Synthesis method of tetrandrine

Abstract

The present invention provides a method for synthesizing tetrandrine using a mixture of tetrandrine and tetrandrine as raw materials, avoiding pre-separation of the raw materials and significantly reducing industrial costs. In the presence of dimethyl carbonate as a methylating agent and a catalyst, the tetrandrine in the mixture can be converted into tetrandrine at a conversion rate of over 80%, reducing the tetrandrine content in the crude tetrandrine product to below 1.5% and the content of ring-opening byproducts to less than 10%. This method significantly increases the application value of the tetrandrine and tetrandrine mixture and reduces the production cost of tetrandrine, thus possessing broad application prospects.

Description

Technical Field

[0001] The invention belongs to the field of medicine, and particularly relates to a method for synthesizing tetrandrine. Background Art

[0002] Tetrandrine is an important alkaloid extracted from the root of Tetrandrine (Henan Chemical Industry, 2010, 27(2), 8-9). It is a new calcium antagonist and the main active ingredient of Tetrandrine. 2+ It has non-competitive antagonistic and calcium channel blocking effects and is a slow-channel blocker. It has multiple pharmacological effects, including anti-inflammatory, analgesic, antihypertensive, anti-sand lung, blood sugar reduction, anti-free radical damage, anti-liver fibrosis and tumor. As a clinical drug in my country, tetrandrine is mainly used to treat patients with sand lung, autoimmune diseases, inflammatory lung diseases, cardiovascular diseases and hypertension (Strait Pharmaceutical Journal, 2008, 20(8), 119-121; WO2013 / 026383A1).

[0003] At present, the industry mainly separates tetrandrine by extracting a mixture of tetrandrine and tetrandrine from the root of Tetrandrine. A large amount of tetrandrine is discarded because it has not yet been found to have good commercial utilization value, which in turn leads to environmental pollution or increased industrial costs due to waste treatment. Since the two components of tetrandrine and tetrandrine are similar in structure and polarity, it is very difficult to separate and obtain high-purity tetrandrine. Therefore, while keeping the tetrandrine component in the extract and the tetrandrine mixture basically stable, the tetrandrine component in the extract is efficiently converted into tetrandrine by chemical synthesis using cheap chemicals. While reducing the difficulty of separating and removing tetrandrine and reducing the production cost of tetrandrine, it can also improve the utilization rate of the extract and the yield of tetrandrine, better serving patients. Therefore, the research on the chemical synthesis process for increasing the content of tetrandrine in the tetrandrine and tetrandrine mixture is of great significance. Summary of the Invention

[0004] In order to improve the above technical problems, the present invention provides a method for synthesizing tetrandrine, comprising: reacting a mixture with a methylating agent in the presence of a base to obtain a crude tetrandrine product;

[0005] The mixture comprises tetrandrine and tetrandrine;

[0006] The methylating agent is selected from at least one of dimethyl carbonate, methyl iodide and dimethyl sulfate, preferably dimethyl carbonate;

[0007] The base may be an organic base, such as an organic base containing nitrogen, such as at least one selected from triethylamine, diisopropylethylamine, pyridine, DMAP, and DBU; preferably, the base may be triethylamine.

[0008] According to an embodiment of the present invention, the content of tetrandrine in the crude product obtained by the synthesis method is higher than the content of tetrandrine in the mixture as a raw material.

[0009] According to an embodiment of the present invention, the mass percentage content of tetrandrine calculated based on the total mass of tetrandrine and tetrandrine in the crude product obtained by the synthesis method is lower than the mass percentage content of tetrandrine calculated based on the total mass of tetrandrine and tetrandrine in the mixture serving as the raw material.

[0010] According to an embodiment of the present invention, in the crude product obtained by the synthesis method, the mass percentage content of tetrandrine is less than 5%, preferably less than 3%, and more preferably less than 2%, for example, less than 1.9%, less than 1.8%, less than 1.7%, less than 1.6%, less than 1.5%, less than 1.4%, less than 1.3%, less than 1.2%, less than 1.1%, less than 1.0%, less than 0.9%, less than 0.8%, less than 0.7%, less than 0.6%, less than 0.5%, less than 0.4%, less than 0.3%, less than 0.2%, less than 0.1% or less than 0.05%.

[0011] According to an embodiment of the present invention, in the crude product obtained by the synthesis method, the mass percentage content of by-products (such as ring-opening products) is less than 20%, preferably less than 18%, more preferably less than 16%, for example, less than 15%, less than 14%, less than 13%, less than 12%, less than 11%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3% or less than 2.8%.

[0012] According to an embodiment of the present invention, the crude product obtained by the synthesis method is simply a product that has not been treated by recrystallization or other purification methods.

[0013] According to an embodiment of the present invention, the reaction can be carried out in the presence of a catalyst, which can be a metal catalyst, for example, selected from a transition metal catalyst, which can be at least one of copper sulfate, copper nitrate, copper chloride, copper oxide, ferric chloride or ferric oxide.

[0014] According to an embodiment of the present invention, in the mixture, the mass percentage of tetrandrine is 0.1%-90%, for example, 1%-80% or 20%-70%, such as 0.1%, 1%, 5%, 10%, 15.5%, 20%, 30%, 40%, 43.5%, 45.5%, 47%, 50%, 53.5%, 53.8%, 55%, 57%, 59%, 60%, 70%, 80% or 90%, based on the total mass of the mixture.

[0015] According to an embodiment of the present invention, in the mixture, the mass percentage content of tetrandrine is ≥10% based on the total mass of the mixture, for example, 10%-99.9% or 20%-99%, such as 10%, 20%, 23%, 27%, 29.8%, 30%, 40%, 48.7%, 50%, 60%, 70%, 78.7%, 80% or 90%.

[0016] According to an embodiment of the present invention, the mixture further comprises an inert substance that does not participate in the reaction.

[0017] According to an embodiment of the present invention, based on the total mass of the mixture, the total mass percentage of tetrandrine and tetrandrine is less than 100%, and the remainder is inert substances that do not participate in the reaction.

[0018] According to an embodiment of the present invention, the inert substance is an inorganic salt and an alkaloid that do not participate in the reaction under the reaction conditions.

[0019] According to an embodiment of the present invention, although the mixture preferably does not contain undesirable impurities that may participate in the reaction, if the mixture contains such impurities, the content of such impurities by mass is preferably less than 5%.

[0020] According to an embodiment of the present invention, the molar ratio of tetrandrine to the base in the mixture is 1:(0.5-8), for example 1:(2-6), such as 1:1, 1:1.5, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7.

[0021] According to an embodiment of the present invention, the molar ratio of tetrandrine to the methylating agent in the mixture is 1:(1-12), for example 1:(2-7), such as 1:1, 1:1.5, 1:2, 1:3, 1:5, 1:8, 1:10, 1:12.

[0022] According to an embodiment of the present invention, the catalyst is 0.01%-20% by weight of the mixture, for example 0.1%-10%, such as 1%, 2%, 3%, 4%, 5%, 6%, 10%.

[0023] According to an embodiment of the present invention, the synthesis method can be carried out in a reaction solvent, and the reaction solvent is, for example, a polar solvent, such as a polar ether solvent, a cyclic ether solvent, an amide solvent, a sulfone solvent, or a sulfoxide solvent; preferably, the polar solvent can be selected from at least one of tetrahydrofuran, dimethylformamide or dimethyl sulfoxide.

[0024] According to an embodiment of the present invention, the mass / volume ratio of the mixture to the reaction solvent is 1:(0.5-50) g / mL, for example 1:(1-20) g / mL, such as 1:2 g / mL, 1:3 g / mL, 1:4 g / mL, 1:5 g / mL, 1:6 g / mL, 1:8 g / mL, 1:10 g / mL, 1:12 g / mL, 1:15 g / mL.

[0025] According to an embodiment of the present invention, the reaction temperature is 60-180°C, for example 80-140°C, such as 80°C, 90°C, 100°C, 110°C, 120°C, 130°C, 140°C.

[0026] According to an embodiment of the present invention, the reaction time is 5-36 h, for example 6-24 h, such as 5 h, 12 h, 15 h, 16 h, 20 h, 24 h, 30 h.

[0027] According to an embodiment of the present invention, the synthesis method comprises the following steps: dispersing the mixture in a reaction solvent, adding triethylamine and dimethyl carbonate and reacting at 80-140° C. to obtain the crude product.

[0028] According to an embodiment of the present invention, the synthesis method can adopt the following exemplary synthesis route:

[0029]

[0030] The present invention also provides a composition comprising the above mixture and the methylating agent.

[0031] The present invention also provides a composition comprising the crude product and the methylating agent.

[0032] According to an embodiment of the present invention, any of the above compositions may further comprise a reaction reagent selected from the above definition, such as one, two, three or more of the base, catalyst or solvent.

[0033] According to an embodiment of the present invention, the content or ratio of the components in the composition may have the definitions described above.

[0034] According to an embodiment of the present invention, the synthesis method may further include a purification step to obtain a purified product.

[0035] According to an embodiment of the present invention, the purification step can be recrystallization, beating or other purification methods known to those skilled in the art.

[0036] According to an embodiment of the present invention, the purification solvent used in the purification step may be at least one of an amide solvent, an alcohol solvent and water; preferably, the purification solvent may be selected from a mixed solvent of an amide solvent, an alcohol solvent and water;

[0037] According to an embodiment of the present invention, the purification solvent is a mixed solvent of ethanol, water and DMF; preferably, the volume ratio of ethanol, water and DMF is (8-12):1:(1-5), for example 8:1:3, 9:1:3, 10:1:3, 10:1:1, 10:1:2, 10:1:4, 10:1:5.

[0038] According to an embodiment of the present invention, the purification temperature in the purification step may be 40-120°C, such as 60-100°C, such as 70°C, 75°C, 80°C, 90°C.

[0039] According to an embodiment of the present invention, the content of tetrandrine in the purified product is 1.5% or less, for example, 1.0% or less, such as 0.5% or less, preferably 0.2% or less.

[0040] The present invention also provides a composition comprising the crude product described above and the solvent used in the purification step.

[0041] The present invention also provides a composition comprising the purified product described above and the solvent used in the purification step.

[0042] According to an embodiment of the present invention, the content or ratio of the components in the composition may have the definitions described above.

[0043] Beneficial effects

[0044] The inventors have found that under the conditions of the existing phenolic hydroxyl methoxylation system, in addition to the reaction between tetrandrine and the methylating agent, tetrandrine also reacts with the methylating agent to generate a ring-opening by-product. The present invention converts tetrandrine in the mixture into tetrandrine by methylation without affecting the tetrandrine in the mixture. In the presence of green, cheap, and low-toxic dimethyl carbonate as a methylating agent and a catalyst, the tetrandrine in the mixture can be converted into tetrandrine with a conversion rate of more than 80%, reducing the content of tetrandrine in the crude tetrandrine to less than 1.5%, and significantly reducing the content of the ring-opening by-product. The starting raw material of the present invention is a mixture of tetrandrine and tetrandrine, which avoids pre-separation, greatly improves the application value of tetrandrine and the mixture of tetrandrine, and significantly reduces the production cost of tetrandrine, and has broad application prospects. DETAILED DESCRIPTION

[0045] The technical solutions of the present invention will be described in further detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanations of the present invention and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are encompassed within the scope of protection that the present invention is intended to protect.

[0046] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0047] In the following examples, tetrandrine is referred to as tetrandrine A; tetrandrine B is referred to as tetrandrine B. The diethyl carbonate (DMC) used in these examples is a colorless, transparent, aromatic, and non-corrosive oily liquid with a moderate volatility. Its toxicity is similar to that of anhydrous ethanol, avoiding production process hazards, equipment corrosion, and environmental pollution.

[0048] Unless otherwise stated, in the mixtures of the following examples, the percentage content of the mixed solvent is by volume, and the percentage content of tetrandrine (abbreviated as "a"), tetrandrine B (abbreviated as "B"), and the ring-opening product are all by mass percentage.

[0049]

[0050] The methods for obtaining the raw materials of the mixtures in the following examples and detecting the purity thereof by HPLC (high performance liquid chromatography) are as follows.

[0051] The raw material preparation steps are as follows: the dried root powder of the Chinese medicinal powder Stephania tetrandra, lime powder and methanol with a concentration of 70% (volume ratio) are placed in an extraction tank at a mass ratio of 10:1:70, and hot reflux extraction is performed several times. The extracts are combined, and the extracts are concentrated by vacuum distillation and allowed to stand. After aging is completed, the extracts are filtered and dried to obtain the mixture raw materials in the following examples.

[0052] Purity test method: Accurately weigh 0.1 g of tetrandrine sample prepared in the example above over a 40-mesh filter. Add 4 mL of mobile phase to a 5 mL volumetric flask and refrigerate for 12 hours. Ultrasonic extraction is performed for 30 minutes, and 5 mL of the supernatant is injected. A 250 mm x 4 mm ID stainless steel column was used, packed with YWG-C18 gas. The mobile phase consisted of methanol-acetonitrile-water (3:1:1 volume ratio) containing 0.06% diethylamine, and ultrasonic degassed. The temperature was 20-25°C, the flow rate was 1.0 mL / min, the λ value was 242 mm, and the paper speed was 0.25 mm / min. The linear range was between 0.2 and 1.5 μg.

[0053] Example 1

[0054] 100g of mixture 1 (15.5% methylamine; 78.7% ethylamine; the remainder is inorganic salts and alkaloids not involved in the reaction), 0.1g of ferric chloride (analytical grade), 500mL of dimethyl sulfoxide (analytical grade), 16mL of dimethyl carbonate (DMC), and 30mL of triethylamine were added sequentially to a 1L two-necked flask. The mixture was heated with an electric heating mantle at 90°C for 12 hours. After the reaction, the DMF was removed, water was added, the mixture was stirred, and the mixture was filtered to dryness. The crude product, 98.9g (85% methylamine; 0.6% ethylamine; 3.1% ring-opening product), was obtained. The crude product was dissolved in 150mL of ethanol-water-DMF (volume ratio 10:1:3) by heating under reflux at 75-80°C. After cooling to room temperature, the mixture was stored at -5°C for 8 hours. The mixture was filtered and dried to obtain 76.2g of pure tetrandrine with an HPLC purity of 99.6%. The solid recovered from the mother liquor was recrystallized twice (respectively using 10 mL and 8 mL of ethanol-water-DMF (volume ratio of 10:1:3) for dissolution at reflux at 75-80°C) to obtain 1.2 g of pure tetrandrine with an HPLC purity of 99.5%. The two fractions of pure product totaled 77.4 g, for a yield of 82% (the total mass of tetrandrine and tetrandrine in the raw materials is calculated as 100 g * (15.5% + 78.7%)). The content of the ring-opening product was less than 0.01%.

[0055] Example 2

[0056] 100g of mixture 2 (57% methylamine; 27% ethylamine; the remainder is inorganic salts and alkaloids not involved in the reaction), 0.1g of ferric chloride (analytical grade), 400mL of DMF (analytical grade), 16mL of dimethyl carbonate (DMC), and 35mL of triethylamine were added sequentially to a 1L two-necked flask. The mixture was heated with an electric heating mantle and reacted at 126°C for 10 hours. After the reaction, the DMF was removed, water was added, the mixture was stirred, and the mixture was filtered to dryness. The crude product (90g of tetrandrine) (89% methylamine; 0.6% ethylamine; 2.1% ring-opening product) was obtained. The crude product was dissolved in 160mL of ethanol-water-DMF (volume ratio 10:1:3) by heating under reflux at 75-80°C. After cooling to room temperature, the mixture was stored at -5°C for 8 hours. The mixture was filtered and dried to obtain 77.1g of pure tetrandrine with an HPLC purity of 99.5%. The solid recovered from the mother liquor was recrystallized twice (respectively using 12 mL and 9 mL of ethanol-water-DMF (volume ratio of 10:1:3) for dissolution at reflux at 75-80°C) to yield 1.6 g of pure tetrandrine with an HPLC purity of 99.5%. The two fractions of pure product totaled 78.7 g, for a yield of 93% (the total mass of tetrandrine and tetrandrine in the raw materials is calculated as 100 g * (57% + 27%)). The content of the ring-opening product was less than 0.01%.

[0057] Example 3

[0058] 100 g of mixture 3 (15.5% methylamine; 48.7% ethylamine; the remainder being inorganic salts and alkaloids not participating in the reaction), 1.0 g of copper sulfate (analytical grade), 500 mL of DMF (analytical grade), 30 mL of dimethyl carbonate, and 45 mL of diisopropylethylamine were added sequentially to a 1-liter two-necked flask, heated with an electric heating mantle, and reacted at 80°C for 12 hours. After the reaction, the DMF was removed, water was added, the mixture was stirred, and filtered to dryness. Drying gave 77.5 g of crude tetrandrine (75% methylamine; 0.8% ethylamine; 4.1% ring-opening product).

[0059] Example 4

[0060] 100 g of mixture 4 (45.5% methylamine; 30% ethylamine; the remainder being inorganic salts and alkaloids not participating in the reaction), 5.0 g of copper oxide (analytical grade), 500 mL of DMF (analytical grade), 6 mL of dimethyl carbonate (DMC), and 11.4 mL of pyridine were added sequentially to a 1 L two-necked flask, heated with an electric heating mantle, and reacted at 140°C for 20 hours. After the reaction, the DMF was removed, water was added, the mixture was stirred, and the mixture was filtered to dryness. The mixture was dried to obtain 91 g of crude tetrandrine (78% methylamine; 0.5% ethylamine; 2.6% ring-opening product).

[0061] Example 5

[0062] 100 g of mixture 5 (55% methylamine; 30% ethylamine; the remainder being inorganic salts not involved in the reaction), 10.0 g of ferric oxide (analytical grade), 500 mL of DMF (analytical grade), 21 mL of dimethyl carbonate (DMC), and 23 mL of DMAP were added sequentially to a 1-liter two-necked flask, heated with an electric heating mantle, and reacted at 130°C for 30 hours. After the reaction, the DMF was removed, water was added, the mixture was stirred, and filtered to dryness. Drying yielded 92 g of crude tetrandrine (84% methylamine; 0.1% ethylamine; 4.5% ring-opening product).

[0063] Example 6

[0064] 100 g of mixture 5 (55% methylamine; 30% ethylamine; the remainder being inorganic salts and alkaloids not participating in the reaction), 2.0 g of copper chloride (analytical grade), 500 mL of DMF (analytical grade), 21 mL of dimethyl carbonate (DMC), and 23 mL of DBU were added sequentially to a 1-liter two-necked flask, heated with an electric heating mantle, and reacted at 130°C for 16 hours. After the reaction, the DMF was removed, water was added, the mixture was stirred, and filtered to dryness. Drying gave 90 g of crude tetrandrine (83% methylamine; 1.1% ethylamine; 6.6% ring-opening product).

[0065] Example 7

[0066] 100 g of mixture 6 (59% methylamine; 20% ethylamine; the remainder being inorganic salts and alkaloids not participating in the reaction), 2.0 g of copper nitrate (analytical grade), 300 mL of DMF (analytical grade), 22 mL of dimethyl carbonate (DMC), and 25 mL of diisopropylethylamine were added sequentially to a 1 L two-necked flask, heated with an electric heating mantle, and reacted at 140°C for 24 hours. After the reaction, the DMF was removed, water was added, the mixture was stirred, and the mixture was filtered to dryness. The mixture was dried to obtain 86 g of crude tetrandrine (80% methylamine; 1.0% ethylamine; 7.4% ring-opening product).

[0067] Example 8

[0068] 100 g of mixture 7 (53.8% methylamine content; 27% ethylamine content; the remainder being inorganic salts and alkaloids not participating in the reaction), 4.0 g of copper chloride (analytical grade), 400 mL of DMF (analytical grade), 60 mL of dimethyl carbonate (DMC), and 65 mL of pyridine were added sequentially to a 1 L two-necked flask, heated with an electric heating mantle, and reacted at 140°C for 5 hours. After the reaction, the DMF was removed, water was added, the mixture was stirred, and filtered to dryness. Drying gave 86 g of crude tetrandrine (82.5% methylamine content; 0.6% ethylamine content; 5.3% ring-opening product).

[0069] Example 9

[0070] 100g of mixture 8 (40% methylamine; 27% ethylamine; the remainder being inorganic salts and alkaloids not participating in the reaction), 5.0g of ferric oxide (analytical grade), 400mL of tetrahydrofuran (analytical grade), 25mL of dimethyl carbonate (DMC), and 28mL of triethylamine were added sequentially to a 1L stainless steel pressure vessel, sealed, and reacted in an oil bath at 140°C for 15 hours. After completion, the tetrahydrofuran was removed, water was added, the mixture was stirred, and filtered to dryness. Drying gave 81g of crude tetrandrine (71% methylamine; 1.0% ethylamine; 7.8% ring-opening product).

[0071] Example 10

[0072] 100g of mixture 8 (40% methylamine; 27% ethylamine; the remainder being inorganic salts and alkaloids not participating in the reaction), copper oxide (analytical grade, 2.5g), tetrahydrofuran (analytical grade, 400mL), DMC (dimethyl carbonate, 25mL), and 30mL of triethylamine were added sequentially to a 1L stainless steel pressure vessel, sealed, and reacted in an oil bath at 140°C for 15 hours. After completion, the tetrahydrofuran was removed, water was added, the mixture was stirred, and suction filtered to dryness. Drying afforded 84g of crude tetrandrine (65% methylamine; 1.0% ethylamine; 8.7% ring-opening product).

[0073] Example 11

[0074] 10g of mixture 9 (47% methylamine; 27% ethylamine; the remainder being inorganic salts and alkaloids not involved in the reaction), 2.5g of copper oxide (analytical grade), 40mL of tetrahydrofuran (analytical grade), 3mL of dimethyl carbonate (DMC), and 4mL of triethylamine were added sequentially to a 100mL stainless steel pressure vessel, sealed, and reacted in an oil bath at 140°C for 12 hours. After reaction, the tetrahydrofuran was removed, water was added, the mixture was stirred, filtered to dryness, and dried to obtain 9g of crude tetrandrine (72% methylamine; 0.9% ethylamine; 6.6% ring-opening product).

[0075] Example 12

[0076] 100 g of mixture 10 (53.5% methylamine; 23% ethylamine; the remainder being inorganic salts and alkaloids not participating in the reaction), 500 mL of dimethyl sulfoxide (analytical grade), 4 mL of dimethyl carbonate (DMC), and 10 mL of triethylamine were added sequentially to a 1 L two-necked flask, heated with an electric heating mantle, and reacted at 110°C for 12 hours. After completion, DMF was removed, water was added, the mixture was stirred, and filtered to dryness. Drying afforded 90 g of crude tetrandrine (70.3% methylamine; 0.6% ethylamine; 12.6% ring-opening product).

[0077] Example 13

[0078] 100 g of mixture 10 (53.5% methylamine; 23% ethylamine; the remainder being inorganic salts and alkaloids not participating in the reaction), 500 mL of DMF (analytical grade), 8 mL of dimethyl sulfate, and 10 mL of triethylamine were added sequentially to a 1 L two-necked flask, heated with an electric heating mantle, and reacted at 80°C for 12 hours. After completion, the DMF was removed, water was added, the mixture was stirred, and filtered to dryness. Drying yielded 90 g of crude tetrandrine (65.4% methylamine; 6.2% ethylamine; 11.2% ring-opening product).

[0079] Example 14

[0080] 100 g of mixture 11 (43.5% methylamine content; 29.8% ethylamine content; the remainder being inorganic salts and alkaloids not participating in the reaction), 50 mL of DMF (analytical grade), 0.9 mL of iodomethane, and 1 mL of triethylamine were added sequentially to a 100 mL stainless steel pressure vessel, sealed, and reacted at 80°C for 12 hours. After completion, the DMF was removed, water was added, the mixture was stirred, and filtered to dryness. Drying gave 85 g of crude tetrandrine (58.3% methylamine content; 8.2% ethylamine content; 14.2% ring-opening product).

[0081] The above is an exemplary description of the implementation methods of the technical solution of the present invention. It should be understood that the scope of protection of the present invention is not limited to the above implementation methods. Any modifications, equivalent substitutions, improvements, etc. made by those skilled in the art within the spirit and principles of the present invention shall be included in the scope of protection of the claims of this application.

Claims

1. A method for preparing tetrandrine, comprising reacting a mixture with a methylating agent in the presence of a base to obtain tetrandrine; The mixture comprises tetrandrine and tetrandrine, wherein the molar ratio of tetrandrine to the methylating agent is 1:(1-12), and the molar ratio of tetrandrine to the base is 1:(0.5-8); The methylating agent is selected from dimethyl carbonate; The base is selected from at least one of triethylamine, diisopropylethylamine, pyridine, DMAP, and DBU; The reaction is carried out in the presence of a catalyst, wherein the catalyst is selected from at least one of copper sulfate, copper nitrate, copper chloride, copper oxide, ferric chloride or ferric oxide; The reaction is carried out in a solvent, and the solvent is selected from at least one of tetrahydrofuran, dimethylformamide or dimethyl sulfoxide; The reaction temperature is 60-180°C.

2. The method according to claim 1, characterized in that Based on the total mass of the mixture, the mass percentage of tetrandrine is ≥10%, and the mass percentage of tetrandrine is 0.1%-90%.

3. The method according to claim 1, characterized in that Based on the total mass of the mixture, the mass percentage of tetrandrine is 20%-70%.

4. The method according to claim 1, wherein Based on the total mass of the mixture, the mass percentage of tetrandrine is 0.1%, 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% and 90%.

5. The method according to claim 1, wherein Based on the total mass of the mixture, the mass percentage of tetrandrine is 20%-99%.

6. The method according to claim 1, wherein Based on the total mass of the mixture, the mass percentage of tetrandrine is 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% and 90%.

7. The method according to claim 2, characterized in that The mixture may also contain inert substances which do not participate in the reaction.

8. The method according to claim 1, characterized in that The molar ratio of tetrandrine to the base in the mixture is 1:(2-6).

9. The method according to claim 1, characterized in that The molar ratio of tetrandrine to the methylating agent in the mixture is 1:(2-7).

10. The method according to claim 1, characterized in that The catalyst is present in an amount of 0.01% to 10% by weight of the mixture.

11. The method according to claim 1, wherein The catalyst is present in an amount of 1% to 6% by weight of the mixture.

12. The method according to claim 1, characterized in that The mass / volume ratio of the mixture to the solvent is 1:(0.5-50) g / mL.

13. The method according to claim 1, wherein The reaction time is 5-36 hours.

14. The method according to claim 1, wherein The reaction temperature is 80-140°C; And / or, the reaction time is 6-24 hours.

15. The method according to claim 1, wherein The method comprises the following steps: dispersing the mixture in a polar solvent, adding triethylamine and dimethyl carbonate, and reacting at 80-140° C. to obtain tetrandrine.

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