WO2022257519A1 - Process for preparing hydroxytyrosol - Google Patents

Abstract

Disclosed in the present invention is a process for preparing hydroxytyrosol. According to the process, 1,3-benzodioxole as a starting material is firstly subjected to a Friedel-Crafts alkylation reaction together with ethylene oxide to prepare piperonyl alcohol, and the piperonyl alcohol is then subjected to a catalytic hydrolysis reaction to prepare hydroxytyrosol. The process for preparing hydroxytyrosol disclosed in the present invention has the characteristics of easily-available and low-price raw materials, a simple operation process, safety, environmental protection, etc.

Description

A kind of technique for preparing hydroxytyrosol technical field

The invention belongs to the field of organic synthesis, and in particular relates to a process for preparing hydroxytyrosol.

Background technique

Hydroxytyrosol is a natural polyphenol compound with strong antioxidant activity, mainly in the form of esters in olive fruits and leaves.

Hydroxytyrosol has a variety of biological and pharmacological activities, the main functions are: (1) prevent cancer, promote late cancer recovery and improve the effect of chemotherapy; (2) prevent and treat cardiovascular and cerebrovascular diseases, the effect is better than similar drugs; (3) Improve the function of the endocrine system, promote metabolism, and promote wound healing; (4) Eliminate free radicals in the body, prevent brain failure, and delay aging; (5) Enhance skin elasticity and moisture, wrinkle and anti-aging.

Data research shows that domestic olive planting area is relatively small. In 2018, the national olive oil output was 45,000 tons, accounting for only 1.5% of the global total output. The cost of obtaining hydroxytyrosol by extraction is relatively high, and the output is relatively small. The main source of hydroxytyrosol in China is chemical synthesis, and it is of practical significance to study the preparation of hydroxytyrosol by chemical synthesis.

The applicant investigated the process data (A) for the synthesis of hydroxytyrosol, the process data (B) for the synthesis of the key intermediate pepper ethanol, and the process data (C) for the preparation of hydroxytyrosol from pepper ethanol. The details are as follows. A, the synthesis technique of hydroxytyrosol

The applicant investigated the main synthesis processes of hydroxytyrosol. There are mainly four types, which are respectively included in CN103038203B ^[1] , CN103420804B ^[2] , CN104030894B ^[3] , and CN106866384B ^[4]. The details are as follows:

Guangdong Nansha Lonza Co., Ltd. ^[1] proposed a process for preparing hydroxytyrosol with eugenol in 2010. The details are as follows:

This route uses eugenol as the starting material to prepare hydroxytyrosol. The reaction process needs to be carried out at -78°C, the reaction conditions are harsh, and the reaction process also requires reagents such as sodium borohydride with a high price.

Ling Xiao ^[2] and others announced a process for preparing hydroxytyrosol from 3,4-dihydroxyphenylacetic acid methyl ester in 2013. The specific route is as follows:

This route uses methyl 3,4-dihydroxyphenylacetate as the starting material, and the starting material is expensive, while using relatively expensive reagents such as sodium borohydride, and the process cost is relatively high.

Wacker Chemie AG ^[3] announced in 2014 a process for preparing hydroxytyrosol from methyl 3,4-dimethoxyphenylacetate. The specific route is as follows:

This route uses 3,4-dimethoxyphenylacetic acid as the starting material, and the starting material is expensive, and simultaneously uses relatively expensive reagents such as dibutyl aluminum hydride, and the process cost is relatively high.

Shaanxi Jiahe Pharmaceutical Co., Ltd. ^[4] announced a process for preparing hydroxytyrosol from 3,4-dimethoxyphenylacetic acid in 2016. The specific route is as follows:

The route uses 3,4-dimethoxyphenylacetic acid as the starting material to prepare hydroxytyrosol through esterification, reduction, and demethylation reactions. Genotoxic reagents such as methyl sulfate and boron trifluoride are used in the reaction process. and other highly toxic reagents. The price of starting materials is high, reagents such as aluminum triiodide and sodium borohydride are expensive, and the overall process cost is relatively high. B. Preparation process of key intermediate pepper ethanol

The applicant has searched and sorted out the synthetic method of the key intermediate piperonyl alcohol of hydroxytyrosol, which mainly contains the following: route 1, the method ^[5-7] for preparing piperonyl alcohol by bromopipercycline; route 2, by safrole Method for preparing pepper ethanol ^[8-10] ; route 3, method for preparing pepper ethanol from pepper acetic acid ^[11-13] . The specific content is as follows:

In route 1, metal magnesium is used in the reaction process, the cost is high, anhydrous and oxygen-free conditions are required, and the operating conditions are harsh. The raw material of safrole in route 2 is expensive, requires -78°C, and the reaction conditions are harsh. In route 3, reagents and raw materials with higher prices such as lithium hydride and pepper alcohol are used.

C, the preparation process of hydroxytyrosol by pepper ethanol

The applicant searched and sorted out the synthetic process of preparing hydroxytyrosol by the hydrolysis of pepper ethanol. There are mainly the following types: route 1, boron tribromide method ^[14,15] ; route 2, metal sodium method ^[16] .

It is reported in the literature that in the process of preparing hydroxytyrosol by ethanol hydrolysis of pepper, route 1 uses boron tribromide, which is a highly toxic reagent and has a high price. Use expensive metal sodium in route 2, and the high temperature of 170 ℃ is needed in the reaction process.

references:

1. CN103038203B

2. CN103420804B

3. CN104030894B

4. CN106866384B

5. Huang Hongxia, Lin Yuan; A new method for the synthesis of 3,4-methylenedioxyphenethylamine

6. Xu Chao et al., Research on the Synthesis Technology of Hydroxytyrosol

7. He, Yun et al. A Versatile Total Synthesis of 8-Oxyberberine and Oxohomoberberines[J], Chinese Journal of Chemistry, 32(11), 1121-1127; 2014

8. Quteishat, Laith et al.An unexpected pentacarbonyl chromium complexation of a cyano group of the ABC core of cephalotaxine[J].Journal of Organometallic Chemistry,776,35-42;2015

9. Romeiro, Luiz A.S. et al. Discovery of LASSBio-772, a 1,3-benzodioxole N-phenylpiperazine derivative with potent alpha 1A/D-Adrenergic receptor blocking properties[J]. European Journal of Medicinal Chemistry), 46( ,3000-3012; 2011

10、Cabral,Lucio M.and Barreiro,Eliezer J.Synthesis of bioactive compounds from abundant natural products.13.The synthesis and analgesic properties of new spiroisochromanyl acid derivatives synthesized from natural safrole[J].Journal of Heterocyclic Chemistry,32(3 ), 959-62; 1995

11. CN 102617543

12. Xu, Xiaoming et al.Ytterbium-Catalyzed Intramolecular[3+2]Cycloaddition based on Furan Dearomatization to Construct Fused Triazoles[J].Organic Letters,22(13),5176-5181;

2020

13. Jiao, Ke-Jin et al, Nickel-Catalyzed Electrochemical Reductive Relay Cross-Coupling of Alkyl Halides to Aryl Halides[J]. Angewandte Chemie, International Edition, 59(16), 6520-6524; 2020

14. CN103664536

15. Xu, Chao et al. Process research of hydroxytyrosol synthesis [J]. JingxiHuagong, 27(12), 1209-1212; 2010

16. WO2009153374

Contents of the invention

Aiming at many problems in the above synthesis process, the present invention proposes a process for preparing hydroxytyrosol, the process is mainly divided into two steps, in step 1, the Friedel-Crafts alkylation reaction of piperonyl ring and ethylene oxide directly prepares piperonyl alcohol, The process route is short, the raw materials are easy to obtain, ethylene oxide belongs to a large chemical product, the cost is low, and the yield is high; in step 2, pepper ethanol is hydrolyzed under the action of a solid acid catalyst to prepare hydroxytyrosol, and the purity is higher than 98%. To avoid highly toxic reagents, and to complete at close to room temperature. The process for preparing hydroxytyrosol in the present invention combines two-step reactions, and has the characteristics of low cost, mild reaction conditions, simple aftertreatment, safety and environmental protection, and the like.

The technical scheme that the present invention solves its technical problem adopts is:

A kind of technique of preparing hydroxytyrosol of the present invention, reaction route is as follows:

Concretely, a kind of technique for preparing hydroxytyrosol of the present invention comprises the following steps:

Step 1, the preparation of 5-hydroxymethylbenzo-1,3-dioxolane (piperethanol): add piperonyl, catalyst, and then add ethylene oxide to react in the reaction flask, and the reaction temperature is -20 ~10°C, the reaction time is 0.5-1h, quenched after the reaction is completed, pickled, washed with water, concentrated and distilled to obtain peppery alcohol;

Step 2, the preparation of 3,4-dihydroxyphenylethanol (hydroxytyrosol): add protonic acid, the pepper alcohol obtained in step 1, a catalyst, and react at 20-60°C under nitrogen protection for 5-36h in the reaction flask, adjust The pH was adjusted to 10, washed with DCM, the pH of the aqueous layer was adjusted to 1-2, extracted with methyl tert-butyl ether, dried, decolorized, and concentrated to obtain hydroxytyrosol.

As a preferred technical solution of the present application, in the step 1, the catalyst is a Lewis acid, and the Lewis acid is selected from one of AlBr ₃ , AlCl ₃ , FeCl ₃ , SbCl ₅ , SnCl ₄ , BF ₃ , TiCl ₄ , and ZnCl ₂ A combination of one or more; preferably AlCl ₃ , FeCl ₃ , more preferably AlCl ₃ . Using halides as catalysts, the reaction conditions are mild.

As a preferred technical solution of the present application, in the step 1, the reaction temperature is -15°C to -5°C, preferably -10°C to -5°C.

As a preferred technical solution of the present application, in the step 1, the molar ratio of piperonyl ring to catalyst is 5-10:1, preferably 5-8:1, more preferably 8:1; As a reaction solvent, when the piperonyl ring and the catalyst feed (mol) ratio were less than 5, the reaction solution became viscous and unfavorable for stirring during the reaction; the mol ratio of the catalyst to ethylene oxide was 1:1-5, preferably Preferably it is 1:3-3.5; when the feed ratio of ethylene oxide to catalyst is less than 3.0, the yield will decrease obviously, and when the feed (molar) ratio is 3.0-3.5, the yield will be relatively high.

As a preferred technical solution of the present application, in the step 1, the molar ratio of piperonyl ring, catalyst, and ethylene oxide is 5-10:1:1-5, more preferably 8:1:3-3.5.

As a preferred technical solution of the present application, in the step 1, ethylene oxide is added by slowly feeding ethylene oxide gas under rapid stirring.

As the preferred technical scheme of the present application, in the step 1, the quenching reagent is 2M HCl.

As a preferred technical solution of the present application, in the 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.

Preferably, the protonic acid is hydrochloric acid.

As a preferred technical solution of the present application, the catalyst is a solid strong acid or a solid superacid, selected from HND-32 solid superacid catalyst, HND-34 solid superacid catalyst, Amberlyst15 solid strong acid catalyst, HNF-5W perfluorosulfonic acid resin , NKC-9 catalytic resin any one or more.

Preferably, the combination of protonic acid and catalyst is hydrochloric acid/Amberlyst15 solid strong acid catalyst, hydrochloric acid/HND-32 solid super acid catalyst.

As a preferred technical solution of the present application, in the step 2, the mass ratio of pepper to ethanol to catalyst = 1: 0.001-0.02, preferably 0.002-0.01.

Among them, when the Amberlyst15 solid strong acid catalyst is used as the catalyst, the mass ratio of pepper to ethanol and the catalyst is 1:0.01.

Among them, when HND-32 solid superacid is used as catalyst, the mass ratio of pepper alcohol and HND-32 solid superacid catalyst is 1:0.002.

As a preferred technical solution of the present application, in the step 2, the reaction temperature is 20-60°C, preferably 20-30°C.

Beneficial effect

The invention provides a process for preparing hydroxytyrosol. In the process, piperonyl cyclocycline is used as a starting material, and ethylene oxide is reacted with Friedel-Crafts alkylation to prepare pepper ethanol, and the pepper ethanol is hydrolyzed to prepare hydroxy tyrosol. The process has the characteristics of low cost and high yield:

(1) In step 1 of the present invention, reaction type, reaction substrate, catalyst are studied, and the yield of intermediate pepper ethanol is promoted to 60-70% by about 20%, and simultaneously this process raw material is easy to get, cheap, The cost is lower, and the operation process is simple, safe and environmentally friendly;

(2) In step 2 of the present invention, the combination of protonic acid and fixed strong acid/solid superacid is used to prepare hydroxytyrosol with a purity of more than 98% and a yield of more than 85%;

(3) Avoid using highly toxic reagents such as boron bromide, low cost, mild reaction conditions and safer and more environmentally friendly.

Description of drawings

Fig. 1 is the ¹ H-NMR of hydroxytyrosol obtained in Example 8 of the present invention.

Detailed ways

The technical solution of the present invention will be further described in a non-limiting manner in conjunction with several preferred implementation examples below. The reagents or instruments used are not indicated by the manufacturer, and they are all regarded as conventional products that can be purchased through the market.

Embodiment 1: the preparation of 5-hydroxymethylbenzo-1,3-dioxolane (piperethanol)

At room temperature, 880.5g (7.21mol, 8eq) of piperonylcycline and 120.0g (0.901mol, 1.0eq) of aluminum trichloride were added to the four-neck flask, and the temperature was lowered to -10°C to -5°C. 139.0 g (3.155 mol, 3.5 eq) of ethylene oxide was introduced in the form of gas, and the reaction was continued for 1 h after the addition was complete. Add 1L of dichloromethane and 1.5L of 2M hydrochloric acid solution to the reaction solution, stir at room temperature for 30 minutes, separate the layers, and wash the DCM organic layer twice with 1M hydrochloric acid solution and three times with water, dry over anhydrous sodium sulfate, and filter. The filtrate was distilled under reduced pressure to collect the piperonine, and the fraction at 115-120°C was collected to obtain 102.0 g of pepper ethanol, yield: 68.1%, and HPLC purity: 98.305%.

Embodiment 2: Preparation of 5-hydroxymethylbenzo-1,3-dioxolane (piperethanol)

At room temperature, 733.8g (6.009mol, 8eq) of piperonylcycline and 100.0g (0.751mol, 1.0eq) of aluminum trichloride were added to the four-neck flask, and the temperature was lowered to -10°C to -5°C. 99.3g (2.253mol, 3.0eq) of ethylene oxide was introduced in the form of gas, and the reaction was continued for 1h after the addition was complete. Add 800ml of dichloromethane to the reaction solution, stir 1.2L of 2M hydrochloric acid solution at room temperature for 30min, separate the layers, wash the DCM organic layer twice with 1M hydrochloric acid solution, wash three times with water, dry over anhydrous sodium sulfate, and filter. The filtrate was distilled under reduced pressure to collect the peppercycline, and the fraction at 115-120°C was collected to obtain 73.2 g of pepper ethanol, yield: 58.7%, and HPLC purity: 97.565%.

Embodiment 3: Preparation of 5-hydroxymethylbenzo-1,3-dioxolane (piperethanol)

At room temperature, 542.1g (4.439mol, 8eq) of piperonylcycline and 90.0g (0.555mol, 1.0eq) of ferric trichloride were added to the four-necked flask, and the temperature was lowered to -10°C to -5°C. 85.5g (1.942mol, 3.5eq) of ethylene oxide was introduced in the form of gas, and the reaction was continued for 1h after the addition. Add 800ml of dichloromethane to the reaction solution, stir 1.2L 2M hydrochloric acid solution at room temperature for 30min, separate the layers, wash the DCM organic layer twice with 1M hydrochloric acid solution, wash three times with water, dry over anhydrous sodium sulfate, and filter. The filtrate was distilled under reduced pressure to collect the peppercycline, and the fraction at 115-120°C was collected to obtain pepper alcohol: 19.0 g, yield: 20.6%, HPLC purity: 98.119%.

Embodiment 4: Preparation of 5-hydroxymethylbenzo-1,3-dioxolane (piperethanol)

At room temperature, 481.8g (3.946mol, 8eq) of piperonylcycline and 80.0g (0.493mol, 1.0eq) of ferric trichloride were added to the four-neck flask, and the temperature was lowered to -10°C to -5°C. 65.2g (1.480mol, 3.0eq) of ethylene oxide was introduced in the form of gas, and the reaction was continued for 1h after the addition was complete. Add 600ml of dichloromethane to the reaction solution, stir 1.0L of 2M hydrochloric acid solution at room temperature for 30min, separate the layers, wash the DCM organic layer twice with 1M hydrochloric acid solution, wash three times with water, dry over anhydrous sodium sulfate, and filter. The filtrate was distilled under reduced pressure to collect the peppercycline, and the fraction at 115-120°C was collected to obtain 14.8 g of pepper ethanol, yield: 18.1%, and HPLC purity: 98.645%.

Embodiment 5: Preparation of 5-hydroxymethylbenzo-1,3-dioxolane (piperethanol)

At room temperature, 183.4g (1.502mol, 4eq) of piperonylcycline and 50.0g (0.376mol, 1.0eq) of aluminum trichloride were added to the four-neck flask, and the temperature was lowered to -10°C to -5°C. 57.9g (1.314mol, 3.5eq) of ethylene oxide was introduced in the form of gas, and the reaction was continued for 1h after the addition was complete. Add 0.5L dichloromethane and 0.75L 2M hydrochloric acid solution to the reaction solution, stir at room temperature for 30 minutes, separate the layers, wash the DCM organic layer twice with 1M hydrochloric acid solution, wash three times with water, dry over anhydrous sodium sulfate, and filter. The filtrate was distilled under reduced pressure to collect the peppercycline, and the fraction at 115-120°C was collected to obtain 27.2 g of pepper ethanol, yield: 43.6%, and HPLC purity: 98.155%.

Embodiment 6: Preparation of 5-hydroxymethylbenzo-1,3-dioxolane (piperethanol)

At room temperature, 336.9g (3.004mol, 8eq) of piperonylcycline and 50.0g (0.376mol, 1.0eq) of aluminum trichloride were added to the four-neck flask, and the temperature was lowered to -10°C to -5°C. 33.1g (0.751mol, 2.0eq) of ethylene oxide was introduced in the form of gas, and the reaction was continued for 1h after the addition was completed. Add 0.5L dichloromethane and 0.75L 2M hydrochloric acid solution to the reaction solution, stir at room temperature for 30 minutes, separate the layers, wash the DCM organic layer twice with 1M hydrochloric acid solution, wash three times with water, dry over anhydrous sodium sulfate, and filter. The filtrate was distilled under reduced pressure to collect the peppercycline, and the fraction at 115-120°C was collected to obtain 24.5 g of pepper ethanol, yield: 39.3%, and HPLC purity: 98.359%.

Embodiment 7: Preparation of 5-hydroxymethylbenzo-1,3-dioxolane (piperethanol)

Using the feed ratio and operation of Example 1, when the Lewis acid is selected as BF ₃ and ZnCl ₂ , there is no product; when TiCl ₄ is selected, the yield is 4.1%.

Adjusting the feed ratio of ethylene oxide and catalyst can find that the yield when feed ratio is 3.5 is significantly better than that of 3.0; choosing different catalysts also has a great influence on the yield of pepper ethanol, and aluminum trichloride is better than trichloride Iron, superior to other Lewis acids.

Embodiment 8: Preparation of 3,4-dihydroxyphenylethanol (hydroxytyrosol)

Add 55.0g (0.331mol, 1.0eq) pepper ethanol, 134.2g (1.324mol, 4.0eq) 36% hydrochloric acid, 0.55g Amberlyst15 solid strong acid catalyst to the four-necked flask at room temperature, and react at 20-30°C for 36h under nitrogen protection. The reaction is completed, filtered, and the filtrate is adjusted to pH 10 with 3ml NaOH solution in an ice-water bath, washed twice with 150ml DCM, the aqueous layer is adjusted to pH 1-2 with 3M HCl solution, extracted 5 times with 300ml methyl tert-butyl ether, The methyl tert-butyl ether was combined, dried over anhydrous sodium sulfate, decolorized with 5% activated carbon, concentrated by rotary evaporation to obtain an orange-yellow oil, and dried in vacuo to obtain 43.4 g. Yield: 85.1%, HPLC purity: 98.858%.

¹ H NMR(DMSO-D6)δ,ppm:8.060(s,1H),6.875-6.846(m,1H),6.725-6.710(m,1H),5.989(s,2H),2.976-2.946(m, 2H),2.848-2.818(m,2H).

Embodiment 9: Preparation of 3,4-dihydroxyphenethyl alcohol (hydroxytyrosol)

Add 80.0g (0.481mol, 1.0eq) pepper ethanol, 195.2g (1.926mol, 4.0eq) 36% hydrochloric acid, 0.16g HND-32 solid superacid catalyst to the four-necked flask at room temperature, under nitrogen protection at 20-30°C Reaction 28h. The reaction is completed, filtered, and the filtrate is adjusted to pH 10 with 3ml NaOH solution in an ice-water bath, washed twice with 150ml DCM, the aqueous layer is adjusted to pH 1-2 with 3M HCl solution, extracted 5 times with 300ml methyl tert-butyl ether, The methyl tert-butyl ether was combined, dried over anhydrous sodium sulfate, decolorized with 5% activated carbon, concentrated by rotary evaporation to obtain an orange-yellow oil, and dried in vacuo to obtain 64.8 g. Yield: 87.3%, HPLC purity: 98.566%.

Comparative Example 1: Preparation of 3,4-dihydroxyphenylethanol (hydroxytyrosol)

Add 60.0g (0.361mol, 1.0eq) of pepper alcohol and 182.6g (1.083mol, 3.0eq) of 48% hydrobromic acid to the four-neck flask at room temperature, raise the temperature to 20-30°C under the protection of nitrogen, react for 12 hours, and monitor by TLC The starting material disappeared, and the reaction ended. Adjust the pH of the reaction solution to 10 with 3ml NaOH solution in an ice-water bath, wash twice with 200ml DCM, adjust the pH of the aqueous layer to 1-2 with 3M HCl solution, extract 5 times with 400ml methyl tert-butyl ether, and combine methyl tert-butyl ether , dried over anhydrous sodium sulfate, decolorized with 5% activated carbon, concentrated by rotary evaporation to obtain an orange-yellow oil, dried in vacuo to obtain 6.5 g, yield 11.6%, HPLC purity: 98.232%.

Comparative Example 2: Preparation of 3,4-dihydroxyphenylethanol (hydroxytyrosol)

Add 50.0g (0.301mol, 1.0eq) pepper ethanol, 122.0g (1.204mol, 4.0eq) 36% hydrochloric acid to the four-neck flask at room temperature, raise the temperature to 50-60°C under nitrogen protection, react for 6h, and monitor the raw materials by reaction TLC When it disappears, the reaction ends. The reaction solution was adjusted to pH 10 with 3ml NaOH solution in an ice-water bath, washed twice with 180ml DCM, the aqueous layer was adjusted to pH 1-2 with 3M HCl solution, extracted 5 times with 350ml methyl tert-butyl ether, and combined with methyl tert-butyl ether , dried over anhydrous sodium sulfate, decolorized with 5% activated carbon, concentrated by rotary evaporation to obtain an orange-yellow oil, and dried in vacuo to obtain 11.9 g. Yield 25.6%, HPLC purity: 98.686%.

The protection content of the present invention is not limited to the above embodiments. Without departing from the spirit and scope of the inventive concept, changes and advantages that can be conceived by those skilled in the art are all included in the present invention, and the appended claims are the protection scope.

Claims (10)

1. A kind of technique for preparing hydroxytyrosol, is characterized in that, comprises the steps:

   Step 1, the preparation of pepper ethanol: add piperonyl ring and catalyst to the reaction bottle, and then feed ethylene oxide gas to react. The reaction temperature is -20-10°C, and the reaction time is 0.5-1h. After acid washing, water washing, concentration and distillation, the key intermediate pepper ethanol is obtained;

   Step 2, preparation of hydroxytyrosol: add protonic acid, pepper alcohol obtained in step 1, catalyst, nitrogen protection at 20-60°C to the reaction flask, and react for 5-36 hours; after the reaction, adjust the pH to 10±0.5, DCM Wash and adjust the pH of the aqueous layer to 1-2, then extract with methyl tert-butyl ether, dry, decolorize, and concentrate to obtain hydroxytyrosol.
2. The process for preparing hydroxytyrosol according to claim 1, wherein in step 1, the catalyst is a Lewis acid selected from AlBr ₃ , AlCl ₃ , FeCl ₃ , SbCl ₅ , SnCl ₄ , BF ₃ , TiCl _4. A combination of one or more of ZnCl ₂ , preferably AlCl ₃ , FeCl ₃ , more preferably AlCl ₃ .
3. The process for preparing hydroxytyrosol according to claim 1 or 2, characterized in that, in step 1, the reaction temperature is -10 to -5°C.
4. The process for preparing hydroxytyrosol according to claim 1, characterized in that, in step 1, the molar ratio of piperonyl ring to catalyst is 5-10:1, preferably 5-8:1.
5. The process for preparing hydroxytyrosol according to claim 1 or 4, characterized in that, in step 1, the molar ratio of the catalyst to ethylene oxide is 1:1-5, preferably 1:3-3.5.
6. The process for preparing hydroxytyrosol according to claim 1, wherein in step 2, the protonic acid is selected from any of hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and nitric acid. one or more.
7. The process for preparing hydroxytyrosol according to claim 6, wherein the protonic acid is hydrochloric acid.
8. The process for preparing hydroxytyrosol according to claim 1, wherein in step 2, the catalyst is a solid strong acid or a solid superacid, selected from HND-32 solid superacid catalyst, HND-34 solid superacid catalyst , Amberlyst15 solid strong acid catalyst, HNF-5W perfluorosulfonic acid resin, NKC-9 catalytic resin any one or more.
9. The process for preparing hydroxytyrosol according to claim 8, wherein the catalyst is HND-32 solid superacid catalyst or Amberlyst15 solid strong acid catalyst.
10. The process for preparing hydroxytyrosol according to claim 1, wherein the combination of protonic acid and catalyst is hydrochloric acid/Amberlyst15 solid strong acid catalyst, or hydrochloric acid/HND-32 solid superacid catalyst.

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