CN112250546A - Synthesis method of (E) -3, 5-dihydroxy-4-isopropyl stilbene - Google Patents

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

Info

Publication number
CN112250546A
CN112250546A CN202011093791.9A CN202011093791A CN112250546A CN 112250546 A CN112250546 A CN 112250546A CN 202011093791 A CN202011093791 A CN 202011093791A CN 112250546 A CN112250546 A CN 112250546A
Authority
CN
China
Prior art keywords
acid
dihydroxy
reaction
ethyl acetate
isopropylphenyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN202011093791.9A
Other languages
Chinese (zh)
Other versions
CN112250546B (en
Inventor
邹永
魏书贤
张骞中
蒋毅
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
National Sun Yat Sen University
Original Assignee
National Sun Yat Sen University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by National Sun Yat Sen University filed Critical National Sun Yat Sen University
Priority to CN202011093791.9A priority Critical patent/CN112250546B/en
Publication of CN112250546A publication Critical patent/CN112250546A/en
Application granted granted Critical
Publication of CN112250546B publication Critical patent/CN112250546B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
    • C07C51/377—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups
    • C07C51/38—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups by decarboxylation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
    • C07C37/01—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis
    • C07C37/055—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis the substituted group being bound to oxygen, e.g. ether group
    • C07C37/0555—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis the substituted group being bound to oxygen, e.g. ether group being esterified hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
    • C07C37/50—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by reactions decreasing the number of carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
    • C07C51/353—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by isomerisation; by change of size of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/09—Geometrical isomers
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/584—Recycling of catalysts

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

The invention discloses a method for synthesizing (E) -3, 5-dihydroxy-4-isopropyl stilbene, which takes 3, 5-dihydroxy-2, 4-diethoxy carbonyl ethyl phenylacetate which is a raw material from biomass as an initiator to synthesize the (E) -3, 5-dihydroxy-4-isopropyl stilbene through the reaction steps of hydrolysis decarboxylation, isopropylation, condensation, decarboxylation, isomerization and the like. The invention can adopt biomass derived raw materials as the starting materials, has simple and convenient operation and simple steps, does not need the protection and deprotection of functional groups and has good atom economy; the intermediate can be put into the next reaction without complex separation and purification, and 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 green and environment-friendly.

Description

Synthesis method of (E) -3, 5-dihydroxy-4-isopropyl stilbene
Technical Field
The invention belongs to the field of drug synthesis, and particularly 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 Benvitimod (Benvitimod), belongs to stilbene compounds, was first discovered and reported in 1981 as a natural product present in Xenorhabdus spp (Xenorhabdus spp.) and was subsequently developed and marketed as a psoriasis treatment drug (J.chem.Ecol.,1981,7(3), 589-. The vismod is the first innovative generation of non-hormone micromolecule compound for treating inflammatory and autoimmune diseases in the world, and is the first therapeutic aromatic hydrocarbon receptor modulator (TAMA) in the world.
The external cream taking the danimod as the active ingredient is mainly used for locally treating adult psoriasis vulgaris with light to medium stability, is successfully marketed in mainland China, and is a first-in-class medicine. The foreign product is Tapinarof (DMVT-505) from Dermavant Sciences, Inc., and phase III clinical trials have been successfully completed and are planned to submit New Drug Applications (NDA) to the U.S. Food and Drug Administration (FDA) in 2021 for use as topical creams in the treatment of mild, moderate and severe plaque psoriasis in adults. (E) The structural formula of the (E) -3, 5-dihydroxy-4-isopropyl stilbene is shown as a formula-1:
Figure BDA0002722996210000011
in recent years, (E) -3, 5-dihydroxy-4-isopropylstilbene (formula-1) reported in domestic and foreign literature can be synthesized by Wittig-Horner reaction (U.S. Pat. No. 4,7868047, CN1319959, CN101434517, CN1688535, CN101648851, CN105884581, CN104003848, CN103172497, CN101838173, CN101830764, CN101531571, adv.Mat. Res.,2011,236,2378-. The Wittig-Horner reaction route has certain advantages by comprehensively considering all factors such as yield and the like; however, the route still involves the protection and deprotection processes, and more reagents with high toxicity, high risk, strong corrosivity and great harm to the environment are used, such as a high-toxicity reagent dimethyl sulfate is used in the methylation reaction step; flammable potassium borohydride and lithium aluminum hydride are used in the reduction step; thionyl chloride with strong corrosiveness is used in the chlorination reaction step; in the demethylation step, two solvents such as pyridine, toluene and the like which have great harm to the environment are used. In addition, the Wittig-Horner reaction step generates phosphorus-containing waste liquid; the substituted benzyl alcohol is oxidized by pyridinium chlorochromate (PCC) or Pyridinium Dichlorochromate (PDC) to generate the substituted benzaldehyde, and the chromium-containing waste liquid is generated. Meanwhile, the reaction operation has high danger, toxic gases such as borane, sulfur dioxide, hydrogen chloride and the like are generated in the reaction process, the harm to the environment and human bodies is large, and the industrial implementation is not facilitated.
Disclosure of Invention
The invention aims to overcome the defects in the prior art and provide a method for synthesizing (E) -3, 5-dihydroxy-4-isopropyl stilbene, which takes biomass derived raw materials as starting materials, has the advantages of cheap and easily obtained raw materials, simple and convenient operation, simple steps, no need of functional group protection and deprotection, good atom economy, capability of recycling waste acid and catalyst compounds generated in the reaction, low cost, less emission and environmental protection.
The purpose of the invention is realized by the following technical scheme:
a synthesis method of (E) -3, 5-dihydroxy-4-isopropyl stilbene comprises using 3, 5-dihydroxy-2, 4-diethoxycarbonyl phenylacetic acid ethyl ester (formula-2) as starting material, performing hydrolysis and decarboxylation reaction to obtain 3, 5-dihydroxy phenylacetic acid (formula-3), performing isopropylation reaction to obtain 3, 5-dihydroxy-4-isopropyl phenylacetic acid (formula-4), performing condensation reaction with benzaldehyde to obtain (E/Z) -2- (3, 5-dioxy substituent-4-isopropyl phenyl) -3-phenyl acrylic acid (formula-5), performing decarboxylation reaction to obtain (E/Z) -3, 5-dihydroxy-4-isopropyl stilbene (formula-6), finally (E) -3, 5-dihydroxy-4-isopropyl stilbene (formula-1) is obtained through isomerization reaction.
The general technical route involved in the invention is as follows:
Figure BDA0002722996210000031
preferably, the method for synthesizing (E) -3, 5-dihydroxy-4-isopropyl stilbene comprises the following steps:
(1) preparation of 3, 5-dihydroxyphenylacetic acid (formula-3): in the alkali A, 3, 5-dihydroxy-2, 4-diethoxycarbonyl ethyl phenylacetate (formula-2) undergoes hydrolysis reaction; adding acid A for decarboxylation reaction; after the reaction is finished, obtaining 3, 5-dihydroxy phenylacetic acid (formula-3) through post treatment;
(2) preparation of 3, 5-dihydroxy-4-isopropylphenylacetic acid (formula-4): in the excess of acid B, 3, 5-dihydroxyphenylacetic acid (formula-3) is isopropylated with isopropanol; after the reaction is finished, carrying out post-treatment to obtain 3, 5-dihydroxy-4-isopropylphenylacetic acid (formula-4);
(3) preparation of (E/Z) -2- (3, 5-dioxy substituent-4-isopropylphenyl) -3-phenylacrylic acid (formula-5): in a solvent B, in the presence of a base B, carrying out condensation reaction on 3, 5-dihydroxy-4-isopropylphenylacetic acid (formula-4) and benzaldehyde; after the reaction is finished, carrying out post-treatment to obtain (E/Z) -2- (3, 5-dioxy substituent-4-isopropyl phenyl) -3-phenyl acrylic acid (formula-5); the oxygen-containing substituent groups can be hydroxyl or acetoxy respectively;
(4) preparation of (E/Z) -3, 5-dihydroxy-4-isopropylstilbene (formula-6): in a solvent C, in the presence of a catalyst C and a ligand C, decarboxylation reaction is carried out on (E/Z) -2- (3, 5-dioxy substituent-4-isopropyl phenyl) -3-phenyl acrylic acid (formula-5); after the reaction is finished, (E/Z) -3, 5-dihydroxy-4-isopropyl stilbene (formula-6) is obtained by post-treatment;
(5) preparation of (E) -3, 5-dihydroxy-4-isopropylstilbene (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 an isomerization reaction; after the reaction is finished, (E) -3, 5-dihydroxy-4-isopropyl stilbene (formula-1) is obtained by post-treatment.
Based on the above general technical route, a plurality of specific synthetic routes for (E) -3, 5-dihydroxy-4-isopropylstilbene (formula-1) can be formed. Wherein, the specific route I can be represented as follows:
Figure BDA0002722996210000041
the specific scheme I comprises the following steps:
(1) preparation of 3, 5-dihydroxyphenylacetic acid (formula-3): in the alkali A, 3, 5-dihydroxy-2, 4-diethoxycarbonyl ethyl phenylacetate (formula-2) undergoes hydrolysis reaction; adding acid A for decarboxylation reaction; after the reaction is finished, obtaining 3, 5-dihydroxy phenylacetic acid (formula-3) through post treatment;
(2) preparation of 3, 5-dihydroxy-4-isopropylphenylacetic acid (formula-4): in the excess of acid B, 3, 5-dihydroxyphenylacetic acid (formula-3) is isopropylated with isopropanol; after the reaction is finished, carrying out post-treatment to obtain 3, 5-dihydroxy-4-isopropylphenylacetic acid (formula-4);
(3) preparation of (E) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid (formula-5E): in a solvent B, in the presence of a base B, carrying out condensation reaction on 3, 5-dihydroxy-4-isopropylphenylacetic acid (formula-4) and benzaldehyde; after the reaction is finished, obtaining (E) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid (formula-5E) through post treatment;
(4) preparation of (Z) -3, 5-dihydroxy-4-isopropylstilbene (formula-6Z): in a solvent C, in the presence of a catalyst C and a ligand C, decarboxylation reaction is carried out on (E) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid (formula-5E); after the reaction is finished, obtaining (Z) -3, 5-dihydroxy-4-isopropyl stilbene (formula-6Z) through post treatment;
(5) preparation of (E) -3, 5-dihydroxy-4-isopropylstilbene (formula-1): in a solvent D, in the presence of a catalyst D, carrying out an isomerization reaction on (Z) -3, 5-dihydroxy-4-isopropyl stilbene (formula-6Z); after the reaction is finished, (E) -3, 5-dihydroxy-4-isopropyl stilbene (formula-1) is obtained by 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, and preferably the alkali A is sodium hydroxide; the external temperature of the hydrolysis reaction is 80-150 ℃, the preferable external temperature of the reaction is 90-130 ℃, and the more preferable external temperature of the reaction is 120 ℃; the hydrolysis reaction time is 2-5 h, and the preferable reaction time is 3 h; 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 preferable reaction temperature is 65 ℃; the decarboxylation reaction time is 1-4 h, and the preferable reaction time is 1 h; the molar ratio of the ethyl 3, 5-dihydroxy-2, 4-diethoxycarbonyl-phenylacetate to the base A to the acid A is 1 (4-7) to (2-8), preferably 1:5: 3.
In the step (1), the post-treatment is to extract and wash the reaction solution by dichloromethane, extract the reaction solution by ethyl acetate, collect an ethyl acetate layer, dry and concentrate the ethyl acetate layer to obtain the 3, 5-dihydroxy phenylacetic acid (formula-3).
In the 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 Dowex50 WX4 or Dowex50WX8, and 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, and the preferable reaction time is 6 h; the molar ratio of the 3, 5-dihydroxy phenylacetic acid to the isopropanol to the acid A is 1 (1.0-1.5) to 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 post-treatment is to pour the reaction liquid into ice water, stir vigorously, generate a large amount of sticky substances, pour out the excessive acid liquid on the upper layer, add ethyl acetate into the acid liquid for extraction, use the obtained water layer as waste acid liquid, recover the waste acid liquid to obtain excessive acid B, and 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); and dissolving the obtained organic layer in the dope, concentrating, adding a sodium hydroxide solution for dissolving, adding hydrochloric acid for acidification until the pH value is 2-3 and a little of scorch-like substances are generated, performing suction filtration, extracting and washing the obtained filtrate with dichloromethane, extracting with ethyl acetate, collecting an ethyl acetate layer, drying, and concentrating to obtain the 3, 5-dihydroxy-4-isopropylphenylacetic acid (formula-4).
In the step (3), the solvent B is acetic anhydride; the base B comprises but is not limited to sodium acetate, potassium carbonate or triethylamine, and 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, and the preferable reaction time is 4 h; the molar ratio of the 3, 5-dihydroxy-4-isopropylphenylacetic acid to the benzaldehyde to the base B to the solvent B is 1 (1.0-1.2) to (2-4) to (4-6), and the molar ratio of the 3, 5-dihydroxy-4-isopropylphenylacetic acid to the benzaldehyde to the base B to the solvent B is preferably 1:1.1:3: 6.
In the step (3), the post-treatment is to pour the reaction liquid into ice water, stir vigorously, and generate a large amount of sticky substances, namely (E/Z) -2- (3, 5-diacetoxy-4-isopropylphenyl) -phenyl acrylic acid; and (2) pouring out the supernatant, adding a sodium hydroxide solution into the viscous substance, 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, carrying out suction filtration and washing with water, collecting a filter cake, and drying to obtain the (E) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid (formula-5E).
In the 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, and preferably the solvent C is polyethylene glycol-400; the catalyst C includes but is not limited to copper powder, copper sulfate, copper acetate, copper oxide, cuprous bromide or cuprous iodide, and the catalyst C is preferably cuprous iodide; the ligand C comprises but is not limited to 1, 10-phenanthroline, 2' -bipyridine or 8-hydroxyquinoline, and the preferred ligand C is 1, 10-phenanthroline; the decarboxylation reaction temperature is 160-210 ℃, and the preferable reaction temperature is 190 ℃; the reaction time is 4-10 h, and the preferable reaction time is 6 h; (E) the molar ratio of (E) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid, the catalyst C, the ligand C and the solvent C is 1 (0.05-0.2) to (5-15), and the molar ratio of (E) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid, the catalyst C, the ligand C and the 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, pump-filter, wash the filter cake with a small amount of ethyl acetate to obtain a crystal which is a compound of the catalyst C and the ligand C and can be recycled 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-dihydroxy-4-isopropyl stilbene (formula-6Z).
In the step (5), the solvent D includes but is not limited to dichloromethane, chloroform, 1, 2-dichloroethane, acetonitrile, tetrahydrofuran or 1, 4-dioxane, and preferably the solvent D is acetonitrile; the catalyst D includes but is not limited to elementary iodine or aluminum triiodide, and preferably the catalyst D is elementary iodine; the temperature of the isomerization reaction is 40-110 ℃, the preferable reaction temperature is 90 ℃, the reaction time is 4-10 h, and the preferable reaction time is 6 h; the molar ratio of (Z) -3, 5-dihydroxy-4-isopropyl stilbene to catalyst D is 1 (0.1-1.0), preferably 1: 0.5.
In the step (5), the post-treatment is to cool the reaction solution to room temperature, add saturated sodium sulfite solution for quenching, extract with ethyl acetate, collect the organic phase, dry, concentrate, and separate and purify by recrystallization or column chromatography to obtain (E) -3, 5-dihydroxy-4-isopropyl stilbene (formula-1).
A specific synthetic route II for (E) -3, 5-dihydroxy-4-isopropylstilbene (formula-1) can also be formed based on the above general technical route, as follows:
Figure BDA0002722996210000071
the specific route II comprises the following steps:
(1) preparation of 3, 5-dihydroxyphenylacetic acid (formula-3): in the alkali A, 3, 5-dihydroxy-2, 4-diethoxycarbonyl ethyl phenylacetate (formula-2) undergoes hydrolysis reaction; adding acid A for decarboxylation reaction; after the reaction is finished, obtaining 3, 5-dihydroxy phenylacetic acid (formula-3) through post treatment;
(2) preparation of 3, 5-dihydroxy-4-isopropylphenylacetic acid (formula-4): in the excess of acid B, 3, 5-dihydroxyphenylacetic acid (formula-3) is isopropylated with isopropanol; after the reaction is finished, carrying out post-treatment to obtain 3, 5-dihydroxy-4-isopropylphenylacetic acid (formula-4);
(3) preparation of (Z) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid (formula-5Z): in a solvent B, 3, 5-dihydroxy-4-isopropylphenylacetic acid (formula-4) is subjected to a condensation reaction with benzaldehyde in the presence of a base B. After the reaction is finished, (Z) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid (formula-5Z) is obtained by post treatment.
(4) Preparation of (E) -3, 5-dihydroxy-4-isopropylstilbene (formula-1): in a solvent C, in the presence of a catalyst C and a ligand C, decarboxylation reaction is carried out on (Z) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid (formula-5Z); after the reaction is finished, (E) -3, 5-dihydroxy-4-isopropyl stilbene (formula-1) is obtained by post-treatment.
The reaction raw materials, reaction conditions and post-treatment method of the step (1) are the same as those of the step (1) of the scheme I.
The reaction raw materials, reaction conditions and post-treatment method of the step (2) are the same as those of the step (2) of the scheme I.
The reaction raw materials and reaction conditions of the step (3) are the same as those of the step (3) of the route I.
In the step (3), the post-treatment is to pour the reaction liquid into ice water, stir vigorously, and generate a large amount of sticky substances, namely (E/Z) -2- (3, 5-diacetoxy-4-isopropylphenyl) -3-phenyl acrylic acid; pouring out supernatant, adding a sodium hydroxide solution into the sticky matter, stirring and dissolving, extracting and washing with dichloromethane, acidifying with hydrochloric acid until the pH value is 4-5, separating out solids, and performing suction filtration to obtain a filter cake (E) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid (formula-5E) of the specific route I; and 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-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid (formula-5Z).
In the 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, and preferably the solvent C is polyethylene glycol-400; the catalyst C includes but is not limited to copper powder, copper sulfate, copper acetate, copper oxide, cuprous bromide or cuprous iodide, and the catalyst C is preferably cuprous iodide; the ligand C comprises but is not limited to 1, 10-phenanthroline, 2' -bipyridine or 8-hydroxyquinoline, and the preferred ligand C is 1, 10-phenanthroline; the decarboxylation reaction temperature is 160-210 ℃, and the preferable reaction temperature is 190 ℃; the reaction time is 4-10 h, and the preferable reaction time is 6 h; the molar ratio of the (Z) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid, the catalyst C, the ligand C and the solvent C is 1 (0.05-0.2) to (5-15), and the molar ratio of the (Z) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid, the catalyst C, the ligand C and the 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, pump-filter, wash the filter cake with a small amount of ethyl acetate to obtain a crystal which is a compound of the catalyst C and the ligand C and can be recycled and reused; diluting the obtained filtrate with ice water, adding ethyl acetate for extraction, collecting an organic phase, drying and concentrating to obtain (E) -3, 5-dihydroxy-4-isopropyl stilbene (formula-1).
A specific scheme III for (E) -3, 5-dihydroxy-4-isopropylstilbene (formula-1) can also be formed based on the above general technical scheme, as follows:
Figure BDA0002722996210000091
the specific route III comprises the following steps:
(1) preparation of 3, 5-dihydroxyphenylacetic acid (formula-3): in the alkali A, 3, 5-dihydroxy-2, 4-diethoxycarbonyl ethyl phenylacetate (formula-2) undergoes hydrolysis reaction; adding acid A for decarboxylation reaction; after the reaction is finished, obtaining 3, 5-dihydroxy phenylacetic acid (formula-3) through post treatment;
(2) preparation of 3, 5-dihydroxy-4-isopropylphenylacetic acid (formula-4): in the excess of acid B, 3, 5-dihydroxyphenylacetic acid (formula-3) is isopropylated with isopropanol; after the reaction is finished, carrying out post-treatment to obtain 3, 5-dihydroxy-4-isopropylphenylacetic acid (formula-4);
(3) preparation of (E/Z) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid (formula-5E/Z): in a solvent B, in the presence of a base B, carrying out condensation reaction on 3, 5-dihydroxy-4-isopropylphenylacetic acid (formula-4) and benzaldehyde; after the reaction is finished, (E/Z) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid (formula-5E/Z) is obtained by post treatment;
(4) preparation of (E/Z) -3, 5-dihydroxy-4-isopropylstilbene (formula-6Z/formula-1): in a solvent C, in the presence of a catalyst C and a ligand C, decarboxylation reaction is carried out on (E/Z) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid (formula-5E/Z); after the reaction is finished, (E/Z) -3, 5-dihydroxy-4-isopropyl stilbene (formula-6Z/formula-1) is obtained by post-treatment;
(5) preparation of (E) -3, 5-dihydroxy-4-isopropylstilbene (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 an isomerization reaction; after the reaction is finished, (E) -3, 5-dihydroxy-4-isopropyl stilbene (formula-1) is obtained by post-treatment.
The reaction raw materials, reaction conditions and post-treatment method of the step (1) are the same as those of the step (1) of the scheme I.
The reaction raw materials, reaction conditions and post-treatment method of the step (2) are the same as those of the step (2) of the scheme I.
The reaction raw materials and reaction conditions of the step (3) are the same as those of the step (3) of the route I.
In the step (3), the post-treatment is to pour the reaction liquid into ice water, stir vigorously, and generate a large amount of sticky substances, namely (E/Z) -2- (3, 5-diacetoxy-4-isopropylphenyl) -phenyl acrylic acid; and (2) pouring out a supernatant, adding a sodium hydroxide solution into the viscous substance, stirring and dissolving, extracting and washing with dichloromethane, acidifying with hydrochloric acid until the pH value is 1-2, extracting with ethyl acetate, collecting an organic phase, drying, and concentrating to obtain (E/Z) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid (formula-5E/Z). It should be noted that the ratio of formula-5E to formula-5Z varies with the variation or deviation of the reaction and separation conditions, and the molar ratio of formula-5E to formula-5Z in the product obtained from a single separation and purification batch may vary from 1:9 to 9: 1.
In the 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, and preferably the solvent C is polyethylene glycol-400; the catalyst C includes but is not limited to copper powder, copper sulfate, copper acetate, copper oxide, cuprous bromide or cuprous iodide, and the catalyst C is preferably cuprous iodide; the ligand C comprises but is not limited to 1, 10-phenanthroline, 2' -bipyridine or 8-hydroxyquinoline, and the preferred ligand C is 1, 10-phenanthroline; the decarboxylation reaction temperature is 160-210 ℃, and the preferable reaction temperature is 190 ℃; the reaction time is 4-10 h, and the preferable reaction time is 6 h; the molar ratio of (E/Z) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid, the catalyst C, the ligand C and the solvent C is 1 (0.05-0.2) to (5-15), and the molar ratio of (E/Z) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid, the catalyst C, the ligand C and the 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, pump-filter, wash the filter cake with a small amount of ethyl acetate to obtain fine needle-like crystals which are a compound of the catalyst C and the ligand C and can be recycled and reused; diluting the obtained filtrate with ice water, adding ethyl acetate for extraction, collecting organic phase, drying, and concentrating to obtain (E/Z) -3, 5-dihydroxy-4-isopropyl stilbene (formula-6Z/formula-1).
In the step (5), the solvent D includes but is not limited to dichloromethane, chloroform, 1, 2-dichloroethane, acetonitrile, tetrahydrofuran or 1, 4-dioxane, and preferably the solvent D is acetonitrile; the catalyst D includes but is not limited to elementary iodine or aluminum triiodide, and preferably the catalyst D is elementary iodine; the temperature of the isomerization reaction is 40-110 ℃, the preferred temperature is 90 ℃, the reaction time is 4-10 h, and the preferred time is 6 h; the molar ratio of (E/Z) -3, 5-dihydroxy-4-isopropyl stilbene to catalyst D is 1 (0.1-1.0), preferably 1: 0.5.
In the step (5), the post-treatment is to cool the reaction solution to room temperature, add saturated sodium sulfite solution for quenching, extract with ethyl acetate, collect the organic phase, dry, concentrate, and separate and purify by recrystallization or column chromatography to obtain (E) -3, 5-dihydroxy-4-isopropyl stilbene (formula-1).
A specific synthetic route IV for (E) -3, 5-dihydroxy-4-isopropylstilbene (formula-1) can also be formed based on the above general technical route, as follows:
Figure BDA0002722996210000111
the specific route IV comprises the following steps:
(1) preparation of 3, 5-dihydroxyphenylacetic acid (formula-3): in the alkali A, 3, 5-dihydroxy-2, 4-diethoxycarbonyl ethyl phenylacetate (formula-2) undergoes hydrolysis reaction; adding acid A for decarboxylation reaction; after the reaction is finished, obtaining 3, 5-dihydroxy phenylacetic acid (formula-3) through post treatment;
(2) preparation of 3, 5-dihydroxy-4-isopropylphenylacetic acid (formula-4): in the excess of acid B, 3, 5-dihydroxyphenylacetic acid (formula-3) is isopropylated with isopropanol; after the reaction is finished, carrying out post-treatment to obtain 3, 5-dihydroxy-4-isopropylphenylacetic acid (formula-4);
(3) preparation of (E/Z) -2- (3, 5-diacetoxy-4-isopropylphenyl) -3-phenylacrylic acid (formula-5 Ac): in a solvent B, in the presence of a base B, carrying out condensation reaction on 3, 5-dihydroxy-4-isopropylphenylacetic acid (formula-4) and benzaldehyde; after the reaction is finished, carrying out 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-isopropylstilbene (formula-6Z/formula-1): in a solvent C, in the presence of a catalyst C and a ligand C, (E/Z) -2- (3, 5-diacetoxy-4-isopropylphenyl) -3-phenylacrylic acid (formula-5 Ac) undergoes decarboxylation and hydrolysis reaction; after the reaction is finished, (E/Z) -3, 5-dihydroxy-4-isopropyl stilbene (formula-6Z/formula-1) is obtained by post-treatment;
(5) preparation of (E) -3, 5-dihydroxy-4-isopropylstilbene (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 an isomerization reaction; after the reaction is finished, (E) -3, 5-dihydroxy-4-isopropyl stilbene (formula-1) is obtained by post-treatment.
The reaction raw materials, reaction conditions and post-treatment method of the step (1) are the same as those of the step (1) of the scheme I.
The reaction raw materials, reaction conditions and post-treatment method of the step (2) are the same as those of the step (2) of the scheme I.
The reaction raw materials and reaction conditions of the step (3) are the same as those of the step (3) of the route I.
In the step (3), the post-treatment is to pour the reaction solution into ice water, stir vigorously to generate a large amount of dope, pour out supernatant, wash the dope to neutrality with a large amount of water, collect the dope, and dry to obtain (E/Z) -2- (3, 5-diacetoxy-4-isopropylphenyl) -phenylacrylic acid (formula-5 Ac).
In the 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, and preferably the solvent C is polyethylene glycol-400; the catalyst C includes but is not limited to copper powder, copper sulfate, copper acetate, copper oxide, cuprous bromide or cuprous iodide, and the catalyst C is preferably cuprous iodide; the ligand C comprises but is not limited to 1, 10-phenanthroline, 2' -bipyridine or 8-hydroxyquinoline, and the preferred ligand C is 1, 10-phenanthroline; the decarboxylation reaction temperature is 160-210 ℃, and the preferable reaction temperature is 190 ℃; the reaction time is 4-10 h, and the preferable reaction time is 6 h; the molar ratio of (E/Z) -2- (3, 5-diacetoxy-4-isopropylphenyl) -3-phenylacrylic acid, the catalyst C, the ligand C and the solvent C is 1 (0.05-0.2) to (5-15), and the molar ratio of (E/Z) -2- (3, 5-diacetoxy-4-isopropylphenyl) -3-phenylacrylic acid, the catalyst C, the ligand C and the 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, pump-filter, wash the filter cake with a small amount of ethyl acetate to obtain fine needle-like crystals which are a compound of the catalyst C and the ligand C and can be recycled and reused; diluting the obtained filtrate with ice water, adding ethyl acetate for extraction, collecting organic phase, drying, and concentrating to obtain (E/Z) -3, 5-dihydroxy-4-isopropyl stilbene (formula-6Z/formula-1).
In the step (5), the solvent D includes but is not limited to dichloromethane, chloroform, 1, 2-dichloroethane, acetonitrile, tetrahydrofuran or 1, 4-dioxane, and preferably the solvent D is acetonitrile; the catalyst D includes but is not limited to elementary iodine or aluminum triiodide, and preferably the catalyst D is elementary iodine; the temperature of the isomerization reaction is 40-110 ℃, the preferred temperature is 90 ℃, the reaction time is 4-10 h, and the preferred time is 6 h; the molar ratio of (E/Z) -3, 5-dihydroxy-4-isopropyl stilbene to catalyst D is 1 (0.1-1.0), preferably 1: 0.5.
In the step (5), the post-treatment is to cool the reaction solution to room temperature, add saturated sodium sulfite solution for quenching, extract with ethyl acetate, collect the organic phase, dry, concentrate, and separate and purify by recrystallization or column chromatography to obtain (E) -3, 5-dihydroxy-4-isopropyl stilbene (formula-1).
The invention proves that: the single compound 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 formula-5Z obtained in the synthesis process can be directly subjected to decarboxylation reaction to obtain the formula-1. ③ the mixture of the formula-5E and the formula-5Z obtained in the synthesis process can directly carry out the subsequent decarboxylation and isomerization reaction without separation, and finally the formula-1 is obtained. And fourthly, the formula-5 Ac obtained in the synthesis process can also be directly subjected to subsequent decarboxylation, hydrolysis and isomerization without post-treatment, and finally the formula-1 is obtained.
The 3, 5-dihydroxy-2, 4-diethoxycarbonyl ethyl phenylacetate (formula-2) adopted by the invention is derived from renewable biomass, and is obtained by taking 1, 3-acetone dicarboxylic acid diethyl ester as a raw material through condensation and aromatization reactions (the specific reaction process is shown in Justus Liebigs Ann. chem.,1950,570, 15-33; Helv. Chim. acta,1966,49,1283-1290 and CN 106748662B).
It is to be noted that the starting material ethyl 3, 5-dihydroxy-2, 4-diethoxycarbonylphenylacetate (formula-2) according to the invention can be replaced by methyl 3, 5-dihydroxy-2, 4-dimethoxycarbonylbenzeneacetate, which is also derived from renewable biomass and can achieve the same technical effect. Therefore, a technical route using methyl 3, 5-dihydroxy-2, 4-dimethoxycarbonylphenylacetate and the like as starting materials is also included in the present invention.
It is to be noted that, in the step (2), the production of 3, 5-dihydroxy-4-isopropylphenylacetic acid (formula-4) requires the discharge of an excess amount of acid B, which is recovered and utilized by the present invention when the acid B is sulfuric acid, hydrochloric acid or nitric acidCan be used as acid A for preparing 3, 5-dihydroxy phenylacetic acid (formula-3); in step (4), the resulting crystal, preferably a complex of cuprous iodide with 1, 10-phenanthroline ([ CuI (1,10-phen)]2) The present invention recovers and reuses 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, has simple and convenient operation and simple steps, does not need the protection and deprotection of functional groups, has good atom economy and green and environment-friendly operation process.
(2) The starting raw materials, the reagents 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 favorable for large-scale preparation.
(3) The excessive waste acid and the catalyst compound generated by the invention can be recycled, so that the cost of the process is reduced, the emission is reduced, and the environment is protected.
Drawings
FIG. 1 is a schematic representation of 3, 5-dihydroxyphenylacetic acid1HNMR spectra (400MHz, DMSO-d)6)；
FIG. 2 is a diagram of 3, 5-dihydroxy-4-isopropylphenylacetic acid1HNMR spectra (400MHz, DMSO-d)6)；
FIG. 3 is a schematic representation of (E) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid1HNMR spectra (400MHz, DMSO-d)6)；
FIG. 4 is a schematic representation of (Z) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid1HNMR spectra (400MHz, DMSO-d)6)；
FIG. 5 is a schematic representation of (E/Z) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid1HNMR spectra (400MHz, DMSO-d)6)；
FIG. 6 shows the preparation of (Z) -3, 5-dihydroxy-4-isopropylstilbene1HNMR spectra (400MHz, DMSO-d)6)；
FIG. 7 shows the preparation of (Z) -3, 5-dihydroxy-4-isopropylstilbene1HNMR spectra (125MHz, DMSO-d)6)；
FIG. 8 shows the preparation of (E/Z) -3, 5-dihydroxy-4-isopropylstilbene1HNMR spectra (400MHz, DMSO-d)6)；
FIG. 9 shows the preparation of (E) -3, 5-dihydroxy-4-isopropylstilbene1HNMR spectra (400MHz, DMSO-d)6)；
FIG. 10 shows the preparation of (E) -3, 5-dihydroxy-4-isopropylstilbene1HNMR spectra (100MHz, DMSO-d)6)。
Detailed Description
In order that the invention may be readily understood, reference will now be made in detail to the specific embodiments of the invention.
(E) -3, 5-dihydroxy-4-isopropylstilbene (formula-1) scheme I: (examples 1 to 25)
Example 1: preparation of 3, 5-dihydroxyphenylacetic acid
Adding 3, 5-dihydroxy-2, 4-diethoxycarbonyl phenylacetic acid ethyl ester (34.03g,100mmol) into a round-bottom flask, adding a 5mol/L NaOH solution (100mL,500mmol), stirring for dissolving, heating at 120 ℃, and stirring for 3 hours; and cooling the reaction liquid, adding 98% sulfuric acid (16mL,300mmol), stirring at 65 ℃ for 1h, wherein bubbles are continuously generated in the process, and the pH of the reaction liquid is about 2-3 after the dripping is finished. After the reaction, the reaction mixture was washed with dichloromethane (50 mL. times.2), extracted with ethyl acetate (100 mL. times.2), and the ethyl acetate layer was collected, dried, and concentrated to give a brown yellow solid, i.e., 14.97g of 3, 5-dihydroxybenzeneacetic acid, in 89% yield. The melting point is 70-72 ℃;1H NMR(400MHz,DMSO-d6) δ 12.22(s,1H),9.16(s,2H),6.10(d, J ═ 2.0Hz,2H),6.07(t, J ═ 2.0Hz,1H),3.38(s,2H) (as shown in fig. 1).
Example 2: preparation of 3, 5-dihydroxyphenylacetic acid
Adding 3, 5-dihydroxy-2, 4-diethoxycarbonyl phenylacetic acid ethyl ester (34.03g,100mmol) into a round-bottom flask, adding a 5mol/L NaOH solution (120mL,600mmol), stirring for dissolving, heating at 150 ℃, and stirring for 2 hours; and cooling the reaction liquid, adding 98% sulfuric acid (21mL,400mmol), stirring at 80 ℃ for 1h, wherein bubbles are continuously generated in the process, and the pH of the reaction liquid is about 2-3 after the dripping is finished. After the reaction, the reaction solution was washed with dichloromethane (50 mL. times.2), extracted with ethyl acetate (100 mL. times.2), and the ethyl acetate layer was collected, dried, and concentrated to give a brown yellow solid, i.e., 14.61g of 3, 5-dihydroxybenzeneacetic acid, in 87% yield.
Example 3: preparation of 3, 5-dihydroxyphenylacetic acid
Adding 3, 5-dihydroxy-2, 4-diethoxycarbonyl phenylacetic acid ethyl ester (34.03g,100mmol) into a round-bottom flask, adding a 5mol/L NaOH solution (120mL,600mmol), stirring for dissolving, heating at 120 ℃ and stirring for 3 hours; and cooling the reaction liquid, adding 37% hydrochloric acid (650mL,800mmol), stirring at 30 ℃ for 4 hours, wherein bubbles are continuously generated in the process, and the pH of the reaction liquid is about 2-3 after the dripping is finished. After the reaction, the reaction mixture was washed with dichloromethane (50 mL. times.2), extracted with ethyl acetate (100 mL. times.2), and the ethyl acetate layer was collected, dried, and concentrated to give a tan solid, i.e., 12.94g of 3, 5-dihydroxybenzeneacetic acid, in 77% yield.
Example 4: preparation of 3, 5-dihydroxyphenylacetic acid
Adding 3, 5-dihydroxy-2, 4-diethoxycarbonyl phenylacetic acid ethyl ester (34.03g,100mmol) into a round-bottom flask, adding a 5mol/L NaOH solution (100mL,500mmol), stirring for dissolving, heating at 120 ℃, and stirring for 3 hours; cooling the reaction solution, adding the acid solution (70mL,300mmol) recovered in the example 6-10, stirring at 65 ℃ for 2h, wherein bubbles are continuously generated in the process, and the pH of the reaction solution is about 2-3 after the dripping is finished. After the reaction, the reaction solution was extracted and 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 a brown yellow solid, i.e., 15.46g of 3, 5-dihydroxybenzeneacetic acid, in 92% yield.
Example 5: preparation of 3, 5-dihydroxyphenylacetic acid
Adding 3, 5-dihydroxy-2, 4-diethoxycarbonyl phenylacetic acid ethyl ester (170.16g,0.5mol) into a round-bottom flask, adding a 5mol/L NaOH solution (500mL,2.5mol), stirring for dissolving, heating at 120 ℃ and stirring for 3 hours; cooling the reaction solution, adding the acid solution (350mL,1.5mol) recovered in the example 6-10, stirring at 65 ℃ for 4h, wherein bubbles are continuously generated in the process, and the pH of the reaction solution is about 2-3 after dropping. After the reaction, the reaction solution was extracted and 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 brown yellow solid, i.e., 74.03g of 3, 5-dihydroxybenzeneacetic acid, with a yield of 88%.
Example 6: preparation of 3, 5-dihydroxy-4-isopropylphenylacetic acid
Roasting to round bottom3, 5-Dihydroxyphenylacetic acid (6.73g,40mmol) and 90% sulfuric acid (25mL,400mmol) were added to the flask, and dissolved with stirring, and isopropyl alcohol (3.7mL,48mmol) was added thereto, followed by stirring at 80 ℃ for 6 hours. After the reaction is finished, pouring the reaction solution into ice water, stirring vigorously to generate a large amount of sticky substances, pouring out excessive acid liquor on the upper layer, adding ethyl acetate into the acid liquor for extraction, and taking the obtained water layer as waste acid liquor to recycle the waste acid liquor for the step (1); and dissolving the obtained organic layer in the dope, concentrating, adding a sodium hydroxide solution for dissolving, adding hydrochloric acid for acidifying until the pH is 2-3 and a little scorched substance is generated, performing suction filtration, washing the obtained filtrate with dichloromethane, extracting with ethyl acetate, collecting an ethyl acetate layer, drying, and concentrating to obtain a tawny dope, namely 6.81g of 3, 5-dihydroxy-4-isopropylphenylacetic acid, with the yield of 81%. The melting point is 115-117 ℃;1H NMR(400MHz,DMSO-d6) δ 12.14(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 ═ 6.8Hz,6H) (as shown in fig. 2).
Example 7: preparation of 3, 5-dihydroxy-4-isopropylphenylacetic acid
To a round-bottomed flask was added 3, 5-dihydroxybenzeneacetic acid (6.73g,40mmol), 90% sulfuric acid (37mL,600mmol), dissolved with stirring, added isopropanol (3.7mL,48mmol), and stirred at 60 ℃ for 8 h. After the reaction is finished, pouring the reaction solution into ice water, stirring vigorously to generate a large amount of sticky substances, pouring out excessive acid liquor on the upper layer, adding ethyl acetate into the acid liquor for extraction, and taking the obtained water layer as waste acid liquor to recycle the waste acid liquor for the step (1); and dissolving the obtained organic layer in the dope, concentrating, adding a sodium hydroxide solution for dissolving, adding hydrochloric acid for acidifying until the pH is 2-3 and a little scorched substance is generated, performing suction filtration, washing the obtained filtrate with dichloromethane, extracting with ethyl acetate, collecting an ethyl acetate layer, drying, and concentrating to obtain a tawny dope, namely 6.14g of 3, 5-dihydroxy-4-isopropylphenylacetic acid, with the yield of 73%.
Example 8: preparation of 3, 5-dihydroxy-4-isopropylphenylacetic acid
A round-bottomed flask was charged with 3, 5-dihydroxybenzeneacetic acid (6.73g,40mmol) and 90% sulfuric acid (25mL,400mmol), dissolved with stirring, added with isopropanol (4.2mL,60mmol), and stirred at 100 ℃ for 4 h. After the reaction is finished, pouring the reaction solution into ice water, stirring vigorously to generate a large amount of sticky substances, pouring out excessive acid liquor on the upper layer, adding ethyl acetate into the acid liquor for extraction, and taking the obtained water layer as waste acid liquor to recycle the waste acid liquor for the step (1); and dissolving the obtained organic layer in the dope, concentrating, adding a sodium hydroxide solution for dissolving, adding hydrochloric acid for acidifying until the pH is 2-3 and a little scorched substance is generated, performing suction filtration, washing the obtained filtrate with dichloromethane, extracting with ethyl acetate, collecting an ethyl acetate layer, drying, and concentrating to obtain a tawny dope, namely 6.31g of 3, 5-dihydroxy-4-isopropylphenylacetic acid, with the yield of 75%.
Example 9: preparation of 3, 5-dihydroxy-4-isopropylphenylacetic acid
To a round-bottomed flask was added 3, 5-dihydroxybenzeneacetic acid (6.73g,40mmol) and 90% sulfuric acid (25mL,400mmol), dissolved with stirring, added isopropanol (3.7mL,48mmol), and stirred at 60 ℃ for 6 h. After the reaction is finished, pouring the reaction solution into ice water, stirring vigorously to generate a large amount of sticky substances, pouring out excessive acid liquor on the upper layer, adding ethyl acetate into the acid liquor for extraction, and taking the obtained water layer as waste acid liquor to recycle the waste acid liquor for the step (1); and dissolving the obtained organic layer in the dope, concentrating, adding a sodium hydroxide solution for dissolving, adding hydrochloric acid for acidifying until the pH is 2-3 and a little scorched substance is generated, performing suction filtration, washing the obtained filtrate with dichloromethane, extracting with ethyl acetate, collecting an ethyl acetate layer, drying, and concentrating to obtain a tawny dope, namely 5.97g of 3, 5-dihydroxy-4-isopropylphenylacetic acid, wherein the yield is 71%.
Example 10: preparation of 3, 5-dihydroxy-4-isopropylphenylacetic acid
A round-bottomed flask was charged with 3, 5-dihydroxybenzeneacetic acid (6.73g,40mmol) and 90% sulfuric acid (25mL,400mmol), dissolved with stirring, added with isopropanol (3.7mL,48mmol), and stirred at 80 ℃ for 10 hours. After the reaction is finished, pouring the reaction solution into ice water, stirring vigorously to generate a large amount of sticky substances, pouring out excessive acid liquor on the upper layer, adding ethyl acetate into the acid liquor for extraction, and taking the obtained water layer as waste acid liquor to recycle the waste acid liquor for the step (1); and dissolving the obtained organic layer in the dope, concentrating, adding a sodium hydroxide solution for dissolving, adding hydrochloric acid for acidifying until the pH is 2-3 and a little scorched substance is generated, performing suction filtration, washing the obtained filtrate with dichloromethane, extracting with ethyl acetate, collecting an ethyl acetate layer, drying, and concentrating to obtain a tawny dope, namely 6.39g of 3, 5-dihydroxy-4-isopropylphenylacetic acid, wherein the yield is 76%.
Example 11: (E) preparation of (E) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid
Adding 3, 5-dihydroxy-4-isopropylphenylacetic acid (5.47g,26mmol) and benzaldehyde (2.97g,28mmol) into a round-bottom flask, adding acetic anhydride (15.93g,156mmol), and stirring to dissolve; triethylamine (7.89g,78mmol) was added slowly and stirred at 110 ℃ for 4 h. After the reaction is finished, pouring the reaction liquid into ice water, and violently stirring to generate a sticky substance; and (2) pouring out a supernatant, adding a sodium hydroxide solution into the viscous substance, 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, performing suction filtration and water washing, collecting a filter cake, and drying to obtain a light brown yellow solid, namely (E) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid 5.90g, wherein the yield is 76%. The melting point is 124-126 ℃;1H NMR(400MHz,DMSO-d6) δ 12.56(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 ═ 7.2Hz,6H) (as shown in fig. 3).
Example 12: (E) preparation of (E) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid
Adding 3, 5-dihydroxy-4-isopropylphenylacetic acid (5.47g,26mmol) and benzaldehyde (2.97g,28mmol) into a round-bottom flask, adding acetic anhydride (10.62g,104mmol), and stirring for dissolving; triethylamine (5.26g,52mmol) was added slowly and stirred at 110 ℃ for 6 h. After the reaction is finished, pouring the reaction liquid into ice water, and violently stirring to generate a sticky substance; and (2) pouring out a supernatant, adding a sodium hydroxide solution into the viscous substance, 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, performing suction filtration and water washing, collecting a filter cake, and drying to obtain a light brown yellow solid, namely (E) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid 5.51g, wherein the yield is 71%.
Example 13: (E) preparation of (E) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid
Adding 3, 5-dihydroxy-4-isopropylphenylacetic acid (5.47g,26mmol) and benzaldehyde (2.97g,28mmol) into a round-bottom flask, adding acetic anhydride (15.93g,156mmol), and stirring to dissolve; sodium acetate (6.40g,78mmol) was added slowly and stirred at 110 ℃ for 4 h. After the reaction is finished, pouring the reaction liquid into ice water, and violently stirring to generate a sticky substance; and (2) pouring out a supernatant, adding a sodium hydroxide solution into the viscous substance, 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, performing suction filtration and water washing, collecting a filter cake, and drying to obtain a light brown yellow solid, namely (E) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid 5.66g, wherein the yield is 73%.
Example 14: (E) preparation of (E) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid
Adding 3, 5-dihydroxy-4-isopropylphenylacetic acid (5.47g,26mmol) and benzaldehyde (2.97g,28mmol) into a round-bottom flask, adding acetic anhydride (15.93g,156mmol), and stirring to dissolve; potassium acetate (7.65g,78mmol) was added slowly and the mixture was stirred at 110 ℃ for 4 h. After the reaction is finished, pouring the reaction liquid into ice water, and violently stirring to generate a sticky substance; and (2) pouring out a supernatant, adding a sodium hydroxide solution into the viscous substance, 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, performing suction filtration and water washing, collecting a filter cake, and drying to obtain a light brown yellow solid, namely (E) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid 5.82g, wherein the yield is 75%.
Example 15: (E) preparation of (E) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid
Adding 3, 5-dihydroxy-4-isopropylphenylacetic acid (5.47g,26mmol) and benzaldehyde (2.97g,28mmol) into a round-bottom flask, adding acetic anhydride (15.93g,156mmol), and stirring to dissolve; triethylamine (7.89g,78mmol) was added slowly and stirred at 140 ℃ for 4 h. After the reaction is finished, pouring the reaction liquid into ice water, and violently stirring to generate a sticky substance; and (2) pouring out a supernatant, adding a sodium hydroxide solution into the viscous substance, 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, performing suction filtration and water washing, collecting a filter cake, and drying to obtain a light brown yellow solid, namely (E) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid 5.43g, wherein the yield is 70%.
Example 16: (E) preparation of (E) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid
Adding 3, 5-dihydroxy-4-isopropylphenylacetic acid (5.47g,26mmol) and benzaldehyde (2.97g,28mmol) into a round-bottom flask, adding acetic anhydride (15.93g,156mmol), and stirring to dissolve; triethylamine (7.89g,78mmol) was added slowly and stirred at 110 ℃ for 8 h. After the reaction is finished, pouring the reaction liquid into ice water, and violently stirring to generate a sticky substance; and (2) pouring out a supernatant, adding a sodium hydroxide solution into the viscous substance, 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, performing suction filtration and water washing, collecting a filter cake, and drying to obtain a light brown yellow solid, namely (E) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid 5.59g, wherein the yield is 72%.
Example 17: preparation of (Z) -3, 5-dihydroxy-4-isopropyl stilbene
To a round-bottomed flask were added (E) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid (5.97g,20mmol), cuprous iodide (0.38g,2mmol), 1, 10-phenanthroline (0.36g,2mmol) and polyethylene glycol-400 (50mL,140mmol), and the mixture was stirred at 190 ℃ for 6 h. After the reaction is finished, filtering, washing a filter cake by a small amount of ethyl acetate to obtain a brick-red fine needle-shaped crystal, namely a compound of cuprous iodide and 1, 10-phenanthroline ([ CuI (1, 10-phen))]2)0.61g, yield 83%, which was recovered and reused. Ice water (100mL) was added to the filtrate to dilute it, and the mixture was extracted with ethyl acetate (50 mL. times.3), and the organic layer was collected, dried and concentrated to give a tan paste, that is, 4.47g of (Z) -3, 5-dihydroxy-4-isopropylstilbene, in 88% yield. The melting point is 112-114 ℃;1H NMR(400MHz,DMSO-d6) δ 8.86(s,2H),7.31-7.23(m,4H),7.21-7.16(m,1H),6.44(d, J ═ 12.4Hz,1H),6.37(d, J ═ 12.4Hz,1H),6.19(s,2H),3.40(dq, J ═ 14.0,7.2Hz,1H),1.21(d, J ═ 7.2Hz,6H) (as shown in fig. 6);13C NMR(125MHz,DMSO-d6) δ 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-bottomed flask were added (E) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid (5.97g,20mmol), cuprous iodide (0.19g,1mmol), 1, 10-phenanthroline (0.18g,1mmol), and polyethylene glycol-400 (50mL,140mmol), and the mixture was stirred at 190 ℃ for 10 h. After the reaction is finished, filtering, washing a filter cake by a small amount of ethyl acetate to obtain a brick-red fine needle-shaped crystal, 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 (100mL) was added to the filtrate to dilute it, and the mixture was extracted with ethyl acetate (50 mL. times.3), and the organic layer was collected, dried and concentrated to give a tan paste, that is, 3.55g of (Z) -3, 5-dihydroxy-4-isopropylstilbene, in a yield of 70%.
Example 19: preparation of (Z) -3, 5-dihydroxy-4-isopropyl stilbene
To a round-bottomed flask were added (E) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid (5.97g,20mmol), cuprous iodide (0.76g,4mmol), 1, 10-phenanthroline (0.72g,4mmol) and polyethylene glycol-200 (55mL,300mmol), and the mixture was stirred at 190 ℃ for 6 h. After the reaction is finished, filtering, washing a filter cake by a small amount of ethyl acetate to obtain a brick-red fine needle-shaped crystal, namely a compound of cuprous iodide and 1, 10-phenanthroline ([ CuI (1, 10-phen))]2)1.26g, 85% yield, which was recovered and reused. Ice water (100mL) was added to the filtrate for dilution, followed by extraction with ethyl acetate (50 mL. times.3), and the organic layer was collected, dried, and concentrated to give a tan paste, i.e., (Z) -3, 5-dihydroxy-4-isopropylstilbene, 4.16g, in 82% yield.
Example 20: preparation of (Z) -3, 5-dihydroxy-4-isopropyl stilbene
To a round-bottom flask were added (E) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid (5.97g,20mmol), cuprous iodide (0.38g,2mmol), 2' -bipyridine (0.31g,2mmol) and polyethylene glycol-400 (50mL,140mmol), and the mixture was stirred at 190 ℃ for 6 h. After the reaction, filtration was performed, and ice water (100mL) was added to the obtained filtrate to dilute the solution, followed by extraction with ethyl acetate (50 mL. times.3), followed by collection of the organic layer, drying and concentration to obtain a tan paste, that is, (Z) -3, 5-dihydroxy-4-isopropylstilbene, 3.82g, with a yield of 75%.
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 (5.97g,20mmol), and the resulting [ CuI (1,10-phen) recovered]2(0.74g,1mmol) and polyethylene glycol-400 (50mL,140mmol), and stirred at 190 ℃ for 6 h. After the reaction, filtration was performed, and ice water (100mL) was added to the filtrate to dilute the solution, followed by extraction with ethyl acetate (50 mL. times.3), followed by collection of the organic layer, drying and concentration to obtain a tan paste, i.e., (Z) -3, 5-dihydroxy-4-isopropylstilbene (4.26 g), with a yield of 84%.
Example 22: (E) preparation of (E) -3, 5-dihydroxy-4-isopropylstilbene
(Z) -3, 5-dihydroxy-4-isopropylstilbene (2.54g,10mmol) and acetonitrile (20mL) were added to a round-bottomed flask, dissolved with stirring, and elemental iodine (1.27g,5mmol) was added thereto, and the mixture was stirred at 90 ℃ for 6 hours. After the reaction, saturated sodium sulfite solution (15mL) was added to quench, ethyl acetate extraction (50 mL. times.2) was performed, the organic layer was collected, dried, concentrated, and separated and purified by column chromatography (petroleum ether-ethyl acetate) to obtain 2.08g of white solid, i.e., (E) -3, 5-dihydroxy-4-isopropylstilbene, with a yield of 82%. The melting point is 142-144 ℃;1H NMR(400MHz,DMSO-d6) δ 9.05(s,2H),7.57(d, J ═ 7.6Hz,2H),7.36(t, J ═ 7.6Hz,2H),7.25(t, J ═ 7.2Hz,1H),7.01(d, J ═ 16.0Hz,1H),6.88(d, J ═ 16.4Hz,1H),6.48(s,2H),3.44(dt,13.6,6.8Hz,1H),1.25(d, J ═ 6.8Hz,6H) (as shown in fig. 9);13C NMR(101MHz,DMSO-d6) δ 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-isopropylstilbene
(Z) -3, 5-dihydroxy-4-isopropylstilbene (2.54g,10mmol) and acetonitrile (20mL) were added to a round-bottomed flask, dissolved with stirring, and elemental iodine (0.63g,2.5mmol) was added thereto, and the mixture was stirred at 90 ℃ for 10 hours. After the reaction, saturated sodium sulfite solution (10mL) was added to quench, ethyl acetate extraction (50 mL. times.2) was performed, the organic layer was collected, dried, concentrated, and separated and purified by column chromatography (petroleum ether-ethyl acetate) to obtain a white solid, i.e., (E) -3, 5-dihydroxy-4-isopropylstilbene, 1.81g, with a yield of 72%.
Example 24: (E) preparation of (E) -3, 5-dihydroxy-4-isopropylstilbene
(Z) -3, 5-dihydroxy-4-isopropylstilbene (2.54g,10mmol) and 1, 2-dichloroethane (20mL) were added to a round-bottomed flask, dissolved with stirring, and elemental iodine (2.54g,10mmol) was added thereto, and the mixture was stirred at 90 ℃ for 6 hours. After the reaction, saturated sodium sulfite solution (25mL) was added to quench, ethyl acetate extraction (50 mL. times.2) was performed, the organic layer was collected, dried, and separated and purified by column chromatography (petroleum ether-ethyl acetate) to obtain a white solid, i.e., (E) -3, 5-dihydroxy-4-isopropylstilbene, 1.78g, with a yield of 70%.
Example 25: (E) preparation of (E) -3, 5-dihydroxy-4-isopropylstilbene
(Z) -3, 5-dihydroxy-4-isopropylstilbene (2.54g,10mmol) and acetonitrile (20mL) were added to a round-bottomed flask, dissolved with stirring, and elemental iodine (1.27g,5mmol) was added thereto, and the mixture was stirred at 90 ℃ for 6 hours. After the reaction was completed, saturated sodium sulfite solution (15mL) was added to quench, ethyl acetate extraction (50 mL. times.2) was performed, the organic layer was collected, dried, concentrated, and recrystallized from petroleum ether-chloroform to obtain a pale yellow solid, i.e., (E) -3, 5-dihydroxy-4-isopropylstilbene, 1.83g, with a yield of 72%.
(E) Specific scheme II for 3, 5-dihydroxy-4-isopropylstilbene (formula-1): (examples 1 to 10 and 26 to 36)
Preparation of 3, 5-dihydroxyphenylacetic acid: the same as in examples 1 to 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
Adding 3, 5-dihydroxy-4-isopropylphenylacetic acid (5.47g,26mmol) and benzaldehyde (2.97g,28mmol) into a round-bottom flask, adding acetic anhydride (15.93g,156mmol), and stirring to dissolve; triethylamine (7.89g,78mmol) was added slowly and stirred at 110 ℃ for 4 h. After the reaction is finished, pouring the reaction liquid into ice water, and violently stirring to generate a sticky substance; pouring out supernatant, adding sodium hydroxide into the viscous substanceStirring and dissolving the solution, washing with dichloromethane, acidifying with 10% hydrochloric acid until the pH value is 4-5, separating out a solid, and performing suction filtration to obtain a filter cake (E) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid (formula-5E) of the specific route I; the filtrate was acidified with 10% hydrochloric acid to pH 1 to 2, extracted with ethyl acetate (50mL × 2), and the organic layer was collected, dried, and concentrated to obtain a dark brown-yellow solid, i.e., (Z) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid (1.47 g), with a yield of 19.0%. The melting point is 120-122 ℃;1H NMR(400MHz,DMSO-d6) δ 12.47(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 ═ 2.0Hz,1H),5.82(d, J ═ 2.0Hz,1H),2.71(dt, J ═ 13.6,6.8Hz,1H),1.18(d, J ═ 6.8Hz,3H),1.01(d, J ═ 6.8Hz,3H) (as shown in fig. 4).
Example 27: preparation of (Z) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid
Adding 3, 5-dihydroxy-4-isopropylphenylacetic acid (5.47g,26mmol) and benzaldehyde (2.97g,28mmol) into a round-bottom flask, adding acetic anhydride (10.62g,104mmol), and stirring for dissolving; triethylamine (5.26g,52mmol) was added slowly and stirred at 110 ℃ for 6 h. After the reaction is finished, pouring the reaction liquid into ice water, and violently stirring to generate a sticky substance; pouring out supernatant, adding a sodium hydroxide solution into the sticky matter, stirring and dissolving, extracting and washing with dichloromethane, acidifying with 10% hydrochloric acid until the pH value is 4-5, separating out solids, and performing suction filtration to obtain a filter cake (E) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid (formula-5E) of the specific route I; the obtained filtrate was acidified with 10% hydrochloric acid to pH 1 to 2, extracted with ethyl acetate (50mL × 2), and the organic layer was collected, dried, and concentrated to obtain a dark brown-yellow solid, i.e., (Z) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid (1.38 g), with a yield of 17.8%.
Example 28: preparation of (Z) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid
Adding 3, 5-dihydroxy-4-isopropylphenylacetic acid (5.47g,26mmol) and benzaldehyde (2.97g,28mmol) into a round-bottom flask, adding acetic anhydride (15.93g,156mmol), and stirring to dissolve; sodium acetate (6.40g,78mmol) was added slowly and stirred at 110 ℃ for 4 h. After the reaction is finished, pouring the reaction liquid into ice water, and violently stirring to generate a sticky substance; pouring out supernatant, adding a sodium hydroxide solution into the sticky matter, stirring and dissolving, extracting and washing with dichloromethane, acidifying with 10% hydrochloric acid until the pH value is 4-5, separating out solids, and performing suction filtration to obtain a filter cake (E) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid (formula-5E) of the specific route I; the obtained filtrate was acidified with 10% hydrochloric acid to pH 1 to 2, extracted with ethyl acetate (50mL × 2), and the organic layer was collected, dried, and concentrated to obtain a brown yellow solid, i.e., 1.42g of (Z) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid, with a yield of 18.3%.
Example 29: preparation of (Z) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid
Adding 3, 5-dihydroxy-4-isopropylphenylacetic acid (5.47g,26mmol) and benzaldehyde (2.97g,28mmol) into a round-bottom flask, adding acetic anhydride (15.93g,156mmol), and stirring to dissolve; potassium acetate (7.65g,78mmol) was added slowly and the mixture was stirred at 110 ℃ for 4 h. After the reaction is finished, pouring the reaction liquid into ice water, and violently stirring to generate a sticky substance; pouring out supernatant, adding a sodium hydroxide solution into the sticky matter, stirring and dissolving, extracting and washing with dichloromethane, acidifying with 10% hydrochloric acid until the pH value is 4-5, separating out solids, and performing suction filtration to obtain a filter cake (E) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid (formula-5E) of the specific route I; the obtained filtrate was acidified with 10% hydrochloric acid to pH 1 to 2, extracted with ethyl acetate (50mL × 2), and the organic layer was collected, dried, and concentrated to obtain a brown yellow solid, that is, 1.46g of (Z) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid, with a yield of 18.8%.
Example 30: preparation of (Z) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid
Adding 3, 5-dihydroxy-4-isopropylphenylacetic acid (5.47g,26mmol) and benzaldehyde (2.97g,28mmol) into a round-bottom flask, adding acetic anhydride (15.93g,156mmol), and stirring to dissolve; triethylamine (7.89g,78mmol) was added slowly and stirred at 140 ℃ for 4 h. After the reaction is finished, pouring the reaction liquid into ice water, and violently stirring to generate a sticky substance; pouring out supernatant, adding a sodium hydroxide solution into the sticky matter, stirring and dissolving, extracting and washing with dichloromethane, acidifying with 10% hydrochloric acid until the pH value is 4-5, separating out solids, and performing suction filtration to obtain a filter cake (E) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid (formula-5E) of the specific route I; the obtained filtrate was acidified with 10% hydrochloric acid to pH 1 to 2, extracted with ethyl acetate (50mL × 2), and the organic layer was collected, dried, and concentrated to obtain a brown yellow solid, that is, 1.36g of (Z) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid, with a yield of 17.5%.
Example 31: preparation of (Z) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid
Adding 3, 5-dihydroxy-4-isopropylphenylacetic acid (5.47g,26mmol) and benzaldehyde (2.97g,28mmol) into a round-bottom flask, adding acetic anhydride (15.93g,156mmol), and stirring to dissolve; triethylamine (7.89g,78mmol) was added slowly and stirred at 110 ℃ for 8 h. After the reaction is finished, pouring the reaction liquid into ice water, and violently stirring to generate a sticky substance; pouring out supernatant, adding a sodium hydroxide solution into the sticky matter, stirring and dissolving, extracting and washing with dichloromethane, acidifying with 10% hydrochloric acid until the pH value is 4-5, separating out solids, and performing suction filtration to obtain a filter cake (E) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid (formula-5E) of the specific route I; the obtained filtrate was acidified with 10% hydrochloric acid to pH 1 to 2, extracted with ethyl acetate (50mL × 2), and the organic layer was collected, dried, and concentrated to obtain a brown yellow solid, that is, 1.40g of (Z) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid, with a yield of 18.0%.
Example 32: (E) preparation of (E) -3, 5-dihydroxy-4-isopropylstilbene
To a round-bottom flask were added (Z) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid (1.49g,5mmol), cuprous iodide (95mg,0.5mmol), 1, 10-phenanthroline (90mg,0.5mmol), and polyethylene glycol-400 (12mL,35mmol), and the mixture was stirred at 190 ℃ for 6 h. After the reaction is finished, filtering, washing a filter cake by a small amount of ethyl acetate to obtain a brick-red fine needle-shaped crystal, namely a compound of cuprous iodide and 1, 10-phenanthroline ([ CuI (1, 10-phen))]2)0.15g, yield 81%, was recovered and reused. Diluting the filtrate with ice water (50mL), extracting with ethyl acetate (30 mL. times.3), collecting the organic layer, drying, and concentrating to obtain a brown yellow solid (E) -3,51.13g of (E) -dihydroxy-4-isopropylstilbene was obtained, the yield was 89%.
Example 33: (E) preparation of (E) -3, 5-dihydroxy-4-isopropylstilbene
To a round-bottom flask were added (Z) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid (1.49g,5mmol), cuprous iodide (95mg,0.5mmol), 1, 10-phenanthroline (90mg,0.5mmol), and polyethylene glycol-400 (12mL,35mmol), and the mixture was stirred at 190 ℃ for 10 h. After the reaction is finished, filtering, washing a filter cake by a small amount of ethyl acetate to obtain a brick-red fine needle-shaped crystal, namely a compound of cuprous iodide and 1, 10-phenanthroline ([ CuI (1, 10-phen))]2)0.13g, yield 72%, which was recovered and reused. Ice water (50mL) was added to the filtrate for dilution, ethyl acetate extraction (30 mL. times.3) was performed, and the organic layer was collected, dried and concentrated to obtain a tan solid, i.e., (E) -3, 5-dihydroxy-4-isopropylstilbene, 0.90g, with a yield of 71%.
Example 34: (E) preparation of (E) -3, 5-dihydroxy-4-isopropylstilbene
To a round-bottomed flask were added (Z) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid (1.49g,5mmol), cuprous iodide (0.19g,1mmol), 1, 10-phenanthroline (0.18g,1mmol), and polyethylene glycol-200 (13mL,75mmol), and the mixture was stirred at 190 ℃ for 6 h. After the reaction is finished, filtering, washing a filter cake by a small amount of ethyl acetate to obtain a brick-red fine needle-shaped crystal, namely a compound of cuprous iodide and 1, 10-phenanthroline ([ CuI (1, 10-phen))]2)0.31g, yield 83%, which was recovered and reused. Ice water (50mL) was added to the filtrate for dilution, and ethyl acetate extraction (30 mL. times.3) was performed to collect the organic layer, which was dried and concentrated to obtain a brown yellow solid, i.e., (E) -3, 5-dihydroxy-4-isopropylstilbene, 2.14g, yield 84%.
Example 35: (E) preparation of (E) -3, 5-dihydroxy-4-isopropylstilbene
To a round-bottom flask were added (Z) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid (1.49g,5mmol), cuprous iodide (95mg,0.5mmol), 2' -bipyridine (78mg,0.5mmol), and polyethylene glycol-400 (12mL,35mmol), and the mixture was stirred at 190 ℃ for 6 h. After the reaction, filtration was carried out, and ice water (100mL) was added to the obtained filtrate to dilute the solution, followed by extraction with ethyl acetate (50 mL. times.3), followed by collection of the organic layer, drying and concentration to obtain a tan solid, i.e., (E) -3, 5-dihydroxy-4-isopropylstilbene, in an amount of 0.99g, in a yield of 78%.
Example 36: (E) preparation of (E) -3, 5-dihydroxy-4-isopropylstilbene
To a round bottom flask was added (Z) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid (1.49g,5mmol) and the resulting [ CuI (1,10-phen) recovered]2(185mg,0.25mmol) and polyethylene glycol-400 (12mL,35mmol) were stirred at 190 ℃ for 6 h. After the reaction, filtration was performed, ice water (50mL) was added to the filtrate to dilute the solution, ethyl acetate was used for extraction (30 mL. times.3), and the organic layer was collected, dried and concentrated to obtain a tan solid, i.e., (E) -3, 5-dihydroxy-4-isopropylstilbene, in an amount of 1.08g, with a yield of 85%.
(E) Specific scheme III for the synthesis of 3, 5-dihydroxy-4-isopropylstilbene (formula-1): (examples 1 to 10 and 37 to 51)
Preparation of 3, 5-dihydroxyphenylacetic acid: the same as in examples 1 to 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
Adding 3, 5-dihydroxy-4-isopropylphenylacetic acid (5.47g,26mmol) and benzaldehyde (2.97g,28mmol) into a round-bottom flask, adding acetic anhydride (15.93g,156mmol), and stirring to dissolve; triethylamine (7.89g,78mmol) was added slowly and stirred at 110 ℃ for 4 h. After the reaction is finished, pouring the reaction liquid into ice water, and violently stirring to generate a sticky substance; the supernatant was decanted, and sodium hydroxide solution was added to the dope to dissolve it, followed by extraction with dichloromethane, acidification with 10% hydrochloric acid until pH 1-2, extraction with ethyl acetate (100mL × 2), collection of the organic phase, drying, and concentration to obtain a dark brown-yellow dope, i.e., (E/Z) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid (7.37 g), with a yield of 95%.1H NMR (400MHz, DMSO-d6) 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 ═ 7.2Hz, 6H); formula-5Z δ 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 ═ 2.4Hz,1H),5.82(d, J ═ 2.4 Hz)1H),2.71(dt, J ═ 14.0,7.2Hz,1H),18(d, J ═ 7.2Hz,3H),1.01(d, J ═ 7.2Hz,3H) (see fig. 5, which is a partial product of this experiment1H NMR spectrum).
Example 38: preparation of (E/Z) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid
Adding 3, 5-dihydroxy-4-isopropylphenylacetic acid (5.47g,26mmol) and benzaldehyde (2.97g,28mmol) into a round-bottom flask, adding acetic anhydride (10.62g,104mmol), and stirring for dissolving; triethylamine (5.26g,52mmol) was added slowly and stirred at 110 ℃ for 6 h. After the reaction is finished, pouring the reaction liquid into ice water, and violently stirring to generate a sticky substance; the supernatant was decanted, and sodium hydroxide solution was added to the dope to dissolve it, followed by extraction with dichloromethane, acidification with 10% hydrochloric acid until pH 1-2, extraction with ethyl acetate (100mL × 2), collection of the organic phase, drying, and concentration to obtain a dark brown-yellow dope, i.e., (E/Z) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid (6.90 g), with a yield of 89%.
Example 39: preparation of (E/Z) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid
Adding 3, 5-dihydroxy-4-isopropylphenylacetic acid (5.47g,26mmol) and benzaldehyde (2.97g,28mmol) into a round-bottom flask, adding acetic anhydride (15.93g,156mmol), and stirring to dissolve; sodium acetate (6.40g,78mmol) was added slowly and stirred at 110 ℃ for 4 h. After the reaction is finished, pouring the reaction liquid into ice water, and violently stirring to generate a sticky substance; and (3) pouring out a supernatant, adding a sodium hydroxide solution into the viscous substance to dissolve, extracting and washing with dichloromethane, acidifying with 10% hydrochloric acid until the pH value is 1-2, extracting with ethyl acetate (100mL multiplied by 2), collecting an organic phase, drying and concentrating to obtain a dark brown yellow viscous substance, namely (E/Z) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid 7.08g, wherein the yield is 91%.
Example 40: preparation of (E/Z) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid
Adding 3, 5-dihydroxy-4-isopropylphenylacetic acid (5.47g,26mmol) and benzaldehyde (2.97g,28mmol) into a round-bottom flask, adding acetic anhydride (15.93g,156mmol), and stirring to dissolve; potassium acetate (7.65g,78mmol) was added slowly and the mixture was stirred at 110 ℃ for 4 h. After the reaction is finished, pouring the reaction liquid into ice water, and violently stirring to generate a sticky substance; the supernatant was decanted, and sodium hydroxide solution was added to the dope to dissolve it, followed by extraction with dichloromethane, acidification with 10% hydrochloric acid until pH 1-2, extraction with ethyl acetate (100mL × 2), collection of the organic phase, drying, and concentration to obtain a dark brown-yellow dope, i.e., (E/Z) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid (7.28 g), with a yield of 94%.
Example 41: preparation of (E/Z) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid
Adding 3, 5-dihydroxy-4-isopropylphenylacetic acid (5.47g,26mmol) and benzaldehyde (2.97g,28mmol) into a round-bottom flask, adding acetic anhydride (15.93g,156mmol), and stirring to dissolve; triethylamine (7.89g,78mmol) was added slowly and stirred at 140 ℃ for 4 h. After the reaction is finished, pouring the reaction liquid into ice water, and violently stirring to generate a sticky substance; the supernatant was decanted, and sodium hydroxide solution was added to the dope to dissolve it, followed by extraction with dichloromethane, acidification with 10% hydrochloric acid until pH 1-2, extraction with ethyl acetate (100mL × 2), collection of the organic phase, drying, and concentration to obtain a dark brown-yellow dope, i.e., (E/Z) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid (6.82 g), with a yield of 88%.
Example 42: preparation of (E/Z) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid
Adding 3, 5-dihydroxy-4-isopropylphenylacetic acid (5.47g,26mmol) and benzaldehyde (2.97g,28mmol) into a round-bottom flask, adding acetic anhydride (15.93g,156mmol), and stirring to dissolve; triethylamine (7.89g,78mmol) was added slowly and stirred at 110 ℃ for 8 h. After the reaction is finished, pouring the reaction liquid into ice water, and violently stirring to generate a sticky substance; and (3) pouring out a supernatant, adding a sodium hydroxide solution into the viscous substance to dissolve, extracting and washing with dichloromethane, acidifying with 10% hydrochloric acid until the pH value is 1-2, extracting with ethyl acetate (100mL multiplied by 2), collecting an organic phase, drying and concentrating to obtain a dark brown yellow viscous substance, namely (E/Z) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid 6.98g, wherein the yield is 90%.
Example 43: preparation of (E/Z) -3, 5-dihydroxy-4-isopropyl stilbene
(E/Z) -2- (3,5-Dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid (5.97g,20mmol), cuprous iodide (0.38g,2mmol), 1, 10-phenanthroline (0.36g,2mmol) and polyethylene glycol-400 (50mL,140mmol) were stirred at 190 ℃ for 6 h. After the reaction is finished, filtering, washing a filter cake by a small amount of ethyl acetate to obtain a brick-red fine needle-shaped crystal, namely a compound of cuprous iodide and 1, 10-phenanthroline ([ CuI (1, 10-phen))]2)0.61g, yield 82%, which is recovered and reused. Ice water (100mL) was added to the filtrate to dilute it, and the mixture was 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-isopropylstilbene, 4.57g, with a yield of 90%.1H NMR(400MHz,DMSO-d6) formula-6Z δ 8.87(s,2H),7.29-7.16(m,5H),6.44(d, J ═ 12.4Hz,1H),6.37(d, J ═ 12.4Hz,1H),6.19(s,2H),3.40(dt, J ═ 14.4,7.2Hz,1H),1.21(d, J ═ 7.2Hz, 6H); formula-1:δ9.05(s,2H),7.56(d, J ═ 7.2Hz,2H),7.35(t, J ═ 7.6Hz,2H),7.25(t, J ═ 7.2Hz,1H),7.00(d, J ═ 16.4Hz,1H),6.87(d, J ═ 16.4Hz,1H),6.47(s,2H),3.44(dt,14.4,7.2Hz,1H),1.24(d, J ═ 7.2Hz,6H) (as shown in fig. 8, which is a partial product obtained in this experiment)1H NMR spectrum).
Example 44: preparation of (E/Z) -3, 5-dihydroxy-4-isopropyl stilbene
To a round-bottomed flask were added (E/Z) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid (5.97g,20mmol), cuprous iodide (0.19g,1mmol), 1, 10-phenanthroline (0.18g,1mmol), and polyethylene glycol-400 (50mL,140mmol), and the mixture was stirred at 190 ℃ for 10 h. After the reaction is finished, filtering, washing a filter cake by a small amount of ethyl acetate to obtain a brick-red fine needle-shaped crystal, namely a compound of cuprous iodide and 1, 10-phenanthroline ([ CuI (1, 10-phen))]2)0.26g, yield 70%, which was recovered and reused. Ice water (100mL) was added to the filtrate to dilute it, and the mixture was extracted with ethyl acetate (50 mL. times.3), and the organic layer was collected, dried and concentrated to give a tan paste, that is, (E/Z) -3, 5-dihydroxy-4-isopropylstilbene, 3.70g, in 73% yield.
Example 45: preparation of (E/Z) -3, 5-dihydroxy-4-isopropyl stilbene
Adding (E/Z) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid into a round-bottom flask(5.97g,20mmol), cuprous iodide (0.76g,4mmol), 1, 10-phenanthroline (0.72g,4mmol) and polyethylene glycol-200 (55mL,300mmol), and stirred at 190 deg.C for 6 h. After the reaction is finished, filtering, washing a filter cake by a small amount of ethyl acetate to obtain a brick-red fine needle-shaped crystal, namely a compound of cuprous iodide and 1, 10-phenanthroline ([ CuI (1, 10-phen))]2)1.26g, 85% yield, which was recovered and reused. Ice water (100mL) was added to the filtrate to dilute it, and the mixture was 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-isopropylstilbene, 4.27g, in 84% yield.
Example 46: preparation of (E/Z) -3, 5-dihydroxy-4-isopropyl stilbene
To a round bottom flask were added (E/Z) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid (5.97g,20mmol), cuprous iodide (0.38g,2mmol), 2' -bipyridine (0.31g,2mmol) and polyethylene glycol-400 (50mL,140mmol), and the mixture was stirred at 190 ℃ for 6 h. After the reaction, filtration was carried out, and ice water (100mL) was added to the obtained filtrate to dilute the solution, followed by extraction with ethyl acetate (50 mL. times.3), followed by collection of the organic layer, drying and concentration to obtain a tan paste, i.e., (E/Z) -3, 5-dihydroxy-4-isopropylstilbene (3.91 g), in 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 (5.97g,20mmol), and the resulting [ CuI (1,10-phen) recovered]2(0.74g,1mmol) and polyethylene glycol-400 (50mL,140mmol), and stirred at 190 ℃ for 6 h. After the reaction, filtration was carried out, and ice water (100mL) was added to the filtrate to dilute the solution, followed by extraction with ethyl acetate (50 mL. times.3), followed by collection of the organic layer, drying and concentration to obtain a tan paste (E/Z) -3, 5-dihydroxy-4-isopropylstilbene) (4.37 g, yield 86%).
Example 48: (E) preparation of (E) -3, 5-dihydroxy-4-isopropylstilbene
(E/Z) -3, 5-dihydroxy-4-isopropylstilbene (2.54g,10mmol) and acetonitrile (20mL) were added to a round-bottomed flask, dissolved with stirring, and elemental iodine (1.27g,5mmol) was added, and stirred at 90 ℃ for 6 h. After the reaction, saturated sodium sulfite solution (15mL) was added to quench, ethyl acetate extraction (50 mL. times.2) was performed, the organic layer was collected, dried, concentrated, and separated and purified by column chromatography (petroleum ether-ethyl acetate) to obtain 2.13g of white solid, i.e., (E) -3, 5-dihydroxy-4-isopropylstilbene, with a yield of 84%.
Example 49: (E) preparation of (E) -3, 5-dihydroxy-4-isopropylstilbene
(E/Z) -3, 5-dihydroxy-4-isopropylstilbene (2.54g,10mmol) and acetonitrile (20mL) were added to a round-bottomed flask, dissolved with stirring, and elemental iodine (0.63g,2.5mmol) was added, and stirred at 90 ℃ for 10 hours. After the reaction, saturated sodium sulfite solution (10mL) was added to quench, ethyl acetate extraction (50mL × 2) was performed, the organic layer was collected, dried, concentrated, and separated and purified by column chromatography (petroleum ether-ethyl acetate) to obtain a white solid, i.e., (E) -3, 5-dihydroxy-4-isopropylstilbene, 1.90g, with a yield of 75%.
Example 50: (E) preparation of (E) -3, 5-dihydroxy-4-isopropylstilbene
(E/Z) -3, 5-dihydroxy-4-isopropylstilbene (2.54g,10mmol) and 1, 2-dichloroethane (20mL) were added to a round-bottomed flask, and dissolved with stirring, and elemental iodine (2.54g,10mmol) was added thereto, followed by stirring at 90 ℃ for 6 hours. After the reaction, saturated sodium sulfite solution (25mL) was added to quench, ethyl acetate extraction (50 mL. times.2) was performed, the organic layer was collected, dried, concentrated, and separated and purified by column chromatography (petroleum ether-ethyl acetate) to obtain a white solid, i.e., (E) -3, 5-dihydroxy-4-isopropylstilbene, 1.83g, with a yield of 72%.
Example 51: (E) preparation of (E) -3, 5-dihydroxy-4-isopropylstilbene
(E/Z) -3, 5-dihydroxy-4-isopropylstilbene (2.54g,10mmol) and acetonitrile (20mL) were added to a round-bottomed flask, dissolved with stirring, and elemental iodine (1.27g,5mmol) was added, and stirred at 90 ℃ for 6 h. After the reaction was completed, saturated sodium sulfite solution (15mL) was added to quench, ethyl acetate extraction (50 mL. times.2) was performed, the organic layer was collected, dried, concentrated, and recrystallized from petroleum ether-chloroform to obtain a pale yellow solid, i.e., (E) -3, 5-dihydroxy-4-isopropylstilbene, 1.85g, in a yield of 73%.
(E) Specific scheme IV of 3, 5-dihydroxy-4-isopropylstilbene (formula-1): (examples 1 to 10, examples 52 to 62)
Preparation of 3, 5-dihydroxyphenylacetic acid: the same as in examples 1 to 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
Adding 3, 5-dihydroxy-4-isopropylphenylacetic acid (5.47g,26mmol) and benzaldehyde (2.97g,28mmol) into a round-bottom flask, adding acetic anhydride (15.93g,156mmol), and stirring to dissolve; triethylamine (7.89g,78mmol) was added slowly and stirred at 110 ℃ for 4 h. After the reaction is finished, pouring the reaction liquid into ice water, stirring vigorously, pouring out an upper-layer aqueous solution, repeating the operations until the aqueous solution is colorless and clear, and the viscous substance is solidified into brown yellow powder, performing suction filtration, washing with water, and drying to obtain brown yellow solid, namely (E/Z) -2- (3, 5-diacetoxy-4-isopropylphenyl) -3-phenylacrylic acid 9.34g, wherein the yield is 94%.1H NMR (400MHz, DMSO-d6) formula 5Ac-E δ 12.83(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 ═ 7.2Hz, 6H); δ 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
Adding 3, 5-dihydroxy-4-isopropylphenylacetic acid (5.47g,26mmol) and benzaldehyde (2.97g,28mmol) into a round-bottom flask, adding acetic anhydride (10.62g,104mmol), and stirring for dissolving; triethylamine (5.26g,52mmol) was added slowly and stirred at 110 ℃ for 6 h. After the reaction is finished, pouring the reaction liquid into ice water, stirring vigorously, pouring out an upper-layer aqueous solution, repeating the operations until the aqueous solution is colorless and clear, and the viscous substance is solidified into brown yellow powder, performing suction filtration, washing with water, and drying to obtain brown yellow solid, namely 8.75g of (E/Z) -2- (3, 5-diacetoxy-4-isopropylphenyl) -3-phenylacrylic acid, wherein the yield is 88%.
Example 54: preparation of (E/Z) -2- (3, 5-diacetoxy-4-isopropylphenyl) -3-phenylacrylic acid
Adding 3, 5-dihydroxy-4-isopropylphenylacetic acid (5.47g,26mmol) and benzaldehyde (2.97g,28mmol) into a round-bottom flask, adding acetic anhydride (15.93g,156mmol), and stirring to dissolve; sodium acetate (6.40g,78mmol) was added slowly and stirred at 110 ℃ for 4 h. After the reaction is finished, pouring the reaction liquid into ice water, stirring vigorously, pouring out an upper-layer aqueous solution, repeating the operations until the aqueous solution is colorless and clear, and the viscous substance is solidified into brown yellow powder, performing suction filtration, washing with water, and drying to obtain 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
Adding 3, 5-dihydroxy-4-isopropylphenylacetic acid (5.47g,26mmol) and benzaldehyde (2.97g,28mmol) into a round-bottom flask, adding acetic anhydride (15.93g,156mmol), and stirring to dissolve; potassium acetate (7.65g,78mmol) was added slowly and the mixture was stirred at 110 ℃ for 4 h. After the reaction, the reaction solution was poured into ice water, stirred vigorously, a large amount of dope was formed, the upper aqueous solution was poured out, the above operations were repeated until the aqueous solution was colorless and clear, and the dope solidified to give a tan powder, and a tan solid, i.e., (E/Z) -2- (3, 5-diacetoxy-4-isopropylphenyl) -3-phenylpropenoic acid (9.24 g) was obtained with a yield of 93%.
Example 56: preparation of (E/Z) -2- (3, 5-diacetoxy-4-isopropylphenyl) -3-phenylacrylic acid
Adding 3, 5-dihydroxy-4-isopropylphenylacetic acid (5.47g,26mmol) and benzaldehyde (2.97g,28mmol) into a round-bottom flask, adding acetic anhydride (15.93g,156mmol), and stirring to dissolve; triethylamine (7.89g,78mmol) was added slowly and stirred at 140 ℃ for 4 h. After the reaction is finished, pouring the reaction liquid into ice water, stirring vigorously, pouring out an upper-layer aqueous solution, repeating the operations until the aqueous solution is colorless and clear, and the viscous substance is solidified into brown yellow powder, performing suction filtration, washing with water, and drying to obtain 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
Adding 3, 5-dihydroxy-4-isopropylphenylacetic acid (5.47g,26mmol) and benzaldehyde (2.97g,28mmol) into a round-bottom flask, adding acetic anhydride (15.93g,156mmol), and stirring to dissolve; triethylamine (7.89g,78mmol) was added slowly and stirred at 110 ℃ for 8 h. After the reaction is finished, pouring the reaction liquid into ice water, stirring vigorously, pouring out an upper-layer aqueous solution, repeating the operations until the aqueous solution is colorless and clear, and the viscous substance is solidified into brown yellow powder, performing suction filtration, washing with water, and drying to obtain brown yellow solid, namely (E/Z) -2- (3, 5-diacetoxy-4-isopropylphenyl) -3-phenylacrylic acid 9.04g, wherein the yield is 91%.
Example 58: preparation of (E/Z) -3, 5-dihydroxy-4-isopropyl stilbene
To a round bottom flask were added (E/Z) -2- (3, 5-diacetoxy-4-isopropylphenyl) -3-phenylacrylic acid (7.65g,20mmol), cuprous iodide (0.38g,2mmol), 1, 10-phenanthroline (0.36g,2mmol), and polyethylene glycol-400 (50mL,140mmol, without anhydrous treatment), and stirred at 190 ℃ for 6 h. After the reaction is finished, filtering, washing a filter cake by a small amount of ethyl acetate to obtain a brick-red fine needle-shaped crystal, namely a compound of cuprous iodide and 1, 10-phenanthroline ([ CuI (1, 10-phen))]2)0.62g, yield 84%, which was recovered and reused. Ice water (100mL) was added to the filtrate to dilute it, and the mixture was 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-isopropylstilbene, 4.62g, with a yield of 91%.
Example 59: preparation of (E/Z) -3, 5-dihydroxy-4-isopropyl stilbene
To a round bottom flask were added (E/Z) -2- (3, 5-diacetoxy-4-isopropylphenyl) -3-phenylacrylic acid (7.65g,20mmol), cuprous iodide (0.19g,1mmol), 1, 10-phenanthroline (0.18g,1mmol), and polyethylene glycol-400 (50mL,140mmol, without anhydrous treatment), and stirred at 190 ℃ for 10 h. After the reaction is finished, filtering, washing the filter cake with a small amount of ethyl acetate to obtain brick red fine needle-shaped crystals, namely cuprous iodide and 1, 10-orthoPhenanthroline complex ([ CuI (1,10-phen)]2)0.55g, yield 75%, which was recovered and reused. Ice water (100mL) was added to the filtrate to dilute it, and the mixture was 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-isopropylstilbene, 3.66g, in a yield of 72%.
Example 60: preparation of (E/Z) -3, 5-dihydroxy-4-isopropyl stilbene
To a round bottom flask were added (E/Z) -2- (3, 5-diacetoxy-4-isopropylphenyl) -3-phenylacrylic acid (7.65g,20mmol), cuprous iodide (0.76g,4mmol), 1, 10-phenanthroline (0.72g,4mmol) and polyethylene glycol-200 (55mL,300mmol, without anhydrous treatment), and stirred at 190 ℃ for 6 h. After the reaction is finished, filtering, washing a filter cake by a small amount of ethyl acetate to obtain a brick-red fine needle-shaped crystal, 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 (100mL) was added to the filtrate to dilute it, and the mixture was 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-isopropylstilbene, 4.37g, with a yield of 86%.
Example 61: preparation of (E/Z) -3, 5-dihydroxy-4-isopropyl stilbene
To a round bottom flask were added (E/Z) -2- (3, 5-diacetoxy-4-isopropylphenyl) -3-phenylacrylic acid (7.65g,20mmol), cuprous iodide (0.38g,2mmol), 2' -bipyridine (0.31g,2mmol) and polyethylene glycol-400 (50mL,140mmol, without anhydrous treatment), and stirred at 190 ℃ for 6 h. After the reaction, filtration was carried out, and ice water (100mL) was added to the obtained filtrate to dilute the solution, followed by extraction with ethyl acetate (50 mL. times.3), followed by collection of the organic layer, drying and concentration to obtain a tan paste, i.e., (E/Z) -3, 5-dihydroxy-4-isopropylstilbene (4.06 g), with a yield of 80%.
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 (7.65g,20mmol), and the resulting [ CuI (1,10-phen) recovered]2(0.74g,1mmol) and polyethylene glycol-400 (50mL,140mmol, not shown)Anhydrous treatment is carried out), and the mixture is heated and stirred for 6h at 190 ℃. After the reaction, filtration was carried out, and ice water (100mL) was added to the filtrate to dilute the solution, followed by extraction with ethyl acetate (50 mL. times.3), followed by collection of the organic layer, drying and concentration to obtain a tan paste (E/Z) -3, 5-dihydroxy-4-isopropylstilbene) (4.37 g, yield 86%).
(E) Preparation of 3, 5-dihydroxy-4-isopropylstilbene: the same as in examples 48 to 51.
The above description is only an example of the present invention, but the present invention is not limited to the above example, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention and are equivalent to each other are included in the protection scope of the present invention.

Claims (10)

1. A method for synthesizing (E) -3, 5-dihydroxy-4-isopropyl stilbene is characterized in that: 3, 5-dihydroxy-2, 4-diethoxycarbonyl phenylacetic acid ethyl ester is used as a starting material, 3, 5-dihydroxy phenylacetic acid is obtained through hydrolysis and decarboxylation, isopropylation is carried out to obtain 3, 5-dihydroxy-4-isopropylphenylacetic acid, the 3, 5-dihydroxy-4-isopropylphenylacetic acid and benzaldehyde are subjected to condensation reaction to obtain (E/Z) -2- (3, 5-dioxy substituent-4-isopropylphenyl) -3-phenylacrylic acid, decarboxylation is carried out to obtain (E/Z) -3, 5-dihydroxy-4-isopropylstilbene, and finally isomerization reaction is carried out to obtain (E) -3, 5-dihydroxy-4-isopropylstilbene.
2. The method for synthesizing (E) -3, 5-dihydroxy-4-isopropylstilbene according to claim 1 comprising the steps of:
(1) preparation of 3, 5-dihydroxyphenylacetic acid: in the alkali A, 3, 5-dihydroxy-2, 4-diethoxy carbonyl ethyl phenylacetate undergoes hydrolysis reaction; adding acid A for decarboxylation reaction; after the reaction is finished, obtaining 3, 5-dihydroxy phenylacetic acid through post-treatment;
(2) preparation of 3, 5-dihydroxy-4-isopropylphenylacetic acid: in the excess acid B, 3, 5-dihydroxyphenylacetic acid is isopropylated with isopropanol; after the reaction is finished, carrying out post-treatment to obtain 3, 5-dihydroxy-4-isopropylphenylacetic acid;
(3)(E/Z)-2-(preparation of 3, 5-dioxy-4-isopropylphenyl) -3-phenyl acrylic acid: in a solvent B, in the presence of alkali B, carrying out condensation reaction on 3, 5-dihydroxy-4-isopropylphenylacetic acid and benzaldehyde; after the reaction is finished, (E/Z) -2-(3, 5-dioxy-4-isopropylphenyl) -3-phenyl acrylic acid; the oxygen-containing substituent groups can be hydroxyl or acetoxy respectively;
(4) preparation of (E/Z) -3, 5-dihydroxy-4-isopropylstilbene: in a solvent C in the presence of a catalyst C and a ligand C, (E/Z) -2-(Decarboxylation reaction is carried out on 3, 5-dioxy substituent-4-isopropylphenyl) -3-phenyl acrylic acid; after the reaction is finished, (E/Z) -3, 5-dihydroxy-4-isopropyl stilbene is obtained by post-treatment;
(5) preparation of (E) -3, 5-dihydroxy-4-isopropylstilbene: in a solvent D, in the presence of a catalyst D, carrying out an isomerization reaction on (E/Z) -3, 5-dihydroxy-4-isopropyl stilbene; after the reaction is finished, (E) -3, 5-dihydroxy-4-isopropyl stilbene is obtained by post-treatment.
3. The method for synthesizing (E) -3, 5-dihydroxy-4-isopropylstilbene according to claim 1 comprising the steps of:
(1) preparation of 3, 5-dihydroxyphenylacetic acid: in the alkali A, 3, 5-dihydroxy-2, 4-diethoxy carbonyl ethyl phenylacetate undergoes hydrolysis reaction; adding acid A for decarboxylation reaction; after the reaction is finished, obtaining 3, 5-dihydroxy phenylacetic acid through post-treatment;
(2) preparation of 3, 5-dihydroxy-4-isopropylphenylacetic acid: in the excess acid B, 3, 5-dihydroxyphenylacetic acid is isopropylated with isopropanol; after the reaction is finished, carrying out post-treatment to obtain 3, 5-dihydroxy-4-isopropylphenylacetic acid;
(3)(E)-2-(preparation of 3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid: in a solvent B, in the presence of alkali B, carrying out condensation reaction on 3, 5-dihydroxy-4-isopropylphenylacetic acid and benzaldehyde; after the reaction is finished, (E) -2-(3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid;
(4) (Z) -3, 5-dihydroxy-preparation of 4-isopropylstilbene: in a solvent C in the presence of a catalyst C and a ligand C, (E) -2-(3, 5-dihydroxy-4-isopropylphenyl) -3-phenyl acrylic acid is subjected to decarboxylation reaction; after the reaction is finished, obtaining (Z) -3, 5-dihydroxy-4-isopropyl stilbene through post-treatment;
(5) preparation of (E) -3, 5-dihydroxy-4-isopropylstilbene: in a solvent D, in the presence of a catalyst D, carrying out an isomerization reaction on (Z) -3, 5-dihydroxy-4-isopropyl stilbene; after the reaction is finished, (E) -3, 5-dihydroxy-4-isopropyl stilbene is obtained by post-treatment.
4. The method for synthesizing (E) -3, 5-dihydroxy-4-isopropylstilbene according to claim 3, wherein the method comprises the following steps:
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 hours; 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 molar ratio of the 3, 5-dihydroxy-2, 4-diethoxycarbonyl ethyl phenylacetate to the alkali A to the acid A is 1 (4-7) to 2-8; the post-treatment comprises the steps of washing the reaction solution by dichloromethane, extracting by ethyl acetate, collecting an ethyl acetate layer, drying and concentrating to obtain 3, 5-dihydroxy phenylacetic 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 Dowex50WX 8; the temperature of the isopropylation reaction is 50-100 ℃, and the reaction time is 4-10 h; the molar ratio of the 3, 5-dihydroxy phenylacetic acid to the isopropanol to the acid A is 1 (1.0-1.5) to 5-15; pouring the reaction solution into ice water, stirring vigorously to generate a large amount of sticky substances, pouring out the excessive acid solution on the upper layer, adding ethyl acetate into the acid solution for extraction, taking the obtained water layer as waste acid solution, and recovering the waste acid solution to obtain excessive acid B; dissolving the obtained organic layer in the dope, concentrating, adding a sodium hydroxide solution for dissolving, adding hydrochloric acid for acidification until the pH value is 2-3, and a little of scorched substances are generated, performing 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-dihydroxy-4-isopropylphenylacetic acid;
in the step (3), the solvent B is acetic anhydride; the alkali B is sodium acetate, potassium carbonate or triethylamine; the condensation reaction temperature is 100-140 ℃, and the reaction time is 2-8 h; the molar ratio of the 3, 5-dihydroxy-4-isopropylphenylacetic acid to the benzaldehyde to the alkali B to the solvent B is 1 (1.0-1.2) to 2-4 to 4-6; the post-treatment is that the reaction liquid 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 a sodium hydroxide solution into the sticky 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, carrying out suction filtration and washing with water, collecting a filter cake, and drying to obtain (E) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid;
in the step (4), the solvent C is ethylene glycol, diethylene glycol, triethylene glycol, polyethylene glycol-200, polyethylene glycol-400, polyethylene glycol-600 or quinoline; the catalyst C is copper powder, copper sulfate, copper acetate, copper oxide, cuprous bromide or cuprous iodide; the ligand C is 1, 10-phenanthroline, 2' -bipyridyl or 8-hydroxyquinoline; the decarboxylation reaction temperature is 160-210 ℃, and the reaction time is 4-10 h; (E) -2-(The molar ratio of the 3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid to the catalyst C to the ligand C to the solvent C is 1 (0.05-0.2) to (5-15); the post-treatment is to cool the reaction liquid to room temperature, pump-filter, wash the filter cake with a small amount of ethyl acetate to obtain a crystal which is a compound of the catalyst C and the ligand C and can be recycled 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-dihydroxy-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 elementary iodine or aluminum triiodide; the isomerization reaction temperature is 40-110 ℃, and the reaction time is 4-10 h; the molar ratio of the (Z) -3, 5-dihydroxy-4-isopropyl stilbene to the catalyst D is 1 (0.1-1.0); and the post-treatment comprises the steps of cooling the reaction liquid to room temperature, adding saturated sodium sulfite solution for quenching, extracting by ethyl acetate, collecting an organic phase, drying, concentrating, and separating and purifying by recrystallization or column chromatography to obtain the (E) -3, 5-dihydroxy-4-isopropyl stilbene.
5. The method for synthesizing (E) -3, 5-dihydroxy-4-isopropylstilbene according to claim 1 comprising the steps of:
(1) preparation of 3, 5-dihydroxyphenylacetic acid: in the alkali A, 3, 5-dihydroxy-2, 4-diethoxy carbonyl ethyl phenylacetate undergoes hydrolysis reaction; adding acid A for decarboxylation reaction; after the reaction is finished, obtaining 3, 5-dihydroxy phenylacetic acid through post-treatment;
(2) preparation of 3, 5-dihydroxy-4-isopropylphenylacetic acid: in the excess acid B, 3, 5-dihydroxyphenylacetic acid is isopropylated with isopropanol; after the reaction is finished, carrying out post-treatment to obtain 3, 5-dihydroxy-4-isopropylphenylacetic acid;
(3)(Z)-2-(preparation of 3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid: in a solvent B, in the presence of alkali B, carrying out condensation reaction on 3, 5-dihydroxy-4-isopropylphenylacetic acid and benzaldehyde; after the reaction is finished, (Z) -2-(3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid;
(4) preparation of (E) -3, 5-dihydroxy-4-isopropylstilbene: in a solvent C in the presence of a catalyst C and a ligand C, (Z) -2-(3, 5-dihydroxy-4-isopropylphenyl) -3-phenyl acrylic acid is subjected to decarboxylation reaction; after the reaction is finished, (E) -3, 5-dihydroxy-4-isopropyl stilbene is obtained by post-treatment.
6. The method for synthesizing (E) -3, 5-dihydroxy-4-isopropylstilbene according to claim 5, wherein the method comprises the following steps:
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 hours; 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 molar ratio of the 3, 5-dihydroxy-2, 4-diethoxycarbonyl ethyl phenylacetate to the alkali A to the acid A is 1 (4-7) to 2-8; the post-treatment comprises the steps of washing the reaction solution by dichloromethane, extracting by ethyl acetate, collecting an ethyl acetate layer, drying and concentrating to obtain 3, 5-dihydroxy phenylacetic 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 Dowex50WX 8; the temperature of the isopropylation reaction is 50-100 ℃, and the reaction time is 4-10 h; the molar ratio of the 3, 5-dihydroxy phenylacetic acid to the isopropanol to the acid A is 1 (1.0-1.5) to 5-15; pouring the reaction solution into ice water, stirring vigorously to generate a large amount of sticky substances, pouring out the excessive acid solution on the upper layer, adding ethyl acetate into the acid solution for extraction, taking the obtained water layer as waste acid solution, and recovering the waste acid solution to obtain excessive acid B; dissolving the obtained organic layer in the dope, concentrating, adding a sodium hydroxide solution for dissolving, adding hydrochloric acid for acidification until the pH value is 2-3, and a little of scorched substances are generated, performing 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-dihydroxy-4-isopropylphenylacetic acid;
in the step (3), the solvent B is acetic anhydride; the alkali B is sodium acetate, potassium carbonate or triethylamine; the condensation reaction temperature is 100-140 ℃, and the reaction time is 2-8 h; the molar ratio of the 3, 5-dihydroxy-4-isopropylphenylacetic acid to the benzaldehyde to the alkali B to the solvent B is 1 (1.0-1.2) to 2-4 to 4-6; the post-treatment is that the reaction liquid 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 sticky matter, stirring and dissolving, extracting and washing by using dichloromethane, acidifying by using hydrochloric acid until the pH value is 4-5, separating out solids, and performing suction filtration to obtain a filter cake which is (E) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylpropaneAn olefinic 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-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid;
in the step (4), the solvent C is ethylene glycol, diethylene glycol, triethylene glycol, polyethylene glycol-200, polyethylene glycol-400, polyethylene glycol-600 or quinoline; the catalyst C is copper powder, copper sulfate, copper acetate, copper oxide, cuprous bromide or cuprous iodide; the ligand C is 1, 10-phenanthroline, 2' -bipyridyl or 8-hydroxyquinoline; the decarboxylation reaction temperature is 160-210 ℃, and the reaction time is 4-10 h; (Z) -2-(The molar ratio of the 3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid to the catalyst C to the ligand C to the solvent C is 1 (0.05-0.2) to (5-15); the post-treatment is to cool the reaction liquid to room temperature, pump-filter, wash the filter cake with a small amount of ethyl acetate to obtain a crystal which is a compound of the catalyst C and the ligand C and can be recycled and reused; diluting the obtained filtrate with ice water, adding ethyl acetate for extraction, collecting an organic phase, drying and concentrating to obtain the (E) -3, 5-dihydroxy-4-isopropyl stilbene.
7. The method for synthesizing (E) -3, 5-dihydroxy-4-isopropylstilbene according to claim 1 comprising the steps of:
(1) preparation of 3, 5-dihydroxyphenylacetic acid: in the alkali A, 3, 5-dihydroxy-2, 4-diethoxy carbonyl ethyl phenylacetate undergoes hydrolysis reaction; adding acid A for decarboxylation reaction; after the reaction is finished, obtaining 3, 5-dihydroxy phenylacetic acid through post-treatment;
(2) preparation of 3, 5-dihydroxy-4-isopropylphenylacetic acid: in the excess acid B, 3, 5-dihydroxyphenylacetic acid is isopropylated with isopropanol; after the reaction is finished, carrying out post-treatment to obtain 3, 5-dihydroxy-4-isopropylphenylacetic acid;
(3)(E/Z)-2-(preparation of 3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid: in a solvent B, in the presence of a base B, carrying out condensation reaction on 3, 5-dihydroxy-4-isopropylphenylacetic acid (formula-4) and benzaldehyde; after the reaction is finished, (E/Z) -2-(3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid;
(4) preparation of (E/Z) -3, 5-dihydroxy-4-isopropylstilbene: in a solvent C in the presence of a catalyst C and a ligand C, (E/Z) -2-(3, 5-dihydroxy-4-isopropylphenyl) -3-phenyl acrylic acid is subjected to decarboxylation reaction; after the reaction is finished, (E/Z) -3, 5-dihydroxy-4-isopropyl stilbene is obtained by post-treatment;
(5) preparation of (E) -3, 5-dihydroxy-4-isopropylstilbene: in a solvent D, in the presence of a catalyst D, carrying out an isomerization reaction on (E/Z) -3, 5-dihydroxy-4-isopropyl stilbene; after the reaction is finished, (E) -3, 5-dihydroxy-4-isopropyl stilbene is obtained by post-treatment.
8. The method for synthesizing (E) -3, 5-dihydroxy-4-isopropylstilbene according to claim 7, wherein the method comprises the following steps:
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 hours; 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 molar ratio of the 3, 5-dihydroxy-2, 4-diethoxycarbonyl ethyl phenylacetate to the alkali A to the acid A is 1 (4-7) to 2-8; the post-treatment comprises the steps of washing the reaction solution by dichloromethane, extracting by ethyl acetate, collecting an ethyl acetate layer, drying and concentrating to obtain 3, 5-dihydroxy phenylacetic 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 Dowex50WX 8; the temperature of the isopropylation reaction is 50-100 ℃, and the reaction time is 4-10 h; the molar ratio of the 3, 5-dihydroxy phenylacetic acid to the isopropanol to the acid A is 1 (1.0-1.5) to 5-15; pouring the reaction solution into ice water, stirring vigorously to generate a large amount of sticky substances, pouring out the excessive acid solution on the upper layer, adding ethyl acetate into the acid solution for extraction, taking the obtained water layer as waste acid solution, and recovering the waste acid solution to obtain excessive acid B; dissolving the obtained organic layer in the dope, concentrating, adding a sodium hydroxide solution for dissolving, adding hydrochloric acid for acidification until the pH value is 2-3, and a little of scorched substances are generated, performing 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-dihydroxy-4-isopropylphenylacetic acid;
in the step (3), the solvent B is acetic anhydride; the alkali B is sodium acetate, potassium carbonate or triethylamine; the condensation reaction temperature is 100-140 ℃, and the reaction time is 2-8 h; the molar ratio of the 3, 5-dihydroxy-4-isopropylphenylacetic acid to the benzaldehyde to the alkali B to the solvent B is 1 (1.0-1.2) to 2-4 to 4-6; the post-treatment is that the reaction liquid 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 the supernatant, adding a sodium hydroxide solution into the sticky matter, stirring and dissolving, extracting and washing with dichloromethane, acidifying with hydrochloric acid until the pH value is 1-2, extracting with ethyl acetate, collecting an organic phase, drying, and concentrating to obtain (E/Z) -2- (3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid;
in the step (4), the solvent C is ethylene glycol, diethylene glycol, triethylene glycol, polyethylene glycol-200, polyethylene glycol-400, polyethylene glycol-600 or quinoline; the catalyst C is copper powder, copper sulfate, copper acetate, copper oxide, cuprous bromide or cuprous iodide; the ligand C is 1, 10-phenanthroline, 2' -bipyridyl or 8-hydroxyquinoline; the decarboxylation reaction temperature is 160-210 ℃, and the reaction time is 4-10 h; (E/Z) -2-(The molar ratio of the 3, 5-dihydroxy-4-isopropylphenyl) -3-phenylacrylic acid to the catalyst C to the ligand C to the solvent C is 1 (0.05-0.2) to (5-15); the post-treatment is to cool the reaction liquid to room temperature, pump-filter, wash the filter cake with a small amount of ethyl acetate to obtain fine needle-like crystals which are a compound of the catalyst C and the ligand C and can be recycled 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-dihydroxy-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 elementary iodine or aluminum triiodide; the isomerization reaction temperature is 40-110 ℃, and the reaction time is 4-10 h; the molar ratio of (E/Z) -3, 5-dihydroxy-4-isopropyl stilbene to the catalyst D is 1 (0.1-1.0); and the post-treatment comprises the steps of cooling the reaction liquid to room temperature, adding saturated sodium sulfite solution for quenching, extracting by ethyl acetate, collecting an organic phase, drying, concentrating, and separating and purifying by recrystallization or column chromatography to obtain the (E) -3, 5-dihydroxy-4-isopropyl stilbene.
9. The method for synthesizing (E) -3, 5-dihydroxy-4-isopropylstilbene according to claim 1 comprising the steps of:
(1) preparation of 3, 5-dihydroxyphenylacetic acid: in the alkali A, 3, 5-dihydroxy-2, 4-diethoxy carbonyl ethyl phenylacetate undergoes hydrolysis reaction; adding acid A for decarboxylation reaction; after the reaction is finished, obtaining 3, 5-dihydroxy phenylacetic acid through post-treatment;
(2) preparation of 3, 5-dihydroxy-4-isopropylphenylacetic acid: in the excess acid B, 3, 5-dihydroxyphenylacetic acid is isopropylated with isopropanol; after the reaction is finished, carrying out post-treatment to obtain 3, 5-dihydroxy-4-isopropylphenylacetic acid;
(3)(E/Z)-2-(preparation of 3, 5-diacetoxy-4-isopropylphenyl) -3-phenylacrylic acid: in a solvent B, in the presence of alkali B, carrying out condensation reaction on 3, 5-dihydroxy-4-isopropylphenylacetic acid and benzaldehyde; after the reaction is finished, (E/Z) -2-(3, 5-diacetoxy-4-isopropylphenyl) -3-phenylacrylic acid;
(4) preparation of (E/Z) -3, 5-dihydroxy-4-isopropylstilbene: in a solvent C in the presence of a catalyst C and a ligand C, (E/Z) -2-(Decarboxylation and hydrolysis reaction are carried out on the 3, 5-diacetoxy-4-isopropylphenyl) -3-phenyl acrylic acid; after the reaction is finished, (E/Z) -3, 5-dihydroxy-4-isopropyl stilbene is obtained by post-treatment;
(5) preparation of (E) -3, 5-dihydroxy-4-isopropylstilbene: in a solvent D, in the presence of a catalyst D, carrying out an isomerization reaction on (E/Z) -3, 5-dihydroxy-4-isopropyl stilbene; after the reaction is finished, (E) -3, 5-dihydroxy-4-isopropyl stilbene is obtained by post-treatment.
10. The method for synthesizing (E) -3, 5-dihydroxy-4-isopropylstilbene according to claim 9, wherein the method comprises the steps of:
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 hours; 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 molar ratio of the 3, 5-dihydroxy-2, 4-diethoxycarbonyl ethyl phenylacetate to the alkali A to the acid A is 1 (4-7) to 2-8; the post-treatment comprises the steps of washing the reaction solution by dichloromethane, extracting by ethyl acetate, collecting an ethyl acetate layer, drying and concentrating to obtain 3, 5-dihydroxy phenylacetic 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 Dowex50WX 8; the temperature of the isopropylation reaction is 50-100 ℃, and the reaction time is 4-10 h; the molar ratio of the 3, 5-dihydroxy phenylacetic acid to the isopropanol to the acid A is 1 (1.0-1.5) to 5-15; pouring the reaction solution into ice water, stirring vigorously to generate a large amount of sticky substances, pouring out the excessive acid solution on the upper layer, adding ethyl acetate into the acid solution for extraction, taking the obtained water layer as waste acid solution, and recovering the waste acid solution to obtain excessive acid B; dissolving the obtained organic layer in the dope, concentrating, adding a sodium hydroxide solution for dissolving, adding hydrochloric acid for acidification until the pH value is 2-3, and a little of scorched substances are generated, performing 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-dihydroxy-4-isopropylphenylacetic acid;
in the step (3), the solvent B is acetic anhydride; the alkali B is sodium acetate, potassium carbonate or triethylamine; the condensation reaction temperature is 100-140 ℃, and the reaction time is 2-8 h; the molar ratio of 3, 5-dihydroxy-4-isopropylphenylacetic acid, benzaldehyde, base B and solvent B1 (1.0-1.2), (2-4), (4-6); the post-treatment comprises pouring the reaction solution into ice water, stirring vigorously to generate a large amount of dope, pouring out the supernatant, washing the dope with a large amount of water to neutrality, collecting the dope, and drying to obtain (E/Z) -2-(3, 5-diacetoxy-4-isopropylphenyl) -3-phenylacrylic acid;
in the step (4), the solvent C is ethylene glycol, diethylene glycol, triethylene glycol, polyethylene glycol-200, polyethylene glycol-400, polyethylene glycol-600 or quinoline; the catalyst C is copper powder, copper sulfate, copper acetate, copper oxide, cuprous bromide or cuprous iodide; the ligand C is 1, 10-phenanthroline, 2' -bipyridyl or 8-hydroxyquinoline; the decarboxylation reaction temperature is 160-210 ℃, and the reaction time is 4-10 h; (E/Z) -2-(The molar ratio of the 3, 5-diacetoxy-4-isopropylphenyl) -3-phenylacrylic acid to the catalyst C to the ligand C to the solvent C is 1 (0.05-0.2) to (5-15); the post-treatment is to cool the reaction liquid to room temperature, pump-filter, wash the filter cake with a small amount of ethyl acetate to obtain fine needle-like crystals which are a compound of the catalyst C and the ligand C and can be recycled 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-dihydroxy-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 elementary iodine or aluminum triiodide; the isomerization reaction temperature is 40-110 ℃, and the reaction time is 4-10 h; the molar ratio of (E/Z) -3, 5-dihydroxy-4-isopropyl stilbene to the catalyst D is 1 (0.1-1.0); and the post-treatment comprises the steps of cooling the reaction liquid to room temperature, adding saturated sodium sulfite solution for quenching, extracting by ethyl acetate, collecting an organic phase, drying, concentrating, and separating and purifying by recrystallization or column chromatography to obtain the (E) -3, 5-dihydroxy-4-isopropyl stilbene.
CN202011093791.9A 2020-10-14 2020-10-14 Synthesis method of (E) -3, 5-dihydroxyl-4-isopropyl stilbene Active CN112250546B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202011093791.9A CN112250546B (en) 2020-10-14 2020-10-14 Synthesis method of (E) -3, 5-dihydroxyl-4-isopropyl stilbene

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202011093791.9A CN112250546B (en) 2020-10-14 2020-10-14 Synthesis method of (E) -3, 5-dihydroxyl-4-isopropyl stilbene

Publications (2)

Publication Number Publication Date
CN112250546A true CN112250546A (en) 2021-01-22
CN112250546B CN112250546B (en) 2023-05-12

Family

ID=74243072

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202011093791.9A Active CN112250546B (en) 2020-10-14 2020-10-14 Synthesis method of (E) -3, 5-dihydroxyl-4-isopropyl stilbene

Country Status (1)

Country Link
CN (1) CN112250546B (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116265421A (en) * 2021-12-17 2023-06-20 上海泽德曼医药科技有限公司 Compounds for preventing or treating central nervous system related diseases
WO2023109859A1 (en) * 2021-12-15 2023-06-22 上海泽德曼医药科技有限公司 Stilbene compound and application thereof in prevention and/or treatment for central nervous system-related diseases

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101481300A (en) * 2009-02-20 2009-07-15 中国科学院广州化学研究所 Preparation of trans-polyhydroxy diphenyl ethylene
CN101665418A (en) * 2009-08-03 2010-03-10 中国科学院广州化学研究所 Methods for preparing E-3,5-dimethoxy-4'-oxhydryl diphenylethene and derivative thereof
CN102675064A (en) * 2012-05-11 2012-09-19 中科院广州化学有限公司 Preparation method and application of Z-3,4,4',5-tetramethoxy-2',3'-dihydroxy diphenylethylene
CN102924300A (en) * 2012-10-15 2013-02-13 中科院广州化学有限公司 Method for preparing diphenyl ethylene compound through decarboxylic reaction
CN104003848A (en) * 2013-02-25 2014-08-27 武汉诺安药业有限公司 (E)-3,5-dihydroxy-4-isopropyl stilbene preparation method
CN105884581A (en) * 2014-12-30 2016-08-24 上海复星医药产业发展有限公司 Method for preparing 2-(1-methylethyl)-5-[(E)-2-phenylethenyl]benzene-1,3-diol
CN106748662A (en) * 2016-11-16 2017-05-31 广州中大南沙科技创新产业园有限公司 A kind of synthetic method of the tetrahydroxystilbenes of natural products E 2,3 ', 4,5 '

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101481300A (en) * 2009-02-20 2009-07-15 中国科学院广州化学研究所 Preparation of trans-polyhydroxy diphenyl ethylene
CN101665418A (en) * 2009-08-03 2010-03-10 中国科学院广州化学研究所 Methods for preparing E-3,5-dimethoxy-4'-oxhydryl diphenylethene and derivative thereof
CN102675064A (en) * 2012-05-11 2012-09-19 中科院广州化学有限公司 Preparation method and application of Z-3,4,4',5-tetramethoxy-2',3'-dihydroxy diphenylethylene
CN102924300A (en) * 2012-10-15 2013-02-13 中科院广州化学有限公司 Method for preparing diphenyl ethylene compound through decarboxylic reaction
CN104003848A (en) * 2013-02-25 2014-08-27 武汉诺安药业有限公司 (E)-3,5-dihydroxy-4-isopropyl stilbene preparation method
CN105884581A (en) * 2014-12-30 2016-08-24 上海复星医药产业发展有限公司 Method for preparing 2-(1-methylethyl)-5-[(E)-2-phenylethenyl]benzene-1,3-diol
CN106748662A (en) * 2016-11-16 2017-05-31 广州中大南沙科技创新产业园有限公司 A kind of synthetic method of the tetrahydroxystilbenes of natural products E 2,3 ', 4,5 '

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
KEIRA GAUKROGER等: "Novel Syntheses of Cis and Trans Isomers of Combretastatin A-4", 《J. ORG. CHEM.》 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023109859A1 (en) * 2021-12-15 2023-06-22 上海泽德曼医药科技有限公司 Stilbene compound and application thereof in prevention and/or treatment for central nervous system-related diseases
CN116265421A (en) * 2021-12-17 2023-06-20 上海泽德曼医药科技有限公司 Compounds for preventing or treating central nervous system related diseases
CN116265421B (en) * 2021-12-17 2024-01-02 上海泽德曼医药科技有限公司 Compounds for preventing or treating central nervous system related diseases

Also Published As

Publication number Publication date
CN112250546B (en) 2023-05-12

Similar Documents

Publication Publication Date Title
CN112250546A (en) Synthesis method of (E) -3, 5-dihydroxy-4-isopropyl stilbene
CN112174989B (en) Preparation method of clenbuterol
JPH01125343A (en) 2, 5-bis (2, 2, 2-trifluoroethoxy)-alpha, aplha, alpha-trichloroacetophenone and its production
CN100543004C (en) 1,7,8-three fluoro-beta naphthals and the preparation method who utilizes its liquid crystalline cpd
CN106146457B (en) 5-chloro-2-acyl chloride thiophene intermediate and preparation method thereof
CN112300071A (en) Synthetic method of high-purity chloroquine phosphate
CN112390707B (en) Preparation and application of (Z) -3, 5-dihydroxy-4-isopropyl stilbene
SU895282A3 (en) Method of preparing phenylalkylcarboxalic acids
JPS61152673A (en) Production of dibenzo(b,e)oxepine derivative
JP4418048B2 (en) Process for producing 13-cis-retinoic acid
CN112745216A (en) Preparation method of methyl 4-bromomethylbenzoate and derivatives thereof
CN102924373A (en) Method for preparing 4-(3-methoxy propoxy)-2,3-dimethyl pyridine-N-oxide
CN109836322B (en) Preparation method of royal jelly acid
CN115304477B (en) Preparation method of aromatic carboxylic ester
CN100588643C (en) Process for preparing retinoid compounds containing twice substituted adamantyl radical
CN103435450B (en) A kind of synthetic method of the TMHQ of environmental protection
CN112159347B (en) Preparation method of picolitamide
JPS61152674A (en) Production of dibenzo(b,e)oxepine derivative
JPS61152675A (en) Production of dibenzo(b,e)oxepine derivative
CN106748884A (en) A kind of preparation method of Bicalutamide intermediate
WO2001083419A1 (en) Process for the preparation of alicyclic ketones and alkyl-substituted alicyclic esters
CN113214111A (en) Preparation method of 3- (2-cyanophenyl) propionic acid and 4-cyano-1-indanone
CN111377814A (en) Preparation method of α -acyloxyketone compound
CN113087648A (en) Synthetic method for improving purity of fluorochloridone
CN117534613A (en) Preparation method of 3-aminopyridine-2-carboxylic acid methyl ester

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant