethoxide.

[0028] In some embodiments, the current density is 1200-1500 A / m 2 .

[0029] Preferably, in some embodiments, the current density is 1500 A / m 2 .

[0030] In some embodiments, the electrolysis potential is 2.2-3.0 V.

[0031] Preferably, in some embodiments, the electrolysis potential is 2.5 V.

[0032] In some embodiments, the reaction temperature is 25-80℃.

[0033] Preferably, in some embodiments, the reaction temperature is 40-80℃.

[0034] More preferably, in some embodiments, the reaction temperature is 60-80℃.

[0035] In some embodiments, the reaction pressure is 1-5 MPa.

[0036] Preferably, in some embodiments, the reaction pressure is 2-5 MPa.

[0037] More preferably, in some embodiments, the reaction pressure is 2-4 MPa.

[0038] In some embodiments, the time of the electrochemical reaction is 1-24 h.

[0039] Preferably, the time of the electrochemical reaction is 1-12 h.

[0040] More preferably, the time of the electrochemical reaction is 3-10 h.

[0041] More preferably, the time of the electrochemical reaction is 5-8 h.

[0042] In some embodiments, the concentration of free berberine dissolved in the organic solvent in the mixed electrolyte is 0.1-10.0 mol / L. Preferably, the concentration of free berberine dissolved in the organic solvent is 0.5-8.0 mol / L. More preferably, the concentration of free berberine dissolved in the organic solvent is 1.0-5.0 mol / L. More preferably, the concentration of free berberine dissolved in the organic solvent is 1.5-4.0 mol / L.

[0043] In some embodiments, the free berberine (compound 3) is obtained by neutralization of a salt of berberine in a second organic solvent with a base; the second organic solvent is selected from one or more of dichloromethane, methanol, acetonitrile, acetone ethanol, water, chloroform, ethyl acetate; and the base is selected from one or more of triethylamine, sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate.

[0044] Preferably, the salt of berberine is berberine hydrochloride.

[0045] More preferably, the molar ratio of the amount of base to berberine hydrochloride is 1.1-3 times.

[0046] More preferably, the reaction temperature of the neutralization reaction is 0-30℃.

[0047] More preferably, the reaction time of the neutralization reaction is 3-6h.

[0048] In some embodiments, the electrolysis reactor is a diaphragmless high pressure electrolysis reactor.

[0049] In some embodiments, the shape of the cathode and the anode is rod-like, sheet-like or net-like. The shape of the cathode and the anode does not constitute any limitation to the present application.

[0050] In some embodiments, in the mixed electrolyte, the concentration of the free berberine dissolved in the organic solvent is 0.1-10.0 mol / L, the molar amount of the electrolyte is 20-40% of the molar amount of the free berberine, and the berberine reduction product is dihydroberberine.

[0051] Preferably, the molar amount of the electrolyte is 20-35% of the molar amount of the free berberine. More preferably, the molar amount of the electrolyte is 20-30% of the molar amount of the free berberine.

[0052] Preferably, the berberine reduction product is dihydroberberine, and the dihydroberberine is refined to obtain a product. More preferably, the refining method is to beat the dihydroberberine with an ethanol / water solution, to perform suction filtration, and to collect the filter cake. Further preferably, the ethanol / water solution is an ethanol / water solution with a mass fraction of 50%-80%. Still further preferably, the ethanol / water solution is an ethanol / water solution with a mass fraction of 60%-75%. More preferably, the ethanol / water solution is an ethanol / water solution with a mass fraction of 60%. The refined dihydroberberine product has a purity of ≥99%.

[0053] Preferably, in some embodiments, the method further comprises the following steps:

[0054] (1) separating the dihydroberberine;

[0055] (2) mixing the separated dihydroberberine with a first organic solvent and an electrolyte to form a mixed electrolyte, and performing an electrochemical reaction on the mixed electrolyte in an electrolysis reactor provided with an anode and a cathode plate;

[0056] The material of the anode is metal Mg, Al, Zn, Pt, or an alloy or plating layer containing at least two or more of Mg, Al, Zn and Pt, and the material of the cathode is metal Pt, Ni, Cu, Ag, Au, Pb, or an alloy or plating layer containing at least two or more of Pt, Ni, Cu, Ag, Au and Pb.

[0057] The first organic solvent is selected from one or more of methanol, ethanol, propanol, toluene, acetonitrile, N, N-dimethylformamide, dimethyl sulfoxide; the electrolyte is selected from one or more of sodium methoxide, sodium ethoxide, sodium hydroxide, potassium tert-butoxide; in the mixed electrolyte, the concentration of free berberine dissolved in the organic solvent is 0.1-10.0 mol / L, and the molar amount of the electrolyte is 20-40% of the molar amount of the free berberine.

[0058] During the power-on, the current density is maintained at 1200-1800 A / m 2 , and the electrolytic potential is 1.5-3.0 V.

[0059] In the electrochemical reaction, the reaction temperature is 0-80℃, and the reaction pressure is 0.5-5 MPa.

[0060] The berberine reduction product is tetrahydroberberine.

[0061] More preferably, the molar amount of the electrolyte is 20-30% of the molar amount of the free berberine.

[0062] More preferably, the molar amount of the electrolyte is 20-30% of the molar amount of the free berberine.

[0063] In some embodiments, in the mixed electrolyte, the concentration of free berberine dissolved in the organic solvent is 0.1-10.0 mol / L, the molar amount of the electrolyte is 40-100% of the molar amount of the free berberine, and the berberine reduction product is tetrahydroberberine.

[0064] Preferably, the molar amount of the electrolyte is 40-80% of the molar amount of the free berberine.

[0065] More preferably, the molar amount of the electrolyte is 40-60% of the molar amount of the free berberine.

[0066] Preferably, the separation of the dihydroberberine includes refining the dihydroberberine. More preferably, the refining method is to pulp the dihydroberberine with an ethanol / water solution, to extract and filter, and to collect the filter cake. Further preferably, the ethanol / water solution is an ethanol / water solution with a mass fraction of 50%-80%. Still further preferably, the ethanol / water solution is an ethanol / water solution with a mass fraction of 60%-75%. More preferably, the ethanol / water solution is an ethanol / water solution with a mass fraction of 60%.

[0067] Preferably, the berberine reduction product is tetrahydroberberine, and the tetrahydroberberine is refined to obtain a product. More preferably, the refining method is to pulp the tetrahydroberberine with an ethanol / water solution, to extract the filter cake. Further preferably, the ethanol / water solution is an ethanol / water solution with a mass fraction of 50% to 80%. Still further preferably, the ethanol / water solution is an ethanol / water solution with a mass fraction of 60% to 75%. Still more preferably, the ethanol / water solution is an ethanol / water solution with a mass fraction of 75%. The refined tetrahydroberberine product has a purity of ≥99%.

[0068] The present application provides a synthetic method of dihydroberberine and tetrahydroberberine suitable for industrial production. The synthetic method is simple and easy to operate, and dihydroberberine and tetrahydroberberine with high purity and good stability are obtained.

[0069] The beneficial effects of the present application include:

[0070] (1) The method of the present application is simple to operate and avoids the use of noble metal catalysts, providing a new option for the preparation of dihydroberberine or tetrahydroberberine.

[0071] (2) The method of the present application has mild reaction conditions, high product yield, good purity, and few by-products. The purity of dihydroberberine or tetrahydroberberine is 99% as detected by HPLC.

[0072] (3) The method of the present application can obtain a crude product by concentrating and filtering the reaction solution after the reaction is completed, and the product can be obtained after further refining. This method is efficient and environmentally friendly, the solvent is easy to recover, the filtrate can be reused, the cost is low, and each step is suitable for industrial production. BRIEF DESCRIPTION OF DRAWINGS

[0073] Figure 1 The flowchart shows the preparation of dihydroberberine (compound 1) and tetrahydroberberine (compound 2) by the method of the present application.

[0074] Figure 2 A representative H NMR spectrum of dihydroberberine prepared by the method of the present application. 1

[0075] Figure 3 A representative H NMR spectrum of tetrahydroberberine prepared by the method of the present application. 1 DETAILED DESCRIPTION

[0076] ​​The technical solutions of the present application will be described clearly and completely below. Obviously, the described embodiments are part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative work fall within the scope of protection of the present application.

[0077] The experimental materials involved in the present application can be obtained from the market channels unless otherwise specified.

[0078] The free berberine (compound 3) involved in the following embodiments is obtained by referring to the following preparation method:

[0079] The raw material berberine hydrochloride (400 g, 1.08 mol) is dispersed in 1 L of acetone solution, and an aqueous solution (100 mL) of potassium hydroxide (90 g, 1.62 mmol) is added. Stirring is carried out at room temperature for 5 h, and yellow solid is precipitated. Filtration is performed, the solid is washed with 200 mL of acetone, and drying is performed to obtain 361 g of free berberine with a yield of 100%.

[0080] In the following embodiments, the HPLC purity detection conditions of the product are as follows: a C18 chromatographic column, a mobile phase of methanol: water: trifluoroacetic acid = 60:35:5, a flow rate of 1.0 mL / min, and a column temperature of 20°C.

[0081] In the following embodiments, the purification method of the product dihydroberberine is beating in an ethanol / water system. For example, a specific operation method is as follows: the crude product is beaten with a 60% ethanol / water solution, stirring is performed for 1 h, and then filtration is performed. The collected filter cake is dried at 50°C under vacuum to obtain dihydroberberine as a light yellow solid.

[0082] In the following embodiments, the purification method of the product tetrahydroberberine is beating in an ethanol / water system. For example, a specific operation method is as follows: the crude product is beaten with a 75% ethanol / water solution, stirring is performed for 1 h, and then filtration is performed. The collected filter cake is dried at 50°C under vacuum to obtain tetrahydroberberine as a yellow solid.

[0083] Example 1

[0084] 360 g of free berberine (compound 3, 1.07 mol), 16 g of sodium methoxide (0.30 mol), and 265 g of methanol (about 335 ml) are mixed and dissolved. The mixed solution is added to a 2 L high-pressure electrolysis reactor, replaced with N2, and pressurized to 2.0 MPaG. The temperature of the reactor is increased to 50°C. The anode of the electrolysis reactor is Mg, and the cathode is Ag, both of which are mesh electrodes with an electrolysis area of 0.1 m 2 The electrolysis potential is set to 2.5 V, and the electrolysis current density is 1500 A / m 2The reaction was ended after 5h, vented to normal pressure, and the solvent was recovered at a vacuum of 0.01 MPaG and a temperature of 50°C. The crude berberine (compound 1) was obtained by hot filtration, 357g, and after purification, 350g of berberine was obtained, a yield of 97.8%, and a purity of 99% by HPLC. 1 HNMR (400 MHz, DMSO-d6) δ 7.30 (s, 1H), 6.90 (d, J = 8.32 Hz, 1H), 6.76 (s, 1H), 6.70 (d, J = 8.28 Hz, 1H), 6.06 (s, 1H), 6.01 (s, 2H), 4.21 (s, 2H), 3.77 (s, 3H), 3.72 (s, 3H), 3.06 (t, J = 5.88 Hz, 2H), 2.80 (t, J = 5.88 Hz, 2H).

[0085] 330g of berberine (0.98mol), 15g of sodium methoxide (0.28mol), and 260g of methanol (about 330ml) were mixed and dissolved, the mixed solution was added to a 2L high-pressure electrolysis reactor, replaced with N2, and pressurized to 2.0 MPaG. The temperature of the reactor was raised to 60°C. The anode of the electrolysis reactor was Mg and the cathode was Ag, both were mesh electrodes, and the electrolysis area was 0.1m2. 2 The electrolysis potential was set to 2.5V and the electrolysis current density was 1500A / m 2 The reaction was ended after 8h, vented to normal pressure, and the solvent was recovered at a vacuum of -0.02 MPaG and a temperature of 50°C. The crude tetrahydroberberine (compound 2) was obtained by hot filtration, 325g, and after purification, 315g of tetrahydroberberine was obtained, a yield of 96.6%, and a purity of 99% by HPLC. 1 HNMR (400 MHz, DMSO-d6) δ 6.92 (s, 1H), 6.88-6.85 (m, 2H), 6.67 (s, 1H), 5.95 (s, 2H), 4.06 (d, J = 4.2 Hz, 1H), 3.78 (s, 3H), 3.73 (s, 3H), 3.28-3.28 (m, 2H), 3.11-3.07 (m, 1H), 2.95-2.87 (m, 1H), 2.62-2.56 (m, 2H), 2.50-2.42 (m, 1H).

[0086] Preparation of dihydroberberine and tetrahydroberberine

[0087] Dissolve 360 g of free berberine (compound 3, 1.07 mol), 16 g of sodium methoxide (0.30 mol) and 265 g of methanol (about 335 ml) in a mixture. Add the mixed solution to a 2 L high-pressure electrolysis reactor, replace it with N2, pressurize it to 3.0 MPaG, and raise the temperature of the reactor to 70°C. Among them, the anode of the electrolysis reactor is Al, and the cathode is Pt, both of which are mesh electrodes, and the electrolysis area is 0.1 m 2 2.5 V and the electrolysis current density is 1500 A / m 2 . After 6 h of reaction, it is released to normal pressure, and the solvent is recovered at a vacuum degree of 0.01 MPaG and a temperature of 70°C. Hot filtration gives a crude product of dihydroberberine (compound 1) 355 g, and after purification, dihydroberberine 338 g is obtained, with a yield of 94.0% and a HPLC purity of 99%. 1 HNMR (400 MHz, DMSO-d6) δ 7.30 (s, 1H), 6.90 (d, J = 8.32 Hz, 1H), 6.76 (s, 1H), 6.70 (d, J = 8.28 Hz, 1H), 6.06 (s, 1H), 6.01 (s, 2H), 4.21 (s, 2H), 3.77 (s, 3H), 3.72 (s, 3H), 3.06 (t, J = 5.88 Hz, 2H), 2.80 (t, J = 5.88 Hz, 2H).

[0088] Dissolve 330 g of dihydroberberine (0.98 mol), 15 g of sodium ethoxide (0.22 mol) and 260 g of ethanol (329.53 ml) in a mixture. Add the mixed solution to a 2 L high-pressure electrolysis reactor, replace it with N2, pressurize it to 3.0 MPaG, and raise the temperature of the reactor to 70°C. Among them, the anode of the electrolysis reactor is Al, and the cathode is Pt, both of which are mesh electrodes, and the electrolysis area is 0.1 m 2 2.5 V and the electrolysis current density is 1500 A / m 2 . After 8 h of reaction, it is released to normal pressure, and the solvent is recovered at a vacuum degree of -0.01 MPaG and a temperature of 70°C. Hot filtration gives a crude product of tetrahydroberberine (compound 2) 326 g, and after purification, tetrahydroberberine 310 g is obtained, with a yield of 95.4% and a HPLC purity of 99%. 1HNMR (400 MHz, DMSO-d6) δ 6.92 (s, 1H), 6.88-6.85 (m, 2H), 6.67 (s, 1H), 5.95 (s, 2H), 4.06 (d, J = 4.2 Hz, 1H), 3.78 (s, 3H), 3.73 (s, 3H), 3.28-3.28 (m, 2H), 3.11-3.07 (m, 1H), 2.95-2.87 (m, 1H), 2.62-2.56 (m, 2H), 2.50-2.42 (m, 1H).

[0089] In conclusion, the above-mentioned embodiments are only the preferred embodiments of the present application, and are not used to limit the protection scope of the present application. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application shall be included in the protection scope of the present application.

Claims

1. A method for electrochemically preparing a berberine reduction product, characterized in that, An electrochemical reaction is carried out by applying electricity to a mixed electrolyte in an electrolysis reactor provided with an anode and a cathode plate; The material of the anode is metal Mg, Al, Zn, Pt, or an alloy or plating layer containing at least two or more of Mg, Al, Zn, and Pt, and the material of the cathode is metal Pt, Ni, Cu, Ag, Au, Pb, or an alloy or plating layer containing at least two or more of Pt, Ni, Cu, Ag, Au, and Pb; The mixed electrolyte contains a first organic solvent, an electrolyte, and free berberine; the first organic solvent is selected from one or more of methanol, ethanol, propanol, toluene, acetonitrile, N,N-dimethylformamide, and dimethyl sulfoxide; the electrolyte is selected from one or more of sodium methoxide, sodium ethoxide, sodium hydroxide, and potassium tert-butoxide; in the mixed electrolyte, the concentration of free berberine dissolved in the organic solvent is 0.1-10.0 mol / L, and the molar amount of the electrolyte is 20-100% of the molar amount of free berberine; The current density is maintained at 1200-1800 A / m 2 , and the electrolytic potential is 1.5-3.0 V. In the electrochemical reaction, the reaction temperature is 0-80°C, and the reaction pressure is 0.5-5 MPa; The berberine reduction product is dihydroberberine and / or tetrahydroberberine.

2. The method of claim 1, wherein, The material of the anode is metal Mg or Al.

3. The method of claim 1, wherein, The material of the cathode is metal Ag or Pt.

4. The method of claim 1, wherein, The first organic solvent is methanol or ethanol.

5. The method of claim 1, wherein, The electrolyte is sodium methoxide or sodium ethoxide.

6. The method of claim 1, wherein, The current density is 1200-1500 A / m 2 The electrolysis potential is 2.2-3.0 V.

7. The method of claim 1, wherein, The reaction temperature is 25-80°C.

8. The method of claim 1, wherein, The reaction temperature is 40-80°C.

9. The method of claim 1, wherein, The reaction temperature is 60-80°C.

10. The method of claim 1, wherein, The reaction pressure is 1-5 MPa.

11. The method of claim 1, wherein, The reaction pressure is 2-5 MPa.

12. The method of claim 1, wherein, The reaction pressure is 2-4 MPa.

13. The method of claim 1, wherein, In the mixed electrolyte, the concentration of free berberine dissolved in the organic solvent is 0.5-8.0 mol / L.

14. The method of claim 1, wherein, The concentration of free berberine dissolved in the organic solvent is 1.0-5.0 mol / L.

15. The method of claim 1, wherein, The concentration of free berberine dissolved in the organic solvent is 1.5-4.0 mol / L.

16. The method of claim 1, wherein, In the mixed electrolyte, the concentration of free berberine dissolved in the organic solvent is 0.1-10.0 mol / L, the molar amount of the electrolyte is 20-40% of the molar amount of free berberine, and the berberine reduction product is dihydroberberine.

17. The method of claim 16, wherein, The molar amount of the electrolyte is 20-35% of the molar amount of free berberine.

18. The method of claim 16, wherein, The molar amount of the electrolyte is 20-30% of the molar amount of free berberine.

19. The method of any one of claims 1-18, wherein, The method further comprises the following steps: (1) separating the dihydroberberine; (2) mixing the separated dihydroberberine with a first organic solvent and an electrolyte to form a mixed electrolyte, and carrying out an electrochemical reaction by applying electricity to the mixed electrolyte in an electrolysis reactor provided with an anode and a cathode plate; The material of the anode is metal Mg, Al, Zn, Pt, or an alloy or plating layer containing at least two or more of Mg, Al, Zn, and Pt, and the material of the cathode is metal Pt, Ni, Cu, Ag, Au, Pb, or an alloy or plating layer containing at least two or more of Pt, Ni, Cu, Ag, Au, and Pb; The first organic solvent is selected from one or more of methanol, ethanol, propanol, toluene, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide; the electrolyte is selected from one or more of sodium methoxide, sodium ethoxide, sodium hydroxide, potassium tert-butoxide; in the mixed electrolyte, the concentration of free berberine dissolved in the organic solvent is 0.1-10.0 mol / L, and the molar amount of the electrolyte is 20-40% of the molar amount of the free berberine; The current density is maintained at 1200-1800 A / m 2 The electrolytic potential is 1.5-3.0 V. In the electrochemical reaction, the reaction temperature is 0-80℃, and the reaction pressure is 0.5-5 MPa. The berberine reduction product is tetrahydroberberine.

20. The method of claim 19, wherein, The molar amount of the electrolyte is 20-35% of the molar amount of the free berberine.

21. The method of claim 19, wherein, The molar amount of the electrolyte is 20-30% of the molar amount of the free berberine.

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