CN103664536A - Synthetic method of hydroxytyrosol - Google Patents

Abstract

The invention belongs to the technical field of medicament synthesis, and in particular relates to a chemical synthetic method of hydroxytyrosol. The chemical synthetic method comprises the steps of (1) protecting two phenolic hydroxyl groups of catechol by using dichloromethane, and enabling catechol to react with dichloromethane to prepare 1,2-methylenedioxybenzene; (2) enabling 1,2-methylenedioxybenzene to react with various monoesters of oxalyl chloride to prepare 3,4-methylenedioxy phenylglyoxylic acid ester; (3) preparing 3,4-methylenedioxy phenylacetic acid by using 3,4-methylenedioxy phenylglyoxylic acid ester through a Wollff-kishner-Huang Minglong reduction reaction; and (4) reducing the 3,4-methylenedioxy phenylacetic acid by using lithium aluminum hydride, lithium borohydride or sodium borohydride to prepare 3,4-methylenedioxy phenethyl alcohol, and then removing methylene protection of the 3,4-methylenedioxy phenethyl alcohol by using boron tribromide or palladium on activated carbon to prepare hydroxytyrosol. A reactive reagent used in the synthetic method disclosed by the invention is easy to obtain and low in price, the reaction condition is mild, and the final yield of the whole reaction is 23%.

Description

A kind of synthetic method of hydroxytyrosol

technical field

The invention belongs to the technical field of drug synthesis, and in particular relates to a chemical synthesis method of hydroxytyrosol.

Background technique

Hydroxytyrosol, also known as 3,4 dihydroxyphenylethanol, mainly exists in various parts of olives in the form of esterified oleuropein, and free hydroxytyrosol can be obtained after oleuropein is hydrolyzed. It is a natural polyphenolic compound with strong antioxidant properties. In recent years, a large number of studies at home and abroad have confirmed that hydroxytyrosol has many biopharmacological activities beneficial to human health (1) hydroxytyrosol has a positive effect on lowering blood pressure and preventing cardiovascular diseases; (2) hydroxytyrosol has a positive effect on bone (3) Hydroxytyrosol is also used in anti-cancer and anti-cancer; (4) Hydroxytyrosol has antibacterial effect; (5) Hydroxytyrosol can effectively reduce and inhibit the harm of smoking to the human body. Due to its excellent physiological activity, it has been valued by the biological and medical circles in recent years.

At present, hydroxytyrosol is mainly obtained by the following methods: (1) extracting hydroxytyrosol from waste water produced by pressing olive oil. The advantage of this method is that the waste water produced in the production of olive oil is used to reduce the pollution to the environment. However, this method needs to consume a large amount of solvent, and the yield of hydroxytyrosol is low, so it is not suitable for industrial production; (2) obtain hydroxytyrosol by biological fermentation. The method involves genetically engineered bacteria, which has relatively high technical requirements and a long production period, and the current technology is immature; (3) the method of chemical synthesis is used to prepare hydroxytyrosol. The artificial synthesis method of hydroxytyrosol reported in the literature in recent years is mainly prepared by reducing 3,4-dihydroxyphenylacetic acid or oxidizing tyrosol. But the raw material stability of above route is poor, and cost is higher. DSM has also applied for a patent on the method for preparing hydroxytyrosol using catechol as a raw material, but expensive chemical reagents such as palladium carbon are used in the route, so it is necessary to study a more economical method for synthesizing hydroxytyrosol .

Contents of the invention

The purpose of the present invention is to provide a more economical synthesis method of hydroxytyrosol, which greatly reduces the cost of synthesizing hydroxytyrosol while keeping the overall yield unchanged from other published methods.

In order to achieve the above object, the technical scheme adopted in the present invention is: a kind of synthetic method of hydroxytyrosol, comprises the following steps:

(1) protect two phenolic hydroxyl groups of catechol with dichloromethane: react catechol with dichloromethane to prepare 1,2-methylenedioxybenzene;

(2) With the various monoesters of oxalyl chloride shown in general structural formula a as the raw material of Friedel-Crafts reaction, prepare 3,4-methylenedioxyacetophenone by reacting with 1,2-methylenedioxybenzene ester, R in a is C ₁ -C ₆ alkyl or C ₆ H ₅ CH ₂ .

(3) 3,4-methylenedioxyacetophenone ester is prepared by Wolff-Kishner-Huang Minglong reduction reaction to prepare 3,4-methylenedioxyphenylacetic acid;

(4) Use lithium aluminum hydride or lithium borohydride or sodium borohydride to reduce 3,4-methylenedioxyphenylacetic acid to prepare 3,4-methylenedioxyphenethyl alcohol, and then use boron tribromide or palladium carbon to desorb Preparation of hydroxytyrosol by removing the methylene protection of 3,4-methylenedioxyphenethyl alcohol.

A specific preparation method of hydroxytyrosol comprises the following steps:

(1) Dissolve tetrabutylammonium bromide (TBAB) in dimethyl sulfoxide, heat to reflux at 110°C, and simultaneously add catechol dimethyl sulfoxide solution and 50% inorganic base dropwise Solution, after the continuous reaction, add water, continue heating and distilling, collect fractions at 99-104°C, and treat the distillate to obtain 1,2-methylenedioxybenzene;

Wherein, the inorganic base is sodium hydroxide or potassium hydroxide, and the molar ratio of the phase transfer catalyst TBAB to catechol is 0.05～0.1:1;

(2) Add aluminum trichloride to anhydrous dichloromethane and stir until suspended. Add dropwise oxalyl chloride monoester to it under ice bath condition, after fully stirring, add piperonylcycline dropwise to the system, after the reaction at room temperature, add water to quench the reaction, separate and purify to obtain 3,4-methylene di Oxyacetophenone ester;

Wherein, the molar ratio of the 1,2-methylenedioxybenzene, anhydrous aluminum trichloride and oxalyl chloride monoester is 1:1.15:1.05～1.15;

(3) Dissolve 3,4-methylenedioxyacetophenone ester and hydrazine hydrate in ethylene glycol, slowly heat up, heat to reflux, after the reaction is over, cool to room temperature, add ground potassium hydroxide, heat , evaporate low boilers while raising the temperature, after the end, reflux for a few hours, cool to room temperature, drop dilute hydrochloric acid solution to adjust the pH to 2-3, preliminary post-treatment, recrystallization with ethyl acetate-petroleum ether system , to obtain 3,4-methylenedioxyphenylacetic acid;

(4) According to the prior art, use lithium aluminum hydride or lithium borohydride or sodium borohydride to reduce 3,4-methylenedioxyphenylacetic acid to prepare 3,4-methylenedioxyphenylethyl alcohol, and then use tribrominated The methylene protection of 3,4-methylenedioxyphenethyl alcohol was removed by boron or palladium carbon to prepare hydroxytyrosol.

Compared with the prior art, the present invention has the following advantages and effects:

The reaction reagent used in the invention is easy to obtain, cheap, mild reaction conditions, the final yield of the whole reaction is 23%, the reaction cost is greatly reduced, and has good industrial application prospect.

Description of drawings

Fig. 1 is the synthetic route schematic diagram of preparing hydroxytyrosol in embodiment one;

Fig. 2 is the proton nuclear magnetic resonance spectrum analysis figure of 1,2-methylenedioxybenzene in embodiment one;

Fig. 3 is the proton nuclear magnetic resonance spectrum analysis figure of 3,4-methylenedioxyacetophenone ethyl ester in embodiment one;

Fig. 4 is the proton nuclear magnetic resonance spectrum analysis figure of 3,4-methylenedioxyphenylacetic acid in embodiment one;

Fig. 5 is the proton nuclear magnetic resonance spectrum analysis figure of 3,4-methylenedioxyphenethyl alcohol in embodiment one;

Fig. 6 is the H NMR spectrum analysis diagram of hydroxytyrosol in Example 1.

Detailed ways

The present invention will be further described below in conjunction with accompanying drawing and embodiment:

Embodiment one: Synthetic hydroxytyrosol according to the synthetic route shown in Figure 1

1. Preparation of 1,2-methylenedioxybenzene (3)

Add DMSO (80ml), dichloromethane (20ml), and TBAB (1.9g, 6mmol) to a 250ml three-necked flask, and slowly heat up to 110°C. When reflux is seen, slowly add catechol ( 11g, 0.1mol) of DMSO (60mL) solution, add dropwise 50% sodium hydroxide aqueous solution (sodium hydroxide 8g, 0.2mol, water 8mL) at the same time, add dropwise for about 2h, continue to react for about 1h, and monitor the reaction by TLC Finish.

Add 100mL of water to the reaction flask, continue heating, and collect the fraction at 99-104°C. This distillate is an azeotrope of water and 1,2-methylenedioxybenzene, which is white and turbid. When the distillate is clear, it does not contain 1,2-methylenedioxybenzene. The distillate was treated to obtain a colorless transparent liquid (9.97 g, 81.7%).

Carry out NMR analysis, get Fig. 2, the result is as follows:

¹ H-NMR (CDCl ₃ ): δ/ppm 5.97 (2H, s, CH ₂ ), 6.87 (4H, s, Ar H ).

The above results show that the obtained product is 1,2-methylenedioxybenzene.

2. Preparation of ethyl 3,4-methylenedioxyacetophenone (4)

Add anhydrous dichloromethane (60 mL) and aluminum trichloride (5.85 g, 0.043 mol) into a 250 ml three-necked flask, and stir until suspended. Monoethyl oxalyl chloride (5.88 g, 0.043 mol) was slowly added dropwise, and the addition was completed within about 30 min. Stir at room temperature for 10 min, and the solution turned pale yellow. 3 (5 g, 0.041 mol) was added dropwise in an ice bath, and the dropwise addition was completed in about 10 minutes. The ice bath was removed, and the reaction was carried out at room temperature for 1 hour, and the reaction was monitored by TLC.

Slowly add 3 times the equivalent of water under ice bath, extract three times with ethyl acetate, combine the organic phases, and wash the organic phases successively with 5% aqueous sodium bicarbonate solution (30ml×2) and water (40ml×2), anhydrous sodium sulfate After drying and filtering, the filtrate was concentrated under reduced pressure, and the obtained product was separated by column chromatography [V (petroleum ether): V (ethyl acetate) = 40: 1] to obtain a light yellow oil (6.5 g, 72.3%).

Carry out NMR analysis, get Fig. 3, the result is as follows:

¹ H-NMR (CDCl ₃ ): δ/ppm 1.41-1.45 (3H, t, CH ₂ CH ₃ ), 4.42-4.47 (2H, m, CH ₂ CH ₃ ), 6.10 (2H, s, CH ₂ ), 6.90-6.92 (1H, d, Ar H ), 7.49-7.50 (1H, d, Ar H ), 7.62-7.64 (1H, dd, Ar H ).

The above results show that the obtained product is ethyl 3,4-methylenedioxyacetophenone.

3. Preparation of 3,4-methylenedioxyphenylacetic acid (5)

Add 4 (6.7g, 0.03mol), ethylene glycol (60ml) and 85% hydrazine hydrate (8.85g, 0.15mol) into a 250ml three-necked flask, and slowly raise the temperature to 120°C for 2h. After cooling to room temperature, potassium hydroxide (5 g, 0.09 mol) was added, heated to 180° C., low boilers were evaporated (about 2 h) while the temperature was raised, and then refluxed for 4 h. Cool to room temperature after the reaction, add 6mol/L hydrochloric acid to adjust the pH to 2-3. Water (60ml) was added, extracted with ethyl acetate (50ml×4), and the organic phases were combined. After washing with water (50ml×2), drying over anhydrous sodium sulfate and suction filtration, the filtrate was concentrated to dryness under reduced pressure, and the residue was recrystallized with ethyl acetate-petroleum ether (1:1) to obtain a white solid (3.39g, 62.8%).

Carry out nuclear magnetic analysis, get Fig. 4, the result is as follows:

¹ H-NMR (CDCl3): δ/ppm 3.59 (2H, s, CH ₂ COOH), 5.97 (2H, s, CH ₂ ), 6.73-6.75 (1H, dd, Ar H ), 6.78 (1H, s, Ar H ), 6.80-6.81 (1H, d, Ar H ).

The above results show that the product obtained is 3,4-methylenedioxyphenylacetic acid.

4. Preparation of 3,4-methylenedioxyphenethyl alcohol (6)

Add 5 (3 g, 0.017 mol) and anhydrous tetrahydrofuran (30 mL) into a 100 ml three-necked flask, and mix well under ice bath conditions. Lithium aluminum hydride (1.7 g, 0.05 mol) was added carefully, the reaction was refluxed for 4 h, and the reaction was completed by TLC monitoring.

Under the condition of ice bath, slowly add 3 times equivalent of NaOH solution (1mol/L), 3 times of equivalent of water. Filter, wash the filter cake with dichloromethane, concentrate, mix the sample onto a silica gel column, petroleum ether: ethyl acetate = 3:1 to obtain a slightly yellow transparent oil (2.28g, 81%).

¹ H-NMR (CDCl ₃ ): δ/ppm 1.55 (1H, s, CH ₂ CH ₂ OH ), 2.79-2.82 (2H, t, CH ₂ CH ₂ OH), 3.82-3.85 (2H, t, CH ₂ CH ₂ OH), 5.95 (2H, s, CH ₂ ), 6.69-6.71 (1H, dd, ArH), 6.74-6.75 (1H, d, Ar H ), 6.77-6.79 (1H, d, Ar H ).

The above results show that the resulting product is 3,4-methylenedioxyphenethyl alcohol.

5. Preparation of hydroxytyrosol (1)

Add 6 (0.2g, 1.20mmol) and anhydrous dichloromethane (25ml) into a 50ml reaction flask, cool to -40°C, add boron tribromide dichloromethane solution dropwise with a syringe (containing boron tribromide 1.78mol /L) 4.3ml. After the dropwise addition was completed, the reaction was carried out at room temperature for 2 h, and the reaction was detected by TLC. The reaction was quenched by adding 10 ml of methanol dropwise in an ice bath, concentrated, and the residue was separated by liquid column chromatography to obtain hydroxytyrosol 1 as a white powder (0.141 g, 76%).

¹ H-NMR (CDCl ₃ ): δ/ppm 3.03-3.07 (2H, t, CH ₂ CH ₂ OH), 3.49-3.53 (2H, t, CH ₂ CH ₂ OH), 5.04 (1H, s, Ar OH ), 5.14 (1H, s, Ar OH ), 6.64-6.66 (1H, dd, Ar H ), 6.73-6.74 (1H, d, Ar H ), 6.80-6.82 (1H, d, Ar H ).

The above results show that the resulting product is hydroxytyrosol.

Claims (2)

1. a synthetic method for Hydroxytyrosol, is characterized in that, comprises the following steps:

(1) with methylene dichloride, protect two phenolic hydroxyl groups of pyrocatechol: pyrocatechol reacts preparation 1,2-methylenedioxybenzenes with methylene dichloride;

(2) take the raw material that the various monoesters of the oxalyl chloride shown in general structure a are Friedel-Crafts reaction, with 1,2-methylenedioxybenzenes reaction preparation, 3,4-methylene-dioxy benzoylformic acid ester, the R in a is C ₁-C ₆alkyl or C ₆h ₅cH ₂.

(3) 3,4-methylene-dioxy benzoylformic acid esters are by Wolff-Kishner-Huang Min-lon reduction reaction preparation 3,4-methylene-dioxy toluylic acid;

(4) use lithium aluminium hydride or lithium borohydride or sodium borohydride reduction 3,4-methylene-dioxy toluylic acid is prepared 3,4-methylene-dioxy phenylethyl alcohol, then with the methylene radical protection that boron tribromide or palladium carbon are taken off 3,4-methylene-dioxy phenylethyl alcohol, prepares Hydroxytyrosol.

2. synthetic method according to claim 1, is characterized in that, comprises the following steps:

(1) Tetrabutyl amonium bromide (TBAB) is dissolved in to dimethyl sulfoxide (DMSO), be heated to 110 ℃ of backflows, drip wherein the dimethyl sulphoxide solution of pyrocatechol simultaneously, and 50% inorganic alkali solution, after sustained reaction finishes, add water, continue to add thermal distillation, collect 99～104 ℃ of cuts, by distillate process 1,2-methylenedioxybenzenes;

Wherein, described mineral alkali is sodium hydroxide or potassium hydroxide, and the mol ratio of phase-transfer catalyst TBAB and pyrocatechol is 0.05～0.1: 1;

(2) aluminum chloride is added in anhydrous methylene chloride, be stirred to suspension.Under condition of ice bath, drip wherein oxalyl chloride monoesters, after fully stirring, then drip piperonyl cyclonene in system, after room temperature condition reaction finishes, add the shrend reaction of going out, separating-purifying, obtains 3,4-methylene-dioxy benzoylformic acid ester;

Wherein, described 1, the mol ratio of 2-methylenedioxybenzenes, aluminum trichloride (anhydrous) and oxalyl chloride monoesters is 1: 1.15: 1.05～1.15;

(3) 3,4-methylene-dioxy benzoylformic acid ester and hydrazine hydrate are dissolved in to ethylene glycol, slowly heat up, reflux, after reaction finishes, adds ground potassium hydroxide after being cooled to room temperature, heating, intensification limit, limit steams low-boiling-point substance, after finishing, back flow reaction is several hours again, is cooled to room temperature, drips dilute hydrochloric acid solution and adjusts pH to 2～3, preliminary aftertreatment, with ethyl acetate-sherwood oil system recrystallization, obtain 3,4-methylene-dioxy toluylic acid;

(4) according to prior art; use lithium aluminium hydride or lithium borohydride or sodium borohydride reduction 3,4-methylene-dioxy toluylic acid is prepared 3,4-methylene-dioxy phenylethyl alcohol; then with the methylene radical protection that boron tribromide or palladium carbon are taken off 3,4-methylene-dioxy phenylethyl alcohol, prepare Hydroxytyrosol.

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