CN113735847B

CN113735847B - Synthetic preparation method of berberine hydrochloride

Info

Publication number: CN113735847B
Application number: CN202111064168.5A
Authority: CN
Inventors: 陈芬儿; 唐培�; 李伟剑; 蒋龙
Original assignee: Shanghai Yan'an Pharmaceutical Yangpu Co ltd; Sichuan University
Current assignee: Shanghai Yan'an Pharmaceutical Yangpu Co ltd; Sichuan University
Priority date: 2021-09-10
Filing date: 2021-09-10
Publication date: 2022-06-07
Anticipated expiration: 2041-09-10
Also published as: CN113735847A

Abstract

The invention belongs to the field of organic chemistry, and relates to a synthetic method of berberine hydrochloride, which comprises the following steps: s1: preparing N- [2- (3, 4-dioxy phenyl-5-group) ethyl ] -1- (5-halogeno-2, 3-dimethoxy benzyl) azomethine by using 5-halogenated veratraldehyde and piperonylethylamine; s2: to obtain 2- (3, 4-dioxy phenyl) -N- (5-bromo-2, 3-dimethoxy benzyl) ethylamine; s3: to obtain 2- (3, 4-dioxy phenyl) -N- (5-bromo-2, 3-dimethoxy benzyl) ethylamine hydrochloride; s4: to prepare 12-halogenated berberine derivatives; s5: making berberine. The method gets rid of the restriction of synthesizing the o-veratraldehyde raw material by using the by-product o-vanillin, synthesizes the 5-substituted o-veratraldehyde and piperonylethylamine, and utilizes the two to prepare the berberine hydrochloride, and has the advantages of easily obtained raw materials, mild reaction conditions, simple and convenient operation, high chemical yield, low cost and the like.

Description

Synthetic preparation method of berberine hydrochloride

Technical Field

The invention belongs to the field of organic chemistry, relates to a preparation method of a natural product, and particularly relates to a synthetic preparation method of berberine hydrochloride.

Background

Berberine hydrochloride is an isoquinoline alkaloid with numerous pharmacological activities extracted from rhizome of plants such as Coptidis rhizoma, cortex Phellodendri, and radix Berberidis. Is widely used in Chinese traditional Chinese patent medicine, and has the functions of clearing heat, detoxifying, purging fire and the like. Initially in clinic, berberine hydrochloride mainly exerts antibacterial effect and is used for treating indications such as bacterial gastrointestinal inflammation and bacillary dysentery. And simultaneously has good curative effect on diarrhea caused by irritable bowel syndrome. In recent years, berberine hydrochloride is found to have the activities of regulating blood sugar and lipid metabolism, preventing atherosclerosis, resisting arrhythmia, inhibiting tumor cell proliferation, resisting virus and the like. Therefore, berberine becomes one of the research hotspots in the chemical field of natural medicines at home and abroad.

At present, berberine hydrochloride mainly comprises two preparation methods, one is obtained by extracting and separating medicinal Chinese medicinal materials such as phellodendron, coptis chinensis, barberry root and the like. The other method of chemical synthesis is that veratraldehyde is used as raw material and is prepared by multi-step reactions such as condensation, coupling, cyclization and the like with piperonylethylamine. Because of the limitation of plant resources, the research work of chemically fully synthesizing berberine has high economic value.

A preparation process of berberine is described in 'national raw material medicine process assembly' published in 1980, wherein piperonyl-cyamine is used as a raw material, is subjected to chloromethylation, cyanoylation and reduction respectively to prepare piperonyl-amine, and then is subjected to condensation, reduction, ring closing and other multi-step reactions with veratraldehyde to prepare berberine hydrochloride.

In addition, berberine hydrochloride is prepared by a similar route adopted in a patent ZL01106089.1 reported in northeast pharmaceutical factories. The process comprises the steps of respectively preparing homopiperony lamine by using catechol as a raw material through etherification, chloromethylation, Dazen condensation, decarboxylation and amination reduction, and then preparing berberine hydrochloride through multi-step reactions such as condensation, reduction and ring closure with veratraldehyde.

The above method has the following drawbacks: 1. virulent sodium cyanide is used in the process of preparing the piperonylethylamine; 2. a copper catalyst is used in the ring closing process, so that a large amount of copper-containing wastewater is generated, the treatment cost is increased, and the environment is polluted; 3. the synthesis steps are relatively complicated and the operation is complex; 4. the preparation of the veratraldehyde needs to use o-vanillin as a raw material, but o-vanillin is a drug intermediate, can be used for synthesizing various drugs and spices, and is mainly derived from byproducts for producing vanillin and ethyl vanillin, so that the yield is low and the price is high.

Disclosure of Invention

In view of the above, it is necessary to provide a method for synthesizing berberine hydrochloride with high efficiency and low cost. The restriction of the raw material for synthesizing the o-veratraldehyde by using the byproduct o-vanillin is eliminated by innovatively synthesizing the 5-substituted o-veratraldehyde, and the berberine hydrochloride is further prepared by taking the 5-substituted o-veratraldehyde as the raw material and piperonylethylamine.

The invention is realized by the following technical scheme:

the total yield of the berberine hydrochloride I synthetic method is more than 20%. The synthetic route is as follows:

wherein R is selected from Cl, Br and I halogen groups.

Based on the synthetic circuit diagram of the berberine hydrochloride (I), the synthetic method of the berberine hydrochloride (I) comprises the following steps:

s1: preparing N- [2- (3, 4-dioxy phenyl-5-group) ethyl ] -1- (5-halogeno-2, 3-dimethoxy benzyl) azomethine (compound VII) by using 5-halogeno veratraldehyde (compound IX) and piperonylethylamine (compound VIII);

s2: preparing 2- (3, 4-dioxy phenyl) -N- (5-bromo-2, 3-dimethoxy benzyl) ethylamine (namely a compound VI) by using the compound VII of S1;

s3: preparing 2- (3, 4-dioxy phenyl) -N- (5-bromo-2, 3-dimethoxy benzyl) ethylamine hydrochloride (namely compound V) by using a compound VI of S2;

s4: preparing 12-halogenated berberine derivative (compound II) from compound V of S3

S5: preparing berberine (i.e. compound I) from compound II of S4;

in a first aspect, the synthesis method of berberine hydrochloride (I) comprises the following steps:

s1: under the action of a water removal agent, carrying out dehydration condensation reaction on the compound IX and the compound VIII in an organic solvent to obtain a compound VII;

s2: reducing the compound VII of S1 in an organic solvent under the action of a borohydride reducing agent to obtain a compound VI;

s3: under the action of ethyl ether hydrochloride, reacting the compound VI described in S2 into hydrochloride in an organic solvent to obtain a compound V;

s4: the compound V of S3 is used to prepare 12-halogenated berberine derivative (i.e. compound II), which comprises:

s41 a: under the catalysis of protonic acid and the addition of a water removal agent, carrying out a Pickert-Sbigeler reaction (P-S reaction) on the compound V described in S3 and glyoxal monoacetal in an organic solvent to obtain a compound IV (6- (5-bromo-2, 3-dimethoxybenzyl) -5- (dimethoxymethyl) -5,6,7, 8-tetrahydro- [1,3] dioxapentane [4,5-g ] isoquinoline);

s42 a: under the acid catalysis condition, carrying out electrophilic reaction on the compound IV described in S41a in an organic solvent to close the ring to prepare a compound III (12-halogenated dihydroberberine);

s43 a: putting an organic solvent in an air environment, and carrying out oxidation aromatization reaction on the compound III in S42a to prepare a compound II;

s5: under the action of palladium-carbon catalysis and a hydrogen source, the compound II described in S43a is subjected to hydrogenation reaction in an organic solvent in the presence of alkali to prepare the compound I.

Further, in the condensation reaction described in S1,

the water removal agent is any one of 4AMS, anhydrous magnesium sulfate, anhydrous sodium sulfate or anhydrous potassium carbonate, and has a good water removal effect. Optimally 4A MS, wide source and economic and reasonable.

The mass ratio of the water removing agent to the compound VIII is 1-5: 1 (preferably 2-3: 1), and can achieve good water removal effect and promote the reaction. A compound IX: the molar ratio of the compound VIII is 1:1 to 1.5; preferred compounds (IX): the molar ratio of the compound (VIII) is 1: 1-1.2.

The organic solvent comprises at least one of dichloromethane, tetrahydrofuran, diethyl ether, dioxane, chloroform and ethyl acetate; preferably anhydrous dichloromethane. When the organic solvent is a mixed solvent of dichloromethane and any one of the other substances, the volume ratio is within the range of 1: 0.1-0.9. The solvents are wide in source, cheap and easy to obtain, and convenient to recover.

The condensation reaction of S1 has a reaction temperature of 0-50 deg.C, preferably 0-30 deg.C; the reaction time is 12-48 h, preferably 24-30 h.

In the reduction reaction described in S2,

the borohydride is potassium borohydride or sodium borohydride. Preferably potassium borohydride, and the reducing agent has stable chemical property and is cheap and easy to obtain.

And (3) a compound VII: the molar ratio of borohydride is 1: 1-5, preferably 1: 1.5-3, the reaction can be smoothly carried out.

The organic solvent is at least one of methanol, tetrahydrofuran, diethyl ether, dioxane, anhydrous dichloromethane, chloroform, and ethyl acetate; when the organic solvent is a mixed solvent of methanol and any one of the other substances, the volume ratio is within the range of 1: 0.1-0.9; preferably, the mixed solvent of methanol and anhydrous dichloromethane is the best, and the volume ratio range of the mixed solvent is 1: 0.3-0.9. The solvents are wide in source, cheap and easy to obtain, and convenient to recover.

S2, the reaction temperature of the reduction reaction is-10 ℃ to 50 ℃, and preferably-10 ℃ to 10 ℃; the reaction time is 0.5-4 h, preferably 1-2 h.

In the salt-forming reaction described in S3,

the hydrochloric ether solution has a good salt forming effect within the molar concentration range of 0.5-5 mol/L; preferably in the range of 1 to 3 moles per liter.

Compound vi: the molar ratio of the hydrochloric acid is 1: the salt forming reaction can be completed within 1-5 hours; preferably 1: 2 to 4.

The organic solvent is at least one of tetrahydrofuran, anhydrous diethyl ether, dioxane, dichloromethane, chloroform, and ethyl acetate; preferably anhydrous diethyl ether; the solvents are wide in source, cheap and easy to obtain, and convenient to recover.

The reaction temperature of the salt forming reaction of S3 is-30 ℃ to 30 ℃, and is preferably-30 ℃ to-10 ℃; the reaction time is 0.5-6 h, preferably 1-3 h.

In the P-S reaction described in S41a,

the aldehyde is any one of glyoxal monoacetal (A); has high reaction activity, mild reaction condition, simple operation and high yield. Preference is given to glyoxal dimethyl acetal or glyoxal-5, 5-dimethyl-1, 3-dioxane acetal.

In the formula R₁And R₂Each independently selected from the same C₁-C₆Straight or branched alkyl or different C₁-C₆A linear or branched alkyl group; or R₁And R₂Connection formation C₂-C₆Straight or branched chain alkylene.

The protonic acid such as anhydrous formic acid, anhydrous acetic acid, trifluoroacetic acid, sulfuric acid or hydrochloric ether solution can be used for catalyzing the P-S ring closure reaction. The protonic acids are cheap and easily available and have wide sources. Preferably anhydrous formic acid.

The compound V: glyoxal monoacetal: the molar ratio of protonic acid is 1: 2-5: 5-20, and the reaction can be smoothly finished. Preferably 1: 2-3: 13 to 15.

The used water removing agent is anhydrous magnesium sulfate, anhydrous sodium sulfate or 4A MS, preferably anhydrous magnesium sulfate, and the mass ratio of the compound V to the water removing agent is 1: 2-30, preferably 1: 2 to 25, can promote the reaction to proceed smoothly.

The organic solvent comprises at least one of dichloromethane, tetrahydrofuran, diethyl ether, dioxane, chloroform or 1, 2-dichloroethane; preferably dichloromethane; when the organic solvent is a mixed solvent of dichloromethane and any one of the other substances, the volume ratio is in the range of 1: 0.1-0.9. The solvents are wide in source, cheap and easy to obtain, and convenient to recover.

The reaction temperature of the P-S reaction of S41a is 25-50 ℃, preferably 40-50 ℃; the reaction time is 12-36 h, preferably 20-30 h.

In the electrophilic substitution reaction described in S42a,

the acid is a protonic acid or a Lewis acid; the protonic acid comprises any one of concentrated sulfuric acid, concentrated hydrochloric acid, concentrated nitric acid, phosphoric acid or trifluoromethanesulfonic acid; the Lewis acid comprises any one of anhydrous aluminum trichloride, anhydrous ferric trichloride, anhydrous stannic chloride or anhydrous zinc chloride; preferably concentrated sulfuric acid. The Lewis acid is cheap and easy to obtain, and has good catalytic effect.

And (2) a compound IV: the molar ratio of the acid is 1: 1.5-8, preferably 1: 3-6; the reaction can be smoothly carried out.

The solvent for the reaction comprises at least one of formic acid, acetic acid or propionic acid; preferably acetic acid; the solvents are wide in source, cheap and easy to obtain, and convenient to recover.

The reaction temperature of the electrophilic substitution reaction described in S42a is-20 to 50 ℃, preferably 20 to 30 ℃; the reaction time is 6-18 h, preferably 10-14 h.

In the aromatization reaction described in S43a,

the organic solvent comprises at least one of tetrahydrofuran, methanol, diethyl ether, dioxane, dichloromethane, chloroform or 1, 2-dichloroethane, preferably methanol; when the organic solvent is a mixed solvent of methanol and any one of the other substances, the volume ratio is within the range of 1: 0.1-0.9. The solvents are wide in source, cheap and convenient to recover.

The reaction temperature of the aromatization reaction of S43a is 25-50 ℃, and the optimum reaction temperature is 25 ℃; the reaction time is 36-72 h, preferably 46-50 h.

In the hydrogenation reaction described in S5,

the palladium loading capacity of the palladium carbon can be 5% or 10%, and the using amount of the palladium carbon can be 5wt% -50 wt%; preferably, the palladium loading is 10% and the palladium on carbon is 20% wt.

The compound II: the molar ratio of the hydrogen source is 1: 2 to 6.

The hydrogen source used can be any one of ammonium formate, formic acid-triethylamine complex or hydrogen; the hydrogen sources are cheap and easy to obtain, and have good hydrogenation effect.

The organic solvent comprises at least one of methanol, ethanol, isopropanol, water or acetic acid; when the organic solvent is a mixed solvent of acetic acid and any one of the other substances, the volume ratio is within the range of 1: 0.1-0.9, and a 50% acetic acid aqueous solution is preferred. The solvents are wide in source, cheap and convenient to recover.

The reaction temperature of the hydrogenation reaction of S5 is 25-50 ℃; the reaction time is 8-36 h.

Specifically, in the transfer hydrogenation reaction, the compound ii: the molar ratio of the hydrogen source is 1: 4-5; the reaction can be smoothly carried out; the hydrogen source is ammonium formate; the organic solvent is an aqueous solution of acetic acid with a final concentration of 50%.

The reaction temperature of the transfer hydrogenation reaction is 45-55 ℃; the reaction time is 23-25 h.

Specifically, in the hydrogenation reaction in which hydrogen is the hydrogen source, the pressure of hydrogen in the system is 1atm to 5atm, and preferably the pressure of hydrogen is 1 atm.

The compound II: the molar ratio of the alkali is 1: 1-2; the alkali used is preferably sodium bicarbonate, and has wide source and low cost. The organic solvent is methanol, the effect is optimal, the source is wide and the price is low.

In the hydrogen hydrogenation reaction, the optimum reaction temperature and reaction time are 25-30 ℃ and 11-13 h.

In a second aspect, the synthesis method of berberine hydrochloride I, steps S1, S2, S3 and S5 are the same as in the first aspect; the step S4 is: directly preparing 12-halogenated berberine derivatives (i.e. compound II) by using the compound V of S3, comprising the following steps:

under the catalysis of inorganic protonic acid and the condition of adding metal inorganic salt as a water removal agent, 2- (3, 4-dioxygen phenyl) -N- (5-bromine-2, 3-dimethoxy benzyl) ethylamine hydrochloride (compound V) and glyoxal carry out ring closure reaction in an organic acid solvent to prepare a 12-halogenated berberine derivative II; the total yield is more than 25%.

Further, in the step S4,

the inorganic protonic acid comprises concentrated hydrochloric acid, concentrated sulfuric acid, phosphoric acid or nitric acid; the acid is cheap and easy to obtain, has wide sources, and can be used for catalyzing the ring closure reaction; the best is concentrated hydrochloric acid, and the source is wide, economic and reasonable.

The metal inorganic salt water removal agent such as anhydrous copper sulfate, anhydrous copper chloride, anhydrous ferric sulfate or anhydrous ferric chloride can promote the reaction to be smoothly carried out; anhydrous copper sulfate is preferred.

The solvent for the reaction, such as anhydrous acetic acid, anhydrous formic acid and anhydrous trifluoroacetic acid, can be a single solvent or a mixed solvent, and the volume ratio of the mixed solvent is 1: 0.1-0.9. These solvents are widely available.

The compound V: glyoxal: inorganic protic acid: the molar ratio of the metal inorganic salt is 1: 1.5-3: 1.5-2.5: 1.5 to 3; the preferred molar ratio is 1: 2-3: 2-2.5: 1.5 to 2.

The reaction temperature is controlled between 50 ℃ and 100 ℃, and preferably between 80 ℃ and 100 ℃; the reaction time is controlled to be between 8 and 12 hours.

The invention also provides a synthesis method of the piperonylethylamine, the total yield is more than 22%, and the synthesis route is as follows:

based on the synthetic circuit diagram of the piperonylethylamine, the synthetic method of the piperonylethylamine provided by the invention comprises the following steps:

preparing 3, 4-dihydroxy mandelic acid (III) from catechol (II);

3, 4-dihydroxy benzaldehyde (IV) is prepared by using 3, 4-dihydroxy mandelic acid (III);

preparing piperonal (V) by using the prepared 3, 4-dihydroxy benzaldehyde (IV);

preparing beta-nitro-3, 4-dioxy methyl styrene (VI) by piperonal (V);

beta-nitro-3, 4-dioxy methyl styrene (VI) is used for preparing piperonylethylamine (I).

Further, the specific operation of "preparing 3, 4-dihydroxymandelic acid (III) by using catechol (II)" comprises:

the method comprises the following steps of carrying out electrophilic substitution reaction on catechol (II) and glyoxylic acid aqueous solution in a solvent under the catalysis of inorganic base and the addition of alumina as an additive to prepare the 3, 4-dihydroxy mandelic acid (III).

Preferably, the amount of solvent water for the electrophilic substitution reaction is 5mL to 15mL per gram of substrate, and more preferably 13mL per gram of substrate.

Preferably, catechol (II): inorganic base: alumina: the molar ratio of glyoxylic acid is 1.5-1.0: 3-1.5: 0.2-1.0: 1.0; more preferably 1.1: 1.8: 0.4: 1.0.

preferably, the electrophilic substitution reaction is suitably carried out at a reaction temperature of from 25 ℃ to 100 ℃, more preferably from 55 ℃ to 65 ℃; the reaction time is 6-24 h, and more preferably 11-13 h.

Preferably, in the electrophilic substitution reaction,

the inorganic base is sodium hydroxide or potassium hydroxide, and both have good catalytic effects; sodium hydroxide is further preferred, so that the effect is excellent, and the source is wide and cheap;

the alumina is neutral alumina or alkaline alumina; the alumina is cheap and easy to obtain, and can be used as a load agent to promote homogeneous reaction in water as a solvent; more preferably, alkaline alumina powder, which has the best reaction promoting effect;

the mass fraction of the glyoxylic acid aqueous solution is 40-50% (preferably 50%), and the glyoxylic acid aqueous solution is cheap and easy to obtain and has a good reaction effect;

the solvent of the reaction is water, and the solvent is wide in source, economical and environment-friendly.

Further, the specific operation of "obtaining 3, 4-dihydroxybenzaldehyde (IV) from 3, 4-dihydroxymandelic acid (III)" comprises:

oxidizing the 3, 4-dihydroxymandelic acid (III) with a metal inorganic salt in a reaction environment comprising a mixed solvent of an organic solvent and water or water alone (preferably water alone) to perform a decarboxylation oxidation reaction to produce the 3, 4-dihydroxybenzaldehyde (IV).

Preferably, the 3, 4-dihydroxymandelic acid (III): the molar ratio of the metal inorganic salt is 1: 1.0 to 3.0; more preferably 1: 1.1.

preferably, the dosage of the solvent using the mixed solvent or water of the decarboxylation oxidation reaction as a single solvent is 5 mL-15 mL per gram of the substrate, and more preferably 14mL per gram of the substrate.

Preferably, the reaction temperature of the decarboxylation oxidation reaction is controlled at 50-100 ℃, and further preferably 80-90 ℃; the reaction time is controlled to be 9-18 h, and more preferably 12-13 h.

Preferably, in the decarboxylation oxidation reaction,

the metal inorganic salt is any one of ferric chloride hydrate, cupric oxide, cuprous oxide or cupric hydroxide, and has good catalytic oxidation reaction effect; copper chloride dihydrate is further preferred, so that the copper chloride dihydrate is stable in chemical property, low in price and easy to obtain;

the organic solvent comprises tetrahydrofuran, ethyl acetate, 1, 2-dichloroethane, chloroform or acetonitrile; the ratio of the organic solvent to the water is 1.0-0: 1.0, the solvents have wide sources, are cheap and easy to obtain, are convenient to recover and can ensure that the reaction can be well carried out.

Further, the specific operation of "obtaining piperonal (V) using the obtained 3, 4-dihydroxybenzaldehyde (IV)" includes:

in the presence of alkali, in organic solvent or without solvent (preferably without solvent), the phase transition catalyst catalyzes the reaction of the 3, 4-dihydroxy benzaldehyde (IV) and dichloromethane to prepare piperonal (V) through etherizing reaction.

Preferred, 3, 4-dihydroxybenzaldehyde (IV): alkali: phase transfer catalyst: the molar ratio of dichloromethane is 1: 1-5: 0.1-1: 2-50; optimally 1: 2: 0.5: 43.

preferably, the reaction temperature suitable for the ether-forming cyclization reaction is 50-100 ℃ (preferably 75-80 ℃); the reaction time is 4-24 h (preferably 12-14 h).

Preferably, in the ether-forming cyclization reaction,

the alkali is inorganic alkali or organic alkali; wherein the inorganic base is any one of sodium carbonate, potassium carbonate, sodium bicarbonate, sodium hydroxide or potassium hydroxide (sodium hydroxide is the most preferred); the organic base is triethylamine (Et)₃N)、Any one of N, N-Diisopropylethylamine (DIPEA), Pyridine (Pyridine), and 4-N, N-Dimethylpyridine (DMAP); the alkali can well catalyze the methylation reaction;

the phase-transfer catalyst is any one of tetrabutylammonium bromide (TBAB), triethylbenzylammonium chloride (TEBAC), polyethylene glycol 400, polyethylene glycol 600 or polyethylene glycol 800 (tetrabutylammonium bromide is the best); the phase-transfer catalysts are cheap and easy to obtain, and can promote the reaction to be well completed.

Preferably, the reaction solvent such as tetrahydrofuran, ethyl acetate, methanol, ethanol, isopropanol and acetonitrile can be a single solvent, and the solvents are wide in source, cheap and easy to obtain and convenient to recover.

Further, the specific operation of preparing the beta-nitro-3, 4-dioxy methyl styrene (VI) by piperonal (V) comprises the following steps:

under the catalysis of alkali, the piperonal (V) and nitromethane generate a Henry reaction in a mixed solvent of alcohol and water, and the beta-nitro-3, 4-dioxygen methyl styrene (VI) is prepared by dehydration in a 6M hydrochloric acid solution.

Preferably, piperonal (V): alkali: the molar ratio of nitromethane is 1: 1.2-5: 1.2-5, the reaction can be smoothly carried out; further preferred is a molar ratio of 1: 3.6: 3.6.

preferably, the reaction temperature of the Henry reaction is controlled to be-20-10 ℃ (optimally-5-0 ℃); the reaction time is controlled to be 1-4 h (preferably 2-3 h), and the reaction is smoothly completed.

Preferably, in the Henry reaction,

the alkali is inorganic alkali or organic alkali; wherein the inorganic base is any one of sodium carbonate, potassium carbonate, sodium bicarbonate, sodium hydroxide or potassium hydroxide, and the organic base is triethylamine (Et)₃Any one of N), N-Diisopropylethylamine (DIPEA), Pyridine (Pyridine), and 4-N, N-Dimethylpyridine (DMAP); the alkali has good catalytic effect; most preferably sodium hydroxide, has optimal effect, wide source and low cost;

the alcohol used by the reaction solvent is methanol, ethanol or isopropanol, which are cheap and easily available, and the alcohol is preferably methanol; the volume ratio of the alcohol to the water is 1: 1-3 (the volume ratio of the solvent alcohol to the water is 1: 1.6 optimally) can ensure that the reaction is complete in a homogeneous system.

Further, the "obtaining piperonylethylamine (I) using β -nitro-3, 4-dioxomethylstyrene (VI)" includes: in an organic solvent, reducing the beta-nitro-3, 4-dioxy methyl styrene (VI) by a reducing agent to prepare piperonylethylamine (I).

Preferably, in the reduction reaction,

the reducing agent is any one of borohydride and boron trifluoride diethyl etherate or borane dimethyl ether complex, and has good reducing effect, wherein the borohydride can be any one of sodium borohydride or potassium borohydride, and the reducing agent has stable chemical property, low price and easy obtaining.

Further preferably, the optimal reducing reagent is sodium borohydride and boron trifluoride diethyl etherate, and the source is wide, cheap and easy to obtain; the compatible molar ratio of the sodium borohydride to the boron trifluoride diethyl etherate is as follows: 1: 1-1.5, wherein the preferable compatible molar ratio of sodium borohydride to boron trifluoride diethyl etherate is 1: 1.2.

Preferably, the β -nitro-3, 4-dioxomethylstyrene (VI): the molar ratio of the reducing agent is 1: 1.2-5 (the most preferable molar ratio is 1: 4.8), so that the reaction can be smoothly carried out;

the organic solvent comprises one or two of tetrahydrofuran, diethyl ether, 1, 2-dichloroethane, chloroform or absolute ethyl alcohol; most preferably anhydrous tetrahydrofuran; two organic solvents are mixed according to the volume ratio of 1: 0.1-0.9, wherein tetrahydrofuran is the main component. The solvents are wide in source, cheap and easy to obtain, and convenient to recover.

Preferably, the reaction temperature of the reduction reaction is 25-70 ℃, and the optimal temperature is 65-70 ℃; the reaction time is 3-8 h, and the optimal time is 4-6 h.

The invention also provides a synthesis method of the 5-halogenated veratraldehyde (IX), which comprises the following steps:

carrying out electrophilic substitution reaction on 4-halogenated guaiacol (XV) and glyoxylic acid aqueous solution in a water solvent under the catalysis of inorganic base and the addition of alumina as an additive to prepare 2-hydroxy-3-methoxy-5-halogenated mandelic acid (XVI);

carrying out decarboxylation oxidation reaction in a mixed solvent of an organic solvent and water under the oxidation of a metal inorganic salt to obtain 5-halogenated o-vanillin (XVII);

the 5-halogenated veratraldehyde (IX) is prepared by methylation reaction of the alpha-amino acid and a methylating agent in the presence of inorganic base and a phase-transfer catalyst in an organic solvent or in the absence of a solvent, and the total yield is more than 60%.

The synthetic method of the 5-halogenated veratraldehyde comprises the following synthetic route:

wherein R is selected from Cl, Br and I halogen groups.

Further, in the electrophilic substitution reaction:

the inorganic alkali is sodium hydroxide or potassium hydroxide; further preferred is sodium hydroxide.

The aluminum oxide (Al)₂O₃) Neutral alumina or basic alumina; further preferred is basic alumina.

The mass fraction of the glyoxylic acid aqueous solution is 40-50%; further preferably 50%.

The solvent for the reaction is water.

Preferably, the 4-halogenated guaiacol: inorganic base: alumina: the molar ratio of glyoxylic acid is 1.5-1.0: 3-1.5: 0.2 to 1.0: 1.0; further preferably, the molar ratio is 1.1: 1.8: 0.4: 1.0.

preferably, the reaction temperature of the electrophilic substitution reaction is 25 ℃ to 100 ℃; the reaction time is 6-24 h.

Further preferably, the reaction temperature of the electrophilic substitution reaction is 55 ℃ to 65 ℃; the reaction time is 11-13 h, and 12h is optimal.

Further, in the decarboxylation oxidation reaction:

the metal inorganic salt is any one of ferric chloride hydrate, cupric oxide, cuprous oxide or cupric hydroxide; further preferably, the metal inorganic salt is ferric chloride hexahydrate, and the oxidant is stable in chemical property, low in price and easy to obtain.

The 2-hydroxy-3-methoxy-5-halogenated mandelic acid: the molar ratio of the metal inorganic salt is 1.0: 1.0 to 3.0; further preferably, the molar ratio is 1.0: 1.5.

the organic solvent comprises one or two of tetrahydrofuran, ethyl acetate, 1, 2-dichloroethane, chloroform or toluene; when the organic solvent is a mixed reagent, the mixing proportion is that the volume ratio is 1:0.1 to 0.9; further preferably, the organic solvent is toluene.

The ratio of the organic solvent to the water is 5-1: 1; further preferably, the ratio of organic solvent to water is 2: 1.

preferably, the reaction temperature of the decarboxylation oxidation reaction is 50-100 ℃; the reaction time is 2-12 h.

Further preferably, the reaction temperature of the decarboxylation oxidation reaction is 90 ℃; the reaction time is 4-5 h, and 4h is optimal.

Further, in the methylation reaction,

the inorganic base is any one of sodium carbonate, potassium carbonate, sodium bicarbonate, sodium hydroxide or potassium hydroxide; further preferably, the inorganic base is potassium carbonate.

The phase-transfer catalyst is any one of tetrabutylammonium bromide (TBAB), triethylbenzylammonium chloride (TEBAC), polyethylene glycol 400, polyethylene glycol 600 or polyethylene glycol 800; further preferably, the phase transfer catalyst is tetrabutylammonium bromide (TBAB).

The methylating agent is dimethyl carbonate.

The 5-halogenated o-vanillin: inorganic base: phase transfer catalyst: the molar ratio of methylating agent is 1.0: 1.0-5.0: 0.1 to 1.0: 2.0 to 10; further preferably, the molar ratio is 1.0: 2.0: 0.5: 10.

the reaction may use a single organic solvent such as tetrahydrofuran, dichloromethane, chloroform or 1, 2-dichloroethane. It is preferable that the reaction is carried out without using an additional organic solvent and is carried out smoothly only by dispersing in the methylating agent.

Preferably, the reaction temperature of the methylation reaction is 50-120 ℃; the reaction time is 12-48 h.

Further preferably, the reaction temperature of the methylation reaction is 100-110 ℃, and is optimally selected to be 110 ℃; the reaction time is 23-25 h, and 24h is optimal.

The invention has the beneficial effects that:

the method has the advantages of easily available raw materials, mild reaction conditions, simple and convenient operation, high chemical yield and low cost, and is suitable for industrial production.

The synthesis method of 5-halogenated o-veratraldehyde adopts 4-halogenated guaiacol as a raw material, and overcomes the problems of limited source and low productivity of o-vanillin.

The synthesis method of the 5-halogenated o-veratraldehyde does not adopt the synthesis principle of the reaction of o-vanillin and dimethyl sulfate, and can achieve good catalytic effect without using dimethyl sulfate or even additional organic solvent in the methylation reaction, thereby avoiding toxic and harmful raw materials and reducing the labor protection cost.

According to the synthesis method of the 5-halogenated veratraldehyde, the used other raw materials explain common and easily-obtained raw materials, and through optimization of a reaction program, the reaction condition is mild, the operation is simple and convenient, the chemical yield is high, the cost is low, and the synthesis method is very suitable for industrial production.

Detailed Description

In order to better explain the problems to be solved, the technical solutions adopted and the beneficial effects achieved by the technical solutions of the present invention, further description will be given with reference to specific embodiments. It should be noted that the technical solutions of the present invention include, but are not limited to, the following embodiments.

The specific techniques or conditions not specified in the examples of the present invention are performed according to the techniques or conditions described in the literature in the art or according to the product specification. The reagents or instruments used are not indicated by manufacturers, and are all conventional products which can be obtained by commercial purchase and the like.

EXAMPLE 14 preparation of bromoguaiacol

Guaiacol (25g, 201mmol) was uniformly dispersed in 125mL of chloroform under the protection of argon, and the reaction mixture was pre-cooled at-5 ℃ for 10 minutes, and then a solution of bromine (10.3mL, 201mmol) in chloroform (75mL) was slowly added dropwise to the mixture to maintain the system as colorless as possible. After the dripping is finished, the reaction is moved to room temperature for 1 hour, and the reaction is detected by a TLC point plate. Using 150mL Sat. NaHSO₃(aq) quench reaction, separate in separatory funnel, aqueous layer extract 3 times with chloroform, combine organic phases, after washing once with saturated brine, dry with anhydrous sodium sulfate and spin dry to get light yellow crystal crude product. Distilling under reduced pressure (97-100 deg.C/2 mmHg, Lit.119-120 deg.C/5 mmHg) to obtain 4-bromoguaiacol (40g, 94%, mp: 31-32 deg.C).

¹H NMR(400MHz,Chloroform-d)δ6.99(dd,J＝8.4,2.0Hz,1H),6.96(d,J＝2.0Hz,1H),6.80(d,J＝8.4Hz,1H),5.59(s,1H),3.87(s,3H).

EXAMPLE 22 preparation of hydroxy-3-methoxy-5-bromomandelic acid

4-Bromoguaiacol (2g, 9.8mmol) was gradually added dropwise to a solution of sodium hydroxide (692mg, 17.3mmol) in water (12mL) under ice bath, to which was gradually added aluminum oxide powder (441.3mg, 4.33 mmol). After stirring for 5 minutes in an ice bath, an aqueous glyoxylic acid solution (50% by weight in H) was slowly added dropwise thereto₂O, 1.54g, 10.4mmol), the pH value of the reaction solution is 9-10. Then, the reaction mixture was transferred to an oil bath at 60 ℃ for 6 hours, and the reaction was monitored by TLC. After the reaction liquid is cooled to room temperature, the alumina powder is removed by suction filtration, and a small amount of 20% sodium hydroxide is used for washing a filter cake. Collecting filtrate, adjusting pH of the filtrate to 3-4 with concentrated hydrochloric acid, extracting water layer with toluene for 4 times, mixing organic phases, drying with anhydrous sodium sulfate, and spin-drying to recover 4-bromoguaiacol (741mg, conversion rate 63%). The aqueous layer was then further adjusted to pH 1 with concentrated HCl, the aqueous layer was extracted 5 times with EA, the combined organic phases were dried over anhydrous sodium sulfate and spin dried, and the yellow solid product, 2-hydroxy-3-methoxy-5-bromomandelic acid (1.3g, 75%, decomp) was collected.>200℃)。

¹H NMR(400MHz,DMSO-d₆)δ12.44(br s,1H),9.11(br s,1H),7.05(d,J＝2.0Hz,1H),7.01(d,J＝2.0Hz,1H),5.80(br s,1H),5.25(s,1H),3.81(s,3H)。LC-MS(ESI)m/z calcd for[C₉H₈BrO₅]^-276.0,found 276.0

Example preparation of 32-hydroxy-3-methoxy-5-bromobenzaldehyde

Fully and uniformly mixing 25mL of aqueous solution of a crude product (5g, 18mmol) of 2-hydroxy-3-methoxy-5-bromomandelic acid with 100mL of toluene at room temperature, moving the mixture to a 90 ℃ oil bath for heating, slowly adding 20% of ferric trichloride aqueous solution (22mL,27mmol) into a reaction system, continuing to heat the mixture for reaction for 4 hours at the 90 ℃ oil bath after dripping is finished, and monitoring the reaction by TLC. Cooling the reaction solution to room temperature, adding appropriate amount of toluene to dilute the reaction solution, extracting the reaction solution with toluene in a separating funnel for 4 times, combining organic phases, washing the organic phases with water, washing with saturated salt solution, and washing with anhydrous Na₂SO₄After drying, spin-drying to obtain a pale yellow solid, 2-hydroxy-3-methoxy-5-bromobenzaldehyde (2.4g, 85%, mp ═ 115 ℃ C.). The pH value of the water layer is continuously adjusted to 1 by concentrated hydrochloric acid, the water layer is extracted for 5 times by EA, the organic phases are combined and dried by anhydrous sodium sulfate, and then the 2-hydroxy-3-methoxy-5-bromomandelic acid (1.5g, the conversion rate is 70%) is recovered.

¹H NMR(400MHz,Chloroform-d)δ11.04(s,1H),9.85(s,1H),7.32(d,J＝2.0Hz,1H),7.18(d,J＝2.0Hz,1H),3.92(s,3H).。

Example preparation of 42, 3-dimethoxy-5-bromobenzaldehyde

2-hydroxy-3-methoxy-5-bromobenzaldehyde (4g, 17.3mmol), 24.6mL of dimethyl carbonate, tetrabutylammonium bromide (2.64g, 8.2mmol) and potassium carbonate (4.8g, 34.6mmol) were added in this order to disperse uniformly at room temperature, then the temperature was raised to 110 ℃ for 12 hours, and the reaction was monitored by TLC. Adding appropriate amount of water into the reaction system, extracting with diethyl ether in a separating funnel for 3 times, mixing organic phases, washing the organic phase with water and saturated salt solution respectively once, and passing through anhydrous Na₂SO₄Drying and spin-drying to obtain a brownish red solid crude product of 2, 3-dimethoxy-5-bromobenzaldehyde (4.038g, 98%, mp ═ 77-78 ℃).

¹H NMR(400MHz,Chloroform-d)δ10.34(s,1H),7.53(d,J＝2.0Hz,1H),7.23(d,J＝2.0Hz,1H),3.97(s,3H),3.91(s,3H)。

EXAMPLE 54 preparation of chloroguaiacol

Guaiacol (12.4g, 100mmol) was dispersed uniformly in 50mL chloroform under argon protection in a cold salt bath (-5 deg.C) and sulfuryl chloride (13mL, 160mmol) was slowly added dropwise thereto. After the dripping is finished, the mixture is moved to 60 ℃ for reflux reaction for 24 hours, and the reaction is monitored by a TLC point plate. Under ice bath, 50mL Sat. Na is used₂S₂O₃The solution was quenched, separated in a separatory funnel, the aqueous layer was extracted 3 times with chloroform, the organic phases were combined, back washed once with saturated brine, dried over anhydrous sodium sulfate and spin dried to give 16.7g of crude brown yellow liquid. Reduced pressure distillation (82-90 deg.C/2 mmHg, lit.130 deg.C/7.5 mmHg) gave 4-chloroguaiacol as a pale yellow oily liquid (12.7g, 80%) with a content of 87% (GC-MS).

¹H NMR(400MHz,Chloroform-d)δ6.84(s,3H),5.61(s,1H),3.86(s,3H).

EXAMPLE 62 preparation of hydroxy-3-methoxy-5-chloromandelic acid

4-chloroguaiacol (10g, 63mmol) was gradually added dropwise to a 75mL aqueous solution containing sodium hydroxide (4.1g, 102mmol) under ice-cooling, and then alumina powder (2.57g, 25.2mmol) was gradually added thereto. After stirring for 5 minutes in an ice bath, an aqueous glyoxylic acid solution (50% by weight in H) was slowly added dropwise thereto₂O, 8.5g, 57mmol), the pH of the reaction solution is 9-10. Then, the reaction mixture was transferred to an oil bath at 60 ℃ for 6 hours, and the reaction was monitored by TLC. After the reaction liquid is cooled to room temperature, the alumina powder is removed by suction filtration, and a small amount of 20% sodium hydroxide is used for washing a filter cake. Collecting filtrate, adjusting pH of the filtrate to 3-4 with concentrated hydrochloric acid, extracting water layer with toluene for 4 times, mixing organic phases, drying with anhydrous sodium sulfate, and spin-drying to recover 4-chloroguaiacol (4.9g, conversion rate 51%). The aqueous layer was then further adjusted to pH 1 with concentrated hydrochloric acid, the aqueous layer was extracted 5 times with EA, the combined organic phases were dried over anhydrous sodium sulfate and then spin-dried, and the yellow solid product, 2-hydroxy-3-methoxy-5-chloromandelic acid (5.7g, 86%, mp ═ 123-.

¹H NMR(400MHz,DMSO-d₆)δ6.94(d,J＝2.5Hz,1H),6.87(d,J＝2.5Hz,1H),5.25(s,1H),3.81(s,3H).LC-MS(ESI)m/z calcd for[C₉H₈ClO₅]^-231.6,found 231.6

Example 72 preparation of hydroxy-3-methoxy-5-chlorobenzaldehyde

Fully and uniformly mixing 25mL of aqueous solution of 2-hydroxy-3-methoxy-5-chloromandelic acid crude product (5g, 21.5mmol) and 100mL of toluene at room temperature, moving the mixture to a 90 ℃ oil bath for heating, slowly adding 20% ferric trichloride aqueous solution (26mL,32.2mmol) into the reaction system, continuing to heat the mixture in the 90 ℃ oil bath for 4 hours after dripping is finished, and monitoring the reaction by TLC. Cooling the reaction solution to room temperature, adding appropriate amount of toluene to dilute the reaction solution, extracting the reaction solution with toluene in a separating funnel for 4 times, combining organic phases, washing the organic phases with water and saturated salt solution respectively, and washing with anhydrous Na₂SO₄After drying, the crude product was obtained as a pale green solid (2.4g, 86%, mp 92-96 ℃) and 82% (GC-MS) of 2-hydroxy-3-methoxy-5-chlorobenzaldehyde. The pH value of the water layer is continuously adjusted to 1 by concentrated hydrochloric acid, the water layer is extracted for 5 times by EA, the organic phases are combined and dried by anhydrous sodium sulfate and then are spin-dried, and the raw material 2-hydroxy-3-methoxyl-5-chloromandelic acid (1.5g, the conversion rate is 70%) is recovered.

¹H NMR(400MHz,Chloroform-d)δ10.97(s,1H),9.86(s,1H),7.17(d,J＝2.4Hz,1H),7.05(d,J＝2.4Hz,1H),3.92(s,3H).

Example 82 preparation of 3, 3-dimethoxy-5-chlorobenzaldehyde

2-hydroxy-3-methoxy-5-chlorobenzaldehyde (2.3g, 12.3mmol), 17.5mL dimethyl carbonate, tetrabutylammonium bromide (1.88g, 5.83mmol) and potassium carbonate (3.41g, 24.6mmol) were added in this order to disperse uniformly at room temperature, then the temperature was raised to 110 ℃ for 12 hours, and the reaction was monitored by TLC. Adding appropriate amount of water into the reaction system, extracting with diethyl ether in a separating funnel for 3 times, mixing organic phases, washing the organic phase with water and saturated salt solution once respectively, and passing through anhydrous Na₂SO₄After drying, spin-drying to give a brown solid crude 2, 3-dimethoxy-5-chlorobenzaldehyde (2.3g, 95%, mp ═ 80-84 ℃ C.), with a content of 96% (HPLC).

¹H NMR(400MHz,Chloroform-d)δ10.36(s,1H),7.38(d,J＝2.4Hz,1H),7.09(d,J＝2.4Hz,1H),3.97(s,3H),3.91(s,3H).

Example 93 preparation of 4-Dihydroxymandelic acid 3

To an aqueous solution (240mL) of sodium hydroxide (17.6g, 441mmol) was gradually added catechol (30g, 272mmol) under ice-bath, and the mixture was stirred until completely dissolved. Then, alkaline alumina (11g) was added thereto, and after stirring uniformly, the mixture was transferred to a 60 ℃ oil bath to be preheated. An aqueous solution of glyoxylic acid (50% by weight, 36.7g) was gradually added dropwise thereto under heating at 60 ℃ and the reaction was continued for 12 hours under heating at 60 ℃ after the addition was completed, and the reaction was monitored by TLC. Adjusting the pH of the reaction solution to 3-4 with concentrated hydrochloric acid, extracting the water layer with methyl tert-butyl ether, drying with anhydrous sodium sulfate, spin-drying, recovering 7.8g of raw material, and converting 55%. The pH of the aqueous phase was adjusted to 1 with concentrated hydrochloric acid, and the aqueous layer was extracted with ethyl acetate, dried over anhydrous sodium sulfate and then spin-dried to obtain a crude product (26.6g, 70%, m.p.: 119-propanoid 121 ℃ C.) as a light brown solid. The crude product was directly subjected to the next reaction without purification.

¹H NMR(400MHz,DMSO-d₆)δ12.36(s,1H),8.89(s,1H),8.81(s,1H),6.80(d,J＝1.6Hz,1H),6.66(s,1H),6.65(d,J＝1.6Hz,1H),5.55(s,1H),4.80(s,1H).

Example 103 preparation of 4, 4-dihydroxybenzaldehyde 4

The crude 3, 4-dihydroxymandelic acid (2g, 10.8mmol) and copper chloride dihydrate (1.8g, 10.86mmol) were dispersed homogeneously in water (28mL) at room temperature, after which the reaction was monitored by TLC after moving to 90 ℃ under reflux with 3 oxygen changes. The reaction solution was filtered through celite, the filter cake was washed with EA, and the filtrate was collected. The filtrate was extracted 4 times with EA and the organic phases were combined. Then washed with water and saturated brine once respectively, dried by anhydrous sodium sulfate and dried to obtain the crude product of the 3, 4-dihydroxy aldehyde (756mg, 54%, m.p.: 142 ℃ C.) at 145 ℃). The crude product is directly subjected to the next reaction without purification.

¹H NMR(400MHz,DMSO-d₆)δ10.11(s,1H),9.69(s,1H),9.55(s,1H),7.27(dd,J＝8.0,2.0Hz,1H),7.23(d,J＝2.0Hz,1H),6.90(d,J＝8.0Hz,1H).

EXAMPLE 11 preparation of piperonal 5

After dispersing crude 3, 4-dihydroxyaldehyde (2g, 14.5mmol) in methylene chloride (40mL) at room temperature in a reaction kettle, tetrabutylammonium bromide (2.33g, 7.2mmol) and sodium hydroxide (1.2g, 29.0mmol) are added in this order and dispersed uniformly. Then, the reaction kettle is heated to 80 ℃, the temperature is kept for reaction for 12 hours, and the reaction is monitored by TLC. The reaction solution was filtered through celite, and the filtrate was collected and dichloromethane was removed by rotation. Redissolving the residue with methyl tert-butyl ether and water, extracting the aqueous layer with methyl tert-butyl ether for 3 times, combining the organic phases, washing the organic phase with water and saturated brine for 1 time, drying over anhydrous sodium sulfate, and spin-drying to obtain a crude product of piperonal (2g, 90%). The crude product is directly subjected to the next reaction without purification.

¹H NMR(400MHz,Chloroform-d)δ9.80(s,1H),7.40(dd,J＝8.0 1.6Hz,1H),7.32(d,J＝1.6Hz,1H),6.92(d,J＝8.0Hz,1H),6.07(s,2H).

EXAMPLE 12 preparation of beta-nitro-3, 4-dioxomethylstyrene 6

Piperonal (10g, 66.6mmol) was dissolved in MeOH (150mL) at room temperature, to which CH was added₃NO₂(13.1mL, 241.2mmol) until dispersed uniformly. Then the reaction solution is transferred to 0 ℃ for precooling, and 1M NaOH (240mL) solution is dripped at 0 ℃ to obtain a light yellow clear reaction solution. After the dripping is finished, the reaction is carried out for 2h at the temperature of 0 ℃, and the reaction is detected by a TLC point plate. The reaction solution was slowly added dropwise to 6M HCl (400mL) solution at 0 deg.C to instantly yield yellow insoluble solid, and stirring was continued for 15min after the addition. And carrying out suction filtration on the post reaction liquid, and washing the filter cake for 3 times by using a small amount of water to obtain a bright yellow filter cake. The filter cake was dried in a vacuum oven to obtain crude β -nitro-3, 4-dioxytoluylene styrene (10.5g, 80%, mp 159-. The crude product can be directly subjected to the next reaction without purification.

¹H NMR(600MHz,Chloroform-d)δ7.93(d,J＝13.2Hz,1H),7.48(d,J＝13.2Hz,1H),7.09(dd,J＝7.8,1.8Hz,1H),7.00(d,J＝1.8Hz,1H),6.88(d,J＝8.0Hz,1H),6.07(s,2H).

EXAMPLE 13 preparation of Homopiperony lamine

Baking the reaction system for 3 times, pumping out argon for 3 times, and introducing NaBH at 0 DEG C₄(1.86g, 49.2mmol) of tetrahydrofuran dispersion was gradually added dropwise with BF₃·Et₂O complex (8mL, 62.1mmol), and stirring at room temperature for 15 minutes was completed after dropwise addition. Then, a tetrahydrofuran solution of beta-nitro-3, 4-dioxytoluylene (2g, 10.3mmol) was slowly dropped thereinto to obtain a reaction solutionIt was yellow and turbid. The reaction was then transferred to a 70 ℃ oil bath and refluxed for 5 hours, and the reaction was checked by TLC spot plate. After the reaction solution was cooled to room temperature, 160mL of ice water and 160mL of 1M HCl solution were slowly added to the reaction system, and the mixture was stirred and refluxed at 80 ℃ for 2 hours. After removal of tetrahydrofuran under reduced pressure, the aqueous phase was extracted 3 times with diethyl ether and collected. The pH of the aqueous phase was adjusted to 12 with 20% NaOH solution, a small amount of NaCl solid was added, the aqueous layer was extracted with ether 3 times, the organic layers were combined, dried over anhydrous sodium sulfate and spin dried to give a crude pale yellow oil (1.371g, 80%) with 87% content (GC-MS).

¹H NMR(400MHz,Chloroform-d)δ6.74(d,J＝8.0Hz,1H),6.69(d,J＝1.6Hz,1H),6.64(dd,J＝8.0,1.6Hz,1H),5.93(s,2H),2.91(t,J＝6.8Hz,2H),2.66(t,J＝6.8Hz,2H).。

EXAMPLE 142 preparation of 3, 4-Dioxyphenyl-N- (5-bromo-2, 3-dimethoxybenzyl) ethylamine

Under the protection of argon, 15g of a 4A molecular sieve is placed in a reactor, a reaction system is roasted for 3 times, then 80mL of dichloromethane solution of piperonylethylamine (5g, 30.2mmol) and 80mL of dichloromethane solution of 5-bromo-o-veratraldehyde (7.3g, 30mmol) are injected into the reaction system in sequence and mixed uniformly, the reaction solution is brownish yellow turbid, the reaction is carried out at room temperature for 16 hours, and the reaction is detected by TLC point plate. The 4A molecular sieve was removed by filtration through celite, the filter cake was washed with a small amount of dichloromethane, and the filtrate was collected and the solvent was removed by rotary removal under reduced pressure to give 11.7g of the imine intermediate. The crude imine intermediate was redissolved in methanol-dichloromethane (100mL, v: v ═ 1:1) under argon, and the reaction was then transferred to 0 ℃ with a 10 min pre-cool. Sodium borohydride (1.7g, 45mmol) was added thereto in portions, the reaction turned from brown to light yellow and clarified, the reaction was stirred at 0 ℃ for further 30min, and the reaction was monitored by TLC spot plates. Adding Sat. NH into the reaction system₄And (3) quenching the reaction by using a Cl solution, performing decompression and rotary removal on excessive methanol and dichloromethane solvent, re-dissolving the residue by using ether, extracting the residue by using water/ether for 3 times, combining organic phases, performing back washing on the organic phases by using saturated saline solution for one time, drying the organic phases by using anhydrous sodium sulfate, and performing rotary drying to obtain a yellow oily crude product (12g and 99%) of the 2- (3, 4-dioxyphenyl) -N- (5-bromo-2, 3-dimethoxybenzyl) ethylamine.

¹H NMR(400MHz,Chloroform-d)δ7.00(d,J＝2.0Hz,1H),6.93(d,J＝2.0Hz,1H),6.73(d,J＝7.6Hz,1H),6.69(s,1H),6.64(d,J＝7.6Hz,1H),5.92(s,2H),3.84(s,3H),3.76(s,5H),2.80(t,J＝6.4Hz,2H),2.72(t,J＝6.4Hz,2H).

¹³C NMR(100MHz,Chloroform-d)δ153.26,147.67,146.41,145.91,135.63,133.77,124.25,121.57,116.32,114.74,109.11,108.25,100.83,60.72,56.00,50.60,48.16,36.09.

HRMS(ESI)m/z calcd for C₁₈H₂₁BrNO₄[M+H]⁺:394.0648,found:394.0646.

EXAMPLE 152 preparation of (3, 4-Dioxyphenyl) -N- (5-bromo-2, 3-dimethoxybenzyl) ethylamine hydrochloride

Crude 2- (3, 4-dioxyphenylen) -N- (5-bromo-2, 3-dimethoxybenzyl) ethylamine (12g, 30mmol) was dissolved in diethyl ether and transferred to a-20 ℃ freezer overnight, insoluble material was removed by filtration and the filtrate was collected. Transferring the filtrate into-20 deg.C, stirring, pre-cooling for 10 min, and slowly adding HCl and Et dropwise into the system₂O (20mL, 3mol/L), an off-white solid gradually precipitated from the solution. After dripping is finished, stirring is continued for 2 hours at the temperature of minus 20 ℃ until salt forming is complete. The reaction mixture was filtered, the filter cake was washed with a small amount of glacial ethyl ether and dried under an infrared lamp to give 2- (3, 4-dioxyphenyl) -N- (5-bromo-2, 3-dimethoxybenzyl) ethylamine hydrochloride (11.7g, 90%, mp ═ 168-.

¹H NMR(400MHz,DMSO-d₆)δ9.03(s,2H),7.35(d,J＝2.0Hz,1H),7.32(d,J＝2.0Hz,1H),6.87(d,J＝7.8Hz,2H),6.71(d,J＝8.6Hz,1H),5.99(s,2H),4.12(s,2H),3.85(s,3H),3.79(s,3H),3.15–3.06(m,2H),2.92–2.83(m,2H).

¹³C NMR(100MHz,Chloroform-d)δ153.02,147.88,147.21,146.61,130.22,125.82,125.25,122.00,117.35,116.59,109.27,108.53,101.03,61.37,56.07,47.75,44.51,31.99.

HRMS(ESI)m/z calcd for C₁₈H₂₁BrNO₄[M-Cl]⁺:394.0648,found:394.0649.

EXAMPLE 162 preparation of (3, 4-Dioxyphenyl) -N- (5-chloro-2, 3-dimethoxybenzyl) ethylamine

Under the protection of argon, 8.6g of 4A molecular sieve is placed in a reactor, a reaction system is roasted for 3 times, then 80mL of dichloromethane solution of piperonylethylamine (2.8g, 17.4mmol) and 80mL of dichloromethane solution of 5-bromo-o-veratraldehyde (3.5g, 17.4mmol) are injected into the reaction system in sequence and mixed uniformly, a reaction solution is brownish yellow turbid, the reaction is carried out at room temperature for 16 hours, and the reaction is detected by TLC point plates. The 4A molecular sieve was removed by filtration through celite, the filter cake was washed with a small amount of dichloromethane, and the filtrate was collected and the solvent was removed by rotary removal under reduced pressure to give 7.6g of the imine intermediate. The crude imine intermediate was redissolved in methanol-dichloromethane (75mL, v: v ═ 1:1) under argon, after which the reaction was transferred to 0 ℃ for 10 min with precooling. Sodium borohydride (1.25g, 33mmol) was added thereto in portions, the reaction turned from brown to light yellow and clarified, the reaction was stirred at 0 ℃ for further 30min, and the reaction was monitored by TLC plates. Adding Sat. NH into the reaction system₄The reaction was quenched with Cl solution, excess methanol and dichloromethane solvent were removed by rotary evaporation under reduced pressure, the residue was redissolved with ether, extracted with water/ether for 3 times, the organic phases were combined, and the organic phase was back washed with saturated brine, dried over anhydrous sodium sulfate and then dried by rotary evaporation to give a yellow oil, crude 2- (3, 4-dialkoxyphenyl) -N- (5-chloro-2, 3-dimethoxybenzyl) ethylamine (5.9g, 98%).

¹H NMR(400MHz,Chloroform-d)δ6.85(d,J＝2.4Hz,1H),6.79(d,J＝2.4Hz,1H),6.72(d,J＝8.0Hz,1H),6.68(d,J＝1.6Hz,1H),6.63(dd,J＝8.0,1.6Hz,1H),5.90(s,2H),3.82(s,3H),3.75(s,5H),2.81(t,J＝6.8Hz,2H),2.72(t,J＝6.8Hz,2H).

¹³C NMR(100MHz,Chloroform-d)δ153.15,147.72,145.96,135.33,133.88,128.83,121.59,121.25,111.93,109.14,108.27,100.84,60.78,56.01,50.68,48.28,36.19.

HRMS(ESI)m/z calcd for C₁₈H₂₁ClNO₄[M+H]⁺:350.1154,found:354.1156.

EXAMPLE 172 preparation of (3, 4-Dioxyphenyl) -N- (5-chloro-2, 3-dimethoxybenzyl) ethylamine hydrochloride

2- (3, 4-dioxy phenyl) -N- (5-chloro-2, 3-dimethoxy benzyl)Crude (5.9g, 17.4mmol) ethylamine was dissolved in diethyl ether and transferred to a-20 ℃ freezer overnight, insoluble material was removed by filtration and the filtrate collected. Transferring the filtrate into a system with the temperature of minus 20 ℃, stirring and precooling for 10 minutes, and slowly dripping HCl & Et into the system₂O (11mL, 3mol/L), an off-white solid gradually precipitated from the solution. After dripping is finished, stirring is continued for 2 hours at the temperature of minus 20 ℃ until salt forming is complete. The reaction mixture was filtered by suction, the filter cake was washed with a small amount of glacial ethyl ether and dried under an infrared lamp to give 2- (3, 4-dioxyphenyl) -N- (5-chloro-2, 3-dimethoxybenzyl) ethylamine hydrochloride (6.1g, 92%, mp 159 ℃ C.).

¹H NMR(400MHz,Chloroform-d)δ9.86(s,2H),7.28(d,J＝2.4Hz,1H),6.85(d,J＝2.4Hz,1H),6.74–6.67(m,1H),6.67–6.62(m,2H),5.90(s,2H),4.17(s,2H),3.88(s,3H),3.81(s,3H),3.14–3.06(m,2H),3.06–2.96(m,2H).

HRMS(ESI)m/z calcd for C₁₈H₂₁ClNO₄[M-Cl]⁺:350.1154,found:354.1158.

The reaction sequence for examples 18-24 is as follows:

EXAMPLE 18 preparation of Compound 5b1

25g of anhydrous magnesium sulfate and an aqueous glyoxal dimethylacetal solution (60 wt.% in water, 5.35mL, 34.8mmol) were placed in a reaction vessel, uniformly dispersed with 25mL of dried methylene chloride, and dehydrated by oil bath at 50 ℃ for 1 hour. Then 2- (3, 4-dioxyphenyl) -N- (5-bromo-2, 3-dimethoxybenzyl) ethylamine hydrochloride (1g,2.32mmol) was added at room temperature until dispersed uniformly, and then the mixture was stirred at-5 ℃ for precooling for 5 minutes. Then, anhydrous formic acid (3.5mL,92.8mmol) was slowly added dropwise to the reaction system, and after completion of the addition, the reaction system was transferred to an oil bath at 50 ℃ for 12 hours, and the reaction was monitored by TLC plates. The reaction solution was filtered through celite, anhydrous magnesium sulfate solid was filtered off, and the filter cake was washed with a small amount of dichloromethane. NaHCO is used for filtrate₃Adjusting pH of the solution to 8-9, separating in a separating funnel, extracting water phase with dichloromethane for 3 times, mixing organic phases, and collecting organic phaseThe phases were back-washed once more with saturated brine, dried over anhydrous sodium sulfate and spin-dried to give crude 5b1 as a yellow oil (811mg, 73%).

¹H NMR(400MHz,Chloroform-d)δ7.33(d,J＝2.4Hz,1H),6.93(d,J＝2.4Hz,1H),6.77(s,1H),6.57(s,1H),5.90(d,J＝4.4Hz,2H),4.38(d,J＝5.2Hz,1H),3.84(s,3H),3.75(d,J＝6.5Hz,2H),3.71(s,3H),3.62(d,J＝5.2Hz,1H),3.37(s,3H),3.34(s,3H),3.30–3.21(m,1H),2.93–2.75(m,2H),2.55–2.48(m,1H).

¹³C NMR(100MHz,Chloroform-d)δ153.38,146.80,146.34,145.40,135.22,128.90,126.31,124.89,116.51,114.40,109.91,108.27,108.06,100.63,62.78,60.84,56.74,56.05,54.20,51.84,45.06,24.88.

HRMS(ESI)m/z calcd for C₂₂H₂₇BrNO₆[M+H]⁺:480.1016,found:480.1020.

EXAMPLE 19 preparation of Compound 5b2

2- (3, 4-Dioxyphenyl) -N- (5-bromo-2, 3-dimethoxybenzyl) ethylamine hydrochloride (1g,2.32mmol) and 4g of anhydrous magnesium sulfate were dispersed with 10mL of dry dichloromethane under an argon atmosphere, and then a solution of glyoxal neopentyl glycol acetal (1g,6.96mmol) in 15mL of dichloromethane was injected into the reaction system to disperse uniformly. The reaction mixture was then transferred to-5 ℃ and pre-cooled for 10 minutes, to which anhydrous formic acid (1.2mL,30.8mmol) was slowly added dropwise. After the addition, the reaction solution was transferred to a 50 ℃ oil bath and refluxed for 12 hours, and the reaction was monitored by TLC spot plate. NaHCO for reaction liquid₃The solution was quenched and the pH was adjusted to 8-9, then placed in a separatory funnel for separation, the aqueous phase was extracted 3 times with DCM, the organic phases were combined, the organic phase was back washed once with saturated brine, dried over anhydrous sodium sulfate and spin dried to give crude 5b2 as an off-white solid (1.1g, 86%, mp ═ 48.5-50.0 ℃).

¹H NMR(400MHz,Chloroform-d)δ7.41(d,J＝2.4Hz,1H),6.93(d,J＝2.4Hz,1H),6.89(s,1H),6.57(s,1H),5.89(d,J＝3.0Hz,2H),4.68(d,J＝3.0Hz,1H),3.88–3.85(m,1H),3.84(s,3H),3.81–3.74(m,2H),3.70(s,3H),3.69–3.65(m,1H),3.57(dd,J＝10.8,3.0Hz,1H),3.44(d,J＝10.8Hz,1H),3.38(d,J＝10.8Hz,1H),3.32–3.25(m,1H),2.89–2.81(m,1H),2.80–2.72(m,1H),2.56–2.48(m,1H),1.11(s,3H),0.69(s,3H).

¹³C NMR(100MHz,Chloroform-d)δ153.31,146.66,146.19,145.31,135.32,128.80,126.16,124.73,116.63,114.37,109.66,108.26,104.46,100.58,64.04,60.78,56.04,52.08,45.35,30.23,25.43,23.15,21.87.

HRMS(ESI)m/z calcd for C₂₅H₃₁BrNO₆[M+H]⁺:520.1329,found:520.1326.

EXAMPLE 205 b1 preparation of 12-Bromodihydroberberine

0.1mL of concentrated sulfuric acid was slowly added dropwise to a 1.25mL solution of 5b1(200mg, 0.416mmol) in glacial acetic acid under argon protection in an ice bath. After the dripping is finished, stirring is continued for 10 minutes at the temperature of 0 ℃, then the reaction solution is moved to the room temperature for continuing the reaction for 11 hours, and the TLC point plate detects the reaction. Quenching the reaction solution by using sat sodium bicarbonate aqueous solution under ice bath, adding dichloromethane to dilute the reaction solution, extracting the reaction solution for 3 times by using dichloromethane in a separating funnel, combining organic phases, backwashing the organic phases once by using saturated saline solution, drying the organic phases by using anhydrous sodium sulfate, and then spin-drying the organic phases to obtain a yellow-brown foamy solid crude 12-bromodihydroberberine product (147mg, 85 percent, mp ═ 60.5-62.4 ℃).

¹H NMR(400MHz,Chloroform-d)δ7.24(s,1H),6.95(s,1H),6.57(s,1H),6.13(s,1H),5.95(s,2H),4.30(s,2H),3.82(s,3H),3.81(s,3H),3.13(t,J＝6.0Hz,2H),2.86(t,J＝6.0Hz,2H).

¹³C NMR(100MHz,Chloroform-d)δ150.33,147.76,146.87,143.90,143.50,129.10,127.70,124.31,123.26,115.36,112.93,107.91,104.26,101.22,94.97,60.83,56.18,49.51,48.86,29.76.

EXAMPLE 215 b2 preparation of 12-Bromodihydroberberine

0.1mL of concentrated sulfuric acid was slowly added dropwise to a 1.2mL solution of 5b1(200mg, 0.384mmol) in glacial acetic acid under argon protection in an ice bath. After the dripping is finished, stirring is continued for 10 minutes at the temperature of 0 ℃, then the reaction solution is moved to the room temperature for continuing the reaction for 11 hours, and the TLC point plate detects the reaction. Quenching the reaction solution by using sat sodium bicarbonate aqueous solution under ice bath, adding dichloromethane to dilute the reaction solution, extracting the reaction solution for 3 times by using dichloromethane in a separating funnel, combining organic phases, backwashing the organic phases once by using saturated saline solution, drying the organic phases by using anhydrous sodium sulfate, and then spin-drying the organic phases to obtain a yellow-brown foamy solid crude product of 12-bromodihydroberberine (136mg, 85 percent, mp ═ 60.0-62.2 ℃).

¹H NMR(400MHz,Chloroform-d)δ7.24(s,1H),6.95(s,1H),6.58(s,1H),6.14(s,1H),5.95(s,2H),4.30(s,2H),3.82(s,3H),3.81(s,3H),3.13(t,J＝6.0Hz,2H),2.86(t,J＝6.0Hz,2H).

¹³C NMR(100MHz,Chloroform-d)δ150.37,147.80,146.91,143.93,143.54,129.14,127.73,124.34,123.29,115.40,112.97,107.95,104.30,101.25,95.02,60.87,56.22,49.54,48.90,29.79.

Example 2212 preparation of Bromobberberine 7b

At room temperature, the crude 12-bromodihydroberberine (181mg,0.434mmol) was dispersed with 20mL of methanol to be uniform and not completely dissolved. Then, the reaction solution was left at room temperature and stirred for 48 hours. The reaction solution changed from bright yellow turbidity to orange yellow clarity and the reaction was monitored by TLC spot plate. Most of the methanol was removed from the reaction solution by rotation, and then the reaction solution was alkalified with 20% sodium hydroxide solution and stirred at room temperature for 5 minutes. Then the 12-bromoberberine hydroxide salt in the aqueous phase is extracted with dichloromethane 4 times, the organic phases are combined, the organic phase is extracted with 1M hydrochloric acid 2 times, the organic phase is extracted with warm pure water 4-5 times, the aqueous phases are combined and spin-dried to obtain 12-bromoberberine (185mg, 85%, mp 183.0 ℃) as a yellow solid.

¹H NMR(400MHz,DMSO-d₆)δ10.01(s,1H),8.53(s,1H),8.51(s,1H),7.94(s,1H),7.11(s,1H),6.19(s,2H),4.97(t,J＝6.0Hz,2H),4.15–4.06(m,6H),3.21(t,J＝6.0Hz,2H).

¹³C NMR(100MHz,DMSO-d₆)δ150.33,150.20,147.83,146.74,144.02,138.85,131.26,131.14,129.97,121.95,120.03,118.48,115.01,108.42,105.94,102.17,62.12,57.62,55.28,26.23.

HRMS(ESI)m/z calcd for C₂₀H₁₇BrNO₄[M-Cl]⁺:414.0335,found:414.0333.

EXAMPLE 23 preparation of Compound 5a1

25g of anhydrous magnesium sulfate and an aqueous glyoxal dimethylacetal solution (60 wt.% in water, 5.35mL, 35.5mmol) were placed in a reaction vessel, uniformly dispersed with dry 25mL of dichloromethane, and dehydrated by placing in an oil bath at 50 ℃ under heat for 1 hour. Then 2- (3, 4-dioxyphenyl) -N- (5-chloro-2, 3-dimethoxybenzyl) ethylamine hydrochloride (1g, 2.59mmol) was added at room temperature until dispersed uniformly, and then the mixture was stirred at-5 ℃ for precooling for 5 minutes. Then, anhydrous formic acid (3.5mL,92.8mmol) was slowly added dropwise to the reaction system, and after completion of the addition, the reaction system was transferred to an oil bath at 50 ℃ for 12 hours, and the reaction was monitored by TLC plates. The reaction solution was filtered through celite, anhydrous magnesium sulfate solid was filtered off, and the filter cake was washed with a small amount of dichloromethane. NaHCO is used for filtrate₃The solution was adjusted to pH 8-9, then placed in a separatory funnel for separation, the aqueous phase was extracted 3 times with dichloromethane, the organic phases were combined, the organic phase was back-washed once with saturated brine, dried over anhydrous sodium sulfate and spin-dried to give crude yellow oil 5a1(880mg, 78%).

¹H NMR(400MHz,Chloroform-d)δ7.17(d,J＝2.4Hz,1H),6.79(d,J＝2.4Hz,1H),6.77(s,1H),6.57(s,1H),5.89(dd,J＝5.6,1.6Hz,2H),4.38(d,J＝5.2Hz,1H),3.84(s,3H),3.76(d,J＝12.0Hz,2H),3.71(s,3H),3.63(d,J＝5.2Hz,1H),3.37(s,3H),3.34(s,3H),3.28–3.23(m,1H),2.91–2.76(m,2H),2.56–2.45(m,1H).

¹³C NMR(100MHz,Chloroform-d)δ153.23,146.35,146.30,145.41,134.76,128.98,128.93,126.35,121.81,111.56,109.93,108.28,108.06,100.64,62.84,60.92,56.76,56.03,54.16,51.93,45.04,24.90.

HRMS(ESI)m/z calcd for C₂₂H₂₇ClNO₆[M+H]⁺:436.1521,found:436.1527.

EXAMPLE 24 preparation of Compound 5a2

2- (3, 4-Dioxyphenyl) -N- (5-bromo-2, 3-dimethoxybenzyl) ethylamine hydrochloride (1g,2.58mmol) and 2g anhydrous magnesium sulfate were dispersed with 10mL of dry dichloromethane under an argon atmosphere, and then a solution of glyoxal neopentyl glycol acetal (1g,6.96mmol) in 15mL of dichloromethane was injected into the reaction system to disperse uniformly. Then the reaction solution is transferred to-5 ℃ for precooling for 10 minutes, and anhydrous formic acid is slowly dripped into the reaction solution(1.2mL,30.8 mmol). After the addition, the reaction solution was transferred to a 50 ℃ oil bath and refluxed for 12 hours, and the reaction was monitored by TLC spot plate. NaHCO for reaction liquid₃The solution quenched the reaction and adjusted the pH to 8-9, then placed in a separatory funnel for separation, the aqueous phase was extracted 3 times with DCM, the organic phases were combined, and the organic phase was back washed once with saturated brine, dried over anhydrous sodium sulfate and spin dried to give crude off-white gum 5a2(1.04g, 85%).

¹H NMR(400MHz,Chloroform-d)δ7.25(d,J＝2.4Hz,1H),6.89(s,1H),6.79(d,J＝2.4Hz,1H),6.57(s,1H),5.89(q,J＝1.6Hz,2H),4.68(d,J＝3.2Hz,1H),3.84(s,3H),3.81(d,J＝12.0Hz,2H),3.71(s,1H),3.71(s,3H),3.67(dd,J＝12.0,2.8Hz,1H),3.56(dd,J＝12.0,2.8Hz,1H),3.43(d,J＝12.0Hz,1H),3.38(d,J＝12.0Hz,1H),3.32–3.23(m,1H),2.90–2.80(m,1H),2.79–2.71(m,1H),2.52(dt,J＝16.0,4.0Hz,1H),1.10(s,3H),0.68(s,3H).

¹³C NMR(101MHz,Chloroform-d)δ153.16,146.19,146.15,145.31,134.88,129.05,128.84,126.20,121.68,111.51,109.64,108.27,104.52,100.58,77.54,77.13,64.10,60.86,56.01,52.19,45.33,30.23,25.48,23.12,21.86.

HRMS(ESI)m/z calcd for C₂₅H₃₁ClNO₆[M+H]⁺:476.1834,found:476.1832.

Example 2512 preparation of chloro Berberine

0.1mL of concentrated sulfuric acid was slowly added dropwise to a 1.25mL solution of glacial acetic acid (5 a, 0.45mmol) under an ice bath under argon atmosphere, and the mixture was poured into the reaction system. After the dripping is finished, stirring is continued for 10 minutes at the temperature of 0 ℃, then the reaction solution is moved to the room temperature for continuing the reaction for 11 hours, and the TLC point plate detects the reaction. Quenching the reaction solution by using sat sodium bicarbonate aqueous solution under ice bath, adding dichloromethane to dilute the reaction solution, extracting the reaction solution for 3 times by using dichloromethane in a separating funnel, combining organic phases, backwashing the organic phases once by using saturated saline solution, drying the organic phases by using anhydrous sodium sulfate, and then spin-drying the organic phases to obtain a yellow-brown foamy solid crude 12-chlorodihydroberberine product (154mg, 92%). Then, at room temperature, the crude 12-chlorodihydroberberine (154mg,0.414mmol) was dispersed with 20mL of methanol to be uniform and not completely dissolved. Then, the reaction solution was left at room temperature and stirred for reaction for 48 hours. The reaction solution changed from bright yellow turbidity to orange yellow clarity and the reaction was monitored by TLC spot plate. Most of the methanol was removed from the reaction solution by rotation, and then the reaction solution was alkalified with 20% sodium hydroxide solution and stirred at room temperature for 5 minutes. Then the 12-chloro berberine hydroxide salt in the aqueous phase is extracted with dichloromethane 4 times, the organic phases are combined, the organic phase is extracted with 1M hydrochloric acid 2 times, the organic phase is extracted with warm pure water 4-5 times, the aqueous phases are combined and spin-dried to obtain 12-chloro berberine (164mg, 98%, mp 188.0 ℃ Decomp) as a yellow solid.

¹H NMR(400MHz,DMSO-d₆)δ10.03(s,1H),8.62(s,1H),8.39(s,1H),7.99(s,1H),7.10(s,1H),6.18(s,2H),4.97(t,J＝6.2Hz,2H),4.10(s,6H),3.21(t,J＝6.3Hz,2H).

¹³C NMR(150MHz,DMSO-d₆)δ150.30,150.20,147.84,146.83,143.54,138.77,131.29,129.81,126.56,125.38,121.82,120.14,116.24,108.44,106.17,102.20,62.25,57.64,55.37,26.25.

HRMS(ESI)m/z calcd for C₂₀H₁₇ClNO₄[M-Cl]⁺:370.0841,found:370.0845.

Example 26 preparation of copper (II) -catalyzed 12-Bromobberberine

Under the protection of argon, glyoxal aqueous solution (40% wt, 1mL, 9mmol), anhydrous copper sulfate (1.1g, 6.96mmol) and sodium chloride (713mg, 12.2mmol) were dispersed uniformly with 6mL anhydrous formic acid, and then transferred into a 55 ℃ oil bath for heat preservation and dehydration for 30 minutes. 2- (3, 4-Dioxyphenyl) -N- (5-bromo-2, 3-dimethoxybenzyl) ethylamine hydrochloride (1.5g, 3.48mmol) was then added to the reaction and the temperature was gradually raised to 100 ℃ for 45 minutes. Concentrated hydrochloric acid (0.1mL, 1.2mmol) was added to the system every 45 minutes for a total of 5 additions. After the last addition of concentrated hydrochloric acid, the reaction was continued for 2 hours at 100 ℃ and monitored by TLC plate. The reaction was allowed to stand at room temperature and then transferred to a 4 ℃ refrigerator overnight. The reaction solution was filtered by suction and the filter cake was washed with a small amount of water. And drying the filter cake in the infrared, dispersing the filter cake in 3-4mL of water after drying, and preserving the heat at 85 ℃ for desalting for 4 hours. Then, the reaction solution was cooled to room temperature and transferred to a refrigerator at 4 ℃ overnight. The reaction solution is filtered again, and the filter cake is washed with a small amount of water. The filter cake is dried by exposure to infrared radiation, and after drying the filter cake is dispersed in water with 500mL of methanol and 9mL of water and heated at 75 ℃ under reflux. And calcium oxide powder is used for adjusting the pH value of the system to 8-9, and the reflux heating is continued at the temperature of 75 ℃ for 4 hours. Then, the mixture was filtered while hot, and the filter cake was washed with methanol. Collecting filtrate, removing excessive solvent, dispersing residue with 30mL water, transferring into 100 deg.C, reflux heating, adjusting pH to 1-2 with 30% HCl methanol solution, adding 150mg activated carbon powder into the reaction system, and reflux heating at 100 deg.C for 4 hr. Then filtered hot, the filter cake was washed with a small amount of water, the filtrate was collected and spin-dried to give 12-bromoberberine (1.1g, 73%, mp: 187.1 ℃ Decomp).

HRMS(ESI)m/z calcd for C₂₀H₁₇BrNO₄[M-Cl]⁺:414.0335,found:414.0333.

Example 27 preparation of iron (III) -catalyzed 12-Bromobberberine

Under the protection of argon, glyoxal aqueous solution (40% wt, 1mL, 9mmol), anhydrous ferric trichloride (1.1g, 6.96mmol) and sodium chloride (713mg, 12.2mmol) were dispersed uniformly with 6mL anhydrous formic acid, and then transferred into a 55 ℃ oil bath for heat preservation and dehydration for 30 minutes. 2- (3, 4-Dioxyphenyl) -N- (5-bromo-2, 3-dimethoxybenzyl) ethylamine hydrochloride (1.5g, 3.48mmol) was then added to the reaction and the reaction was incubated for 45 minutes with gradual warming to 100 ℃. Concentrated hydrochloric acid (0.1mL, 1.2mmol) was added to the system every 45 minutes for a total of 5 additions. After the last addition of concentrated hydrochloric acid, the reaction was continued for 2 hours at 100 ℃ and monitored by TLC plate. The reaction was allowed to stand at room temperature and then transferred to a 4 ℃ refrigerator overnight. The reaction solution was filtered by suction and the filter cake was washed with a small amount of water. And drying the filter cake in the infrared, dispersing the filter cake in 3-4mL of water after drying, and preserving the heat at 85 ℃ for desalting for 4 hours. Then the reaction solution is cooled to room temperature and moved to a refrigerator at 4 ℃ overnight. The reaction solution is filtered again, and the filter cake is washed with a small amount of water. The filter cake is dried by exposure to infrared radiation, and after drying the filter cake is dispersed in water with 500mL of methanol and 9mL of water and heated at 75 ℃ under reflux. And calcium oxide powder is used for adjusting the pH value of the system to 8-9, and the reflux heating is continued at 75 ℃ for 4 hours. Then, the mixture was filtered while hot, and the filter cake was washed with methanol. Collecting filtrate, removing excessive solvent, dispersing residue with 30mL water, transferring into 100 deg.C, reflux heating, adjusting pH to 1-2 with 30% HCl methanol solution, adding 150mg activated carbon powder into the reaction system, and reflux heating at 100 deg.C for 4 hr. Then filtered hot, the filter cake was washed with a small amount of water, the filtrate was collected and spin-dried to give 12-bromoberberine (1.3g, 83%, mp 183.0 ℃ Decomp). The structural identification was the same as in example 17 above.

Example 28 preparation of copper (II) -catalyzed 12-Chlorobetaine

Under the protection of argon, glyoxal aqueous solution (40% wt, 1.1mL, 10.1mmol), anhydrous copper sulfate (1.2g, 7.76mmol) and sodium chloride (794mg, 13.6mmol) were dispersed uniformly with 6mL anhydrous formic acid, and then transferred into a 55 ℃ oil bath to be dehydrated for 30 minutes under heat preservation. 2- (3, 4-Dioxyphenyl) -N- (5-chloro-2, 3-dimethoxybenzyl) ethylamine hydrochloride (1.5g, 3.88mmol) was then added to the reaction and the reaction was incubated for 45 minutes with gradual warming to 100 ℃. Concentrated hydrochloric acid (0.1mL, 1.2mmol) was added to the system every 45 minutes for a total of 5 additions. After the last addition of concentrated hydrochloric acid, the reaction was continued for 2 hours at 100 ℃ and monitored by TLC plate. The reaction was allowed to stand at room temperature and then transferred to a 4 ℃ refrigerator overnight. The reaction solution was filtered by suction and the filter cake was washed with a small amount of water. And drying the filter cake in the infrared, dispersing the filter cake in 3-4mL of water after drying, and preserving the heat at 85 ℃ for desalting for 4 hours. Then, the reaction solution was cooled to room temperature and transferred to a refrigerator at 4 ℃ overnight. The reaction solution is filtered again, and the filter cake is washed with a small amount of water. The filter cake is dried by exposure to infrared radiation, and after drying the filter cake is dispersed in water with 300mL of methanol and 6mL of water and heated at 75 ℃ under reflux. And calcium oxide powder is used for adjusting the pH value of the system to 8-9, and the reflux heating is continued at 75 ℃ for 4 hours. Then, the mixture was filtered while hot, and the filter cake was washed with methanol. Collecting filtrate, removing excessive solvent, dispersing residue with 20mL water, transferring into 100 deg.C, heating under reflux, adjusting pH to 1-2 with 30% HCl methanol solution, adding 150mg activated carbon powder into the reaction system, and heating under reflux at 100 deg.C for 4 hr. Then filtered hot, the filter cake was washed with a small amount of water, the filtrate was collected and spin dried to give 12-bromoberberine (1.3g, 83%, mp ═ 182.8 ℃ Decomp).

HRMS(ESI)m/z calcd for C₂₀H₁₇ClNO₄[M-Cl]⁺:370.0841,found:370.0845.

Example 29 preparation of iron (III) -catalyzed 12-Chlorobetaine

Under the protection of argon, glyoxal aqueous solution (40% wt, 0.764mL, 6.7mmol), anhydrous ferric trichloride (840mg, 5.2mmol) and sodium chloride (529mg, 9.1mmol) were dispersed uniformly with 4.5mL anhydrous formic acid, and then transferred into a 55 ℃ oil bath to be dehydrated for 30 minutes under heat preservation. 2- (3, 4-Dioxyphenyl) -N- (5-chloro-2, 3-dimethoxybenzyl) ethylamine hydrochloride (1g, 2.59mmol) was then added to the reaction and the reaction was incubated for 45 minutes with gradual warming to 100 ℃. Concentrated hydrochloric acid (69. mu.L, 0.8mmol) was added to the system every 45 minutes for a total of 5 times. After the last addition of concentrated hydrochloric acid, the reaction was continued for 2 hours at 100 ℃ and monitored by TLC plate. The reaction was allowed to stand at room temperature and then transferred to a 4 ℃ refrigerator overnight. The reaction solution was filtered by suction and the filter cake was washed with a small amount of water. And (3) drying the filter cake under infrared, dispersing the filter cake in 3-4mL of water after drying, and preserving heat at 85 ℃ for desalting for 4 hours. Then, the reaction solution was cooled to room temperature and transferred to a refrigerator at 4 ℃ overnight. The reaction solution is filtered again, and the filter cake is washed with a small amount of water. The filter cake is dried by exposure to infrared radiation, and after drying the filter cake is dispersed in water with 300mL of methanol and 6mL of water and heated at 75 ℃ under reflux. And calcium oxide powder is used for adjusting the pH value of the system to 8-9, and the reflux heating is continued at 75 ℃ for 4 hours. Then, the mixture was filtered while hot, and the filter cake was washed with methanol. Collecting filtrate, removing excessive solvent, dispersing residue with 20mL water, transferring into 100 deg.C, heating under reflux, adjusting pH to 1-2 with 30% HCl methanol solution, adding 150mg activated carbon powder into the reaction system, and heating under reflux at 100 deg.C for 4 hr. Then filtered hot, the filter cake was washed with a small amount of water, the filtrate was collected and spin-dried to give 12-bromoberberine (755mg, 72%, mp 188.0 ℃ decomp). The structural identification was the same as in example 17c above.

Example 30 method a transfer hydrogenation process preparation of berberine: preparation of berberine hydrochloride by dechlorinating 12-chloro berberine

12-chloro berberine hydrochloride (800mg, 1.97mmol), ammonium formate (658mg, 10.44mmol) and 10% palladium on carbon (160mg, 20% wt), respectively, were placed in a round bottom flask under argon and dispersed with 10mL 50% aqueous acetic acid, transferred to a 50 ℃ oil bath and heated for 24 hours and the reaction monitored by HPLC. The reaction solution was filtered through celite to remove 10% palladium on carbon, and the filter cake was washed with a small amount of methanol and dichloromethane, and the filtrate was collected. The pH of the filtrate was adjusted to 9-10 with saturated sodium carbonate solution in ice bath. The aqueous layer was then extracted 4 times with dichloromethane, the organic phases were combined and washed once with saturated brine and the dried crude berberine hydroxide salt (661mg, 95%) was dried over anhydrous sodium sulfate. Then the crude powder is dispersed in 10mL water at 100 ℃ and heated under reflux, the pH value of the solution is adjusted to 1 by 30 percent hydrochloric acid methanol solution, then 100mg of activated carbon powder is added, and the reflux heating at 100 ℃ is continued for 3 to 4 hours. Filtering while hot, washing the filter cake with a small amount of hot water, standing the filtrate at room temperature, and standing in a refrigerator at 4 ℃ overnight for crystallization. After sufficient crystallization, the mixture was filtered while cold and the filter cake was washed with a small amount of ice water. The filter cake was then dried under infrared to give yellow solid berberine (337mg, 46%, mp 203.2-204.8 ℃), content 92% (HPLC).

¹H NMR(400MHz,DMSO-d₆)δ9.92(s,1H),9.01(s,1H),8.21(d,J＝8.8Hz,1H),8.02(d,J＝8.8Hz,1H),7.82(s,1H),7.09(s,1H),6.17(s,2H),4.95(t,J＝6.4Hz,2H),4.09(s,3H),4.07(s,3H),3.20(t,J＝6.4Hz,2H).

¹³C NMR(100MHz,DMSO-d₆)δ150.37,149.79,147.66,145.44,143.67,137.45,132.99,130.65,126.74,123.52,121.39,120.42,120.20,108.41,105.43,102.07,61.93,57.08,55.18,26.33.

HRMS(ESI)m/z calcd for C₂₀H₁₈NO₄[M-Cl]⁺:336.1230,found:336.1226.

Example 31 method a transfer hydrogenation process preparation of berberine: preparation of berberine hydrochloride by dechlorinating 12-bromine berberine

12-Bromobifida hydrochloride (800mg, 1.77mmol), ammonium formate (593mg, 9.4mmol) and 10% palladium on carbon (160mg, 20% wt) were placed in a round bottom flask and dispersed with 10mL 50% aqueous acetic acid under argon, respectively, transferred to a 50 ℃ oil bath and heated for 24 hours and the reaction monitored by HPLC. The reaction solution was filtered through celite to remove 10% palladium on carbon, and the filter cake was washed with a small amount of methanol and dichloromethane, and the filtrate was collected. The pH of the filtrate was adjusted to 9-10 with saturated sodium carbonate solution in ice bath. The aqueous layer was then extracted 4 times with dichloromethane, the organic phases were combined and washed once with saturated brine and the dried crude berberine hydroxide salt (595mg, 95%) was dried over anhydrous sodium sulfate. Then the crude powder is dispersed in 10mL water at 100 ℃ and heated under reflux, the pH value of the solution is adjusted to 1 by 30 percent hydrochloric acid methanol solution, then 100mg of activated carbon powder is added, and the reflux heating at 100 ℃ is continued for 3 to 4 hours. Filtering while hot, washing the filter cake with a small amount of hot water, standing the filtrate at room temperature, and standing in a refrigerator at 4 ℃ overnight for crystallization. After sufficient crystallization, the mixture was filtered while cold and the filter cake was washed with a small amount of ice water. The filter cake was then dried under infrared to give berberine (340mg, 51%, mp ═ 204.3-205.2 ℃) as a yellow solid, which was 89% (HPLC). The structure was identified as in example 30 above.

Example 32 method B preparation of berberine by hydrogen hydrogenation: preparation of berberine hydrochloride by dechlorinating 12-chloro berberine

Compound 12-chloroberberine hydrochloride (100mg, 0.246mmol), 10% palladium on carbon (20mg, 20% wt), sodium bicarbonate (22.7mg, 0.27mmol) were dispersed uniformly in 10mL of methanol at room temperature, then the hydrogen gas was replaced with a hydrogen balloon 5 times and reacted at room temperature for 12 hours, and the reaction was monitored by TLC spot plate. The reaction solution was filtered through celite, most of the methanol was removed by rotation, and then the reaction solution was alkalified with 20% sodium hydroxide solution and stirred at room temperature for 5 minutes. Then extracting berberine hydroxide salt in the water phase with dichloromethane, extracting with dichloromethane for 4 times, combining organic phases, extracting the organic phase with 1M hydrochloric acid for 2 times, extracting the organic phase with warm pure water for 4-5 times, combining water phases, and spin-drying to obtain yellow solid berberine hydrochloride (83mg, 91%, mp 203.8-204.4 ℃) with the content of 95% (HPLC). The structure was identified as in example 30 above.

Example 33 method B preparation of berberine by hydrogen hydrogenation: preparation of berberine hydrochloride by dechlorinating 12-bromine berberine

Compound 12-bromoberberine hydrochloride (100mg, 0.202mmol), 10% palladium on carbon (20mg, 20% wt), sodium bicarbonate (18.7mg, 0.22mmol) was dispersed uniformly in 10mL of methanol at room temperature, then the hydrogen was replaced with a hydrogen balloon 5 times and reacted at room temperature for 12 hours, and the reaction was monitored by TLC spot plate. The reaction solution was filtered through celite, most of the methanol was removed by rotation, and then the reaction solution was alkalified with 20% sodium hydroxide solution and stirred at room temperature for 5 minutes. Then extracting berberine hydroxide salt in water phase with dichloromethane, extracting with dichloromethane for 4 times, mixing organic phases, extracting organic phase with 1M hydrochloric acid for 2 times, extracting organic phase with warm pure water for 4-5 times, mixing water phases, and spin drying to obtain yellow solid berberine hydrochloride (68mg, 91%, mp ═ 202.5-203.1 deg.C), with content of 91% (HPLC). The structure was identified as in example 30 above.

The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the present invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.

Claims

1. A synthetic method of berberine hydrochloride is characterized in that,

the synthesis method of the berberine hydrochloride comprises the following steps:

s4: the compound V of S3 is used to prepare 12-halogenated berberine derivative, i.e. compound II, which comprises:

s41 a: under the catalysis of protonic acid and the addition of a water removal agent, reacting the compound V described in S3 with glyoxal monoacetal in an organic solvent to obtain 6- (5-bromo-2, 3-dimethoxybenzyl) -5- (dimethoxymethyl) -5,6,7, 8-tetrahydro- [1,3] dioxolane [4,5-g ] isoquinoline, namely a compound IV;

s42 a: under the acid catalysis condition, carrying out electrophilic reaction on the compound IV described in S41a in an organic solvent to close the ring to prepare 12-halogenated dihydroberberine, namely a compound III;

2. The method for synthesizing berberine hydrochloride according to claim 1,

in the reaction described in S41a,

the protonic acid is anhydrous formic acid, anhydrous acetic acid, trifluoroacetic acid, sulfuric acid or hydrochloric ether solution;

the compound V: glyoxal monoacetal: the molar ratio of protonic acid is 1: 2-5: 5-20;

the used water removing agent is anhydrous magnesium sulfate, anhydrous sodium sulfate or 4A MS, and the mass ratio of the compound V to the water removing agent is 1: 2-30;

the organic solvent comprises at least one of tetrahydrofuran, diethyl ether, dioxane, dichloromethane, chloroform or 1, 2-dichloroethane;

the reaction temperature of the S41a is 25-50 ℃; the reaction time is 12-36 h;

in the electrophilic substitution reaction described in S42a,

the acid is a protonic acid or a Lewis acid; the protonic acid comprises any one of concentrated sulfuric acid, concentrated hydrochloric acid, concentrated nitric acid, phosphoric acid or trifluoromethanesulfonic acid; the Lewis acid comprises any one of anhydrous aluminum trichloride, anhydrous ferric trichloride, anhydrous stannic chloride or anhydrous zinc chloride;

a compound IV: the molar ratio of the acid is 1: 1.5-8;

the solvent for the reaction comprises at least one of formic acid, acetic acid or propionic acid;

the reaction temperature of the electrophilic substitution reaction of S42a is-20 ℃ to 50 ℃; the reaction time is 6-18 h;

in the aromatization reaction described in S43a,

the organic solvent comprises at least one of tetrahydrofuran, methanol, diethyl ether, dioxane, dichloromethane, chloroform or 1, 2-dichloroethane;

the reaction temperature of the aromatization reaction of S43a is 25-50 ℃; the reaction time is 36-72 h.

3. The method for synthesizing berberine hydrochloride according to claim 1, wherein the method for synthesizing berberine hydrochloride comprises:

s4: under the catalysis of inorganic protonic acid and the condition of adding metal inorganic salt as a water removal agent, carrying out ring closure reaction on a compound V of S3 and glyoxal in an organic acid solvent to prepare a compound II;

s5: and under the action of palladium-carbon catalysis and a hydrogen source, carrying out hydrogenation reaction on the compound II in an organic solvent to obtain a compound I.

4. The method for synthesizing berberine hydrochloride according to claim 3, wherein in S4,

the inorganic protonic acid comprises concentrated hydrochloric acid, concentrated sulfuric acid, phosphoric acid or nitric acid;

the metal inorganic salt water removing agent is anhydrous copper sulfate, anhydrous copper chloride, anhydrous ferric sulfate or anhydrous ferric chloride;

the solvent of the reaction is at least one of anhydrous acetic acid, anhydrous formic acid or anhydrous trifluoroacetic acid;

the compound V is as follows: glyoxal: inorganic protic acid: the molar ratio of the metal inorganic salt is 1: 1.5-3: 1.5-2.5: 1.5 to 3;

the reaction temperature is controlled to be 50-100 ℃; the reaction time is controlled to be between 8 and 12 hours.

5. The method for synthesizing berberine hydrochloride according to claim 1 or 3,

in the condensation reaction described in S1,

the water removing agent is any one of 4AMS, anhydrous magnesium sulfate, anhydrous sodium sulfate or anhydrous potassium carbonate;

the mass ratio of the water removing agent to the compound VIII is 1-5: 1; a compound IX: the molar ratio of compound VIII is 1:1 to 1.5;

the organic solvent comprises at least one of tetrahydrofuran, diethyl ether, dioxane, dichloromethane, chloroform and ethyl acetate;

the reaction temperature of the condensation reaction of S1 is 0-50 ℃; the reaction time is 12-48 h.

6. The method for synthesizing berberine hydrochloride according to claim 1 or 3,

in the reduction reaction described in S2,

the borohydride is potassium borohydride or sodium borohydride;

the compound VII: the molar ratio of borohydride is 1: 1-5;

the organic solvent is at least one of methanol, tetrahydrofuran, diethyl ether, dioxane, anhydrous dichloromethane, chloroform and ethyl acetate;

s2, the reaction temperature of the reduction reaction is-10 ℃ to 50 ℃; the reaction time is 0.5-4 h.

7. The method for synthesizing berberine hydrochloride according to claim 1 or 3,

in the salt-forming reaction described in S3,

the molar concentration range of the ethyl ether hydrochloride solution is 0.5-5 mol/L;

compound vi: the molar ratio of the hydrochloric acid is 1: 1-5;

the organic solvent is at least one of tetrahydrofuran, anhydrous diethyl ether, dioxane, dichloromethane, chloroform, and ethyl acetate;

the reaction temperature of the salt forming reaction of S3 is-30 ℃ to 30 ℃; the reaction time is 0.5-6 h.

8. The method for synthesizing berberine hydrochloride according to claim 1 or 3,

in the hydrogenation reaction described in S5,

the palladium loading capacity of the palladium carbon can be 5% or 10%, and the using amount of the palladium carbon can be 5wt% -50 wt%;

the compound II: the molar ratio of the hydrogen source is 1: 2-6;

the hydrogen source used can be any one of ammonium formate, formic acid-triethylamine complex or hydrogen;

the organic solvent comprises at least one of methanol, ethanol, isopropanol, water or acetic acid;

9. The method for synthesizing berberine hydrochloride according to claim 8,

the hydrogenation reaction comprises transfer hydrogenation reaction and hydrogen hydrogenation reaction;

in transfer hydrogenation, the compound ii: the molar ratio of the hydrogen source is 1: 4-5; the hydrogen source is ammonium formate; the organic solvent is an acetic acid aqueous solution with the final concentration of 50%;

the reaction temperature of the transfer hydrogenation reaction is 45-55 ℃; the reaction time is 23-25 h;

in the hydrogen hydrogenation reaction in which hydrogen is used as a hydrogen source,

the pressure of the hydrogen in the system is 1 atm-5 atm;

the compound II: the molar ratio of the alkali is 1: 1-2; the alkali is sodium bicarbonate; the organic solvent is methanol;

in the hydrogen hydrogenation reaction, the reaction temperature and the reaction time are 25-30 ℃ and 11-13 h.