CN112250546B - Synthesis method of (E) -3, 5-dihydroxyl-4-isopropyl stilbene - Google Patents

Synthesis method of (E) -3, 5-dihydroxyl-4-isopropyl stilbene Download PDF

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CN112250546B
CN112250546B CN202011093791.9A CN202011093791A CN112250546B CN 112250546 B CN112250546 B CN 112250546B CN 202011093791 A CN202011093791 A CN 202011093791A CN 112250546 B CN112250546 B CN 112250546B
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邹永
魏书贤
张骞中
蒋毅
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Sun Yat Sen University
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Abstract

The invention discloses a synthesis method of (E) -3, 5-dihydroxyl-4-isopropyl stilbene, which takes a raw material 3, 5-dihydroxyl-2, 4-diethyl oxycarbonyl phenylacetate derived from biomass as an initiator, and synthesizes the (E) -3, 5-dihydroxyl-4-isopropyl stilbene through reaction steps such as hydrolysis decarboxylation, isopropylation, condensation, decarboxylation, isomerization and the like. The method can adopt biomass derived raw materials as the starting materials, is simple and convenient to operate, has simple steps, does not need functional group protection and deprotection, and has good atom economy; the intermediate can be put into the next reaction without complex separation and purification, which is beneficial to large-scale preparation; the produced excessive waste acid and the catalyst compound can be recycled, so that the cost of the process is reduced, the emission is reduced, and the method is environment-friendly.

Description

Synthesis method of (E) -3, 5-dihydroxyl-4-isopropyl stilbene
Technical Field
The invention belongs to the field of medicine synthesis, and in particular relates to a synthesis method of (E) -3, 5-dihydroxy-4-isopropyl stilbene.
Background
(E) 3, 5-dihydroxy-4-isopropyl stilbene, the drug name of benvimod, a stilbene compound, was first discovered and reported in 1981 as a natural product present in Xenorhabdus entomonospora (Xenorhabdus spp.) (j. Chem. Ecl., 1981,7 (3), 589-597) and subsequently developed for the market as a psoriasis treatment drug. The present valmod is a non-hormonal small molecule compound for treating inflammatory and autoimmune diseases, which is the first therapeutic aromatic hydrocarbon receptor modulator (TAMA) worldwide.
The external cream taking the vitamin mod as an active ingredient is mainly used for locally treating the light-to-moderate stability psoriasis vulgaris of adults, has been successfully marketed in China, and is a first-in-class globally. The foreign and same product of the product is Tapinarof (DMVT-505) of Dermavant Sciences company, the phase III clinical test is successfully completed, and a New Drug Application (NDA) is planned to be submitted to the United states Food and Drug Administration (FDA) in 2021 as an external cream for treating mild, moderate and severe plaque psoriasis in adults. (E) The structural formula of the (E) -3, 5-dihydroxy-4-isopropyl stilbene is shown as the formula-1:
Figure SMS_1
in recent years, the synthesis of (E) -3, 5-dihydroxy-4-isopropyl stilbene (formula-1) reported in the literature at home and abroad can be achieved by Wittig-Horner reaction (U.S. Pat. No. 7868047, CN1319959, CN101434517, CN1688535, CN101648851, CN105884581, CN104003848, CN103172497, CN101838173, CN101830764, CN101531571, adv. Mat. Res.,2011,236,2378-2382), heck reaction (U.S. Pat. No. 20080255245, U.S. Pat. No. 3, 7868047, CN 1688535) and Grignard reaction (J.org. Chem.,1992,57,4040-4043, CN 101434517) and the like. The Wittig-Horner reaction route has certain advantages by comprehensively considering various factors such as yield and the like; however, the route still involves the protection and deprotection process, using more highly toxic, high-risk, highly corrosive and environmentally hazardous reagents, such as dimethyl sulfate, which is a highly toxic reagent in the methylation reaction step; flammable potassium borohydride and lithium aluminum hydride are used in the reduction step; in the chlorination reaction step, thionyl chloride with stronger corrosiveness is used; in the demethylation reaction step, two solvents such as pyridine and toluene which are harmful to the environment are used. In addition, the Wittig-Horner reaction step produces a phosphorus-containing waste stream; the substituted benzyl alcohol is oxidized by pyridinium chlorochromate (PCC) or Pyridinium Dichlorochromate (PDC) to generate substituted benzaldehyde, and the chromium-containing waste liquid is generated. Meanwhile, the reaction operation has high risk, and the toxic gases such as borane, sulfur dioxide, hydrogen chloride and the like are generated in the reaction process, so that the method has high harm to the environment and human bodies and is not beneficial to industrial implementation.
Disclosure of Invention
The invention aims to overcome the defects in the prior art and provide a method for synthesizing (E) -3, 5-dihydroxyl-4-isopropyl stilbene, which takes biomass derived raw materials as an initiator, has the advantages of low price and easy acquisition of raw materials, simple and convenient operation, simple and quick steps, no need of functional group protection and deprotection, good atom economy, recycle of waste acid and catalyst compound generated in the reaction, low cost, reduced emission and environmental protection.
The aim of the invention is achieved by the following technical scheme:
a synthetic method of (E) -3, 5-dihydroxyl-4-isopropyl stilbene is characterized in that 3, 5-dihydroxyl-2, 4-diethyl oxycarbonyl phenylacetic acid ethyl ester (formula-2) is taken as a starting material, 3, 5-dihydroxyl phenylacetic acid (formula-3) is obtained through hydrolysis and decarboxylation, 3, 5-dihydroxyl-4-isopropyl phenylacetic acid (formula-4) is obtained through isopropylation, condensation reaction is carried out on the 3, 5-dihydroxyl-4-isopropyl phenylacetic acid (formula-4) and benzaldehyde to obtain (E/Z) -2- (3, 5-dioxyl-4-isopropyl phenyl) -3-phenyl acrylic acid (formula-5), and (E/Z) -3, 5-dihydroxyl-4-isopropyl stilbene (formula-6) is obtained through decarboxylation, and finally (E) -3, 5-dihydroxyl-4-isopropyl stilbene (formula-1) is obtained through isomerization reaction.
The general technical route related to the invention is as follows:
Figure SMS_2
Preferably, the synthesis method of the (E) -3, 5-dihydroxyl-4-isopropyl stilbene comprises the following steps:
(1) Preparation of 3, 5-dihydroxyphenylacetic acid (formula-3): in the alkali A, 3, 5-dihydroxyl-2, 4-diethyl oxo-phenylacetic acid ethyl ester (formula-2) undergoes hydrolysis reaction; adding acid A to perform decarboxylation reaction; after the reaction is finished, 3, 5-dihydroxyphenylacetic acid (formula-3) is obtained through post-treatment;
(2) Preparation of 3, 5-dihydroxy-4-isopropylphenylacetic acid (formula-4): in excess of acid B, isopropylating 3, 5-dihydroxyphenylacetic acid (formula-3) with isopropanol; after the reaction is finished, 3, 5-dihydroxyl-4-isopropylphenylacetic acid (formula-4) is obtained through post treatment;
(3) Preparation of (E/Z) -2- (3, 5-dioxy substituent-4-isopropylphenyl) -3-phenylacrylic acid (formula-5): in a solvent B, 3, 5-dihydroxyl-4-isopropylphenylacetic acid (formula-4) and benzaldehyde are subjected to condensation reaction in the presence of a base B; after the reaction is finished, performing post-treatment to obtain (E/Z) -2- (3, 5-dioxy substituent-4-isopropylphenyl) -3-phenylacrylic acid (formula-5); the oxygen-containing substituents may be hydroxyl or acetoxy, respectively;
(4) Preparation of (E/Z) -3, 5-dihydroxy-4-isopropyl stilbene (formula-6): decarboxylation of (E/Z) -2- (3, 5-dioxy-4-isopropylphenyl) -3-phenylacrylic acid (formula-5) in the presence of catalyst C and ligand C in solvent C; after the reaction is finished, performing post-treatment to obtain (E/Z) -3, 5-dihydroxy-4-isopropyl stilbene (formula-6);
(5) Preparation of (E) -3, 5-dihydroxy-4-isopropyl stilbene (formula-1): in a solvent D, in the presence of a catalyst D, (E/Z) -3, 5-dihydroxy-4-isopropyl stilbene (formula-6) is subjected to isomerization reaction; after the reaction is finished, the (E) -3, 5-dihydroxyl-4-isopropyl stilbene (formula-1) is obtained through post treatment.
A number of specific synthetic routes for (E) -3, 5-dihydroxy-4-isopropyl stilbene (formula-1) can be formed based on the general technical route described above. Wherein, the specific route I can be represented as follows:
Figure SMS_3
the specific route I comprises the following steps:
(1) Preparation of 3, 5-dihydroxyphenylacetic acid (formula-3): in the alkali A, 3, 5-dihydroxyl-2, 4-diethyl oxo-phenylacetic acid ethyl ester (formula-2) undergoes hydrolysis reaction; adding acid A to perform decarboxylation reaction; after the reaction is finished, 3, 5-dihydroxyphenylacetic acid (formula-3) is obtained through post-treatment;
(2) Preparation of 3, 5-dihydroxy-4-isopropylphenylacetic acid (formula-4): in excess of acid B, isopropylating 3, 5-dihydroxyphenylacetic acid (formula-3) with isopropanol; after the reaction is finished, 3, 5-dihydroxyl-4-isopropylphenylacetic acid (formula-4) is obtained through post treatment;
(3) Preparation of (E) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid (formula-5E): in a solvent B, 3, 5-dihydroxyl-4-isopropylphenylacetic acid (formula-4) and benzaldehyde are subjected to condensation reaction in the presence of a base B; after the reaction is finished, performing post-treatment to obtain (E) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid (formula-5E);
(4) Preparation of (Z) -3, 5-dihydroxy-4-isopropyl stilbene (formula-6Z): decarboxylation of (E) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid (formula-5E) in the presence of catalyst C and ligand C in solvent C; after the reaction is finished, obtaining (Z) -3, 5-dihydroxyl-4-isopropyl stilbene (formula-6Z) through post treatment;
(5) Preparation of (E) -3, 5-dihydroxy-4-isopropyl stilbene (formula-1): in a solvent D, in the presence of a catalyst D, (Z) -3, 5-dihydroxy-4-isopropyl stilbene (formula-6Z) is subjected to isomerization reaction; after the reaction is finished, the (E) -3, 5-dihydroxyl-4-isopropyl stilbene (formula-1) is obtained through post treatment.
In the step (1), the alkali A includes, but is not limited to, sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate or potassium carbonate, preferably the alkali A is sodium hydroxide; the external temperature of the hydrolysis reaction is 80-150 ℃, preferably 90-130 ℃, more preferably 120 ℃; the hydrolysis reaction time is 2-5 h, preferably 3h; the acid A includes but is not limited to sulfuric acid, hydrochloric acid or nitric acid, preferably the acid A is sulfuric acid; the decarboxylation reaction temperature is 30-100 ℃, and the reaction temperature is preferably 65 ℃; the decarboxylation reaction time is 1-4 h, preferably 1h; the mol ratio of the 3, 5-dihydroxyl-2, 4-diethyl oxycarbonyl phenylacetic acid ethyl ester to the alkali A to the acid A is 1 (4-7): (2-8), and the mol ratio of the 3, 5-dihydroxyl-2, 4-diethyl oxycarbonyl phenylacetic acid ethyl ester to the alkali A to the acid A is 1:5:3.
In the step (1), the post-treatment is to extract and wash the reaction liquid with dichloromethane, then extract the reaction liquid with ethyl acetate, collect an ethyl acetate layer, dry and concentrate the ethyl acetate layer to obtain 3, 5-dihydroxyphenylacetic acid (formula-3).
In step (2), the acid B includes, but is not limited to, sulfuric acid, phosphoric acid, hydrochloric acid, nitric acid, p-toluenesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, phosphotungstic acid, phosphomolybdic acid, cation exchange resin Dowex 50WX4 or Dowex 50WX8, preferably the acid B is sulfuric acid; the temperature of the isopropylation reaction is 50-100 ℃, and the preferable reaction temperature is 80 ℃; the reaction time is 4-10 h, preferably 6h; the mol ratio of 3, 5-dihydroxyphenylacetic acid, isopropanol and acid A is 1 (1.0-1.5) (5-15); preferably, the molar ratio of 3, 5-dihydroxyphenylacetic acid, isopropanol and acid A is 1:1.2:10.
In the step (2), the reaction solution is poured into ice water, and is stirred vigorously, a large amount of sticky matters are generated, the upper layer of excessive acid solution is poured out, ethyl acetate is added into the acid solution for extraction, the obtained water layer is used as the waste acid solution, and the excessive acid B is recovered, particularly, when the acid B is sulfuric acid, hydrochloric acid or nitric acid, the recovered acid B can be used as the acid A in the step (1); the obtained organic layer was used to dissolve the above-mentioned viscous material, concentrated, dissolved in sodium hydroxide solution, acidified to ph=2 to 3 with hydrochloric acid, and little scorched black material was formed, suction filtered, the obtained filtrate was extracted with dichloromethane, extracted with ethyl acetate, the ethyl acetate layer was collected, dried, and concentrated to obtain 3, 5-dihydroxy-4-isopropylphenylacetic acid (formula-4).
In the step (3), the solvent B is acetic anhydride; the base B includes but is not limited to sodium acetate, potassium carbonate or triethylamine, preferably the base B is triethylamine; the condensation reaction temperature is 100-140 ℃, and the preferable reaction temperature is 110 ℃; the reaction time is 2-8 h, preferably 4h; the molar ratio of 3, 5-dihydroxyl-4-isopropylphenylacetic acid, benzaldehyde, alkali B and solvent B is 1 (1.0-1.2): (2-4): (4-6), preferably the molar ratio of 3, 5-dihydroxyl-4-isopropylphenylacetic acid, benzaldehyde, alkali B and solvent B is 1:1.1:3:6.
In the step (3), the reaction solution is poured into ice water and stirred vigorously, and a large amount of sticky substances are generated, namely (E/Z) -2- (3, 5-diacetoxy-4-isopropylphenyl) -phenylacrylic acid; pouring out supernatant, adding sodium hydroxide solution into the thick matter, stirring and dissolving, extracting and washing with dichloromethane, acidifying with hydrochloric acid until the pH value is=4-5, precipitating a large amount of solid, filtering, washing with water, collecting filter cakes, and drying to obtain (E) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid (formula-5E).
In step (4), the solvent C includes, but is not limited to, ethylene glycol, diethylene glycol, triethylene glycol, polyethylene glycol-200, polyethylene glycol-400, polyethylene glycol-600 or quinoline, preferably the solvent C is polyethylene glycol-400; catalyst C includes but is not limited to copper powder, copper sulfate, copper acetate, copper oxide, cuprous bromide or cuprous iodide, preferably catalyst C is cuprous iodide; the ligand C comprises but is not limited to 1, 10-phenanthroline, 2' -bipyridine or 8-hydroxyquinoline, preferably the ligand C is 1, 10-phenanthroline; the decarboxylation reaction temperature is 160-210 ℃, and the reaction temperature is 190 ℃ preferably; the reaction time is 4-10 h, preferably 6h; (E) The molar ratio of (E) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid, catalyst C, ligand C and solvent C is 1 (0.05-0.2): (5-15), preferably the molar ratio of (E) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid, catalyst C, ligand C and solvent C is 1:0.1:0.1:7.
In the step (4), the post-treatment is to cool the reaction liquid to room temperature, suction-filter, wash the filter cake with a small amount of ethyl acetate to obtain a crystal substance which is a compound of the catalyst C and the ligand C, and can be recovered and reused; the obtained filtrate was diluted with ice water, extracted with ethyl acetate, and the organic phase was collected, dried and concentrated to give (Z) -3, 5-dihydroxy-4-isopropyl stilbene (formula-6Z).
In step (5), the solvent D includes, but is not limited to, dichloromethane, chloroform, 1, 2-dichloroethane, acetonitrile, tetrahydrofuran or 1, 4-dioxane, preferably the solvent D is acetonitrile; the catalyst D comprises, but is not limited to, elemental iodine or aluminum triiodide, preferably the catalyst D is elemental iodine; the isomerization reaction temperature is 40-110 ℃, the preferable reaction temperature is 90 ℃, the reaction time is 4-10 h, and the preferable reaction time is 6h; the molar ratio of the (Z) -3, 5-dihydroxyl-4-isopropyl stilbene to the catalyst D is 1 (0.1-1.0), and the molar ratio of the (Z) -3, 5-dihydroxyl-4-isopropyl stilbene to the catalyst D is 1:0.5.
In the step (5), the post-treatment is to cool the reaction liquid to room temperature, add saturated sodium sulfite solution for quenching, extract with ethyl acetate, collect organic phase, dry, concentrate, and separate and purify by recrystallization or column chromatography to obtain (E) -3, 5-dihydroxyl-4-isopropyl stilbene (formula-1).
Based on the general technical scheme described above, a specific synthetic scheme II for (E) -3, 5-dihydroxy-4-isopropylstilbene (formula-1) can also be formed, as follows:
Figure SMS_4
the specific route II comprises the following steps:
(1) Preparation of 3, 5-dihydroxyphenylacetic acid (formula-3): in the alkali A, 3, 5-dihydroxyl-2, 4-diethyl oxo-phenylacetic acid ethyl ester (formula-2) undergoes hydrolysis reaction; adding acid A to perform decarboxylation reaction; after the reaction is finished, 3, 5-dihydroxyphenylacetic acid (formula-3) is obtained through post-treatment;
(2) Preparation of 3, 5-dihydroxy-4-isopropylphenylacetic acid (formula-4): in excess of acid B, isopropylating 3, 5-dihydroxyphenylacetic acid (formula-3) with isopropanol; after the reaction is finished, 3, 5-dihydroxyl-4-isopropylphenylacetic acid (formula-4) is obtained through post treatment;
(3) Preparation of (Z) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid (formula-5Z): in solvent B, 3, 5-dihydroxyl-4-isopropylphenylacetic acid (formula-4) and benzaldehyde are subjected to condensation reaction in the presence of base B. After the reaction is finished, the (Z) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid (formula-5Z) is obtained through post treatment.
(4) Preparation of (E) -3, 5-dihydroxy-4-isopropyl stilbene (formula-1): decarboxylation of (Z) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid (formula-5Z) in the presence of catalyst C and ligand C in solvent C; after the reaction is finished, the (E) -3, 5-dihydroxyl-4-isopropyl stilbene (formula-1) is obtained through post treatment.
The reaction raw materials, the reaction conditions and the post-treatment method in the step (1) are the same as those in the step (1) of the route I.
And (2) the reaction raw materials, the reaction conditions and the post-treatment method in the step (2) are the same as those in the step (2) of the route I.
The reaction raw materials and the reaction conditions in the step (3) are the same as those in the step (3) in the route I.
In the step (3), the reaction solution is poured into ice water and stirred vigorously, and a large amount of sticky substances are generated, namely (E/Z) -2- (3, 5-diacetoxy-4-isopropylphenyl) -3-phenylacrylic acid; pouring out supernatant, adding sodium hydroxide solution into the thick matter, stirring and dissolving, extracting and washing with dichloromethane, acidifying with hydrochloric acid until the pH value is=4-5, separating out solid, and suction-filtering to obtain a filter cake which is (E) -2- (3, 5-dihydroxyl-4-isopropylphenyl) -3-phenylacrylic acid (formula-5E) in the specific route I; the obtained filtrate was further acidified with hydrochloric acid to ph=1 to 2, extracted with ethyl acetate, and the organic phase was collected, dried, and concentrated to give (Z) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid (formula-5Z).
In step (4), the solvent C includes, but is not limited to, ethylene glycol, diethylene glycol, triethylene glycol, polyethylene glycol-200, polyethylene glycol-400, polyethylene glycol-600 or quinoline, preferably the solvent C is polyethylene glycol-400; catalyst C includes but is not limited to copper powder, copper sulfate, copper acetate, copper oxide, cuprous bromide or cuprous iodide, preferably catalyst C is cuprous iodide; the ligand C comprises but is not limited to 1, 10-phenanthroline, 2' -bipyridine or 8-hydroxyquinoline, preferably the ligand C is 1, 10-phenanthroline; the decarboxylation reaction temperature is 160-210 ℃, and the reaction temperature is 190 ℃ preferably; the reaction time is 4-10 h, preferably 6h; the molar ratio of (Z) -2- (3, 5-dihydroxyl-4-isopropylphenyl) -3-phenylacrylic acid, catalyst C, ligand C and solvent C is 1 (0.05-0.2): (5-15), preferably the molar ratio of (Z) -2- (3, 5-dihydroxyl-4-isopropylphenyl) -3-phenylacrylic acid, catalyst C, ligand C and solvent C is 1:0.1:0.1:7.
In the step (4), the post-treatment is to cool the reaction liquid to room temperature, suction-filter, wash the filter cake with a small amount of ethyl acetate to obtain a crystal substance which is a compound of the catalyst C and the ligand C, and can be recovered and reused; the obtained filtrate was diluted with ice water, extracted with ethyl acetate, and the organic phase was collected, dried and concentrated to give (E) -3, 5-dihydroxy-4-isopropyl stilbene (formula-1).
Based on the general technical route described above, a specific synthetic route III can also be formed for (E) -3, 5-dihydroxy-4-isopropylstilbene (formula-1), as follows:
Figure SMS_5
the specific route III comprises the following steps:
(1) Preparation of 3, 5-dihydroxyphenylacetic acid (formula-3): in the alkali A, 3, 5-dihydroxyl-2, 4-diethyl oxo-phenylacetic acid ethyl ester (formula-2) undergoes hydrolysis reaction; adding acid A to perform decarboxylation reaction; after the reaction is finished, 3, 5-dihydroxyphenylacetic acid (formula-3) is obtained through post-treatment;
(2) Preparation of 3, 5-dihydroxy-4-isopropylphenylacetic acid (formula-4): in excess of acid B, isopropylating 3, 5-dihydroxyphenylacetic acid (formula-3) with isopropanol; after the reaction is finished, 3, 5-dihydroxyl-4-isopropylphenylacetic acid (formula-4) is obtained through post treatment;
(3) Preparation of (E/Z) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid (formula-5E/Z): in a solvent B, 3, 5-dihydroxyl-4-isopropylphenylacetic acid (formula-4) and benzaldehyde are subjected to condensation reaction in the presence of a base B; after the reaction is finished, performing post-treatment to obtain (E/Z) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid (formula-5E/Z);
(4) Preparation of (E/Z) -3, 5-dihydroxy-4-isopropyl stilbene (formula-6Z/formula-1): decarboxylation of (E/Z) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid (formula-5E/Z) in the presence of catalyst C and ligand C in solvent C; after the reaction is finished, performing post-treatment to obtain (E/Z) -3, 5-dihydroxy-4-isopropyl stilbene (formula-6Z/formula-1);
(5) Preparation of (E) -3, 5-dihydroxy-4-isopropyl stilbene (formula-1): in a solvent D, in the presence of a catalyst D, (E/Z) -3, 5-dihydroxy-4-isopropyl stilbene (formula-6Z/formula-1) is subjected to isomerization reaction; after the reaction is finished, the (E) -3, 5-dihydroxyl-4-isopropyl stilbene (formula-1) is obtained through post treatment.
The reaction raw materials, the reaction conditions and the post-treatment method in the step (1) are the same as those in the step (1) of the route I.
And (2) the reaction raw materials, the reaction conditions and the post-treatment method in the step (2) are the same as those in the step (2) of the route I.
The reaction raw materials and the reaction conditions in the step (3) are the same as those in the step (3) in the route I.
In the step (3), the reaction solution is poured into ice water and stirred vigorously, and a large amount of sticky substances are generated, namely (E/Z) -2- (3, 5-diacetoxy-4-isopropylphenyl) -phenylacrylic acid; pouring out supernatant, adding sodium hydroxide solution into the thick matter, stirring and dissolving, extracting and washing with dichloromethane, acidifying with hydrochloric acid to pH=1-2, extracting with ethyl acetate, collecting organic phase, drying and concentrating to obtain (E/Z) -2- (3, 5-dihydroxyl-4-isopropylphenyl) -3-phenylacrylic acid (formula-5E/Z). It should be noted that the ratio of formula-5E to formula-5Z varies with the reaction and separation conditions or variations, and that the molar ratio of formula-5E to formula-5Z may vary from 1:9 to 9:1 in the product obtained in a single separation and purification batch.
In step (4), the solvent C includes, but is not limited to, ethylene glycol, diethylene glycol, triethylene glycol, polyethylene glycol-200, polyethylene glycol-400, polyethylene glycol-600 or quinoline, preferably the solvent C is polyethylene glycol-400; catalyst C includes but is not limited to copper powder, copper sulfate, copper acetate, copper oxide, cuprous bromide or cuprous iodide, preferably catalyst C is cuprous iodide; the ligand C comprises but is not limited to 1, 10-phenanthroline, 2' -bipyridine or 8-hydroxyquinoline, preferably the ligand C is 1, 10-phenanthroline; the decarboxylation reaction temperature is 160-210 ℃, and the reaction temperature is 190 ℃ preferably; the reaction time is 4-10 h, preferably 6h; the molar ratio of (E/Z) -2- (3, 5-dihydroxyl-4-isopropylphenyl) -3-phenylacrylic acid, catalyst C, ligand C and solvent C is 1 (0.05-0.2): (5-15), preferably the molar ratio of (E/Z) -2- (3, 5-dihydroxyl-4-isopropylphenyl) -3-phenylacrylic acid, catalyst C, ligand C and solvent C is 1:0.1:0.1:7.
In the step (4), the post-treatment is to cool the reaction liquid to room temperature, suction-filter, wash the filter cake with a small amount of ethyl acetate to obtain fine needle-like crystals, which are the compound of the catalyst C and the ligand C, and can be recovered and reused; the obtained filtrate was diluted with ice water, extracted with ethyl acetate, and the organic phase was collected, dried and concentrated to give (E/Z) -3, 5-dihydroxy-4-isopropyl stilbene (formula-6Z/formula-1).
In step (5), the solvent D includes, but is not limited to, dichloromethane, chloroform, 1, 2-dichloroethane, acetonitrile, tetrahydrofuran or 1, 4-dioxane, preferably the solvent D is acetonitrile; the catalyst D comprises, but is not limited to, elemental iodine or aluminum triiodide, preferably the catalyst D is elemental iodine; the isomerization reaction temperature is 40-110 ℃, preferably 90 ℃, the reaction time is 4-10 h, preferably 6h; the molar ratio of the (E/Z) -3, 5-dihydroxyl-4-isopropyl stilbene to the catalyst D is 1 (0.1-1.0), and the molar ratio of the (E/Z) -3, 5-dihydroxyl-4-isopropyl stilbene to the catalyst D is 1:0.5.
In the step (5), the post-treatment is to cool the reaction liquid to room temperature, add saturated sodium sulfite solution for quenching, extract with ethyl acetate, collect organic phase, dry, concentrate, and separate and purify by recrystallization or column chromatography to obtain (E) -3, 5-dihydroxyl-4-isopropyl stilbene (formula-1).
Specific synthetic routes IV for (E) -3, 5-dihydroxy-4-isopropylstilbene (formula-1) can also be formed based on the general technical route described above, as follows:
Figure SMS_6
the specific route IV comprises the following steps:
(1) Preparation of 3, 5-dihydroxyphenylacetic acid (formula-3): in the alkali A, 3, 5-dihydroxyl-2, 4-diethyl oxo-phenylacetic acid ethyl ester (formula-2) undergoes hydrolysis reaction; adding acid A to perform decarboxylation reaction; after the reaction is finished, 3, 5-dihydroxyphenylacetic acid (formula-3) is obtained through post-treatment;
(2) Preparation of 3, 5-dihydroxy-4-isopropylphenylacetic acid (formula-4): in excess of acid B, isopropylating 3, 5-dihydroxyphenylacetic acid (formula-3) with isopropanol; after the reaction is finished, 3, 5-dihydroxyl-4-isopropylphenylacetic acid (formula-4) is obtained through post treatment;
(3) Preparation of (E/Z) -2- (3, 5-diacetoxy-4-isopropylphenyl) -3-phenylacrylic acid (formula-5 Ac): in a solvent B, 3, 5-dihydroxyl-4-isopropylphenylacetic acid (formula-4) and benzaldehyde are subjected to condensation reaction in the presence of a base B; after the reaction is finished, performing post-treatment to obtain (E/Z) -2- (3, 5-diacetoxy-4-isopropylphenyl) -3-phenylacrylic acid (formula-5 Ac);
(4) Preparation of (E/Z) -3, 5-dihydroxy-4-isopropyl stilbene (formula-6Z/formula-1): in a solvent C, in the presence of a catalyst C and a ligand C, decarboxylation and hydrolysis reactions are carried out on (E/Z) -2- (3, 5-diacetoxy-4-isopropylphenyl) -3-phenylacrylic acid (formula-5 Ac); after the reaction is finished, performing post-treatment to obtain (E/Z) -3, 5-dihydroxy-4-isopropyl stilbene (formula-6Z/formula-1);
(5) Preparation of (E) -3, 5-dihydroxy-4-isopropyl stilbene (formula-1): in a solvent D, in the presence of a catalyst D, (E/Z) -3, 5-dihydroxy-4-isopropyl stilbene (formula-6Z/formula-1) is subjected to isomerization reaction; after the reaction is finished, the (E) -3, 5-dihydroxyl-4-isopropyl stilbene (formula-1) is obtained through post treatment.
The reaction raw materials, the reaction conditions and the post-treatment method in the step (1) are the same as those in the step (1) of the route I.
And (2) the reaction raw materials, the reaction conditions and the post-treatment method in the step (2) are the same as those in the step (2) of the route I.
The reaction raw materials and the reaction conditions in the step (3) are the same as those in the step (3) in the route I.
In the step (3), the reaction solution is poured into ice water, stirred vigorously, a large amount of sticky matters are formed, the supernatant is poured out, the sticky matters are washed to be neutral by a large amount of water, the sticky matters are collected and dried, and the (E/Z) -2- (3, 5-diacetoxy-4-isopropylphenyl) -phenylacrylic acid (formula-5 Ac) is obtained.
In step (4), the solvent C includes, but is not limited to, ethylene glycol, diethylene glycol, triethylene glycol, polyethylene glycol-200, polyethylene glycol-400, polyethylene glycol-600 or quinoline, preferably the solvent C is polyethylene glycol-400; catalyst C includes but is not limited to copper powder, copper sulfate, copper acetate, copper oxide, cuprous bromide or cuprous iodide, preferably catalyst C is cuprous iodide; the ligand C comprises but is not limited to 1, 10-phenanthroline, 2' -bipyridine or 8-hydroxyquinoline, preferably the ligand C is 1, 10-phenanthroline; the decarboxylation reaction temperature is 160-210 ℃, and the reaction temperature is 190 ℃ preferably; the reaction time is 4-10 h, preferably 6h; the molar ratio of (E/Z) -2- (3, 5-diacetoxy-4-isopropylphenyl) -3-phenylacrylic acid, catalyst C, ligand C and solvent C is 1 (0.05-0.2): (5-15), preferably the molar ratio of (E/Z) -2- (3, 5-diacetoxy-4-isopropylphenyl) -3-phenylacrylic acid, catalyst C, ligand C and solvent C is 1:0.1:0.1:7.
In the step (4), the post-treatment is to cool the reaction liquid to room temperature, suction-filter, wash the filter cake with a small amount of ethyl acetate to obtain fine needle-like crystals, which are the compound of the catalyst C and the ligand C, and can be recovered and reused; the obtained filtrate was diluted with ice water, extracted with ethyl acetate, and the organic phase was collected, dried and concentrated to give (E/Z) -3, 5-dihydroxy-4-isopropyl stilbene (formula-6Z/formula-1).
In step (5), the solvent D includes, but is not limited to, dichloromethane, chloroform, 1, 2-dichloroethane, acetonitrile, tetrahydrofuran or 1, 4-dioxane, preferably the solvent D is acetonitrile; the catalyst D comprises, but is not limited to, elemental iodine or aluminum triiodide, preferably the catalyst D is elemental iodine; the isomerization reaction temperature is 40-110 ℃, preferably 90 ℃, the reaction time is 4-10 h, preferably 6h; the molar ratio of the (E/Z) -3, 5-dihydroxyl-4-isopropyl stilbene to the catalyst D is 1 (0.1-1.0), and the molar ratio of the (E/Z) -3, 5-dihydroxyl-4-isopropyl stilbene to the catalyst D is 1:0.5.
In the step (5), the post-treatment is to cool the reaction liquid to room temperature, add saturated sodium sulfite solution for quenching, extract with ethyl acetate, collect organic phase, dry, concentrate, and separate and purify by recrystallization or column chromatography to obtain (E) -3, 5-dihydroxyl-4-isopropyl stilbene (formula-1).
The invention proves that: (1) the single compound of formula-5E obtained in the synthesis process can be subjected to subsequent decarboxylation and isomerization reactions to finally obtain (E) -3, 5-dihydroxy-4-isopropyl stilbene (formula-1). (2) The single compound of formula-5Z obtained in the synthesis may be directly subjected to decarboxylation to give formula-1. (3) The mixture of the formula-5E and the formula-5Z obtained in the synthesis process can be directly subjected to subsequent decarboxylation and isomerization reactions without separation, and finally the formula-1 is obtained. (4) In addition, the formula-5 Ac obtained in the synthesis process can be directly subjected to subsequent decarboxylation, hydrolysis and isomerization reactions without post-treatment, and finally the formula-1 is obtained.
The 3, 5-dihydroxyl-2, 4-diethyl oxycarbonyl phenylacetic acid ethyl ester (formula-2) adopted by the invention is derived from renewable biomass, is prepared by taking 1, 3-diethyl acetonedicarboxylate as a raw material and carrying out condensation and aromatization reactions (specific reaction processes are shown in Julus Liebigs Ann.chem.,1950,570,15-33; helv.Chim. Acta,1966,49,1283-1290; CN106748662B).
It should be noted that the starting material ethyl 3, 5-dihydroxy-2, 4-diethoxycarbonyl phenylacetate (formula-2) of the present invention can be replaced by methyl 3, 5-dihydroxy-2, 4-dimethoxycarbonyl phenylacetate, which is also derived from renewable biomass and achieves the same technical result. Thus, technical routes employing methyl 3, 5-dihydroxy-2, 4-dimethoxycarbonyl phenylacetate and the like as starting materials are also encompassed by the present invention.
It should be specifically noted that in the step (2), the preparation of 3, 5-dihydroxy-4-isopropylphenylacetic acid (formula-4) requires the discharge of excess acid B, and when the acid B is sulfuric acid, hydrochloric acid or nitric acid, the acid B is recycled and can be used as acid a for the preparation of 3, 5-dihydroxyphenylacetic acid (formula-3); in step (4), the resulting crystals are preferably a complex of cuprous iodide with 1, 10-phenanthroline ([ CuI (1, 10-phen) ]] 2 ) The invention recovers and recycles the same for the decarboxylation reaction of step (4).
Compared with the prior art, the invention has the following advantages and effects:
(1) The method can adopt biomass derived raw materials as the starting materials, is simple and convenient to operate, has simple and convenient steps, does not need functional group protection and deprotection, has good atom economy, and is environment-friendly in operation process.
(2) The initial raw materials, the reagent and the solvent are cheap and easy to obtain, and the intermediate can be put into the next reaction without complex separation and purification, so that the method is beneficial to large-scale preparation.
(3) The excessive waste acid and the catalyst compound produced by the method can be recycled, so that the cost of the process is reduced, the emission is reduced, and the method is environment-friendly.
Drawings
FIG. 1 is a schematic diagram of 3, 5-dihydroxyphenylacetic acid 1 HNMR spectra (400 MHz, DMSO-d) 6 )；
FIG. 2 is a schematic diagram of 3, 5-dihydroxy-4-isopropylphenylacetic acid 1 HNMR spectra (400 MHz, DMSO-d) 6 )；
FIG. 3 is a schematic illustration of (E) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid 1 HNMR spectra (400 MHz, DMSO-d) 6 )；
FIG. 4 shows (Z) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid 1 HNMR spectra (400 MHz, DMSO-d) 6 )；
FIG. 5 shows (E/Z) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid 1 HNMR spectra (400 MHz, DMSO-d) 6 )；
FIG. 6 is a graph of (Z) -3, 5-dihydroxy-4-isopropyl stilbene 1 HNMR spectra (400 MHz, DMSO-d) 6 )；
FIG. 7 is a schematic diagram of (Z) -3, 5-dihydroxy-4-isopropyl stilbene 1 HNMR spectra (125 MHz, DMSO-d) 6 )；
FIG. 8 is a schematic diagram of (E/Z) -3, 5-dihydroxy-4-isopropyl stilbene 1 HNMR spectra (400 MHz, DMSO-d) 6 )；
FIG. 9 is a schematic diagram of (E) -3, 5-dihydroxy-4-isopropyl stilbene 1 HNMR spectra (400 MHz, DMSO-d) 6 )；
FIG. 10 is a drawing of (E) -3, 5-dihydroxy-4-isopropyl stilbene 1 HNMR spectra (100 MHz, DMSO-d) 6 )。
Detailed Description
In order that the invention may be readily understood, a detailed description of the invention will be provided below with reference to specific examples.
(E) Specific synthetic route I for 3, 5-dihydroxy-4-isopropyl stilbene (formula-1): examples 1 to 25
Example 1: preparation of 3, 5-dihydroxyphenylacetic acid
To the round bottom flask was added ethyl 3, 5-dihydroxy-2, 4-diethyloxycarbonyl phenylacetate (34.03 g,100 mmol), 5mol/L NaOH solution (100 mL,500 mmol), and the mixture was stirred and dissolved, and heated and stirred at 120℃for 3h; the reaction solution was cooled, 98% sulfuric acid (16 mL,300 mmol) was added thereto, and the mixture was stirred at 65℃for 1 hour, wherein bubbles were continuously generated during the reaction, and the pH of the reaction solution was about 2 to 3 after the completion of the dropping. After completion of the reaction, the reaction mixture was washed with dichloromethane (50 mL) X 2) and ethyl acetate (100 mL x 2), the ethyl acetate layer was collected, dried and concentrated to give 14.97g of 3, 5-dihydroxyphenylacetic acid as a tan solid in 89% yield. Melting point is 70-72 ℃; 1 H NMR(400MHz,DMSO-d 6 ) δ12.22 (s, 1H), 9.16 (s, 2H), 6.10 (d, j=2.0 hz, 2H), 6.07 (t, j=2.0 hz, 1H), 3.38 (s, 2H) (as shown in fig. 1).
Example 2: preparation of 3, 5-dihydroxyphenylacetic acid
3, 5-dihydroxy-2, 4-diethyl carbonyl phenylacetate (34.03 g,100 mmol) was added to a round bottom flask, 5mol/L NaOH solution (120 mL,600 mmol) was added, and the mixture was stirred and dissolved, and heated and stirred at 150℃for 2h; the reaction solution was cooled, 98% sulfuric acid (21 mL,400 mmol) was added thereto, and the mixture was stirred at 80℃for 1 hour, wherein bubbles were continuously generated during the reaction, and the pH of the reaction solution was about 2 to 3 after the completion of the dropping. After the completion of the reaction, the reaction mixture was washed with methylene chloride (50 mL. Times.2), extracted with ethyl acetate (100 mL. Times.2), and the ethyl acetate layer was collected, dried and concentrated to give 14.61g of 3, 5-dihydroxyphenylacetic acid as a tan solid in 87% yield.
Example 3: preparation of 3, 5-dihydroxyphenylacetic acid
3, 5-dihydroxy-2, 4-diethyl carbonyl phenylacetate (34.03 g,100 mmol) was added to a round bottom flask, 5mol/L NaOH solution (120 mL,600 mmol) was added, and the mixture was stirred and dissolved, and heated and stirred at 120℃for 3h; the reaction solution was cooled, and 37% hydrochloric acid (650 mL,800 mmol) was added thereto, followed by stirring at 30℃for 4 hours, whereby bubbles were continuously generated, and the pH of the reaction solution was about 2 to 3 after the completion of the dropping. After the completion of the reaction, the reaction mixture was washed with methylene chloride (50 mL. Times.2), extracted with ethyl acetate (100 mL. Times.2), and the ethyl acetate layer was collected, dried and concentrated to give 12.94g of 3, 5-dihydroxyphenylacetic acid as a tan solid in 77% yield.
Example 4: preparation of 3, 5-dihydroxyphenylacetic acid
To the round bottom flask was added ethyl 3, 5-dihydroxy-2, 4-diethyloxycarbonyl phenylacetate (34.03 g,100 mmol), 5mol/L NaOH solution (100 mL,500 mmol), and the mixture was stirred and dissolved, and heated and stirred at 120℃for 3h; the reaction mixture was cooled, the acid solution (70 mL,300 mmol) obtained in examples 6-10 was added, and the mixture was stirred at 65℃for 2 hours, wherein bubbles were generated continuously, and the pH of the reaction mixture was about 2 to 3 after the completion of the dropping. After the reaction, the reaction mixture was washed with dichloromethane (50 mL. Times.2), extracted with ethyl acetate (100 mL. Times.2), and the organic phase was collected, dried and concentrated to give 15.46g of 3, 5-dihydroxyphenylacetic acid as a tan solid in 92% yield.
Example 5: preparation of 3, 5-dihydroxyphenylacetic acid
3, 5-dihydroxy-2, 4-diethyl carbonyl phenylacetic acid ethyl ester (170.16 g,0.5 mol) is added into a round bottom flask, 5mol/L NaOH solution (500 mL,2.5 mol) is added, stirring and dissolution are carried out, and heating and stirring are carried out at 120 ℃ for 3h; the reaction mixture was cooled, the acid solution (350 mL,1.5 mol) recovered in examples 6-10 was added, and the mixture was stirred at 65℃for 4 hours, wherein bubbles were generated continuously, and the pH of the reaction mixture was about 2 to 3 after the completion of the dropping. After the reaction, the reaction mixture was washed with dichloromethane (100 mL. Times.2), extracted with ethyl acetate (150 mL. Times.3), and the organic phase was collected, dried and concentrated to give a tan solid, 74.03g of 3, 5-dihydroxyphenylacetic acid, in 88% yield.
Example 6: preparation of 3, 5-dihydroxy-4-isopropylphenylacetic acid
To the round bottom flask was added 3, 5-dihydroxyphenylacetic acid (6.73 g,40 mmol), 90% sulfuric acid (25 mL,400 mmol), dissolved with stirring, isopropanol (3.7 mL,48 mmol) was added and heated at 80℃with stirring for 6h. After the reaction is finished, pouring the reaction solution into ice water, vigorously stirring, forming a large amount of sticky matters, pouring out excessive acid liquor on the upper layer, adding ethyl acetate into the acid liquor for extraction, and recovering the obtained water layer as waste acid liquor for use in the step (1); the obtained organic layer was used to dissolve the above-mentioned viscous material, concentrated, dissolved in sodium hydroxide solution, acidified to ph=2 to 3 with hydrochloric acid, and some coke black material was formed, suction filtered, the obtained filtrate was extracted with dichloromethane, extracted with ethyl acetate, the ethyl acetate layer was collected, dried and concentrated to obtain a tan viscous material, i.e. 6.81g of 3, 5-dihydroxy-4-isopropylphenylacetic acid, yield 81%. The melting point is 115-117 ℃; 1 H NMR(400MHz,DMSO-d 6 ) δ12.14 (s, 1H), 8.90 (s, 2H), 6.15 (s, 2H), 3.39 (dt, j=14.0, 6.8hz, 1H), 3.25 (s, 2H), 1.21 (d, j=6.8 hz, 6H) (as shown in fig. 2).
Example 7: preparation of 3, 5-dihydroxy-4-isopropylphenylacetic acid
To the round bottom flask was added 3, 5-dihydroxyphenylacetic acid (6.73 g,40 mmol), 90% sulfuric acid (37 mL,600 mmol), dissolved with stirring, isopropanol (3.7 mL,48 mmol) was added and heated at 60℃with stirring for 8h. After the reaction is finished, pouring the reaction solution into ice water, vigorously stirring, forming a large amount of sticky matters, pouring out excessive acid liquor on the upper layer, adding ethyl acetate into the acid liquor for extraction, and recovering the obtained water layer as waste acid liquor for use in the step (1); the obtained organic layer was used to dissolve the above-mentioned viscous material, concentrated, dissolved in sodium hydroxide solution, acidified to ph=2 to 3 with hydrochloric acid, and some coke black material was formed, suction filtered, the obtained filtrate was extracted with dichloromethane, extracted with ethyl acetate, the ethyl acetate layer was collected, dried and concentrated to obtain 6.14g of a tan viscous material, i.e. 3, 5-dihydroxy-4-isopropylphenylacetic acid, with a yield of 73%.
Example 8: preparation of 3, 5-dihydroxy-4-isopropylphenylacetic acid
To the round bottom flask was added 3, 5-dihydroxyphenylacetic acid (6.73 g,40 mmol), 90% sulfuric acid (25 mL,400 mmol), dissolved with stirring, isopropanol (4.2 mL,60 mmol) was added, and heated at 100deg.C for 4h with stirring. After the reaction is finished, pouring the reaction solution into ice water, vigorously stirring, forming a large amount of sticky matters, pouring out excessive acid liquor on the upper layer, adding ethyl acetate into the acid liquor for extraction, and recovering the obtained water layer as waste acid liquor for use in the step (1); the obtained organic layer was used to dissolve the above-mentioned viscous material, concentrated, dissolved in sodium hydroxide solution, acidified to ph=2 to 3 with hydrochloric acid, and some coke black material was formed, suction filtered, the obtained filtrate was extracted with dichloromethane, extracted with ethyl acetate, the ethyl acetate layer was collected, dried and concentrated to obtain 6.31g of a tan viscous material, i.e. 3, 5-dihydroxy-4-isopropylphenylacetic acid, yield 75%.
Example 9: preparation of 3, 5-dihydroxy-4-isopropylphenylacetic acid
To the round bottom flask was added 3, 5-dihydroxyphenylacetic acid (6.73 g,40 mmol), 90% sulfuric acid (25 mL,400 mmol), dissolved with stirring, isopropanol (3.7 mL,48 mmol) was added and heated at 60℃with stirring for 6h. After the reaction is finished, pouring the reaction solution into ice water, vigorously stirring, forming a large amount of sticky matters, pouring out excessive acid liquor on the upper layer, adding ethyl acetate into the acid liquor for extraction, and recovering the obtained water layer as waste acid liquor for use in the step (1); the obtained organic layer was used to dissolve the above-mentioned viscous material, concentrated, dissolved in sodium hydroxide solution, acidified to ph=2 to 3 with hydrochloric acid, and some coke black material was formed, suction filtered, the obtained filtrate was extracted with dichloromethane, extracted with ethyl acetate, the ethyl acetate layer was collected, dried and concentrated to obtain a tan viscous material, i.e. 5.97g of 3, 5-dihydroxy-4-isopropylphenylacetic acid, yield 71%.
Example 10: preparation of 3, 5-dihydroxy-4-isopropylphenylacetic acid
To the round bottom flask was added 3, 5-dihydroxyphenylacetic acid (6.73 g,40 mmol), 90% sulfuric acid (25 mL,400 mmol), dissolved with stirring, isopropanol (3.7 mL,48 mmol) was added and heated at 80℃with stirring for 10h. After the reaction is finished, pouring the reaction solution into ice water, vigorously stirring, forming a large amount of sticky matters, pouring out excessive acid liquor on the upper layer, adding ethyl acetate into the acid liquor for extraction, and recovering the obtained water layer as waste acid liquor for use in the step (1); the obtained organic layer was used to dissolve the above-mentioned viscous material, concentrated, dissolved in sodium hydroxide solution, acidified to ph=2 to 3 with hydrochloric acid, and some coke black material was formed, suction filtered, the obtained filtrate was extracted with dichloromethane, extracted with ethyl acetate, the ethyl acetate layer was collected, dried and concentrated to obtain a tan viscous material, i.e. 6.39g of 3, 5-dihydroxy-4-isopropylphenylacetic acid, yield 76%.
Example 11: (E) Preparation of (E) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid
3, 5-dihydroxy-4-isopropylphenylacetic acid (5.47 g,26 mmol) and benzaldehyde (2.97 g,28 mmol) were added to a round bottom flask, acetic anhydride (15.93 g,156 mmol) was added and dissolved with stirring; triethylamine (7.89 g,78 mmol) was slowly added and stirred at 110℃for 4h. After the reaction is finished, pouring the reaction solution into ice water, and stirring vigorously to form sticky matters; pouring out supernatant, adding sodium hydroxide solution into the thick matter, stirring and dissolving, extracting and washing with dichloromethane, acidifying with 10% hydrochloric acid until the pH value is=4-5, precipitating a large amount of solid, filtering, washing with water, collecting filter cakes, and drying to obtain light brown yellow solid, namely (E) -2- (3, 5-dihydroxyl-4-isopropylphenyl) -3-phenylacrylic acid, 5.90g, and the yield is 76%. Melting point is 124-126 ℃; 1 H NMR(400MHz,DMSO-d 6 )δ12.56(s,1H),8.96(s,2H),7.59(s,1H),7.24-7.19 (m, 3H), 7.16-7.14 (m, 2H), 6.06 (s, 2H), 3.46 (td, j=14.0, 7.2hz, 1H), 1.27 (d, j=7.2 hz, 6H) (as shown in fig. 3).
Example 12: (E) Preparation of (E) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid
3, 5-dihydroxy-4-isopropylphenylacetic acid (5.47 g,26 mmol) and benzaldehyde (2.97 g,28 mmol) were added to a round bottom flask, acetic anhydride (10.62 g,104 mmol) was added and dissolved with stirring; triethylamine (5.26 g,52 mmol) was slowly added and stirred at 110℃for 6h. After the reaction is finished, pouring the reaction solution into ice water, and stirring vigorously to form sticky matters; pouring out supernatant, adding sodium hydroxide solution into the thick matter, stirring and dissolving, extracting and washing with dichloromethane, acidifying with 10% hydrochloric acid until the pH value is=4-5, precipitating a large amount of solid, filtering, washing with water, collecting filter cakes, and drying to obtain light brown yellow solid, namely (E) -2- (3, 5-dihydroxyl-4-isopropylphenyl) -3-phenylacrylic acid, 5.51g, and the yield is 71%.
Example 13: (E) Preparation of (E) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid
3, 5-dihydroxy-4-isopropylphenylacetic acid (5.47 g,26 mmol) and benzaldehyde (2.97 g,28 mmol) were added to a round bottom flask, acetic anhydride (15.93 g,156 mmol) was added and dissolved with stirring; sodium acetate (6.40 g,78 mmol) was slowly added and heated to 110℃with stirring for 4h. After the reaction is finished, pouring the reaction solution into ice water, and stirring vigorously to form sticky matters; pouring out supernatant, adding sodium hydroxide solution into the thick matter, stirring and dissolving, extracting and washing with dichloromethane, acidifying with 10% hydrochloric acid until the pH value is=4-5, precipitating a large amount of solid, filtering, washing with water, collecting filter cakes, and drying to obtain light brown yellow solid, namely (E) -2- (3, 5-dihydroxyl-4-isopropylphenyl) -3-phenylacrylic acid, 5.66g, and the yield is 73%.
Example 14: (E) Preparation of (E) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid
3, 5-dihydroxy-4-isopropylphenylacetic acid (5.47 g,26 mmol) and benzaldehyde (2.97 g,28 mmol) were added to a round bottom flask, acetic anhydride (15.93 g,156 mmol) was added and dissolved with stirring; potassium acetate (7.65 g,78 mmol) was slowly added thereto and heated at 110℃with stirring for 4h. After the reaction is finished, pouring the reaction solution into ice water, and stirring vigorously to form sticky matters; pouring out supernatant, adding sodium hydroxide solution into the thick matter, stirring and dissolving, extracting and washing with dichloromethane, acidifying with 10% hydrochloric acid until the pH value is=4-5, precipitating a large amount of solid, filtering, washing with water, collecting filter cakes, and drying to obtain light brown yellow solid, namely (E) -2- (3, 5-dihydroxyl-4-isopropylphenyl) -3-phenylacrylic acid, 5.82g, and the yield is 75%.
Example 15: (E) Preparation of (E) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid
3, 5-dihydroxy-4-isopropylphenylacetic acid (5.47 g,26 mmol) and benzaldehyde (2.97 g,28 mmol) were added to a round bottom flask, acetic anhydride (15.93 g,156 mmol) was added and dissolved with stirring; triethylamine (7.89 g,78 mmol) was slowly added and stirred at 140℃for 4h. After the reaction is finished, pouring the reaction solution into ice water, and stirring vigorously to form sticky matters; pouring out supernatant, adding sodium hydroxide solution into the thick matter, stirring and dissolving, extracting and washing with dichloromethane, acidifying with 10% hydrochloric acid until the pH value is=4-5, precipitating a large amount of solid, filtering, washing with water, collecting filter cakes, and drying to obtain light brown yellow solid, namely (E) -2- (3, 5-dihydroxyl-4-isopropylphenyl) -3-phenylacrylic acid, 5.43g, and the yield is 70%.
Example 16: (E) Preparation of (E) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid
3, 5-dihydroxy-4-isopropylphenylacetic acid (5.47 g,26 mmol) and benzaldehyde (2.97 g,28 mmol) were added to a round bottom flask, acetic anhydride (15.93 g,156 mmol) was added and dissolved with stirring; triethylamine (7.89 g,78 mmol) was slowly added and stirred at 110℃for 8h. After the reaction is finished, pouring the reaction solution into ice water, and stirring vigorously to form sticky matters; pouring out supernatant, adding sodium hydroxide solution into the thick matter, stirring and dissolving, extracting and washing with dichloromethane, acidifying with 10% hydrochloric acid until the pH value is=4-5, precipitating a large amount of solid, filtering, washing with water, collecting filter cakes, and drying to obtain light brown yellow solid, namely (E) -2- (3, 5-dihydroxyl-4-isopropylphenyl) -3-phenylacrylic acid, 5.59g, and the yield is 72%.
Example 17: preparation of (Z) -3, 5-dihydroxy-4-isopropyl stilbene
To a round bottom flask was added (E) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid (5.97g,20 mmol), cuprous iodide (0.38 g,2 mmol), 1, 10-phenanthroline (0.36 g,2 mmol) and polyethylene glycol-400 (50 mL,140 mmol), and stirring at 190℃for 6h. After the reaction is finished, filtering, washing a filter cake with a small amount of ethyl acetate to obtain brick red fine needle-like crystals, namely, a compound of cuprous iodide and 1, 10-phenanthroline ([ CuI (1, 10-phen)) ] 2 ) 0.61g, yield 83%, and recovered and reused. Ice water (100 mL) was added to the filtrate for dilution, ethyl acetate extraction (50 mL. Times.3), the organic layer was collected, dried and concentrated to give a tan paste, i.e. (Z) -3, 5-dihydroxy-4-isopropyl stilbene 4.47g, yield 88%. Melting point is 112-114 ℃; 1 H NMR(400MHz,DMSO-d 6 ) Delta 8.86 (s, 2H), 7.31-7.23 (m, 4H), 7.21-7.16 (m, 1H), 6.44 (d, j=12.4 hz, 1H), 6.37 (d, j=12.4 hz, 1H), 6.19 (s, 2H), 3.40 (dq, j=14.0, 7.2hz, 1H), 1.21 (d, j=7.2 hz, 6H) (as shown in fig. 6); 13 C NMR(125MHz,DMSO-d 6 ) Delta 156.09,136.85,134.63,130.43,128.78,128.60,128.21,127.07,119.23,106.87,23.57,20.64 (shown in fig. 7).
Example 18: preparation of (Z) -3, 5-dihydroxy-4-isopropyl stilbene
To a round bottom flask was added (E) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid (5.97 g,20 mmol), cuprous iodide (0.19 g,1 mmol), 1, 10-phenanthroline (0.18 g,1 mmol) and polyethylene glycol-400 (50 mL,140 mmol), and heated and stirred at 190℃for 10h. After the reaction is finished, filtering, washing a filter cake with a small amount of ethyl acetate to obtain brick red fine needle-like crystals, namely, a compound of cuprous iodide and 1, 10-phenanthroline ([ CuI (1, 10-phen))] 2 ) 0.25g, yield 68%, which was recovered and reused. Ice water (100 mL) was added to the filtrate for dilution, ethyl acetate extraction (50 mL. Times.3), the organic layer was collected, dried and concentrated to give a tan paste, 3.55g of (Z) -3, 5-dihydroxy-4-isopropyl stilbene, in 70% yield.
Example 19: preparation of (Z) -3, 5-dihydroxy-4-isopropyl stilbene
To the round bottom flask was added (E) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid (5.97 g,20 mmol), cuprous iodide (0.76 g,4 mmol), 1, 10-phenanthroline (0.72 g,4 mmol) and polyethylene glycol-200 (55 mL,300 mmol), which was heated and stirred at 190℃for 6h. Reverse-rotationAfter the completion of the filtration, a small amount of ethyl acetate is used for washing the filter cake to obtain brick red fine needle-like crystals, namely, the compound of cuprous iodide and 1, 10-phenanthroline ([ CuI (1, 10-phen))] 2 ) 1.26g, yield 85%, which was recovered and reused. Ice water (100 mL) was added to the filtrate for dilution, ethyl acetate extraction (50 mL. Times.3), the organic layer was collected, dried and concentrated to give a tan paste, i.e. (Z) -3, 5-dihydroxy-4-isopropyl stilbene 4.16g, yield 82%.
Example 20: preparation of (Z) -3, 5-dihydroxy-4-isopropyl stilbene
To a round bottom flask was added (E) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid (5.97 g,20 mmol), copper iodide (0.38 g,2 mmol), 2' -bipyridine (0.31 g,2 mmol) and polyethylene glycol-400 (50 mL,140 mmol), and heated to 190℃for 6h. After the reaction, ice water (100 mL) was added to the filtrate for dilution, ethyl acetate extraction (50 mL. Times.3) was used, the organic layer was collected, dried and concentrated to give a tan paste (3.82 g of (Z) -3, 5-dihydroxy-4-isopropyl stilbene in 75% yield.
Example 21: preparation of (Z) -3, 5-dihydroxy-4-isopropyl stilbene
To a round bottom flask was added (E) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid (5.97 g,20 mmol), recovered [ CuI (1, 10-phen)] 2 (0.74 g,1 mmol) and polyethylene glycol-400 (50 mL,140 mmol), with stirring at 190℃for 6h. After the reaction, ice water (100 mL) was added to the filtrate for dilution, ethyl acetate extraction (50 mL. Times.3), and the organic layer was collected, dried and concentrated to give a tan paste (4.26 g of (Z) -3, 5-dihydroxy-4-isopropyl stilbene in 84% yield.
Example 22: (E) Preparation of (E) -3, 5-dihydroxy-4-isopropyl stilbene
To a round bottom flask was added (Z) -3, 5-dihydroxy-4-isopropyl stilbene (2.54 g,10 mmol) and acetonitrile (20 mL), dissolved with stirring, elemental iodine (1.27 g,5 mmol) was added and heated at 90℃with stirring for 6h. After the reaction, the mixture was quenched with saturated sodium sulfite solution (15 mL), extracted with ethyl acetate (50 mL. Times.2), and the organic layer was collected, dried, concentrated, and purified by column chromatography (petroleum ether-ethyl acetate) to give a white colorThe solid was 2.08g of (E) -3, 5-dihydroxy-4-isopropyl stilbene, and the yield was 82%. Melting point is 142-144 ℃; 1 H NMR(400MHz,DMSO-d 6 ) Delta 9.05 (s, 2H), 7.57 (d, j=7.6 hz, 2H), 7.36 (t, j=7.6 hz, 2H), 7.25 (t, j=7.2 hz, 1H), 7.01 (d, j=16.0 hz, 1H), 6.88 (d, j=16.4 hz, 1H), 6.48 (s, 2H), 3.44 (dt, 13.6,6.8hz, 1H), 1.25 (d, j=6.8 hz, 6H) (as shown in fig. 9); 13 C NMR(101MHz,DMSO-d 6 ) Delta 156.39,137.03,134.75,128.92,128.66,127.37,126.72,126.36,120.10,105.15,23.67,20.59 (as shown in fig. 10).
Example 23: (E) Preparation of (E) -3, 5-dihydroxy-4-isopropyl stilbene
To a round bottom flask was added (Z) -3, 5-dihydroxy-4-isopropyl stilbene (2.54 g,10 mmol) and acetonitrile (20 mL), dissolved with stirring, elemental iodine (0.63 g,2.5 mmol) was added and heated at 90℃with stirring for 10h. After the reaction, saturated sodium sulfite solution (10 mL) was added to quench, ethyl acetate was added to extract (50 mL. Times.2), the organic layer was collected, dried, concentrated, and purified by column chromatography (petroleum ether-ethyl acetate) to give (E) -3, 5-dihydroxy-4-isopropyl stilbene as a white solid (1.81 g) in 72% yield.
Example 24: (E) Preparation of (E) -3, 5-dihydroxy-4-isopropyl stilbene
To the round bottom flask were added (Z) -3, 5-dihydroxy-4-isopropyl stilbene (2.54 g,10 mmol) and 1, 2-dichloroethane (20 mL), dissolved with stirring, elemental iodine (2.54 g,10 mmol) was added and heated at 90℃with stirring for 6h. After the reaction, saturated sodium sulfite solution (25 mL) was added to quench, ethyl acetate was added to extract (50 mL. Times.2), the organic layer was collected, dried, and separated and purified by column chromatography (petroleum ether-ethyl acetate) to give (E) -3, 5-dihydroxy-4-isopropyl stilbene as a white solid (1.78 g) in a yield of 70%.
Example 25: (E) Preparation of (E) -3, 5-dihydroxy-4-isopropyl stilbene
To a round bottom flask was added (Z) -3, 5-dihydroxy-4-isopropyl stilbene (2.54 g,10 mmol) and acetonitrile (20 mL), dissolved with stirring, elemental iodine (1.27 g,5 mmol) was added and heated at 90℃with stirring for 6h. After the completion of the reaction, a saturated sodium sulfite solution (15 mL) was added to quench, extraction was performed with ethyl acetate (50 mL. Times.2), the organic layer was collected, dried, concentrated, and recrystallized from petroleum ether-chloroform to give 1.83g of (E) -3, 5-dihydroxy-4-isopropylstilbene as a pale yellow solid in a yield of 72%.
(E) Specific synthetic route II for 3, 5-dihydroxy-4-isopropyl stilbene (formula-1): examples 1 to 10 and examples 26 to 36
Preparation of 3, 5-dihydroxyphenylacetic acid: as in examples 1-5.
Preparation of 3, 5-dihydroxy-4-isopropylphenylacetic acid: the same as in examples 6-10.
Example 26: preparation of (Z) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid
3, 5-dihydroxy-4-isopropylphenylacetic acid (5.47 g,26 mmol) and benzaldehyde (2.97 g,28 mmol) were added to a round bottom flask, acetic anhydride (15.93 g,156 mmol) was added and dissolved with stirring; triethylamine (7.89 g,78 mmol) was slowly added and stirred at 110℃for 4h. After the reaction is finished, pouring the reaction solution into ice water, and stirring vigorously to form sticky matters; pouring out supernatant, adding sodium hydroxide solution into the thick matter, stirring and dissolving, extracting and washing with dichloromethane, acidifying with 10% hydrochloric acid to pH=4-5, precipitating solid, and suction filtering to obtain filter cake which is (E) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid (formula-5E) in the specific route I; the filtrate was further acidified with 10% hydrochloric acid to ph=1-2, extracted with ethyl acetate (50 ml×2), the organic layer was collected, dried and concentrated to give a dark brown yellow solid, i.e. (Z) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid 1.47g, yield 19.0%. Melting point is 120-122 ℃; 1 H NMR(400MHz,DMSO-d 6 ) δ12.47 (s, 1H), 9.08 (s, 1H), 8.95 (s, 1H), 7.64 (s, 1H), 7.24-7.19 (m, 3H), 7.16-7.14 (m, 2H), 6.28 (d, j=2.0 hz, 1H), 5.82 (d, j=2.0 hz, 1H), 2.71 (dt, j=13.6, 6.8hz, 1H), 1.18 (d, j=6.8 hz, 3H), 1.01 (d, j=6.8 hz, 3H) (as shown in fig. 4).
Example 27: preparation of (Z) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid
3, 5-dihydroxy-4-isopropylphenylacetic acid (5.47 g,26 mmol) and benzaldehyde (2.97 g,28 mmol) were added to a round bottom flask, acetic anhydride (10.62 g,104 mmol) was added and dissolved with stirring; triethylamine (5.26 g,52 mmol) was slowly added and stirred at 110℃for 6h. After the reaction is finished, pouring the reaction solution into ice water, and stirring vigorously to form sticky matters; pouring out supernatant, adding sodium hydroxide solution into the thick matter, stirring and dissolving, extracting and washing with dichloromethane, acidifying with 10% hydrochloric acid to pH=4-5, precipitating solid, and suction filtering to obtain filter cake which is (E) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid (formula-5E) in the specific route I; the filtrate was further acidified with 10% hydrochloric acid to ph=1-2, extracted with ethyl acetate (50 ml×2), the organic layer was collected, dried and concentrated to give a dark brown yellow solid, i.e. (Z) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid 1.38g, yield 17.8%.
Example 28: preparation of (Z) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid
3, 5-dihydroxy-4-isopropylphenylacetic acid (5.47 g,26 mmol) and benzaldehyde (2.97 g,28 mmol) were added to a round bottom flask, acetic anhydride (15.93 g,156 mmol) was added and dissolved with stirring; sodium acetate (6.40 g,78 mmol) was slowly added and heated to 110℃with stirring for 4h. After the reaction is finished, pouring the reaction solution into ice water, and stirring vigorously to form sticky matters; pouring out supernatant, adding sodium hydroxide solution into the thick matter, stirring and dissolving, extracting and washing with dichloromethane, acidifying with 10% hydrochloric acid to pH=4-5, precipitating solid, and suction filtering to obtain filter cake which is (E) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid (formula-5E) in the specific route I; the filtrate was further acidified with 10% hydrochloric acid to ph=1 to 2, extracted with ethyl acetate (50 ml×2), the organic layer was collected, dried and concentrated to give (Z) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid as a tan solid 1.42g in 18.3% yield.
Example 29: preparation of (Z) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid
3, 5-dihydroxy-4-isopropylphenylacetic acid (5.47 g,26 mmol) and benzaldehyde (2.97 g,28 mmol) were added to a round bottom flask, acetic anhydride (15.93 g,156 mmol) was added and dissolved with stirring; potassium acetate (7.65 g,78 mmol) was slowly added thereto and heated at 110℃with stirring for 4h. After the reaction is finished, pouring the reaction solution into ice water, and stirring vigorously to form sticky matters; pouring out supernatant, adding sodium hydroxide solution into the thick matter, stirring and dissolving, extracting and washing with dichloromethane, acidifying with 10% hydrochloric acid to pH=4-5, precipitating solid, and suction filtering to obtain filter cake which is (E) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid (formula-5E) in the specific route I; the filtrate was further acidified with 10% hydrochloric acid to ph=1-2, extracted with ethyl acetate (50 ml×2), the organic layer was collected, dried, and concentrated to give (Z) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid as a tan solid, 1.46g, yield 18.8%.
Example 30: preparation of (Z) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid
3, 5-dihydroxy-4-isopropylphenylacetic acid (5.47 g,26 mmol) and benzaldehyde (2.97 g,28 mmol) were added to a round bottom flask, acetic anhydride (15.93 g,156 mmol) was added and dissolved with stirring; triethylamine (7.89 g,78 mmol) was slowly added and stirred at 140℃for 4h. After the reaction is finished, pouring the reaction solution into ice water, and stirring vigorously to form sticky matters; pouring out supernatant, adding sodium hydroxide solution into the thick matter, stirring and dissolving, extracting and washing with dichloromethane, acidifying with 10% hydrochloric acid to pH=4-5, precipitating solid, and suction filtering to obtain filter cake which is (E) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid (formula-5E) in the specific route I; the filtrate was further acidified with 10% hydrochloric acid to ph=1-2, extracted with ethyl acetate (50 ml×2), the organic layer was collected, dried, and concentrated to give (Z) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid as a tan solid, 1.36g, yield 17.5%.
Example 31: preparation of (Z) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid
3, 5-dihydroxy-4-isopropylphenylacetic acid (5.47 g,26 mmol) and benzaldehyde (2.97 g,28 mmol) were added to a round bottom flask, acetic anhydride (15.93 g,156 mmol) was added and dissolved with stirring; triethylamine (7.89 g,78 mmol) was slowly added and stirred at 110℃for 8h. After the reaction is finished, pouring the reaction solution into ice water, and stirring vigorously to form sticky matters; pouring out supernatant, adding sodium hydroxide solution into the thick matter, stirring and dissolving, extracting and washing with dichloromethane, acidifying with 10% hydrochloric acid to pH=4-5, precipitating solid, and suction filtering to obtain filter cake which is (E) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid (formula-5E) in the specific route I; the filtrate was further acidified with 10% hydrochloric acid to ph=1-2, extracted with ethyl acetate (50 ml×2), the organic layer was collected, dried, and concentrated to give (Z) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid as a tan solid, 1.40g, yield 18.0%.
Example 32: (E) Preparation of (E) -3, 5-dihydroxy-4-isopropyl stilbene
To a round bottom flask was added (Z) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid (1.49 g,5 mmol), cuprous iodide (95 mg,0.5 mmol), 1, 10-phenanthroline (90 mg,0.5 mmol) and polyethylene glycol-400 (12 mL,35 mmol), which were heated and stirred at 190℃for 6h. After the reaction is finished, filtering, washing a filter cake with a small amount of ethyl acetate to obtain brick red fine needle-like crystals, namely, a compound of cuprous iodide and 1, 10-phenanthroline ([ CuI (1, 10-phen))] 2 ) 0.15g, yield 81%, and recovered and reused. Ice water (50 mL) was added to the filtrate for dilution, ethyl acetate extraction (30 mL. Times.3), the organic layer was collected, dried and concentrated to give (E) -3, 5-dihydroxy-4-isopropyl stilbene as a tan solid (1.13 g) in 89% yield.
Example 33: (E) Preparation of (E) -3, 5-dihydroxy-4-isopropyl stilbene
To a round bottom flask was added (Z) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid (1.49 g,5 mmol), cuprous iodide (95 mg,0.5 mmol), 1, 10-phenanthroline (90 mg,0.5 mmol) and polyethylene glycol-400 (12 mL,35 mmol), which were heated and stirred at 190℃for 10h. After the reaction is finished, filtering, washing a filter cake with a small amount of ethyl acetate to obtain brick red fine needle-like crystals, namely, a compound of cuprous iodide and 1, 10-phenanthroline ([ CuI (1, 10-phen)) ] 2 ) 0.13g, yield 72%, and recovered and reused. Ice water (50 mL) was added to the filtrate for dilution, ethyl acetate extraction (30 mL. Times.3), the organic layer was collected, dried and concentrated to give (E) -3, 5-dihydroxy-4-isopropyl stilbene as a tan solid (0.90 g) in 71% yield.
Example 34: (E) Preparation of (E) -3, 5-dihydroxy-4-isopropyl stilbene
Into a round bottom flask was charged (Z) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid (1.49 g,5 mmol), cuprous iodide (0.19 g,1 mmol), 1, 10-phenanthroline (0.18 g,1 mmol)l) and polyethylene glycol-200 (13 mL,75 mmol), and stirring at 190℃for 6h. After the reaction is finished, filtering, washing a filter cake with a small amount of ethyl acetate to obtain brick red fine needle-like crystals, namely, a compound of cuprous iodide and 1, 10-phenanthroline ([ CuI (1, 10-phen))] 2 ) 0.31g, yield 83%, and recovered and reused. Ice water (50 mL) was added to the filtrate for dilution, ethyl acetate extraction (30 mL. Times.3), the organic layer was collected, dried and concentrated to give (E) -3, 5-dihydroxy-4-isopropyl stilbene as a tan solid (2.14 g) in 84% yield.
Example 35: (E) Preparation of (E) -3, 5-dihydroxy-4-isopropyl stilbene
To a round bottom flask was added (Z) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid (1.49 g,5 mmol), cuprous iodide (95 mg,0.5 mmol), 2' -bipyridine (78 mg,0.5 mmol) and polyethylene glycol-400 (12 mL,35 mmol), and the mixture was heated and stirred at 190℃for 6h. After the completion of the reaction, the filtrate was suction-filtered, diluted with ice water (100 mL), extracted with ethyl acetate (50 mL. Times.3), and the organic layer was collected, dried and concentrated to give 0.99g of (E) -3, 5-dihydroxy-4-isopropyl stilbene as a tan solid in 78% yield.
Example 36: (E) Preparation of (E) -3, 5-dihydroxy-4-isopropyl stilbene
To a round bottom flask was added (Z) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid (1.49 g,5 mmol) and the resulting [ CuI (1, 10-phen)] 2 (185 mg,0.25 mmol) and polyethylene glycol-400 (12 mL,35 mmol), and was heated and stirred at 190℃for 6h. After the reaction, the filtrate was filtered by suction, diluted with ice water (50 mL), extracted with ethyl acetate (30 mL. Times.3), and the organic layer was collected, dried and concentrated to give (E) -3, 5-dihydroxy-4-isopropyl stilbene as a tan solid (1.08 g) in 85% yield.
(E) Specific synthetic route III for 3, 5-dihydroxy-4-isopropyl stilbene (formula-1): examples 1 to 10 and examples 37 to 51
Preparation of 3, 5-dihydroxyphenylacetic acid: as in examples 1-5.
Preparation of 3, 5-dihydroxy-4-isopropylphenylacetic acid: the same as in examples 6-10.
Example 37: preparation of (E/Z) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid
3, 5-dihydroxy-4-isopropylphenylacetic acid (5.47 g,26 mmol) and benzaldehyde (2.97 g,28 mmol) were added to a round bottom flask, acetic anhydride (15.93 g,156 mmol) was added and dissolved with stirring; triethylamine (7.89 g,78 mmol) was slowly added and stirred at 110℃for 4h. After the reaction is finished, pouring the reaction solution into ice water, and stirring vigorously to form sticky matters; pouring out supernatant, adding sodium hydroxide solution into the thick matter to dissolve, extracting and washing with dichloromethane, acidifying with 10% hydrochloric acid to pH=1-2, extracting with ethyl acetate (100 mL×2), collecting organic phase, drying, concentrating to obtain dark brown yellow thick matter, namely (E/Z) -2- (3, 5-dihydroxyl-4-isopropylphenyl) -3-phenylacrylic acid 7.37g, and the yield is 95%. 1 H NMR (400 MHz, DMSO-d 6) formula-5E: δ12.52 (s, 1H), 8.96 (s, 2H), 7.59 (s, 1H), 7.30-7.19 (m, 3H), 7.18-7.10 (m, 2H), 6.06 (s, 2H), 3.46 (dt, J=14.0, 7.2Hz, 1H), 1.27 (d, J=7.2 Hz, 6H); delta 12.52 (s, 1H), 9.08 (s, 1H), 8.95 (s, 1H), 7.63 (s, 1H), 7.30-7.19 (m, 3H), 7.18-7.10 (m, 2H), 6.28 (d, J=2.4 Hz, 1H), 5.82 (d, J=2.4 Hz, 1H), 2.71 (dt, J=14.0, 7.2Hz, 1H), 18 (d, J=7.2 Hz, 3H), 1.01 (d, J=7.2 Hz, 3H) (as shown in FIG. 5, which is the partial product obtained in this experiment 1 H NMR spectrum).
Example 38: preparation of (E/Z) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid
3, 5-dihydroxy-4-isopropylphenylacetic acid (5.47 g,26 mmol) and benzaldehyde (2.97 g,28 mmol) were added to a round bottom flask, acetic anhydride (10.62 g,104 mmol) was added and dissolved with stirring; triethylamine (5.26 g,52 mmol) was slowly added and stirred at 110℃for 6h. After the reaction is finished, pouring the reaction solution into ice water, and stirring vigorously to form sticky matters; pouring out supernatant, adding sodium hydroxide solution into the thick matter to dissolve, extracting and washing with dichloromethane, acidifying with 10% hydrochloric acid to pH=1-2, extracting with ethyl acetate (100 mL multiplied by 2), collecting organic phase, drying, concentrating to obtain dark brown yellow thick matter, namely (E/Z) -2- (3, 5-dihydroxyl-4-isopropylphenyl) -3-phenyl acrylic acid 6.90g, and the yield is 89%.
Example 39: preparation of (E/Z) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid
3, 5-dihydroxy-4-isopropylphenylacetic acid (5.47 g,26 mmol) and benzaldehyde (2.97 g,28 mmol) were added to a round bottom flask, acetic anhydride (15.93 g,156 mmol) was added and dissolved with stirring; sodium acetate (6.40 g,78 mmol) was slowly added and heated to 110℃with stirring for 4h. After the reaction is finished, pouring the reaction solution into ice water, and stirring vigorously to form sticky matters; pouring out supernatant, adding sodium hydroxide solution into the thick matter to dissolve, extracting and washing with dichloromethane, acidifying with 10% hydrochloric acid to pH=1-2, extracting with ethyl acetate (100 mL multiplied by 2), collecting organic phase, drying, concentrating to obtain dark brown yellow thick matter, namely (E/Z) -2- (3, 5-dihydroxyl-4-isopropylphenyl) -3-phenyl acrylic acid 7.08g, and the yield is 91%.
Example 40: preparation of (E/Z) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid
3, 5-dihydroxy-4-isopropylphenylacetic acid (5.47 g,26 mmol) and benzaldehyde (2.97 g,28 mmol) were added to a round bottom flask, acetic anhydride (15.93 g,156 mmol) was added and dissolved with stirring; potassium acetate (7.65 g,78 mmol) was slowly added thereto and heated at 110℃with stirring for 4h. After the reaction is finished, pouring the reaction solution into ice water, and stirring vigorously to form sticky matters; pouring out supernatant, adding sodium hydroxide solution into the thick matter to dissolve, extracting and washing with dichloromethane, acidifying with 10% hydrochloric acid to pH=1-2, extracting with ethyl acetate (100 mL multiplied by 2), collecting organic phase, drying, concentrating to obtain dark brown yellow thick matter, namely (E/Z) -2- (3, 5-dihydroxyl-4-isopropylphenyl) -3-phenyl acrylic acid 7.28g, and the yield is 94%.
Example 41: preparation of (E/Z) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid
3, 5-dihydroxy-4-isopropylphenylacetic acid (5.47 g,26 mmol) and benzaldehyde (2.97 g,28 mmol) were added to a round bottom flask, acetic anhydride (15.93 g,156 mmol) was added and dissolved with stirring; triethylamine (7.89 g,78 mmol) was slowly added and stirred at 140℃for 4h. After the reaction is finished, pouring the reaction solution into ice water, and stirring vigorously to form sticky matters; pouring out supernatant, adding sodium hydroxide solution into the thick matter to dissolve, extracting and washing with dichloromethane, acidifying with 10% hydrochloric acid to pH=1-2, extracting with ethyl acetate (100 mL multiplied by 2), collecting organic phase, drying, concentrating to obtain dark brown yellow thick matter, namely (E/Z) -2- (3, 5-dihydroxyl-4-isopropylphenyl) -3-phenyl acrylic acid 6.82g, and the yield is 88%.
Example 42: preparation of (E/Z) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid
3, 5-dihydroxy-4-isopropylphenylacetic acid (5.47 g,26 mmol) and benzaldehyde (2.97 g,28 mmol) were added to a round bottom flask, acetic anhydride (15.93 g,156 mmol) was added and dissolved with stirring; triethylamine (7.89 g,78 mmol) was slowly added and stirred at 110℃for 8h. After the reaction is finished, pouring the reaction solution into ice water, and stirring vigorously to form sticky matters; pouring out supernatant, adding sodium hydroxide solution into the thick matter to dissolve, extracting and washing with dichloromethane, acidifying with 10% hydrochloric acid to pH=1-2, extracting with ethyl acetate (100 mL multiplied by 2), collecting organic phase, drying, concentrating to obtain dark brown yellow thick matter, namely (E/Z) -2- (3, 5-dihydroxyl-4-isopropylphenyl) -3-phenyl acrylic acid 6.98g, and the yield is 90%.
Example 43: preparation of (E/Z) -3, 5-dihydroxy-4-isopropyl stilbene
To a round bottom flask was added (E/Z) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid (5.97 g,20 mmol), copper iodide (0.38 g,2 mmol), 1, 10-phenanthroline (0.36 g,2 mmol) and polyethylene glycol-400 (50 mL,140 mmol), which were heated and stirred at 190℃for 6h. After the reaction is finished, filtering, washing a filter cake with a small amount of ethyl acetate to obtain brick red fine needle-like crystals, namely, a compound of cuprous iodide and 1, 10-phenanthroline ([ CuI (1, 10-phen))] 2 ) 0.61g, yield 82%, and recovered and reused. Ice water (100 mL) was added to the filtrate for dilution, ethyl acetate extraction (50 mL. Times.3), the organic layer was collected, dried and concentrated to give a tan paste, i.e. (E/Z) -3, 5-dihydroxy-4-isopropyl stilbene 4.57g, yield 90%. 1 H NMR(400MHz,DMSO-d 6 ) Delta 8.87 (s, 2H), 7.29-7.16 (m, 5H), 6.44 (d, j=12.4 hz, 1H), 6.37 (d, j=12.4 hz, 1H), 6.19 (s, 2H), 3.40 (dt, j=14.4, 7.2hz, 1H), 1.21 (d, j=7.2 hz, 6H); delta 9.05 (s, 2H), 7.56 (d, J=7.2 Hz, 2H), 7.35 (t, J=7.6 Hz, 2H), 7.25 (t, J=7.2 Hz, 1H), 7.00 (d, J=16.4 Hz, 1H), 6.87 (d, J=16.4 Hz, 1H), 6.47 (s, 2H), 3.44 (dt, 14.4,7.2Hz, 1H), 1.24 (d, J=7.2 Hz, 6H) (as shown in FIG. 8, which is the partial product obtained in this experiment 1 H NMR spectrum).
Example 44: preparation of (E/Z) -3, 5-dihydroxy-4-isopropyl stilbene
To a round bottom flask was added (E/Z) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid (5.97 g,20 mmol), copper iodide (0.19 g,1 mmol), 1, 10-phenanthroline (0.18 g,1 mmol) and polyethylene glycol-400 (50 mL,140 mmol), and the mixture was heated and stirred at 190℃for 10h. After the reaction is finished, filtering, washing a filter cake with a small amount of ethyl acetate to obtain brick red fine needle-like crystals, namely, a compound of cuprous iodide and 1, 10-phenanthroline ([ CuI (1, 10-phen))] 2 ) 0.26g, yield 70%, and recovered and reused. Ice water (100 mL) was added to the filtrate for dilution, ethyl acetate extraction (50 mL. Times.3), the organic layer was collected, dried and concentrated to give a tan paste, i.e. (E/Z) -3, 5-dihydroxy-4-isopropyl stilbene 3.70g, yield 73%.
Example 45: preparation of (E/Z) -3, 5-dihydroxy-4-isopropyl stilbene
To the round bottom flask was added (E/Z) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid (5.97 g,20 mmol), cuprous iodide (0.76 g,4 mmol), 1, 10-phenanthroline (0.72 g,4 mmol) and polyethylene glycol-200 (55 mL,300 mmol), which were heated and stirred at 190℃for 6h. After the reaction is finished, filtering, washing a filter cake with a small amount of ethyl acetate to obtain brick red fine needle-like crystals, namely, a compound of cuprous iodide and 1, 10-phenanthroline ([ CuI (1, 10-phen)) ] 2 ) 1.26g, yield 85%, which was recovered and reused. Ice water (100 mL) was added to the filtrate for dilution, ethyl acetate extraction (50 mL. Times.3), the organic layer was collected, dried and concentrated to give a tan paste, i.e. (E/Z) -3, 5-dihydroxy-4-isopropyl stilbene 4.27g, yield 84%.
Example 46: preparation of (E/Z) -3, 5-dihydroxy-4-isopropyl stilbene
To a round bottom flask was added (E/Z) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid (5.97 g,20 mmol), copper iodide (0.38 g,2 mmol), 2' -bipyridine (0.31 g,2 mmol) and polyethylene glycol-400 (50 mL,140 mmol), which were heated and stirred at 190℃for 6h. After the reaction, the filtrate was suction-filtered, diluted with ice water (100 mL), extracted with ethyl acetate (50 mL. Times.3), and the organic layer was collected, dried and concentrated to give a tan paste, i.e., (E/Z) -3, 5-dihydroxy-4-isopropyl stilbene 3.91g, at 77% yield.
Example 47: preparation of (E/Z) -3, 5-dihydroxy-4-isopropyl stilbene
To a round bottom flask was added (E/Z) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid (5.97 g,20 mmol), recovered [ CuI (1, 10-phen)] 2 (0.74 g,1 mmol) and polyethylene glycol-400 (50 mL,140 mmol), with stirring at 190℃for 6h. After the reaction, ice water (100 mL) was added to the filtrate for dilution, ethyl acetate extraction (50 mL. Times.3), and the organic layer was collected, dried and concentrated to give a tan paste (E/Z) -3, 5-dihydroxy-4-isopropyl stilbene 4.37g in 86% yield.
Example 48: (E) Preparation of (E) -3, 5-dihydroxy-4-isopropyl stilbene
To a round bottom flask was added (E/Z) -3, 5-dihydroxy-4-isopropyl stilbene (2.54 g,10 mmol) and acetonitrile (20 mL), dissolved with stirring, elemental iodine (1.27 g,5 mmol) was added and heated at 90℃with stirring for 6h. After the completion of the reaction, saturated sodium sulfite solution (15 mL) was added to quench, ethyl acetate was used for extraction (50 mL. Times.2), the organic layer was collected, dried, concentrated, and purified by column chromatography (petroleum ether-ethyl acetate) to give 2.13g of (E) -3, 5-dihydroxy-4-isopropyl stilbene as a white solid in a yield of 84%.
Example 49: (E) Preparation of (E) -3, 5-dihydroxy-4-isopropyl stilbene
To a round bottom flask was added (E/Z) -3, 5-dihydroxy-4-isopropyl stilbene (2.54 g,10 mmol) and acetonitrile (20 mL), dissolved with stirring, elemental iodine (0.63 g,2.5 mmol) was added and heated at 90℃with stirring for 10h. After the reaction, saturated sodium sulfite solution (10 mL) was added to quench, ethyl acetate was added to extract (50 mL. Times.2), the organic layer was collected, dried, concentrated, and purified by column chromatography (petroleum ether-ethyl acetate) to give 1.90g of (E) -3, 5-dihydroxy-4-isopropyl stilbene as a white solid in 75% yield.
Example 50: (E) Preparation of (E) -3, 5-dihydroxy-4-isopropyl stilbene
To the round bottom flask were added (E/Z) -3, 5-dihydroxy-4-isopropyl stilbene (2.54 g,10 mmol) and 1, 2-dichloroethane (20 mL), dissolved with stirring, elemental iodine (2.54 g,10 mmol) was added and heated at 90℃with stirring for 6h. After the reaction, saturated sodium sulfite solution (25 mL) was added to quench, ethyl acetate was added to extract (50 mL. Times.2), the organic layer was collected, dried, concentrated, and purified by column chromatography (petroleum ether-ethyl acetate) to give 1.83g of (E) -3, 5-dihydroxy-4-isopropyl stilbene as a white solid in a yield of 72%.
Example 51: (E) Preparation of (E) -3, 5-dihydroxy-4-isopropyl stilbene
To a round bottom flask was added (E/Z) -3, 5-dihydroxy-4-isopropyl stilbene (2.54 g,10 mmol) and acetonitrile (20 mL), dissolved with stirring, elemental iodine (1.27 g,5 mmol) was added and heated at 90℃with stirring for 6h. After the completion of the reaction, a saturated sodium sulfite solution (15 mL) was added to quench, extraction was performed with ethyl acetate (50 mL. Times.2), the organic layer was collected, dried, concentrated, and recrystallized from petroleum ether-chloroform to give 1.85g of (E) -3, 5-dihydroxy-4-isopropylstilbene as a pale yellow solid in 73% yield.
(E) Specific synthetic route IV for 3, 5-dihydroxy-4-isopropylstilbene (formula-1): examples 1 to 10 and examples 52 to 62
Preparation of 3, 5-dihydroxyphenylacetic acid: as in examples 1-5.
Preparation of 3, 5-dihydroxy-4-isopropylphenylacetic acid: the same as in examples 6-10.
Example 52: preparation of (E/Z) -2- (3, 5-diacetoxy-4-isopropylphenyl) -3-phenylacrylic acid
3, 5-dihydroxy-4-isopropylphenylacetic acid (5.47 g,26 mmol) and benzaldehyde (2.97 g,28 mmol) were added to a round bottom flask, acetic anhydride (15.93 g,156 mmol) was added and dissolved with stirring; triethylamine (7.89 g,78 mmol) was slowly added and stirred at 110℃for 4h. After the reaction, pouring the reaction solution into ice water, vigorously stirring, pouring out an upper aqueous solution, repeating the above operation until the aqueous solution is colorless and clear, solidifying the viscous solution into brown yellow powder, carrying out suction filtration, washing with water, and drying to obtain a brown yellow solid, namely 9.34g of (E/Z) -2- (3, 5-diacetoxy-4-isopropylphenyl) -3-phenylacrylic acid, with the yield of 94%. 1 H NMR (400 mhz, dmso-d 6) formula 5Ac-E δ12.83 (s, 1H), 7.75 (s, 1H), 7.27-7.12 (m, 5H), 6.81 (s, 2H), 3.08 (dq, j=14.4, 7.2hz, 1H), 2.34 (s, 3H), 2.27 (s, 6H), 1.20 (d, j=7.2 hz, 6H); delta 12.83 (s, 1H), 7.79 (s, 1H)),7.27-7.12(m,5H),7.00(d,J＝2.4Hz,1H),6.74(d,J＝2.4Hz,1H),2.88(dt,J＝14.4,7.2Hz,1H),2.31(s,3H),2.21(s,3H),1.13(d,J＝7.2Hz,3H),0.94(d,J＝6.8Hz,3H).
Example 53: preparation of (E/Z) -2- (3, 5-diacetoxy-4-isopropylphenyl) -3-phenylacrylic acid
3, 5-dihydroxy-4-isopropylphenylacetic acid (5.47 g,26 mmol) and benzaldehyde (2.97 g,28 mmol) were added to a round bottom flask, acetic anhydride (10.62 g,104 mmol) was added and dissolved with stirring; triethylamine (5.26 g,52 mmol) was slowly added and stirred at 110℃for 6h. After the reaction, pouring the reaction solution into ice water, vigorously stirring, pouring out an upper aqueous solution, repeating the above operation until the aqueous solution is colorless and clear, solidifying the viscous solution into brown yellow powder, carrying out suction filtration, washing with water, and drying to obtain a brown yellow solid, namely 8.75g of (E/Z) -2- (3, 5-diacetoxy-4-isopropylphenyl) -3-phenylacrylic acid, and the yield is 88%.
Example 54: preparation of (E/Z) -2- (3, 5-diacetoxy-4-isopropylphenyl) -3-phenylacrylic acid
3, 5-dihydroxy-4-isopropylphenylacetic acid (5.47 g,26 mmol) and benzaldehyde (2.97 g,28 mmol) were added to a round bottom flask, acetic anhydride (15.93 g,156 mmol) was added and dissolved with stirring; sodium acetate (6.40 g,78 mmol) was slowly added and heated to 110℃with stirring for 4h. After the reaction, pouring the reaction solution into ice water, vigorously stirring, pouring out an upper aqueous solution, repeating the above operation until the aqueous solution is colorless and clear, solidifying the viscous solution into brown yellow powder, carrying out suction filtration, washing with water, and drying to obtain a brown yellow solid, namely 8.95g of (E/Z) -2- (3, 5-diacetoxy-4-isopropylphenyl) -3-phenylacrylic acid, wherein the yield is 90%.
Example 55: preparation of (E/Z) -2- (3, 5-diacetoxy-4-isopropylphenyl) -3-phenylacrylic acid
3, 5-dihydroxy-4-isopropylphenylacetic acid (5.47 g,26 mmol) and benzaldehyde (2.97 g,28 mmol) were added to a round bottom flask, acetic anhydride (15.93 g,156 mmol) was added and dissolved with stirring; potassium acetate (7.65 g,78 mmol) was slowly added thereto and heated at 110℃with stirring for 4h. After the reaction, pouring the reaction solution into ice water, vigorously stirring, pouring out an upper aqueous solution, repeating the above operation until the aqueous solution is colorless and clear, solidifying the viscous solution into brown yellow powder, carrying out suction filtration, washing with water, and drying to obtain a brown yellow solid, namely 9.24g of (E/Z) -2- (3, 5-diacetoxy-4-isopropylphenyl) -3-phenylacrylic acid, wherein the yield is 93%.
Example 56: preparation of (E/Z) -2- (3, 5-diacetoxy-4-isopropylphenyl) -3-phenylacrylic acid
3, 5-dihydroxy-4-isopropylphenylacetic acid (5.47 g,26 mmol) and benzaldehyde (2.97 g,28 mmol) were added to a round bottom flask, acetic anhydride (15.93 g,156 mmol) was added and dissolved with stirring; triethylamine (7.89 g,78 mmol) was slowly added and stirred at 140℃for 4h. After the reaction, pouring the reaction solution into ice water, vigorously stirring, pouring out an upper aqueous solution, repeating the above operation until the aqueous solution is colorless and clear, solidifying the viscous solution into brown yellow powder, carrying out suction filtration, washing with water, and drying to obtain a brown yellow solid, namely 8.84g of (E/Z) -2- (3, 5-diacetoxy-4-isopropylphenyl) -3-phenylacrylic acid, wherein the yield is 89%.
Example 57: preparation of (E/Z) -2- (3, 5-diacetoxy-4-isopropylphenyl) -3-phenylacrylic acid
3, 5-dihydroxy-4-isopropylphenylacetic acid (5.47 g,26 mmol) and benzaldehyde (2.97 g,28 mmol) were added to a round bottom flask, acetic anhydride (15.93 g,156 mmol) was added and dissolved with stirring; triethylamine (7.89 g,78 mmol) was slowly added and stirred at 110℃for 8h. After the reaction, pouring the reaction solution into ice water, vigorously stirring, pouring out an upper aqueous solution, repeating the above operation until the aqueous solution is colorless and clear, solidifying the viscous solution into brown yellow powder, carrying out suction filtration, washing with water, and drying to obtain a brown yellow solid, namely 9.04g of (E/Z) -2- (3, 5-diacetoxy-4-isopropylphenyl) -3-phenylacrylic acid, and the yield is 91%.
Example 58: preparation of (E/Z) -3, 5-dihydroxy-4-isopropyl stilbene
To a round bottom flask was added (E/Z) -2- (3, 5-diacetoxy-4-isopropylphenyl) -3-phenylacrylic acid (7.65 g,20 mmol), cuprous iodide (0.38 g,2 mmol), 1, 10-phenanthroline (0.36 g,2 mmol) and polyethylene glycol-400 (50 mL,140mmol, without anhydrous treatment), 190℃CAnd (5) stirring for 6h. After the reaction is finished, filtering, washing a filter cake with a small amount of ethyl acetate to obtain brick red fine needle-like crystals, namely, a compound of cuprous iodide and 1, 10-phenanthroline ([ CuI (1, 10-phen)) ] 2 ) 0.62g, yield 84%, and recovered and reused. Ice water (100 mL) was added to the filtrate for dilution, ethyl acetate extraction (50 mL. Times.3), the organic layer was collected, dried and concentrated to give a tan paste, i.e. (E/Z) -3, 5-dihydroxy-4-isopropyl stilbene 4.62g, yield 91%.
Example 59: preparation of (E/Z) -3, 5-dihydroxy-4-isopropyl stilbene
To a round bottom flask was added (E/Z) -2- (3, 5-diacetoxy-4-isopropylphenyl) -3-phenylacrylic acid (7.65 g,20 mmol), cuprous iodide (0.19 g,1 mmol), 1, 10-phenanthroline (0.18 g,1 mmol) and polyethylene glycol-400 (50 mL,140mmol, without anhydrous treatment), and heated and stirred at 190℃for 10h. After the reaction is finished, filtering, washing a filter cake with a small amount of ethyl acetate to obtain brick red fine needle-like crystals, namely, a compound of cuprous iodide and 1, 10-phenanthroline ([ CuI (1, 10-phen))] 2 ) 0.55g, 75% yield, which was recovered and reused. Ice water (100 mL) was added to the filtrate for dilution, ethyl acetate extraction (50 mL. Times.3), the organic layer was collected, dried and concentrated to give a tan paste, i.e. (E/Z) -3, 5-dihydroxy-4-isopropyl stilbene 3.66g, yield 72%.
Example 60: preparation of (E/Z) -3, 5-dihydroxy-4-isopropyl stilbene
To a round bottom flask was added (E/Z) -2- (3, 5-diacetoxy-4-isopropylphenyl) -3-phenylacrylic acid (7.65 g,20 mmol), cuprous iodide (0.76 g,4 mmol), 1, 10-phenanthroline (0.72 g,4 mmol) and polyethylene glycol-200 (55 mL,300mmol, without anhydrous treatment), which was heated and stirred at 190℃for 6h. After the reaction is finished, filtering, washing a filter cake with a small amount of ethyl acetate to obtain brick red fine needle-like crystals, namely, a compound of cuprous iodide and 1, 10-phenanthroline ([ CuI (1, 10-phen))] 2 ) 1.23g, yield 83%, which was recovered and reused. Ice water (100 mL) was added to the filtrate for dilution, ethyl acetate extraction (50 mL. Times.3), the organic layer was collected, dried and concentrated to give a tan paste, i.e. (E/Z) -3, 5-dihydroxy-4-isopropyl stilbene 4.37g, yield 86%.
Example 61: preparation of (E/Z) -3, 5-dihydroxy-4-isopropyl stilbene
To a round bottom flask was added (E/Z) -2- (3, 5-diacetoxy-4-isopropylphenyl) -3-phenylacrylic acid (7.65 g,20 mmol), cuprous iodide (0.38 g,2 mmol), 2' -bipyridine (0.31 g,2 mmol) and polyethylene glycol-400 (50 mL,140mmol, without anhydrous treatment), which was heated and stirred at 190℃for 6h. After the reaction, the filtrate was suction-filtered, diluted with ice water (100 mL), extracted with ethyl acetate (50 mL. Times.3), and the organic layer was collected, dried and concentrated to give a tan paste, i.e., (E/Z) -3, 5-dihydroxy-4-isopropyl stilbene 4.06g, at 80% yield.
Example 62: preparation of (E/Z) -3, 5-dihydroxy-4-isopropyl stilbene
To a round bottom flask was added (E/Z) -2- (3, 5-diacetoxy-4-isopropylphenyl) -3-phenylacrylic acid (7.65 g,20 mmol), and the resulting [ CuI (1, 10-phen)] 2 (0.74 g,1 mmol) and polyethylene glycol-400 (50 mL,140mmol, without anhydrous treatment), were heated and stirred at 190℃for 6h. After the reaction, ice water (100 mL) was added to the filtrate for dilution, ethyl acetate extraction (50 mL. Times.3), and the organic layer was collected, dried and concentrated to give a tan paste (E/Z) -3, 5-dihydroxy-4-isopropyl stilbene 4.37g in 86% yield.
(E) -preparation of 3, 5-dihydroxy-4-isopropyl stilbene: the same as in examples 48-51.
The foregoing is illustrative of the present invention, and the present invention is not limited to the above embodiments, but is capable of other modifications, adaptations, alternatives, combinations, and simplifications without departing from the spirit and principles of the invention.

Claims (9)

1. A method for synthesizing (E) -3, 5-dihydroxyl-4-isopropyl stilbene, which is characterized by comprising the following steps:
(1) Preparation of 3, 5-dihydroxyphenylacetic acid: in the alkali A, 3, 5-dihydroxyl-2, 4-diethyl oxo-phenylacetic acid ethyl ester is subjected to hydrolysis reaction; adding acid A to perform decarboxylation reaction; after the reaction is finished, obtaining 3, 5-dihydroxyphenylacetic acid through post-treatment;
(2) Preparation of 3, 5-dihydroxy-4-isopropylphenylacetic acid: in the excessive acid B, the 3, 5-dihydroxyphenylacetic acid and isopropanol undergo isopropylation reaction; after the reaction is finished, 3, 5-dihydroxyl-4-isopropylphenylacetic acid is obtained through post-treatment;
(3) Preparation of (E) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid: in a solvent B, 3, 5-dihydroxyl-4-isopropylphenylacetic acid and benzaldehyde are subjected to condensation reaction in the presence of a base B; after the reaction is finished, performing post-treatment to obtain (E) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid; the post-treatment is to pour the reaction solution into ice water, stir vigorously, and generate a large amount of sticky matters, namely (E/Z) -2- (3, 5-diacetoxy-4-isopropylphenyl) -3-phenylacrylic acid; pouring out supernatant, adding sodium hydroxide solution into the thick matter, stirring and dissolving, extracting and washing with dichloromethane, acidifying with hydrochloric acid until the pH value is=4-5, precipitating a large amount of solids, carrying out suction filtration and washing with water, collecting filter cakes, and drying to obtain (E) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid; the solvent B is acetic anhydride; the alkali B is sodium acetate, potassium carbonate or triethylamine;
(4) Preparation of (Z) -3, 5-dihydroxy-4-isopropyl stilbene: decarboxylation of (E) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid in solvent C in the presence of catalyst C and ligand C; after the reaction is finished, obtaining (Z) -3, 5-dihydroxyl-4-isopropyl stilbene through post-treatment; the solvent C is polyethylene glycol-200 or polyethylene glycol-400; the catalyst C is cuprous iodide; the ligand C is 1, 10-phenanthroline or 2,2' -bipyridine;
(5) Preparation of (E) -3, 5-dihydroxy-4-isopropyl stilbene: in a solvent D, in the presence of a catalyst D, (Z) -3, 5-dihydroxy-4-isopropyl stilbene undergoes isomerization reaction; after the reaction is finished, the (E) -3, 5-dihydroxyl-4-isopropyl stilbene is obtained through post-treatment.
2. The method for synthesizing (E) -3, 5-dihydroxy-4-isopropyl stilbene according to claim 1, wherein:
in the step (1), the alkali is sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate or potassium carbonate, the external temperature of the hydrolysis reaction is 80-150 ℃, and the time of the hydrolysis reaction is 2-5 h; the acid A is sulfuric acid, hydrochloric acid or nitric acid, the decarboxylation reaction temperature is 30-100 ℃, and the decarboxylation reaction time is 1-4 hours; the mol ratio of the 3, 5-dihydroxyl-2, 4-diethyl carbonyl phenylacetic acid ethyl ester, the alkali A and the acid A is 1 (4-7) (2-8); the post-treatment is to extract and wash the reaction liquid with dichloromethane, then extract the reaction liquid with ethyl acetate, collect an ethyl acetate layer, dry and concentrate the ethyl acetate layer to obtain 3, 5-dihydroxyphenylacetic acid;
in the step (2), the acid B is sulfuric acid, phosphoric acid, hydrochloric acid, nitric acid, p-toluenesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, phosphotungstic acid, phosphomolybdic acid, cation exchange resin Dowex50 WX4 or Dowex50WX8; the temperature of the isopropylation reaction is 50-100 ℃ and the reaction time is 4-10 h; the mol ratio of 3, 5-dihydroxyphenylacetic acid, isopropanol and acid B is 1 (1.0-1.5) (5-15); the post-treatment is to pour the reaction solution into ice water, stir vigorously, have a large amount of sticky matter to produce, pour out the excessive acid liquor of upper strata, and add ethyl acetate to extract into acid liquor, the aqueous layer obtained is regarded as the acid pickle, reclaim it and get excessive acid B; the obtained organic layer is used for dissolving the sticky matters, concentrating, adding sodium hydroxide solution for dissolving, adding hydrochloric acid for acidification until the pH value is=2-3, generating a little of scorched black matters, carrying out suction filtration, extracting and washing the obtained filtrate with dichloromethane, extracting with ethyl acetate, collecting an ethyl acetate layer, drying and concentrating to obtain 3, 5-dihydroxyl-4-isopropylphenylacetic acid;
In the step (3), the temperature of the condensation reaction is 100-140 ℃ and the reaction time is 2-8 h; the mol ratio of the 3, 5-dihydroxyl-4-isopropylphenylacetic acid, benzaldehyde, alkali B and the solvent B is 1 (1.0-1.2) (2-4) (4-6);
in the step (4), the decarboxylation reaction temperature is 160-210 ℃ and the reaction time is 4-10 h; (E) The molar ratio of the (E) -2- (3, 5-dihydroxyl-4-isopropylphenyl) -3-phenylacrylic acid, the catalyst C, the ligand C and the solvent C is 1 (0.05-0.2) to 0.05-0.2 to 5-15); the post-treatment is to cool the reaction liquid to room temperature, suction-filter, wash the filter cake with a small amount of ethyl acetate to obtain a crystal, wherein the crystal is a compound of the catalyst C and the ligand C, and the compound can be recovered and reused; diluting the obtained filtrate with ice water, adding ethyl acetate for extraction, collecting an organic phase, drying and concentrating to obtain (Z) -3, 5-dihydroxyl-4-isopropyl stilbene;
in the step (5), the solvent D is dichloromethane, chloroform, 1, 2-dichloroethane, acetonitrile, tetrahydrofuran or 1, 4-dioxane; the catalyst D is elemental iodine or aluminum triiodide; the isomerization reaction temperature is 40-110 ℃ and the reaction time is 4-10 h; the mol ratio of the (Z) -3, 5-dihydroxyl-4-isopropyl stilbene and the catalyst D is 1 (0.1-1.0); the post-treatment is to cool the reaction liquid to room temperature, add saturated sodium sulfite solution for quenching, extract with ethyl acetate, collect organic phase, dry, concentrate, and separate and purify by recrystallization or column chromatography to obtain (E) -3, 5-dihydroxy-4-isopropyl stilbene.
3. A method for synthesizing (E) -3, 5-dihydroxyl-4-isopropyl stilbene, which is characterized by comprising the following steps:
(1) Preparation of 3, 5-dihydroxyphenylacetic acid: in the alkali A, 3, 5-dihydroxyl-2, 4-diethyl oxo-phenylacetic acid ethyl ester is subjected to hydrolysis reaction; adding acid A to perform decarboxylation reaction; after the reaction is finished, obtaining 3, 5-dihydroxyphenylacetic acid through post-treatment;
(2) Preparation of 3, 5-dihydroxy-4-isopropylphenylacetic acid: in the excessive acid B, the 3, 5-dihydroxyphenylacetic acid and isopropanol undergo isopropylation reaction; after the reaction is finished, 3, 5-dihydroxyl-4-isopropylphenylacetic acid is obtained through post-treatment;
(3) Preparation of (Z) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid: in a solvent B, 3, 5-dihydroxyl-4-isopropylphenylacetic acid and benzaldehyde are subjected to condensation reaction in the presence of a base B; after the reaction is finished, performing post-treatment to obtain (Z) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid; the post-treatment is to pour the reaction solution into ice water, stir vigorously, and generate a large amount of sticky matters, namely (E/Z) -2- (3, 5-diacetoxy-4-isopropylphenyl) -3-phenylacrylic acid; pouring out supernatant, adding sodium hydroxide solution into the thick matter, stirring and dissolving, extracting and washing with dichloromethane, acidifying with hydrochloric acid until the pH value is=4-5, separating out solid, and carrying out suction filtration to obtain a filter cake which is (E) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid; acidifying the obtained filtrate with hydrochloric acid until the pH value is=1-2, extracting with ethyl acetate, collecting an organic phase, drying and concentrating to obtain (Z) -2- (3, 5-dihydroxyl-4-isopropylphenyl) -3-phenylacrylic acid; the solvent B is acetic anhydride; the alkali B is sodium acetate, potassium carbonate or triethylamine;
(4) Preparation of (E) -3, 5-dihydroxy-4-isopropyl stilbene: decarboxylation of (Z) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid in solvent C in the presence of catalyst C and ligand C; after the reaction is finished, obtaining (E) -3, 5-dihydroxyl-4-isopropyl stilbene through post-treatment; the solvent C is polyethylene glycol-200 or polyethylene glycol-400; the catalyst C is cuprous iodide; the ligand C is 1, 10-phenanthroline or 2,2' -bipyridine.
4. A process for the synthesis of (E) -3, 5-dihydroxy-4-isopropyl stilbene according to claim 3, characterized in that:
in the step (1), the alkali is sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate or potassium carbonate, the external temperature of the hydrolysis reaction is 80-150 ℃, and the time of the hydrolysis reaction is 2-5 h; the acid A is sulfuric acid, hydrochloric acid or nitric acid, the decarboxylation reaction temperature is 30-100 ℃, and the decarboxylation reaction time is 1-4 hours; the mol ratio of the 3, 5-dihydroxyl-2, 4-diethyl carbonyl phenylacetic acid ethyl ester, the alkali A and the acid A is 1 (4-7) (2-8); the post-treatment is to extract and wash the reaction liquid with dichloromethane, then extract the reaction liquid with ethyl acetate, collect an ethyl acetate layer, dry and concentrate the ethyl acetate layer to obtain 3, 5-dihydroxyphenylacetic acid;
In the step (2), the acid B is sulfuric acid, phosphoric acid, hydrochloric acid, nitric acid, p-toluenesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, phosphotungstic acid, phosphomolybdic acid, cation exchange resin Dowex50 WX4 or Dowex50WX8; the temperature of the isopropylation reaction is 50-100 ℃ and the reaction time is 4-10 h; the mol ratio of 3, 5-dihydroxyphenylacetic acid, isopropanol and acid B is 1 (1.0-1.5) (5-15); the post-treatment is to pour the reaction solution into ice water, stir vigorously, have a large amount of sticky matter to produce, pour out the excessive acid liquor of upper strata, and add ethyl acetate to extract into acid liquor, the aqueous layer obtained is regarded as the acid pickle, reclaim it and get excessive acid B; the obtained organic layer is used for dissolving the sticky matters, concentrating, adding sodium hydroxide solution for dissolving, adding hydrochloric acid for acidification until the pH value is=2-3, generating a little of scorched black matters, carrying out suction filtration, extracting and washing the obtained filtrate with dichloromethane, extracting with ethyl acetate, collecting an ethyl acetate layer, drying and concentrating to obtain 3, 5-dihydroxyl-4-isopropylphenylacetic acid;
in the step (3), the temperature of the condensation reaction is 100-140 ℃ and the reaction time is 2-8 h; the mol ratio of the 3, 5-dihydroxyl-4-isopropylphenylacetic acid, benzaldehyde, alkali B and the solvent B is 1 (1.0-1.2) (2-4) (4-6);
In the step (4), the decarboxylation reaction temperature is 160-210 ℃ and the reaction time is 4-10 h; the mol ratio of (Z) -2- (3, 5-dihydroxyl-4-isopropylphenyl) -3-phenylacrylic acid, catalyst C, ligand C and solvent C is 1 (0.05-0.2): 5-15); the post-treatment is to cool the reaction liquid to room temperature, suction-filter, wash the filter cake with a small amount of ethyl acetate to obtain a crystal, wherein the crystal is a compound of the catalyst C and the ligand C, and the compound can be recovered and reused; the obtained filtrate is diluted by ice water, added with ethyl acetate for extraction, and the organic phase is collected, dried and concentrated to obtain (E) -3, 5-dihydroxyl-4-isopropyl stilbene.
5. A method for synthesizing (E) -3, 5-dihydroxyl-4-isopropyl stilbene, which is characterized by comprising the following steps:
(1) Preparation of 3, 5-dihydroxyphenylacetic acid: in the alkali A, 3, 5-dihydroxyl-2, 4-diethyl oxo-phenylacetic acid ethyl ester is subjected to hydrolysis reaction; adding acid A to perform decarboxylation reaction; after the reaction is finished, obtaining 3, 5-dihydroxyphenylacetic acid through post-treatment;
(2) Preparation of 3, 5-dihydroxy-4-isopropylphenylacetic acid: in the excessive acid B, the 3, 5-dihydroxyphenylacetic acid and isopropanol undergo isopropylation reaction; after the reaction is finished, 3, 5-dihydroxyl-4-isopropylphenylacetic acid is obtained through post-treatment;
(3) Preparation of (E/Z) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid: in a solvent B, 3, 5-dihydroxyl-4-isopropylphenylacetic acid (formula-4) and benzaldehyde are subjected to condensation reaction in the presence of a base B; after the reaction is finished, performing post-treatment to obtain (E/Z) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid; the post-treatment is to pour the reaction solution into ice water, stir vigorously, and generate a large amount of sticky matters, namely (E/Z) -2- (3, 5-diacetoxy-4-isopropylphenyl) -3-phenylacrylic acid; pouring out supernatant, adding sodium hydroxide solution into the thick matter, stirring and dissolving, extracting and washing with dichloromethane, acidifying with hydrochloric acid to pH=1-2, extracting with ethyl acetate, collecting organic phase, drying and concentrating to obtain (E/Z) -2- (3, 5-dihydroxyl-4-isopropylphenyl) -3-phenylacrylic acid; the solvent B is acetic anhydride; the alkali B is sodium acetate, potassium carbonate or triethylamine;
(4) Preparation of (E/Z) -3, 5-dihydroxy-4-isopropyl stilbene: decarboxylation of (E/Z) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid in solvent C in the presence of catalyst C and ligand C; after the reaction is finished, obtaining (E/Z) -3, 5-dihydroxy-4-isopropyl stilbene through post-treatment; the solvent C is polyethylene glycol-200 or polyethylene glycol-400; the catalyst C is cuprous iodide; the ligand C is 1, 10-phenanthroline or 2,2' -bipyridine;
(5) Preparation of (E) -3, 5-dihydroxy-4-isopropyl stilbene: in a solvent D, in the presence of a catalyst D, (E/Z) -3, 5-dihydroxy-4-isopropyl stilbene undergoes isomerization reaction; after the reaction is finished, the (E) -3, 5-dihydroxyl-4-isopropyl stilbene is obtained through post-treatment.
6. The method for synthesizing (E) -3, 5-dihydroxy-4-isopropyl stilbene according to claim 5, wherein:
in the step (1), the alkali is sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate or potassium carbonate, the external temperature of the hydrolysis reaction is 80-150 ℃, and the time of the hydrolysis reaction is 2-5 h; the acid A is sulfuric acid, hydrochloric acid or nitric acid, the decarboxylation reaction temperature is 30-100 ℃, and the decarboxylation reaction time is 1-4 hours; the mol ratio of the 3, 5-dihydroxyl-2, 4-diethyl carbonyl phenylacetic acid ethyl ester, the alkali A and the acid A is 1 (4-7) (2-8); the post-treatment is to extract and wash the reaction liquid with dichloromethane, then extract the reaction liquid with ethyl acetate, collect an ethyl acetate layer, dry and concentrate the ethyl acetate layer to obtain 3, 5-dihydroxyphenylacetic acid;
in the step (2), the acid B is sulfuric acid, phosphoric acid, hydrochloric acid, nitric acid, p-toluenesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, phosphotungstic acid, phosphomolybdic acid, cation exchange resin Dowex50 WX4 or Dowex50WX8; the temperature of the isopropylation reaction is 50-100 ℃ and the reaction time is 4-10 h; the mol ratio of 3, 5-dihydroxyphenylacetic acid, isopropanol and acid B is 1 (1.0-1.5) (5-15); the post-treatment is to pour the reaction solution into ice water, stir vigorously, have a large amount of sticky matter to produce, pour out the excessive acid liquor of upper strata, and add ethyl acetate to extract into acid liquor, the aqueous layer obtained is regarded as the acid pickle, reclaim it and get excessive acid B; the obtained organic layer is used for dissolving the sticky matters, concentrating, adding sodium hydroxide solution for dissolving, adding hydrochloric acid for acidification until the pH value is=2-3, generating a little of scorched black matters, carrying out suction filtration, extracting and washing the obtained filtrate with dichloromethane, extracting with ethyl acetate, collecting an ethyl acetate layer, drying and concentrating to obtain 3, 5-dihydroxyl-4-isopropylphenylacetic acid;
In the step (3), the temperature of the condensation reaction is 100-140 ℃ and the reaction time is 2-8 h; the mol ratio of the 3, 5-dihydroxyl-4-isopropylphenylacetic acid, benzaldehyde, alkali B and the solvent B is 1 (1.0-1.2) (2-4) (4-6);
in the step (4), the decarboxylation reaction temperature is 160-210 ℃ and the reaction time is 4-10 h; the mol ratio of (E/Z) -2- (3, 5-dihydroxyl-4-isopropylphenyl) -3-phenylacrylic acid, catalyst C, ligand C and solvent C is 1 (0.05-0.2): 5-15); the post-treatment is to cool the reaction liquid to room temperature, suction-filter, wash the filter cake with a small amount of ethyl acetate to obtain fine needle-like crystals, which are the compound of the catalyst C and the ligand C and can be recovered and reused; diluting the obtained filtrate with ice water, adding ethyl acetate for extraction, collecting an organic phase, drying and concentrating to obtain (E/Z) -3, 5-dihydroxyl-4-isopropyl stilbene;
in the step (5), the solvent D is dichloromethane, chloroform, 1, 2-dichloroethane, acetonitrile, tetrahydrofuran or 1, 4-dioxane; the catalyst D is elemental iodine or aluminum triiodide; the isomerization reaction temperature is 40-110 ℃ and the reaction time is 4-10 h; the mol ratio of the (E/Z) -3, 5-dihydroxyl-4-isopropyl stilbene and the catalyst D is 1 (0.1-1.0); the post-treatment is to cool the reaction liquid to room temperature, add saturated sodium sulfite solution for quenching, extract with ethyl acetate, collect organic phase, dry, concentrate, and separate and purify by recrystallization or column chromatography to obtain (E) -3, 5-dihydroxy-4-isopropyl stilbene.
7. A method for synthesizing (E) -3, 5-dihydroxyl-4-isopropyl stilbene, which is characterized by comprising the following steps:
(1) Preparation of 3, 5-dihydroxyphenylacetic acid: in the alkali A, 3, 5-dihydroxyl-2, 4-diethyl oxo-phenylacetic acid ethyl ester is subjected to hydrolysis reaction; adding acid A to perform decarboxylation reaction; after the reaction is finished, obtaining 3, 5-dihydroxyphenylacetic acid through post-treatment;
(2) Preparation of 3, 5-dihydroxy-4-isopropylphenylacetic acid: in the excessive acid B, the 3, 5-dihydroxyphenylacetic acid and isopropanol undergo isopropylation reaction; after the reaction is finished, 3, 5-dihydroxyl-4-isopropylphenylacetic acid is obtained through post-treatment;
(3) Preparation of (E/Z) -2- (3, 5-diacetoxy-4-isopropylphenyl) -3-phenylacrylic acid: in a solvent B, 3, 5-dihydroxyl-4-isopropylphenylacetic acid and benzaldehyde are subjected to condensation reaction in the presence of a base B; after the reaction is finished, performing post-treatment to obtain (E/Z) -2- (3, 5-diacetoxy-4-isopropylphenyl) -3-phenylacrylic acid; the post-treatment is to pour the reaction solution into ice water, stir vigorously, have a large amount of sticky matter to form, pour out supernatant, wash the sticky matter to neutrality with a large amount of water, collect the sticky matter, dry, get (E/Z) -2- (3, 5-diacetoxy-4-isopropylphenyl) -3-phenylacrylic acid; the solvent B is acetic anhydride; the alkali B is sodium acetate, potassium carbonate or triethylamine;
(4) Preparation of (E/Z) -3, 5-dihydroxy-4-isopropyl stilbene: in a solvent C, in the presence of a catalyst C and a ligand C, decarboxylation and hydrolysis reactions are carried out on (E/Z) -2- (3, 5-diacetoxy-4-isopropylphenyl) -3-phenylacrylic acid; after the reaction is finished, obtaining (E/Z) -3, 5-dihydroxy-4-isopropyl stilbene through post-treatment; the solvent C is polyethylene glycol-200 or polyethylene glycol-400; the catalyst C is cuprous iodide; the ligand C is 1, 10-phenanthroline or 2,2' -bipyridine;
(5) Preparation of (E) -3, 5-dihydroxy-4-isopropyl stilbene: in a solvent D, in the presence of a catalyst D, (E/Z) -3, 5-dihydroxy-4-isopropyl stilbene undergoes isomerization reaction; after the reaction is finished, the (E) -3, 5-dihydroxyl-4-isopropyl stilbene is obtained through post-treatment.
8. The method for synthesizing (E) -3, 5-dihydroxy-4-isopropyl stilbene according to claim 7, wherein:
in the step (1), the alkali is sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate or potassium carbonate, the external temperature of the hydrolysis reaction is 80-150 ℃, and the time of the hydrolysis reaction is 2-5 h; the acid A is sulfuric acid, hydrochloric acid or nitric acid, the decarboxylation reaction temperature is 30-100 ℃, and the decarboxylation reaction time is 1-4 hours; the mol ratio of the 3, 5-dihydroxyl-2, 4-diethyl carbonyl phenylacetic acid ethyl ester, the alkali A and the acid A is 1 (4-7) (2-8); the post-treatment is to extract and wash the reaction liquid with dichloromethane, then extract the reaction liquid with ethyl acetate, collect an ethyl acetate layer, dry and concentrate the ethyl acetate layer to obtain 3, 5-dihydroxyphenylacetic acid;
In the step (2), the acid B is sulfuric acid, phosphoric acid, hydrochloric acid, nitric acid, p-toluenesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, phosphotungstic acid, phosphomolybdic acid, cation exchange resin Dowex50 WX4 or Dowex50WX8; the temperature of the isopropylation reaction is 50-100 ℃ and the reaction time is 4-10 h; the mol ratio of 3, 5-dihydroxyphenylacetic acid, isopropanol and acid B is 1 (1.0-1.5) (5-15); the post-treatment is to pour the reaction solution into ice water, stir vigorously, have a large amount of sticky matter to produce, pour out the excessive acid liquor of upper strata, and add ethyl acetate to extract into acid liquor, the aqueous layer obtained is regarded as the acid pickle, reclaim it and get excessive acid B; the obtained organic layer is used for dissolving the sticky matters, concentrating, adding sodium hydroxide solution for dissolving, adding hydrochloric acid for acidification until the pH value is=2-3, generating a little of scorched black matters, carrying out suction filtration, extracting and washing the obtained filtrate with dichloromethane, extracting with ethyl acetate, collecting an ethyl acetate layer, drying and concentrating to obtain 3, 5-dihydroxyl-4-isopropylphenylacetic acid;
in the step (3), the temperature of the condensation reaction is 100-140 ℃ and the reaction time is 2-8 h; the mol ratio of the 3, 5-dihydroxyl-4-isopropylphenylacetic acid, benzaldehyde, alkali B and the solvent B is 1 (1.0-1.2) (2-4) (4-6);
In the step (4), the decarboxylation reaction temperature is 160-210 ℃ and the reaction time is 4-10 h; (E/Z) -2- ( The mol ratio of the 3, 5-diacetoxy-4-isopropylphenyl) -3-phenylacrylic acid, the catalyst C, the ligand C and the solvent C is 1 (0.05-0.2), 0.05-0.2 and 5-15; the post-treatment is to cool the reaction liquid to room temperature, suction-filter, wash the filter cake with a small amount of ethyl acetate to obtain fine needle-like crystals, which are the compound of the catalyst C and the ligand C and can be recovered and reused; diluting the obtained filtrate with ice water, adding ethyl acetate for extraction, collecting an organic phase, drying and concentrating to obtain (E/Z) -3, 5-dihydroxyl-4-isopropyl stilbene;
in the step (5), the solvent D is dichloromethane, chloroform, 1, 2-dichloroethane, acetonitrile, tetrahydrofuran or 1, 4-dioxane; the catalyst D is elemental iodine or aluminum triiodide; the isomerization reaction temperature is 40-110 ℃ and the reaction time is 4-10 h; the mol ratio of the (E/Z) -3, 5-dihydroxyl-4-isopropyl stilbene and the catalyst D is 1 (0.1-1.0); the post-treatment is to cool the reaction liquid to room temperature, add saturated sodium sulfite solution for quenching, extract with ethyl acetate, collect organic phase, dry, concentrate, and separate and purify by recrystallization or column chromatography to obtain (E) -3, 5-dihydroxy-4-isopropyl stilbene.
9. The method for synthesizing (E) -3, 5-dihydroxy-4-isopropyl stilbene according to claim 2, 4, 6, 8, wherein: in the step (2), when the acid B is sulfuric acid, hydrochloric acid or nitric acid, the recovered acid B can be used as the acid A in the step (1); in the step (4), when the complex of the catalyst C and the ligand C is a complex of cuprous iodide and 1, 10-phenanthroline, the complex is recovered and reused for the decarboxylation reaction of the step (4).
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