Intermediate for preparing optically pure berbamine and spirosine and preparation method of intermediate

Abstract

The invention discloses an intermediate for preparing optically pure berbamine and spirosine and a preparation method of the intermediate. The intermediate is a compound (S)-1-(4-(5-(((R)-8-bromo-6, 7-dimethoxy-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline-1-yl) methyl)-2-hydroxyphenoxy) benzyl)-6-methoxy-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline-7-alcohol (20a) or a compound (S)-1-(3-(4-(((R)-8-bromo-6, 7-dimethoxy-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline-1, 2, 3, 4-tetrahydroisoquinoline-1, 2, 3, 4-tetrahydroisoquinoline-1, 2, 3, 4-tetrahydroisoquinoline-1, 2, 3, 4-tetrahydroisoquinoline-1, 2, 3, 4-tetrahydroisoquinoline-1, 2, 3, 4-tetrahydroisoquinoline-1 The preparation method comprises the following steps: firstly, carrying out a multi-step reaction on 5-bromovanillin, 4-hydroxyphenylacetic acid and 4-benzyloxy-3-methoxybenzaldehyde which are used as initial raw materials to obtain optical pure berbamine and spirosine, and then, carrying out a multi-step reaction on the optical pure berbamine and spirosine to obtain the optical pure berbamine and spirosine, and carrying out a reaction on the optical pure berbamine and spirosine to obtain the optical pure berbamine and spirosine. The synthesis route adopts a convergent synthesis mode, the synthesis efficiency is high, the reaction condition is mild, the safety is high, and the operation is simple and convenient.

Description

Technical Field

[0001] This invention relates to the field of drug synthesis technology, specifically to an intermediate of optically pure berberine and scutellarin and its preparation method. Background Technology

[0002] Berbamine (BBM) and oxyacanthine are dibenzylisoquinoline alkaloids extracted and isolated from the roots of Berberis vulgaris and Berberis thunbergii (European berberis), respectively. They are composed of two benzylisoquinoline units linked by an ether bond, and their structures are as follows:

[0003]

[0004] Berberine has a wide range of effects, including promoting leukocyte proliferation, anti-inflammation, lowering blood pressure, antithrombosis, antitumor, anti-myocardial ischemia, antiarrhythmia, and antifibrosis, showing great potential in clinical applications. The marketed drug berberine hydrochloride tablets (also known as Shengbai'an) are clinically used for leukopenia caused by various reasons and can also be used to prevent leukopenia after cancer radiotherapy and chemotherapy. As a natural extract, berberine has few adverse reactions, is inexpensive, and convenient to take, making it a routine medication for preventing and treating leukopenia in chemotherapy patients. Berberine also possesses antiviral, antitumor, and anti-inflammatory pharmacological activities, showing great potential for clinical application.

[0005] Currently, berberine and scutellarin circulating in the market are obtained by extraction and separation from the roots of Berberis plants. Cheng et al. (J Nat Prod.2025;88(1):191-198) identified samples labeled with Berbamine from 14 suppliers and proved that the structure is scutellarin, and that berberine cannot yet be obtained through chemical synthesis.

[0006] Currently, there are no reports on the total synthesis of berberine and scutellarin. Production methods using extraction and separation from plants have drawbacks such as technical complexity, high production costs, low efficiency, low yield, significant environmental impact, and unsuitability for industrial-scale production. In contrast, chemical synthesis methods offer advantages such as readily available and inexpensive raw materials, economic efficiency, environmental friendliness, and the ability for continuous production. Therefore, developing chemical synthesis methods for optically pure berberine and scutellarin is of great significance. Summary of the Invention

[0007] The present invention aims to provide an intermediate for preparing optically pure berberine and scutellarin, and a method thereof, wherein the intermediate is compound 20a(S)-1-(4-(5-(((R)-8-bromo-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline-1-yl)methyl)-2-hydroxyphenoxy)benzyl)-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline-7-ol and compound 20b(S)-1-(3-(4-((((R)-8-bromo-6,7-) Dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline-1-yl)methyl)phenoxy)-4-hydroxybenzyl)-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline-7-ol was synthesized from 5-bromovanillin, 4-hydroxyphenylacetic acid, and 4-benzyloxy-3-methoxybenzaldehyde through a multi-step reaction to obtain optically pure berberine and spiky base intermediates 20a and 20b. The synthetic route of this invention adopts a "convergent" synthetic method, which has high synthetic efficiency, mild reaction conditions, high safety, and simple operation.

[0008] The present invention discloses an intermediate for preparing optically pure berberine and scutellarin, the structural formula of which is as follows:

[0009]

[0010] Among them, the name of compound 20a is (S)-1-(4-(5-(((R)-8-bromo-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline-1-yl)methyl)-2-hydroxyphenoxy)benzyl)-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline-7-ol;

[0011] The name of compound 20b is (S)-1-(3-(4-(((R)-8-bromo-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline-1-yl)methyl)phenoxy)-4-hydroxybenzyl)-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline-7-ol.

[0012] The method for preparing an intermediate for optically pure berberine and scutellarin is carried out according to the following steps:

[0013] B1. The starting material compound 1, 5-bromovanillin, is added to a solvent such as dichloromethane, chloroform, methanol, ethanol, acetone, acetonitrile, tetrahydrofuran, benzene, toluene, or water. A methylating agent such as dimethyl sulfate, dimethyl carbonate, iodomethane, bromomethane, or methyl p-toluenesulfonate is added. Under alkaline conditions such as potassium carbonate, sodium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, pyridine, or triethylamine, the reaction is carried out at a temperature of 20-100℃ for 2-20 hours to synthesize compound 2, 3-bromo-4,5-dimethoxybenzaldehyde. The molar ratio of compound 1 to the methylating agent is 1:1-1:4.

[0014] B2. The obtained compound 2, 3-bromo-4,5-dimethoxybenzaldehyde, is added to a solvent such as methanol, ethanol, isopropanol, acetic acid, N,N-dimethylformamide, or dimethyl sulfoxide, and reacted with nitromethane in the presence of potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, potassium tert-butoxide, sodium methoxide, ammonium acetate, or triethylamine at a temperature of 50-100℃ for 10-20 hours via the Henry reaction to synthesize compound 3(E)-1-bromo-2,3-dimethoxy-5-(2-nitrobenzene)benzene, wherein the molar ratio of compound 2 to nitromethane is 1:0.1-1:1.

[0015] B3. The obtained compound 3(E)-1-bromo-2,3-dimethoxy-5-(2-nitrovinyl)benzene is added to a solvent such as methanol, ethanol, tetrahydrofuran, benzene or toluene, and then subjected to a reducing agent such as sodium borohydride, potassium borohydride, lithium aluminum hydride or borane at a temperature of 0-66℃ for 3-20 hours to synthesize compound 4, 2-(3-bromo-4,5-dimethoxyphenyl)ethylamine, wherein the molar ratio of compound 3 to the reducing agent is 1:1-1:10;

[0016] B4. The raw material compound 5,4-hydroxyphenylacetic acid is reacted with liquid bromine at a molar ratio of 1:1 to 1:2 under acidic acetic acid, aluminum trichloride, ferric trichloride, ferric tribromide, or zinc dichloride conditions at 0°C to room temperature for 10 minutes to 2 hours via a halogenation reaction to synthesize compound 6,2-(3-bromo-4-hydroxyphenyl)acetic acid.

[0017] B5. Compound 6, 2-(3-bromo-4-hydroxyphenyl)acetic acid, is added to solvents such as methanol, ethanol, isopropanol, dichloromethane, chloroform, pyridine, or N,N-dimethylformamide. Under alkaline conditions, using potassium carbonate, sodium carbonate, ammonium acetate, potassium hydroxide, sodium hydroxide, sodium methoxide, potassium tert-butoxide, or triethylamine, compound 7, 2-(4-(benzyloxy)-3-bromophenyl)acetic acid is synthesized via trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, triisopropylsilyl, benzyl, p-methoxybenzyl, methoxymethyl, or 2-ethoxyethyl, at a temperature of 30-80°C for 1-5 hours. The molar ratio of compound 6 to the hydroxyl protecting agent is 1:1-1:4.

[0018] B6. Compound 4,2-(3-bromo-4,5-dimethoxyphenyl)ethylamine is reacted with compound 7,2-(4-(benzyloxy)-3-bromophenyl)acetic acid or the starting compound 5,4-hydroxyphenylacetic acid in a molar ratio of 1:1 to 1:1.5 under the action of condensing agents N,N'-carbonyldiimidazole, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, or O-benzotriazole-tetramethylurea hexafluorophosphate at 0°C to room temperature for 3-20 hours via an acid-amine condensation reaction to synthesize compound 8a,2-(4-(benzyloxy)-3-bromophenyl)-N-(3-bromo-4,5-dimethoxyphenylethyl)acetamide or compound 8b. N-(3-bromo-4,5-dimethoxyphenethyl)-2-(4-hydroxyphenyl)acetamide, wherein the molar ratio of compound 7 or 5 to the condensing agent is 1:1 to 1:3;

[0019] B7. Compound 8a 2-(4-(benzyloxy)-3-bromophenyl)-N-(3-bromo-4,5-dimethoxyphenethyl)acetamide or compound 8b N-(3-bromo-4,5-dimethoxyphenethyl)-2-(4-hydroxyphenyl)acetamide are subjected to intramolecular condensation in inert solvents such as dichloromethane, trichloromethane, acetonitrile, tetrahydrofuran, benzene, toluene, or nitrobenzene, with the aid of dehydrating agents such as phosphorus oxychloride, phosphorus pentoxide, polyphosphoric acid, or trifluoroacetic anhydride. The reaction temperature is 0-65℃, and the time is 1-8 hours. Dehydration and cyclization are then performed to synthesize compound 9a 1-(4-(benzyloxy)-3-bromobenzyl)-8-bromo-6,7-dimethoxy-3,4-dihydroisoquinoline or compound 9b. 4-((8-bromo-6,7-dimethoxy-3,4-dihydroisoquinoline-1-yl)methyl)phenol, wherein the molar ratio of compound 8a or compound 8b to the dehydrating agent is 1:1 to 1:20;

[0020] B8. Compound 9a 1-(4-(benzyloxy)-3-bromobenzyl)-8-bromo-6,7-dimethoxy-3,4-dihydroisoquinoline or compound 9b 4-((8-bromo-6,7-dimethoxy-3,4-dihydroisoquinoline-1-yl)methyl)phenol were added to solvents such as dichloromethane, trichloromethane, tetrahydrofuran, acetonitrile, ethanol, methanol, isopropanol, toluene, or N,N-dimethylformamide, respectively, and subjected to an asymmetric hydrogenation reaction in the presence of a chiral catalyst and a reducing agent at 0°C to room temperature for 12-24 hours to synthesize the chiral compound 10a(R)-1-(4-(benzyloxy)-3-bromobenzyl)-8 -bromo-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline or compound 10b(S)-4-((8-bromo-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-1-yl)methyl)phenol; wherein the chiral catalyst is (1S,2S)-N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine, [(S,S)-N-(2-amino-1,2-diphenylethyl)-p-methylbenzenesulfonamide] ruthenium(II) chloride (p-cymene) Ruthenium(II) diacetic acid [(R)-(+)-2,2'-bis(diphenylphosphine)-1,1'-binaphthyl], (1R,2R)-N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine, [(R,R)-N-(2-amino-1,2-diphenylethyl)-p-methylbenzenesulfonamide] ruthenium(II) chloride (p-cymene) or ruthenium(II) diacetic acid [(S)-(+)-2,2'-bis(diphenylphosphine)-1,1'-binaphthyl]; the reducing agent is Sodium borohydride, potassium borohydride, formic acid / triethylamine or ammonium formate; the amount of chiral catalyst is 1.0-5.0 mol%, based on the molar amount of compound 9a or 9b being 100%; wherein the reducing agent is not formic acid / triethylamine, and the molar ratio of compound 9a or 9b to the reducing agent is 1:1-1:5; or the reducing agent is formic acid / triethylamine, and the molar ratio of compound 9a or 9b to formic acid and triethylamine is: compound 9a or 9b: formic acid: triethylamine = 1:1:1-1:25:10;

[0021] B9. Compound 10a(R)-1-(4-(benzyloxy)-3-bromobenzyl)-8-bromo-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline or compound 10b(S)-4-((8-bromo-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-1-yl)methyl)phenol is added to solvents formic acid, acetonitrile, tetrahydrofuran, acetone, or N,N-dimethylformamide, and reacted with methylating agents such as iodomethane, dimethyl sulfate, dimethyl carbonate, methyl p-toluenesulfonate, or formic acid / formaldehyde at a temperature of 25-100℃ for 30 minutes to 6 hours to synthesize compound 11a(R)-1-(4-(benzyloxy)-3-bromobenzyl)-8-bromo-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline. -(benzyloxy)-3-bromobenzyl)-8-bromo-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline or compound 11b(S)-4-((8-bromo-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline-1-yl)methyl)phenol; wherein the methylating agent is not formic acid / formaldehyde, and the molar ratio of compound 10a or 10b to the methylating agent is 1:1-1:100; or the methylating agent is formic acid / formaldehyde, and the molar ratio of compound 10a or 10b to formaldehyde and formic acid is: compound 10a or 10b:formaldehyde:formic acid = 1:20:200-1:80:400;

[0022] B10. Add the raw material compound 12, 4-benzyloxy-3-methoxybenzaldehyde, to the solvents methanol, ethanol, isopropanol, acetic acid, N,N-dimethylformamide, or dimethyl sulfoxide, and react it with nitromethane in the presence of catalysts such as potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, potassium tert-butoxide, sodium methoxide, ammonium acetate, or triethylamine at a temperature of 50-95℃ for 5-20 hours to synthesize compound 13(E)-1-(benzyloxy)-2-methoxy-4-(2-nitrobenzene)benzene; wherein the molar ratio of compound 12 to nitromethane is 1:1-1:10; and the molar ratio of compound 12 to catalyst is 1:0.1-1:1.

[0023] B11. Compound 13(E)-1-(benzyloxy)-2-methoxy-4-(2-nitrovinyl)benzene is added to the solvent methanol, ethanol, tetrahydrofuran, benzene or toluene, and then reduced with sodium borohydride, potassium borohydride, lithium aluminum hydride or borane at 0-70℃ for 3-20 hours to synthesize compound 14 2-(4-benzyloxy-3-methoxyphenyl)ethylamine, wherein the molar ratio of compound 13 to reducing agent is 1:1-1:10.

[0024] B12, Compound 14, 2-(4-benzyloxy-3-methoxyphenyl)ethylamine, and Compound 5, 4-hydroxyphenylacetic acid, or Compound 7, 2-(4-(benzyloxy)-3-bromophenyl)acetic acid, respectively, are reacted with dichloromethane, trichloromethane, and N,N-dimethylformamide in condensing agents such as N,N'-carbonyldiimidazole, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, or O-benzotriazole-tetramethylurea hexafluorophosphate at 0°C to room temperature for 3-20 hours to synthesize Compound 15a, N-(4-(benzyloxy)-3-methoxyphenylethyl)-2-(4-hydroxyphenyl)acetamide, or Compound 15b. 2-(4-benzyloxy-3-bromophenyl)-N-(4-benzyloxy-3-methoxyphenethyl)acetamide; wherein the molar ratio of compound 5 or compound 7 to compound 14 is 1:1 to 1:1.5; and the molar ratio of compound 5 or compound 7 to the condensing agent is 1:1 to 1:3;

[0025] B13. Compound 15a N-(4-(benzyloxy)-3-methoxyphenethyl)-2-(4-hydroxyphenyl)acetamide or compound 15b 2-(4-benzyloxy-3-bromophenyl)-N-(4-benzyloxy-3-methoxyphenethyl)acetamide are subjected to intramolecular condensation in inert solvents such as dichloromethane, trichloromethane, acetonitrile, tetrahydrofuran, benzene, toluene, or nitrobenzene, with dehydrating agents such as phosphorus oxychloride, phosphorus pentoxide, polyphosphoric acid, or trifluoroacetic anhydride, at a temperature of 0-70°C for 2-8 hours, to synthesize compound 16a 4-((7-benzyloxy-6-methoxy-3,4-dihydroisoquinoline-1-yl)methyl)phenol or compound 16b 7-Benzyloxy-1-(4-Benzyloxy-3-bromobenzyl)-6-methoxy-3,4-dihydroisoquinoline; wherein the molar ratio of compound 15a or compound 15b to the dehydrating agent is 1:1 to 1:20;

[0026] B14, Compound 16a 4-((7-benzyloxy-6-methoxy-3,4-dihydroisoquinoline-1-yl)methyl)phenol or Compound 16b 7-benzyloxy-1-(4-benzyloxy-3-bromobenzyl)-6-methoxy-3,4-dihydroisoquinoline were synthesized by catalytic asymmetric hydrogenation reaction under the action of chiral catalyst and reducing agent, at a temperature of 0℃ to room temperature for 12-24 hours, to synthesize chiral compound 17a(S)-4-((7-benzyloxy-6-methoxy-1,2,3, 4-Tetrahydroisoquinoline-1-yl)methyl)phenol or compound 17b(R)-7-benzyloxy-1-(4-benzyloxy-3-bromobenzyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline; wherein the chiral catalyst is (1S,2S)-N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine, [(S,S)-N-(2-amino-1,2-diphenylethyl)-p-methylbenzenesulfonamide]chlorinated (p-cymene)ruthenium(II), diacetic acid [(R)] Ruthenium(II)-(+)-2,2'-bis(diphenylphosphine)-1,1'-binaphthyl]ruthenium(II), (1R,2R)-N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine, [(R,R)-N-(2-amino-1,2-diphenylethyl)-p-methylbenzenesulfonamide] ruthenium(II) chloride (p-cymene), ruthenium(II) diacetic acid [(S)-(+)-2,2'-bis(diphenylphosphine)-1,1'-binaphthyl]ruthenium(II), with sodium borohydride and borohydride as reducing agents. Potassium, formic acid / triethylamine or ammonium formate; the amount of chiral catalyst is 1.0-5.0 mol%, based on the molar amount of compound 16a or 16b being 100%; wherein the reducing agent is not formic acid / triethylamine, and the molar ratio of compound 16a or 16b to the reducing agent is 1:1-1:5; or the reducing agent is formic acid / triethylamine, and the molar ratio of compound 16a or 16b to formic acid and triethylamine is: compound 16a or 16b: formic acid: triethylamine = 1:1:1-1:25:10;

[0027] B15. Compound 17a(S)-4-((7-benzyloxy-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-yl)methyl)phenol or compound 17b(R)-7-benzyloxy-1-(4-benzyloxy-3-bromobenzyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline is added to solvents acetonitrile, tetrahydrofuran, acetone, or N,N-dimethylformamide or formic acid, respectively, and reacted with methylating agents iodomethane, dimethyl sulfate, dimethyl carbonate, methyl p-toluenesulfonate, or formic acid / formaldehyde at a temperature of 25-100℃ for 1-6 hours to synthesize compound 18a(S)-4-((7-)methyl)phenol or compound 17b(R)-7-benzyloxy-1-(4-benzyloxy-3-bromobenzyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline. Benzyloxy-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline-1-yl)methyl)phenol or compound 18b(R)-7-benzyloxy-1-(4-benzyloxy-3-bromobenzyl)-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline; wherein the methylating agent is not formic acid / formaldehyde, and the molar ratio of compound 17a or 17b to the methylating agent is 1:1-1:100; or the methylating agent is formic acid / formaldehyde, and the molar ratio of compound 17a or 17b to formaldehyde and formic acid is: compound 17a or 17b:formaldehyde:formic acid = 1:20:200-1:80:400;

[0028] B16. Compound 11a(R)-1-(4-(benzyloxy)-3-bromobenzyl)-8-bromo-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline or compound 11b(S)-4-((8-bromo-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline-1-yl)methyl)phenol and compound 18a(S)-4-((7-benzyloxy-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline-1-yl)methyl)phenol or compound 18b(R)-7-benzyloxy-1-(4-benzyloxy- 3-Bromobenzyl)-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline was added to solvents such as dioxane, acetonitrile, pyridine, o-xylene, toluene, dimethyl sulfoxide, or N,N-dimethylformamide, and then subjected to intermolecular Ullmann coupling reactions under catalytic, ligand, and basic reagent conditions at 70-140°C for 12-96 hours to synthesize compound 19a(R)-1-(4-(benzyloxy)-3-(4-(((S)-7-(benzyloxy)-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline-1-yl)methyl) The compound is phenoxybenzyl)-8-bromo-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline or compound 19b(R)-1-(4-(2-benzyloxy-5-(((S)-7-benzyloxy-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline-1-yl)methyl)phenoxybenzyl)-8-bromo-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline; wherein the catalyst is copper powder, copper oxide, cuprous oxide, cuprous chloride, cuprous bromide, cuprous iodide or cuprous dimethyl sulfide, and the alkaline reagent is sodium hydroxide, hydrogen... Potassium oxide, potassium tert-butoxide, potassium phosphate, potassium carbonate, sodium carbonate, cesium carbonate, or triethylamine; ligands are benzoyl peroxide, 1,10-phenanthroline, ethyl acetate, trimethylolethane, 1-pyridin-2-yl-2-propanone, or N,N-dimethylglycine; the molar ratio of compound 11a or 11b to compound 18a or 18b is 0.5:1 to 2:1; the molar ratio of compound 11a or 11b to base is 1:1 to 1:10; the molar ratio of compound 11a or 11b to catalyst is 1:0.1 to 1:5; the molar ratio of compound 11a or 11b to ligand is 1:0.1 to 1:5.

[0029] B17. Compound 19a(R)-1-(4-(benzyloxy)-3-(4-(((S)-7-(benzyloxy)-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline-1-yl)methyl)phenoxy)benzyl)-8-bromo-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline or compound 19b(R)-1-(4-(2-benzyloxy-5-(((S)-7-benzyloxy-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline-1-yl)methyl)phenoxy)benzyl)-8-bromo-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline, respectively, is added to the solvents methanol, ethanol, or isopropanol, and the hydroxyl groups are removed under acidic conditions of sulfuric acid, hydrochloric acid, acetic acid, trifluoroacetic acid, or hydrobromic acid. The compounds 20a (S)-1-(4-(5-(((R)-8-bromo-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline-1-yl)methyl)-2-hydroxyphenoxy)benzyl)-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline-7-ol or 20b (S)-1-(3-(4-((((R)-8-bromo-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline-1-yl)methyl)phenoxy)-4-hydroxybenzyl)-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline-7-ol) were synthesized by protecting the group with a base, at a temperature of 40-82℃ for 1-10 hours; wherein the molar ratio of compound 19a or 19b to the acidic reagent was 1:20-1:200.

[0030] The method for preparing intermediates for optically pure berberine and spicule base involves using compound 20a(S)-1-(4-(5-(((R)-8-bromo-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline-1-yl)methyl)-2-hydroxyphenoxy)benzyl)-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline-7-ol or compound 20b(S)-1-(3-(4-((((R)-8-bromo-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline-1-yl)methyl)phenoxy)-4-hydroxybenzyl)-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline-1-yl)methyl)phenoxy)-4-hydroxybenzyl)-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline-1-yl)methyl)phenoxy)-4-hydroxybenzyl)-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline-1-yl)methyl)phenoxy)-4-hydroxybenzyl)-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline-7-ol). -Tetrahydroisoquinoline-7-ol was added to a solvent of dioxane, acetonitrile, pyridine, o-xylene, toluene, dimethyl sulfoxide or N,N-dimethylformamide, and the catalyst was copper powder, copper oxide, cuprous oxide, cuprous chloride, cuprous bromide, cuprous iodide and cuprous bromide dimethyl sulfide. The alkaline reagent was sodium hydroxide, potassium hydroxide, potassium carbonate, cesium carbonate and triethylamine. The reaction was carried out under high temperature conditions via intramolecular Ullmann reaction at 70-200℃ for 12-96 hours to synthesize optically pure berberine (21) and spiky base (22). The molar ratio of compound 20a or 20b to the base was 1:1-1:10. The molar ratio of compound 20a or 20b to the catalyst was 1:1-1:5.

[0031] The alkaline reagent in B1 is potassium carbonate; the methylating agent is dimethyl sulfate; and the solvent is acetone.

[0032] The catalyst in B2 is ammonium acetate; the solvent is acetic acid.

[0033] The reducing agent in B3 is sodium borohydride; the solvent is tetrahydrofuran.

[0034] The acidic reagent in B4 is acetic acid;

[0035] The alkaline reagent in B5 is sodium hydroxide; the hydroxyl protecting group is benzyl; and the solvent is ethanol.

[0036] The condensing agent in B6 is N,N'-carbonyldiimidazole; the solvent is dichloromethane.

[0037] The dehydrating agent in B7 is phosphorus oxychloride; the inert solvent is acetonitrile.

[0038] The amount of chiral catalyst in B8 is 1.0-5.0 mol%, based on the molar amount of compound 9a or 9b being 100%; the reducing agent is not formic acid / triethylamine, and the molar ratio of compound 9a or 9b to the reducing agent is 1:1-1:5; or the reducing agent is formic acid / triethylamine, and the molar ratio of compound 9a or 9b to formic acid and triethylamine is: compound 9a or 9b: formic acid: triethylamine = 1:1:1-1:25:10;

[0039] In B9, the methylating agent is not formic acid / formaldehyde, and the molar ratio of compound 10a or 10b to the methylating agent is 1:1-1:100; or the methylating agent is formic acid / formaldehyde, the solvent is formic acid, and the molar ratio of compound 10a or 10b to formaldehyde and formic acid is: compound 10a or 10b:formaldehyde:formic acid = 1:20:200-1:80:400;

[0040] The catalyst in B10 is ammonium acetate; the solvent is acetic acid.

[0041] The reducing agent in B11 is sodium borohydride; the solvent is tetrahydrofuran.

[0042] The raw materials in B12 are compounds 5 and 14, the condensing agent is 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, and the solvent is dichloromethane; or the raw materials are compounds 7 and 14, the condensing agent is N,N'-carbonyldiimidazole, and the solvent is dichloromethane;

[0043] In the B14 formulation, the raw material is compound 16a, the chiral catalyst is (R,R)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene)ruthenium chloride; the reducing agent is formic acid / triethylamine; and the solvent is acetonitrile; or the raw material is compound 16b, the chiral catalyst is (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene)ruthenium chloride; the reducing agent is formic acid / triethylamine; and the solvent is acetonitrile.

[0044] The methylating agent in B15 is not formic acid / formaldehyde, and the molar ratio of compound 17a or 17b to the methylating agent is 1:1 to 1:100; or the methylating agent is formic acid / formaldehyde, and the molar ratio of compound 17a or 17b to formaldehyde and formic acid is: compound 17a or 17b:formaldehyde:formic acid = 1:20:200-1:80:400;

[0045] The catalyst in B16 is cuprous iodide; the basic reagent is cesium carbonate; the ligand is ethyl acetate; and the solvent is pyridine.

[0046] The acidic reagent in B17 is hydrochloric acid; the solvent is ethanol.

[0047] The catalyst is cuprous dimethyl sulfide bromide; the base is cesium carbonate; and the solvent is pyridine.

[0048] The present invention discloses an intermediate for preparing optically pure berberine and scutellarin, a method for preparing the intermediate, and its application. In B1, the molar ratio of compound 1,5-bromovanillin to the methylating agent is 1:1 to 1:4, for example, 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, but not limited thereto.

[0049] The molar ratio of compound 2 to nitromethane in B2 is from 1:1 to 1:10, for example, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, but not limited thereto. The molar ratio of compound 2 to the catalyst is from 1:0.1 to 1:1, for example, 1:0.2, 1:0.3, 1:0.4, 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, but not limited thereto.

[0050] The molar ratio of compound 3 to reducing agent in B3 is 1:1 to 1:10, for example, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, but not limited thereto.

[0051] The molar ratio of compound 5 to liquid bromine in B4 is 1:1 to 1:2, for example, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, but not limited thereto.

[0052] The molar ratio of compound 6 to the hydroxyl protecting agent in B5 is 1:1 to 1:4, for example, 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, but not limited thereto.

[0053] The molar ratio of compound 7 or compound 5 to compound 4 in B6 is 1:1 to 1:1.5, for example, 1:1.1, 1:1.2, 1:1.3, 1:1.4, but not limited thereto; and the molar ratio of compound 7 or compound 5 to condensing agent is 1:1 to 1:3, for example, 1:1.5, 1:2, 1:2.5, but not limited thereto.

[0054] The molar ratio of compound 8a or 8b in B7 to the dehydrating agent is from 1:1 to 1:20, for example, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, but not limited thereto.

[0055] The B8 is based on a 100% molar amount of compound 9a or 9b, and the amount of chiral catalyst is 1.0 to 5.0 mol%, for example, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5 mol%, but not limited thereto. The reducing agent is not formic acid / triethylamine; the molar ratio of compound 9a or 9b to the reducing agent is 1:1 to 1:5, for example, 1:2, 1:3, 1:4, 1:5. If the reducing agent is formic acid / triethylamine, the molar ratio of compound 9a or 9b to formic acid and triethylamine is 9a or 9b:formic acid:triethylamine = 1:1:1 to 1:25:10, for example, 1:2:2, 1:5:5, 1:10:10, 1:15:5, 1:20:5, 1:25:10, 1:25:5, 1:20:8, 1:15:9, 1:10:6, 1:6:3, 1:4:10.

[0056] The methylating agent in B9 is not formic acid / formaldehyde; the molar ratio of compound 10a or 10b to the methylating agent is 1:1 to 1:100, for example, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:15, 1:20, 1:25, 1:30, 1:35, 1:40, 1:45, 1:50, 1:55, 1:60, 1:70, 1:80, 1:90, but not limited to these; the methylating agent is formic acid / formaldehyde; solution The agent is formic acid, and the molar ratio of compound 10a or 10b to formaldehyde and formic acid is: compound 10a or 10b:formaldehyde:formic acid = 1:20:200 to 1:80:400, for example 1:25:200, 1:30:250, 1:40:200, 1:50:250, 1:60:200, 1:70:250, 1:25:300, 1:30:350, 1:40:400, 1:50:350, 1:60:400, 1:70:350.

[0057] The molar ratio of compound 12 to nitromethane in B10 is from 1:1 to 1:10, for example, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, but not limited thereto; and the molar ratio of compound 12 to catalyst is from 1:0.1 to 1:1, for example, 1:0.2, 1:0.3, 1:0.4, 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, but not limited thereto.

[0058] The molar ratio of compound 13 to reducing agent in B11 is 1:1 to 1:10, for example, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, but not limited thereto.

[0059] The molar ratio of compound 5 or 7 to compound 14 in B12 is 1:1 to 1:1.5, for example, 1:1.1, 1:1.2, 1:1.3, 1:1.4; the molar ratio of compound 5 or 7 to condensing agent is 1:1 to 1:3, for example, 1:1, 1:1.5, 1:2, 1:2.5, but not limited thereto.

[0060] The molar ratio of compound 15a or 15b in B13 to the dehydrating agent is from 1:1 to 1:20, for example, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, but not limited thereto.

[0061] The amount of chiral catalyst in B14 is 1.0 to 5.0 mol%, for example, 1.0, 1.5, 2.0, 2.5, 3.2, 3.5, 4.0, 4.5, 5.0 mol%, based on the molar amount of compound 16a or 16b being 100%; the reducing agent is not formic acid / triethylamine, and the molar ratio of compound 16a or 16b to the reducing agent is 1:1 to 1:5, for example, 1:2, 1:3, 1:4, 1:5; reduction The agent is formic acid / triethylamine. The molar ratio of compound 16a or 16b to formic acid and triethylamine is: compound 16a or 16b: formic acid: triethylamine = 1:1:1 to 1:25:10, for example 1:2:2, 1:5:5, 1:10:10, 1:15:5, 1:20:5, 1:25:10, 1:25:5, 1:20:8, 1:15:9, 1:10:6, 1:6:3, 1:4:10.

[0062] The methylating agent in B15 is not formic acid / formaldehyde, and the molar ratio of compound 17a or 17b to the methylating agent is 1:1 to 1:100, for example, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:15, 1:20, 1:25, 1:30, 1:35, 1:40, 1:45, 1:50, 1:55, 1:60, 1:70, 1:80, 1:90, but not limited thereto. The methylating agent is formic acid / formaldehyde; the solvent is formic acid, and the molar ratio of compound 17a or 17b to formaldehyde and formic acid is: compound 17a or 17b:formaldehyde:formic acid = 1:20:200 to 1:80:400, for example 1:25:200, 1:30:250, 1:40:200, 1:50:250, 1:60:200, 1:70:250, 1:25:300, 1:30:350, 1:40:400, 1:50:350, 1:60:400, 1:70:350.

[0063] In B16, the molar ratio of compound 11a or 11b to compound 18a or 18b is 0.5:1 to 2:1, for example, 0.75:1, 1:1, 1.25:1, 1.5:1, 1.75:1; the molar ratio of compound 11a or 11b to the base is 1:1 to 1:10, for example, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9; compound 11a or The molar ratio of 11b to the catalyst is from 1:0.1 to 1:5, for example, 1:0.2, 1:0.5, 1:0.75, 1:1, 1:1.5, 1:2, 1:3, 1:4; the molar ratio of compound 11a or 11b to the ligand is from 1:0.1 to 1:5, for example, 1:0.2, 1:0.5, 1:0.75, 1:1, 1:1.5, 1:2, 1:3, 1:4, but not limited thereto.

[0064] The molar ratio of compound 19a or 19b in B17 to the acidic reagent is from 1:20 to 1:200, for example, 1:25, 1:50, 1:75, 1:100, 1:150, 1:175, but not limited thereto.

[0065] The molar ratio of compound 20a or 20b to the base is from 1:1 to 1:10, for example, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9; the molar ratio of compound 20a or 20b to the catalyst is from 1:1 to 1:5, for example, 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, but not limited thereto.

[0066] The intermediate for preparing optically pure berberine and scutellarin, and its preparation method described in this invention, have the following advantages compared with existing technologies:

[0067] This invention provides for the first time important intermediates 20a and 20b for the preparation of optically pure berberine and scutellarin, as well as their preparation methods and applications. The synthetic route of this invention employs a convergent synthesis approach, simultaneously synthesizing compounds 4, 7, and 14 to obtain compounds 11a, 11b, and 18a, 18b. Compounds 11a and 18a, and compounds 11b and 18b, respectively, undergo intermolecular condensation reactions and deprotection to obtain compounds 20a and 20b, which are then subjected to intramolecular condensation to obtain compounds berberine (21) and scutellarin (22). The synthesis efficiency is high. The reaction conditions in this application are mild and the safety is high. Post-processing methods include pulping, recrystallization, and column chromatography purification, making the operation simple. Detailed Implementation

[0068] The following embodiments further illustrate the present invention, but do not limit the scope of the invention.

[0069] Unless otherwise specified, the raw materials, reagents, and methods used in the embodiments are all conventional raw materials, reagents, and methods in the art.

[0070] Example 1

[0071] The synthetic routes for compounds 20a and berberine (21) are shown below:

[0072]

[0073] The synthetic routes for compounds 20b and spiky base (22) are shown below:

[0074]

[0075] Example 2

[0076] (1) Synthesis of compound 2:

[0077]

[0078] 17 g (73.93 mmol) of compound 1,5-bromovanillin was added to 110 mL of acetone, followed by 15.23 g (110.89 mol) of potassium carbonate and 8.4 mL (88.72 mmol) of dimethyl sulfate. The mixture was heated to 56 °C and stirred for 4 hours until the reaction was complete. The reaction solution was cooled to room temperature and poured into 170 g of ice water. The mixture was stirred for 30 minutes, filtered, and the filter cake was washed three times with water. The mixture was then placed in a vacuum drying oven at 50 °C overnight to obtain 15.13 g of white solid compound 2,3-bromo-4,5-dimethoxybenzaldehyde, with a yield of 84%.

[0079] 1 H NMR (500MHz, DMSO-d6) δ9.89 (d, J = 1.4 Hz, 1H), 7.78 (dd, J = 2.6, 1.4 Hz, 1H), 7.54 (d, J = 1.9 Hz, 1H), 3.92 (s, 3H), 3.84 (s, 3H).

[0080] (2) Synthesis of compound 3:

[0081]

[0082] 15 g (61.48 mmol) of compound 2,3-bromo-4,5-dimethoxybenzaldehyde was added to 68 mL of acetic acid, followed by 4.72 g (61.48 mmol) of ammonium acetate and 22.42 g (368.88 mmol) of nitromethane. The mixture was heated to 100 °C and stirred for 3 hours until the reaction was complete. The reaction solution was cooled to room temperature and stirred in an ice bath for 30 minutes. The mixture was filtered, and the filter cake was washed three times with ice water and dried overnight in a vacuum oven at 60 °C to obtain 13.44 g of a yellow solid compound 3(E)-1-bromo-2,3-dimethoxy-5-(2-nitrovinyl)benzene, with a yield of 76%.

[0083] 1 H NMR (500MHz, DMSO-d6) δ 8.31 (d, J = 13.5 Hz, 1H), 8.06 (d, J = 13.7 Hz, 1H), 7.76 (d, J = 1.9 Hz, 1H), 7.61 (d, J = 1.9 Hz, 1H), 3.89 (s, 3H), 3.80 (s, 3H).

[0084] (3) Synthesis of compound 4:

[0085]

[0086] 8.82 g (234.15 mmol) of sodium borohydride was added to 150 mL of tetrahydrofuran. The mixture was stirred in an ice bath for 10 minutes, then 36.43 g (257.57 mmol) of boron trifluoride ether was added dropwise. After stirring for 45 minutes, a tetrahydrofuran solution containing 13.44 g (46.83 mmol) of compound 3(E)-1-bromo-2,3-dimethoxy-5-(2-nitrovinyl)benzene was added dropwise to 130 mL. The mixture was heated to 66 °C and stirred for 3 hours until the reaction was complete. The reaction solution was cooled to room temperature, and 20 mL of water was added dropwise in an ice bath until no gas was produced. Then, 85 mL (257.56 mmol) of 3M dilute hydrochloric acid was added dropwise. The mixture was heated to 66 °C and stirred for 90 minutes. The reaction solution was cooled to room temperature, and 150 mL of water was added. The pH was adjusted to approximately 10 with a 5M sodium hydroxide aqueous solution. The mixture was extracted with dichloromethane, and the organic phase was washed successively with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a pale yellow oily compound 4. 12.71 g of crude 2-(3-bromo-4,5-dimethoxyphenyl)ethylamine was used directly in the next step;

[0087] 1 H NMR (400MHz, DMSO-d6) δ7.06 (d, J = 1.8 Hz, 1H), 6.97 (d, J = 1.9 Hz, 1H), 3.83 (s, 3H), 3.70 (s, 3H), 3.01 (t, J = 7.5 Hz, 2H), 2.78 (t, J = 7.5 Hz, 2H). MS m / z=261.99[M+H]+ .

[0088] (4) Synthesis of compound 6:

[0089]

[0090] 16 g of compound 5,4-hydroxyphenylacetic acid (105.23 mmol) was added to 80 mL of acetic acid and stirred in an ice bath for 5 minutes. Then, a solution of 16.9 g of liquid bromine (105.23 mmol) in 16 mL of acetic acid was added dropwise. After 20 minutes, the reaction was complete. The reaction solution was poured into 160 g of ice water and stirred. 5 mL of saturated sodium thiosulfate aqueous solution was added, followed by 270 mL of ethyl acetate and 110 mL of water. The mixture was extracted and separated into layers. The organic phase was washed twice with water, dried over anhydrous sodium sulfate, concentrated, and slurried with 80 mL of n-heptane. The mixture was filtered, and the filter cake was dried in a vacuum drying oven to obtain 20.39 g of compound 6,2-(3-bromo-4-hydroxyphenyl)acetic acid, a white crystalline powder, with a yield of 84%.

[0091] 1 H NMR (400MHz, DMSO-d6) δ 12.27 (s, 1H), 10.09 (s, 1H), 7.36 (d, J = 2.1Hz, 1H), 7.05 (dd, J = 8.3, 2.2Hz, 1H), 6.88 (d, J = 8.3Hz, 1H), 3.46 (s, 2H). MS m / z=460.70[2M-H] - .

[0092] (5) Synthesis of compound 7:

[0093]

[0094] 8.4 g of sodium hydroxide (211.33 mmol) was added to 145 mL of 95% ethanol and stirred at 65 °C until dissolved. Then, 18 g of 6-2-(3-bromo-4-hydroxyphenyl)acetic acid (78.27 mmol) was added. After the reaction solution was clear, 22 mL of an ethanol solution containing 21.7 g of benzyl chloride (172.19 mmol) was added dropwise. The mixture was heated to 80 °C and stirred for 70 minutes until the reaction was complete. The reaction solution was poured into 180 g of ice water, and 1 M sodium hydroxide aqueous solution was added to adjust the pH to 9-10. Isopropyl ether was then added and stirred to separate the layers. The aqueous layer was stirred in an ice bath for 20 minutes. Concentrated hydrochloric acid was added dropwise to adjust the pH to 4, and a large amount of solid precipitated out. The mixture was stirred for another 2 hours, filtered, and the filter cake was washed twice with an appropriate amount of ice water and dried in a vacuum drying oven at 60 °C to obtain 19.79 g of a white solid compound 7-2-(4-(benzyloxy)-3-bromophenyl)acetic acid, with a yield of 79%.

[0095] 1H NMR(400MHz,DMSO-d6)δ12.33(s,1H),7.51–7.45(m,3H),7.43–7.38(m,2H),7.36–7.3 0(m,1H),7.20(dd,J=8.4,2.1Hz,1H),7.13(d,J=8.5Hz,1H),5.19(s,2H),3.52(s,2H).

[0096] (6) Synthesis of compound 8a:

[0097]

[0098] 14.95 g (46.72 mmol) of compound 7, 2-(4-(benzyloxy)-3-bromophenyl)acetic acid was added to 150 mL of dichloromethane and stirred at room temperature for 5 minutes. Then, 8.29 g (51.39 mmol) of N,N'-carbonyldiimidazole was added in portions, and the mixture was stirred at room temperature for 50 minutes. Then, a solution of 12.71 g (49.06 mmol) of compound 4, 2-(3-bromo-4,5-dimethoxyphenyl)ethylamine in 15 mL of dichloromethane was quickly added. After 10 minutes, the reaction was complete. 100 mL of dichloromethane and 170 mL of water were added, and the mixture was stirred to separate into layers. The organic phase was washed sequentially with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, recrystallized from isopropanol, filtered again, and the filter cake was dried in a vacuum drying oven at 60 °C to obtain a white solid, compound 8a. 21.34 g of 2-(4-(benzyloxy)-3-bromophenyl)-N-(3-bromo-4,5-dimethoxyphenylethyl)acetamide, 2-step yield 81%;

[0099] 1 H NMR(600MHz,DMSO-d6)δ8.06(t,J=5.6Hz,1H),7.48–7.45(m,3H),7.42–7.3 9(m,2H),7.35–7.31(m,1H),7.14(dd,J=8.4,2.1Hz,1H),7.09(d,J=8.5Hz,1 H),6.97(d,J=1.9Hz,1H),6.87(d,J=1.9Hz,1H),5.18(s,2H),3.77(s,3H),3 .69(s,3H),3.32(s,2H),3.27(td,J=7.0,5.6Hz,2H),2.65(t,J=7.0Hz,2H). 13C NMR(151MHz,DMSO-d6)δ169.9,153.2,153.0,143.9,137.2,136.7,133.3,130.4,129.2 ,128.5,127.8,127.3,124.0,116.3,113.9,113.0,110.8,70.0,59.9,55.9,40.8,34.3. HRMS(ESI)m / z:[M+H] + calcd forC 25 H 26 Br2NO4 562.0223; Found 562.0224.

[0100] (7) Synthesis of compound 8b:

[0101]

[0102] 7 g (46 mmol) of compound 5, 4-hydroxyphenylacetic acid, was added to 150 mL of dichloromethane and stirred at room temperature for 5 minutes. Then, 8.9 g (55 mmol) of N,N'-carbonyldiimidazole was added in portions and stirred at room temperature for 50 minutes. After that, 12 g (46 mmol) of compound 4, 2-(3-bromo-4,5-dimethoxyphenyl)ethylamine, in 15 mL of dichloromethane was quickly added. After 12 hours, the reaction of the starting material was complete. Dichloromethane and water were added, and the mixture was stirred to separate the layers. The organic phase was washed successively with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (dichloromethane:methanol: 200:1 → 80:1) to give 12 g of white solid 8b, N-(3-bromo-4,5-dimethoxyphenylethyl)-2-(4-hydroxyphenyl)acetamide, with a yield of 66%.

[0103] 1 H NMR(500MHz,DMSO-d6)δ9.19(s,1H),7.95(t,J=5.6Hz,1H),6.99–6.96(m,3H),6.88(d,J=1.9Hz,1H),6.6 7–6.63(m,2H),3.77(s,3H),3.69(s,3H),3.27(dd,J=7.2,5.8Hz,2H),3.24(s,2H),2.65(t,J=7.0Hz,2H). 13 C NMR (126MHz, DMSO-d6) δ170.6,155.8,153.2,143.9,137.3,129.8,126.5,124.0,116.3,115.0,113.0,60.0,55.9,54.9,41.6,34.4.

[0104] (8) Synthesis of compound 9a:

[0105]

[0106] 22.07 g and 39.20 mmol of compound 8a 2-(4-(benzyloxy)-3-bromophenyl)-N-(3-bromo-4,5-dimethoxyphenethyl)acetamide were added to 220 mL of acetonitrile. After stirring in an ice bath for 5 minutes, 30.0 g and 196.0 mmol of phosphorus oxychloride were slowly added dropwise. The mixture was heated to 65 °C and stirred for 2 hours until the reaction was complete. The mixture was concentrated, and 35 mL of methanol was added. The mixture was stirred at 55 °C until dissolved. 165 mL of methyl tert-butyl ether was added, and the mixture was cooled to room temperature and stirred for 30 minutes. The mixture was then stirred in an ice bath for 30 minutes. The mixture was filtered, and the filter cake was washed twice with a small amount of methyl tert-butyl ether and dried in a vacuum drying oven at 50 °C to obtain 18.17 g of the off-white solid compound 9a1-(4-(benzyloxy)-3-bromobenzyl)-8-bromo-6,7-dimethoxy-3,4-dihydroisoquinoline, with a yield of 80%.

[0107] 1 H NMR (800MHz, DMSO-d6) δ14.31(s,1H),7.60(dd,J=2.2,1.1Hz,1H),7.43(d,J=7 .6Hz,2H),7.38(td,J=7.7,1.7Hz,2H),7.32(tt,J=7.9,1.4Hz,1H),7.30(s,1H) ,7.22–7.20(m,1H),7.12–7.09(m,1H),5.15(s,2H),4.94–4.89(m,2H),3.95–3 .94 (m, 3H), 3.74 (t, J = 7.3Hz, 2H), 3.69 (d, J = 1.3Hz, 3H), 3.04 (t, J = 7.4Hz, 2H). 13 C NMR(201MHz,DMSO-d6)δ175.0,158.4,153.9,146.1,141.1,136.4,133.3,129.2,128.5,12 7.9,127.5,127.4,119.4,118.4,114.2,112.2,111.3,70.0,60.1,57.0,40.0,38.2,27.1. HRMS(ESI)m / z:[M+H] + calcd for C 25 H 24 Br2NO3544.0117; Found 544.0114.

[0108] (9) Synthesis of compound 9b:

[0109]

[0110] 9 g and 23 mmol of compound 8b N-(3-bromo-4,5-dimethoxyphenethyl)-2-(4-hydroxyphenyl)acetamide were added to 100 mL of acetonitrile. After stirring in an ice bath for 5 minutes, 27.3 g and 180.0 mmol of phosphorus oxychloride were slowly added dropwise. The mixture was heated to 65 °C and stirred for 2 hours until the reaction was complete. The mixture was concentrated, and 10 mL of methanol was added. The mixture was stirred at 55 °C until dissolved. 50 mL of methyl tert-butyl ether was added, and the mixture was cooled to room temperature and stirred for 30 minutes. The mixture was then stirred in an ice bath for 30 minutes. The mixture was filtered, and the filter cake was washed twice with a small amount of methyl tert-butyl ether. The cake was then dried in a vacuum drying oven at 50 °C to obtain 6.4 g of 4-((8-bromo-6,7-dimethoxy-3,4-dihydroisoquinoline-1-yl)methyl)phenol, with a yield of 68%.

[0111] 1 H NMR (400MHz, Methanol-d4) δ7.18 (s, 1H), 7.09 (d, J = 8.3Hz, 2H), 6.76–6.72 (m, 2H), 4.81 (s, 2H), 4.01 (s, 3H), 3.80 (s, 3H), 3.77 (t, J = 7.6Hz, 2H), 3.08 (t, J = 7.3Hz, 2H). 13 C NMR (126MHz, DMSO-d6) δ175.8,158.2,157.0,146.1,141.0,129.7,123.6,119.3,118.4,115.7,112.1,60.1,56.9,38.6,27.2.

[0112] (10) Synthesis of compound 10a:

[0113]

[0114] Compound 9a, 1-(4-(benzyloxy)-3-bromobenzyl)-8-bromo-6,7-dimethoxy-3,4-dihydroisoquinoline 20.0 g (34.42 mmol) was added to 120 mL of N,N-dimethylformamide, followed by catalyst (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene) ruthenium chloride 765 mg (3.5 mol%) under nitrogen protection. After stirring for 5 minutes, 36.3 g (774.45 mmol) of 98% formic acid and 31.3 g (30 mmol) of triethylamine were slowly added dropwise. A 60 mL solution of 9.78 mmol N,N-dimethylformamide was stirred at room temperature for 20 hours until the reaction was complete. The reaction solution was poured into 320 g of ice water, the pH was adjusted to 9 with ammonia, and extracted with 320 mL of ethyl acetate. The organic phase was washed successively with 200 mL × 2 of saturated ammonium chloride aqueous solution and 150 mL × 2 of saturated saline solution, dried over anhydrous sodium sulfate, concentrated, and slurried with 30 mL of isopropyl acetate. The mixture was stirred at room temperature for 1 hour, filtered, and the filter cake was washed with a small amount of isopropyl acetate and dried under vacuum to obtain 9.2 g of a light gray-green solid 10a. The mother liquor was concentrated and separated by column chromatography (petroleum ether:ethyl acetate: 3:1 → 2:1) to obtain 4.1 g of a yellowish-brown oily substance 10a(R)-1-(4-(benzyloxy)-3-bromobenzyl)-8-bromo-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline, with a total yield of 71%.

[0115] 1 H NMR (500MHz, CDCl3) δ7.53(d,J=2.1Hz,1H),7.48(d,J=7.2Hz,2H),7.39(dd,J=8.4,6.8Hz,2H),7.34–7.30(m,1H) ,7.23(dd,J=8.3,2.1Hz,1H),6.92(d,J=8.3Hz,1H),6.64(s,1H),5.16(s,2H),4.29(dd,J=10.7,2.8Hz,1H),3.86 (s,3H),3.85(s,3H),3.27(ddd,J=12.5,11.2,4.8Hz,1H),3.16(dd,J=14.3,2.8Hz,1H),3.04(ddd,J=12.6,6.8,2 .0Hz, 1H), 2.91 (ddd, J=17.5, 11.1, 6.8Hz, 1H), 2.78 (dd, J=14.3, 10.7Hz, 1H), 2.69 (ddd, J=16.7, 4.9, 2.0Hz, 1H). 13C NMR (126MHz, CDCl3) δ153.9,152.1,145.0,136.8,134.1,133.7,132.0,130.1,129.2,12 8.7,128.1,127.2,118.8,114.2,112.7,112.5,71.1,60.7,57.0,56.2,37.0,36.9,28.9. HRMS(ESI)m / z:[M+H] + calcd for C 25 H 26 Br2NO3 546.0274; Found 546.0271. ee value: 72%. (c 0.157,MeOH).

[0116] (11) Synthesis of compound 10b:

[0117]

[0118] Compound 9b, 4-((8-bromo-6,7-dimethoxy-3,4-dihydroisoquinoline-1-yl)methyl)phenol, 5.8 g, 14 mmol, was added to 50 mL of acetonitrile. Then, catalyst (R,R)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene), ruthenium chloride, 356 mg, 0.56 mmol, was added. Under nitrogen protection, 8.04 g, 175 mmol of 98% formic acid and 11.9 g, 117.55 mL of triethylamine were slowly added dropwise. The mixture of ol and methanol was stirred at room temperature for 12 hours until the reaction was complete. The reaction was extracted with ethyl acetate, and the organic phase was washed successively with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (dichloromethane:methanol: 200:1 → 20:1) to obtain 4.3 g of dark green foamy solid 10b(S)-4-((8-bromo-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-1-yl)methyl)phenol, with a yield of 81%.

[0119] 1 H NMR(400MHz, DMSO-d6)δ9.15(s,1H),7.15–7.10(m,2H),6.83(s,1H),6.73–6.68(m,2H),3.95(dd,J= 10.8, 2.5Hz, 1H), 3.80 (s, 3H), 3.71 (s, 3H), 3.18 (ddd, J=12.7, 10.8, 5.1Hz, 1H), 2.93–2.58 (m, 5H). 13C NMR (151MHz, DMSO-d6) δ155.6,151.2,143.7,132.6,131.1,130.3,130.0,117.6,115.0,112.8,59.9,56.8,55.9,36.9,36.1,28.4. ee=87%. (c=0.375,MeOH).

[0120] (12) Synthesis of compound 11a:

[0121]

[0122] 9 g (16.45 mmol) of compound 10a(R)-1-(4-(benzyloxy)-3-bromobenzyl)-8-bromo-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline was added to 80 mL of 85% formic acid, followed by 8.59 g (115.15 mmol) of 40% formaldehyde aqueous solution. The mixture was heated to 100 °C and stirred under reflux for 40 minutes until the reaction was complete. The mixture was concentrated, and 100 mL of ice water was added. The pH was adjusted to 9 with ammonia water, and the mixture was extracted with 120 mL of ethyl acetate. The organic phase was washed sequentially with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (petroleum ether:ethyl acetate: 2.5:1) to give 8.5 g (90%) of a pale yellow oil, 11a(R)-1-(4-(benzyloxy)-3-bromobenzyl)-8-bromo-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline.

[0123] 1 H NMR (600MHz, CDCl3) δ7.51–7.46(m,3H),7.41–7.37(m,2H),7.34–7.30(m,1H),7.19(dd,J=8. 4,2.1Hz,1H),6.86(d,J=8.4Hz,1H),6.61(s,1H),5.14(s,2H),3.97–3.91(m,1H),3.86(s,3H ),3.85(s,3H),3.37(ddd,J=13.1,10.3,5.2Hz,1H),3.00–2.93(m,1H),2.92–2.85(m,1H),2. 81(ddd,J=13.4,6.7,2.3Hz,1H),2.75(d,J=10.1Hz,1H),2.44(d,J=16.5Hz,1H),2.35(s,3H). 13C NMR (151MHz, CDCl3) δ153.5,151.9,145.0,137.0,134.8,134.0,131.8,129.1,128.7,12 8.0,127.2,119.8,113.8,112.2,112.1,71.0,64.3,60.7,56.2,44.2,42.5,38.6,23.2. HRMS(ESI)m / z:[M+H] + calcd for C 26 H 28 Br2NO3 560.043; Found 560.0431.

[0124] (13) Synthesis of compound 11b:

[0125]

[0126] 4.0 g and 10.6 mmol of compound 10b(S)-4-((8-bromo-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-1-yl)methyl)phenol were added to 30 mL of 98% formic acid at 10°C, followed by 10 mL of 37% formaldehyde at 3°C. The mixture was heated to 100°C and stirred under reflux. After 1 hour, the reaction was complete. Ammonia was added to adjust the pH of the reaction solution to 7. The mixture was extracted with ethyl acetate, and the organic phase was washed successively with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (dichloromethane:methanol: 200:1 → 30:1) to give 2.4 g of white solid 11b(S)-4-((8-bromo-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline-1-yl)methyl)phenol, with a yield of 59%.

[0127] 1 H NMR(400MHz,DMSO-d6)δ9.08(s,1H),7.10–7.05(m,2H),6.84(s,1H),6.68–6.63(m,2H),3.81(s,3H),3. 74(d,J=2.9Hz,1H),3.71(s,3H),3.40–3.34(m,1H),2.90–2.59(m,4H),2.48–2.40(m,1H),2.18(s,3H). 13 C NMR (126MHz, DMSO-d6) δ155.4,151.2,143.9,131.7,130.6,129.8,128.9,118.7,114.7,112.5,64.3,59.9,55.9,43.0,41.9,38.4,21.9. (c=0.502,MeOH).

[0128] (14) Synthesis of compound 13:

[0129]

[0130] 31.27 g and 129.16 mmol of compound 12, 4-benzyloxy-3-methoxybenzaldehyde were added to 250 mL of acetic acid, followed by 9.96 g and 129.16 mmol of ammonium acetate and 47.27 g and 774.96 mmol of nitromethane. The mixture was heated to 95 °C and stirred. After 8 hours, the reaction was complete. The reaction system was then stirred in an ice bath for 1 hour, resulting in the precipitation of a large amount of solid. The solid was filtered, the filter cake was washed with ice water, and dried in a vacuum drying oven at 50 °C to obtain 27 g of the yellow solid compound 13(E)-1-(benzyloxy)-2-methoxy-4-(2-nitrovinyl)benzene, with a yield of 73%.

[0131] 1 H NMR (400MHz, DMSO-d6) δ8.21(d,J=13.4Hz,1H),8.06(d,J=13.4Hz,1H),7.52(d,J=2.0Hz,1H),7.47–7.43(m ,2H),7.40(ddd,J=7.6,4.6,2.6Hz,3H),7.37–7.32(m,1H),7.14(d,J=8.4Hz,1H),5.18(s,2H),3.83(s,3H). MS m / z=286.19[M+H] + .

[0132] (15) Synthesis of compound 14:

[0133]

[0134] 16.06 g (424.95 mmol) of sodium borohydride was placed in a round-bottom flask, and 250 mL of tetrahydrofuran was added. The mixture was stirred for 10 minutes in an ice bath, followed by dropwise addition of 59.3 mL (467.45 mmol) of boron trifluoride diethyl ether. The mixture was stirred at room temperature for 20 minutes. Then, a solution of 24.23 g (84.99 mmol) of compound 13(E)-1-(benzyloxy)-2-methoxy-4-(2-nitrovinyl)benzene in 200 mL of tetrahydrofuran was added. The mixture was heated to 70 °C and stirred for 4 hours. After cooling to room temperature, the reaction solution was cooled, and water was added dropwise in an ice bath until no more bubbles were produced. Then, 170 mL (679.92 mmol) of 4M dilute hydrochloric acid was added, and the mixture was heated to 70 °C and stirred for 90 minutes. After cooling to room temperature, the pH was adjusted to 10 with 4M sodium hydroxide aqueous solution. The mixture was extracted with ethyl acetate, and the organic phase was washed successively with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give a yellow oily compound 14. 11.52 g of crude 2-(4-benzyloxy-3-methoxyphenyl)ethylamine was used directly in the next step. MS m / z = 258.18 [M+H] + .

[0135] (16) Synthesis of compound 15a:

[0136]

[0137] Compound 5, 4-hydroxyphenylacetic acid 5.93 g (38.96 mmol) was added to 100 mL of dichloromethane, followed by 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride 8.96 g (46.75 mmol) and 1-hydroxybenzotriazole 526.3 mg (3.90 mmol). The mixture was stirred at room temperature for 1 hour. Then, compound 14, 2-(4-benzyloxy-3-methoxyphenyl)ethylamine 11.52 g (44.80 mmol) and N,N-diisopropylethylamine 12.58 g (97.40 mmol) were added. The mixture was stirred at room temperature for another 4 hours until the reaction was complete. The mixture was extracted with ethyl acetate, and the organic phase was washed successively with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (dichloromethane:methanol:40:1) to give a yellow foamy solid 15a. 24.9 g of N-(4-(benzyloxy)-3-methoxyphenylethyl)-2-(4-hydroxyphenyl)acetamide, 75% yield in 2 steps;

[0138] 1H NMR(400MHz, DMSO-d6)δ9.20(s,1H),7.92(t,J=5.6Hz,1H),7.45–7.42(m,2H),7.41–7.36(m,2H),7.35–7.29(m,1H),7.03–6.98(m,2H ),6.91(d,J=8.2Hz,1H),6.80(d,J=2.0Hz,1H),6.69–6.62(m,3H),5.03(s,2H),3.73(s,3H),3.27–3.20(m,4H),2.62(t,J=7.2Hz,2H). 13 C NMR(101MHz,DMSO-d6)δ170.5,155.8,149.0,146.2,137.4,132.4,129.8,128.4 ,127.7,127.7,126.6,120.4,114.9,113.7,112.8,70.0,55.4,41.6,40.4,34.7. HRMS(ESI)m / z:[M+H] + calcd for C 24 H 26 NO4 392.1856; Found 392.1855.

[0139] (17) Synthesis of compound 15b:

[0140]

[0141] 15 g and 47 mmol of compound 14, 2-(4-benzyloxy-3-methoxyphenyl)ethylamine, were added to 150 mL of dichloromethane and stirred at room temperature for 5 minutes. Then, 9.2 g and 56 mmol of N,N'-carbonyldiimidazole were added in portions and stirred at room temperature for 60 minutes. After that, a solution of 12 g and 47 mmol of compound 7, 2-(4-(benzyloxy)-3-bromophenyl)acetic acid in 15 mL of dichloromethane was quickly added. After 13 hours, the reaction of the starting material was complete. Dichloromethane and water were added, and the mixture was stirred to separate into layers. The organic phase was washed successively with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, recrystallized from isopropanol, filtered, and the filter cake was dried in a vacuum drying oven at 60 °C to obtain 17.8 g of white solid 15b, 2-(4-benzyloxy-3-bromophenyl)-N-(4-benzyloxy-3-methoxyphenylethyl)acetamide, with a yield of 68%.

[0142] 1H NMR (500MHz, CDCl3) δ7.47–7.44(m,2H),7.43–7.37(m,5H),7.37–7.32(m,3H),7.31– 7.27(m,1H),7.00(dd,J=8.3,2.2Hz,1H),6.83(d,J=8.4Hz,1H),6.76(d,J=8.2Hz,1H ),6.64(d,J=2.0Hz,1H),6.47(dd,J=8.1,2.0Hz,1H),5.41–5.34(m,1H),5.14(s,2H) ,5.11(s,2H),3.83(s,3H),3.44(q,J=6.6Hz,2H),3.41(s,2H),2.67(t,J=6.8Hz,2H).

[0143] (18) Synthesis of compound 16a:

[0144]

[0145] 25 g and 64 mmol of compound 15a N-(4-(benzyloxy)-3-methoxyphenethyl)-2-(4-hydroxyphenyl)acetamide were added to 250 mL of acetonitrile. 49.06 g and 320 mmol of phosphorus oxychloride were added dropwise under ice bath conditions. The mixture was heated to 70 °C and stirred for 3 hours. After concentration to remove phosphorus oxychloride, 40 mL of methanol was added in one go. The mixture was heated to 60 °C and stirred until dissolved. 190 mL of methyl tert-butyl ether was added dropwise, resulting in the precipitation of a large amount of solid. The mixture was cooled and stirred under ice bath conditions for another 2 hours. After filtration, the filter cake was dried in a vacuum drying oven at 50 °C to obtain 19.6 g of a white solid, 16a 4-((7-benzyloxy-6-methoxy-3,4-dihydroisoquinoline-1-yl)methyl)phenol, with a yield of 75%.

[0146] 1 H NMR(400MHz,DMSO-d6)δ12.87(s,1H),9.49(s,1H),7.67(s,1H),7.43–7.33(m,5H),7.15(s,1H),7.13–7.09(m ,2H),6.71–6.66(m,2H),5.16(s,2H),4.35(s,2H),3.90(s,3H),3.81(t,J=8.0Hz,2H),2.98(t,J=8.0Hz,2H). 13CNMR(101MHz,DMSO-d6)δ174.9,156.8,156.0,146.6,136.4,134.6,130.1,128.5 ,128.0,127.7,123.8,116.7,115.8,114.8,111.9,70.3,56.4,40.4,36.5,24.4. HRMS(ESI)m / z:[M+H] + calcd for C 24 H 24 NO3374.1751;Found 374.1749.

[0147] (19) Synthesis of compound 16b:

[0148]

[0149] 12 g (21.4 mmol) of compound 15b 2-(4-benzyloxy-3-bromophenyl)-N-(4-benzyloxy-3-methoxyphenethyl)acetamide was added to 100 mL of acetonitrile. After stirring in an ice bath for 5 minutes, 25.6 g (167.0 mmol) of phosphorus oxychloride was slowly added dropwise. The mixture was heated to 70 °C and stirred for 3 hours until the reaction was complete. The mixture was concentrated, and 25 mL of methanol was added. The mixture was stirred at 55 °C until dissolved. 140 mL of methyl tert-butyl ether was added, and the mixture was cooled to room temperature and stirred for 30 minutes. The mixture was then stirred in an ice bath for 30 minutes. The mixture was filtered, and the filter cake was washed twice with a small amount of methyl tert-butyl ether. The cake was then dried in a vacuum drying oven at 50 °C to obtain 11 g of a white solid 16b 7-benzyloxy-1-(4-benzyloxy-3-bromobenzyl)-6-methoxy-3,4-dihydroisoquinoline, with a yield of 88%.

[0150] (20) Synthesis of compound 17a:

[0151]

[0152] 10 g (24.0 mmol) of compound 16a 4-((7-benzyloxy-6-methoxy-3,4-dihydroisoquinoline-1-yl)methyl)phenol was added to 100 mL of acetonitrile, followed by 500 mg (0.79 mmol) of (R,R)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene)ruthenium chloride. Under nitrogen protection, 13.8 g (30.0 mmol) of 98% formic acid and 20.7 g (20.0 mmol) of triethylamine were slowly added dropwise. The mixed solution of 1.5:1 was stirred at room temperature. After 17 hours, the reaction of the starting material was complete. The mixture was extracted with ethyl acetate, and the organic phase was washed successively with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (dichloromethane:methanol: 50:1 → 20:1) to obtain 6.9 g of dark green foamy solid 17a(S)-4-((7-benzyloxy-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-yl)methyl)phenol, with a yield of 75%.

[0153] 1 H NMR(400MHz,DMSO-d6)δ9.43(s,1H),7.41–7.29(m,5H),7.11–7.06(m,2H),6.79–6.74(m,3H),6.59(s,1H),4.89–4 .80(m,2H),4.44(t,J=7.0Hz,1H),3.75(s,3H),3.41–3.24(m,2H),3.19–3.04(m,3H),2.90(qt,J=16.8,6.0Hz,2H). 13 C NMR(101MHz,DMSO-d6)δ156.4,148.4,145.8,136.9,130.7,128.4,127.8,127.6 ,126.5,124.8,124.5,115.4,112.1,112.0,69.9,55.5,55.2,38.8,38.5,25.0. HRMS(ESI)m / z:[M+H] + calcd forC 24 H 26 NO3 376.1907; Found 376.1905. ee value: 94%. (c 0.108,MeOH).

[0154] (21) Synthesis of compound 17b:

[0155]

[0156] Compound 16b, 7-benzyloxy-1-(4-benzyloxy-3-bromobenzyl)-6-methoxy-3,4-dihydroisoquinoline, 6.4 g (11 mmol) was added to 60 mL of acetonitrile. Then, catalyst (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene), ruthenium chloride 280 mg (4 mol%) was added under nitrogen protection. After stirring for 5 minutes, a mixed solution of 98% formic acid (6.33 g, 137.5 mmol) and triethylamine (9.35 g, 92.4 mmol) was slowly added dropwise under ice bath. After stirring at room temperature for 20 hours, the reaction was complete. The reaction solution was poured into 100g of ice water, the pH was adjusted to 9 with sodium bicarbonate solution, and extracted with 100mL of ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (dichloromethane:methanol:200:1→60:1) to obtain 4.5g of a yellowish-brown oily substance 17b(R)-7-benzyloxy-1-(4-benzyloxy-3-bromobenzyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline, with a yield of 75%.

[0157] 1 H NMR (400MHz, Acetone-d6) δ7.55–7.50(m,3H),7.50–7.46(m,2H),7.43–7.34( m,5H),7.34–7.27(m,1H),7.20(dd,J=8.4,2.1Hz,1H),7.08(dd,J=8.4,1.6Hz, 1H),6.90(s,1H),6.67(s,1H),5.19(s,2H),5.04(s,2H),4.04(dd,J=9.3,4.1 Hz,1H),3.79(s,3H),3.20–3.04(m,2H),2.88–2.74(m,2H),2.72–2.55(m,2H). 13 C NMR(126MHz,DMSO-d6)δ152.7,147.4,145.6,137.4,136.8,134.1,133.8,130.6,129.9,128.4,1 28.4,128.3,127.8,127.8,127.3,113.8,112.3,110.8,70.1,70.0,56.3,55.5,54.9,40.6,28.8. ee=78%.

[0158] (22) Synthesis of compound 18a:

[0159]

[0160] 7.5 g and 20 mmol of compound 17a(S)-4-((7-benzyloxy-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-yl)methyl)phenol were added to 80 mL of 98% formic acid at 10°C, followed by 160 mL of 40% formaldehyde at 20°C. The mixture was heated to 100°C and stirred under reflux. After 1 hour, the reaction was complete. Ammonia was added to adjust the pH of the reaction solution to 7. The mixture was extracted with ethyl acetate, and the organic phase was washed successively with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (dichloromethane:methanol: 40:1 → 30:1) to obtain 6.39 g of white foamy solid 18a(S)-4-((7-benzyloxy-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline-1-yl)methyl)phenol, with a yield of 82%.

[0161] 1 H NMR(400MHz,DMSO-d6)δ9.09(s,1H),7.41–7.29(m,5H),6.89–6.84(m,2H), 6.63–6.59(m,3H),6.41(s,1H),4.81(s,2H),3.70(s,3H),3.53(t,J=6.1Hz, 1H),3.05(ddd,J=12.8,8.3,4.9Hz,1H),2.89(dd,J=13.9,6.2Hz,1H),2.72 –2.63(m,2H),2.57(dt,J=12.1,4.9Hz,1H),2.48–2.40(m,1H),2.36(s,3H). 13 C NMR(101MHz,DMSO-d6)δ155.3,147.2,145.2,137.3,130.5,130.0,129.4,128.3,1 27.7,127.6,126.5,114.6,113.2,111.8,69.8,64.2,55.4,54.9,46.6,42.4,25.0. HRMS(ESI)m / z:[M+H] + calcd for C 25 H 28 NO3390.2064;Found 390.206. (c0.148,MeOH).

[0162] (23) Synthesis of compound 18b:

[0163]

[0164] 4.5 g and 8.3 mmol of compound 17b(R)-7-benzyloxy-1-(4-benzyloxy-3-bromobenzyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline were added to 45 mL of 88% formic acid, followed by 15 mL of 37% formaldehyde aqueous solution. The mixture was heated to 100 °C and stirred under reflux for 3 hours until the reaction was complete. The mixture was concentrated, and 80 mL of ice water was added. The pH was adjusted to 9 with sodium bicarbonate solution, and the mixture was extracted with 80 mL of ethyl acetate. The organic phase was washed successively with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (dichloromethane:methanol: 200:1 → 60:1) to give 3.4 g of a pale yellow oil, 18b(R)-7-benzyloxy-1-(4-benzyloxy-3-bromobenzyl)-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline, with a yield of 74%.

[0165] 1 H NMR (400MHz, DMSO-d6) δ7.46–7.30(m,11H),7.03(s,2H),6.63(s,1H),6.57(s,1H),5.13(s,2H),4.87(s,2H),3.71(s,3H),3.59(d,J=6.3Hz,1H ), 3.09(ddd,J=12.9,8.2,4.9Hz,1H),2.86(ddd,J=45.0,14.0,6.1Hz,2H),2.64(ddt,J=32.5,10.9,5.0Hz,2H),2.48–2.39(m,1H),2.36(s,3H). 13 C NMR(151MHz,DMSO-d6)δ152.5,147.3,145.5,137.3,136.8,134.0,133.9,130.0,128.4,128.4,127.8,1 27.8,127.7,127.3,126.6,113.4,113.1,111.9,110.4,70.0,63.8,55.4,54.9,46.5,42.3,38.7,24.7. ee=91%. (c=0.332,MeOH).

[0166] (24) Synthesis of compound 19a:

[0167]

[0168] Compound 11a(R)-1-(4-(benzyloxy)-3-bromobenzyl)-8-bromo-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline 7.9 g (14.08 mmol), compound 18a(S)-4-((7-benzyloxy-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline-1-yl)methyl)phenol 5.5 g (14.08 mmol), cesium carbonate 6.91 g (21.12 mmol), cuprous iodide 1.34 g (7.04 mmol), and ethyl acetate 3.74 g (42.24 mmol) were sequentially added to a sealing tube, followed by 70 mL of pyridine and nitrogen gas. The mixture was replaced three times, heated to 130℃ and stirred. After 80 hours, 80 mL of ethyl acetate was added to the reaction solution, filtered, the filter cake was washed with ethyl acetate, the filtrate was concentrated, and separated by column chromatography (dichloromethane:methanol:100:1 → dichloromethane:amine / methanol:40:1) to obtain a yellowish-brown oily substance 19a(R)-1-(4-(benzyloxy)-3-(4-(((S)-7-(benzyloxy)-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline-1-yl)methyl)phenoxy)benzyl)-8-bromo-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline 4.85 g, yield 40%;

[0169] 1 H NMR (500MHz, CDCl3) δ7.35–7.26(m,5H),7.25–7.17(m,5H),7.04–7.01(m,2H),6.96(d,J=8.2Hz,2H),6.91(d,J=8.4Hz,1H),6.88– 6.84(m,2H),6.59(s,1H),6.57(s,1H),6.13(s,1H),5.02(s,2H),4.87(dd,J=12.3,2.8Hz,1H),4.77(dd,J=12.5,1.9Hz,1H),3.92 (dd,J=9.9,3.0Hz,1H),3.84–3.83(m,6H),3.82(s,3H),3.73(d,J=6.5Hz,1H),3.35–3.26(m,1H),3.23(dd,J=11.4,5.9Hz,2H),2. 94–2.87(m,2H),2.87–2.81(m,2H),2.80–2.74(m,2H),2.73(m,2H),2.55(s,3H),2.42(ddt,J=16.8,5.2,2.6Hz,1H),2.31(s,3H). 13C NMR (126MHz, CDCl3) δ157.2,151.7,148.9,148.4,146.0,144.9,144.9,137.3, 137.3,134.5,131.8,131.8,130.9,129.7,128.6,128.4,127.8,127.7,127.4, 127.2,125.5,119.8,116.6,115.2,113.9,112.0,111.8,71.1,71.0,65.0,64. 3,60.6,56.1,56.1,46.7,44.2,44.2,42.6,42.5,42.2,40.6,38.9,23.4,23.3. HRMS(ESI)m / z:[M+H] + calcdfor C 51 H 54 BrN2O6 869.316; Found 869.3159.

[0170] (25) Synthesis of compound 19b:

[0171]

[0172] Compound 11b(S)-4-((8-bromo-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline-1-yl)methyl)phenol 2.3 g, 5.86 mmol; compound 18b(R)-7-benzyloxy-1-(4-benzyloxy-3-bromobenzyl)-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline 3.28 g, 5.86 mmol; cesium carbonate 5.72 g, 17.58 mmol; and cuprous dimethyl sulfide bromide 1.2 g, 5.86 mmol were added sequentially to a sealing tube. 20 mL of pyridine was added, the tube was purged with nitrogen three times, and then heated. Stirred at 140℃ for 80 hours, then add 30 mL of dichloromethane to the reaction solution, filter, wash the filter cake with dichloromethane, concentrate the filtrate, and separate by column chromatography (dichloromethane:methanol:250:1 → dichloromethane:amine / methanol:30:1) to obtain 1.5 g of a yellowish-brown oily substance 19b(R)-1-(4-(2-benzyloxy-5-(((S)-7-benzyloxy-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline-1-yl)methyl)phenoxy)benzyl)-8-bromo-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline, yield 30%;

[0173] 11H NMR (500 MHz, CDCl3) δ 7.36 (d, J = 7.4 Hz, 2H), 7.31 (t, J = 7.5 Hz, 3H), 7.27 (d, J = 2.3 Hz, 2H), 7.23 (dd, J = 8.2, 6.3 Hz, 5H), 6.88 (d, J = 8.3 Hz, 1H), 6.85 (d, J = 8.4 Hz, 2H), 6.80 (d, J = 2.1 Hz, 1H), 6.72 (dd, J = 8.3, 2.2 Hz, 1H), 6.63 (s, 1H), 6.56 (s, 1H), 6.18 (s, 1H), 5.30 (s, 2H), 5.05 (s, 2H), 3.99 (dd, J = 10.2, 2.9 Hz, 1H), 3.86 (s, 6H), 3.85 (s, 3H), 3.62 (t, J = 6.2 Hz, 1H), 3.42 (ddd, J = 13.3, 10.8, 5.4 Hz, 1H), 3.13 (ddd, J = 13.0, 8.2, 5.0 Hz, 1H), 3.00 (dt, J = 14.2, 5.3 Hz, 2H), 2.91 (ddd, J = 16.9, 10.8, 6.6 Hz, 1H), 2.85–2.68 (m, 6H), 2.56 (dt, J = 15.4, 4.7 Hz, 1H), 2.49 (s, 3H), 2.33 (s, 3H). 13 13C NMR (126 MHz, CDCl3) δ 156.6, 151.7, 148.9, 148.1, 145.8, 145.5, 144.9, 137.4, 137.3, 134.6, 133.6, 131.8, 130.2, 130.0, 128.6, 128.5, 127.8, 127.8, 127.5, 127.2, 125.9, 123.1, 119.9, 116.8, 115.1, 113.8, 112.0, 111.8, 71.2, 71.0, 64.7, 64.4, 60.6, 56.1, 53.6, 47.3, 44.2, 42.8, 42.6, 40.3, 39.1, 25.8, 23.3. HRMS (ESI) m / z: [M+H] + calcd for C 51 H 54 BrN2O6 869.316; Found 869.3158.

[0174] (26) Synthesis of Compound 20a:

[0175]

[0176] 4.07 g and 4.69 mmol of compound 19a(R)-1-(4-(benzyloxy)-3-(4-(((S)-7-(benzyloxy)-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline-1-yl)methyl)phenoxy)benzyl)-8-bromo-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline were added to 35 mL of 95% ethanol, followed by 35 mL of 37% hydrochloric acid. The mixture was heated to 80 °C and stirred. After 2 hours, the reaction was complete. The mixture was concentrated, and 100 mL of saturated saline solution was added. Ammonia was then added dropwise to adjust the concentration. pH adjusted to 7-8, extracted with dichloromethane (100 mL × 2), the organic phase was washed successively with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (dichloromethane:methanol:30:1) to give 2.95 g of a pale yellow foamy solid compound 20a(S)-1-(4-(5-(((R)-8-bromo-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline-1-yl)methyl)-2-hydroxyphenoxy)benzyl)-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline-7-ol, yield 91%;

[0177] 1 H NMR(500MHz, CDCl3)δ7.05(dd,J=8.5,4.0Hz,2H),6.95–6.87(m,5H),6.58(s,1H),6.53(s,1H), 6.31(s,1H),3.91(dd,J=9.7,3.6Hz,1H),3.84(s,3H),3.83(s,3H),3.82(s,3H),3.69(t,J=6.1H z,1H),3.30(ddd,J=13.5,10.5,5.5Hz,1H),3.22–3.14(m,1H),3.10(dd,J=14.0,5.7Hz,1H),2.9 3–2.68(m,7H),2.59–2.50(m,1H),2.48(s,3H),2.42(ddd,J=16.6,5.6,2.4Hz,1H),2.30(s,3H). 13C NMR (126MHz, CDCl3) δ155.4,151.7,145.8,145.4,144.8,143.5,143.2,134.8,132.9,131.7,130.9,129.9,129.7,125.5,125.2 ,120.1,119.8,117.6,115.9,113.9,112.0,110.7,64.7,64.3,60.6,56.1,55.9,47.2,44.2,42.7,42.5,40.6,39.1,25.4,23.3. HRMS(ESI)m / z:[M+H] + calcd for C 37 H 42 BrN2O6689.2221; Found 689.2218.

[0178] (27) Synthesis of compound 20b:

[0179]

[0180] 1.45 g and 1.67 mmol of compound 19b(R)-1-(4-(2-benzyloxy-5-(((S)-7-benzyloxy-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline-1-yl)methyl)phenoxy)benzyl)-8-bromo-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline were added to 5 mL of ethanol, followed by 5 mL of 37% hydrochloric acid. The mixture was heated to 82 °C and stirred. After 2 hours, the reaction proceeded completely. The mixture was concentrated, 40 mL of water was added, and the pH was adjusted to 7 by adding saturated sodium bicarbonate solution dropwise. -8, extracted with ethyl acetate (100 mL × 2), the organic phase was washed successively with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (dichloromethane:methanol:30:1) to give 960 mg of the pale yellow foamy solid compound 20b(S)-1-(3-(4-(((R)-8-bromo-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline-1-yl)methyl)phenoxy)-4-hydroxybenzyl)-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline-7-ol, yield 83%;

[0181] 1H NMR(500MHz, CDCl3)δ7.28(s,1H),6.89–6.77(m,4H),6.64(s,1H),6.56–6.31(m,4H),4.11–4.08(m,1H),3.87(s,3H),3.86(s,3H),3.83(s,3H) ,3.63(t,J=5.5Hz,1H),3.46(ddd,J=13.4,10.9,5.7Hz,1H),3.06–2.76 (m,8H),2.68–2.57(m,2H),2.54–2.49(m,1H),2.47(s,3H),2.36(s,3H). 13 C NMR (126MHz, CDCl3) δ151.9,145.2,144.9,143.7,143.4,135.4,131.8,131.4,130.4,130.3,129.5,125.6, 119.9,118.3,115.4,113.9,112.2,110.5,64.5,64.0,60.7,56.2,55.7,43.6,43.0,42.2,40.1,39.2,22.7. HRMS(ESI)m / z:[M+H] + calcd for C 37 H 42 BrN2O6 689.2221; Found 689.2222.

[0182] (28) Synthesis of compound Berbamine (21):

[0183]

[0184] Compound 20a(S)-1-(4-(5-(((R)-8-bromo-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline-1-yl)methyl)-2-hydroxyphenoxy)benzyl)-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline-7-ol 95 mg, 0.138 mmol, cesium carbonate 404.6 mg, 1.242 mmol, cuprous dimethyl sulfide 85.1 mg, 0.414 mmol, and pyridine 2 mL were sequentially added to a sealed tube. The tube was purged with nitrogen three times, heated to 150 °C, and stirred. After 12 hours, the reaction solution was cooled to room temperature, diluted with methyl tert-butyl ether, filtered, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to thin-layer chromatography (dichloromethane:amine / methanol: 40:1) to give a white solid 21. 8 mg, yield 10%, 1H NMR and 1C NMR data are consistent with literature reports (Hostalkova A et al. J Nat Prod. 2019; 82(2):239-248; Cheng Y et al. J Nat Prod. 2025; 88(1):191-198);

[0185] 1 H NMR (600MHz, CDCl3) δ7.30 (dd, J=8.1, 2.2Hz, 1H), 7.12–7.08 (m, 1H), 6.83 (d, J=7.9Hz, 1H), 6. 81–6.76(m,1H),6.63–6.58(m,1H),6.52(s,1H),6.50–6.34(m,2H),6.27(s,1H),5.98(s,1H),3 .96–3.84(m,2H),3.75(s,3H),3.58(s,3H),3.50–3.41(m,1H),3.35–3.25(m,2H),3.12(s,3H), 3.05(d,J=13.9Hz,1H),2.97–2.77(m,6H),2.63(m,1H),2.59(s,3H),2.48(m,1H),2.27(s,3H). 13 C NMR (126MHz, CDCl3) δ153.9,152.1,150.1,148.2,147.5,143.8,143.6,137.1,135.7,134.9,132.4,130.4,129.5,128.8,127.2,12 3.7,121.8,121.5,119.9,115.3,114.7,111.3,105.5,63.9,62.6,60.7,55.9,55.7,46.1,44.9,43.0,42.9,38.6,37.9,25.6,23.9.

[0186] (29) Synthesis of compound Oxyacanthine (22):

[0187]

[0188] Compound 20b(S)-1-(3-(4-(((R)-8-bromo-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline-1-yl)methyl)phenoxy)-4-hydroxybenzyl)-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline-7-ol 900 mg, 1.31 mmol, cesium carbonate 3.84 g, 11.79 mmol, cuprous dimethyl sulfide bromide 808 mg, 3.93 mmol, and pyridine 7 mL were sequentially added to a sealed tube. The tube was purged with nitrogen three times, heated to 140 °C with stirring, and after 12 hours, the reaction solution was cooled to room temperature, diluted with dichloromethane, filtered, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (dichloromethane:amine / methanol: 40:1) to give a pale yellow solid 22. 95 mg, yield 12%, 1H NMR and 1C NMR data are consistent with literature reports (Cheng Y et al. J Nat Prod. 2025; 88(1):191-198);

[0189] 1 H NMR(500MHz, CDCl3)δ7.43(dd,J=8.4,2.3Hz,1H),6.97–6.92(m,2H),6.79–6.75(m,1H),6.75–6.72(m,1H),6.6 2(s,1H),6.35(s,1H),6.32(dd,J=8.2,2.5Hz,1H),6.30(s,1H),5.42(d,J=2.0Hz,1H),4.19(d,J=5.7Hz,1H),3. 78(s,3H),3.61(s,4H),3.32(d,J=6.3Hz,1H),3.17(s,4H),3.11(d,J=3.6Hz,1H),3.08–3.01(m,1H),2.96–2.8 9(m,1H),2.84–2.78(m,2H),2.77–2.72(m,1H),2.72–2.66(m,1H),2.64(s,3H),2.55(s,3H),2.40–2.36(m,3H). 13C NMR (126MHz, CDCl3) δ152.0,151.7,148.3,147.7,147.2,143.8,143.4,139.6,137.1,131.7,131.1,130.2,128.2,128.0,127.8,124.4 ,123.0,122.2,121.0,116.9,116.2,114.3,111.0,105.8,64.1,61.6,60.6,56.1,55.0,50.9,45.3,43.8,42.1,40.0,37.7,28.7,25.2. HRMS(ESI)m / z:[M+H] + calcd for C 37 H 41 N2O6 609.2959; Found609.2958.

[0190] It should be understood that the above embodiments are all exemplary, and various modifications and changes can be made to the above embodiments without departing from the scope of this disclosure. Similarly, the various technical features of the above embodiments can be arbitrarily combined to form other embodiments of the present invention that may not be explicitly described. Therefore, the above embodiments only illustrate several implementation methods of the present invention and do not limit the scope of protection of the present invention.

Claims

1. An intermediate for preparing optically pure berberine and scutellarin, characterized in that... The structural formula of the intermediate is: Among them, the name of compound 20a is (S)-1-(4-(5-(((R)-8-bromo-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline-1-yl)methyl)-2-hydroxyphenoxy)benzyl)-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline-7-ol; The name of compound 20b is (S)-1-(3-(4-(((R)-8-bromo-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline-1-yl)methyl)phenoxy)-4-hydroxybenzyl)-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline-7-ol.

2. The method for preparing an intermediate for optically pure berberine and scutellarin as described in claim 1, characterized in that... Follow these steps: B1. The starting material compound 1, 5-bromovanillin, is added to a solvent such as dichloromethane, chloroform, methanol, ethanol, acetone, acetonitrile, tetrahydrofuran, benzene, toluene, or water. A methylating agent such as dimethyl sulfate, dimethyl carbonate, iodomethane, bromomethane, or methyl p-toluenesulfonate is added. Under alkaline conditions such as potassium carbonate, sodium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, pyridine, or triethylamine, the reaction is carried out at a temperature of 20-100℃ for 2-20 hours to synthesize compound 2, 3-bromo-4,5-dimethoxybenzaldehyde. The molar ratio of compound 1 to the methylating agent is 1:1-1:

4. B2. The obtained compound 2, 3-bromo-4,5-dimethoxybenzaldehyde, is added to a solvent such as methanol, ethanol, isopropanol, acetic acid, N,N-dimethylformamide, or dimethyl sulfoxide, and reacted with nitromethane in the presence of potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, potassium tert-butoxide, sodium methoxide, ammonium acetate, or triethylamine at a temperature of 50-100℃ for 10-20 hours via the Henry reaction to synthesize compound 3(E)-1-bromo-2,3-dimethoxy-5-(2-nitrobenzene)benzene, wherein the molar ratio of compound 2 to nitromethane is 1:0.1-1:

1. B3. The obtained compound 3(E)-1-bromo-2,3-dimethoxy-5-(2-nitrovinyl)benzene is added to a solvent such as methanol, ethanol, tetrahydrofuran, benzene or toluene, and then subjected to a reducing agent such as sodium borohydride, potassium borohydride, lithium aluminum hydride or borane at a temperature of 0-66℃ for 3-20 hours to synthesize compound 4, 2-(3-bromo-4,5-dimethoxyphenyl)ethylamine, wherein the molar ratio of compound 3 to the reducing agent is 1:1-1:10; B4. The raw material compound 5,4-hydroxyphenylacetic acid is reacted with liquid bromine at a molar ratio of 1:1 to 1:2 under acidic acetic acid, aluminum trichloride, ferric trichloride, ferric tribromide, or zinc dichloride conditions at 0°C to room temperature for 10 minutes to 2 hours via a halogenation reaction to synthesize compound 6,2-(3-bromo-4-hydroxyphenyl)acetic acid. B5. Compound 6, 2-(3-bromo-4-hydroxyphenyl)acetic acid, is added to solvents such as methanol, ethanol, isopropanol, dichloromethane, chloroform, pyridine, or N,N-dimethylformamide. Under alkaline conditions, using potassium carbonate, sodium carbonate, ammonium acetate, potassium hydroxide, sodium hydroxide, sodium methoxide, potassium tert-butoxide, or triethylamine, compound 7, 2-(4-(benzyloxy)-3-bromophenyl)acetic acid is synthesized via trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, triisopropylsilyl, benzyl, p-methoxybenzyl, methoxymethyl, or 2-ethoxyethyl, at a temperature of 30-80°C for 1-5 hours. The molar ratio of compound 6 to the hydroxyl protecting agent is 1:1-1:

4. B6. Compound 4,2-(3-bromo-4,5-dimethoxyphenyl)ethylamine is reacted with compound 7,2-(4-(benzyloxy)-3-bromophenyl)acetic acid or the starting compound 5,4-hydroxyphenylacetic acid in a molar ratio of 1:1 to 1:1.5 under the action of condensing agents N,N'-carbonyldiimidazole, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, or O-benzotriazole-tetramethylurea hexafluorophosphate at 0°C to room temperature for 3-20 hours via an acid-amine condensation reaction to synthesize compound 8a,2-(4-(benzyloxy)-3-bromophenyl)-N-(3-bromo-4,5-dimethoxyphenylethyl)acetamide or compound 8b. N-(3-bromo-4,5-dimethoxyphenethyl)-2-(4-hydroxyphenyl)acetamide, wherein the molar ratio of compound 7 or 5 to the condensing agent is 1:1 to 1:3; B7. Compound 8a 2-(4-(benzyloxy)-3-bromophenyl)-N-(3-bromo-4,5-dimethoxyphenethyl)acetamide or compound 8b N-(3-bromo-4,5-dimethoxyphenethyl)-2-(4-hydroxyphenyl)acetamide were subjected to intramolecular condensation in inert solvents such as dichloromethane, trichloromethane, acetonitrile, tetrahydrofuran, benzene, toluene, or nitrobenzene, with the aid of dehydrating agents such as phosphorus oxychloride, phosphorus pentoxide, polyphosphoric acid, or trifluoroacetic anhydride. The reaction temperature was 0-65℃, and the reaction time was 1-8 hours. Dehydration and cyclization were then performed to synthesize compound 9a. 1-(4-(benzyloxy)-3-bromobenzyl)-8-bromo-6,7-dimethoxy-3,4-dihydroisoquinoline or compound 9b4-((8-bromo-6,7-dimethoxy-3,4-dihydroisoquinoline-1-yl)methyl)phenol, wherein the molar ratio of compound 8a or compound 8b to the dehydrating agent is 1:1 to 1:20; B8. Compound 9a 1-(4-(benzyloxy)-3-bromobenzyl)-8-bromo-6,7-dimethoxy-3,4-dihydroisoquinoline or compound 9b 4-((8-bromo-6,7-dimethoxy-3,4-dihydroisoquinoline-1-yl)methyl)phenol were added to solvents such as dichloromethane, trichloromethane, tetrahydrofuran, acetonitrile, ethanol, methanol, isopropanol, toluene, or N,N-dimethylformamide, respectively, and subjected to an asymmetric hydrogenation reaction in the presence of a chiral catalyst and a reducing agent at 0°C to room temperature for 12-24 hours to synthesize the chiral compound 10a(R)-1-(4-(benzyloxy)-3-bromobenzyl)-8 -bromo-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline or compound 10b(S)-4-((8-bromo-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-1-yl)methyl)phenol; wherein the chiral catalyst is (1S,2S)-N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine, [(S,S)-N-(2-amino-1,2-diphenylethyl)-p-methylbenzenesulfonamide] ruthenium(II) chloride (p-cymene) Ruthenium(II) diacetic acid [(R)-(+)-2,2'-bis(diphenylphosphine)-1,1'-binaphthyl], (1R,2R)-N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine, [(R,R)-N-(2-amino-1,2-diphenylethyl)-p-methylbenzenesulfonamide] ruthenium(II) chloride (p-cymene) or ruthenium(II) diacetic acid [(S)-(+)-2,2'-bis(diphenylphosphine)-1,1'-binaphthyl]; the reducing agent is Sodium borohydride, potassium borohydride, formic acid / triethylamine or ammonium formate; the amount of chiral catalyst is 1.0-5.0 mol%, based on the molar amount of compound 9a or 9b being 100%; wherein the reducing agent is not formic acid / triethylamine, and the molar ratio of compound 9a or 9b to the reducing agent is 1:1-1:5; or the reducing agent is formic acid / triethylamine, and the molar ratio of compound 9a or 9b to formic acid and triethylamine is: compound 9a or 9b: formic acid: triethylamine = 1:1:1-1:25:10; B9. Compound 10a(R)-1-(4-(benzyloxy)-3-bromobenzyl)-8-bromo-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline or compound 10b(S)-4-((8-bromo-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-1-yl)methyl)phenol is added to solvents formic acid, acetonitrile, tetrahydrofuran, acetone, or N,N-dimethylformamide, and reacted with methylating agents such as iodomethane, dimethyl sulfate, dimethyl carbonate, methyl p-toluenesulfonate, or formic acid / formaldehyde at a temperature of 25-100℃ for 30 minutes to 6 hours to synthesize compound 11a(R)-1-(4-(benzyloxy)-3-bromobenzyl)-8-bromo-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline. -(benzyloxy)-3-bromobenzyl)-8-bromo-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline or compound 11b(S)-4-((8-bromo-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline-1-yl)methyl)phenol; wherein the methylating agent is not formic acid / formaldehyde, and the molar ratio of compound 10a or 10b to the methylating agent is 1:1-1:100; or the methylating agent is formic acid / formaldehyde, and the molar ratio of compound 10a or 10b to formaldehyde and formic acid is: compound 10a or 10b:formaldehyde:formic acid = 1:20:200-1:80:400; B10. Add the raw material compound 12, 4-benzyloxy-3-methoxybenzaldehyde, to the solvents methanol, ethanol, isopropanol, acetic acid, N,N-dimethylformamide, or dimethyl sulfoxide, and react it with nitromethane in the presence of catalysts such as potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, potassium tert-butoxide, sodium methoxide, ammonium acetate, or triethylamine at a temperature of 50-95℃ for 5-20 hours to synthesize compound 13(E)-1-(benzyloxy)-2-methoxy-4-(2-nitrobenzene)benzene; wherein the molar ratio of compound 12 to nitromethane is 1:1-1:10; and the molar ratio of compound 12 to catalyst is 1:0.1-1:

1. B11. Compound 13(E)-1-(benzyloxy)-2-methoxy-4-(2-nitrovinyl)benzene is added to the solvent methanol, ethanol, tetrahydrofuran, benzene or toluene, and then reduced with sodium borohydride, potassium borohydride, lithium aluminum hydride or borane at 0-70℃ for 3-20 hours to synthesize compound 14 2-(4-benzyloxy-3-methoxyphenyl)ethylamine, wherein the molar ratio of compound 13 to reducing agent is 1:1-1:

10. B12, Compound 14, 2-(4-benzyloxy-3-methoxyphenyl)ethylamine, and Compound 5, 4-hydroxyphenylacetic acid, or Compound 7, 2-(4-(benzyloxy)-3-bromophenyl)acetic acid, respectively, are reacted with dichloromethane, trichloromethane, and N,N-dimethylformamide in condensing agents such as N,N'-carbonyldiimidazole, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, or O-benzotriazole-tetramethylurea hexafluorophosphate at 0°C to room temperature for 3-20 hours to synthesize Compound 15a, N-(4-(benzyloxy)-3-methoxyphenylethyl)-2-(4-hydroxyphenyl)acetamide, or Compound 15b. 2-(4-benzyloxy-3-bromophenyl)-N-(4-benzyloxy-3-methoxyphenethyl)acetamide; wherein the molar ratio of compound 5 or compound 7 to compound 14 is 1:1 to 1:1.5; and the molar ratio of compound 5 or compound 7 to the condensing agent is 1:1 to 1:3; B13. Compound 15a N-(4-(benzyloxy)-3-methoxyphenethyl)-2-(4-hydroxyphenyl)acetamide or compound 15b 2-(4-benzyloxy-3-bromophenyl)-N-(4-benzyloxy-3-methoxyphenethyl)acetamide are subjected to intramolecular condensation in inert solvents such as dichloromethane, trichloromethane, acetonitrile, tetrahydrofuran, benzene, toluene, or nitrobenzene, with dehydrating agents such as phosphorus oxychloride, phosphorus pentoxide, polyphosphoric acid, or trifluoroacetic anhydride, at a temperature of 0-70°C for 2-8 hours, to synthesize compound 16a 4-((7-benzyloxy-6-methoxy-3,4-dihydroisoquinoline-1-yl)methyl)phenol or compound 16b 7-Benzyloxy-1-(4-Benzyloxy-3-bromobenzyl)-6-methoxy-3,4-dihydroisoquinoline; wherein the molar ratio of compound 15a or compound 15b to the dehydrating agent is 1:1 to 1:20; B14, Compound 16a 4-((7-benzyloxy-6-methoxy-3,4-dihydroisoquinoline-1-yl)methyl)phenol or Compound 16b 7-benzyloxy-1-(4-benzyloxy-3-bromobenzyl)-6-methoxy-3,4-dihydroisoquinoline were synthesized by catalytic asymmetric hydrogenation reaction under the action of chiral catalyst and reducing agent, at a temperature of 0℃ to room temperature for 12-24 hours, to synthesize chiral compound 17a(S)-4-((7-benzyloxy-6-methoxy-1,2,3, 4-Tetrahydroisoquinoline-1-yl)methyl)phenol or compound 17b(R)-7-benzyloxy-1-(4-benzyloxy-3-bromobenzyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline; wherein the chiral catalyst is (1S,2S)-N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine, [(S,S)-N-(2-amino-1,2-diphenylethyl)-p-methylbenzenesulfonamide]chlorinated (p-cymene)ruthenium(II), diacetic acid [(R)] Ruthenium(II)-(+)-2,2'-bis(diphenylphosphine)-1,1'-binaphthyl]ruthenium(II), (1R,2R)-N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine, [(R,R)-N-(2-amino-1,2-diphenylethyl)-p-methylbenzenesulfonamide] ruthenium(II) chloride (p-cymene), ruthenium(II) diacetic acid [(S)-(+)-2,2'-bis(diphenylphosphine)-1,1'-binaphthyl]ruthenium(II), with sodium borohydride and borohydride as reducing agents. Potassium, formic acid / triethylamine or ammonium formate; the amount of chiral catalyst is 1.0-5.0 mol%, based on the molar amount of compound 16a or 16b being 100%; wherein the reducing agent is not formic acid / triethylamine, and the molar ratio of compound 16a or 16b to the reducing agent is 1:1-1:5; or the reducing agent is formic acid / triethylamine, and the molar ratio of compound 16a or 16b to formic acid and triethylamine is: compound 16a or 16b: formic acid: triethylamine = 1:1:1-1:25:10; B15. Compound 17a(S)-4-((7-benzyloxy-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-yl)methyl)phenol or compound 17b(R)-7-benzyloxy-1-(4-benzyloxy-3-bromobenzyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline is added to solvents acetonitrile, tetrahydrofuran, acetone, or N,N-dimethylformamide or formic acid, respectively, and reacted with methylating agents iodomethane, dimethyl sulfate, dimethyl carbonate, methyl p-toluenesulfonate, or formic acid / formaldehyde at a temperature of 25-100℃ for 1-6 hours to synthesize compound 18a(S)-4-((7-)methyl)phenol or compound 17b(R)-7-benzyloxy-1-(4-benzyloxy-3-bromobenzyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline. Benzyloxy-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline-1-yl)methyl)phenol or compound 18b(R)-7-benzyloxy-1-(4-benzyloxy-3-bromobenzyl)-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline; wherein the methylating agent is not formic acid / formaldehyde, and the molar ratio of compound 17a or 17b to the methylating agent is 1:1-1:100; or the methylating agent is formic acid / formaldehyde, and the molar ratio of compound 17a or 17b to formaldehyde and formic acid is: compound 17a or 17b:formaldehyde:formic acid = 1:20:200-1:80:400; B16. Compound 11a(R)-1-(4-(benzyloxy)-3-bromobenzyl)-8-bromo-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline or compound 11b(S)-4-((8-bromo-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline-1-yl)methyl)phenol and compound 18a(S)-4-((7-benzyloxy-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline-1-yl)methyl)phenol or compound 18b(R)-7-benzyloxy-1-(4-benzyloxy- 3-Bromobenzyl)-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline was added to solvents such as dioxane, acetonitrile, pyridine, o-xylene, toluene, dimethyl sulfoxide, or N,N-dimethylformamide, and then subjected to intermolecular Ullmann coupling reactions under catalytic, ligand, and basic reagent conditions at 70-140°C for 12-96 hours to synthesize compound 19a(R)-1-(4-(benzyloxy)-3-(4-(((S)-7-(benzyloxy)-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline-1-yl)methyl) The compound is phenoxybenzyl)-8-bromo-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline or compound 19b(R)-1-(4-(2-benzyloxy-5-(((S)-7-benzyloxy-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline-1-yl)methyl)phenoxybenzyl)-8-bromo-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline; wherein the catalyst is copper powder, copper oxide, cuprous oxide, cuprous chloride, cuprous bromide, cuprous iodide or cuprous dimethyl sulfide, and the alkaline reagent is sodium hydroxide, hydrogen... Potassium oxide, potassium tert-butoxide, potassium phosphate, potassium carbonate, sodium carbonate, cesium carbonate, or triethylamine; ligands are benzoyl peroxide, 1,10-phenanthroline, ethyl acetate, trimethylolethane, 1-pyridin-2-yl-2-propanone, or N,N-dimethylglycine; the molar ratio of compound 11a or 11b to compound 18a or 18b is 0.5:1 to 2:1; the molar ratio of compound 11a or 11b to base is 1:1 to 1:10; the molar ratio of compound 11a or 11b to catalyst is 1:0.1 to 1:5; the molar ratio of compound 11a or 11b to ligand is 1:0.1 to 1:

5. B17. Compound 19a(R)-1-(4-(benzyloxy)-3-(4-(((S)-7-(benzyloxy)-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline-1-yl)methyl)phenoxy)benzyl)-8-bromo-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline or compound 19b(R)-1-(4-(2-benzyloxy-5-(((S)-7-benzyloxy-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline-1-yl)methyl)phenoxy)benzyl)-8-bromo-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline, respectively, is added to the solvents methanol, ethanol, or isopropanol, and the hydroxyl groups are removed under acidic conditions of sulfuric acid, hydrochloric acid, acetic acid, trifluoroacetic acid, or hydrobromic acid. The compounds 20a (S)-1-(4-(5-(((R)-8-bromo-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline-1-yl)methyl)-2-hydroxyphenoxy)benzyl)-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline-7-ol or 20b (S)-1-(3-(4-((((R)-8-bromo-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline-1-yl)methyl)phenoxy)-4-hydroxybenzyl)-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline-7-ol) were synthesized by protecting the group with a base, at a temperature of 40-82℃ for 1-10 hours; wherein the molar ratio of compound 19a or 19b to the acidic reagent was 1:20-1:

200.

3. The method for preparing an intermediate for optically pure berberine and scutellarin according to claim 2, characterized in that, Compound 20a(S)-1-(4-(5-(((R)-8-bromo-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline-1-yl)methyl)-2-hydroxyphenoxy)benzyl)-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline-7-ol or compound 20b(S)-1-(3-(4-(((R)-8-bromo-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline-1-yl)methyl)phenoxy)-4-hydroxybenzyl)-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline-7-ol) were added to a solvent The reagents are dioxane, acetonitrile, pyridine, o-xylene, toluene, dimethyl sulfoxide, or N,N-dimethylformamide. The catalysts are copper powder, copper oxide, cuprous oxide, cuprous chloride, cuprous bromide, cuprous iodide, and cuprous bromide dimethyl sulfide. The alkaline reagents are sodium hydroxide, potassium hydroxide, potassium carbonate, cesium carbonate, and triethylamine. The reaction is carried out via an intramolecular Ullmann reaction at high temperatures (70-200℃) and time (12-96 hours) to synthesize optically pure berberine (21) and spiky base (22). The molar ratio of compound 20a or 20b to the base is 1:1-1:

10. The molar ratio of compound 20a or 20b to the catalyst is 1:1-1:

5.

4. The method for preparing an intermediate for optically pure berberine and scutellarin according to claim 2, characterized in that, The alkaline reagent in B1 is potassium carbonate; the methylating agent is dimethyl sulfate; and the solvent is acetone. The catalyst in B2 is ammonium acetate; the solvent is acetic acid. The reducing agent in B3 is sodium borohydride; the solvent is tetrahydrofuran. The acidic reagent in B4 is acetic acid; The alkaline reagent in B5 is sodium hydroxide; the hydroxyl protecting group is benzyl; and the solvent is ethanol. The condensing agent in B6 is N,N'-carbonyldiimidazole; the solvent is dichloromethane. The dehydrating agent in B7 is phosphorus oxychloride; the inert solvent is acetonitrile. The amount of chiral catalyst in B8 is 1.0-5.0 mol%, based on the molar amount of compound 9a or 9b being 100%; the reducing agent is not formic acid / triethylamine, and the molar ratio of compound 9a or 9b to the reducing agent is 1:1-1:5; or the reducing agent is formic acid / triethylamine, and the molar ratio of compound 9a or 9b to formic acid and triethylamine is: compound 9a or 9b: formic acid: triethylamine = 1:1:1-1:25:10; In B9, the methylating agent is not formic acid / formaldehyde, and the molar ratio of compound 10a or 10b to the methylating agent is 1:1-1:100; or the methylating agent is formic acid / formaldehyde, the solvent is formic acid, and the molar ratio of compound 10a or 10b to formaldehyde and formic acid is: compound 10a or 10b:formaldehyde:formic acid = 1:20:200-1:80:400; The catalyst in B10 is ammonium acetate; the solvent is acetic acid. The reducing agent in B11 is sodium borohydride; the solvent is tetrahydrofuran. The raw materials in B12 are compounds 5 and 14, the condensing agent is 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, and the solvent is dichloromethane; or the raw materials are compounds 7 and 14, the condensing agent is N,N'-carbonyldiimidazole, and the solvent is dichloromethane; In the B14 formulation, the raw material is compound 16a, the chiral catalyst is (R,R)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene)ruthenium chloride; the reducing agent is formic acid / triethylamine; and the solvent is acetonitrile; or the raw material is compound 16b, the chiral catalyst is (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene)ruthenium chloride; the reducing agent is formic acid / triethylamine; and the solvent is acetonitrile. The methylating agent in B15 is not formic acid / formaldehyde, and the molar ratio of compound 17a or 17b to the methylating agent is 1:1 to 1:100; or the methylating agent is formic acid / formaldehyde, and the molar ratio of compound 17a or 17b to formaldehyde and formic acid is: compound 17a or 17b:formaldehyde:formic acid = 1:20:200-1:80:400; The catalyst in B16 is cuprous iodide; the basic reagent is cesium carbonate; the ligand is ethyl acetate; and the solvent is pyridine. The acidic reagent in B17 is hydrochloric acid; the solvent is ethanol.

5. The method for preparing an intermediate for optically pure berberine and scutellarin according to claim 3, characterized in that, The catalyst is cuprous dimethyl sulfide bromide; the base is cesium carbonate; and the solvent is pyridine.

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