Reduction method of stilbenoids

Abstract

The application discloses a reducing method of stilbene compounds and belongs to the technical field of organic synthesis. The method comprises the following steps: (a) taking E-4-isopropyl-3,5-dimethoxy-stilbene as raw material, and reducing the raw material to obtain E-4-isopropyl-3,5-dimethoxy-diphenylmethane; (b) taking E-4-isopropyl-3,5-dimethoxy-stilbene as raw material, and reducing and demethylating the raw material to obtain 4-isopropyl-3,5-dihydroxy-diphenylmethane; (c) taking E-4-isopropyl-3,5-dihydroxy-stilbene as raw material, and reducing the raw material to obtain 4-isopropyl-3,5-dihydroxy-diphenylmethane; the reducing condition is that an alcohol solvent is used as a solvent; in the reactions (a) and (b), formic acid or a formic compound is used as a hydrogen donor; in the reaction (c), formic acid or formic amine is used as a hydrogen donor; a catalyst is palladium-carbon and zinc powder; the mass ratio of the palladium-carbon to the zinc powder is 3-8:1.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, specifically to a method for reducing stilbene compounds, and more particularly to an industrial production method for stilbene compounds. Background Technology

[0002] Benzenemod, or 3,5-dihydroxy-4-isopropyltrans-stilbene, is the world's first aromatic hydrocarbon receptor agonist drug, belonging to the stilbene class of compounds. 3,5-dihydroxy-4-isopropyldiphenylethane and related compounds are pioneering new drugs developed by Wuhan Yingnashi Pharmaceutical Co., Ltd., showing great promise in the treatment of immune system diseases and inflammation (Li Jianxiong, CN201310477097.0, A diphenylethane derivative and its application). The structural formula of 3,5-dihydroxy-4-isopropyldiphenylethane is as follows:

[0003] .

[0004] The traditional reduction of double bonds in stilbene compounds to alkyl groups requires hydrogen gas under pressure via palladium-on-carbon catalysis. Hydrogen catalytic reduction is flammable and explosive, and industrial production demands strict approval and regulation, resulting in substantial investment. Furthermore, industrial hydrogenation requires specialized pipelines and pressure vessels, necessitating dedicated hydrogenation workshops. Moreover, safety supervision for hydrogenation production is extremely complex, requiring special safety operation permits. Therefore, the industrialization of hydrogen reduction is highly challenging. Summary of the Invention

[0005] This patent directly uses formic acid or formic acid-like compounds as hydrogen donors, and palladium on carbon with a certain proportion of zinc powder as a catalyst. Direct heating reduces the double bonds of stilbene compounds without affecting other active groups, such as alkenes. This method directly reduces benzenemod to 3,5-dihydroxy-4-isopropyldiphenylethane without hydrogen, or directly reduces 3,5-dimethoxy-4-isopropylstilbene to 3,5-dimethoxy-4-isopropyldiphenylethane, followed by demethoxylation to obtain 3,5-dihydroxy-4-isopropyldiphenylethane. The scheme is as follows:

[0006] This invention provides a method for reducing stilbene compounds, which includes the following reactions:

[0007] (a) Using E-4-isopropyl-3,5-dimethoxy-stilbene as a raw material, E-4-isopropyl-3,5-dimethoxy-diphenylethane was obtained by reduction.

[0008] (b) Using E-4-isopropyl-3,5-dimethoxy-stilbene as a raw material, 4-isopropyl-3,5-dihydroxy-diphenylethane was obtained by reduction and demethylation.

[0009] (c) Using E-4-isopropyl-3,5-dihydroxy-stilbene (phenylenemod) as a raw material, 4-isopropyl-3,5-dihydroxy-diphenylethane was obtained by reduction.

[0010] The reduction conditions are as follows: An alcoholic solvent is used. In reactions (a) and (b), formic acid or formic acid compounds are used as hydrogen donors; these formic acid compounds are selected from ammonium formate, potassium formate, sodium formate, lithium formate, methyl formate, or ethyl formate, etc. In reaction (c), formic acid or formic acid amine is used as a hydrogen donor. In reaction (c), potassium formate, sodium formate, and lithium formate cannot be used as hydrogen donors, as the reaction products (alkaline) of the hydrogen donors will cause product decomposition and numerous side reactions. The reduction reaction temperature is 40°C to reflux, preferably 60-65°C. The catalyst is palladium on carbon and zinc powder; the mass ratio of raw materials: hydrogen donor: catalyst is 1:0.3-3.5:0.03-0.2, and the mass ratio of palladium on carbon to zinc powder is 3-8:1. In this patent, the amount of catalyst used is based on the catalytic amount; palladium on carbon is used as the main catalyst, and zinc powder is used as an auxiliary catalyst; their synergistic effect produces unexpected results.

[0011] The alcohol solvent is selected from methanol, ethanol, propanol, or isopropanol, etc. Preferably, the alcohol solvent is methanol.

[0012] Preferably, in reactions (a), (b) and (c), the hydrogen donor is formic acid.

[0013] The reduction reaction takes 6-12 hours.

[0014] Preferably, in reactions (a), (b) and (c), when the hydrogen donor is formate, the solvent is an alcohol-water mixture with a water volume content of 5-50% to avoid sublimation of formate.

[0015] In reaction (b), the demethylation process includes: dissolving 4-isopropyl-3,5-dimethoxy-diphenylethane in dichloromethane, adding anhydrous aluminum trichloride in steps at -20 to 5°C (specifically 0°C), stirring the reaction at room temperature after the addition is complete, and diluting with dichloromethane after the reaction is complete; adding the diluted solution dropwise to dilute hydrochloric acid (specifically 10 wt%) at 0°C to quench the reaction, separating the layers, washing the organic layer with water, evaporating to dryness, and recrystallizing (specifically using cyclohexane) to obtain 4-isopropyl-3,5-dihydroxy-diphenylethane. The mass ratio of anhydrous aluminum trichloride to 4-isopropyl-3,5-dimethoxy-diphenylethane is 0.8-1.5:1. In existing technologies, pyridine hydrochloride is typically used for demethylation at around 180°C, which is high and pyridine hydrochloride is highly toxic. This patent uses a low temperature and anhydrous aluminum trichloride, resulting in a milder reaction. In addition, the applicant found that E-4-isopropyl-3,5-dimethoxy-stilbene cannot be present when anhydrous aluminum trichloride is used as a reactant. If it is present, ethylene will polymerize and break down into various substances, resulting in a high impurity content. Therefore, the purity of the reduction reaction product must be very high.

[0016] Furthermore, after the reduction reaction is complete, the insoluble matter is removed by filtration, and then the temperature is lowered to -20 to -5℃ to obtain the product through solid-liquid separation.

[0017] Specifically, reactions (a) and (b) include: using E-4-isopropyl-3,5-dimethoxy-stilbene as a raw material, formic acid as a hydrogen donor, and methanol as a solvent, a reduction reaction is carried out at 60-65℃; after the reaction is completed, the insoluble matter is removed by filtration, and then the temperature is lowered to -20 to -5℃, and solid-liquid separation is performed to obtain E-4-isopropyl-3,5-dimethoxy-diphenylethane. The mass ratio of E-4-isopropyl-3,5-dimethoxy-stilbene:formic acid:palladium on carbon:zinc powder is 1:0.5:0.05:0.01.

[0018] Specifically, reaction (c) includes: using E-4-isopropyl-3,5-dihydroxy-stilbene as a raw material, formic acid as a hydrogen donor, and methanol as a solvent, a reduction reaction is carried out at 60-65℃; after the reaction is completed, the insoluble matter is removed by filtration, and then the temperature is lowered to -20 to -5℃, and solid-liquid separation is performed to obtain E-4-isopropyl-3,5-dihydroxy-diphenylethane. The mass ratio of E-4-isopropyl-3,5-dihydroxy-stilbene:formic acid:palladium on carbon:zinc powder is 1:0.5:0.05:0.01.

[0019] This invention has the following advantages:

[0020] (1) It does not use hydrogen as a hydrogen donor, the reaction conditions are mild, and it is easy to realize industrially;

[0021] (2) The purification process is simple, and high-purity products can be obtained by simply cooling and two solid-liquid separations;

[0022] (3) In reaction (b), since high-purity E-4-isopropyl-3,5-dimethoxy-diphenylethane was obtained, the subsequent demethylation reaction can use anhydrous aluminum trichloride as a raw material. The reaction conditions are mild, the raw material has low toxicity, and it is easy to realize industrially. Detailed Implementation

[0023] The invention will be further described below through specific embodiments. However, it should be noted that these embodiments are merely illustrative and do not limit the scope of the invention.

[0024] Example 1: Preparation of 4-isopropyl-3,5-dimethoxy-diphenylethane

[0025] 20 kg of 4-isopropyl-3,5-dimethoxy-diphenylethylene, 60 L of methanol, 10 kg of formic acid, 1 kg of palladium on carbon, and 200 g of zinc powder were added to a 100 L reactor. The mixture was heated to 60-65 °C and stirred for 8 h. The palladium on carbon and zinc powder were removed by filtration. The mixture was then cooled to -10 °C, and a white solid precipitated. 18.2 kg of the white solid was obtained by filtration, with a yield of 91% and a purity greater than 98%.

[0026] Example 2

[0027] 20 kg of 4-isopropyl-3,5-dimethoxy-diphenylethylene, 60 L of methanol, 10 kg of potassium formate, 1 kg of palladium on carbon, and 200 g of zinc powder were added to a 100 L reactor. The mixture was heated to 60-65 °C and stirred for 8 h. The palladium on carbon and zinc powder were removed by filtration. The mixture was then cooled to -10 °C, and a white solid precipitated. 17.3 kg of the white solid was obtained by filtration, with a yield of 86% and a purity greater than 98%.

[0028] Example 3

[0029] 20 kg of 4-isopropyl-3,5-dimethoxy-diphenylethylene, 60 L of methanol, 10 kg of sodium formate, 1 kg of palladium on carbon, and 200 g of zinc powder were added to a 100 L reactor. The mixture was heated to 60-65 °C and stirred for 8 h. The palladium on carbon and zinc powder were removed by filtration. The mixture was then cooled to -10 °C, and a white solid precipitated. 17.6 kg of the white solid was obtained by filtration, with a yield of 88% and a purity greater than 98%.

[0030] Example 4

[0031] 20 kg of 4-isopropyl-3,5-dimethoxy-diphenylethylene, 60 L of methanol, 10 L of water, 10 kg of formic acid amine, 1 kg of palladium on carbon, and 200 g of zinc powder were added to a 100 L reactor. The mixture was heated to 60-65 °C and stirred for 8 h. The palladium on carbon and zinc powder were removed by filtration. The mixture was then cooled to -10 °C, and a white solid precipitated. 16.1 kg of the white solid was obtained by filtration, with a yield of 82% and a purity greater than 98%.

[0032] Example 5: Preparation of 4-isopropyl-3,5-dihydroxy-diphenylethane

[0033] 20 kg of 4-isopropyl-3,5-dimethoxy-diphenylethane and 20 L of dichloromethane were added to a 100 L reactor. The mixture was cooled to 0 °C, and 20 kg of anhydrous aluminum trichloride was slowly added. After the addition was complete, the mixture was brought to room temperature and stirred for 5 hours. After dilution with 40 L of dichloromethane, a reddish-black solution was obtained. This solution was then added dropwise in 60 L of a 10 wt% dilute hydrochloric acid solution at 0 °C to quench the reaction. The mixture was separated, and the dichloromethane layer was washed with water to recover the solvent. Cyclohexane crystallization yielded 13.3 kg of a white solid, with a yield of 66.5% and a purity greater than 99%.

[0034] Example 6

[0035] 20 kg of 4-isopropyl-3,5-dihydroxy-diphenylethylene (phenylenemod) 60 L of methanol 10 kg of formic acid 1 kg of palladium on carbon and 200 g of zinc powder were added to a 100 L reactor. The mixture was heated to 60-65 °C and stirred for 8 h. The palladium on carbon and zinc powder were removed by filtration. The mixture was then cooled to -10 °C, and a white solid precipitated. 17.1 kg of the white solid was obtained by filtration, with a yield of 85.5% and a purity greater than 98%.

[0036] Example 7

[0037] 20 kg of 4-isopropyl-3,5-dihydroxy-diphenylethylene (phenylenemod) 60 L of methanol 10 L of water 10 kg of formic acid amine 10 kg of palladium on carbon and 200 g of zinc powder were added to a 100 L reactor. The mixture was heated to 60-65 °C and stirred for 8 h. The palladium on carbon and zinc powder were removed by filtration. The mixture was then cooled to -10 °C, and a white solid precipitated. 15.6 kg of the white solid was obtained by filtration, with a yield of 78% and a purity greater than 98%.

[0038] Comparative Example 1

[0039] 20 kg of 4-isopropyl-3,5-dimethoxy-diphenylethylene, 60 L of methanol, 10 kg of formic acid, and 1 kg of palladium on carbon were added to a 100 L reactor. The mixture was heated to 60-65 °C and stirred for 8 h. The palladium on carbon was removed by filtration and the mixture was cooled to -10 °C. A white solid precipitated out and was filtered to obtain 4.6 kg of white solid, with a yield of 23%.

[0040] Comparative Example 2

[0041] 20 kg of 4-isopropyl-3,5-dimethoxy-diphenylethylene, 60 L of methanol, 10 kg of formic acid, and 5 kg of palladium on carbon were added to a 100 L reactor. The mixture was heated to 60-65 °C and stirred for 8 h. The palladium on carbon was removed by filtration, and the mixture was cooled to -10 °C. A white solid precipitated out and was filtered to obtain 4.5 kg of white solid, with a yield of 22.5%.

[0042] Comparative Example 3

[0043] 20 kg of 4-isopropyl-3,5-dimethoxy-diphenylethylene, 60 L of methanol, 10 kg of formic acid, and 1 kg of palladium on carbon were added to a 100 L reactor. The mixture was heated to 60-65 °C and stirred for 24 h. The palladium on carbon was removed by filtration, and the mixture was cooled to -10 °C. A white solid precipitated out. 4.6 kg of the white solid was obtained by filtration, with a yield of 23%.

[0044] Comparative Example 4

[0045] 20 kg of 4-isopropyl-3,5-dimethoxy-diphenylethylene, 60 L of methanol, 10 kg of formic acid, and 200 g of zinc powder were added to a 100 L reactor. The mixture was heated to 60-65 °C and stirred for 8 h. The zinc powder was removed by filtration, and the mixture was cooled to -10 °C. A white solid precipitated out and was filtered to obtain 0.85 kg of white solid, with a yield of 4.25%.

[0046] Comparative Example 5

[0047] 20 kg of 4-isopropyl-3,5-dimethoxy-diphenylethylene, 60 L of methanol, 10 kg of formic acid and 1.5 g of zinc powder were added to a 100 L reactor. The mixture was heated to 60-65 °C and stirred for 8 h. The zinc powder was removed by filtration and the mixture was cooled to -10 °C. A white solid precipitated out and was filtered to obtain 1.0 kg of white solid, with a yield of 5%.

[0048] Comparative Example 6

[0049] 20 kg of 4-isopropyl-3,5-dimethoxy-diphenylethylene, 60 L of methanol, 10 kg of formic acid, and 1.5 g of zinc powder were added to a 100 L reactor. The mixture was heated to 60-65 °C and stirred for 24 h. The zinc powder was removed by filtration, and the mixture was cooled to -10 °C. A white solid precipitated out and was filtered to obtain 1.0 kg of white solid, with a yield of 5%.

[0050] Comparative Example 7

[0051] 20 kg of 4-isopropyl-3,5-dimethoxy-diphenylethylene, 60 L of methanol, 10 kg of formic acid, 200 g of palladium on carbon, and 1 kg of zinc powder were added to a 100 L reactor. The mixture was heated to 60-65 °C and stirred for 8 h. The palladium on carbon and zinc powder were removed by filtration. The mixture was then cooled to -10 °C, and a white solid precipitated. 1.3 kg of the white solid was obtained by filtration, with a yield of 6.5%.

[0052] Comparative Example 8

[0053] 20 kg of 4-isopropyl-3,5-dimethoxy-diphenylethylene, 60 L of methanol, 10 kg of formic acid, 1 kg of palladium on carbon, and 1 kg of zinc powder were added to a 100 L reactor. The mixture was heated to 60-65 °C and stirred for 8 h. The palladium on carbon and zinc powder were removed by filtration. The mixture was then cooled to -10 °C, and a white solid precipitated. 8.7 kg of the white solid was obtained by filtration, with a yield of 53.5%.

[0054] Comparative Example 9

[0055] Add 20 kg of 4-isopropyl-3,5-dimethoxy-diphenylethylene, 60 L of methanol, 10 kg of acetic acid, 1 kg of palladium on carbon, and 200 g of zinc powder to a 100 L reactor. Heat to 60-65 °C and stir for 8 h. Filter to remove palladium on carbon and zinc powder. Cool to -10 °C. There is basically no white solid precipitation.

[0056] As can be seen from Comparative Examples 1 to 8, both palladium on carbon and zinc powder can catalyze the reaction of 4-isopropyl-3,5-dimethoxy-diphenylethylene and formic acid. However, the catalytic effect of zinc powder is very poor (even with increased dosage and extended reaction time), with a yield of less than 6%. The catalytic effect of palladium on carbon is moderate (even with increased dosage and extended reaction time), with a yield of around 20%. When palladium on carbon and zinc powder work synergistically in a certain ratio, the reaction yield can reach over 80%, thus reducing the difficulty of purification.

[0057] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A method for reducing stilbene compounds, characterized in that, Including the following reactions: (a) Using E-4-isopropyl-3,5-dimethoxy-stilbene as a raw material, E-4-isopropyl-3,5-dimethoxy-diphenylethane was obtained by reduction. (b) Using E-4-isopropyl-3,5-dimethoxy-stilbene as a raw material, 4-isopropyl-3,5-dihydroxy-diphenylethane was obtained by reduction and demethylation. The reduction conditions were as follows: Reactions (a) and (b) included: using E-4-isopropyl-3,5-dimethoxy-stilbene as the raw material, formic acid as the hydrogen donor, methanol as the solvent, and palladium on carbon and zinc powder as the catalysts; the reduction reaction was carried out at 60-65℃; after the reaction was completed, the insoluble matter was removed by filtration, and then the temperature was lowered to -20 to -5℃, and solid-liquid separation was performed to obtain E-4-isopropyl-3,5-dimethoxy-diphenylethane, with a mass ratio of E-4-isopropyl-3,5-dimethoxy-stilbene:formic acid:palladium on carbon:zinc powder of 1:0.5:0.05:0.

01.

2. The method for reducing stilbene compounds according to claim 1, characterized in that, In reaction (b), the demethylation process includes: dissolving 4-isopropyl-3,5-dimethoxy-diphenylethane in dichloromethane, adding anhydrous aluminum trichloride stepwise at -20 to 5°C, stirring the reaction at room temperature, and diluting with dichloromethane after the reaction is complete; adding the diluted solution dropwise to dilute hydrochloric acid at 0°C to quench the reaction, separating the liquids, washing the organic layer with water, evaporating to dryness, and recrystallizing to obtain 4-isopropyl-3,5-dihydroxy-diphenylethane, wherein the mass ratio of anhydrous aluminum trichloride to 4-isopropyl-3,5-dimethoxy-diphenylethane is 0.8-1.5:1.