CN109942593B

CN109942593B - Total synthesis method of racemic tetrandrine

Info

Publication number: CN109942593B
Application number: CN201910297662.2A
Authority: CN
Inventors: 金庆平; 余斌; 葛真真; 戴艳群; 陈宇; 金岩; 周鸣强; 袁伟成
Original assignee: Chengdu Likai Chiral Tech Co ltd; Zhejiang Jinhua Conba Bio Pharm Co ltd
Current assignee: Chengdu Likai Chiral Tech Co ltd; Zhejiang Jinhua Conba Bio Pharm Co ltd
Priority date: 2019-04-15
Filing date: 2019-04-15
Publication date: 2021-08-27
Anticipated expiration: 2039-04-15
Also published as: CN109942593A

Abstract

The invention discloses a total synthesis method of racemic tetrandrine, which belongs to the technical field of drug synthesis, wherein a synthesis route adopts a convergent synthesis mode, 5-bromovanillin, namely a compound 1, and 3-hydroxy-4-methoxyphenylacetic acid, namely a compound 5, are respectively used as starting raw materials to respectively obtain a compound 4 and a compound 6, then the compound 4 and the compound 6 are used as raw materials to synthesize a compound 11, the compound 11 is synthesized to obtain a compound 19, and finally the compound 11 and the compound 19 react, so that the synthesis efficiency is higher, the yield is higher, and the cost is lower; the reaction condition is milder, the operation is simple and convenient, the industrial amplification value is higher, and reference is provided for the total synthesis method of the optical pure tetrandrine.

Description

Total synthesis method of racemic tetrandrine

Technical Field

The invention relates to the technical field of drug synthesis, in particular to a total synthesis method of racemic tetrandrine.

Background

Tetrandrine, also known as tetrandrine or tetrandrine, is an alkaloid existing in the root of tetrandrine of Menispermaceae, and has effects of resisting myocardial ischemia, inhibiting platelet aggregation, relieving spasm, relieving pain, tranquilizing, resisting inflammation, resisting ulcer, protecting liver, regulating immunity and resisting anoxia. Tetrandrine is a drug which is marketed and used for treating diseases such as hypertension, rheumatalgia, arthralgia and neuralgia. It can be used in combination with small dose of radioactive agent for treating lung cancer, and also for treating silicosis in stage I, II, III and every stage.

The tetrandrine is industrially produced by extracting and separating the root of tetrandrine. However, the content of total alkaloids in the root of tetrandrine is 1.5-2.3%, and the content of tetrandrine is about 1%. Therefore, the production of tetrandrine by the method of extraction from the roots of tetrandrine has the following disadvantages: 1. tetrandra root plant resources are gradually scarce and are in short supply. 2. The production efficiency is low, and the extraction process is complex; 3. the production process has large amount of three wastes and large environmental protection pressure.

Although there are reports of using tetrandrine as a raw material to synthesize tetrandrine, the similar problems still exist with tetrandrine as a raw material.

The chemical total synthesis method for producing the medicine has the following advantages: 1. the raw materials are cheap and easy to obtain and are not limited; 2. related raw materials, intermediates, solvents and the like can be recycled and reused for many times in production, and the amount of three wastes is small; 3. can be continuously produced and realize large-scale preparation. Therefore, the development of the chemical synthesis method for producing the tetrandrine has very important significance, and the full synthesis research of the tetrandrine has very important guiding function for developing the chemical synthesis production process of the tetrandrine.

At present, only J, chem, Soc, 1969, 1547-1556 report a total synthesis method of tetrandrine, which comprises the steps of synthesizing 4-benzyloxy-3-methoxyphenylacetic acid by taking 4-methoxy-3-hydroxyacetophenone as a raw material, carrying out acid amine condensation with 3, 4-dimethoxy-5-bromoethylamine, carrying out Bischler-Napieralski reaction and reduction reaction to synthesize a racemic tetrahydroisoquinoline intermediate, carrying out methylation reaction after resolving to obtain S-tetrahydroisoquinoline, carrying out intermolecular Ullmann condensation with N-tert-butoxycarbonyl-3-O-methyldopamine, carrying out hydrogenation debenzylation, carrying out intermolecular Ullmann condensation with methyl p-bromophenylacetate, carrying out ester hydrolysis under alkaline conditions, condensing with p-phenol to synthesize ester, carrying out intramolecular amine ester exchange after removing a Boc protecting group, then carrying out intramolecular Bischler-Napieralski reaction, reduction reaction and methylation reaction, finally salifying with picric acid, and separating to obtain the optical pure tetrandrine.

The method has the disadvantages of long route, complex operation, low resolution efficiency, and difficult realization of industrial production, and the total yield is only about 1%. Therefore, the development of a tetrandrine full synthetic route which can be industrialized is of great significance.

Disclosure of Invention

The invention aims to provide a novel complete synthesis method of racemic tetrandrine to solve the problems.

In order to achieve the purpose, the technical scheme adopted by the invention is as follows: a new total synthesis method of racemic tetrandrine takes vanillin and 5-bromovanillin as starting materials, and racemic tetrandrine is obtained through multi-step reaction, and the synthesis route is as follows:

combining the above synthetic route, the specific steps are:

(1) taking 5-bromovanillin (compound 1) as a starting material, and reacting with a methylating agent under an alkaline condition to synthesize a compound 2;

(2) the compound 2 and nitromethane react with each other under the action of a catalyst to synthesize a compound 3 through a Henry reaction;

(3) reducing the compound 3 by a reducing agent to synthesize a compound 4;

(4) taking 3-hydroxy-4-methoxyphenylacetic acid (compound 5) as a raw material, and synthesizing a compound 6 after hydroxyl protection under an alkaline condition;

(5) under the action of a condensing agent, synthesizing a compound 7 by carrying out acid amine condensation reaction on the compound 4 and the compound 6;

(6) performing intramolecular condensation on the compound 7 in an anhydrous inert solvent under the action of a dehydrating agent, dehydrating and closing a ring to synthesize a compound 8;

(7) reducing the compound 8 by a reducing agent to synthesize a compound 9;

(8) reacting the compound 9 with a methylating agent to synthesize a compound 10;

(9) removing a hydroxyl protecting group from the compound 10 under an acidic condition to synthesize a compound 11;

(10) vanillin (compound 12) is used as a raw material, and a compound 13 is synthesized after hydroxyl protection under an alkaline condition;

(11) compound 13 and nitromethane are reacted to synthesize compound 14 through Henry reaction under the action of a catalyst;

(12) reducing the compound 14 by a reducing agent to synthesize a compound 15;

(13) under the action of a condensing agent, carrying out acid-amine condensation reaction on the compound 15 and p-bromophenylacetic acid to synthesize a compound 16;

(14) performing intramolecular condensation on the compound 16 in an anhydrous inert solvent under the action of a dehydrating agent, dehydrating and ring closing to synthesize a compound 17;

(15) reducing the compound 17 by a reducing agent to synthesize a compound 18;

(16) reacting the compound 18 with a methylating agent to synthesize a compound 19;

(17) under the action of a catalyst, a compound 11 and a compound 19 are subjected to intermolecular Ullmann reaction under the alkaline and high-temperature conditions to synthesize a compound 20;

(18) removing a hydroxyl protecting group from the compound 20 under an acidic condition to synthesize a compound 21;

(19) under the action of a catalyst, the compound 21 is subjected to intramolecular Ullmann reaction under the alkaline and high-temperature conditions to synthesize a compound 22, namely racemic tetrandrine.

As a preferred technical scheme: in the step (1), the alkaline reagent is selected from one of potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, triethylamine or pyridine, and is preferably sodium hydroxide; the methylating agent is selected from one of dimethyl sulfate, dimethyl carbonate, methyl iodide, methyl bromide or methyl p-toluenesulfonate, and is further preferably methyl iodide; the solvent is selected from one or more of dichloromethane, chloroform, methanol, ethanol, acetonitrile, tetrahydrofuran, benzene, toluene or water, and more preferably dichloromethane.

As a preferred technical scheme: in the step (1), the molar ratio of the 5-bromovanillin (compound 1) to the methylating agent is 1: 1-1: 4, and the reaction temperature is 20-100^oAnd C, the reaction time is 2-20 hours.

As a preferred technical scheme: in the step (2), the catalyst is selected from one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, ammonium acetate, sodium methoxide, potassium tert-butoxide or triethylamine, preferably triethylamine; the solvent is selected from one of nitromethane, methanol, ethanol, isopropanol, acetic acid, DMF or DMSO, and ethanol is more preferable.

As a preferred technical scheme: in the step (2), the molar ratio of the compound 2 to the nitromethane is 1: 1-1: 10, the dosage of the catalyst is 10-80% of the weight of the compound 2, and the reaction temperature is 50%^oC, refluxing, wherein the reaction time is 10-20 hours.

As a preferred technical scheme: in the step (3), the reducing agent is selected from one or more of sodium borohydride, potassium borohydride, lithium aluminum hydride or borane, and lithium aluminum hydride is further preferred; the solvent is selected from one of methanol, ethanol, tetrahydrofuran, benzene or toluene, and tetrahydrofuran is more preferable.

As a preferred technical scheme: in the step (3), the molar ratio of the compound 3 to the reducing agent is 1: 1-1: 10, and the reaction temperature is 30^oC, refluxing, wherein the reaction time is 6-20 hours.

As a preferred technical scheme: in the step (4), the alkaline reagent is selected from one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, ammonium acetate, sodium methoxide, potassium tert-butoxide or triethylamine, and sodium hydroxide is further preferable; the hydroxyl protecting group is selected from one of trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, triisopropylsilyl, benzyl, p-methoxybenzyl, methoxymethyl or 2-ethoxyethyl, and is further preferably benzyl; the solvent is selected from one of methanol, ethanol, isopropanol, dichloromethane, chloroform, pyridine or DMF, and preferably methanol.

Has good effectThe selected technical scheme is as follows: in the step (4), the molar ratio of the compound 5 to the hydroxyl protecting reagent is 1: 1-1: 4, and the reaction temperature is 30^oC, refluxing, wherein the reaction time is 3-10 hours.

As a preferred technical scheme: in the step (5), the condensing agent is selected from one of CDI, EDCI, HATU or HBTU, preferably CDI; the solvent is selected from one of dichloromethane, trichloromethane or DMF, and dichloromethane is further preferable.

As a preferred technical scheme: in the step (5), the molar ratio of the compound 4 to the compound 6 is 1: 1-1: 1.5, the molar ratio of the compound 4 to the condensing agent is 1: 1-1: 3, and the reaction temperature is 0-60%^oAnd C, the reaction time is 1-5 hours.

As a preferred technical scheme: in the step (6), the dehydrating agent is selected from one of phosphorus oxychloride, phosphorus pentoxide, polyphosphoric acid or trifluoroacetic anhydride, and phosphorus oxychloride is preferred; the anhydrous inert solvent is selected from one of dichloromethane, trichloromethane, tetrahydrofuran, benzene, toluene or nitrobenzene, and toluene is further preferred.

As a preferred technical scheme: in the step (6), the molar ratio of the compound 7 to the dehydrating agent is 1: 1-1: 20, and the reaction temperature is 30^oC, refluxing, wherein the reaction time is 2-8 hours.

As a preferred technical scheme: in the step (7), the reducing agent is selected from one of sodium borohydride and potassium borohydride, and potassium borohydride is further preferred; the solvent is selected from one of methanol, ethanol, isopropanol or tetrahydrofuran, and ethanol is more preferable.

As a preferred technical scheme: in the step (7), the molar ratio of the compound 8 to the reducing agent is 1: 1-1: 10, and the reaction temperature is 0-50^oAnd C, the reaction time is 1-5 hours.

As a preferred technical scheme: in the step (8), the methylating agent is selected from one of methyl iodide, dimethyl sulfate, dimethyl carbonate, methyl p-toluenesulfonate or formaldehyde/formic acid, and is further preferably methyl p-toluenesulfonate; the solvent is selected from one of tetrahydrofuran, acetonitrile, acetone or DMF, and DMF is further preferred.

As a preferred techniqueThe scheme is as follows: in the step (8), the molar ratio of the compound 9 to the methylating agent is 1: 1-1: 3, and the reaction temperature is 30^oC, refluxing, wherein the reaction time is 2-6 hours.

As a preferred technical scheme: in the step (9), the acidic reagent is selected from one of acetic acid, trifluoroacetic acid, hydrochloric acid or hydrobromic acid, and further preferably trifluoroacetic acid; the solvent is selected from one of methanol, ethanol or isopropanol, and methanol is more preferable.

As a preferred technical scheme: in the step (9), the molar ratio of the compound 10 to the acidic reagent is 1: 20-1: 200, and the reaction temperature is 40^oC, refluxing, wherein the reaction time is 4-10 hours.

As a preferred technical scheme: in the step (10), the alkaline reagent is selected from one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, ammonium acetate, sodium methoxide, potassium tert-butoxide or triethylamine, and sodium hydroxide is further preferred; the hydroxyl protecting group is selected from one of trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, triisopropylsilyl, benzyl, p-methoxybenzyl, methoxymethyl or 2-ethoxyethyl, and is further preferably benzyl; the solvent is selected from one of methanol, ethanol, isopropanol, dichloromethane, chloroform, pyridine or DMF, and more preferably dichloromethane.

As a preferred technical scheme: in the step (10), the molar ratio of vanillin (compound 12) to the hydroxyl protecting reagent is 1: 1-1: 4, and the reaction temperature is 30^oC, refluxing, wherein the reaction time is 3-10 hours.

As a preferred technical scheme: in the step (11), the catalyst is selected from one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, ammonium acetate, sodium methoxide, potassium tert-butoxide or triethylamine, and triethylamine is further preferred; the solvent is selected from one of nitromethane, methanol, ethanol, isopropanol, acetic acid, DMF or DMSO, and ethanol is more preferable.

As a preferred technical scheme: in the step (11), the molar ratio of the compound 13 to the nitromethane is 1: 1-1: 10, the dosage of the catalyst is 10-80% of the weight of the compound 13, and the reaction temperature is 50%^oC toRefluxing, and the reaction time is 10-20 hours.

As a preferred technical scheme: in the step (12), the reducing agent is selected from one or more of sodium borohydride, potassium borohydride, lithium aluminum hydride or borane, and lithium aluminum hydride is further preferred; the solvent is selected from one of methanol, ethanol, tetrahydrofuran, benzene or toluene, and tetrahydrofuran is more preferable.

As a preferred technical scheme: in the step (12), the molar ratio of the compound 14 to the reducing agent is 1: 1-1: 10, and the reaction temperature is 30^oC, refluxing, wherein the reaction time is 6-20 hours.

As a preferred technical scheme: in the step (13), the condensing agent is selected from one of CDI, EDCI, HATU or HBTU, and CDI is further preferred; the solvent is selected from one of dichloromethane, trichloromethane or DMF, and dichloromethane is further preferable.

As a preferred technical scheme: in the step (13), the molar ratio of the compound 15 to the p-bromophenylacetic acid is 1: 1-1: 1.5, the molar ratio of the compound 15 to the condensing agent is 1: 1-1: 3, and the reaction temperature is 0-60%^oAnd C, the reaction time is 1-5 hours.

As a preferred technical scheme: in the step (14), the dehydrating agent is selected from one of phosphorus oxychloride, phosphorus pentoxide, polyphosphoric acid or trifluoroacetic anhydride, and phosphorus oxychloride is further preferred; the anhydrous inert solvent is selected from one of dichloromethane, trichloromethane, tetrahydrofuran, benzene, toluene or nitrobenzene, and toluene is further preferred.

As a preferred technical scheme: in the step (14), the molar ratio of the compound 16 to the dehydrating agent is 1: 1-1: 20, and the reaction temperature is 30^oC, refluxing, wherein the reaction time is 2-10 hours.

As a preferred technical scheme: in the step (15), the reducing agent is selected from one of sodium borohydride and potassium borohydride, and potassium borohydride is further preferred; the solvent is selected from one of methanol, ethanol, isopropanol or tetrahydrofuran, and ethanol is more preferable.

As a preferred technical scheme: in the step (15), the molar ratio of the compound 17 to the reducing agent is 1: 1-1: 10, and the reaction temperature is 0-50^oAnd C, the reaction time is 1-5 hours.

As a preferred technical scheme: in the step (16), the methylating agent is selected from one of methyl iodide, dimethyl sulfate, dimethyl carbonate, methyl p-toluenesulfonate or formaldehyde/formic acid, and is further preferably methyl p-toluenesulfonate; the solvent is selected from one of tetrahydrofuran, acetonitrile, acetone or DMF, and DMF is further preferred.

As a preferred technical scheme: in the step (16), the molar ratio of the compound 18 to the methylating agent is 1: 1-1: 3, and the reaction temperature is 50^oC, refluxing, wherein the reaction time is 2-6 hours.

As a preferred technical scheme: in the step (17), the catalyst is selected from one of copper powder, cupric oxide, cuprous iodide or cuprous bromide dimethyl sulfide mixture, and cuprous iodide is further preferred; the alkaline reagent is selected from one of sodium hydroxide, potassium carbonate, cesium carbonate or triethylamine, and cesium carbonate is further preferred; the solvent is selected from one of pyridine, acetonitrile, toluene, DMF or DMSO, and DMF is more preferable.

As a preferred technical scheme: in the step (17), the molar ratio of the compound 11 to the compound 19 is 1: 0.5-1: 2, the molar ratio of the compound 11 to the alkaline reagent is 1: 1-1: 5, the amount of the catalyst is 5-50% of the weight of the compound 11, and the reaction temperature is 70%^oC, refluxing, wherein the reaction time is 24-72 hours.

As a preferred technical scheme: in the step (18), the acidic reagent is selected from one of acetic acid, trifluoroacetic acid, hydrochloric acid or hydrobromic acid, and further preferably trifluoroacetic acid; the solvent is selected from one of methanol, ethanol or isopropanol, and methanol is more preferable.

As a preferred technical scheme: in the step (18), the molar ratio of the compound 20 to the acidic reagent is 1: 20-1: 200, and the reaction temperature is 40^oC, refluxing, wherein the reaction time is 4-10 hours.

As a preferred technical scheme: in the step (19), the catalyst is selected from one of copper powder, cupric oxide, cuprous iodide or cuprous bromide dimethyl sulfide mixture, and cuprous iodide is further preferred; the alkaline reagent is selected from one of sodium hydroxide, potassium carbonate, cesium carbonate or triethylamine, and cesium carbonate is further preferred; the solvent is selected from one of pyridine, acetonitrile, toluene, DMF or DMSO, and DMF is more preferable.

As a preferred technical scheme: in the step (19), the molar ratio of the compound 21 to the alkaline reagent is 1: 1-1: 5, the dosage of the catalyst is 5-50% of the weight of the compound 21, and the reaction temperature is 70%^oC, refluxing, wherein the reaction time is 24-72 hours.

Compared with the prior art, the invention has the advantages that: the synthesis route of the invention adopts a convergent synthesis mode, namely a compound 4 and a compound 6 can be simultaneously and respectively synthesized to obtain a compound 11, then the compound 11 is synthesized to obtain a compound 19, and finally the compound 11 is reacted with the compound 19, so that the synthesis efficiency is higher, the yield of the method can reach 1.7-2.2%, under the condition of not considering solvent recovery, the cost of the method reported by the existing literature is about 15.6 ten thousand yuan/kg, the cost of the method is about 5.5 ten thousand yuan/kg, and the cost of the method for synthesizing the target product completely is greatly reduced; the reaction condition of the method is milder, in the method reported in the literature, the reaction temperature in the acid amine condensation step reaches about 190 ℃, the Ullmann condensation reaction temperature is about 145-150 ℃, the temperature greatly exceeds the boiling point of a reaction solvent, and a large risk exists. The post-treatment of the method adopts extraction, water washing, concentration or crystallization and other modes, the operation is simple and convenient, the method has industrial amplification value, and reference is provided for the total synthesis method of the optical pure tetrandrine.

Detailed Description

The present invention will be further described with reference to the following examples.

Example 1

(1) Preparation of Compound 2

100 g of 5-bromovanillin and 1000 g of dichloromethane are added into a 3L three-necked flask, and the mixture is stirred at room temperature, dissolved and clarified. 200g of 20% NaOH solution was added thereto, and the mixture was reacted at room temperature for 1 hour. 100 g of methyl iodide is added, and the mixture is heated to reflux reaction for 10 hours, so that the raw materials are completely reacted. The reaction solution was cooled to room temperature, and the reaction solution was allowed to stand for liquid separation, and the aqueous phase was extracted twice with 200g of dichloromethane. The methylene chloride phases were combined, washed once with 500 g of saturated brine and once with 500 g of water, and dried over anhydrous sodium sulfate. Filtering, concentrating the filtrate under reduced pressure to dryness to obtain yellow solid 90.3 g, namely the compound 2 with the yield of 85.1%.

(2) Preparation of Compound 3

100 g of compound 2, 62 g of triethylamine, 125 g of nitromethane and 500 g of absolute ethyl alcohol are added into a 2L three-necked flask, and the mixture is heated until reflux reaction is carried out for 12 hours, so that the raw materials are reacted completely. The reaction solution was cooled to room temperature, and 500 g of water was added to precipitate a large amount of solid. Filtering, washing the filter cake twice with water and twice with isopropanol 60^oAnd C, drying to obtain 89.4 g of yellow solid, namely the compound 3, wherein the yield is 76.1%.

(3) Preparation of Compound 4

Adding 570 g of tetrahydrofuran and 22.8 g of lithium aluminum hydride into a 2L three-necked bottle, and cooling to-5%^oC, about; 57 g of the compound 3 is dissolved in 228 g of tetrahydrofuran, slowly and dropwise added into the three-necked flask, and after the dropwise addition, the mixture is heated to reflux for reaction for 8 hours, so that the raw materials are completely reacted. Cooling to 0^oAbout C, 280 g of ethyl acetate and 150 g of water are sequentially added dropwise to quench and react. Sodium sulfate was added, the mixture was stirred for half an hour and then filtered, the filtrate was concentrated to dryness under reduced pressure, pH =2 was adjusted with 10% dilute hydrochloric acid, and 500 g of ethyl acetate was used to extract impurities twice. The aqueous phase was adjusted to pH =10 with 20% sodium hydroxide solution and extracted twice with 500 g dichloromethane. The dichloromethane phases were combined, washed twice with 200g of water and dried over anhydrous sodium sulfate. Filtering, concentrating the filtrate under reduced pressure to dryness to obtain yellow oily matter 38.8 g, cooling and solidifying to obtain compound 4 with yield of 75.4%.

(4) Preparation of Compound 6

A1L three-necked flask was charged with 45 g of Compound 5, 1.6 g of potassium iodide, 38 g of potassium hydroxide and 350 g of methanol, and 64 g of benzyl bromide was added dropwise at room temperature. After dropping, the mixture is heated to reflux and reacted for 8 hours, and the raw materials are completely reacted. After cooling to room temperature, 150 g of water was added, and pH =1 was adjusted with 10% dilute hydrochloric acid to precipitate a large amount of solid. Filtering, washing filter cake twice with water, 60^oC, drying to obtain 61.8 g of yellow solid,this gave compound 6 in a yield of 91.9%.

(5) Preparation of Compound 7

30 g of Compound 6 and 500 g of methylene chloride were placed in a 1L three-necked flask, and after dissolution and clarification, 21 g of CDI were added in portions. After the addition, the reaction was continued for 2 hours at room temperature, 26 g of Compound 4 was added, and the reaction was continued for 2 hours until the starting material was completely reacted. The reaction was quenched with 260 g of water, allowed to stand for liquid separation, and the aqueous phase was extracted twice with 260 g of dichloromethane. The dichloromethane phases were combined, washed twice with 400 g of water and dried over anhydrous sodium sulfate. Filtering, concentrating the filtrate under reduced pressure to dryness to obtain light yellow oily matter, crystallizing with 150 g isopropanol to obtain 37.1 g of light yellow solid, namely the compound 7, with the yield of 72.1%.

(6) Preparation of Compound 8

20g of compound 7, 46.8 g of phosphorus oxychloride and 400 g of toluene are added into a 1L three-necked flask, and the mixture is heated to reflux reaction for 6 hours under the protection of nitrogen, so that the raw materials are reacted completely. The temperature is reduced to room temperature, 300 g of water is slowly dripped into the reaction liquid, and stirring is continued for 1 hour after dripping. The mixture was allowed to stand for liquid separation, and the toluene phase was washed twice with 300 g of water and dried over anhydrous sodium sulfate. Filtering, concentrating the filtrate under reduced pressure to dryness to obtain yellow oily substance 13.5 g, namely the compound 8 with the yield of 69.9%.

(7) Preparation of Compound 9

10 g of compound 8 and 200g of ethanol are added to a 500 mL three-necked flask, and after the mixture is dissolved and clarified, 4g of potassium borohydride are added in portions. Heating to 40 deg.C after adding^oC, reacting for 3 hours, and completely reacting the raw materials. The reaction mixture was concentrated to dryness under reduced pressure, 150 g of water was added, extraction was performed twice with 200g of dichloromethane, the dichloromethane phases were combined, washed twice with 200g of water, and dried over anhydrous sodium sulfate. Filtering, decompressing and concentrating the filtrate to dryness to obtain 9.8 g of yellow oily matter, namely the compound 9 with the yield of 97.6 percent.

(8) Preparation of Compound 10

A250 mL three-necked flask was charged with 9 g of Compound 9 and 45 g of DMF, and the mixture was dissolved and clarified. Cooling to 15 deg.C^oAnd adding 1.5 g of potassium hydroxide into the mixture C, and keeping the temperature to react for 1 hour. 4g of methyl p-toluenesulfonate was dissolved in 9 g of DMF and was added dropwise to the above three-necked flask. After dropping, heating to 50 deg.C^oC, reacting for 4 hours, and completely reacting the raw materials. Concentrating the reaction solution under reduced pressure to dryness, adding45 g of water were added and extracted twice with 90 g of ethyl acetate. The ethyl acetate phases were combined, washed twice with 90 g of water and dried over anhydrous sodium sulfate. Filtering, concentrating the filtrate under reduced pressure to dryness to obtain oily matter, crystallizing with 36 g anhydrous ethanol to obtain white solid 4.8 g, namely the compound 10, with the yield of 51.9%.

(9) Preparation of Compound 11

5 g of compound 10, 33 g of trifluoroacetic acid and 50 g of methanol are added into a 250 mL three-necked flask, and the mixture is heated to reflux under the protection of nitrogen for 6 hours, so that the raw materials are completely reacted. The reaction mixture was concentrated to dryness under reduced pressure, 50 g of water was added, a saturated sodium bicarbonate solution was slowly added dropwise to adjust pH =8, and the mixture was extracted twice with 100 g of dichloromethane. The dichloromethane phases were combined, washed twice with 100 g of water and dried over anhydrous sodium sulfate. Filtering, concentrating the filtrate under reduced pressure to dryness to obtain white solid 3.9 g, namely the compound 11 with the yield of 94.6%.

(10) Preparation of Compound 13

A2L three-necked flask was charged with 152 g of vanillin, 16.6 g of potassium iodide, 48 g of sodium hydroxide and 1200 g of methylene chloride, and 205 g of benzyl bromide was added dropwise at room temperature. After dropping, the mixture is heated to reflux and reacted for 8 hours, and the raw materials are completely reacted. Cooled to room temperature, filtered, and the filtrate was washed twice with 800 g of 5% sodium hydroxide solution, once with 400 g of water, and dried over anhydrous sodium sulfate. Filtering, concentrating the filtrate under reduced pressure to dryness to obtain yellow oily matter, crystallizing with 450 g petroleum ether to obtain white solid 168 g, i.e. compound 13, with a yield of 69.4%.

(11) Preparation of Compound 14

109 g of compound 13, 68 g of triethylamine, 110 g of nitromethane and 545 g of absolute ethyl alcohol are added into a 2L three-necked flask, and the mixture is heated to reflux and react for 12 hours, so that the raw materials are reacted completely. The reaction solution was cooled to room temperature, and 545 g of water was added to precipitate a large amount of solid. Filtering, washing the filter cake twice with water and twice with isopropanol 60^oAnd C, drying to obtain 111 g of yellow solid, namely the compound 14, wherein the yield is 86.5%.

(12) Preparation of Compound 15

572 g tetrahydrofuran and 22.8 g lithium aluminum hydride are added into a 2L three-necked flask, and the temperature is reduced to-5^oC, about; 57.2 g of Compound 14 are dissolved in 229 g of tetrahydrofuran and slowly added dropwise to the above three-necked flaskAfter the dripping is finished, the mixture is heated to reflux reaction for 8 hours, and the raw materials are completely reacted. Cooling to 0^oAbout C, 280 g of ethyl acetate and 150 g of water are sequentially added dropwise to quench and react. Sodium sulfate was added, the mixture was stirred for half an hour and then filtered, the filtrate was concentrated to dryness under reduced pressure, pH =2 was adjusted with 10% dilute hydrochloric acid, and 500 g of ethyl acetate was used to extract impurities twice. The aqueous phase was adjusted to pH =10 with 20% sodium hydroxide solution and extracted twice with 500 g dichloromethane. The dichloromethane phases were combined, washed twice with 200g of water and dried over anhydrous sodium sulfate. Filtering, concentrating the filtrate under reduced pressure to dryness to obtain yellow oily substance 44.8 g, cooling and solidifying to obtain compound 15 with yield of 86.8%.

(13) Preparation of Compound 16

27.9 g of p-bromophenylacetic acid and 500 g of methylene chloride were placed in a 1L three-necked flask, and 32.4 g of CDI was added in portions after dissolution and clarification. After the addition, after reacting at room temperature for 2 hours, 25.7 g of compound 15 was added, and the reaction was continued for 2 hours until the reaction of the starting materials was completed. The reaction was quenched with 260 g of water, allowed to stand for liquid separation, and the aqueous phase was extracted twice with 260 g of dichloromethane. The dichloromethane phases were combined, washed twice with 400 g of water and dried over anhydrous sodium sulfate. Filtering, concentrating the filtrate under reduced pressure to dryness to obtain light yellow oily matter, crystallizing with 129 g isopropanol to obtain 34.4 g of light yellow solid, namely the compound 16, with the yield of 75.7%.

(14) Preparation of Compound 17

22.7 g of compound 16, 61.3 g of phosphorus oxychloride and 454 g of toluene are added into a 1L three-neck flask, and the mixture is heated to reflux reaction for 6 hours under the protection of nitrogen, so that the raw materials are reacted completely. The temperature is reduced to room temperature, 340 g of water is slowly dropped into the reaction solution, and stirring is continued for 1 hour after the dropping is finished. The mixture was allowed to stand for liquid separation, and the toluene phase was washed twice with 300 g of water and dried over anhydrous sodium sulfate. Filtering, concentrating the filtrate under reduced pressure to dryness to obtain yellow oily matter 17.8 g, namely the compound 17, with the yield of 81.6%.

(15) Preparation of Compound 18

10.9 g of Compound 17 and 218 g of ethanol are placed in a 500 mL three-necked flask, and after the mixture is dissolved and clarified, 5.4 g of potassium borohydride are added in portions. Heating to 40 deg.C after adding^oC, reacting for 3 hours, and completely reacting the raw materials. The reaction mixture was concentrated to dryness under reduced pressure, 150 g of water was added, extraction was carried out twice with 200g of dichloromethane, the dichloromethane phases were combined, and 200g of waterWashed twice and dried over anhydrous sodium sulfate. Filtering, concentrating the filtrate under reduced pressure to dryness to obtain yellow oily substance 10.6 g, namely compound 18, with the yield of 96.8%.

(16) Preparation of Compound 19

A250 mL three-necked flask was charged with 8.8 g of Compound 18 and 44 g of DMF, and the mixture was dissolved and clarified. Cooling to 15 deg.C^oAnd adding 1.5 g of potassium hydroxide into the mixture C, and keeping the temperature to react for 1 hour. 4g of methyl p-toluenesulfonate was dissolved in 9 g of DMF and was added dropwise to the above three-necked flask. After dropping, heating to 50 deg.C^oC, reacting for 4 hours, and completely reacting the raw materials. The reaction mixture was concentrated to dryness under reduced pressure, 45 g of water was added thereto, and the mixture was extracted twice with 90 g of ethyl acetate. The ethyl acetate phases were combined, washed twice with 90 g of water and dried over anhydrous sodium sulfate. Filtering, concentrating the filtrate under reduced pressure to dryness to obtain oily substance, crystallizing with 36 g anhydrous ethanol to obtain off-white solid 7.0 g, i.e. compound 19, with yield 77.1%.

(17) Preparation of Compound 20

A250 mL three-necked flask was charged with 2.1 g of Compound 11, 2.3 g of Compound 19, 0.21 g of cuprous iodide, 4.9 g of cesium carbonate, and 42 g of DMF, and the mixture was heated under reflux for 48 hours under nitrogen protection to complete the reaction of the starting materials. The reaction mixture was concentrated to dryness under reduced pressure, 21 g of water was added, pH =3 was adjusted with 10% dilute hydrochloric acid, and extraction was performed twice with 82 g of dichloromethane. The dichloromethane phases were combined, washed twice with 82 g of water and dried over anhydrous sodium sulfate. Filtering, concentrating the filtrate under reduced pressure to dryness to obtain brown solid, and purifying by column chromatography to obtain light yellow solid 2.3 g, which is compound 20, with yield 58.3%.

(18) Preparation of Compound 21

2 g of the compound 20, 28.7 g of trifluoroacetic acid and 40g of methanol are added into a 100 mL three-necked flask, and the mixture is heated to reflux under the protection of nitrogen for 6 hours, so that the raw materials are completely reacted. The reaction mixture was concentrated to dryness under reduced pressure, 40g of water was added thereto, a saturated sodium bicarbonate solution was slowly added dropwise to adjust pH =8, and the mixture was extracted twice with 80 g of dichloromethane. The dichloromethane phases were combined, washed twice with 80 g of water and dried over anhydrous sodium sulfate. Filtering, concentrating the filtrate under reduced pressure to dryness to obtain white solid 1.7 g, namely the compound 21 with the yield of 95.9%.

(19) Preparation of racemic tetrandrine (Compound 22)

A250 mL three-necked flask was charged with 1.5 g of Compound 21, 0.3 g of cuprous iodide, 2.1 g of cesium carbonate, and 75 g of DMF, and the mixture was heated under reflux for 60 hours under nitrogen protection to complete the reaction of the starting materials. The reaction mixture was concentrated to dryness under reduced pressure, 30 g of water was added, pH =3 was adjusted with 10% dilute hydrochloric acid, and extraction was performed twice with 60 g of dichloromethane. The dichloromethane phases were combined, washed twice with 60 g of water and dried over anhydrous sodium sulfate. Filtering, concentrating the filtrate under reduced pressure to dryness to obtain brown solid, and purifying by column chromatography to obtain off-white solid 0.6 g, i.e. racemic tetrandrine, with yield of 45.2%.

Example 2

(1) Preparation of Compound 2

115 g of 5-bromovanillin and 1150 g of chloroform are added into a 3L three-necked flask, and stirred at room temperature to dissolve and clarify. 200g of 20% NaOH solution was added thereto, and the mixture was reacted at room temperature for 1 hour. Then 130 g of methyl iodide is added, and the mixture is heated to reflux reaction for 10 hours, so that the raw materials are completely reacted. The reaction solution was cooled to room temperature, and after standing and separating, the aqueous phase was extracted twice with 200g of chloroform. The chloroform phases were combined, washed once with 500 g of saturated brine and once with 500 g of water, and dried over anhydrous sodium sulfate. Filtering, concentrating the filtrate under reduced pressure to dryness to obtain yellow solid 95.2 g, namely the compound 2 with the yield of 78.0%.

(2) Preparation of Compound 3

131 g of the compound 2, 62 g of potassium carbonate, 98 g of nitromethane and 500 g of acetic acid are added into a 2L three-necked flask, and the mixture is heated to reflux and react for 15 hours, so that the raw materials are completely reacted. The reaction solution was cooled to room temperature, and 500 g of water was added to precipitate a large amount of solid. Filtering, washing the filter cake twice with water and twice with isopropanol 60^oAnd C, drying to obtain 109 g of yellow solid, namely the compound 3, wherein the yield is 70.8%.

(3) Preparation of Compound 4

560 g of tetrahydrofuran and 27.6 g of lithium aluminum hydride are added into a 2L three-necked flask, and the temperature is reduced to-5^oC, about; 70 g of the compound 3 is dissolved in 280 g of tetrahydrofuran, slowly added into the three-necked bottle dropwise, and heated to reflux for reaction for 8 hours after the dropwise addition is finished, so that the raw materials are completely reacted. Cooling to 0^oAbout C, 280 g of ethyl acetate and 150 g of water are sequentially added dropwise to quench and react. Adding sodium sulfate and stirring to half smallAfter filtration, the filtrate was concentrated to dryness under reduced pressure, pH =2 or so with 10% dilute hydrochloric acid, and 500 g of ethyl acetate was used to extract impurities twice. The aqueous phase was adjusted to pH =10 with 20% sodium hydroxide solution and extracted twice with 500 g dichloromethane. The dichloromethane phases were combined, washed twice with 200g of water and dried over anhydrous sodium sulfate. Filtering, concentrating the filtrate under reduced pressure to dryness to obtain yellow oily matter 43.5 g, cooling and solidifying to obtain compound 4 with yield of 68.8%.

(4) Preparation of Compound 6

A1L three-necked flask was charged with 50 g of Compound 5, 2.5 g of potassium iodide, 75.7 g of potassium carbonate and 400 g of ethanol, and 61 g of benzyl bromide was added dropwise at room temperature. After dropping, the mixture is heated to reflux and reacted for 8 hours, and the raw materials are completely reacted. After cooling to room temperature, 150 g of water was added, and pH =1 was adjusted with 10% dilute hydrochloric acid to precipitate a large amount of solid. Filtering, washing filter cake twice with water, 60^oAnd C, drying to obtain 67.5 g of yellow solid, namely the compound 6, wherein the yield is 90.3%.

(5) Preparation of Compound 7

26 g of the compound 4, 30 g of the compound 6, 52 g of HATU and 500 g of dichloromethane are added into a 1L three-necked flask, 26 g of DIPEA is slowly added dropwise, and the reaction is carried out at room temperature for 3 hours after the dropwise addition is finished, so that the raw materials are completely reacted. The filtrate was filtered, washed once with 200g of 10% dilute hydrochloric acid and 200g of saturated sodium bicarbonate, twice with 400 g of water, and dried over anhydrous sodium sulfate. Filtering, concentrating the filtrate under reduced pressure to dryness to obtain yellow solid, crystallizing with 150 g isopropanol to obtain light yellow solid 34.1 g, namely compound 7, with the yield of 66.3%.

(6) Preparation of Compound 8

30 g of compound 7, 75 g of phosphorus oxychloride and 600 g of toluene are added into a 2L three-neck flask, and the mixture is heated to reflux reaction for 7 hours under the protection of nitrogen, so that the raw materials are completely reacted. And cooling to room temperature, slowly dropwise adding 400 g of water into the reaction solution, and continuously stirring for 1 hour after dropwise adding. The mixture was allowed to stand for liquid separation, and the toluene phase was washed twice with 400 g of water and dried over anhydrous sodium sulfate. Filtering, concentrating the filtrate under reduced pressure to dryness to obtain yellow oily substance 19.8 g, namely the compound 8 with the yield of 68.4%.

(7) Preparation of Compound 9

15 g of compound 8 and 300 g of methanol are added into a 500 mL three-necked flask, and 7 is added in portions after dissolution and clarificationg of sodium borohydride. Heating to 40 deg.C after adding^oC, reacting for 3 hours, and completely reacting the raw materials. The reaction mixture was concentrated to dryness under reduced pressure, 150 g of water was added, extraction was performed twice with 200g of dichloromethane, the dichloromethane phases were combined, washed twice with 200g of water, and dried over anhydrous sodium sulfate. Filtering, decompressing and concentrating the filtrate to be dry to obtain 14.2 g of yellow oily matter, namely the compound 9 with the yield of 94.3 percent.

(8) Preparation of Compound 10

In a 500 mL three-necked flask, 15 g of Compound 9 and 150 g of methylene chloride were added, and the mixture was dissolved with stirring at room temperature to be clear. 20g of 20% NaOH solution was added thereto, and the reaction was carried out at room temperature for 1 hour. 6.4 g of methyl iodide was added, and the mixture was heated to reflux reaction for 5 hours, whereby the reaction of the starting materials was completed. The reaction solution was cooled to room temperature, and after standing and separating, the aqueous phase was extracted twice with 100 g of chloroform. The chloroform phases were combined, washed once with 100 g of saturated brine and once with 100 g of water, and dried over anhydrous sodium sulfate. Filtering, concentrating the filtrate under reduced pressure to dryness to obtain yellow solid, crystallizing with isopropanol to obtain white solid 8.9 g, i.e. compound 10, with yield 57.7%.

(9) Preparation of Compound 11

10 g of compound 10, 150 g of hydrochloric acid and 150 g of ethanol are added into a 500 mL three-necked flask, and the mixture is heated to reflux under the protection of nitrogen for 8 hours, so that the raw materials are completely reacted. The reaction mixture was concentrated to dryness under reduced pressure, 50 g of water was added, a saturated sodium bicarbonate solution was slowly added dropwise to adjust pH =8, and the mixture was extracted twice with 100 g of dichloromethane. The dichloromethane phases were combined, washed twice with 100 g of water and dried over anhydrous sodium sulfate. Filtering, concentrating the filtrate under reduced pressure to dryness to obtain white solid 7.6 g, namely the compound 11 with the yield of 92.2%.

(10) Preparation of Compound 13

A1L three-necked flask was charged with vanillin 90 g, potassium iodide 9 g, potassium carbonate 90 g and methylene chloride 450 g, and benzyl bromide 112 g was added dropwise at room temperature. After dropping, the mixture is heated to reflux and reacted for 8 hours, and the raw materials are completely reacted. Cooled to room temperature, filtered, and the filtrate was washed twice with 400 g of 5% sodium hydroxide solution and once with 200g of water, and dried over anhydrous sodium sulfate. Filtering, concentrating the filtrate under reduced pressure to dryness to obtain yellow oily substance, crystallizing with 180 g petroleum ether to obtain white solid 102 g, i.e. compound 13, with yield of 71.2%.

(11) Preparation of Compound 14

121 g of compound 13, 138 g of potassium carbonate, 83 g of nitromethane and 600 g of acetic acid are added into a 2L three-necked flask, and the mixture is heated to reflux for reaction for 13 hours, so that the raw materials are reacted completely. The reaction solution was cooled to room temperature, and 800 g of water was added to precipitate a large amount of solid. Filtering, washing the filter cake twice with water and twice with isopropanol 60^oC, drying to obtain 119 g of yellow solid, namely the compound 14, wherein the yield is 83.5%.

(12) Preparation of Compound 15

500 g of tetrahydrofuran and 30 g of lithium aluminum hydride are added into a 2L three-necked bottle, and the temperature is reduced to-5^oC, about; 50 g of the compound 14 is dissolved in 250 g of tetrahydrofuran, slowly and dropwise added into the three-necked flask, and after the dropwise addition, the mixture is heated to reflux for reaction for 8 hours, so that the raw materials are completely reacted. Cooling to 0^oAbout C, 250 g of ethyl acetate and 150 g of water are sequentially added dropwise to quench and react. Sodium sulfate was added, the mixture was stirred for half an hour and then filtered, the filtrate was concentrated to dryness under reduced pressure, pH =2 was adjusted with 10% dilute hydrochloric acid, and 400 g of ethyl acetate was used to extract impurities twice. The aqueous phase was adjusted to pH =10 with 20% sodium hydroxide solution and extracted twice with 400 g of dichloromethane. The dichloromethane phases were combined, washed twice with 200g of water and dried over anhydrous sodium sulfate. Filtering, concentrating the filtrate under reduced pressure to dryness to obtain 38.1 g of yellow oily matter, cooling and solidifying to obtain the compound 15 with the yield of 84.5%.

(13) Preparation of Compound 16

20g of compound 15, 20g of p-bromophenylacetic acid, 40g of HATU and 400 g of dichloromethane are added into a 1L three-necked flask, 16 g of DIPEA is slowly dripped, and the reaction is carried out at room temperature for 3 hours after dripping is finished, so that the raw materials are completely reacted. The filtrate was filtered, washed once with 200g of 10% dilute hydrochloric acid and 200g of saturated sodium bicarbonate, twice with 400 g of water, and dried over anhydrous sodium sulfate. Filtering, concentrating the filtrate under reduced pressure to dryness to obtain yellow solid, crystallizing with 120 g isopropanol to obtain light yellow solid 26.1 g, namely compound 7, with yield 73.9%.

(14) Preparation of Compound 17

25 g of compound 16, 75 g of phosphorus oxychloride and 500 g of toluene are added into a 1L three-necked flask, and the mixture is heated to reflux reaction for 8 hours under the protection of nitrogen, so that the raw materials are reacted completely. And cooling to room temperature, slowly dropwise adding 350 g of water into the reaction solution, and continuously stirring for 1 hour after dropwise adding. The mixture was allowed to stand for liquid separation, and the toluene phase was washed twice with 300 g of water and dried over anhydrous sodium sulfate. Filtering, concentrating the filtrate under reduced pressure to dryness to obtain yellow oily substance 20g, namely the compound 17, with the yield of 83.3%.

(15) Preparation of Compound 18

15 g of compound 17 and 300 g of methanol are added to a 500 mL three-necked flask, and 9 g of sodium borohydride are added in portions after dissolution and clarification. Heating to 40 deg.C after adding^oC, reacting for 3 hours, and completely reacting the raw materials. The reaction mixture was concentrated to dryness under reduced pressure, 150 g of water was added, extraction was performed twice with 200g of dichloromethane, the dichloromethane phases were combined, washed twice with 200g of water, and dried over anhydrous sodium sulfate. Filtering, decompressing and concentrating the filtrate to be dry to obtain 14.5 g of yellow oily matter, namely the compound 18 with the yield of 96.2 percent.

(16) Preparation of Compound 19

In a 500 mL three-necked flask, 15 g of Compound 18 and 150 g of methylene chloride were added, and the mixture was dissolved with stirring at room temperature to be clear. 20g of 20% NaOH solution was added thereto, and the reaction was carried out at room temperature for 1 hour. 6.8 g of methyl iodide is added, and the mixture is heated until reflux reaction is carried out for 6 hours, so that the raw materials are completely reacted. The reaction solution was cooled to room temperature, and after standing and separating, the aqueous phase was extracted twice with 100 g of chloroform. The chloroform phases were combined, washed once with 100 g of saturated brine and once with 100 g of water, and dried over anhydrous sodium sulfate. Filtering, concentrating the filtrate under reduced pressure to dryness to obtain yellow solid, crystallizing with isopropanol to obtain white solid 11.4 g, i.e. compound 19, with yield 73.6%.

(17) Preparation of Compound 20

A250 mL three-necked flask was charged with 2.4 g of Compound 11, 2.0 g of Compound 19, 0.9 g of a cuprous dimethyl sulfide bromide mixture, 4.2 g of cesium carbonate, and 40g of pyridine, and heated under nitrogen to reflux for 48 hours to complete the reaction. The reaction mixture was concentrated to dryness under reduced pressure, 20g of water was added, pH =3 was adjusted with 10% dilute hydrochloric acid, and extraction was performed twice with 80 g of dichloromethane. The dichloromethane phases were combined, washed twice with 80 g of water and dried over anhydrous sodium sulfate. Filtering, concentrating the filtrate under reduced pressure to dryness to obtain brown solid, and purifying by column chromatography to obtain light yellow solid 1.9 g, which is compound 20, with yield of 54.1%.

(18) Preparation of Compound 21

1.5 g of compound 20, 30 g of hydrochloric acid and 30 g of methanol are added into a 100 mL three-necked flask, and the mixture is heated to reflux under the protection of nitrogen for 6 hours, so that the raw materials are completely reacted. The reaction mixture was concentrated to dryness under reduced pressure, 30 g of water was added thereto, a saturated sodium bicarbonate solution was slowly added dropwise to adjust pH =8, and the mixture was extracted twice with 60 g of dichloromethane. The dichloromethane phases were combined, washed twice with 60 g of water and dried over anhydrous sodium sulfate. Filtering, decompressing and concentrating the filtrate to be dry to obtain 1.3 g of white solid, namely the compound 21 with the yield of 97.8 percent.

(19) Preparation of racemic tetrandrine (Compound 22)

A250 mL three-necked flask was charged with 1.4 g of Compound 21, 0.6 g of a cuprous bromide dimethyl sulfide mixture, 1.8 g of cesium carbonate, and 70 g of DMF, and the mixture was heated under nitrogen atmosphere to reflux for 60 hours to complete the reaction of the starting materials. The reaction mixture was concentrated to dryness under reduced pressure, 30 g of water was added, pH =3 was adjusted with 10% dilute hydrochloric acid, and extraction was performed twice with 60 g of dichloromethane. The dichloromethane phases were combined, washed twice with 60 g of water and dried over anhydrous sodium sulfate. Filtering, concentrating the filtrate under reduced pressure to dryness to obtain brown solid, and purifying by column chromatography to obtain off-white solid 0.5 g, i.e. racemic tetrandrine, with yield of 40.4%.

Example 3

(1) Preparation of Compound 2

50 g of 5-bromovanillin and 500 g of toluene are added into a 1L three-necked flask, and the mixture is stirred at room temperature, dissolved and clarified. Adding 59 g of potassium carbonate, and cooling to 0-5 ℃. 41 g of dimethyl sulfate is slowly added, and after the addition is finished, the mixture is heated to 40 ℃ for reaction for 14 hours, so that the raw materials are completely reacted. The reaction mixture was concentrated to dryness under reduced pressure, 200g of water was added thereto, and the mixture was extracted twice with 500 g of methylene chloride. The methylene chloride phases were combined, washed once with 200g of saturated brine and once with 200g of water, and dried over anhydrous sodium sulfate. Filtering, concentrating the filtrate under reduced pressure to dryness to obtain yellow solid 43.1 g, namely the compound 2 with the yield of 81.2%.

(2) Preparation of Compound 3

A1L three-necked flask is added with 24.5 g of compound 2, 8.2 g of ammonium acetate, 20g of nitromethane and 125 g of isopropanol, heated to 75 ℃ and reacted for 17 hours, and the raw materials are completely reacted. The reaction solution was cooled to room temperature, and 200g of water was added to precipitate a large amount of solid. Filtering, washing the filter cake twice with water, twice with isopropanol, drying at 60 ℃ to obtain 21.2 g of yellow solid, namely the compound 3, with the yield of 73.7%.

(3) Preparation of Compound 4

Adding 200g of tetrahydrofuran and 12.2 g of sodium borohydride into a 1L three-necked flask, cooling to about 15 ℃, and slowly dropwise adding 52 g of boron trifluoride diethyl etherate solution; 14.4 g of the compound 3 is dissolved in 100 g of tetrahydrofuran, slowly added dropwise into the three-necked flask, and heated to reflux for reaction for 9 hours after the dropwise addition, so that the raw materials completely react. The temperature is reduced to about 0 ℃, and 150 g of water is added dropwise to quench the reaction. pH = about 10 adjusted with 20% sodium hydroxide solution, extracted twice with 300 g dichloromethane. The dichloromethane phases were combined, washed twice with 200g of water and dried over anhydrous sodium sulfate. Filtering, concentrating the filtrate under reduced pressure to dryness to obtain yellow oily matter 9.7 g, cooling and solidifying to obtain compound 4 with yield of 74.6%.

(4) Preparation of Compound 6

A500 mL three-necked flask was charged with 18.2 g of Compound 5, 0.5 g of potassium iodide, 13.2 g of sodium hydroxide and 180 g of isopropyl alcohol, and 21.6 g of benzyl chloride was added dropwise at room temperature. After dropping, the mixture was heated to 70 ℃ to react for 6 hours, and the reaction of the raw materials was completed. After cooling to room temperature, 150 g of water was added, and pH =2 was adjusted with 10% dilute hydrochloric acid to precipitate a large amount of solid. Filtering, washing the filter cake twice with water, drying at 60 ℃ to obtain 23.7 g of yellow solid, namely the compound 6, with the yield of 86.9%.

(5) Preparation of Compound 7

A250 mL three-necked flask was charged with 13.6 g of Compound 6, 13 g of Compound 4, and 80 g of DMF, and after dissolution and clarification, 12.5 g of EDCI was added in portions. After the addition, 9 g of DIPEA was slowly added dropwise, and the reaction was carried out for 7 hours by heating to 50 ℃ until the starting material was completely reacted. The reaction mixture was concentrated to dryness under reduced pressure, 80 g of water was added thereto, and the mixture was extracted twice with 150 g of methylene chloride. The dichloromethane phases were combined, washed twice with 100 g of water and dried over anhydrous sodium sulfate. Filtering, concentrating the filtrate under reduced pressure to dryness to obtain light yellow oily matter, crystallizing with 70 g isopropanol to obtain light yellow solid 17.2 g, namely the compound 7, with the yield of 67.1%.

(6) Preparation of Compound 8

17.1 g of the compound 7, 33.8 g of polyphosphoric acid and 340 g of benzene are added into a 1L three-necked flask, and the mixture is heated to reflux under the protection of nitrogen for 5 hours, so that the raw materials are reacted completely. The reaction mixture was cooled to room temperature, 100 g of water was slowly added dropwise to the reaction mixture, and after completion of the addition, the reaction mixture was adjusted to pH =7 with a saturated sodium bicarbonate solution, and stirring was continued for 1 hour. The mixture was allowed to stand for liquid separation, and the benzene phase was washed twice with 300 g of water and dried over anhydrous sodium sulfate. Filtering, concentrating the filtrate under reduced pressure to dryness to obtain yellow oily substance 10.7 g, namely compound 8 with yield of 64.5%.

(7) Preparation of Compound 9

10 g of compound 8 and 200g of isopropanol are introduced into a 500 mL three-necked flask, and after dissolution and clarification 4.2 g of sodium borohydride are added in portions. After the addition, the mixture was heated to 40 ℃ for 3 hours, and the reaction of the starting materials was complete. The reaction mixture was concentrated to dryness under reduced pressure, 150 g of water was added, extraction was performed twice with 200g of dichloromethane, the dichloromethane phases were combined, washed twice with 200g of water, and dried over anhydrous sodium sulfate. Filtering, concentrating the filtrate under reduced pressure to dryness to obtain yellow oily substance 9.1 g, namely the compound 9 with the yield of 90.7%.

(8) Preparation of Compound 10

A250 mL three-necked flask was charged with 10 g of Compound 9 and 50 g of toluene, and the mixture was dissolved and clarified. 5.1 g of potassium carbonate is added, the temperature is reduced to about 5 ℃, and 3.8 g of dimethyl sulfate is slowly added. After the addition, the mixture is heated to about 40 ℃ for reaction for 5 hours, and the raw materials are completely reacted. The reaction mixture was concentrated to dryness under reduced pressure, 45 g of water was added thereto, and the mixture was extracted twice with 90 g of ethyl acetate. The ethyl acetate phases were combined, washed twice with 90 g of water and dried over anhydrous sodium sulfate. Filtering, concentrating the filtrate under reduced pressure to dryness to obtain oily substance, crystallizing with 40g anhydrous ethanol to obtain white solid 5.1 g, i.e. compound 10, with yield 49.2%.

(9) Preparation of Compound 11

4g of compound 10, 30 g of trifluoroacetic acid and 40g of isopropanol are added into a 250 mL three-necked flask, and the mixture is heated to reflux under the protection of nitrogen for 6 hours, so that the raw materials are completely reacted. The reaction mixture was concentrated to dryness under reduced pressure, 50 g of water was added, a saturated sodium bicarbonate solution was slowly added dropwise to adjust pH =8, and the mixture was extracted twice with 80 g of dichloromethane. The dichloromethane phases were combined, washed twice with 80 g of water and dried over anhydrous sodium sulfate. Filtering, concentrating the filtrate under reduced pressure to dryness to obtain white solid 3.1 g, namely the compound 11 with the yield of 95.1%.

(10) Preparation of Compound 13

76 g of vanillin, 7.6 g of potassium iodide, 48 g of sodium hydroxide and 600 g of isopropanol are added into a 2L three-necked flask, and 100 g of benzyl chloride is added dropwise at room temperature. After dropping, the mixture was heated to 70 ℃ to react for 8 hours, and the reaction of the raw materials was completed. After cooling to room temperature, 150 g of water was added, and pH =2 was adjusted with 10% dilute hydrochloric acid to precipitate a large amount of solid. Filtering, washing the filter cake twice with water, drying at 60 ℃ to obtain 81.4 g of white solid, namely the compound 13, with the yield of 67.3%.

(11) Preparation of Compound 14

80.7 g of compound 13, 40g of ammonium acetate, 82 g of nitromethane and 400 g of isopropanol are added into a 1L three-necked flask, and the mixture is heated to reflux and react for 13 hours, so that the raw materials react completely. The reaction solution was cooled to room temperature, and 400 g of water was added to precipitate a large amount of solid. Filtering, washing the filter cake twice with water, twice with isopropanol, drying at 60 ℃ to obtain 75.4 g of yellow solid, namely the compound 14, with the yield of 79.4%.

(12) Preparation of Compound 15

Adding 200g of tetrahydrofuran and 12.2 g of sodium borohydride into a 1L three-necked flask, cooling to about 15 ℃, and slowly dropwise adding 52 g of boron trifluoride diethyl etherate solution; 14.3 g of the compound 3 is dissolved in 100 g of tetrahydrofuran, slowly added dropwise into the three-necked flask, and after the dropwise addition, the mixture is heated to reflux for reaction for 9 hours, so that the raw materials react completely. The temperature is reduced to about 0 ℃, and 150 g of water is added dropwise to quench the reaction. pH = about 10 adjusted with 20% sodium hydroxide solution, extracted twice with 300 g dichloromethane. The dichloromethane phases were combined, washed twice with 200g of water and dried over anhydrous sodium sulfate. Filtering, concentrating the filtrate under reduced pressure to dryness to obtain 11.1 g of yellow oily matter, cooling and solidifying to obtain the compound 15 with the yield of 86.1%.

(13) Preparation of Compound 16

A250 mL three-necked flask was charged with 10.3 g of p-bromophenylacetic acid, 11.2 g of Compound 15 and 100 g of DMF, and after dissolution and clarification, 12.1 g of EDCI was added in portions. After the addition, 8.6 g of DIPEA was slowly added dropwise, and the reaction was carried out for 7 hours by heating to 50 ℃ until the starting material was completely reacted. The reaction mixture was concentrated to dryness under reduced pressure, 80 g of water was added thereto, and the mixture was extracted twice with 150 g of methylene chloride. The dichloromethane phases were combined, washed twice with 100 g of water and dried over anhydrous sodium sulfate. Filtering, concentrating the filtrate under reduced pressure to dryness to obtain light yellow oily matter, crystallizing with 70 g isopropanol to obtain light yellow solid 13.8 g, namely compound 16, with the yield of 69.6%.

(14) Preparation of Compound 17

15.1 g of compound 16, 30.2 g of polyphosphoric acid and 300 g of benzene are added into a 1L three-necked flask, and the mixture is heated to reflux reaction for 5 hours under the protection of nitrogen, so that the raw materials are reacted completely. The reaction mixture was cooled to room temperature, 100 g of water was slowly added dropwise to the reaction mixture, and after completion of the addition, the reaction mixture was adjusted to pH =7 with a saturated sodium bicarbonate solution, and stirring was continued for 1 hour. The mixture was allowed to stand for liquid separation, and the benzene phase was washed twice with 300 g of water and dried over anhydrous sodium sulfate. Filtering, concentrating the filtrate under reduced pressure to dryness to obtain 11.4 g of yellow oily substance, namely the compound 17, with the yield of 78.4%.

(15) Preparation of Compound 18

A500 mL three-necked flask was charged with 8.7 g of Compound 17 and 130 g of isopropanol, and after dissolution and clarification, 6.4 g of sodium borohydride was added in portions. After the addition, the reaction mixture was heated to 35 ℃ for 3 hours, and the reaction of the starting materials was completed. The reaction mixture was concentrated to dryness under reduced pressure, 100 g of water was added, extraction was performed twice with 200g of dichloromethane, the dichloromethane phases were combined, washed twice with 200g of water, and dried over anhydrous sodium sulfate. Filtering, concentrating the filtrate under reduced pressure to dryness to obtain yellow oily matter 8.1 g, namely compound 18, with the yield of 93.1%.

(16) Preparation of Compound 19

A250 mL three-necked flask was charged with 10 g of Compound 18 and 50 g of toluene, and the mixture was dissolved and clarified. 5.1 g of potassium carbonate is added, the temperature is reduced to about 5 ℃, and 3.8 g of dimethyl sulfate is slowly added. After the addition, the mixture is heated to about 40 ℃ for reaction for 5 hours, and the raw materials are completely reacted. The reaction mixture was concentrated to dryness under reduced pressure, 45 g of water was added thereto, and the mixture was extracted twice with 90 g of ethyl acetate. The ethyl acetate phases were combined, washed twice with 90 g of water and dried over anhydrous sodium sulfate. Filtering, concentrating the filtrate under reduced pressure to dryness to obtain oily substance, crystallizing with 40g anhydrous ethanol to obtain off-white solid 7.2 g, i.e. compound 19, with yield 70.0%.

(17) Preparation of Compound 20

A100 mL three-necked flask was charged with 1.4 g of Compound 11, 1.4 g of Compound 19, 0.2 g of cuprous oxide, 3.0 g of potassium carbonate, and 28 g of DMSO, and the mixture was heated to 140 ℃ under nitrogen protection to react for 48 hours, so that the starting materials were completely reacted. The reaction mixture was concentrated to dryness under reduced pressure, 14 g of water was added, pH =3 was adjusted with 10% dilute hydrochloric acid, and extraction was performed twice with 56 g of dichloromethane. The dichloromethane phases were combined, washed twice with 56 g of water and dried over anhydrous sodium sulfate. Filtering, concentrating the filtrate under reduced pressure to dryness to obtain brown solid, and purifying by column chromatography to obtain light yellow solid 1.3 g, which is compound 20, with a yield of 52.9%.

(18) Preparation of Compound 21

1.3 g of the compound 20, 9.3 g of trifluoroacetic acid and 26 g of isopropanol are added into a 100 mL three-necked flask, and the mixture is heated to reflux under the protection of nitrogen for 8 hours, so that the raw materials are completely reacted. The reaction mixture was concentrated to dryness under reduced pressure, 26 g of water was added thereto, a saturated sodium bicarbonate solution was slowly added dropwise to adjust pH =8, and the mixture was extracted twice with 60 g of dichloromethane. The dichloromethane phases were combined, washed twice with 60 g of water and dried over anhydrous sodium sulfate. Filtering, concentrating the filtrate under reduced pressure to dryness to obtain white solid 1.0 g, namely the compound 21 with the yield of 86.8%.

(19) Preparation of racemic tetrandrine (Compound 22)

A250 mL three-necked flask was charged with 1.0 g of Compound 21, 0.2 g of cuprous oxide, 1.5 g of potassium carbonate, and 50 g of DMSO, and heated to 140 ℃ under nitrogen protection to react for 70 hours, so that the starting material was completely reacted. The reaction mixture was concentrated to dryness under reduced pressure, 20g of water was added, pH =3 was adjusted with 10% dilute hydrochloric acid, and extraction was performed twice with 40g of dichloromethane. The dichloromethane phases were combined, washed twice with 40g of water and dried over anhydrous sodium sulfate. Filtering, concentrating the filtrate under reduced pressure to dryness to obtain brown solid, and purifying by column chromatography to obtain off-white solid 0.37 g, i.e. racemic tetrandrine, with yield of 41.8%.

The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention are intended to be included within the scope of the present invention.

Claims

1. A total synthesis method of racemic tetrandrine is characterized by comprising the following steps:

(1) taking 5-bromovanillin, namely a compound 1, as an initial raw material, and reacting with a methylating agent under an alkaline condition to synthesize a compound 2;

(3) reducing the compound 3 by a reducing agent to synthesize a compound 4;

(4) taking 3-hydroxy-4-methoxyphenylacetic acid, namely a compound 5, as a raw material, and synthesizing a compound 6 after hydroxyl protection under an alkaline condition;

(7) reducing the compound 8 by a reducing agent to synthesize a compound 9;

(10) vanillin, namely a compound 12, is taken as a raw material, and a compound 13 is synthesized after hydroxyl protection under an alkaline condition;

(12) reducing the compound 14 by a reducing agent to synthesize a compound 15;

(15) reducing the compound 17 by a reducing agent to synthesize a compound 18;

(19) under the action of a catalyst, the compound 21 is subjected to intramolecular Ullmann reaction under the alkaline and high-temperature conditions to synthesize a compound 22, namely racemic tetrandrine;

wherein the structures of the compounds 1-22 are as follows:

in the above formula, R is a hydroxyl protecting group.

2. The total synthesis method of racemic tetrandrine according to claim 1, which comprises the following steps: in the step (1), the alkaline reagent is selected from one of potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, triethylamine or pyridine; the methylating agent is one of dimethyl sulfate, dimethyl carbonate, methyl iodide, methyl bromide or methyl p-toluenesulfonate; the solvent is one or more selected from dichloromethane, chloroform, methanol, ethanol, acetonitrile, tetrahydrofuran, benzene, toluene or water;

in the step (1), the molar ratio of the 5-bromovanillin, namely the compound 1, to the methylating agent is 1: 1-1: 4, the reaction temperature is 20-100 ℃, and the reaction time is 2-20 hours.

3. The total synthesis method of racemic tetrandrine according to claim 2, wherein: the alkaline reagent is sodium hydroxide; the methylating agent is methyl iodide; the solvent is dichloromethane.

4. The total synthesis method of racemic tetrandrine according to claim 1, which comprises the following steps: in the step (2), the catalyst is selected from one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, ammonium acetate, sodium methoxide, potassium tert-butoxide or triethylamine; the solvent is selected from one of nitromethane, methanol, ethanol, isopropanol, acetic acid, DMF or DMSO;

in the step (2), the molar ratio of the compound 2 to the nitromethane is 1: 1-1: 10, the amount of the catalyst is 10-80% of the weight of the compound 2, the reaction temperature is 50 ℃ to reflux, and the reaction time is 10-20 hours.

5. The total synthesis method of racemic tetrandrine according to claim 4, wherein: the catalyst is triethylamine; the solvent is ethanol.

6. The total synthesis method of racemic tetrandrine according to claim 1, which comprises the following steps: in the step (3), the reducing agent is selected from one or more of sodium borohydride, potassium borohydride, lithium aluminum hydride or borane; the solvent is selected from one of methanol, ethanol, tetrahydrofuran, benzene or toluene;

in the step (3), the molar ratio of the compound 3 to the reducing agent is 1: 1-1: 10, the reaction temperature is 30 ℃ to reflux, and the reaction time is 6-20 hours.

7. The total synthesis method of racemic tetrandrine according to claim 6, wherein: the reducing agent is lithium aluminum hydride; the solvent is tetrahydrofuran.

8. The total synthesis method of racemic tetrandrine according to claim 1, which comprises the following steps: in the step (4), the alkaline reagent is selected from one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, ammonium acetate, sodium methoxide, potassium tert-butoxide or triethylamine; the hydroxyl protecting group is selected from one of trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, triisopropylsilyl, benzyl, p-methoxybenzyl, methoxymethyl or 2-ethoxyethyl; the solvent is selected from one of methanol, ethanol, isopropanol, dichloromethane, chloroform, pyridine or DMF;

in the step (4), the molar ratio of the compound 5 to the hydroxyl protecting reagent is 1: 1-1: 4, the reaction temperature is 30 ℃ to reflux, and the reaction time is 3-10 hours.

9. The total synthesis method of racemic tetrandrine according to claim 8, wherein: the alkaline reagent is sodium hydroxide; the hydroxyl protecting group is benzyl; the solvent is methanol.

10. The total synthesis method of racemic tetrandrine according to claim 1, which comprises the following steps: in the step (5), the condensing agent is selected from one of CDI (carbonyl diimidazole), EDCI (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride), HATU (2- (7-azabenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate) or HBTU (benzotriazole-N, N, N ', N' -tetramethyluronium hexafluorophosphate); the solvent is selected from one of dichloromethane, trichloromethane or DMF;

in the step (5), the molar ratio of the compound 4 to the compound 6 is 1: 1-1: 1.5, the molar ratio of the compound 4 to the condensing agent is 1: 1-1: 3, the reaction temperature is 0-60 ℃, and the reaction time is 1-5 hours.

11. The total synthesis method of racemic tetrandrine according to claim 10, wherein: the condensing agent is CDI; the solvent is dichloromethane.

12. The total synthesis method of racemic tetrandrine according to claim 1, which comprises the following steps: in the step (6), the dehydrating agent is one selected from phosphorus oxychloride, phosphorus pentoxide, polyphosphoric acid or trifluoroacetic anhydride; the anhydrous inert solvent is selected from one of dichloromethane, trichloromethane, tetrahydrofuran, benzene, toluene or nitrobenzene;

in the step (6), the molar ratio of the compound 7 to the dehydrating agent is 1: 1-1: 20, the reaction temperature is 30 ℃ to reflux, and the reaction time is 2-8 hours.

13. The total synthesis method of racemic tetrandrine according to claim 12, wherein: the dehydrating agent is phosphorus oxychloride; the anhydrous inert solvent is toluene.

14. The total synthesis method of racemic tetrandrine according to claim 1, which comprises the following steps: in the step (7), the reducing agent is selected from one of sodium borohydride and potassium borohydride; the solvent is selected from one of methanol, ethanol, isopropanol or tetrahydrofuran;

in the step (7), the molar ratio of the compound 8 to the reducing agent is 1: 1-1: 10, the reaction temperature is 0-50 ℃, and the reaction time is 1-5 hours.

15. The total synthesis method of racemic tetrandrine according to claim 14, wherein: the reducing agent is potassium borohydride; the solvent is ethanol.

16. The total synthesis method of racemic tetrandrine according to claim 1, which comprises the following steps: in the step (8), the methylating agent is selected from one of methyl iodide, dimethyl sulfate, dimethyl carbonate, methyl p-toluenesulfonate, formaldehyde or formic acid; the solvent is one of tetrahydrofuran, acetonitrile, acetone or DMF;

in the step (8), the molar ratio of the compound 9 to the methylating agent is 1: 1-1: 3, the reaction temperature is 30 ℃ to reflux, and the reaction time is 2-6 hours.

17. The total synthesis method of racemic tetrandrine according to claim 16, wherein: the methylating agent is methyl p-toluenesulfonate; the solvent is DMF.

18. The total synthesis method of racemic tetrandrine according to claim 1, which comprises the following steps: in the step (9), the acidic reagent is selected from one of acetic acid, trifluoroacetic acid, hydrochloric acid or hydrobromic acid; the solvent is selected from one of methanol, ethanol or isopropanol;

in the step (9), the molar ratio of the compound 10 to the acidic reagent is 1: 20-1: 200, the reaction temperature is 40 ℃ to reflux, and the reaction time is 4-10 hours.

19. The total synthesis method of racemic tetrandrine according to claim 18, wherein: the acidic reagent is trifluoroacetic acid; the solvent is methanol.

20. The total synthesis method of racemic tetrandrine according to claim 1, which comprises the following steps: in the step (10), the alkaline reagent is selected from one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, ammonium acetate, sodium methoxide, potassium tert-butoxide or triethylamine; the hydroxyl protecting group is selected from one of trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, triisopropylsilyl, benzyl, p-methoxybenzyl, methoxymethyl or 2-ethoxyethyl; the solvent is selected from one of methanol, ethanol, isopropanol, dichloromethane, chloroform, pyridine or DMF;

in the step (10), the molar ratio of vanillin, namely the compound 12, to the hydroxyl protecting reagent is 1: 1-1: 4, the reaction temperature is 30 ℃ to reflux, and the reaction time is 3-10 hours;

in the step (11), the catalyst is selected from one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, ammonium acetate, sodium methoxide, potassium tert-butoxide or triethylamine; the solvent is selected from one of nitromethane, methanol, ethanol, isopropanol, acetic acid, DMF or DMSO;

in the step (11), the molar ratio of the compound 13 to nitromethane is 1: 1-1: 10, the amount of the catalyst is 10-80% of the weight of the compound 13, the reaction temperature is 50 ℃ to reflux, and the reaction time is 10-20 hours;

in the step (12), the reducing agent is selected from one or more of sodium borohydride, potassium borohydride, lithium aluminum hydride or borane; the solvent is selected from one of methanol, ethanol, tetrahydrofuran, benzene or toluene;

in the step (12), the molar ratio of the compound 14 to the reducing agent is 1: 1-1: 10, the reaction temperature is 30 ℃ to reflux, and the reaction time is 6-20 hours;

in the step (13), the condensing agent is selected from one of CDI (carbonyl diimidazole), EDCI (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride), HATU (2- (7-azabenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate) or HBTU (benzotriazole-N, N, N ', N' -tetramethyluronium hexafluorophosphate); the solvent is selected from one of dichloromethane, trichloromethane or DMF;

in the step (13), the molar ratio of the compound 15 to the p-bromophenylacetic acid is 1: 1-1: 1.5, the molar ratio of the compound 15 to the condensing agent is 1: 1-1: 3, the reaction temperature is 0-60 ℃, and the reaction time is 1-5 hours;

in the step (14), the dehydrating agent is one selected from phosphorus oxychloride, phosphorus pentoxide, polyphosphoric acid or trifluoroacetic anhydride; the anhydrous inert solvent is selected from one of dichloromethane, trichloromethane, tetrahydrofuran, benzene, toluene or nitrobenzene;

in the step (14), the molar ratio of the compound 16 to the dehydrating agent is 1: 1-1: 20, the reaction temperature is 30 ℃ to reflux, and the reaction time is 2-10 hours;

in the step (15), the reducing agent is selected from one of sodium borohydride and potassium borohydride; the solvent is selected from one of methanol, ethanol, isopropanol or tetrahydrofuran;

in the step (15), the molar ratio of the compound 17 to the reducing agent is 1: 1-1: 10, the reaction temperature is 0-50 ℃, and the reaction time is 1-5 hours;

in the step (16), the methylating agent is selected from one of methyl iodide, dimethyl sulfate, dimethyl carbonate, methyl p-toluenesulfonate, formaldehyde or formic acid; the solvent is one of tetrahydrofuran, acetonitrile, acetone or DMF;

in the step (16), the molar ratio of the compound 18 to the methylating agent is 1: 1-1: 3, the reaction temperature is 50 ℃ to reflux, and the reaction time is 2-6 hours;

in the step (17), the catalyst is selected from one of copper powder, cupric oxide, cuprous iodide or cuprous bromide dimethyl sulfide mixture; the alkaline reagent is selected from one of sodium hydroxide, potassium carbonate, cesium carbonate or triethylamine; the solvent is selected from one of pyridine, acetonitrile, toluene, DMF or DMSO;

in the step (17), the molar ratio of the compound 11 to the compound 19 is 1: 0.5-1: 2, the molar ratio of the compound 11 to the alkaline reagent is 1: 1-1: 5, the amount of the catalyst is 5-50% of the weight of the compound 11, the reaction temperature is 70 ℃ to reflux, and the reaction time is 24-72 hours;

in the step (18), the acidic reagent is selected from one of acetic acid, trifluoroacetic acid, hydrochloric acid or hydrobromic acid; the solvent is selected from one of methanol, ethanol or isopropanol;

in the step (18), the molar ratio of the compound 20 to the acidic reagent is 1: 20-1: 200, the reaction temperature is 40 ℃ to reflux, and the reaction time is 4-10 hours;

in the step (19), the catalyst is selected from one of copper powder, cupric oxide, cuprous iodide or cuprous bromide dimethyl sulfide mixture; the alkaline reagent is selected from one of sodium hydroxide, potassium carbonate, cesium carbonate or triethylamine; the solvent is selected from one of pyridine, acetonitrile, toluene, DMF or DMSO;

in the step (19), the molar ratio of the compound 21 to the alkaline reagent is 1: 1-1: 5, the amount of the catalyst is 5-50% of the weight of the compound 21, the reaction temperature is 70 ℃ to reflux, and the reaction time is 24-72 hours.

21. The total synthesis method of racemic tetrandrine according to claim 20, wherein: in the step (10), the alkaline reagent is sodium hydroxide; the hydroxyl protecting group is benzyl; the solvent is dichloromethane.

22. The total synthesis method of racemic tetrandrine according to claim 20, wherein: in the step (11), the catalyst is triethylamine; the solvent is ethanol.

23. The total synthesis method of racemic tetrandrine according to claim 20, wherein: in the step (12), the reducing agent is lithium aluminum hydride; the solvent is tetrahydrofuran.

24. The total synthesis method of racemic tetrandrine according to claim 20, wherein: in the step (13), the condensing agent is CDI; the solvent is dichloromethane.

25. The total synthesis method of racemic tetrandrine according to claim 20, wherein: in the step (14), the dehydrating agent is phosphorus oxychloride; the anhydrous inert solvent is toluene.

26. The total synthesis method of racemic tetrandrine according to claim 20, wherein: in the step (15), the reducing agent is potassium borohydride; the solvent is ethanol.

27. The total synthesis method of racemic tetrandrine according to claim 20, wherein: in the step (16), the methylating agent is methyl p-toluenesulfonate; the solvent is DMF.

28. The total synthesis method of racemic tetrandrine according to claim 20, wherein: in the step (17), the catalyst is cuprous iodide; the alkaline reagent is cesium carbonate; the solvent is DMF.

29. The total synthesis method of racemic tetrandrine according to claim 20, wherein: in the step (18), the acidic reagent is trifluoroacetic acid; the solvent is methanol.

30. The total synthesis method of racemic tetrandrine according to claim 20, wherein: in the step (19), the catalyst is cuprous iodide; the alkaline reagent is cesium carbonate; the solvent is DMF.