CN110577464A - Preparation method of resveratrol - Google Patents

Preparation method of resveratrol Download PDF

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Publication number
CN110577464A
CN110577464A CN201810632852.0A CN201810632852A CN110577464A CN 110577464 A CN110577464 A CN 110577464A CN 201810632852 A CN201810632852 A CN 201810632852A CN 110577464 A CN110577464 A CN 110577464A
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compound
resveratrol
raw materials
taking
namely
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Inventor
翟逸
赵秀敏
郭宝柱
刘孟刚
吴永坤
尹训君
刘钦松
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SHANDONG BOAOKE BIOTECHNOLOGY CO Ltd
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SHANDONG BOAOKE BIOTECHNOLOGY CO Ltd
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    • 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
    • C07C37/001—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by modification in a side chain
    • C07C37/002—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by modification in a side chain by transformation of a functional group, e.g. oxo, carboxyl
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/01—Preparation of ethers
    • C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
    • C07C41/22—Preparation of ethers by reactions not forming ether-oxygen bonds by introduction of halogens; by substitution of halogen atoms by other halogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/01—Preparation of ethers
    • C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
    • C07C41/30—Preparation of ethers by reactions not forming ether-oxygen bonds by increasing the number of carbon atoms, e.g. by oligomerisation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/40—Esters thereof
    • C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/4056—Esters of arylalkanephosphonic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/40—Esters thereof
    • C07F9/4071—Esters thereof the ester moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/4075—Esters with hydroxyalkyl compounds

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

the invention belongs to the technical field of preparation of key intermediates of medicaments, and particularly relates to a preparation method of resveratrol. The synthesis preparation method of the resveratrol comprises the following steps: a. synthesizing 3, 5-dimethoxy benzyl bromide (compound A) by using 3, 5-dimethoxy benzyl alcohol and phosphorus tribromide as raw materials; b. taking a compound A, triethyl phosphite and tetrabutylammonium bromide as raw materials, and synthesizing to obtain 3, 5-dimethoxy benzyl diethyl phosphate (a compound B); c. taking a compound B, dimethyl diamide, sodium hydride and anisaldehyde as raw materials, and reacting to synthesize (E)3, 4', 5-trimethoxy stilbene (compound C); d. and (3) taking the compound C and pyridine hydrochloride as raw materials, and reacting and synthesizing to obtain the 3, 4, 5-trihydroxy-1, 2-stilbene, namely the resveratrol. The method has the characteristics of cheap and easily-obtained raw materials, mild reaction conditions, simple and convenient operation, high yield and low cost, and is favorable for industrial production.

Description

Preparation method of resveratrol
Technical Field
The invention belongs to the technical field of preparation of key intermediates of medicaments, and particularly relates to a preparation method of a medicament intermediate resveratrol which has the effects of resisting cancers, mutation, oxidation and free radicals, preventing cardiovascular and cerebrovascular diseases, resisting bacteria and inflammation and regulating an immune system.
Background
Resveratrol is a natural antioxidant, can reduce blood viscosity, inhibit platelet coagulation and vasodilatation, keep blood smooth, prevent cancer occurrence and development, and has effects of resisting atherosclerosis and coronary heart disease, ischemic heart disease, and hyperlipemia. The tumor inhibiting effect also has estrogen-like effect, and can be used for treating diseases such as breast cancer.
Resveratrol is a high-added-value natural product with good application prospect, and has various beneficial physiological activities of cancer prevention and resistance, blood fat reduction, platelet aggregation resistance, Sirtuins antisenility enzyme activation, antioxidation, free radical resistance, antianaphylaxis, antibiosis and antiphlogosis, osteoporosis resistance, skin care and whitening and the like. In recent years, a series of research reports and commendative articles about the bioactivity of resveratrol appear in world famous scientific journals including Science and Nature, and indicate that resveratrol can improve the survival rate of cells and prolong the life of organisms by activating Sirtuins enzyme and stabilizing DNA repetitive sequences. The resveratrol can also effectively resist central nerve ischemic injury, protect neurons in an ischemic area, reduce the infarction range, reduce delayed nerve cell apoptosis caused by ischemia reperfusion, improve limb movement dysfunction caused by cerebral ischemia and the like. The important biological activity and application value of resveratrol are widely concerned by the medical field, the industrial field, the news field and common people, and new pharmaceutical research categories led by resveratrol, such as protein deacetylase activator STACS, cancer chemopreventive agents and neuroprotective agents, become the thermoelectric and frontier fields of scientific research at present.
Resveratrol is mainly extracted from plants, but the application of resveratrol in the aspects of industrialization scale, medicine and functional food is limited due to the extremely low content of resveratrol. At the same time, the predation and destructive mining of resources is also extremely harmful to the ecological environment. Therefore, artificial synthesis of resveratrol has been attracting attention of researchers in various countries.
At present, the chemical synthesis of resveratrol mainly comprises 3 steps of formation of a stilbene skeleton, cis-trans isomerization and deprotection, wherein the key is the formation of the stilbene skeleton. The most studied chemical synthesis methods at present share class 4 classical methods.
Perkin reaction
the Perkin reaction is a reaction of aromatic aldehyde and acid anhydride in the presence of sodium carboxylate salt and potassium carboxylate salt of corresponding acid of the acid anhydride to produce beta-aromatic acrylic acid compound. In 1941, trans-3, 4, 5-trimethoxystilbene was obtained by first Perkin condensation of 3, 5-dimethoxybenzaldehyde and sodium p-methoxybenzoate by Spath et al, but it was not comparable to natural extraction because no crystals could be obtained after decarboxylation. However, Spath was not abandoned and they decarboxylated the product and placed in a mixture of methanol and hydrochloric acid, giving pure trans-crystals after 48 h. In 2003, the method of the Spath is improved by Solladie, 3, 5-diisopropoxybenzaldehyde and p-isopropoxyphenylacetic acid are used as raw materials for synthesis to obtain a product with a single cis-configuration, and the product is subjected to isomerization and protective group removal to obtain trans-structure resveratrol, wherein the total yield of the resveratrol is as high as 55.2%.
Wittig and Wittig-Horner reactions
The Wittig reaction is a reaction for forming a double bond commonly used in organic synthesis, wherein a Wittig reagent (phosphorus ylide) and carbonyl groups of aldehyde and ketone undergo a nucleophilic addition reaction to form new olefin and phosphine oxide. Reimann firstly takes 3, 5-bis (trimethylsiloxy) methyl benzoate as a raw material to prepare resveratrol through a Wittig reaction.
The Wittig-Horner reaction is an improvement on the Wittig reaction, and utilizes simple and easily-obtained phosphite ester to replace a phosphorus ylide reagent prepared from triphenylphosphine to react with aldehyde ketone to form double bonds. The method has mild conditions, simple and convenient operation, high yield and good stereoselectivity. Taking 3, 5-dihydroxy benzoic acid as a raw material, sequentially protecting hydroxyl, reducing, chlorinating and reacting with triethyl phosphite to generate 3, 5-dimethoxy benzyl diethyl phosphonate, then carrying out Wittig-Horner reaction with anisaldehyde, and removing protecting groups in pyridine hydrochloride to finally obtain resveratrol. Phosphite ester has poor atom economy, and expensive boron tribromide is used in the demethylation reaction, which seriously restricts the industrial implementation of the method.
Heck reaction
The Heck reaction is an olefin arylation and alkenylation coupling reaction of a palladium catalyst and has high trans-stereoselectivity. The Heck reaction condition is mild, the operation is simple, and the application in organic synthesis is very wide. 3, 5-dihydroxy benzoic acid is used as an initial raw material, aryl acyl chloride is used for replacing aryl halide to carry out Heck reaction, and the resveratrol is synthesized, wherein the total yield is as high as 53%. The method has simple steps, high selectivity and easy deprotection, but the palladium-containing complex used as the transition metal catalyst has high price and toxicity, and is not suitable for industrial mass production.
4. By condensation of carbanions with carbonyl compounds
The carbanion and carbonyl have nucleophilic addition reaction, and the obtained hydroxyl can form double bonds after elimination, so that the reaction is suitable for synthesis of resveratrol. The silicon derivative of 3, 5-dimethoxybenzyl alcohol is reacted with strong alkali to form benzyl carbanion which attacks the carbonyl group of anisaldehyde, and then the benzyl carbanion is dehydrated and demethylated to finally obtain single trans-resveratrol, wherein the total yield is 21%. The method has certain advantages in configuration selection, but the steps of the synthetic route are complicated, and the nucleophilic reaction yield is low.
The method has the defects of long route, low raw material economy, high cost, complex operation, poor trans-form selectivity, need of cis-trans isomerization, high demethylating reagent cost and the like, so that the continuous search of an efficient, simple and green resveratrol synthesis method has great significance.
In recent years, many scholars at home and abroad carry out more deep research on the bioactivity of resveratrol, and the resveratrol is found to be an important phytoalexin, can prevent the oxidation of low-density lipoprotein, has the effects of preventing and treating cardiovascular diseases, preventing cancer, resisting virus, resisting aging, regulating immunity and the like, and the American institute of natural medicine also finds that the resveratrol has the effect of resisting AIDS. At present, the global resveratrol market demands a lot, and the current production capacity is small, and the demand gap is large.
Disclosure of Invention
The invention aims to solve the technical problems of high cost, low synthesis efficiency, difficult separation and purification and difficult industrialized mass production in the prior art for preparing the resveratrol, and provides a novel method for preparing the resveratrol, which has the advantages of cheap and easily-obtained raw materials, mild reaction conditions, simple and convenient operation, high synthesis efficiency and favorable industrialized production.
Step one, in an organic solvent dichloromethane, 3, 5-dimethoxy benzyl alcohol compound (1) and pyridine and phosphorus tribromide are subjected to hydroxyl protection and bromination, and are concentrated and recrystallized to obtain a compound (2)
Reacting the two compounds (2) with triethyl phosphite and tetrabutylammonium bromide to obtain a compound (3)
Reacting the compound (3) with DMF, sodium hydride and anisaldehyde to obtain a compound (4)
Step four, reacting the compound (4) with pyridine hydrochloride for recrystallization reaction to obtain resveratrol
In the first step, 3, 5-dimethoxy benzyl alcohol reacts with pyridine in dichloromethane, phosphorus tribromide is dropwise added under ice bath, the reaction is carried out for three hours at room temperature, and water is dropwise added after the temperature is reduced to 0-5 ℃.
Step two, the reaction requires 160 ℃ for 8 hours
In the third step, anisaldehyde is added dropwise for one hour, the reaction is carried out for 6 hours at the temperature of 0 ℃, and an ice-water mixture is added.
And step four, reacting with pyridine hydrochloride for 50 minutes at 190 ℃, adding ice water, stirring, extracting with ethyl acetate, and recrystallizing with ethanol water to obtain resveratrol.
The invention has the advantages that: the preparation method of resveratrol provided by the invention has the advantages of cheap and easily available raw materials, mild reaction conditions, simple and convenient operation, high synthesis efficiency and high synthesis purity, is suitable for industrial production, and provides a new way for preparing resveratrol.
Detailed Description
The present invention will be further described with reference to the following examples. It should be understood that the examples are for illustrative purposes only and are not intended to limit the scope of the present invention.
The starting materials or reagents used in the examples are, unless otherwise specified, commercially available.
Adding 3, 5-dimethoxy benzyl alcohol 84g, dichloromethane 280ml and pyridine 1.7ml into a reaction bottle, dropwise adding phosphorus tribromide 29.3ml under ice bath, reacting for three hours at room temperature, cooling to 0-5 ℃, dropwise adding water 200ml, separating out a water layer, extracting with dichloromethane 100ml, concentrating and drying magnesium sulfate, adding methanol 200ml, and recrystallizing to obtain a compound A
80gA and 140ml triethyl phosphite 1.8g tetrabutylammonium bromide are added into a reaction flask for reaction at 160 ℃ for 8 hours, and the triethyl phosphite is recovered under reduced pressure to obtain a product B
Adding 68g of sodium hydride into all B and 400ml of DMF at-10 ℃, dropwise adding 46g of anisaldehyde (dropwise adding for one hour), reacting for 6 hours at 0 ℃, pouring into an ice-water mixture, precipitating a solid, filtering, drying at 45 ℃, and obtaining a product C after 2 hours.
Adding 69.3g of pyridine hydrochloride into 16.2g of C, reacting at 190 ℃ for 50 minutes, pouring into 200ml of ice water, stirring, extracting with 1L of ethyl acetate, layering, washing with water, drying with sodium sulfate, recovering ethyl acetate, and recrystallizing with ethanol water to obtain resveratrol.
Drawings
FIG. 1 is a scheme of synthesis of resveratrol
FIG. 2 is a reversed phase chromatogram of resveratrol.

Claims (5)

1. The synthesis preparation method of resveratrol comprises the following steps:
a. 3, 5-dimethoxy benzyl alcohol and phosphorus tribromide are used as raw materials to react and synthesize to obtain 3, 5-dimethoxy benzyl bromide, namely a compound A;
b. Taking a compound A, triethyl phosphite and tetrabutylammonium bromide as raw materials, and reacting to synthesize 3, 5-dimethoxy benzyl diethyl phosphate, namely a compound B;
c. Taking a compound B, dimethyl diamide, sodium hydride and anisaldehyde as raw materials to react and synthesize (E)3, 4', 5-trimethoxy stilbene, namely a compound C;
d. And (3) taking the compound C and pyridine hydrochloride as raw materials, and reacting and synthesizing to obtain the 3, 4, 5-trihydroxy-1, 2-stilbene, namely the resveratrol.
2. the method for preparing resveratrol according to claim 1, wherein in step a, phosphorus tribromide is added dropwise to dichloromethane, a mixture of 3, 5-dimethoxybenzyl alcohol and pyridine under ice bath conditions, the mixture is reacted for 3h at room temperature, the temperature is reduced to 0-5 ℃, 200mL of water is added, an aqueous layer is separated, extraction is carried out by dichloromethane, magnesium sulfate is concentrated and dried, and recrystallization is carried out by methanol to obtain the compound A.
3. The method for preparing resveratrol according to claim 1 wherein compound a, triethyl phosphite and tetrabutylammonium bromide are reacted to form compound B in step B, the temperature is controlled at 170 ℃ under the reaction conditions, the reaction time is 6-9h, and triethyl phosphite is recovered under reduced pressure.
4. The method of preparing resveratrol according to claim 1, wherein anisaldehyde is added dropwise in step c for 1 hour, then reacted at 0 ℃ for 5.5 to 6.5 hours, added with an ice water mixture, filtered and dried at 40 to 50 ℃.
5. the method for preparing resveratrol according to claim 1, wherein the compound C in step d is reacted with pyridine hydrochloride at 180-200 ℃ for 45-60min, ethyl acetate is stirred and extracted under ice bath, and ethanol water is recrystallized to obtain resveratrol.
CN201810632852.0A 2018-06-09 2018-06-09 Preparation method of resveratrol Pending CN110577464A (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101475451A (en) * 2009-02-13 2009-07-08 南京师范大学 Method for synthesizing trans-resveratrol
CN102617302A (en) * 2012-02-27 2012-08-01 浙江新赛科药业有限公司 Process for synthesizing trimethoxyphenyl stilbene
CN103570508A (en) * 2013-11-01 2014-02-12 湖南科源生物制品有限公司 Total synthesis method of trans-resveratrol

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101475451A (en) * 2009-02-13 2009-07-08 南京师范大学 Method for synthesizing trans-resveratrol
CN102617302A (en) * 2012-02-27 2012-08-01 浙江新赛科药业有限公司 Process for synthesizing trimethoxyphenyl stilbene
CN103570508A (en) * 2013-11-01 2014-02-12 湖南科源生物制品有限公司 Total synthesis method of trans-resveratrol

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