A method for synthesizing hydroxytyrosol and high-purity large-scale thereof

Abstract

The present invention relates to a method for the large-scale synthesis of hydroxytyrosol and high purity thereof. On the one hand, it relates to a method for preparing hydroxytyrosol, comprising the following steps: 4-hydroxyphenylethanol, water, sodium bromide, potassium peroxymonosulfonate, and acetone are sequentially added to a reactor for reaction to obtain an intermediate 1; intermediate 1, cuprous iodide, potassium hydroxide, and water are sequentially added to a reactor to react, and the target is separated to obtain an intermediate 2 as a viscous oily substance; intermediate 2, acetic anhydride, boron trifluoride ether solution, and ethyl acetate / acetone mixed solution are sequentially added to a reactor, and the reaction is performed at room temperature, and intermediate 3 is obtained by post-treatment; intermediate 3, concentrated hydrochloric acid, and methanol are sequentially added to a reactor, and the temperature is raised to react, and after post-treatment, a light yellow oily substance is obtained as a pure product of hydroxytyrosol. The present invention also relates to hydroxytyrosol prepared using the method of the present invention. The present invention provides a method suitable for producing high-purity hydroxytyrosol on an industrial scale.

Description

Technical Field

[0001] The invention belongs to the field of synthesis of active compounds and relates to a method for preparing hydroxytyrosol, namely 3,4-dihydroxyphenylethanol, and in particular to a method suitable for synthesizing high-purity hydroxytyrosol on an industrial scale. Background Art

[0002] Hydroxytyrosol is also known as 3,4-dihydroxyphenylethanol; molecular formula C8H 10 O3, CAS: 10597-60-1, molecular weight: 154.16; its structural formula is as follows:

[0003]

[0004] Hydroxytyrosol is a natural polyphenol compound, which mainly exists in the form of oleuropein in the fruits and leaves of the genus Olive of the Oleaceae family, and is the active ingredient in olive oil. Due to its structure of catechol and phenylethanol, hydroxytyrosol has strong antioxidant properties and has received widespread attention in recent years. Studies have shown that in addition to its extremely strong antioxidant effect, hydroxytyrosol is beneficial for maintaining bone density and preventing osteoporosis; it has anti-cancer and cancer prevention effects; it can effectively reduce the harm of smoking to the human body; it has antibacterial effects; it helps in the treatment of diseases related to mitochondrial dysfunction such as diabetes and obesity, and can reduce the incidence of such diseases. In addition, hydroxytyrosol has a good application prospect as a food additive, cosmetic and health product ingredient.

[0005] The traditional production of hydroxytyrosol mainly adopts the method of plant extraction, from olive fruits and leaves, or from industrial wastewater of olive oil production. For example, the invention patent with publication number CN101298411B discloses that hydroxytyrosol obtained by molecular distillation process has antioxidant activity and is used in medicines, cosmetics, food and health products. The traditional preparation method is to extract from olive oil or olive leaves, but the cost is high and the purity is low.

[0006] People have tried to use chemical synthesis methods to prepare hydroxytyrosol. For example, CN103420804B (Chinese patent application No. 201310199087.5, Lingxiao) discloses a method for preparing high-purity hydroxytyrosol using 3,4-dihydroxyphenylacetic acid methyl ester as a raw material, and the steps are as follows: (1) the synthesis step is to use water as a reaction solvent and sodium borohydride or potassium borohydride as a reducing agent to reduce 3,4-dihydroxyphenylacetic acid methyl ester. After the reaction is completed, acid is added to adjust the pH value to 1-3, and then filtered, extracted with ethyl acetate, and concentrated to obtain a crude hydroxytyrosol product; (2) the purification step is to use the crude hydroxytyrosol product to obtain a crude hydroxytyrosol product; The method of two-stage molecular distillation is used to purify and prepare high-purity hydroxytyrosol; the conditions of the molecular distillation of the first stage are: vacuum degree 10-20Pa, distillation temperature 90-100℃, material flow rate 1-3mL / min, condensation surface temperature 25℃, scraping speed 200-400r / min, and circulating water temperature of the feed port 40-80℃; the conditions of the molecular distillation of the second stage are: vacuum degree 0.1-1Pa, distillation temperature 120-170℃, material flow rate 1-3mL / min, condensation surface temperature 25-70℃, scraping speed 200-400r / min, and circulating water temperature of the feed port 40-80℃. The reaction route uses 3,4-dihydroxyphenylacetic acid methyl ester as the starting material. The starting material is expensive and uses expensive reagents such as sodium borohydride, so the process cost is high. The specific route is as follows:

[0007]

[0008] CN112457171B (Chinese Patent Application No. 202011474334.4, Dickman) discloses a synthetic method for preparing hydroxytyrosol from 4-hydroxyphenylethanol, comprising the following steps: reacting 4-hydroxyphenylethanol with potassium monopersulfate complex salt and bromine salt to prepare 3-bromo-4-hydroxyphenylethanol; reacting 3-bromo-4-hydroxyphenylethanol with alkali metal hydroxide and copper catalyst, wherein the copper catalyst is at least one of 8-hydroxyquinoline copper, copper acetylacetonate, and BFMO-cuprous iodide, wherein the alkali metal hydroxide is sodium hydroxide, potassium hydroxide or lithium hydroxide, and the copper catalyst is preferably 8-hydroxyquinoline copper. It can be seen from this route that 4-hydroxyphenylethanol is used as the starting material, and hydroxyl aldehydes are prepared by bromination and hydroxylation reactions. Organic copper salt 8-hydroxyquinoline copper is used in the reaction process, and the reagent is expensive. At the same time, the finished product is refined by molecular distillation, and the overall process cost is relatively high. The specific route is as follows:

[0009]

[0010] CN113264814B (Chinese patent application number 202110650112.1, Sibei source) discloses a process for directly preparing pepper ethanol by using pepper ring as a starting material and reacting it with ethylene oxide for Friedel-Crafts alkylation, and then opening the ring to obtain hydroxytyrosol, comprising the following steps: Step 1, preparation of pepper ethanol: adding pepper ring and a catalyst to a reaction bottle, and then introducing ethylene oxide gas for reaction, the reaction temperature is -20 to 10°C, the reaction time is 0.5-1h, quenching after the reaction is completed, and then acid washing, water washing, concentration, and distillation to obtain a key intermediate pepper ethanol; Step 2, preparation of hydroxytyrosol: adding a protonic acid, step The pepper ethanol obtained in step 1, the catalyst, and the nitrogen protection are 20-60°C for 5-36 hours; after the reaction, the pH is adjusted to 10±0.5, washed with DCM, the pH of the water layer is adjusted to 1-2, and then extracted with methyl tert-butyl ether, dried, decolorized, and concentrated to obtain hydroxytyrosol; wherein, in step 1, the catalyst is a Lewis acid selected from a combination of one or more of AlBr3, AlCl3, FeCl3, SbCl5, and SnCl4; in step 2, the protonic acid is selected from any one or more of hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and nitric acid; in step 2, the catalyst is a solid strong acid or a solid superacid. The ethylene oxide used in this method belongs to a large chemical product, but ethylene oxide is a flammable and explosive gas, which is not easy to transport over long distances, and there are great safety hazards in production. The specific route of the method is as follows:

[0011]

[0012] CN103038203B (Chinese patent application No. 201080067761.9, Longsha) discloses a method for preparing hydroxytyrosol from eugenol, wherein eugenol is first converted into 4-(2-hydroxyethyl)-2-methoxyphenol, and then converted into hydroxytyrosol. During the conversion of eugenol, in the presence of an oxidant and a catalytic amount of a base, the allyl double bond is oxidized, and the oxidant is selected from ozone, hydrogen peroxide, KMnO4, OsO4, Pd(II) salts combined with oxygen, halogens, RuO4 and CrO3, and the base is a hydroxide, carbonate, bicarbonate, phosphate or carboxylate of an alkali metal or alkaline earth metal. After the oxidation reaction, it is reduced with a reducing agent to obtain 4-(2-hydroxyethyl)-2-methoxyphenol, and the reducing agent is preferably sodium borohydride. Then, demethylation is carried out in the presence of aluminum chloride and ethanethiol to obtain hydroxytyrosol. The reaction process needs to be carried out at -78°C, and the reaction conditions are harsh. At the same time, the reaction process also requires expensive reagents such as sodium borohydride. The specific route of this method is as follows:

[0013]

[0014] CN106866384B (Chinese patent application No. 201611249898.1, Jiahe) discloses a method for preparing hydroxytyrosol, which uses 3,4-dimethoxyphenylacetic acid as a starting material, and prepares hydroxyl tyrosol through esterification, reduction, and demethylation reactions, comprising the following steps: at room temperature, uniformly stirring a solvent, 3,4-dimethoxyphenylethanol, and aluminum triiodide, adding boron trifluoride tetrahydrofuran or boron trifluoride ether, heating and refluxing, and after the reaction is complete, cooling to room temperature, filtering, and adding the filtrate to the filtrate; Add activated carbon, filter again, recover the filtrate to dryness, obtain a light yellow oily residue, then add dichloromethane, reflux, cool to room temperature for pulping, and filter to obtain white powdery solid hydroxytyrosol; the solvent is acetonitrile, tetrahydrofuran, dichloroethane, dichloromethane or toluene; the molar ratio of aluminum triiodide to 3,4-dimethoxyphenylethanol is 2-3:1; the mass ratio of the solvent to 3,4-dimethoxyphenylethanol is 2-5:1; the mass ratio of boron trifluoride tetrahydrofuran or boron trifluoride ether to aluminum triiodide is 0.02:1. This route has the disadvantages of using genotoxic reagents such as methyl sulfate, and the starting material price is relatively high, reagents such as aluminum triiodide and sodium borohydride are expensive, and the overall process cost is relatively high. The specific route is as follows:

[0015]

[0016] WO2007009590 discloses that 3,4-dihydroxymandelic acid is obtained by using catechol and glyoxylic acid as raw materials, sodium bisulfite or sodium pyrosulfite is used as a reducing agent to remove the α-hydroxyl group of 3,4-dihydroxymandelic acid, and hydroxytyrosol is synthesized through four steps of esterification and reduction. Although the raw materials of this method are cheap, the route is long, the Friedel-Crafts reaction has regioselective by-products, which is not conducive to purification, and the use of LiAlH4 reduction is expensive and has safety hazards, and the total yield is low, only about 52%. The specific route is as follows:

[0017]

[0018] In summary, the prior art preparation of hydroxytyrosol is not suitable for industrial-scale production, especially not suitable for industrial-scale production of high-purity hydroxytyrosol. Therefore, those skilled in the art are eager to provide a method suitable for industrial-scale production of high-purity hydroxytyrosol. Summary of the invention

[0019] The object of the present invention is to provide a method for producing high-purity hydroxytyrosol on an industrial scale, in particular, a method for producing high-purity hydroxytyrosol on an industrial scale by chemical synthesis. It has been unexpectedly found that one or more beneficial effects can be obtained by using the method of the present invention, and the present invention is completed based on such findings.

[0020] To this end, the first aspect of the present invention provides a method for preparing hydroxytyrosol, and its overall reaction flow is as follows:

[0021]

[0022] The method comprises the following steps:

[0023] (s1) Preparation of Intermediate 1: 4-Hydroxyphenylethanol, water, sodium bromide, potassium peroxymonosulfonate and acetone were added to a reaction kettle in sequence. After the addition was completed, the mixture was stirred at room temperature to react. The reaction solution was concentrated in vacuo to remove the solvent, and crystals were precipitated. The crystals were filtered and the filter cake was dried in a vacuum drying oven to obtain the intermediate 1 of the following formula:

[0024]

[0025] (s2) Preparation of intermediate 2: intermediate 1, cuprous iodide, potassium hydroxide and water were added to a reaction kettle in sequence, the temperature was raised for reaction, concentrated hydrochloric acid was added to acidify to pH=2 after cooling, insoluble solids were removed by filtration, the filtrate was washed with dichloromethane, sodium chloride was added to the aqueous layer to saturate, the layers were separated, the organic phase was dried over anhydrous sodium sulfate, the organic phase was concentrated to remove the solvent, and the intermediate 2 of the following formula was obtained as a viscous oil:

[0026]

[0027] (s3) Preparation of intermediate 3: intermediate 2, acetic anhydride, boron trifluoride ether solution, and ethyl acetate / acetone mixture are sequentially added to a reaction kettle and reacted at room temperature; after the reaction is completed, the reaction solution is washed with purified water, filtered, the filtrate is dried over anhydrous sodium sulfate, and concentrated to remove the solvent; then ethanol solution is added, and crystals are precipitated after low-temperature stirring, which are filtered and the filter cake is placed in a vacuum drying oven to obtain intermediate 3 of the following formula:

[0028]

[0029] (s4) Preparation of pure hydroxytyrosol: intermediate 3, concentrated hydrochloric acid and methanol are sequentially added to a reaction vessel, the temperature of the reactants is raised, stirred to react, cooled, and then washed with dichloromethane, methyl tert-butyl ether and purified water in sequence. The organic phase is dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent to obtain a light yellow oily substance as pure hydroxytyrosol represented by the following formula:

[0030]

[0031] According to the method of the first aspect of the present invention, in step (s1), the intermediate 1 is prepared by adding materials in the following proportions: 1000 g of 4-hydroxyphenylethanol, 4.5 to 5.5 L of water, 1 to 1.2 kg of sodium bromide, 2.4 to 2.6 kg of potassium peroxymonosulfonate, and 1.8 to 2.2 L of acetone are sequentially added into a reaction kettle, and after the addition is completed, the mixture is stirred at room temperature to react for 2.5 to 3.5 hours; the reaction solution is vacuum concentrated to remove the solvent, crystals are precipitated, filtered, and the filter cake is placed in a vacuum drying oven to dry to obtain the intermediate 1.

[0032] According to the method of the first aspect of the present invention, in step (s2), the reactants are heated to 85-95°C for reaction.

[0033] According to the method of the first aspect of the present invention, in step (s2), the reactants are cooled to 20° C. and then acidified.

[0034] According to the method of the first aspect of the present invention, in step (s2), the intermediate 2 is prepared by adding materials in the following proportions: 1300g of intermediate 1, 0.09-0.11kg of cuprous iodide, 1.25-1.45kg of potassium hydroxide, and 4.5-5.5L of water are sequentially added into a reaction kettle, the temperature is raised to 85-95°C, the reaction is carried out for 4.5 hours, the temperature is lowered to 20°C, concentrated hydrochloric acid is added to acidify to pH=2, the insoluble solid is removed by filtration, the filtrate is washed with 1.5-2.5L of dichloromethane, the aqueous layer is saturated with sodium chloride, the layers are separated, the organic phase is dried with anhydrous sodium sulfate, the organic phase is concentrated to remove the solvent, and the intermediate 2 is obtained as a viscous oil.

[0035] According to the method of the first aspect of the present invention, in step (s3), the ethyl acetate / acetone mixed solution is a mixed solution of ethyl acetate and acetone in a volume ratio of 4:1.

[0036] According to the method of the first aspect of the present invention, in step (s3), the ethanol solution is a 55% to 65% ethanol solution.

[0037] According to the method of the first aspect of the present invention, in step (s3), the low-temperature stirring is stirring at -10°C.

[0038] According to the method of the first aspect of the present invention, in step (s3), the intermediate 3 is prepared by adding materials in the following proportions: 720g of intermediate 2, 1.1-1.2kg of acetic anhydride, 1-1.2kg of boron trifluoride ether solution, and 4.5-5.5L of ethyl acetate / acetone (4:1) are sequentially added into a reactor, and reacted at room temperature; after the reaction is completed, the reaction solution is washed with purified water, filtered, the filtrate is dried over anhydrous sodium sulfate, and concentrated to remove the solvent; then 1L of 55-65% ethanol solution is added, and crystals are precipitated after stirring at -10°C, which are filtered and the filter cake is dried in a vacuum drying oven to obtain intermediate 3.

[0039] According to the method of the first aspect of the present invention, in step (s4), the reactants are heated to 85-95°C for reaction.

[0040] According to the method of the first aspect of the present invention, in step (s4), the reaction is stirred for 2.5 to 3.5 hours.

[0041] According to the method of the first aspect of the present invention, in step (s4), after stirring and reacting for 2.5 to 3.5 hours, the temperature is lowered to 20°C.

[0042] According to the method of the first aspect of the present invention, in step (s4), the following proportions are used to prepare pure hydroxytyrosol: 1055 g of intermediate 3, 1.8-2.2 kg of concentrated hydrochloric acid, and 5.5-6.5 L of methanol are sequentially added into a reactor, the temperature of the reactants is raised to 85-95° C., and the reactants are stirred to react for 2.5-3.5 hours, then the temperature is lowered to 20° C., and then the reactants are sequentially washed with dichloromethane, methyl tert-butyl ether, and purified water, and the organic phase is dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent to obtain a light yellow oily substance as pure hydroxytyrosol.

[0043] The method according to the first aspect of the present invention comprises the steps of feeding materials in the following proportions:

[0044] (s1) Preparation of intermediate 1: 1000 g of 4-hydroxyphenylethanol, 5 L of water, 1.09 kg of sodium bromide, 2.5 kg of potassium peroxymonosulfonate, and 2 L of acetone were added to a reaction kettle in sequence. After the addition was completed, the mixture was stirred at room temperature and reacted for 3 hours. The reaction solution was concentrated in vacuo to remove the solvent, and crystals were precipitated. The crystals were filtered and the filter cake was dried in a vacuum drying oven to obtain intermediate 1.

[0045] (s2) Preparation of intermediate 2: 1300 g of intermediate 1, 0.1 kg of cuprous iodide, 1.35 kg of potassium hydroxide and 5 L of water were added to a reaction kettle in sequence, the temperature was raised to 90° C., the reaction was carried out for 5 hours, the temperature was lowered to 20° C., concentrated hydrochloric acid was added to acidify to pH=2, the insoluble solid was removed by filtration, the filtrate was washed with 2 L of dichloromethane, the aqueous layer was saturated with sodium chloride, the layers were separated, the organic phase was dried over anhydrous sodium sulfate, the organic phase was concentrated to remove the solvent, and intermediate 2 was obtained as a viscous oil;

[0046] (s3) Preparation of intermediate 3: 720 g of intermediate 2, 1.17 kg of acetic anhydride, 1.1 kg of boron trifluoride ether solution, and 5 L of ethyl acetate / acetone (4:1) were added to a reaction kettle in sequence and reacted at room temperature; after the reaction was completed, the reaction solution was washed with purified water, filtered, the filtrate was dried over anhydrous sodium sulfate, and concentrated to remove the solvent; then 1 L of 60% ethanol solution was added, and crystals were precipitated after stirring at -10°C. The crystals were filtered and the filter cake was dried in a vacuum drying oven to obtain intermediate 3;

[0047] (s4) Preparation of pure hydroxytyrosol: 1055 g of intermediate 3, 2 kg of concentrated hydrochloric acid and 6 L of methanol were added to a reaction kettle in sequence, and the temperature of the reactants was raised to 90° C. and stirred for reaction for 3 hours. The temperature was then lowered to 20° C. and the reactants were washed with dichloromethane, methyl tert-butyl ether and purified water in sequence. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent to obtain a light yellow oily substance as pure hydroxytyrosol.

[0048] The method according to the first aspect of the present invention comprises the steps of feeding materials in the following proportions:

[0049] (s1) Preparation of intermediate 1: 1000 g of 4-hydroxyphenylethanol, 5.5 L of water, 1.2 kg of sodium bromide, 2.4 kg of potassium peroxymonosulfonate, and 2.2 L of acetone were added to a reaction kettle in sequence. After the addition was completed, the mixture was stirred at room temperature and reacted for 2.5 hours; the reaction solution was concentrated in vacuo to remove the solvent, crystals were precipitated, filtered, and the filter cake was dried in a vacuum drying oven to obtain intermediate 1;

[0050] (s2) Preparation of intermediate 2: 1300 g of intermediate 1, 0.09 kg of cuprous iodide, 1.45 kg of potassium hydroxide and 4.5 L of water were added to a reaction kettle in sequence, the temperature was raised to 95° C., the reaction was carried out for 4.5 hours, the temperature was lowered to 20° C., concentrated hydrochloric acid was added to acidify to pH=2, the insoluble solid was removed by filtration, the filtrate was washed with 2.5 L of dichloromethane, the aqueous layer was saturated with sodium chloride, the layers were separated, the organic phase was dried over anhydrous sodium sulfate, the organic phase was concentrated to remove the solvent, and intermediate 2 was obtained as a viscous oil;

[0051] (s3) Preparation of intermediate 3: 720 g of intermediate 2, 1.2 kg of acetic anhydride, 1 kg of boron trifluoride ether solution, and 4.5 L of ethyl acetate / acetone (4:1) were added to a reaction kettle in sequence and reacted at room temperature; after the reaction was completed, the reaction solution was washed with purified water, filtered, the filtrate was dried over anhydrous sodium sulfate, and concentrated to remove the solvent; then 1 L of 65% ethanol solution was added, and crystals were precipitated after stirring at -10°C. The crystals were filtered and the filter cake was dried in a vacuum drying oven to obtain intermediate 3;

[0052] (s4) Preparation of pure hydroxytyrosol: 1055 g of intermediate 3, 1.8 kg of concentrated hydrochloric acid and 6.5 L of methanol were added to a reaction kettle in sequence, and the temperature of the reactants was raised to 85° C. and stirred for reaction for 3.5 hours. The temperature was then lowered to 20° C. and the reactants were washed with dichloromethane, methyl tert-butyl ether and purified water in sequence. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent to obtain a light yellow oily substance as pure hydroxytyrosol.

[0053] The method according to the first aspect of the present invention comprises the steps of feeding materials in the following proportions:

[0054] (s1) Preparation of intermediate 1: 1000 g of 4-hydroxyphenylethanol, 4.5 L of water, 1.0 kg of sodium bromide, 2.6 kg of potassium peroxymonosulfonate, and 1.8 L of acetone were added to a reaction kettle in sequence. After the addition was completed, the mixture was stirred at room temperature and reacted for 3.5 hours; the reaction solution was concentrated in vacuo to remove the solvent, crystals were precipitated, and the crystals were filtered. The filter cake was dried in a vacuum drying oven to obtain intermediate 1;

[0055] (s2) Preparation of intermediate 2: 1300 g of intermediate 1, 0.11 kg of cuprous iodide, 1.25 kg of potassium hydroxide and 5.5 L of water were added to a reaction kettle in sequence, the temperature was raised to 85°C, the reaction was carried out for 5.5 hours, the temperature was lowered to 20°C, concentrated hydrochloric acid was added to acidify to pH = 2, the insoluble solid was removed by filtration, the filtrate was washed with 1.5 L of dichloromethane, the aqueous layer was saturated with sodium chloride, the layers were separated, the organic phase was dried over anhydrous sodium sulfate, the organic phase was concentrated to remove the solvent, and intermediate 2 was obtained as a viscous oil;

[0056] (s3) Preparation of intermediate 3: 720 g of intermediate 2, 1.1 kg of acetic anhydride, 1.2 kg of boron trifluoride ether solution, and 5.5 L of ethyl acetate / acetone (4:1) were added to a reaction kettle in sequence and reacted at room temperature; after the reaction was completed, the reaction solution was washed with purified water, filtered, the filtrate was dried over anhydrous sodium sulfate, and concentrated to remove the solvent; then 1 L of 55% ethanol solution was added, and crystals were precipitated after stirring at -10°C. The crystals were filtered and the filter cake was dried in a vacuum drying oven to obtain intermediate 3;

[0057] (s4) Preparation of pure hydroxytyrosol: 1055 g of intermediate 3, 2.2 kg of concentrated hydrochloric acid and 5.5 L of methanol were added to a reaction kettle in sequence, and the temperature of the reactants was raised to 95°C. After stirring and reacting for 2.5 hours, the temperature was lowered to 20°C, and the reactants were washed with dichloromethane, methyl tert-butyl ether and purified water in sequence. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent to obtain a light yellow oily substance as pure hydroxytyrosol.

[0058] Furthermore, the second aspect of the present invention provides a hydroxytyrosol, which is prepared according to a method comprising the following steps:

[0059] (s1) Preparation of Intermediate 1: 4-Hydroxyphenylethanol, water, sodium bromide, potassium peroxymonosulfonate and acetone were added to a reaction kettle in sequence. After the addition was completed, the mixture was stirred at room temperature to react. The reaction solution was concentrated in vacuo to remove the solvent, and crystals were precipitated. The crystals were filtered and the filter cake was dried in a vacuum drying oven to obtain the intermediate 1 of the following formula:

[0060]

[0061] (s2) Preparation of intermediate 2: intermediate 1, cuprous iodide, potassium hydroxide and water were added to a reaction kettle in sequence, the temperature was raised for reaction, concentrated hydrochloric acid was added to acidify to pH=2 after cooling, insoluble solids were removed by filtration, the filtrate was washed with dichloromethane, sodium chloride was added to the aqueous layer to saturate, the layers were separated, the organic phase was dried over anhydrous sodium sulfate, the organic phase was concentrated to remove the solvent, and the intermediate 2 of the following formula was obtained as a viscous oil:

[0062]

[0063] (s3) Preparation of intermediate 3: intermediate 2, acetic anhydride, boron trifluoride ether solution, and ethyl acetate / acetone mixture are sequentially added into a reaction kettle and reacted at room temperature; after the reaction is completed, the reaction solution is washed with purified water, filtered, the filtrate is dried over anhydrous sodium sulfate, and concentrated to remove the solvent; then ethanol solution is added, and crystals are precipitated after low temperature stirring, which are filtered and the filter cake is dried in an oven to obtain intermediate 3 of the following formula;

[0064]

[0065] (s4) Preparation of pure hydroxytyrosol: intermediate 3, concentrated hydrochloric acid and methanol are sequentially added to a reaction vessel, the temperature of the reactants is raised, stirred to react, cooled, and then washed with dichloromethane, methyl tert-butyl ether and purified water in sequence. The organic phase is dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent to obtain a light yellow oily substance as pure hydroxytyrosol represented by the following formula:

[0066]

[0067] According to the hydroxytyrosol of the second aspect of the present invention, in step (s1), the intermediate 1 is prepared by adding materials in the following proportions: 1000g of 4-hydroxyphenylethanol, 4.5-5.5L of water, 1-1.2kg of sodium bromide, 2.4-2.6kg of potassium peroxymonosulfonate, and 1.8-2.2L of acetone are sequentially added into a reaction kettle, and after the addition is completed, the mixture is stirred at room temperature to react for 2.5-3.5 hours; the reaction solution is vacuum concentrated to remove the solvent, crystals are precipitated, and the crystals are filtered, and the filter cake is dried in a vacuum drying oven to obtain the intermediate 1.

[0068] According to the hydroxytyrosol of the second aspect of the present invention, in step (s2), the reactants are heated to 85-95° C. for reaction.

[0069] According to the hydroxytyrosol of the second aspect of the present invention, in step (s2), the reactants are cooled to 20° C. and then acidified.

[0070] According to the second aspect of the present invention, the hydroxytyrosol is prepared in step (s2) by feeding materials in the following proportions: 1300g of intermediate 1, 0.09-0.11kg of cuprous iodide, 1.25-1.45kg of potassium hydroxide, and 4.5-5.5L of water are sequentially added into a reaction kettle, the temperature is raised to 85-95°C, the reaction is carried out for 4.5 hours, the temperature is lowered to 20°C, concentrated hydrochloric acid is added to acidify to pH=2, insoluble solids are removed by filtration, the filtrate is washed with 1.5-2.5L of dichloromethane, the aqueous layer is saturated with sodium chloride, the layers are separated, the organic phase is dried with anhydrous sodium sulfate, the organic phase is concentrated to remove the solvent, and the intermediate 2 is obtained as a viscous oil.

[0071] According to the hydroxytyrosol of the second aspect of the present invention, in step (s3), the ethyl acetate / acetone mixed solution is a mixed solution of ethyl acetate and acetone in a volume ratio of 4:1.

[0072] According to the hydroxytyrosol of the second aspect of the present invention, in step (s3), the ethanol solution is a 55% to 65% ethanol solution.

[0073] According to the hydroxytyrosol of the second aspect of the present invention, in step (s3), the low-temperature stirring is stirring at -10°C.

[0074] According to the second aspect of the present invention, hydroxytyrosol is prepared in step (s3) by adding materials in the following proportions: 720 g of intermediate 2, 1.1-1.2 kg of acetic anhydride, 1-1.2 kg of boron trifluoride ether solution, and 4.5-5.5 L of ethyl acetate / acetone (4:1) are sequentially added into a reactor, and reacted at room temperature; after the reaction is completed, the reaction solution is washed with purified water, filtered, the filtrate is dried over anhydrous sodium sulfate, and concentrated to remove the solvent; then 1 L of 55-65% ethanol solution is added, and crystals are precipitated after stirring at -10°C, which is filtered and the filter cake is dried in a vacuum drying oven to obtain intermediate 3.

[0075] According to the hydroxytyrosol of the second aspect of the present invention, in step (s4), the reactants are heated to 85-95° C. for reaction.

[0076] According to the hydroxytyrosol of the second aspect of the present invention, in step (s4), the reaction is stirred for 2.5 to 3.5 hours.

[0077] According to the hydroxytyrosol of the second aspect of the present invention, in step (s4), after stirring and reacting for 2.5 to 3.5 hours, the temperature is lowered to 20°C.

[0078] According to the hydroxytyrosol of the second aspect of the present invention, in step (s4), the following proportions are used to prepare pure hydroxytyrosol: 1055 g of intermediate 3, 1.8-2.2 kg of concentrated hydrochloric acid, and 5.5-6.5 L of methanol are sequentially added into a reactor, the temperature of the reactants is raised to 85-95° C., and the reactants are stirred to react for 2.5-3.5 hours, then the temperature is lowered to 20° C., and the reactants are sequentially washed with dichloromethane, methyl tert-butyl ether, and purified water, and the organic phase is dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent to obtain a light yellow oily substance as pure hydroxytyrosol.

[0079] The hydroxytyrosol according to the second aspect of the present invention comprises the steps of feeding materials according to the following proportions:

[0080] (s1) Preparation of intermediate 1: 1000 g of 4-hydroxyphenylethanol, 5 L of water, 1.09 kg of sodium bromide, 2.5 kg of potassium peroxymonosulfonate, and 2 L of acetone were added to a reaction kettle in sequence. After the addition was completed, the mixture was stirred at room temperature and reacted for 3 hours. The reaction solution was concentrated in vacuo to remove the solvent, and crystals were precipitated. The crystals were filtered and the filter cake was dried in a vacuum drying oven to obtain intermediate 1.

[0081] (s2) Preparation of intermediate 2: 1300 g of intermediate 1, 0.1 kg of cuprous iodide, 1.35 kg of potassium hydroxide and 5 L of water were added to a reaction kettle in sequence, the temperature was raised to 90° C., the reaction was carried out for 5 hours, the temperature was lowered to 20° C., concentrated hydrochloric acid was added to acidify to pH=2, the insoluble solid was removed by filtration, the filtrate was washed with 2 L of dichloromethane, the aqueous layer was saturated with sodium chloride, the layers were separated, the organic phase was dried over anhydrous sodium sulfate, the organic phase was concentrated to remove the solvent, and intermediate 2 was obtained as a viscous oil;

[0082] (s3) Preparation of intermediate 3: 720 g of intermediate 2, 1.17 kg of acetic anhydride, 1.1 kg of boron trifluoride ether solution, and 5 L of ethyl acetate / acetone (4:1) were added to a reaction kettle in sequence and reacted at room temperature; after the reaction was completed, the reaction solution was washed with purified water, filtered, the filtrate was dried over anhydrous sodium sulfate, and concentrated to remove the solvent; then 1 L of 60% ethanol solution was added, and crystals were precipitated after stirring at -10°C. The crystals were filtered and the filter cake was dried in a vacuum drying oven to obtain intermediate 3;

[0083] (s4) Preparation of pure hydroxytyrosol: 1055 g of intermediate 3, 2 kg of concentrated hydrochloric acid and 6 L of methanol were added to a reaction kettle in sequence, and the temperature of the reactants was raised to 90° C. and stirred for reaction for 3 hours. The temperature was then lowered to 20° C. and the reactants were washed with dichloromethane, methyl tert-butyl ether and purified water in sequence. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent to obtain a light yellow oily substance as pure hydroxytyrosol.

[0084] The hydroxytyrosol according to the second aspect of the present invention comprises the steps of feeding materials according to the following proportions:

[0085] (s1) Preparation of intermediate 1: 1000 g of 4-hydroxyphenylethanol, 5.5 L of water, 1.2 kg of sodium bromide, 2.4 kg of potassium peroxymonosulfonate, and 2.2 L of acetone were added to a reaction kettle in sequence. After the addition was completed, the mixture was stirred at room temperature and reacted for 2.5 hours; the reaction solution was concentrated in vacuo to remove the solvent, crystals were precipitated, filtered, and the filter cake was dried in a vacuum drying oven to obtain intermediate 1;

[0086] (s2) Preparation of intermediate 2: 1300 g of intermediate 1, 0.09 kg of cuprous iodide, 1.45 kg of potassium hydroxide and 4.5 L of water were added to a reaction kettle in sequence, the temperature was raised to 95° C., the reaction was carried out for 4.5 hours, the temperature was lowered to 20° C., concentrated hydrochloric acid was added to acidify to pH=2, the insoluble solid was removed by filtration, the filtrate was washed with 2.5 L of dichloromethane, the aqueous layer was saturated with sodium chloride, the layers were separated, the organic phase was dried over anhydrous sodium sulfate, the organic phase was concentrated to remove the solvent, and intermediate 2 was obtained as a viscous oil;

[0087] (s3) Preparation of intermediate 3: 720 g of intermediate 2, 1.2 kg of acetic anhydride, 1 kg of boron trifluoride ether solution, and 4.5 L of ethyl acetate / acetone (4:1) were added to a reaction kettle in sequence and reacted at room temperature; after the reaction was completed, the reaction solution was washed with purified water, filtered, the filtrate was dried over anhydrous sodium sulfate, and concentrated to remove the solvent; then 1 L of 65% ethanol solution was added, and crystals were precipitated after stirring at -10°C. The crystals were filtered and the filter cake was dried in a vacuum drying oven to obtain intermediate 3;

[0088] (s4) Preparation of pure hydroxytyrosol: 1055 g of intermediate 3, 1.8 kg of concentrated hydrochloric acid and 6.5 L of methanol were added to a reaction kettle in sequence, and the temperature of the reactants was raised to 85° C. and stirred for reaction for 3.5 hours. The temperature was then lowered to 20° C. and the reactants were washed with dichloromethane, methyl tert-butyl ether and purified water in sequence. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent to obtain a light yellow oily substance as pure hydroxytyrosol.

[0089] The hydroxytyrosol according to the second aspect of the present invention comprises the steps of feeding materials according to the following proportions:

[0090] (s1) Preparation of intermediate 1: 1000 g of 4-hydroxyphenylethanol, 4.5 L of water, 1.0 kg of sodium bromide, 2.6 kg of potassium peroxymonosulfonate, and 1.8 L of acetone were added to a reaction kettle in sequence. After the addition was completed, the mixture was stirred at room temperature and reacted for 3.5 hours; the reaction solution was concentrated in vacuo to remove the solvent, crystals were precipitated, and the crystals were filtered. The filter cake was dried in a vacuum drying oven to obtain intermediate 1;

[0091] (s2) Preparation of intermediate 2: 1300 g of intermediate 1, 0.11 kg of cuprous iodide, 1.25 kg of potassium hydroxide and 5.5 L of water were added to a reaction kettle in sequence, the temperature was raised to 85°C, the reaction was carried out for 5.5 hours, the temperature was lowered to 20°C, concentrated hydrochloric acid was added to acidify to pH = 2, the insoluble solid was removed by filtration, the filtrate was washed with 1.5 L of dichloromethane, the aqueous layer was saturated with sodium chloride, the layers were separated, the organic phase was dried over anhydrous sodium sulfate, the organic phase was concentrated to remove the solvent, and intermediate 2 was obtained as a viscous oil;

[0092] (s3) Preparation of intermediate 3: 720 g of intermediate 2, 1.1 kg of acetic anhydride, 1.2 kg of boron trifluoride ether solution, and 5.5 L of ethyl acetate / acetone (4:1) were added to a reaction kettle in sequence and reacted at room temperature; after the reaction was completed, the reaction solution was washed with purified water, filtered, the filtrate was dried over anhydrous sodium sulfate, and concentrated to remove the solvent; then 1 L of 55% ethanol solution was added, and crystals were precipitated after stirring at -10°C. The crystals were filtered and the filter cake was dried in a vacuum drying oven to obtain intermediate 3;

[0093] (s4) Preparation of pure hydroxytyrosol: 1055 g of intermediate 3, 2.2 kg of concentrated hydrochloric acid and 5.5 L of methanol were added to a reaction kettle in sequence, and the temperature of the reactants was raised to 95°C. After stirring and reacting for 2.5 hours, the temperature was lowered to 20°C, and the reactants were washed with dichloromethane, methyl tert-butyl ether and purified water in sequence. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent to obtain a light yellow oily substance as pure hydroxytyrosol.

[0094] The hydroxytyrosol prepared by the method of the invention has high purity and can be produced on an industrial scale. BRIEF DESCRIPTION OF THE DRAWINGS

[0095] Figure 1 : HPLC spectrum of intermediate 1.

[0096] Figure 2 : HPLC spectrum of intermediate 2.

[0097] Figure 3 : HPLC spectrum of intermediate 3.

[0098] Figure 4 : NMR spectrum of intermediate 3.

[0099] Figure 5 : HPLC spectrum of pure hydroxytyrosol. DETAILED DESCRIPTION

[0100] The following examples provided by the present invention are only for explanation purposes and are not intended to be used for, nor should they be construed as limiting the present invention in any way. Those skilled in the art will recognize that conventional changes and modifications may be made to the following examples without exceeding the spirit or scope of the present invention. The present invention provides a general and / or specific description of the materials and test methods used in the test. Although many materials and operating methods used to achieve the purpose of the present invention are well known in the art, the present invention is still described in as much detail as possible herein. It is clear to those skilled in the art that, hereinafter, if not specifically stated, the materials and operating methods used in the present invention are well known in the art.

[0101] The overall synthetic route of hydroxytyrosol of the present invention is summarized as follows:

[0102]

[0103] Briefly, the present invention uses 4-hydroxyphenylethanol as a starting material to obtain intermediate 1, i.e., 3-bromo-4-hydroxyphenylethanol, by bromination, and then uses copper iodide to convert intermediate 1 into intermediate 2, i.e., 3,4-dihydroxyphenylethanol, in the presence of a base, and then uses acetic anhydride to esterify intermediate 2 to obtain intermediate 3, and finally uses hydrochloric acid to hydrolyze to obtain the final product hydroxytyrosol. The following is explained in the form of a specific example. In the following, when it comes to calculating the yield, the chromatographic purity of the product is considered. In this article, if not otherwise specified, the HPLC purity of each material is determined using the method of Test Example 1.

[0104] Example 1: Preparation of Hydroxytyrosol

[0105] 1. Preparation of Intermediate 1

[0106]

[0107] 1000g of 4-hydroxyphenylethanol (Mr=138, 7.246mol), 5L of water, 1.09kg of sodium bromide (Mr=103, 10.583mol), 2.5kg of potassium peroxymonosulfonate (oxone, Mr=615, 4.065mol), and 2L of acetone were added to the reactor in sequence. After the addition was completed, the mixture was stirred at room temperature and reacted for 3 hours. The reaction solution was vacuum concentrated to remove the solvent, crystals were precipitated, filtered, and the filter cake was dried in a vacuum drying oven to obtain 1510g of intermediate 1 (Mr=217, 6.924mol), with a reaction yield of 95.6% and an HPLC purity of 99.5%. The HPLC spectrum of intermediate 1 is shown in Figure 1 shown.

[0108] 2. Preparation of Intermediate 2

[0109]

[0110] 1300g of intermediate 1 (Mr=217, 5.961mol), 0.1kg of cuprous iodide, 1.35kg of potassium hydroxide, and 5L of water were sequentially added into the reactor, and the temperature was raised to 90°C, and the reaction was carried out for 5 hours. The temperature was lowered to 20°C, and concentrated hydrochloric acid was added to acidify to pH=2, and the insoluble solid was removed by filtration. The filtrate was washed with 2L of dichloromethane, and the aqueous layer was saturated with sodium chloride. The layers were separated, and the organic phase was dried with anhydrous sodium sulfate. The organic phase was concentrated to remove the solvent, and 942g of intermediate 2 (Mr=154, 5.572mol) was obtained as a viscous oil, with a reaction yield of 93.5% and an HPLC purity of 91.2%. The HPLC spectrum of intermediate 2 is shown in FIG. Figure 2 shown.

[0111] 3. Preparation of Intermediate 3

[0112]

[0113] 720 g of intermediate 2 (Mr=154, 4.264 mol), 1.17 kg of acetic anhydride, 1.1 kg of boron trifluoride ether solution, and 5 L of ethyl acetate / acetone (4:1) were added to the reactor in sequence and reacted at room temperature; after the reaction was completed, the reaction solution was washed with purified water, filtered, the filtrate was dried over anhydrous sodium sulfate, and concentrated to remove the solvent; 1 L of 60% ethanol solution was added, and crystals precipitated after stirring at -10°C. The crystals were filtered and the filter cake was dried in a vacuum drying oven to obtain 1128 g of intermediate 3 (Mr=280, 3.859 mol), with a reaction yield of 90.5% and a HPLC purity of 95.8%.

[0114] When the HPLC purity of intermediate 3 was determined by the method of Experimental Example 1, the ThermoScientific TM Acclaim TM 120 C18 column system, and the mobile phase was changed to 75% acetonitrile isocratic elution, and other chromatographic conditions remained unchanged; the HPLC spectrum of intermediate 3 is shown in Figure 3 As shown in the figure, the main peak at a retention time of about 11.3 min is intermediate 3. Peak 1 is qualitatively identified as intermediate 2, peak 2 is an incompletely esterified monoester compound, and peak 3 is an incompletely esterified diester compound. Figure 3 The products shown include intermediate 2, monoester compound, diester compound and intermediate 3. The total area normalized purity of the four substances is 99.13%. After complete hydrolysis in the next step, it is expected to obtain high-purity hydroxytyrosol. The nuclear magnetic resonance spectrum of the pure intermediate 3 obtained by preparative HPLC purification is shown in Figure 4 As shown, the calculations show that the test results are consistent with the chemical structure of intermediate 3.

[0115] 4. Preparation of pure hydroxytyrosol

[0116]

[0117] 1055 g of intermediate 3 (Mr=280, 3.611 mol), 2 kg of concentrated hydrochloric acid and 6 L of methanol were added to the reactor in sequence, and the temperature of the reactants was raised to 90° C. After stirring and reacting for 3 hours, the temperature was lowered to 20° C. and then washed with dichloromethane, methyl tert-butyl ether and purified water in sequence. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent to obtain 497 g of light yellow oily substance as pure hydroxytyrosol (Mr=154, 3.207 mol). The reaction yield was 88.8%, and the HPLC purity was 99.37%. The HPLC spectrum of pure hydroxytyrosol is shown in Figure 5 When the intermediate 2 was determined by the method of Experimental Example 1, the above HPLC conditions were used. When the pure hydroxytyrosol product was determined, the mobile phase flow rate was changed to 0.95 ml / min to improve the separation performance, which resulted in Figure 2 and Figure 5 The retention time of the reaction mixture was slightly different. The total yield of the four-step reaction in this embodiment was 71.9%. In this embodiment, it was unexpectedly found that the combination of process conditions of the present invention, such as the combination of acetic anhydride, boron trifluoride, ethyl acetate / acetone mixed solvent, and 60% ethanol in step 3 and the combination of concentrated hydrochloric acid and methanol in step 4, showed excellent results of high yield and high purity product.

[0118] Example 2: Preparation of Hydroxytyrosol

[0119] 1. Preparation of Intermediate 1

[0120] 1000 g of 4-hydroxyphenylethanol, 5.5 L of water, 1.2 kg of sodium bromide, 2.4 kg of potassium peroxymonosulfonate and 2.2 L of acetone were added to the reactor in sequence. After the addition was completed, the mixture was stirred at room temperature and reacted for 2.5 hours. The reaction solution was concentrated in vacuo to remove the solvent, and the crystals were precipitated. The crystals were filtered and the filter cake was dried in a vacuum drying oven to obtain intermediate 1 with a reaction yield of 95.8% and a HPLC purity of 99.4%.

[0121] 2. Preparation of Intermediate 2

[0122] 1300g of intermediate 1, 0.09kg of cuprous iodide, 1.45kg of potassium hydroxide and 4.5L of water were added to the reactor in sequence, the temperature was raised to 95°C, the reaction was carried out for 4.5 hours, the temperature was lowered to 20°C, concentrated hydrochloric acid was added to acidify to pH = 2, the insoluble solid was removed by filtration, the filtrate was washed with 2.5L of dichloromethane, the aqueous layer was saturated with sodium chloride, the organic phase was dried over anhydrous sodium sulfate, the organic phase was concentrated to remove the solvent, and the intermediate 2 was obtained as a viscous oil with a reaction yield of 93.1% and a HPLC purity of 91.4%.

[0123] 3. Preparation of Intermediate 3

[0124] 720 g of intermediate 2, 1.2 kg of acetic anhydride, 1 kg of boron trifluoride ether solution, and 4.5 L of ethyl acetate / acetone (4:1) were added to the reactor in sequence and reacted at room temperature; after the reaction was completed, the reaction solution was washed with purified water, filtered, the filtrate was dried over anhydrous sodium sulfate, and concentrated to remove the solvent; then 1 L of 65% ethanol solution was added, and crystals precipitated after stirring at -10°C. The crystals were filtered and the filter cake was dried in a vacuum drying oven to obtain intermediate 3 with a reaction yield of 91.2%, a HPLC purity of 95.4%, and a nuclear magnetic resonance spectrum consistent with the chemical structure of intermediate 3.

[0125] 4. Preparation of pure hydroxytyrosol

[0126] 1055 g of intermediate 3, 1.8 kg of concentrated hydrochloric acid and 6.5 L of methanol were added to the reactor in sequence, and the temperature of the reactants was raised to 85 ° C. After stirring for 3.5 hours, the temperature was lowered to 20 ° C. and then washed with dichloromethane, methyl tert-butyl ether and purified water in sequence. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent to obtain a light yellow oily substance as pure hydroxytyrosol. The reaction yield was 89.3% and the HPLC purity was 99.24%.

[0127] Example 3: Preparation of Hydroxytyrosol

[0128] 1. Preparation of Intermediate 1

[0129] 1000 g of 4-hydroxyphenylethanol, 4.5 L of water, 1.0 kg of sodium bromide, 2.6 kg of potassium peroxymonosulfonate and 1.8 L of acetone were added to the reactor in sequence. After the addition was completed, the mixture was stirred at room temperature and reacted for 3.5 hours. The reaction solution was concentrated in vacuo to remove the solvent, and crystals were precipitated. The crystals were filtered and the filter cake was dried in a vacuum drying oven to obtain intermediate 1 with a reaction yield of 95.2% and an HPLC purity of 99.1%.

[0130] 2. Preparation of Intermediate 2

[0131] 1300g of intermediate 1, 0.11kg of cuprous iodide, 1.25kg of potassium hydroxide and 5.5L of water were added to the reactor in sequence, the temperature was raised to 85°C, the reaction was carried out for 5.5 hours, the temperature was lowered to 20°C, concentrated hydrochloric acid was added to acidify to pH = 2, the insoluble solid was removed by filtration, the filtrate was washed with 1.5L of dichloromethane, the aqueous layer was saturated with sodium chloride, the organic phase was dried over anhydrous sodium sulfate, the organic phase was concentrated to remove the solvent, and the intermediate 2 was obtained as a viscous oil with a reaction yield of 92.8% and a HPLC purity of 91.7%.

[0132] 3. Preparation of Intermediate 3

[0133] 720 g of intermediate 2, 1.1 kg of acetic anhydride, 1.2 kg of boron trifluoride ether solution, and 5.5 L of ethyl acetate / acetone (4:1) were added to the reactor in sequence and reacted at room temperature; after the reaction was completed, the reaction solution was washed with purified water, filtered, the filtrate was dried over anhydrous sodium sulfate, and concentrated to remove the solvent; then 1 L of 55% ethanol solution was added, and crystals precipitated after stirring at -10°C. The crystals were filtered and the filter cake was dried in a vacuum drying oven to obtain intermediate 3 with a reaction yield of 89.8%, an HPLC purity of 95.2%, and a nuclear magnetic resonance spectrum consistent with the chemical structure of intermediate 3.

[0134] 4. Preparation of pure hydroxytyrosol

[0135] 1055 g of intermediate 3, 2.2 kg of concentrated hydrochloric acid and 5.5 L of methanol were added to the reactor in sequence, and the temperature of the reactants was raised to 95 ° C. After stirring and reacting for 2.5 hours, the temperature was lowered to 20 ° C. and then washed with dichloromethane, methyl tert-butyl ether and purified water in sequence. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent to obtain a light yellow oily substance as pure hydroxytyrosol. The reaction yield was 90.1% and the HPLC purity was 99.33%.

[0136] Example 4: Preparation of Hydroxytyrosol

[0137] Steps 1 and 2 of this embodiment are performed with reference to Example 1, but some changes are made to step 3, as follows.

[0138] Preparation of intermediate 3

[0139] 720 g of intermediate 2, 1.17 kg of acetic anhydride, 1.1 kg of boron trifluoride ether solution, and 5 L of ethyl acetate / acetone (6:1) were added to the reactor in sequence and reacted at room temperature. After the reaction was completed, the reaction solution was washed with purified water, filtered, the filtrate was dried over anhydrous sodium sulfate, and concentrated to remove the solvent. Then 1 L of 60% ethanol solution was added, and crystals precipitated after stirring at -10°C. The crystals were filtered and the filter cake was dried in a vacuum drying oven to obtain intermediate 3 with a reaction yield of 76.5% and a HPLC purity of 87.4%.

[0140] Preparation of intermediate 3

[0141] 720 g of intermediate 2, 1.17 kg of acetic anhydride, 1.1 kg of boron trifluoride ether solution and 5 L of ethyl acetate were added to the reactor in sequence and reacted at room temperature. After the reaction was completed, the reaction solution was washed with purified water, filtered, the filtrate was dried over anhydrous sodium sulfate, and concentrated to remove the solvent. Then 1 L of 60% ethanol solution was added, and crystals precipitated after stirring at -10°C. The crystals were filtered and the filter cake was dried in a vacuum drying oven to obtain intermediate 3 with a reaction yield of 69.8% and a HPLC purity of 89.1%.

[0142] Preparation of intermediate 3

[0143] 720 g of intermediate 2, 1.17 kg of acetic anhydride, 1.1 kg of boron trifluoride ether solution, and 5 L of ethyl acetate / acetone (1:1) were added to the reactor in sequence and reacted at room temperature. After the reaction was completed, the reaction solution was washed with purified water, filtered, the filtrate was dried over anhydrous sodium sulfate, and concentrated to remove the solvent. Then 1 L of 60% ethanol solution was added, and crystals precipitated after stirring at -10°C. The crystals were filtered and the filter cake was dried in a vacuum drying oven to obtain intermediate 3 with a reaction yield of 63.4% and a HPLC purity of 91.4%.

[0144] Preparation of intermediate 3

[0145] 720 g of intermediate 2, 1.17 kg of acetic anhydride, 1.1 kg of boron trifluoride ether solution and 5 L of acetone were added to the reactor in sequence and reacted at room temperature. After the reaction was completed, the reaction solution was washed with purified water, filtered, the filtrate was dried over anhydrous sodium sulfate, and concentrated to remove the solvent. Then 1 L of 60% ethanol solution was added, and crystals were precipitated after stirring at -10°C. The crystals were filtered and the filter cake was dried in a vacuum drying oven to obtain intermediate 3 with a reaction yield of 52.6% and a HPLC purity of 90.6%.

[0146] Since the reaction yield of the step of preparing intermediate 3 was not satisfactory, the product of this step was not used to further proceed to the next step 4. According to the above experiments, changing the solvent and / or ratio of the esterification reaction will significantly affect the reaction yield. After reducing the proportion of acetone, the yield showed a downward trend, and the degree of downward trend was more obvious after reducing the proportion of ethyl acetate. According to the context, using ethyl acetate / acetone (4:1) as a reaction solvent under the conditions of using acetic anhydride and boron trifluoride can obtain the best yield and the product purity is also the highest.

[0147] Example 5: Preparation of Hydroxytyrosol

[0148] Steps 1 and 2 of this embodiment are performed with reference to Example 1, but some changes are made to step 3, as follows.

[0149] Preparation of intermediate 3

[0150] 720 g of intermediate 2, 1.17 kg of acetic anhydride, 1.1 kg of boron trifluoride ether solution, and 5 L of ethyl acetate / acetone (4:1) were added to the reactor in sequence and reacted at room temperature. After the reaction was completed, the reaction solution was washed with purified water, filtered, the filtrate was dried over anhydrous sodium sulfate, and concentrated to remove the solvent. Then 1 L of 35% ethanol solution was added, and crystals precipitated after stirring at -10°C. The crystals were filtered and the filter cake was dried in a vacuum drying oven to obtain intermediate 3 with a reaction yield of 80.3% and a HPLC purity of 94.7%.

[0151] Preparation of intermediate 3

[0152] 720 g of intermediate 2, 1.17 kg of acetic anhydride, 1.1 kg of boron trifluoride ether solution, and 5 L of ethyl acetate / acetone (4:1) were added to the reactor in sequence and reacted at room temperature. After the reaction was completed, the reaction solution was washed with purified water, filtered, the filtrate was dried over anhydrous sodium sulfate, and concentrated to remove the solvent. Then 1 L of 10% ethanol solution was added, and crystals precipitated after stirring at -10°C. The crystals were filtered and the filter cake was dried in a vacuum drying oven to obtain intermediate 3 with a reaction yield of 68.2% and a HPLC purity of 96.1%.

[0153] Preparation of intermediate 3

[0154] 720 g of intermediate 2, 1.17 kg of acetic anhydride, 1.1 kg of boron trifluoride ether solution, and 5 L of ethyl acetate / acetone (4:1) were added to the reactor in sequence and reacted at room temperature. After the reaction was completed, the reaction solution was washed with purified water, filtered, the filtrate was dried over anhydrous sodium sulfate, and concentrated to remove the solvent. 1 L of water was added, and crystals precipitated after stirring at -10°C. The crystals were filtered and the filter cake was dried in a vacuum drying oven to obtain intermediate 3 with a reaction yield of 46.5% and a HPLC purity of 93.5%.

[0155] Preparation of intermediate 3

[0156] 720 g of intermediate 2, 1.17 kg of acetic anhydride, 1.1 kg of boron trifluoride ether solution, and 5 L of ethyl acetate / acetone (4:1) were added to the reactor in sequence and reacted at room temperature. After the reaction was completed, the reaction solution was washed with purified water, filtered, the filtrate was dried over anhydrous sodium sulfate, and concentrated to remove the solvent. Then 1 L of 85% ethanol solution was added, and crystals precipitated after stirring at -10°C. The crystals were filtered and the filter cake was dried in a vacuum drying oven to obtain intermediate 3 with a reaction yield of 82.2% and a HPLC purity of 92.7%.

[0157] Preparation of intermediate 3

[0158] 720 g of intermediate 2, 1.17 kg of acetic anhydride, 1.1 kg of boron trifluoride ether solution, and 5 L of ethyl acetate / acetone (4:1) were added to the reactor in sequence and reacted at room temperature. After the reaction was completed, the reaction solution was washed with purified water, filtered, the filtrate was dried over anhydrous sodium sulfate, and concentrated to remove the solvent. Then 1 L of 98% ethanol solution was added, and crystals precipitated after stirring at -10°C. The crystals were filtered and the filter cake was dried in a vacuum drying oven to obtain intermediate 3 with a reaction yield of 70.4% and a HPLC purity of 94.1%.

[0159] Since the reaction yield of the step of preparing intermediate 3 was not satisfactory, the product of this step was not used to further proceed to the next step 4. According to the above experiments in this example, it can be seen that under the experimental conditions of Example 1, changing the amount of water in the crystallization solvent ethanol will affect the yield, showing that 55-65% ethanol can obtain a significantly higher yield than lower or higher concentrations of ethanol, and has little effect on the purity of the product.

[0160] Example 6: Preparation of Hydroxytyrosol

[0161] Steps 1 and 2 of this embodiment are performed with reference to Example 1, but some changes are made to step 3, as follows.

[0162] Preparation of intermediate 3

[0163] 720 g of intermediate 2, 1.17 kg of acetic anhydride, 150 g of p-toluenesulfonic acid monohydrate, and 5 L of ethyl acetate / acetone (4:1) were added to the reactor in sequence and reacted at room temperature. After the reaction was completed, the reaction solution was washed with purified water, filtered, the filtrate was dried over anhydrous sodium sulfate, and concentrated to remove the solvent. Then 1 L of 60% ethanol solution was added, and crystals precipitated after stirring at -10°C. The crystals were filtered and the filter cake was dried in a vacuum drying oven to obtain intermediate 3 with a reaction yield of 54.8% and a HPLC purity of 87.5%.

[0164] Preparation of intermediate 3

[0165] 720 g of intermediate 2, 1.17 kg of acetic anhydride, 125 g of 4-dimethylaminopyridine (DMAP), and 5 L of ethyl acetate / acetone (4:1) were added to the reactor in sequence and reacted at room temperature. After the reaction was completed, the reaction solution was washed with purified water, filtered, the filtrate was dried over anhydrous sodium sulfate, and concentrated to remove the solvent. Then 1 L of 60% ethanol solution was added, and crystals precipitated after stirring at -10°C. The crystals were filtered and the filter cake was dried in a vacuum drying oven to obtain intermediate 3 with a reaction yield of 65.4% and a HPLC purity of 90.4%.

[0166] Preparation of intermediate 3

[0167] 720 g of intermediate 2, 1.17 kg of acetic anhydride, 150 g of sodium bisulfite-silica complex (NaHSO4·SiO2), and 5 L of ethyl acetate / acetone (4:1) were added to a reactor in sequence and reacted at room temperature. After the reaction was completed, the reaction solution was washed with purified water, filtered, the filtrate was dried over anhydrous sodium sulfate, and concentrated to remove the solvent. Then 1 L of 60% ethanol solution was added, and crystals precipitated after stirring at -10°C. The crystals were filtered and the filter cake was dried in a vacuum drying oven to obtain intermediate 3 with a reaction yield of 60.2% and a HPLC purity of 86.4%.

[0168] Since the reaction yield of the step of preparing intermediate 3 was not satisfactory, the product of this step was not used to further proceed to the next step 4. In this example, it was found that under the experimental conditions of Example 1, when the catalyst for the esterification reaction was changed, the reaction yield and product HPLC purity were significantly lower than those under the conditions of Example 1 using boron trifluoride.

[0169] Example 7: Preparation of Hydroxytyrosol

[0170] Steps 1, 2, and 3 of this embodiment are performed with reference to Example 1, but some changes are made to step 4, as follows.

[0171] 1055 g of intermediate 3, 800 g of potassium hydroxide and 6 L of methanol were added to the reactor in sequence, and the reactants were heated to 90° C. and stirred for reaction for 3 hours. The reactants were then cooled to 20° C. and washed with dichloromethane, methyl tert-butyl ether and purified water in sequence. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to remove the solvent. The obtained product was a dark reddish brown oil, which was a typical state of oxidized hydroxytyrosol (high-purity pure hydroxytyrosol was a light yellow oil, which gradually darkened in color to dark red to brown after being placed in a glass dish open for 2 weeks).

[0172] 1055 g of intermediate 3, 700 g of sodium hydroxide and 6 L of methanol were added to the reactor in sequence, and the temperature of the reactants was raised to 90° C. After stirring and reacting for 3 hours, the temperature was lowered to 20° C. and then washed with dichloromethane, methyl tert-butyl ether and purified water in sequence. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The obtained product was a dark reddish brown oil, which was a typical state of hydroxytyrosol oxidation.

[0173] 1055 g of intermediate 3, 2 kg of concentrated hydrochloric acid and 5 L of ethanol were added to the reactor in sequence, and the temperature of the reactants was raised to 90 ° C. After stirring for 3 hours, the temperature was lowered to 20 ° C. and then washed with dichloromethane, methyl tert-butyl ether and purified water in sequence. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent to obtain a light yellow oily substance as pure hydroxytyrosol. The reaction yield was 87.7% and the HPLC purity was 90.67%.

[0174] 1055 g of intermediate 3, 2 kg of concentrated hydrochloric acid and 5 L of isopropanol were added to the reactor in sequence, and the temperature of the reactants was raised to 90 ° C. After stirring for 3 hours, the temperature was lowered to 20 ° C. and then washed with dichloromethane, methyl tert-butyl ether and purified water in sequence. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent to obtain a light yellow oily substance as pure hydroxytyrosol. The reaction yield was 86.3% and the HPLC purity was 92.13%.

[0175] As is known to all, esters can be hydrolyzed under acidic or alkaline conditions. Generally speaking, alkali is usually used to hydrolyze esters due to the applicability of reaction conditions and production operations. However, the above two experiments show that the use of alkali to hydrolyze esters is likely to cause oxidation of hydroxytyrosol.

[0176] In addition, it can be seen from the above experiments that when concentrated hydrochloric acid is used for hydrolysis, there is no significant difference in reaction yield when methanol, ethanol, and isopropanol are used as solvents, but the purity of the product when ethanol and isopropanol are used is significantly lower than that when methanol is used.

[0177] Test Example 1: HPLC Purity Determination Method for Hydroxytyrosol

[0178] 1. Chromatographic conditions

[0179] Chromatographic column: Servo-AQ C18 (4.6mm*250mm, 5μm);

[0180] Mobile phase A: 10 mmol / L potassium dihydrogen phosphate aqueous solution, pH = 7.00;

[0181] Mobile phase B: methanol;

[0182] Solvent: 50% methanol in water;

[0183] Elution gradient:

[0184] Time (min) A％ B％ 0.00 98.0 2.0 10.00 90.0 10.0 25.00 75.0 25.0 35.00 75.0 25.0 55.00 40.0 60.0 70.00 40.0 60.0 71.00 98.0 2.0 80.00 98.0 2.0

[0185] Detection wavelength: 270nm;

[0186] Flow rate: 1.0ml / min;

[0187] Column temperature: 30°C;

[0188] Injection volume: 10 μl.

[0189] 2. Determination steps

[0190] (1) Mobile phase preparation

[0191] Mobile phase A: Take 1.36g of potassium dihydrogen phosphate, dissolve it in water and dilute it to 1000ml, mix well, adjust the pH value to 7.00 with 1mol / L potassium hydroxide solution, filter through a 0.22μm water filter membrane, and degas by ultrasonication;

[0192] Mobile phase B: Take methanol and degas by ultrasonication.

[0193] (2) Preparation of solvent: Measure 100 ml of methanol and 100 ml of water into a beaker and mix well to obtain a 50% methanol aqueous solution;

[0194] (3) Preparation of test solution

[0195] Blank sample: that is, the solvent, filter, and take the filtrate;

[0196] Starting material (4-hydroxyphenylethanol): Take about 40 mg of 4-hydroxyphenylethanol sample, accurately weigh it, put it in a 10 ml volumetric flask, add solvent to dissolve and dilute to the scale, shake well, filter, and take the filtrate to obtain;

[0197] Intermediate 1: Take about 40 mg of intermediate 1 sample, weigh accurately, put into a 10 ml volumetric flask, add solvent to dissolve and dilute to scale, shake well, filter, and take the filtrate to obtain;

[0198] Intermediate 2 and finished product (hydroxytyrosol): Take about 20-60 mg of hydroxytyrosol sample (it is a viscous oily substance, which is not convenient to weigh. A wider range of amounts can be weighed, and the amount weighed does not affect the HPLC area normalized purity determination), accurately weigh, place in a 10 ml volumetric flask, add solvent to dilute to the scale, shake well, filter, and take the filtrate to obtain.

[0199] The above HPLC conditions were used for the determination of intermediate 2. When the finished product hydroxytyrosol was determined, the mobile phase was changed to 0.95 ml / min to improve the separation performance, which resulted in Figure 2 and Figure 5 In addition, when determining intermediate 3, the Thermo Scientific TM Acclaim TM 120 C18 chromatographic column, and the mobile phase was changed to 75% acetonitrile isocratic elution, and other chromatographic conditions were the same as above.

[0200] Example 8: Preparation of Hydroxytyrosol

[0201] 1. Preparation of Intermediate 1

[0202] 10 kg of 4-hydroxyphenylethanol, 50 L of water, 10.9 kg of sodium bromide, 25 kg of potassium peroxymonosulfonate and 20 L of acetone were added to the reactor in sequence. After the addition was completed, the mixture was stirred at room temperature and reacted for 4 hours. The reaction solution was concentrated in vacuo to remove the solvent, and crystals were precipitated. The crystals were filtered and the filter cake was dried in a vacuum drying oven to obtain intermediate 1. The reaction yield was 93.6% and the HPLC purity was 99.3%.

[0203] 2. Preparation of Intermediate 2

[0204] 13 kg of intermediate 1, 1 kg of cuprous iodide, 13.5 kg of potassium hydroxide and 50 L of water were added to the reactor in sequence, the temperature was raised to 90 ° C, the reaction was carried out for 6 hours, the temperature was lowered to 20 ° C, concentrated hydrochloric acid was added to acidify to pH = 2, the insoluble solid was removed by filtration, the filtrate was washed with 20 L of dichloromethane, the aqueous layer was saturated with sodium chloride, the organic phase was dried over anhydrous sodium sulfate, the organic phase was concentrated to remove the solvent, and the intermediate 2 was obtained as a viscous oil with a reaction yield of 93.1% and an HPLC purity of 91.5%.

[0205] 3. Preparation of Intermediate 3

[0206] 7.2 kg of intermediate 2, 11.7 kg of acetic anhydride, 11 kg of boron trifluoride ether solution, and 50 L of ethyl acetate / acetone (4:1) were added to the reactor in sequence and reacted at room temperature. After the reaction was completed, the reaction solution was washed with purified water, filtered, the filtrate was dried over anhydrous sodium sulfate, and concentrated to remove the solvent. Then 10 L of 60% ethanol solution was added, and crystals precipitated after stirring at -10°C. The crystals were filtered and the filter cake was dried in a vacuum drying oven to obtain intermediate 3 with a reaction yield of 90.7% and an HPLC purity of 95.3%.

[0207] 4. Preparation of pure hydroxytyrosol

[0208] 10.55 kg of intermediate 3, 20 kg of concentrated hydrochloric acid and 60 L of methanol were added to the reactor in sequence, and the temperature of the reactants was raised to 90 ° C. After stirring and reacting for 4 hours, the temperature was lowered to 20 ° C. and then washed with dichloromethane, methyl tert-butyl ether and purified water in sequence. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent to obtain a light yellow oily substance as pure hydroxytyrosol. The reaction yield was 90.2%, the HPLC purity was 99.16%, and the total yield of the four-step reaction was 71.3%.

[0209] Example 9: Preparation of Hydroxytyrosol

[0210] 1. Preparation of Intermediate 1

[0211] 25 kg of 4-hydroxyphenylethanol, 125 L of water, 27.25 kg of sodium bromide, 62.5 kg of potassium peroxymonosulfonate and 50 L of acetone were added to the reactor in sequence. After the addition was completed, the mixture was stirred at room temperature and reacted for 4.5 hours. The reaction solution was concentrated in vacuo to remove the solvent, and crystals were precipitated. The crystals were filtered and the filter cake was dried in a vacuum drying oven to obtain intermediate 1. The reaction yield was 94.2% and the HPLC purity was 99.1%.

[0212] 2. Preparation of Intermediate 2

[0213] 32.5 kg of intermediate 1, 2.5 kg of cuprous iodide, 33.75 kg of potassium hydroxide and 125 L of water were added to the reactor in sequence, the temperature was raised to 90 ° C, the reaction was carried out for 6.5 hours, the temperature was lowered to 20 ° C, concentrated hydrochloric acid was added to acidify to pH = 2, the insoluble solid was removed by filtration, the filtrate was washed with 2 L of dichloromethane, the aqueous layer was saturated with sodium chloride, the organic phase was dried over anhydrous sodium sulfate, the organic phase was concentrated to remove the solvent, and the intermediate 2 was obtained as a viscous oil with a reaction yield of 93.7% and an HPLC purity of 90.7%.

[0214] 3. Preparation of Intermediate 3

[0215] 18 g of intermediate 2, 29.25 kg of acetic anhydride, 27.5 kg of boron trifluoride ether solution, and 125 L of ethyl acetate / acetone (4:1) were added to the reactor in sequence and reacted at room temperature. After the reaction was completed, the reaction solution was washed with purified water, filtered, the filtrate was dried over anhydrous sodium sulfate, and concentrated to remove the solvent. Then 25 L of 60% ethanol solution was added, and crystals precipitated after stirring at -10°C. The crystals were filtered and the filter cake was dried in a vacuum drying oven to obtain intermediate 3 with a reaction yield of 89.8% and an HPLC purity of 96.2%.

[0216] 4. Preparation of pure hydroxytyrosol

[0217] 26.375 kg of intermediate 3, 50 kg of concentrated hydrochloric acid and 150 L of methanol were added to the reactor in sequence, and the temperature of the reactants was raised to 90 ° C. After stirring and reacting for 4 hours, the temperature was lowered to 20 ° C. and then washed with dichloromethane, methyl tert-butyl ether and purified water in sequence. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent to obtain a light yellow oily substance as pure hydroxytyrosol. The reaction yield was 89.4%, the HPLC purity was 99.24%, and the total yield of the four-step reaction was 70.9%.

[0218] In Example 1, Example 8 and Example 9, the feed was respectively added at a scale of 1 k, a scale of 10 kg and a scale of 25 kg. The yields and the product purities were substantially the same during production at different scales, indicating that the method of the present invention is suitable for producing hydroxytyrosol at different scales.

[0219] The present invention illustrates the detailed method of the present invention through the above-mentioned embodiments, but the present invention is not limited to the above-mentioned detailed method, that is, it does not mean that the present invention must rely on the above-mentioned detailed method to be implemented. Those skilled in the art should understand that any improvement of the present invention, equivalent replacement of various raw materials of the product of the present invention, addition of auxiliary components, selection of specific methods, etc., all fall within the protection scope and disclosure scope of the present invention.

Claims

1. A method for preparing hydroxytyrosol, comprising the steps of: (s1) Preparation of Intermediate 1: 4-Hydroxyphenylethanol, water, sodium bromide, potassium peroxymonosulfonate and acetone were added to a reaction kettle in sequence. After the addition was completed, the mixture was stirred at room temperature to react. The reaction solution was concentrated in vacuo to remove the solvent, and crystals were precipitated. The crystals were filtered and the filter cake was dried in a vacuum drying oven to obtain the intermediate 1 of the following formula: ； (s2) Preparation of intermediate 2: intermediate 1, cuprous iodide, potassium hydroxide and water were added to a reaction kettle in sequence, the temperature was raised for reaction, concentrated hydrochloric acid was added to acidify to pH = 2 after cooling, insoluble solids were removed by filtration, the filtrate was washed with dichloromethane, sodium chloride was added to the aqueous layer to saturate, the layers were separated, the organic phase was dried over anhydrous sodium sulfate, the organic phase was concentrated to remove the solvent, and the intermediate 2 of the following formula was obtained as a viscous oil: ； (s3) Preparation of intermediate 3: intermediate 2, acetic anhydride, boron trifluoride ether solution, and ethyl acetate / acetone mixture are sequentially added to a reaction kettle and reacted at room temperature; after the reaction is completed, the reaction solution is washed with purified water, filtered, the filtrate is dried over anhydrous sodium sulfate, and concentrated to remove the solvent; then ethanol solution is added, and crystals are precipitated after low-temperature stirring, which is filtered and the filter cake is dried in a vacuum drying oven to obtain intermediate 3 of the following formula; ； (s4) Preparation of pure hydroxytyrosol: intermediate 3, concentrated hydrochloric acid and methanol are sequentially added to a reaction vessel, the temperature of the reactants is raised, stirred to react, cooled, and then washed with dichloromethane, methyl tert-butyl ether and purified water in sequence. The organic phase is dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent to obtain a light yellow oily substance as pure hydroxytyrosol represented by the following formula: 。 2. The method according to claim 1, wherein in step (s1), the intermediate 1 is prepared by feeding the following materials in the following proportions: 1000 g of 4-hydroxyphenylethanol, 4.5-5.5 L of water, 1-1.2 kg of sodium bromide, 2.4-2.6 kg of potassium peroxymonosulfonate, and 1.8-2.2 L of acetone are sequentially added into a reactor, and after the addition is completed, the mixture is stirred at room temperature to react for 2.5-3.5 hours; the reaction solution is vacuum concentrated to remove the solvent, crystals are precipitated, filtered, and the filter cake is dried in a vacuum drying oven to obtain the intermediate 1.

3. The method according to claim 1, wherein in step (s2), the reactants are heated to 85-95° C. for reaction.

4. The method according to claim 1, wherein in step (s2), the reactants are cooled to 20°C and then acidified.

5. According to the method of claim 1, step (s2) prepares intermediate 2 in the following proportions: 1300g intermediate 1, 0.09-0.11kg cuprous iodide, 1.25-1.45kg potassium hydroxide, and 4.5-5.5L water are sequentially added into a reactor, the temperature is raised to 85-95°C, the reaction is carried out for 4.5 hours, the temperature is lowered to 20°C, concentrated hydrochloric acid is added to acidify to pH=2, insoluble solids are removed by filtration, the filtrate is washed with 1.5-2.5L dichloromethane, the aqueous layer is saturated with sodium chloride, the layers are separated, the organic phase is dried over anhydrous sodium sulfate, the organic phase is concentrated to remove the solvent, and intermediate 2 is obtained as a viscous oil.

6. The method according to claim 1, wherein in step (s3), the ethyl acetate / acetone mixture is a mixture of ethyl acetate and acetone in a volume ratio of 4:

1.

7. according to the method for claim 1, wherein in step (s3), the ethanol solution is 55% ~ 65% ethanol solution.

8. The method according to claim 1, wherein in step (s3), the low-temperature stirring is stirring at -10°C.

9. According to the method of claim 1, in step (s3), the intermediate 3 is prepared by adding materials in the following proportions: 720 g of the intermediate 2, 1.1-1.2 kg of acetic anhydride, 1-1.2 kg of boron trifluoride ether solution, and 4.5-5.5 L of ethyl acetate / acetone with a volume ratio of 4:1 are sequentially added into a reactor, and reacted at room temperature; after the reaction is completed, the reaction solution is washed with purified water, filtered, the filtrate is dried over anhydrous sodium sulfate, and concentrated to remove the solvent; then 1 L of 55-65% ethanol solution is added, and crystals are precipitated after stirring at -10°C, which are filtered and the filter cake is dried in a vacuum drying oven to obtain the intermediate 3.

10. The method according to claim 1, wherein in step (s4), the reactants are heated to 85-95°C for reaction.

11. The method according to claim 1, wherein in step (s4), the reaction is stirred for 2.5 to 3.5 hours.

12. The method according to claim 1, wherein in step (s4), after stirring and reacting for 2.5 to 3.5 hours, the temperature is lowered to 20°C.

13. According to the method of claim 1, in step (s4), the following proportions are used to prepare pure hydroxytyrosol: 1055 g of intermediate 3, 1.8-2.2 kg of concentrated hydrochloric acid, and 5.5-6.5 L of methanol are sequentially added into a reaction kettle, the temperature of the reactants is raised to 85-95° C., stirred and reacted for 2.5-3.5 hours, then cooled to 20° C., and then washed with dichloromethane, methyl tert-butyl ether, and purified water in sequence, the organic phase is dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent to obtain a light yellow oily substance as pure hydroxytyrosol.

14. The method according to claim 1, comprising the step of feeding materials in the following proportions: (s1) Preparation of intermediate 1: 1000 g of 4-hydroxyphenylethanol, 5 L of water, 1.09 kg of sodium bromide, 2.5 kg of potassium peroxymonosulfonate, and 2 L of acetone were added to a reaction kettle in sequence. After the addition was completed, the mixture was stirred at room temperature and reacted for 3 hours. The reaction solution was concentrated in vacuo to remove the solvent, and crystals were precipitated. The crystals were filtered and the filter cake was dried in a vacuum drying oven to obtain intermediate 1. (s2) Preparation of intermediate 2: 1300 g of intermediate 1, 0.1 kg of cuprous iodide, 1.35 kg of potassium hydroxide and 5 L of water were added to a reaction kettle in sequence, the temperature was raised to 90°C, the reaction was carried out for 5 hours, the temperature was lowered to 20°C, concentrated hydrochloric acid was added to acidify to pH = 2, the insoluble solid was removed by filtration, the filtrate was washed with 2 L of dichloromethane, the aqueous layer was saturated with sodium chloride, the layers were separated, the organic phase was dried over anhydrous sodium sulfate, the organic phase was concentrated to remove the solvent, and intermediate 2 was obtained as a viscous oil; (s3) Preparation of intermediate 3: 720 g of intermediate 2, 1.17 kg of acetic anhydride, 1.1 kg of boron trifluoride ether solution, and 5 L of ethyl acetate / acetone with a volume ratio of 4:1 were added to a reaction kettle in sequence, and reacted at room temperature; after the reaction was completed, the reaction solution was washed with purified water, filtered, the filtrate was dried over anhydrous sodium sulfate, and concentrated to remove the solvent; then 1 L of 60% ethanol solution was added, and crystals were precipitated after stirring at -10°C, which were filtered and the filter cake was dried in a vacuum drying oven to obtain intermediate 3; (s4) Preparation of pure hydroxytyrosol: 1055 g of intermediate 3, 2 kg of concentrated hydrochloric acid and 6 L of methanol were added to a reaction kettle in sequence, and the temperature of the reactants was raised to 90° C. and stirred for reaction for 3 hours. The temperature was then lowered to 20° C. and the reactants were washed with dichloromethane, methyl tert-butyl ether and purified water in sequence. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent to obtain a light yellow oily substance as pure hydroxytyrosol.

15. The method according to claim 1, comprising the step of feeding materials in the following proportions: (s1) Preparation of intermediate 1: 1000 g of 4-hydroxyphenylethanol, 5.5 L of water, 1.2 kg of sodium bromide, 2.4 kg of potassium peroxymonosulfonate, and 2.2 L of acetone were added to a reaction kettle in sequence. After the addition was completed, the mixture was stirred at room temperature and reacted for 2.5 hours; the reaction solution was concentrated in vacuo to remove the solvent, crystals were precipitated, filtered, and the filter cake was dried in a vacuum drying oven to obtain intermediate 1; (s2) Preparation of intermediate 2: 1300 g of intermediate 1, 0.09 kg of cuprous iodide, 1.45 kg of potassium hydroxide and 4.5 L of water were added to a reaction kettle in sequence, the temperature was raised to 95°C, the reaction was carried out for 4.5 hours, the temperature was lowered to 20°C, concentrated hydrochloric acid was added to acidify to pH = 2, the insoluble solid was removed by filtration, the filtrate was washed with 2.5 L of dichloromethane, the aqueous layer was saturated with sodium chloride, the layers were separated, the organic phase was dried over anhydrous sodium sulfate, the organic phase was concentrated to remove the solvent, and intermediate 2 was obtained as a viscous oil; (s3) Preparation of intermediate 3: 720 g of intermediate 2, 1.2 kg of acetic anhydride, 1 kg of boron trifluoride ether solution, and 4.5 L of ethyl acetate / acetone with a volume ratio of 4:1 were added to a reaction kettle in sequence, and reacted at room temperature; after the reaction was completed, the reaction solution was washed with purified water, filtered, the filtrate was dried over anhydrous sodium sulfate, and concentrated to remove the solvent; then 1 L of 65% ethanol solution was added, and crystals were precipitated after stirring at -10°C, which were filtered and the filter cake was dried in a vacuum drying oven to obtain intermediate 3; (s4) Preparation of pure hydroxytyrosol: 1055 g of intermediate 3, 1.8 kg of concentrated hydrochloric acid and 6.5 L of methanol were added to a reaction kettle in sequence, and the temperature of the reactants was raised to 85° C. and stirred for reaction for 3.5 hours. The temperature was then lowered to 20° C. and the reactants were washed with dichloromethane, methyl tert-butyl ether and purified water in sequence. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent to obtain a light yellow oily substance as pure hydroxytyrosol.

16. The method according to claim 1, comprising the step of feeding materials in the following proportions: (s1) Preparation of intermediate 1: 1000 g of 4-hydroxyphenylethanol, 4.5 L of water, 1.0 kg of sodium bromide, 2.6 kg of potassium peroxymonosulfonate, and 1.8 L of acetone were added to a reaction kettle in sequence. After the addition was completed, the mixture was stirred at room temperature and reacted for 3.5 hours; the reaction solution was concentrated in vacuo to remove the solvent, crystals were precipitated, and the crystals were filtered. The filter cake was dried in a vacuum drying oven to obtain intermediate 1; (s2) Preparation of intermediate 2: 1300 g of intermediate 1, 0.11 kg of cuprous iodide, 1.25 kg of potassium hydroxide and 5.5 L of water were added to a reaction kettle in sequence, the temperature was raised to 85°C, the reaction was carried out for 5.5 hours, the temperature was lowered to 20°C, concentrated hydrochloric acid was added to acidify to pH = 2, the insoluble solid was removed by filtration, the filtrate was washed with 1.5 L of dichloromethane, the aqueous layer was saturated with sodium chloride, the layers were separated, the organic phase was dried over anhydrous sodium sulfate, the organic phase was concentrated to remove the solvent, and intermediate 2 was obtained as a viscous oil; (s3) Preparation of intermediate 3: 720 g of intermediate 2, 1.1 kg of acetic anhydride, 1.2 kg of boron trifluoride ether solution, and 5.5 L of ethyl acetate / acetone with a volume ratio of 4:1 were added to a reaction kettle in sequence, and reacted at room temperature; after the reaction was completed, the reaction solution was washed with purified water, filtered, the filtrate was dried over anhydrous sodium sulfate, and concentrated to remove the solvent; then 1 L of 55% ethanol solution was added, and crystals were precipitated after stirring at -10°C, which were filtered and the filter cake was dried in a vacuum drying oven to obtain intermediate 3; (s4) Preparation of pure hydroxytyrosol: 1055 g of intermediate 3, 2.2 kg of concentrated hydrochloric acid and 5.5 L of methanol were added to a reaction kettle in sequence, and the temperature of the reactants was raised to 95°C. After stirring and reacting for 2.5 hours, the temperature was lowered to 20°C, and the reactants were washed with dichloromethane, methyl tert-butyl ether and purified water in sequence. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent to obtain a light yellow oily substance as pure hydroxytyrosol.

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