Synthesis method of hydroxytyrosol

Abstract

The invention discloses a synthesis method of hydroxytyrosol. The synthesis method comprises the following steps: (1) reacting p-hydroxyphenethyl alcohol as shown in a formula 1 with a bromination reagent in ethyl acetate at 0-25 DEG C to generate p-hydroxybromophenethyl alcohol as shown in a formula 2; (2) under the protection of nitrogen, reacting p-hydroxybromophenethyl alcohol in an aqueous solution of alkali in the presence of a copper catalyst and a ligand at 80-100 DEG C to generate hydroxytyrosol as shown in a formula 3; the copper catalyst is cuprous bromide; the ligand is phenanthroline. The raw materials and solvents required by the synthesis method are cheap and easy to obtain, the operation process is convenient and easy to implement, the synthesis method is environment-friendly, the reactant yield is high, the quality is good, and the synthesis method is suitable for industrial large-scale production.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of organic chemical synthesis, and particularly relates to a synthesis method of hydroxytyrosol. BACKGROUND

[0002] Hydroxytyrosol is a natural polyphenol compound, widely exists in olive oil and its by-products. Hydroxytyrosol, also known as 3,4-dihydroxyphenylethanol, is a colorless or light yellow oily substance. Recent studies have shown that hydroxytyrosol has multiple effects such as antioxidant, anti-aging, immune enhancement, anticancer, cardiovascular health protection and anti-inflammatory. (1) Hydroxytyrosol has significant antioxidant activity, can scavenge free radicals and reduce oxidative stress damage to cells. (2) Hydroxytyrosol shows potential benefits in cardiovascular health, it can regulate vascular endothelial cell function, inhibit the expression of adhesion molecules related to atherosclerosis, thereby playing a role in anti-atherosclerosis and anti-thrombosis. (3) Hydroxytyrosol can inhibit tumor cell proliferation, induce tumor cell apoptosis, and achieve anti-tumor effect through regulation of cell signaling pathways. (4) Hydroxytyrosol can regulate metabolic processes and reduce complications caused by diabetes. Due to its hydrophilic and lipophilic properties, high bioavailability and low cytotoxicity, hydroxytyrosol is considered as a focus of new drug development.

[0003] Natural hydroxytyrosol mainly exists in olive leaves, fruits and olive oil production wastewater, and it is naturally produced by the hydrolysis of oleuropein. Although extracting hydroxytyrosol from olive oil wastewater has the advantage of waste utilization, its low purity, low recovery rate, high cost, environmental problems and difficulty in large-scale production limit its wide application. The biological transformation method for synthesizing hydroxytyrosol mainly includes yeast fermentation method and enzyme catalysis method. The yeast fermentation method is to breed a yeast strain with high yield of hydroxytyrosol, and then carry out fermentation in a suitable medium. The yeast strain produces hydroxytyrosol through metabolic pathways. The enzyme catalysis method is to use enzyme as a catalyst to convert appropriate substrates into hydroxytyrosol. The biological synthesis method has high cost and the technology is not mature enough, and further optimization is still needed.

[0004] At present, there are many methods for chemically synthesizing hydroxytyrosol reported in the literature: Method one: In 1949, Clemens Schöpf et al. [Justus Liebigs Annalen der Chemie, 1949, 563(1): 86-93] first proposed to use 3,4-dihydroxyphenylacetic acid as the raw material and lithium aluminum hydride as the reducing agent to synthesize hydroxytyrosol. The lithium aluminum hydride reduction method has a significant advantage in efficiency, but it is limited by safety, cost and environmental problems. This synthesis method is only suitable for laboratory scenes with strict control of reaction conditions.

[0005]

[0006] Method 2: Bovicelli et al. [Synthetic Communications, 2007, 37(23): 4245-4252] synthesized hydroxytyrosol from p-hydroxyphenylethanol. This method involves five steps: bromination, methoxylation, esterification, reduction, and hydrochloric acid hydrolysis. It involves the protection and deprotection of hydroxyl groups, resulting in a relatively long reaction route. Furthermore, this route requires the extremely hazardous boron tribromide, the reaction is quite vigorous, and the yield is low, so it is rarely used in laboratories.

[0007]

[0008] Method 3: Bernini Roberta et al. [WO2008IB00598[P]. 2008-12-31] synthesized hydroxytyrosol from p-hydroxyphenylethanol. This method requires protection and deprotection steps, resulting in low synthesis efficiency. Oxidation with high-valent iodine reagents is costly, and industrial production requires significant energy consumption, leading to substantial environmental pressure.

[0009]

[0010] Method 4: Xu Chao et al. [Fine Chemicals, 2010 (12): 1209-1212] used catechol as a raw material. This method synthesizes hydroxytyrosol through five steps: protecting the hydroxyl group of catechol, bromination, preparation of Grignard reagent, reaction of Grignard reagent with ethylene oxide, and deprotection. It involves the protection and deprotection of hydroxyl groups, which increases the reaction cost, and the route is long and the yield is low. It requires the use of bromine and boron tribromide, which cause serious environmental pollution, and the Grignard reagent has harsh conditions for use. Improper operation may lead to an explosion risk.

[0011]

[0012] Method 5: Giovanni Piersanti et al. [Tetrahedron letters, 2011, 52(38): 4938-4940] synthesized hydroxytyrosol from p-hydroxyphenylethanol. This method requires protection and deprotection steps, and the synthetic route is relatively long. The Bayer-Vigliger oxidation reaction depends on m-chloroperoxybenzoic acid, which carries an explosion risk, and the reaction generates m-chlorobenzoic acid as a byproduct, requiring additional purification steps.

[0013]

[0014] Method Six: Kholshin Sergej Viktorovich et al. [RU2019131013A[P]. 2020-05-27] synthesized hydroxytyrosol from p-hydroxyphenylethanol. This method has a short reaction route, but it requires the use of liquid bromine as a brominating reagent, which is highly toxic and corrosive, posing a high operational hazard and causing serious environmental pollution. The hydroxylation process also exhibits low yield and poor selectivity.

[0015]

[0016] Method 7: Yang Chaowen et al. [CN112457171A[P]. 2021-03-09] synthesized hydroxytyrosol using p-hydroxyphenylethanol as a raw material. This method has a short reaction route, but the bromination process requires a large amount of acetone-water mixed solvent (more than 20 times the volume), which greatly increases the cost and waste liquid treatment burden, making it unsuitable for industrial production. The hydroxylation process requires the prior synthesis of 8-hydroxyquinoline copper, copper acetylacetone, and BFMO-cuprous iodide catalyst, which is cumbersome and increases the complexity of the reaction. Moreover, it uses a molecular evaporator for vacuum distillation in the post-treatment to improve product quality, but the molecular evaporator equipment is relatively expensive and has a small throughput, which cannot meet the needs of industrial production.

[0017]

[0018] The methods described above for synthesizing hydroxytyrosol have drawbacks such as high raw material costs, long synthetic routes, and difficulties in industrialization. Therefore, optimizing the hydroxytyrosol production process and technology, and developing a green, sustainable synthetic method with mild reaction conditions, has become one of the important research directions. Summary of the Invention

[0019] The purpose of this invention is to provide a synthetic method for hydroxytyrosol that has high product yield and quality, low cost, mild reaction conditions, simple operation, and is suitable for large-scale industrial production.

[0020] To achieve the above objectives, the present invention adopts the following technical solution: A method for synthesizing hydroxytyrosol includes the following steps: (1) p-hydroxyphenylethanol of Formula 1 reacts with a bromide in ethyl acetate at 0-25°C to produce p-hydroxybromophenylethanol of Formula 2; the bromide is N-bromosuccinimide; (2) Under nitrogen protection, p-hydroxybromophenylethanol is reacted in an aqueous solution of an alkali in the presence of a copper catalyst and a ligand at 80℃-100℃ to produce hydroxytyrosol as shown in Formula 3; the copper catalyst is cuprous bromide; the ligand is o-phenanthroline; the molar ratio of p-hydroxybromophenylethanol to the alkali is 1:2.5-1:10, the molar ratio of p-hydroxybromophenylethanol to the copper catalyst is 1:0.01-1:0.1, and the molar ratio of the copper catalyst to the ligand is 1:1-1:2; .

[0021] Preferably, the reaction temperature in step (1) is 0-5℃, and most preferably 0℃.

[0022] Preferably, in step (1), the molar ratio of p-hydroxyphenylethanol to bromine in the brominating reagent is 1:0.8-1.5, more preferably 1:1.0-1.1.

[0023] Preferably, in step (1), the volume of ethyl acetate used is 3-6 mL / g based on the mass of p-hydroxyphenylethanol, more preferably 5-6 mL / g.

[0024] After the reaction in step (1) of this invention is completed, p-hydroxybromophenylethanol is obtained by the following post-processing operation: After the reaction is completed, ethyl acetate is added for dilution, and saturated sodium bisulfite and water are added for washing several times in sequence. The organic phase is dried with anhydrous sodium sulfate, filtered, and the solvent is concentrated under reduced pressure to obtain a white powder solid, which is p-hydroxybromophenylethanol.

[0025] Preferably, the alkali in step (2) is any one of sodium hydroxide, potassium hydroxide, cesium hydroxide, lithium hydroxide, potassium carbonate, cesium carbonate, and potassium phosphate, and more preferably, the alkali is sodium hydroxide.

[0026] Preferably, the molar ratio of p-hydroxybromophenylethanol to alkali in step (2) is 1:5-10, with 1:5 being the most preferred.

[0027] Preferably, the molar ratio of p-hydroxybromophenylethanol to copper catalyst in step (2) is 1:0.01-0.05, with the most preferred ratio being 1:0.01.

[0028] Preferably, the molar ratio of the copper catalyst to the ligand in step (2) is 1:2.

[0029] In particular, the preferred step (2) of this invention has a molar ratio of p-hydroxybromophenylethanol to base of 1:5, a molar ratio of p-hydroxybromophenylethanol to copper catalyst of 1:0.01, and a molar ratio of copper catalyst to ligand of 1:2.

[0030] Preferably, in step (2), the concentration of the aqueous solution of the alkali is 0.08 g / mL to 0.20 g / mL, more preferably 0.08 g / mL to 0.11 g / mL.

[0031] Preferably, in step (2), the reaction temperature is 90-100℃, and most preferably 100℃.

[0032] After the reaction in step (2) of this invention is completed, hydroxytyrosol is obtained through the following post-treatment: After the reaction is completed, the reaction mixture is cooled to room temperature, 10wt% dilute hydrochloric acid is added to adjust to acidity, and the mixture is extracted with an organic solvent, dried, filtered, and the solvent is concentrated under reduced pressure to obtain a pale yellow oily substance, which is hydroxytyrosol. Preferably, the extraction solvent is any one of ethyl acetate, dichloromethane, and methyl tert-butyl ether, more preferably methyl tert-butyl ether.

[0033] Compared with the prior art, the beneficial effects of the present invention are as follows: (1) The bromination step of the route of the present invention uses N-bromosuccinimide as the brominating reagent, which is non-volatile and non-corrosive. N-bromosuccinimide has high solubility in ethyl acetate, greatly reducing the amount of solvent used and resulting in high product yield, which has economic and environmental advantages. In contrast, the Oxone-NaBr route requires a large amount of acetone-water mixed solvent (more than 20 times the volume), which greatly increases the cost and waste liquid treatment burden.

[0034] (2) In the hydroxylation step of this invention, the N-bromosuccinimide, cuprous bromide, o-phenanthroline, and sodium hydroxide used are all industrial-grade, inexpensive reagents, which can effectively reduce reaction costs. The catalyst does not need to be pre-prepared; cuprous bromide and o-phenanthroline can be directly added to the reaction system to efficiently catalyze hydroxylation, simplifying the operation. The selection of appropriate bases and metal ligands in this invention can effectively reduce the content of tyrosol generated from the debromination of p-hydroxybromophenylethanol, improving product purity. The hydroxytyrosol product is directly soluble in water, and the product can be obtained through simple acidification, extraction, and ordinary vacuum distillation, with a purity greater than 99%. This hydroxylation reaction uses water as a solvent, reducing the use of organic solvents and making it safe and environmentally friendly.

[0035] (3) This invention uses p-hydroxyphenylethanol as the starting material and only requires two steps, bromination and hydroxylation, to synthesize hydroxytyrosol. The cumulative yield can be increased to more than 70%, and the whole route is suitable for large-scale industrial production. Attached Figure Description

[0036] Figure 1 and Figure 2 These are the 1H and 1C spectra of p-hydroxybromophenylethanol synthesized in Example 1.

[0037] Figure 3 and Figure 4 These are the 1H and 1C spectra of the hydroxytyrosol synthesized in Example 1. Detailed Implementation

[0038] The technical features of the present invention will be further clearly and completely described below with reference to specific embodiments. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0039] Example 1: (1) Synthesis of p-hydroxybromophenylethanol To a mixture of 5 g of p-hydroxyphenylethanol (36.19 mmol, 1.0 equivalent) and ethyl acetate (EtOAc, 25 mL), N-bromosuccinimide (NBS, 38 mmol, 1.05 equivalent) was added in multiple equal portions at 0 °C. The mixture was stirred at 0 °C for 3 h, and the reaction was monitored by TLC until the p-hydroxyphenylethanol was completely consumed. After the reaction was complete, the mixture was diluted with 30 mL of ethyl acetate, and washed successively with saturated sodium bisulfite (15 mL × 3) and water (15 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate. The solvent was removed by rotary evaporation, and the filter cake was dried under vacuum to give 7.50 g of white powdery solid, which was p-hydroxybromophenylethanol, with a molar yield of 95.54%.

[0040] Product characterization data: 1 H NMR (400 MHz, CDCl3) δ 7.34 (d, J = 2.1 Hz, 1H), 7.07(dd, J = 8.2, 2.1 Hz, 1H), 6.95 (d, J = 8.3 Hz, 1H), 5.55 (s, 1H), 3.82 (s,2H), 2.78 (t, J = 6.5 Hz, 2H), 1.51 (s, 1H). 13 C NMR (101 MHz, CDCl3) δ150.95, 132.30, 132.19, 129.77, 116.13, 110.19, 63.56, 37.89.

[0041] (2) Synthesis of hydroxytyrosol

[0042] Under nitrogen protection, 2 g of p-hydroxybromophenylethanol (9.214 mmol, 1.0 equivalent), 0.0132 g of cuprous bromide (1 mol%), and 0.0332 g of o-phenanthroline (2 mol%) were added sequentially to a three-necked flask. An aqueous solution of sodium hydroxide (1.84 g sodium hydroxide, 20 mL water) was prepared and added to the reaction system. The resulting mixture was stirred at 100 °C for 10 h, and the reaction progress was monitored by TLC until the p-hydroxybromophenylethanol was completely consumed. After the reaction was complete, the mixture was cooled to room temperature, and the pH was adjusted to 2 with 10 wt% dilute hydrochloric acid. The extract was then extracted with methyl tert-butyl ether, dried, filtered, and the solvent was concentrated under reduced pressure in an oil bath at 50 °C to obtain 1.17 g of a pale yellow oil, which was hydroxytyrosol, with a molar yield of 82.39% and a purity of 99.2%.

[0043] Product characterization data: 1 H NMR (400 MHz, DMSO-d6) δ 8.66 (s, 2H), 6.64 (d, J =8.0 Hz, 1H), 6.61 (d, J = 2.2 Hz, 1H), 6.45 (dd, J = 8.0, 2.2 Hz, 1H), 4.58(t, J = 5.2 Hz, 1H), 3.56 – 3.51 (m, 2H), 2.56 (t, J = 7.3 Hz, 2H). 13 C NMR(101 MHz, DMSO-d6) δ 145.00, 143.44, 130.33, 119.62, 116.42, 115.51, 62.79,38.66.

[0044] Example 2: (1) Synthesis of p-hydroxybromophenylethanol To a mixture of 5 g of p-hydroxyphenylethanol (36.19 mmol, 1.0 equivalent) and ethyl acetate (EtOAc, 25 mL), N-bromosuccinimide (NBS, 38 mmol, 1.05 equivalent) was added in multiple equal portions at 25 °C. The resulting mixture was stirred at 25 °C for 3 h, and the reaction progress was monitored by TLC until the p-hydroxyphenylethanol was completely consumed. After the reaction was complete, the mixture was diluted with 30 mL of ethyl acetate, and washed successively with saturated sodium bisulfite (15 mL × 3) and water (15 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate. The solvent was removed by rotary evaporation, and the filter cake was dried under vacuum to give 7.45 g of white powdery solid, which was p-hydroxybromophenylethanol, with a molar yield of 94.90%.

[0045] (2) Synthesis of hydroxytyrosol

[0046] Under nitrogen protection, 2 g of p-hydroxybromophenylethanol (9.214 mmol, 1.0 equivalent) and 0.132 g of cuprous bromide (10 mol%) were added sequentially to a three-necked flask. An aqueous solution of sodium hydroxide (1.84 g sodium hydroxide, 20 mL water) was prepared and added to the reaction system. The resulting mixture was stirred at 100 °C for 15 h, and the reaction progress was monitored by TLC until the p-hydroxybromophenylethanol was completely consumed. After the reaction was complete, the mixture was cooled to room temperature, and the pH was adjusted to 2 with 10 wt% dilute hydrochloric acid. The extract was obtained with methyl tert-butyl ether, dried, filtered, and the solvent was concentrated under reduced pressure in an oil bath at 50 °C to obtain 0.88 g of a pale yellow oil, which was hydroxytyrosol, with a molar yield of 61.97% and a purity of 95.9%.

[0047] Example 3: (1) Synthesis of p-hydroxybromophenylethanol To a mixture of 5 g of p-hydroxyphenylethanol (36.19 mmol, 1.0 equivalent) and ethyl acetate (EtOAc, 25 mL), 1,3-dibromo-5,5-dimethylhydantoin (DBH, 18.45 mmol, 0.51 equivalent) was added in multiple equal portions at 0 °C. The resulting mixture was stirred at 0 °C for 3 h, and the reaction progress was monitored by TLC until the p-hydroxyphenylethanol was completely consumed. After the reaction was complete, the mixture was diluted with 30 mL of ethyl acetate, and washed successively with saturated sodium bisulfite (15 mL × 3) and water (15 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate. The solvent was removed by rotary evaporation, and the filter cake was dried under vacuum to give 6.70 g of white powdery solid, which was p-hydroxybromophenylethanol, with a molar yield of 85.35%.

[0048] (2) Synthesis of hydroxytyrosol

[0049] Under nitrogen protection, 2 g of p-hydroxybromophenylethanol (9.214 mmol, 1.0 equivalent), 0.023 g of copper sulfate pentahydrate (1 mol%), and 0.0332 g of o-phenanthroline (2 mol%) were added sequentially to a three-necked flask. An aqueous solution of sodium hydroxide (2.76 g sodium hydroxide, 20 mL water) was prepared and added to the reaction system. The resulting mixture was stirred at 100 °C for 10 h, and the reaction progress was monitored by TLC until the p-hydroxybromophenylethanol was completely consumed. After the reaction was complete, the mixture was cooled to room temperature, and the pH was adjusted to 2 with 10 wt% dilute hydrochloric acid. The extract was obtained with methyl tert-butyl ether, dried, filtered, and the solvent was concentrated under reduced pressure in an oil bath at 50 °C to obtain 1.05 g of a pale yellow oil, which was hydroxytyrosol, with a molar yield of 73.94% and a purity of 97.5%.

[0050] Example 4: (1) Synthesis of p-hydroxybromophenylethanol To a mixture of 5 g of p-hydroxyphenylethanol (36.19 mmol, 1.0 equivalent) and ethyl acetate (EtOAc, 25 mL), 1,3-dibromo-5,5-dimethylhydantoin (DBH, 18.45 mmol, 0.51 equivalent) was added in multiple equal portions at 25 °C. The resulting mixture was stirred at 25 °C for 3 h, and the reaction progress was monitored by TLC until the p-hydroxyphenylethanol was completely consumed. After the reaction was complete, the mixture was diluted with 30 mL of ethyl acetate, and washed successively with saturated sodium bisulfite (15 mL × 3) and water (15 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate. The solvent was removed by rotary evaporation, and the filter cake was dried under vacuum to give 6.40 g of white powdery solid, which was p-hydroxybromophenylethanol, with a molar yield of 81.53%.

[0051] (2) Synthesis of hydroxytyrosol

[0052] Under nitrogen protection, 2 g of p-hydroxybromophenylethanol (9.214 mmol, 1.0 equivalent), 0.0264 g of cuprous bromide (2 mol%), and 0.0988 g of 4,4'-di-tert-butyl-2,2'-dipyridine (4 mol%) were added sequentially to a three-necked flask. An aqueous solution of sodium hydroxide (3.68 g sodium hydroxide, 20 mL water) was prepared and added to the reaction system. The resulting mixture was stirred at 100 °C for 10 h, and the reaction progress was monitored by TLC until the p-hydroxybromophenylethanol was completely consumed. After the reaction was complete, the mixture was cooled to room temperature, and the pH was adjusted to 2 with 10 wt% dilute hydrochloric acid. The extract was obtained with methyl tert-butyl ether, dried, filtered, and the solvent was concentrated under reduced pressure in an oil bath at 50 °C to obtain 1.07 g of a pale yellow oil, which was hydroxytyrosol, with a molar yield of 75.35% and a purity of 98.0%.

[0053] Example 5: (1) Synthesis of p-hydroxybromophenylethanol To a mixture of 5 g of p-hydroxyphenylethanol (36.19 mmol, 1.0 equivalent) and ethyl acetate (EtOAc, 15 mL), N-bromosuccinimide (NBS, 38 mmol, 1.05 equivalent) was added in multiple equal portions at 0 °C. The mixture was stirred at 0 °C for 3 h, and the reaction was monitored by TLC until the p-hydroxyphenylethanol was completely consumed. After the reaction was complete, the mixture was diluted with 20 mL of ethyl acetate, and washed successively with saturated sodium bisulfite (10 mL × 3) and water (10 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate. The solvent was removed by rotary evaporation, and the filter cake was dried under vacuum to give 7.27 g of white powdery solid, which was p-hydroxybromophenylethanol, with a molar yield of 92.58%.

[0054] (2) Synthesis of hydroxytyrosol

[0055] Under nitrogen protection, 2 g of p-hydroxybromophenylethanol (9.214 mmol, 1.0 equivalent), 0.0264 g of cuprous bromide (2 mol%), and 0.0576 g of 2,2'-bipyridine (4 mol%) were added sequentially to a three-necked flask. An aqueous solution of sodium hydroxide (2.76 g sodium hydroxide, 20 mL water) was prepared and added to the reaction system. The resulting mixture was stirred at 100 °C for 10 h, and the reaction progress was monitored by TLC until the p-hydroxybromophenylethanol was completely consumed. After the reaction was complete, the mixture was cooled to room temperature, and the pH was adjusted to 2 with 10 wt% dilute hydrochloric acid. The extract was obtained with methyl tert-butyl ether, dried, filtered, and the solvent was concentrated under reduced pressure in an oil bath at 50 °C to obtain 0.94 g of a pale yellow oil, which was hydroxytyrosol, with a molar yield of 66.2% and a purity of 97.8%.

[0056] Example 6: (1) Synthesis of p-hydroxybromophenylethanol Same as Example 1.

[0057] (2) Synthesis of hydroxytyrosol

[0058] Under nitrogen protection, 2 g of p-hydroxybromophenylethanol (9.214 mmol, 1.0 equivalent), 0.0396 g of cuprous bromide (3 mol%), and 0.0636 g of L-proline (6 mol%) were added sequentially to a three-necked flask. An aqueous solution of sodium hydroxide (1.84 g sodium hydroxide, 20 mL water) was prepared and added to the reaction system. The resulting mixture was stirred at 100 °C for 10 h, and the reaction progress was monitored by TLC until the p-hydroxybromophenylethanol was completely consumed. After the reaction was complete, the mixture was cooled to room temperature, and the pH was adjusted to 2 with 10 wt% dilute hydrochloric acid. The extract was obtained with methyl tert-butyl ether, dried, filtered, and the solvent was concentrated under reduced pressure in an oil bath at 50 °C to obtain 0.93 g of a pale yellow oil, which was hydroxytyrosol, with a molar yield of 65.49% and a purity of 97.3%.

[0059] Example 7: (1) Synthesis of p-hydroxybromophenylethanol Same as Example 1.

[0060] (2) Synthesis of hydroxytyrosol

[0061] Under nitrogen protection, 2 g of p-hydroxybromophenylethanol (9.214 mmol, 1.0 equivalent), 0.0396 g of cuprous bromide (3 mol%), and 0.0528 g of 2-pyridone (6 mol%) were added sequentially to a three-necked flask. An aqueous solution of sodium hydroxide (1.84 g sodium hydroxide, 20 mL water) was prepared and added to the reaction system. The resulting mixture was stirred at 100 °C for 10 h, and the reaction progress was monitored by TLC until the p-hydroxybromophenylethanol was completely consumed. After the reaction was complete, the mixture was cooled to room temperature, and the pH was adjusted to 2 with 10 wt% dilute hydrochloric acid. The extract was obtained with methyl tert-butyl ether, dried, filtered, and the solvent was concentrated under reduced pressure in an oil bath at 50 °C to obtain 0.95 g of a pale yellow oil, which was hydroxytyrosol, with a molar yield of 66.90% and a purity of 97.9%.

[0062] Example 8: (1) Synthesis of p-hydroxybromophenylethanol Same as Example 1.

[0063] (2) Synthesis of hydroxytyrosol

[0064] Under nitrogen protection, 2 g of p-hydroxybromophenylethanol (9.214 mmol, 1.0 equivalent), 0.066 g of cuprous bromide (5 mol%), and 0.134 g of 8-hydroxyquinoline (10 mol%) were added sequentially to a three-necked flask. An aqueous solution of sodium hydroxide (1.84 g sodium hydroxide, 20 mL water) was prepared and added to the reaction system. The resulting mixture was stirred at 100 °C for 10 h, and the reaction progress was monitored by TLC until the p-hydroxybromophenylethanol was completely consumed. After the reaction was complete, the mixture was cooled to room temperature, and the pH was adjusted to 2 with 10 wt% dilute hydrochloric acid. The extract was obtained with methyl tert-butyl ether, dried, filtered, and the solvent was concentrated under reduced pressure in an oil bath at 50 °C to obtain 1.00 g of a pale yellow oil, which was hydroxytyrosol, with a molar yield of 70.42% and a purity of 98.1%.

[0065] Example 9: (1) Synthesis of p-hydroxybromophenylethanol Same as Example 1.

[0066] (2) Synthesis of hydroxytyrosol

[0067] Under nitrogen protection, 2 g of p-hydroxybromophenylethanol (9.214 mmol, 1.0 equivalent), 0.066 g of cuprous bromide (5 mol%), and 0.242 g of diphenyl-2-pyridylphosphine (10 mol%) were added sequentially to a three-necked flask. An aqueous solution of sodium hydroxide (1.84 g sodium hydroxide, 20 mL water) was prepared and added to the reaction system. The resulting mixture was stirred at 100 °C for 10 h, and the reaction progress was monitored by TLC until the p-hydroxybromophenylethanol was completely consumed. After the reaction was complete, the mixture was cooled to room temperature, and the pH was adjusted to 2 with 10 wt% dilute hydrochloric acid. The extract was obtained with methyl tert-butyl ether, dried, filtered, and the solvent was concentrated under reduced pressure in an oil bath at 50 °C to obtain 0.89 g of a pale yellow oil, which was hydroxytyrosol, with a molar yield of 62.67% and a purity of 96.7%.

[0068] Example 10: (1) Synthesis of p-hydroxybromophenylethanol Same as Example 1.

[0069] (2) Synthesis of hydroxytyrosol

[0070] Under nitrogen protection, 2 g of p-hydroxybromophenylethanol (9.214 mmol, 1.0 equivalent), 0.066 g of cuprous bromide (5 mol%), and 0.21 g of dibenzoylmethane (10 mol%) were added sequentially to a three-necked flask. An aqueous solution of sodium hydroxide (1.84 g sodium hydroxide, 20 mL water) was prepared and added to the reaction system. The resulting mixture was reacted at 100 °C for 10 h, and the reaction progress was monitored by TLC until the p-hydroxybromophenylethanol was completely consumed. After the reaction was complete, the mixture was cooled to room temperature, and the pH was adjusted to 2 with 10 wt% dilute hydrochloric acid. The extract was obtained with methyl tert-butyl ether, dried, filtered, and the solvent was concentrated under reduced pressure in an oil bath at 50 °C to obtain 0.85 g of a pale yellow oil, which was hydroxytyrosol, with a molar yield of 59.86% and a purity of 96.9%.

[0071] Example 11: (1) Synthesis of p-hydroxybromophenylethanol Same as Example 1.

[0072] (2) Synthesis of hydroxytyrosol

[0073] Under nitrogen protection, 2 g of p-hydroxybromophenylethanol (9.214 mmol, 1.0 equivalent), 0.088 g of cuprous iodide (5 mol%), and 0.23 g of BFMO (10 mol%) were added sequentially to a three-necked flask. An aqueous solution of sodium hydroxide (1.84 g sodium hydroxide, 20 mL water) was prepared and added to the reaction system. The resulting mixture was stirred at 100 °C for 10 h, and the reaction progress was monitored by TLC until the p-hydroxybromophenylethanol was completely consumed. After the reaction was complete, the mixture was cooled to room temperature, and the pH was adjusted to 2 with 10 wt% dilute hydrochloric acid. The extract was obtained with methyl tert-butyl ether, dried, filtered, and the solvent was concentrated under reduced pressure in an oil bath at 50 °C to obtain 0.72 g of a pale yellow oil, which was hydroxytyrosol, with a molar yield of 50.70% and a purity of 96.0%.

[0074] Example 12: (1) Synthesis of p-hydroxybromophenylethanol Same as Example 1.

[0075] (2) Synthesis of hydroxytyrosol

[0076] Under nitrogen protection, 2 g of p-hydroxybromophenylethanol (9.214 mmol, 1.0 equivalent), 0.115 g of copper sulfate pentahydrate (5 mol%), and 0.092 g of acetylacetone (10 mol%) were added sequentially to a three-necked flask. An aqueous solution of sodium hydroxide (1.84 g sodium hydroxide, 20 mL water) was prepared and added to the reaction system. The resulting mixture was stirred at 100 °C for 10 h, and the reaction progress was monitored by TLC until the p-hydroxybromophenylethanol was completely consumed. After the reaction was complete, the mixture was cooled to room temperature, and the pH was adjusted to 2 with 10 wt% dilute hydrochloric acid. The extract was then extracted with methyl tert-butyl ether, dried, filtered, and the solvent was concentrated under reduced pressure in an oil bath at 50 °C to obtain 0.81 g of a pale yellow oil, which was hydroxytyrosol, with a molar yield of 57.04% and a purity of 95.9%.

[0077] Example 13: (1) Synthesis of p-hydroxybromophenylethanol Same as Example 1.

[0078] (2) Synthesis of hydroxytyrosol

[0079] Under nitrogen protection, 2 g of p-hydroxybromophenylethanol (9.214 mmol, 1.0 equivalent), 0.0132 g of cuprous bromide (1 mol%), and 0.0232 g of o-phenanthroline (1 mol%) were added sequentially to a three-necked flask. An aqueous solution of sodium hydroxide (1.84 g sodium hydroxide, 20 mL water) was prepared and added to the reaction system. The resulting mixture was stirred at 100 °C for 10 h, and the reaction progress was monitored by TLC until the p-hydroxybromophenylethanol was completely consumed. After the reaction was complete, the mixture was cooled to room temperature, and the pH was adjusted to 2 with 10 wt% dilute hydrochloric acid. The extract was obtained with methyl tert-butyl ether, dried, filtered, and the solvent was concentrated under reduced pressure in an oil bath at 50 °C to obtain 1.14 g of a pale yellow oil, which was hydroxytyrosol, with a molar yield of 80.28% and a purity of 99.0%.

[0080] Example 14: (1) Synthesis of p-hydroxybromophenylethanol Same as Example 1 (2) Synthesis of hydroxytyrosol Under nitrogen protection, 2 g of p-hydroxybromophenylethanol (9.214 mmol, 1.0 equivalent), 0.0132 g of cuprous bromide (1 mol%), and 0.0498 g of o-phenanthroline (3 mol%) were added sequentially to a three-necked flask. An aqueous solution of sodium hydroxide (1.84 g sodium hydroxide, 20 mL water) was prepared and added to the reaction system. The resulting mixture was stirred at 100 °C for 10 h, and the reaction progress was monitored by TLC until the p-hydroxybromophenylethanol was completely consumed. After the reaction was complete, the mixture was cooled to room temperature, and the pH was adjusted to 2 with 10 wt% dilute hydrochloric acid. The extract was obtained with methyl tert-butyl ether, dried, filtered, and the solvent was concentrated under reduced pressure in an oil bath at 50 °C to obtain 1.01 g of a pale yellow oil, which was hydroxytyrosol, with a molar yield of 71.1% and a purity of 98.5%.

[0081] Example 15: (1) Synthesis of p-hydroxybromophenylethanol N-bromosuccinimide (NBS, 0.38 mol, 1.0 equivalent) was added in multiple equal portions to a mixture of 50 g p-hydroxyphenylethanol (3.6 mol, 1.0 equivalent) and ethyl acetate (EtOAc, 250 mL) at 0 °C. The resulting mixture was stirred at 0 °C for 3 h, and the reaction progress was monitored by TLC until the p-hydroxyphenylethanol was completely consumed. The reaction mixture was washed with saturated sodium bisulfite (150 mL × 3) and water (150 mL × 3), respectively. The combined organic phases were dried over anhydrous sodium sulfate. The solvent was removed by rotary evaporation, and the filter cake was dried under vacuum to give 75.9 g of white powdery solid, which was p-hydroxybromophenylethanol, with a molar yield of 96.7%.

[0082] (2) Synthesis of hydroxytyrosol

[0083] Under nitrogen protection, 30 g of p-hydroxybromophenylethanol (0.138 mol, 1.0 equivalent), 0.198 g of cuprous bromide (1 mol%), and 0.498 g of o-phenanthroline (2 mol%) were added sequentially to a three-necked flask. An aqueous solution of sodium hydroxide (27.64 g sodium hydroxide, 300 mL water) was prepared and added to the reaction system. The resulting mixture was stirred at 100 °C for 10 h, and the reaction progress was monitored by TLC until the p-hydroxybromophenylethanol was completely consumed. After the reaction was complete, the mixture was cooled to room temperature, and 10 wt% dilute hydrochloric acid was added to adjust the pH to 2. The mixture was extracted with methyl tert-butyl ether, dried, filtered, and the solvent was concentrated under reduced pressure in an oil bath at 50 °C to obtain 17.23 g of a pale yellow oil, which was hydroxytyrosol, with a molar yield of 80.89% and a purity of 99.1%.

Claims

1. A method for synthesizing hydroxytyrosol, characterized in that: The synthesis method includes the following steps: (1) p-hydroxyphenylethanol of Formula 1 reacts with a bromide in ethyl acetate at 0-25°C to produce p-hydroxybromophenylethanol of Formula 2; the bromide is N-bromosuccinimide; (2) Under nitrogen protection, p-hydroxybromophenylethanol is reacted in an aqueous solution of an alkali in the presence of a copper catalyst and a ligand at 80℃-100℃ to produce hydroxytyrosol as shown in Formula 3; the copper catalyst is cuprous bromide; the ligand is o-phenanthroline; the molar ratio of p-hydroxybromophenylethanol to the alkali is 1:2.5-1:10, the molar ratio of p-hydroxybromophenylethanol to the copper catalyst is 1:0.01-1:0.1, and the molar ratio of the copper catalyst to the ligand is 1:1-1:2; 。 2. The synthesis method according to claim 1, characterized in that: The reaction temperature in step (1) is 0-5℃, preferably 0℃.

3. The synthesis method as described in claim 1, characterized in that: In step (1), the molar ratio of p-hydroxyphenylethanol to bromine in the brominating reagent is 1:0.8-1.5, preferably 1:1.0-1.1; the volume of ethyl acetate used is 3-6 mL / g based on the mass of p-hydroxyphenylethanol.

4. The synthesis method according to claim 1, characterized in that: The alkali in step (2) is any one of sodium hydroxide, potassium hydroxide, cesium hydroxide, lithium hydroxide, potassium carbonate, cesium carbonate, and potassium phosphate, preferably sodium hydroxide.

5. The synthesis method according to claim 1, characterized in that: In step (2), the molar ratio of p-hydroxybromophenylethanol to the base is 1:5-10, preferably 1:5; the molar ratio of p-hydroxybromophenylethanol to the copper catalyst is 1:0.01-0.05, preferably 1:0.

01.

6. The synthesis method as described in claim 1 or 5, characterized in that: In step (2), the molar ratio of the copper catalyst to the ligand is 1:

2.

7. The synthesis method according to claim 1, characterized in that: In step (2), the concentration of the aqueous solution of the alkali is 0.08 g / mL to 0.20 g / mL, preferably 0.08 g / mL to 0.11 g / mL.

8. The synthesis method according to claim 1, characterized in that: In step (2), the reaction temperature is 90-100℃, with 100℃ being the most preferred.

9. The synthesis method according to claim 1, characterized in that: After the reaction in step (2) is completed, hydroxytyrosol is obtained by the following post-treatment operation: After the reaction is completed, the reaction mixture is cooled to room temperature, dilute hydrochloric acid is added to adjust to acidity, organic solvent is used for extraction, drying, filtration, and solvent is concentrated under reduced pressure to obtain a pale yellow oily substance, which is hydroxytyrosol.

10. The synthesis method according to claim 9, characterized in that: The extraction solvent is any one of ethyl acetate, dichloromethane, and methyl tert-butyl ether.

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