CN1736986A - Polyhydroxy stilbenes compound preparation and uses as drugs for suppressing SARS - Google Patents
Polyhydroxy stilbenes compound preparation and uses as drugs for suppressing SARS Download PDFInfo
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Abstract
The invention provides a group of polyhydroxy stilbene compounds, their preparing process and use for suppressing and eradicating SARS coronavirus. The preparing process comprises, preparing phosphonic ester by reacting multi-alkyl substituted chloro (bromo) methoxyl or pyridine compounds with triethyl phosphate, then reacting phosphonate ester compound with multi-alkyl (oxy) phenylpyridine methyl aldehyde to obtain multi-alkyl (oxy) stilbene compounds. Finally acting with boron tribromide to obtain polyhydroxy stilbene compounds with substituent groups.
Description
Technical field
The present invention relates to medicinal polyhydroxy stilbenes new compound of a class and its production and use.Such new compound is used for suppressing and killing sars coronavirus.
Background technology
Stilbenes compound is the general name with compounds of stibene parent nucleus.At nature, polyhydroxy stilbenes compound exists in many herbal medicine such as black false hellebore, rheum officinale, tiger battle, the tuber of multiflower knotweed and foods such as grape, peanut, mulberry fruit in, have many physiologically actives such as antibiotic, anti-oxidant, reducing blood-fat, antithrombotic, antitumor, desinsection, raising immunological competence.
In WO 02/057219 patent, the setter of a class stilbenes compound as T cell, neutrophil(e) cell, scavenger cell and corresponding cytokine disclosed, be used for the treatment of immunity, inflammation and autoimmune disease.In the structure of WO02/057219 patent disclosure, having only in the phenyl ring has 3,5 to contain alkoxyl group or hydroxyl substituent, and another phenyl ring is that alkane and halohydrocarbon replace substantially, generally has three to replace or four replacements on two in addition keys.
In CN 200410022517.7 patent disclosures, find that curcumine prepares the application of treatment or prevention SARS in the 1%-100% dosage range.
In the CN200410022518.1 patent disclosure, find that the Flavonol polyphenol prepares the application of treatment or prevention SARS in the 1%-100% dosage range.
At Inhibition of SARS-coronavirus infection in vitro byS-nitroso-N-acetylpenicillamine, in a nitric oxide donor compound article [Intrenational Journalof Infectious Diseases (2004) 8,223-226 (periodical source)]
This article duplicates (Vero E6) cell to S-nitroso-group-N-ethanoyl Trolovol (SANP) and two NO compound donators of Nitroprusside ion (SNP) to the coronavirus chain Frankfurt-1 of SARS (Severe actute respiratory syndrome) and suppresses activity experiment and toxicity test on cercopithecus aethiops; S-nitroso-group-N-ethanoyl Trolovol (SANP) wherein, wherein SANP compound 50% suppresses SARS-CoV concentration IC
50Be 222.3 ± 83.7 μ M, 50% poisonous concentration is 587.7 ± 22.5 μ M, and selecting coefficient is 2.6.And SANP does not detect SARS-CoV is had effect.The compound of this research and the polyhydroxystilbene of the present patent application and poly-hydroxy azepine stilbene compounds can suppress SARS-CoV is not had dependency.
The objective of the invention is to develop polyhydroxy stilbenes compound that a class is not reported so far and preparation method thereof and be used for anti-sars type pneumonia sars coronavirus medicine.
Summary of the invention
The present invention is a kind of substituent polyhydroxy stilbenes compound that has, and this compounds has following general structure (I):
In the general formula (I):
When the X=N atomic time,
R
1＝0；
R
2-R
10=identical or different H, OH, OR
1, C
1-C
8Alkyl, C
2-C
8Thiazolinyl, C
2-C
8Alkynyl,
C
3-C
9Cycloalkyl, phenyl, benzyl or by 1-3 phenyl or benzyl that replaces by Y;
R
1=C
1-C
6Alkyl, C
2-C
6Thiazolinyl, C
2-C
6Alkynyl, C
3-C
7Cycloalkyl, phenyl, benzyl or 1-3
Individual phenyl or the benzyl that is replaced by Y;
Y=C
1-C
3Alkyl, C
2-C
4Thiazolinyl, halogen, CN or NO
2
When the X=C atomic time,
R
1-R
10=identical or different H, OH, OR
1, C
1-C
8Thiazolinyl, C
2-C
8Alkynyl, C
3-C
9Cycloalkanes
Base, phenyl, benzyl or by 1-3 phenyl or benzyl that replaces by Y;
R
1=C
1-C
6Alkyl, C
2-C
6Thiazolinyl, C
2-C
6Alkynyl, C
3-C
7Cycloalkyl, phenyl, benzyl or 1-3
Individual phenyl or the benzyl that is replaced by Y;
Y=C
1-C
3Alkyl, C
2-C
4Thiazolinyl, halogen, CN or NO
2Particularly preferred compound is:
1, (E)-2-[2-(2, the 5-dihydroxy phenyl) vinyl]-3, the 4-dihydroxy-pyridine;
2, (E)-2-[2-(3, the 5-dihydroxy phenyl) vinyl]-3, the 4-dihydroxy-pyridine;
3, (E)-2-[2-(2, the 5-dihydroxy phenyl) vinyl]-3,5-dimethyl-4-pyridone; (be called for short: R0303)
4, (E)-2-[2-(4-hydroxy phenyl) vinyl]-3,5-dimethyl-4-pyridone;
5, (E)-2-[2-(3, the 5-dihydroxy phenyl) vinyl]-3,5-dimethyl-4-pyridone;
6, (E)-5-[2-(3, the 5-dihydroxy phenyl) vinyl]-1, the 3-dihydroxy-benzene;
Have another name called (E)-3,3 ', 5,5 '-tetrahydroxy Stilbene
7, (E)-4-[2-(3, the 5-dihydroxy phenyl) vinyl]-1, the 3-dihydroxy-benzene;
Have another name called (E)-2,3 ', 4,5 '-tetrahydroxy Stilbene
8, (E)-2-[2-(3, the 5-dihydroxy phenyl) vinyl]-1, the 3-dihydroxy-benzene; (be called for short: R0305)
Have another name called (E)-2,3 ', 5,5 '-tetrahydroxy Stilbene
9, (E)-4-[2-(4-hydroxy phenyl) vinyl]-1, the 3-dihydroxy-benzene;
Have another name called (E)-2,4,4 '-trihydroxy stilbene
10, (E)-4-[2-(2, the 4-dihydroxy phenyl) vinyl]-1, the 3-dihydroxy-benzene;
Have another name called (E)-2,2 ', 4,4 '-tetrahydroxy Stilbene
11, (E)-4-[2-(2, the 5-Dimethoxyphenyl) vinyl]-1, the 3-dihydroxy-benzene;
Have another name called (E)-2 ', 5 '-dimethoxy-2,4-dihydroxyl Stilbene
12, (E)-5-[2-(4-methoxyl group-3-((E)-3-methyl-1-butene base) phenyl) vinyl]-1, the 3-dimethoxy benzene;
Have another name called (E)-3-[(E)-3-methyl-1-butene base]-3 ', 4,5 '-trimethoxy Stilbene
13, (E)-4-[2-(4-hydroxyl-phenyl) vinyl]-2 ((E)-3-methyl-butenyl) phenol;
Have another name called: (E)-3-((E)-3-methyl-butenyl)-4,4 '-dihydroxyl Stilbene
14, (E)-2-[2-(4-methoxyl group-3-((E)-3-methyl-1-butene base) phenyl) vinyl]-1, the 4-dimethoxy benzene;
Have another name called: (E)-3 '-((E)-3-methyl-1-butene base)-2,4 ', 5-trimethoxy Stilbene
The preparation method of its formula I compound is shown in reaction formula 1-3, and substituting group wherein is except that specializing, all as preceding qualification.
The preparation route of polyhydroxy stilbenes compound can be represented with following reaction formula:
Reaction formula 1
To have alkoxy substituted benzyl chloride or bromide and triethyl-phosphite, in molar ratio 1: the ratio of 1.5-15 is added in the reactor, in the presence of a small amount of tetrabutylammonium iodide, in 95-125 ℃, stir 6-18h, then, underpressure distillation, remove excessive triethyl-phosphite, get phosphonate product III.
Reaction formula 2
Product III phosphonic acid ester is dissolved in the dry tetrahydrofuran (THF), is cooled to below 0 ℃, stirs to add NaH down rapidly, stirs.Stir the THF solution that slowly drips the alkoxy benzene formaldehyde that replaces down, drip, reaction mixture is risen to room temperature, stir 8-16h.Be chilled to 0 ℃, slowly drip water 10mL, cancellation excessive N aH.Reaction solution is neutralized to pH4-6 with HCl solution.With saturated NaCl solution washing, anhydrous sodium sulfate drying reclaims solvent with ethyl acetate extraction, organic phase, and the residue recrystallization gets purified alkoxyl group stilbenes compound II.
Reaction formula 3
To make with extra care alkoxyl group stilbenes compound II and dissolve, be cooled to below 0 ℃, the inflated with nitrogen protection with anhydrous methylene chloride.Stir and slowly drip BBr down
3Anhydrous methylene chloride solution 20mL, dropwise, rise to 25-28 ℃, stir about 3-6h.In reaction solution impouring frozen water, stir, add NaHCO
3Saturated solution is adjusted to pH5-8, the micro emulsion yellow mercury oxide occurs, and directly suction filtration can obtain product I, can carry out the recrystallization to I to solvent.
In above-mentioned reaction expression:
When the X=N atomic time,
R’
1＝0；
R '
2-R '
10=identical or different H, OR
1, C
1-C
8Alkyl, C
2-C
8Thiazolinyl, C
2-C
8Alkynyl, C
3-C
9Cycloalkyl, phenyl, benzyl or by 1-3 phenyl or benzyl that replaces by Y;
R
1=C
1-C
6Alkyl, C
2-C
6Thiazolinyl, C
2-C
6Alkynyl, C
3-C
7Cycloalkyl, phenyl, benzyl or 1-3 phenyl or benzyl that is replaced by Y;
Y=C
1-C
3Alkyl, C
2-C
4Thiazolinyl, halogen, CN or NO
2
When the X=C atomic time,
R '
1-R '
10=identical or different H, OR
1, C
1-C
8Alkyl, C
2-C
8Thiazolinyl, C
2-C
8Alkynyl, C
3-C
9Cycloalkyl, phenyl, benzyl or by 1-3 phenyl or benzyl that replaces by Y;
R
1=C
1-C
6Alkyl, C
2-C
6Thiazolinyl, C
2-C
6Alkynyl, C
3-C
7Cycloalkyl, phenyl, benzyl or 1-3 phenyl or benzyl that is replaced by Y;
Y=C
1-C
3Alkyl, C
2-C
4Thiazolinyl, halogen, CN or NO
2
Polyhydroxy stilbenes compound of the present invention is owing to contain active ingredient, the composition that can constitute with one or more drug excipients or assistant agent, making the polyhydroxystilbene in this pharmaceutical composition is the 0.001-50% weight percentage, is applicable to inhibition and kills sars coronavirus.
Anti-SARS activity test example
Cell: Vero E6 cell, Beijing University of Technology's life science and biotechnology institute cultivate and preserve.
Virus: BJ9-2b, Beijing University of Technology's life science and biotechnology institute cultivate and preserve (Chinese Military Medical Science Institute gives)
Medicine: medicine to be measured is measured maximal non-toxic concentration earlier, during determination of antiviral activity, doubly dilutes 4-5 concentration with the medicine 2-4 of maximal non-toxic concentration.
1. the active detection of anti-SARS
Vero E6 cell is diluted to cell suspension with containing 10%Hyclone foetal calf serum Eagles ' nutrient solution, and every milliliter (ml) contains 1.2 * 10
5Cell adds in the flat 96 porocyte culture plates, every hole 0.1ml, and in 37 ℃, 5%CO
2Incubator cultivates that cell grows up to individual layer after 24-48 hour, and every hole adds 100TCID
50BJ-2B virus was adsorbed 2 hours, drew supernatant (discarding the free virus that does not enter cell), selected maximal non-toxic concentration medicine (TC for use
0) R0303 and R0305,3 concentration of 2 times of dilutions, each concentration 3 multiple hole, every hole 100 μ l add 96 orifice plates respectively, in 37 ℃, 5%CO
2Incubator continues to cultivate, after 72 hours, adopting the CPE method to carry out the result judges, promptly when pathology appears in the hole of virus control group 75% cell, observe the pathology of medicine group, pathology occurs with 75% cell and be " +++", 50% cell pathology occurs and is " ++ ", 25% cell pathology occurs and is "+", and no pathology appears as "-", and test is provided with virus control group, medicine control group, cell control group respectively.Calculate 50% at last and suppress virus disease degree of thickening (IC
50) and therapeutic index (TI).
2. cytotoxic detection
Method is the same substantially, but behind the cell bed board, cell grows up to individual layer after 24-48 hour, and infective virus not only adds the medicine of different concns, in 37 ℃, and 5%CO
2Incubator continues to cultivate, after 72 hours, adopt CPE method judged result, 75% cell pathology occurs and is " +++", it is "+" for pathology appears in " ++ " 25% cell that pathology appears in 50% cell, no pathology appears as "-", and test is provided with medicine control group, cell control group respectively, determines maximal non-toxic concentration at last.
Row table 1 as a result as follows:
Table 1 medicine antivirus action is table as a result
| Sample | Test number (TN) | Cell toxicant 2mg/ml | Drug level (mg/ml) | Virus is to (100TCID 50) | ||
| 2 | 1 | 0.5 | ||||
| R0303 | 1 | - | - | - | - | +++ |
| 2 | - | - | - | - | +++ | |
| 3 | - | - | - | - | +++ | |
| R0305 | 1 | - | - | - | - | +++ |
| 2 | - | - | - | - | +++ | |
| 3 | - | - | - | - | +++ | |
Compound R 0303 and R0305 when 2.0mg/ml concentration, acellular toxic action; When 2.0mg/ml, 1.0mg/ml, 0.5mg/ml concentration, sars coronavirus is killed in the Vero E6 cell, can't breed.
The compounds of this invention or contain its pharmaceutical composition can the unit dosage form administration, route of administration can be divided into enteron aisle or non-enteron aisle, as oral, muscle, subcutaneous, nasal cavity, oral mucosa, skin, peritonaeum or rectum etc., preferred oral.
The compounds of this invention or the route of administration that contains its pharmaceutical composition can be divided into drug administration by injection.Injection comprises intravenous injection, intramuscular injection, subcutaneous injection and intradermal injection etc.
Form of administration can be liquid dosage form, solid dosage.As liquid dosage form can be true solution class, colloidal type, particulate formulations, emulsion-type, mixed suspension form.Other formulation is tablet, capsule, dripping pill, aerosol, pill, pulvis, solution, suspensoid, emulsion, granule, suppository, lyophilisate etc. for example.
Compound of the present invention can be made ordinary preparation, also can be sustained release dosage, control-released agent, targeting preparation and various particulate delivery system.
For the unit form of administration is made tablet, can be extensive use of various carrier well known in the art.Example about carrier is, for example thinner and absorption agent are as starch, dextrin, calcium sulfate, lactose, N.F,USP MANNITOL, sucrose, sodium-chlor, glucose, urea, white bole, Microcrystalline Cellulose, pure aluminium silicate etc.; Wetting agent and tackiness agent are as water, glycerine, polyoxyethylene glycol, ethanol, propyl alcohol, starch slurry, dextrin, syrup, honey, glucose solution, mucialga of arabic gummy, gelatine size, Xylo-Mucine, lac, methylcellulose gum, potassiumphosphate, polyvinylpyrrolidone etc.; Disintegrating agent, for example dry starch, alginates, agar powder, laminaran, sodium bicarbonate and matrimony vine acid, lime carbonate, polyoxyethylene sorbitol fatty acid ester, sodium laurylsulfonate, methylcellulose gum, ethyl cellulose etc.; Disintegration inhibitor, for example sucrose, Tristearoylglycerol, theobroma oil, hydrogenation wet goods; Absorption enhancer, for example quaternary ammonium salt, sodium lauryl sulphate etc.; Lubricant, for example talcum powder, silicon-dioxide, W-Gum, stearic acid, boric acid, whiteruss, polyoxyethylene glycol etc.Other carrier such as polyacrylic resin, liposome, water-soluble carrier such as PEG4000 and PEG6000, PVP etc.Tablet further can also be made coating tablet, for example sugar coated tablet, thin membrane coated tablet, ECT or biplate layer and multi-disc layer.
For example, can be extensive use of various carrier well known in the art for pill is made in the administration unit.Example about carrier is, for example thinner and absorption agent are as glucose, lactose, starch, theobroma oil, hydrogenated vegetable oil, polyvinylpyrrolidone, kaolin, talcum powder etc.; Tackiness agent is as gum arabic, tragacanth gum, gelatin, ethanol, honey, liquid sugar, rice paste or batter etc.; Disintegrating agent is as agar powder, dry starch, alginates, sodium laurylsulfonate, methylcellulose gum, ethyl cellulose etc.
For example for capsule is made in the administration unit, the effective ingredient The compounds of this invention is mixed with above-mentioned each sharp carrier, and the mixture that will obtain thus places hard gelatine capsule or soft capsule.Also the effective constituent The compounds of this invention can be made microcapsule, be suspended in and form suspensoid in the aqueous medium, in the hard capsule of also can packing into or make injection and use.
For example, The compounds of this invention is made injection preparation, as solution, suspension solution agent, emulsion, lyophilisate, this preparation can be moisture or non-water.Can contain acceptable carrier, thinner, tackiness agent, lubricant, sanitas, tensio-active agent or dispersion agent on a kind of and/or multiple pharmacodynamics.Can be selected from water, ethanol, polyoxyethylene glycol, 1 as thinner, the isooctadecanol of ammediol, ethoxylation, the isooctadecanol of polyoxyization, Polyoxyethylene Sorbitol Fatty Acid Esters, Polyoxyl 35 etc.In addition, ooze injection liquid, can in injection preparation, add proper amount of sodium chloride, glucose or glycerine, in addition, can also add conventional solubility promoter, buffer reagent, pH regulator agent etc. in order to prepare etc.These auxiliary materials are that this area is commonly used.
In addition, as needs, also can in medicine, add tinting material, sanitas, spices, correctives, sweeting agent or other materials.
For reaching the medication purpose, strengthen result of treatment, medicine of the present invention or pharmaceutical composition can be with any known medication administrations.
The dosage of extract of the present invention or compound, pharmaceutical composition depends on many factors, for example to prevent or treat the character and the severity of disease, the sex of patient or animal, age, body weight, personality and individual reaction, route of administration, administration number of times, therapeutic purpose, therefore therapeutic dose of the present invention can have large-scale variation.In general, the using dosage of pharmacodynamics composition of the present invention is well known to a person skilled in the art.Can be according to the actual drug quantity that is contained in the preparation last in the The compounds of this invention composition, in addition suitable adjustment to reach the requirement of its treatment significant quantity, is finished the consumption of compound of the present invention, most preferably is the 0.1-20mg/Kg body weight.Above-mentioned dosage can the single dose form or be divided into several, for example two, three or four dosage form administrations, this is subject to administration doctor's clinical experience and comprises the dosage regimen of using other treatment means.This shows, contain the many effects that can produce the present invention's treatment or prevention SARS of general formula compound that the present invention discloses.
Embodiment
Embodiment 1
(E)-and 2-[2-(3, the 5-dihydroxy phenyl) vinyl]-3,5-dimethyl-4-pyridone; (have another name called: (E)-4,6-dimethyl-3 ', 5,5 '-trihydroxy stilbene-2-nitrogen)
3, synthesizing of 5-dimethyl-4-methoxypyridine-2-methylphosphonate: add 2-chloromethyl-3 in the 50mL there-necked flask, 5-dimethyl-4-methoxypyridine (0.01mol), triethyl-phosphite 2.5g (0.016mol), tetrabutylammonium iodide is a small amount of, stir, oil bath is heated to 100-110 ℃, reaction 3-6h.With reactant underpressure distillation below 90 ℃, remove excessive triethyl-phosphite, the shallow orange red dope of residue is directly used in next step reaction in the bottle.
(E)-2-[2-(3, the 5-Dimethoxyphenyl) vinyl]-3,5-dimethyl-4-methoxypyridine synthetic: go up step reaction gained phosphonic acid ester and be dissolved in the 50mL dry tetrahydrofuran (THF), cryosel is bathed and is cooled to below 0 ℃, stir and add NaH powder (0.025mol) down rapidly, stirring 30min.Stir down and slowly drip 3, the THF solution 30mL of 5-dimethoxy benzaldehyde (0.01mol).About 1.5h dropwises, and reaction mixture is risen to room temperature (14-25 ℃), stirs 8-16h.Be chilled to 0 ℃, slowly drip water 10mL, cancellation excessive N aH.Reaction solution is neutralized to pH6 with 1M HCl solution, and (4 * 50mL), organic phase is with the saturated NaCl aqueous solution (30mL) washing, anhydrous sodium sulfate drying with ethyl acetate extraction.Reclaim solvent, residue carries out recrystallization with ethanol, gets white needle-like crystals, productive rate: 34.7%, and mp:94-95 ℃.
1HNMR(CDCl
3)δ：2.27(s，3H，4-CH
3)，2.35(s，3H，6-CH
3)，3.77(s，3H，5-OCH
3)，3.83(s，6H，3，5-OCH
3)，6.42(t，1H，J＝2.0Hz，4-H)，6.75(d，2H，J＝2.0Hz，2，6-H)，8.26(s，1H，3-H)，7.29，7.63(d，2H，J＝15.6Hz，α，β-H)。
(E)-2-[2-(3; the 5-dihydroxy phenyl) vinyl]-3; synthesizing of 5-dimethyl-4-pyridone: add (E)-2-[2-(3 in the 100mL there-necked flask; the 5-Dimethoxyphenyl) vinyl]-3; 5-dimethyl-4-methoxypyridine (0.001mol); with the dissolving of 40mL anhydrous methylene chloride, the cryosel water-bath is cooled to below 0 ℃, the inflated with nitrogen protection.Stir and slowly drip BBr down
3(about 1h dropwises, and rises to 25-28 ℃ for 3.4mL, anhydrous methylene chloride solution 20mL 36mmol), stirs about 3-6h.In reaction solution impouring 200mL frozen water, stir, be little yellow, add NaHCO
3Saturated solution is adjusted to about pH7, the micro emulsion yellow mercury oxide occurs, and directly suction filtration can obtain product, light yellow amorphous powder, and productive rate: 94.0%,
1HNMR (DMSO-d
6) δ: 6.47 (d, 2H, J=2.2Hz, 2,6-H), 6.23 (t, 1H, J=2.2Hz, 4-H), 7.56 (s, 1H, 3-H), 7.05,7.11 (d, 2H, J=16.63Hz, α, β-H), 1.91 (s, 3H, 4-CH
3), 2.06 (s, 3H, 6-CH
3).
Embodiment 2
(E)-and 2-[2-(4-hydroxy phenyl) vinyl]-3,5-dimethyl-4-pyridone (have another name called: (E)-4,6-dimethyl-4,5 '-dihydroxyl Stilbene-2-nitrogen)
3, synthesizing of 5-dimethyl-4-methoxypyridine-2-methylphosphonate: add 2-chloromethyl-3 in the 50mL there-necked flask, 5-dimethyl-4-methoxypyridine (0.01mol), triethyl-phosphite 2.5g (0.016mol), tetrabutylammonium iodide is a small amount of, stir, oil bath is heated to 100-110 ℃, reaction 3-6h.With reactant underpressure distillation below 90 ℃, remove excessive triethyl-phosphite, the shallow orange red dope of residue is directly used in next step reaction in the bottle.
(E)-and 2-[2-(4-p-methoxy-phenyl) vinyl]-3, synthesizing of 5-dimethyl-4-methoxypyridine: go up step reaction gained phosphonic acid ester and be dissolved in the 50mL dry tetrahydrofuran (THF), cryosel is bathed and is cooled to below 0 ℃, stirs to add NaH powder (0.025mol) down rapidly, stirs 30min.Stir the THF solution 30mL that slowly drips 4-methoxybenzaldehyde (0.01mol) down.About 1.5h dropwises, and reaction mixture is risen to room temperature (14-25 ℃), stirs 8-16h.Be chilled to 0 ℃, slowly drip water 10mL, cancellation excessive N aH.Reaction solution is neutralized to slant acidity with 1M HCl solution, and (4 * 50mL), organic phase is with the saturated NaCl aqueous solution (30mL) washing, anhydrous sodium sulfate drying with ethyl acetate extraction.Reclaim solvent, residue carries out recrystallization with ethanol, gets yellow superfine needle-like crystal, productive rate: 60.6%, and mp:131-133 ℃.IR(KBr)cm
-1：2983，2840，2672，2560，1687，1604，1515，1468，1428，1305，1264，1171，1089，1027，970，930，845，，824，773，634，616。
(E)-and 2-[2-(4-hydroxy phenyl) vinyl]-3; synthesizing of 5-dimethyl-4-pyridone: add (E)-2-[2-(4-p-methoxy-phenyl) vinyl in the 100mL there-necked flask]-3; 5-dimethyl-4-methoxypyridine (0.001mol); dissolve with the 40mL anhydrous methylene chloride; the cryosel water-bath is cooled to below 0 ℃, the inflated with nitrogen protection.Stir and slowly drip BBr down
3(about 1h dropwises, and rises to 40-42 ℃ for 3.4mL, anhydrous methylene chloride solution 20mL 36mmol), stirs about 3-6h.In reaction solution impouring 200mL frozen water, stir, be little yellow, add NaHCO
3Saturated solution is adjusted to about pH7, the micro emulsion yellow mercury oxide occurs, and directly suction filtration can obtain product, light yellow amorphous powder, and productive rate: 50.2%,
1HNMR (DMSO-d
6) δ: 6.81 (d, 2H, J=8.4Hz, 2,6-H), 7.47 (d, 2H, J=8.4Hz, 3,5-H), 7.51 (s, 1H, 3-H), 7.03,7.17 (d, 2H, J=16.4Hz, α, β-H), 1.89 (s, 3H, 4-CH
3), 2.05 (s, 3H, 6-CH
3).
Embodiment 3
(E)-and 2-[2-(2, the 5-dihydroxy phenyl) vinyl]-3,5-dimethyl-4-pyridone (have another name called: (E)-4,6-dimethyl-2,5,5 '-trihydroxy stilbene-2-nitrogen)
3, synthesizing of 5-dimethyl-4-methoxypyridine-2-methylphosphonate: add 2-chloromethyl-3 in the 50mL there-necked flask, 5-dimethyl-4-methoxypyridine (0.01mol), triethyl-phosphite 2.5g (0.016mol), tetrabutylammonium iodide is a small amount of, stir, oil bath is heated to 100-110 ℃, reaction 3-6h.With reactant underpressure distillation below 90 ℃, remove excessive triethyl-phosphite, the shallow orange red dope of residue is directly used in next step reaction in the bottle.
(E)-2-[2-(2, the 5-Dimethoxyphenyl) vinyl]-3,5-dimethyl-4-methoxypyridine synthetic: go up step reaction gained phosphonic acid ester and be dissolved in the 50mL dry tetrahydrofuran (THF), cryosel is bathed and is cooled to below 0 ℃, stir and add NaH powder (0.025mol) down rapidly, stirring 30min.Stir down and slowly drip 2, the THF solution 30mL of 5-dimethoxy benzaldehyde (0.01mol).About 1.5h dropwises, and reaction mixture is risen to room temperature (14-25 ℃), stirs 8-16h.Be chilled to 0 ℃, slowly drip water 10mL, cancellation excessive N aH.Reaction solution is neutralized to pH7 with 1M HCl solution, and (4 * 50mL), organic phase is with the saturated NaCl aqueous solution (30mL) washing, anhydrous sodium sulfate drying with ethyl acetate extraction.Reclaim solvent, residue is shallow golden yellow oily, and is non-crystallizable.
(E)-2-[2-(2; the 5-dihydroxy phenyl) vinyl]-3; synthesizing of 5-dimethyl-4-pyridone: add (E)-2-[2-(2 in the 100mL there-necked flask; the 5-Dimethoxyphenyl) vinyl]-3; 5-dimethyl-4-methoxypyridine (0.001mol); with the dissolving of 40mL anhydrous methylene chloride, the cryosel water-bath is cooled to below 0 ℃, the inflated with nitrogen protection.Stir and slowly drip BBr down
3(about 1h dropwises, and rises to 32 ℃ for 3.4mL, anhydrous methylene chloride solution 20mL 36mmol), stirs about 3-6h.In reaction solution impouring 200mL frozen water, stir, be little yellow, add NaHCO
3Saturated solution is adjusted to about pH7, the micro emulsion yellow mercury oxide occurs, and directly suction filtration can obtain product, light yellow amorphous powder, productive rate: 62.8%.
1HNMR(DMSO-d
6)δ：6.719(d，1H，J＝8.5Hz，3-H)，6.950(d，1H，J＝3.0Hz，6-H)，6.608(dd，1H，J＝3.0Hz，J＝8.5Hz，4-H)，7.473(s，1H，3-H)，7.143，7.392(d，2H，J＝16.6Hz，α，β-H)，1.887(s，3H，4-CH
3)，2.031(s，3H，6-CH
3)。
Embodiment 4
(E)-and 2-[2-(3, the 5-dihydroxy phenyl) vinyl]-3, the 4-dihydroxy-pyridine (have another name called: (E)-3 ', 5,5 ', 6-tetrahydroxy Stilbene-2-nitrogen)
3,4-dimethoxy-pyridine-2-methylphosphonate synthetic: add 2-chloromethyl-3,4-dimethoxy-pyridine (0.01mol) in the 50mL there-necked flask, triethyl-phosphite 2.5g (0.016mol), tetrabutylammonium iodide is a small amount of, stirs, oil bath is heated to 100-110 ℃, reaction 3-6h.With reactant underpressure distillation below 90 ℃, remove excessive triethyl-phosphite, the shallow orange red dope of residue is directly used in next step reaction in the bottle.
(E)-2-[2-(3, the 5-Dimethoxyphenyl) vinyl]-3,4-dimethoxy-pyridine synthetic: go up step reaction gained phosphonic acid ester and be dissolved in the 50mL dry tetrahydrofuran (THF), cryosel is bathed and is cooled to below 0 ℃, stir and add NaH powder (0.025mol) down rapidly, stirring 30min.Stir down and slowly drip 3, the THF solution 30mL of 5-dimethoxy benzaldehyde (0.01mol).About 1.5h dropwises, and reaction mixture is risen to room temperature (14-25 ℃), stirs 8-16h.Be chilled to 0 ℃, slowly drip water 10mL, cancellation excessive N aH.Reaction solution is neutralized to pH6 with 1M HCl solution, and (4 * 50mL), organic phase is with the saturated NaCl aqueous solution (30mL) washing, anhydrous sodium sulfate drying with ethyl acetate extraction.Reclaim solvent, residue carries out recrystallization with ethanol, gets yellow superfine needle-like crystal, productive rate: 18.9%, and mp:88-89.5 ℃.
1HNMR(CDCl
3)δ：3.83(s，6H，3，5-OCH
3)，3.88(s，3H，5-OCH
3)，3.93(s，3H，6-OCH
3)，6.43(t，1H，J＝2.0Hz，4-H)，6.78(d，2H，J＝2.0Hz，2，6-H)，6.75(d，1H，J＝5.2Hz，4-H)，8.27(d，1H，J＝5.2Hz，3-H)，7.47，7.71(d，2H，J＝16.0Hz，α，β-H)。
(E)-2-[2-(3; the 5-dihydroxy phenyl) vinyl]-3; synthesizing of 4-dihydroxy-pyridine: add (E)-2-[2-(3 in the 100mL there-necked flask; the 5-Dimethoxyphenyl) vinyl]-3; 4-dimethoxy-pyridine (0.001mol); with the dissolving of 40mL anhydrous methylene chloride, the cryosel water-bath is cooled to below 0 ℃, the inflated with nitrogen protection.Stir and slowly drip BBr down
3(about 1h dropwises, and rises to 20-26 ℃ for 3.4mL, anhydrous methylene chloride solution 20mL 36mmol), stirs about 3-6h.In reaction solution impouring 200mL frozen water, stir, be little yellow, add NaHCO
3Saturated solution is adjusted to about pH7, the micro emulsion yellow mercury oxide occurs, and directly suction filtration can obtain product, light yellow amorphous powder, and productive rate: 98.9%,
1HNMR (DMSO-d
6) δ: 6.17 (d, 2H, J=2.2Hz, 2,6-H) 6.22 (t, 1H, J=2.2Hz, 4-H), 7.51 (d, 1H, J=6.5Hz, 3-H), 6.18 (d, 1H, J=6.5Hz, 4-H), 6.99,7.54 (d, 2H, J=16.5Hz, α, β-H).
Embodiment 5
(E)-and 2-[2-(2, the 5-dihydroxy phenyl) vinyl]-3, the 4-dihydroxy-pyridine (have another name called: (E)-2 ', 5,5 ', 6-tetrahydroxy Stilbene-2-nitrogen)
3,4-dimethoxy-pyridine-2-methylphosphonate synthetic: add 2-chloromethyl-3,4-dimethoxy-pyridine (0.01mol) in the 50mL there-necked flask, triethyl-phosphite 2.5g (0.016mol), tetrabutylammonium iodide is a small amount of, stirs, oil bath is heated to 100-110 ℃, reaction 3-6h.With reactant underpressure distillation below 90 ℃, remove excessive triethyl-phosphite, the shallow orange red dope of residue is directly used in next step reaction in the bottle.
(E)-2-[2-(2, the 5-Dimethoxyphenyl) vinyl]-3,4-dimethoxy-pyridine synthetic: go up step reaction gained phosphonic acid ester and be dissolved in the 50mL dry tetrahydrofuran (THF), cryosel is bathed and is cooled to below 0 ℃, stir and add NaH powder (0.025mol) down rapidly, stirring 30min.Stir down and slowly drip 3, the THF solution 30mL of 5-dimethoxy benzaldehyde (0.01mol).About 1.5h dropwises, and reaction mixture is risen to room temperature (14-25 ℃), stirs 8-16h.Be chilled to 0 ℃, slowly drip water 10mL, cancellation excessive N aH.Reaction solution is neutralized to pH6 with 1M HCl solution, and (4 * 50mL), organic phase is with the saturated NaCl aqueous solution (30mL) washing, anhydrous sodium sulfate drying with ethyl acetate extraction.Reclaim solvent, residue carries out recrystallization with methyl alcohol, gets little yellow styloid, productive rate: 20.7%, and mp:100-101 ℃.
1HNMR(CDCl
3)δ：3.82(s，1H，5-OCH
3)，3.85(s，1H，2-OCH
3)，3.87(s，1H，5-OCH
3)，3.92(s，1H，6-OCH
3)，6.73(d，1H，J＝5.6Hz，4-H)，7.23(d，1H，J＝2.4Hz，6-H)，6.83(m，1H，4-H)，6.84(d，1H，J＝2.8Hz，3-H)，8.28(d，1H，J＝5.6Hz，3-H)，8.08，7.52(d，2H，J＝16.4Hz，α，β-H)。
(E)-2-[2-(2; the 5-dihydroxy phenyl) vinyl]-3; synthesizing of 4-dihydroxy-pyridine: add (E)-2-[2-(3 in the 100mL there-necked flask; the 5-Dimethoxyphenyl) vinyl]-3; 4-dimethoxy-pyridine (0.001mol); with the dissolving of 40mL anhydrous methylene chloride, the cryosel water-bath is cooled to below 0 ℃, the inflated with nitrogen protection.Stir and slowly drip BBr down
3(about 1h dropwises, and rises to 25-35 ℃ for 3.4mL, anhydrous methylene chloride solution 20mL 36mmol), stirs about 3-6h.In reaction solution impouring 200mL frozen water, stir, be little yellow, add NaHCO
3Saturated solution is adjusted to about pH7, the micro emulsion yellow mercury oxide occurs, and directly suction filtration can obtain product, light yellow amorphous powder, and productive rate: 58.3%,
1HNMR (DMSO-d
6) δ: 6.90 (d, 1H, J=8.8Hz, 3-H), 6.73 (d, 1H, J=3.0Hz, 6-H), 6.58 (dd, 1H, J=3.0Hz, J=8.8Hz, 4-H), 7.47 (d, 1H, J=6.7Hz, 3-H), 6.18 (d, 1H, J=6.7Hz, 4-H), 7.16,7.54 (d, 2H, J=16.9Hz, α, β-H).
Embodiment 6
(E)-2,3 ', 5,5 '-tetrahydroxy Stilbene
3,5-dimethoxy-benzyl phosphonic acid ester synthetic: add 3 in the 100mL there-necked flask, 5-dimethoxy-benzyl bromine (0.01mol), triethyl-phosphite (0.015mol), tetrabutylammonium iodide is a small amount of, stirs, and oil bath is heated to 110-115 ℃, reaction 6h.With reactant underpressure distillation below 90 ℃, remove excessive triethyl-phosphite, remaining light golden rod yellow oily matter is product in the bottle, is directly used in next step reaction.
(E)-2,3 ', 5,5 '-tetramethoxy Stilbene synthetic: go up step reaction gained phosphonic acid ester and be dissolved in the 25mL dry tetrahydrofuran (THF), cryosel is bathed and is cooled to below 0 ℃, stirs to add NaH powder (0.025mol) down rapidly, stirs 30min.Stir down and slowly drip 3, the THF solution 25mL of 5-dimethoxy benzaldehyde (0.01mol).Reactant is risen to room temperature (14-25 ℃), stirred 6-8 hour.In reaction solution impouring frozen water, reaction solution is neutralized to slant acidity with 1M HCl solution, with ethyl acetate extraction, organic phase is with saturated NaCl solution washing, anhydrous sodium sulfate drying.Reclaim solvent, add small amount of ethanol-normal hexane recrystallization in the residue, get off-white powder, esterification, condensation two-step reaction total recovery 72.6%, mp:54-55 ℃.
1HNMR(CDCl
3)δ：3.83(s，12H，OCH
3)，6.39(t，1H，J＝2.0Hz，4-H)，6.70(d，2H，J＝2.0Hz，2，6-H)，6.80(dd，1H，J＝2.8Hz，J＝8.4Hz，4-H)，6.83(d，1H，J＝8.4Hz，3-H)，7.13(d，1H，J＝2.8Hz，6-H)，7.42，7.02(d，2H，J＝16.4Hz，α，β-H)。
(E)-2,3 ', 5,5 '-tetrahydroxy Stilbene synthetic: add (E)-2 in the 100mL there-necked flask, 3 ', 5,5 '-tetramethoxy Stilbene (4mmol), with the dissolving of 40mL anhydrous methylene chloride, the cryosel water-bath is cooled to below 0 ℃, the inflated with nitrogen protection.Stir and slowly drip 2.7mL BBr down
3Anhydrous methylene chloride solution 20mL, about 1h dropwises, and rises to 25-30 ℃, stirs 6 hours.In reaction solution impouring 200mL frozen water, stir, produce white precipitate.With ethyl acetate extraction, anhydrous sodium sulfate drying.Remove solvent under reduced pressure,, get the lightpink powder, productive rate with acetone-crystal's system: 91.9%, mp:212-214 ℃.
1HNMR(DMSO-d
6)δ：6.29(s，1H，4-H)，6.53(d，2H，J＝2.0Hz，2，6H)，6.60(m，1H，4-H)，6.71(d，1H，J＝8.4Hz，3-H)，6.99(d，1H，J＝2.8Hz，6-H)，7.34，6.87(d，2H，J＝16.4Hz，α，β-H)。
Embodiment 7
(E)-3,3 ', 5,5 '-tetrahydroxy Stilbene
3,5-dimethoxy-benzyl phosphonic acid ester synthetic: add 3 in the 100mL there-necked flask, 5-dimethoxy-benzyl bromine (0.01mol), triethyl-phosphite (0.015mol), tetrabutylammonium iodide is a small amount of, stirs, and oil bath is heated to 110-115 ℃, reacts 6 hours.With reactant underpressure distillation below 90 ℃, remove excessive triethyl-phosphite, remaining light golden rod yellow oily matter is product in the bottle, is directly used in next step reaction.
(E)-3,3 ', 5,5 '-tetramethoxy Stilbene synthetic: go up step reaction gained phosphonic acid ester and be dissolved in the 25mL dry tetrahydrofuran (THF), cryosel is bathed and is cooled to below 0 ℃, stirs to add NaH powder (0.025mol) down rapidly, stirs 30min.Stir down and slowly drip 3, the THF solution 25mL of 5-dimethoxy benzaldehyde (0.01mol).Reactant is risen to room temperature (14-25 ℃), stirred 6-8 hour.In reaction solution impouring frozen water, reaction solution is neutralized to slant acidity with 1M HCl solution, with ethyl acetate extraction, organic phase is with saturated NaCl solution washing, anhydrous sodium sulfate drying.Reclaim solvent, add small amount of ethanol-methylene dichloride recrystallization in the residue, get off-white powder, esterification, condensation two-step reaction total recovery 83.0%, mp:135-136 ℃.
1HNMR(CDCl
3)δ：3.84(s，12H，OCH
3)，6.40(t，2H，J＝2.0Hz，，4，4-H)，6.67(d，4H，J＝2.0Hz，2，2，6，6-H)，7.01(s，2H，α，β-H)。
(E)-3,3 ', 5,5 '-tetrahydroxy Stilbene synthetic: add (E)-3 in the 100mL there-necked flask, 3 ', 5,5 '-tetramethoxy Stilbene (4mmol), with the dissolving of 40mL anhydrous methylene chloride, ice-water bath is cooled to below 0 ℃, the inflated with nitrogen protection.Stir and slowly drip 3.4mL BBr down
3Anhydrous methylene chloride solution 20mL, 26-40 ℃ was stirred 6 hours.In reaction solution impouring 200mL frozen water, stir, produce white precipitate.With ethyl acetate extraction, anhydrous sodium sulfate drying.Remove solvent under reduced pressure, with acetone crystal system, light yellow little crystal grain, productive rate: 95%, mp＞300 ℃.
1HNMR(DMSO-d
6)δ：6.11(t，2H，J＝1.6Hz，4，4-H)，6.36(d，4H，J＝1.6Hz，2，2，6，6-H)，6.79(s，2H，α，β-H)。
Embodiment 8
(E)-2,2 ', 5,5 '-tetrahydroxy Stilbene
2,5-dimethoxy-benzyl phosphonic acid ester synthetic: add 3 in the 100mL there-necked flask, 5-dimethoxy-benzyl chlorine (0.01mol), triethyl-phosphite (0.015mol), tetrabutylammonium iodide is a small amount of, stirs, and oil bath is heated to 100-115 ℃, reacts 6 hours.With reactant underpressure distillation below 90 ℃, remove excessive triethyl-phosphite, remaining light golden rod yellow oily matter is product in the bottle, is directly used in next step reaction.
(E)-2,2 ', 5,5 '-tetramethoxy Stilbene synthetic: go up step reaction gained phosphonic acid ester and be dissolved in the 25mL dry tetrahydrofuran (THF), cryosel is bathed and is cooled to below 0 ℃, stirs to add NaH powder (0.025mol) down rapidly, stirs 30min.Stir down and slowly drip 2, the THF solution 25mL of 5-dimethoxy benzaldehyde (0.01mol).Reactant is risen to room temperature (14-25 ℃), stirred 6-8 hour.In reaction solution impouring frozen water, reaction solution is neutralized to slant acidity with 1M HCl solution, with ethyl acetate extraction, organic phase is with saturated NaCl solution washing, anhydrous sodium sulfate drying.Reclaim solvent, add small amount of ethanol-recrystallization in the residue, get light yellow needle-like crystal, esterification, condensation two-step reaction total recovery 87.0%, mp 94.5-96 ℃.
1HNMR(CDCl
3)δ：3.82(s，6H，2，2-OCH
3)，3.83(s，6H，5，5-OCH
3)，6.79(dd，2H，J＝9.0Hz，J＝2.4Hz，4，4-H)，6.83(d，2H，J＝9.0Hz，3，3-H)，7.20(d，2H，J＝2.4Hz，6，6-H)，7.43(s，2H，α，β-H)。
(E)-2,2 ', 5,5 '-tetrahydroxy Stilbene synthetic: add (E)-3 in the 100mL there-necked flask, 3 ', 5,5 '-tetramethoxy Stilbene (2mmol), with the dissolving of 40mL anhydrous methylene chloride, the cryosel water-bath is cooled to below 0 ℃, the inflated with nitrogen protection.Stir and slowly drip 3.0mL BBr down
3Anhydrous methylene chloride solution 20mL, 26-30 ℃ was stirred 3-6 hour down.In reaction solution impouring 200mL frozen water, stir, produce white precipitate.Remove methylene chloride under reduced pressure, the pressurization suction filtration gets the oyster white powdery solid, productive rate: 40.2%.
1HNMR(DMSO-d
6)δ：6.49(dd，2H，J＝8.4Hz，J＝2.0Hz，4，4-H)，6.65(d，2H，J＝8.4Hz，3，3-H)，6.91(d，2H，J＝2.4Hz，6，6-H)，7.20(s，2H，α，β-H)。
Embodiment 9
(E)-4,4 '-tetrahydroxy Stilbene
Synthesizing of 4-methoxy-benzyl phosphonic acid ester: add 4-methoxy-benzyl chlorine (0.01mol) in the 100mL there-necked flask, triethyl-phosphite (0.015mol), tetrabutylammonium iodide is a small amount of, stirs, and oil bath is heated to 100-115 ℃, reacts 6 hours.With reactant underpressure distillation below 90 ℃, remove excessive triethyl-phosphite, remaining light golden rod yellow oily matter is product in the bottle, is directly used in next step reaction.
(E)-4,4 '-dimethoxy Stilbene is synthetic: go up step reaction gained phosphonic acid ester and be dissolved in the 25mL dry tetrahydrofuran (THF), cryosel is bathed and is cooled to below 0 ℃, stirs to add NaH powder (0.025mol) down rapidly, stirs 30min.Stir the THF solution 25mL that slowly drips aubepine (0.01mol) down.Reactant is risen to room temperature (14-25 ℃), stirred 6-8 hour.In reaction solution impouring frozen water, reaction solution is neutralized to slant acidity with 1M HCl solution, behind the recovery tetrahydrofuran (THF), the adularescent tabular crystal is separated out, productive rate 79.2%.
1HNMR(CDCl
3)δ：3.82(s，6H，4，4-OCH
3)，6.89(d，4H，J＝8.8Hz，3，3’，5，5’-H)，7.42(d，4H，J＝8.8Hz，2，2’，6，6’-H)，6.93(s，2H，α，β-H)。
(E)-4,4 '-dihydroxyl Stilbene is synthetic: add 1.8mL BBr in the 100mL there-necked flask
3Anhydrous methylene chloride solution 20mL, inflated with nitrogen protection, under 19-20 ℃, with 50mL anhydrous methylene chloride dissolving (E)-4,4 '-dimethoxy Stilbene (2mmol) slowly is added dropwise in the boron tribromide.Dropwise, reaction heats up 30 ℃ and stirred 3-6 hour down.In reaction solution impouring 200mL frozen water, stir, produce white precipitate.Remove methylene chloride under reduced pressure, the pressurization suction filtration gets white powdery solid.
1HNMR(DMSO-d
6)δ：6.74(d，4H，J＝8.4Hz，3，3’，5，5’-H)，7.35(d，4H，J＝8.4Hz，2，2’，6，6’-H)，6.89(s，2H，α，β-H)。
Embodiment 10-12
(E)-3 '-((E)-3-methyl-1-butene)-3,4 ', 5-trimethoxy Stilbene
Synthesizing of 3-chloromethyl-4-methoxybenzaldehyde: add formalin and the 2.5g zinc chloride of 5.0g 37-40% in three mouthfuls of pyriform bottles of 50mL, place water-soluble slowly intensification, simultaneously to wherein leading to HCl gas.When above-mentioned reaction solution reaches 58-60 ℃, the 6.8g aubepine is slowly splashed into, after dropwising, keep this thermotonus 3-8h.In reaction solution impouring separating funnel, add 50mL ethyl acetate and 50mL water, fully vibration divides water-yielding stratum, and organic phase is again with 50mL water and the saturated NaHCO of 50mL
3The aqueous solution washs respectively, at last with anhydrous Na
2SO
4Dewater.After reclaiming ethyl acetate, the resistates cooling is directly separated out the granular crystal of sundown, productive rate 60.7%.
1HNMR(CDCl
3)δ：3.98(s，3H，4-OCH
3)，4.67(s，2H，3-CH
2)，7.02(d，1H，J＝8.4Hz，5-H)，7.86(dd，1H，J＝8.4Hz，J＝2.0Hz，6-H)，7.92(d，1H，J＝2.0Hz，2-H)，9.90(s，1H，1-CHO)。
3,5-dimethoxy-benzyl phosphonic acid ester synthetic: add 3 of 0.01mol in the 50mL there-necked flask, 5-dimethoxy-benzyl bromine, the 0.015mol triethyl-phosphite, tetrabutylammonium iodide is a small amount of, stirs, and oil bath is heated to 110-115 ℃, reaction 3-6h.With reactant underpressure distillation below 90 ℃, remove excessive triethyl-phosphite, remaining light golden rod yellow oily matter is product in the bottle, is directly used in next step reaction.
3 '-chloromethyl-3,4 ', 5-trimethoxy Stilbene synthetic: go up step reaction gained phosphonic acid ester oily matter and be dissolved in the 25mL dry tetrahydrofuran (THF), cryosel is bathed and is cooled to below 0 ℃, stirs to add NaH powder (0.025mol) down rapidly, stirs 30min.Stir the 25mLTHF solution that slowly drips 3-chloromethyl-4-methoxybenzaldehyde of 0.01mol down.Reactant is risen to room temperature (14-25 ℃), stir 6-8h.In reaction solution impouring frozen water, reaction solution is neutralized to slant acidity with 1M HCl solution, with ethyl acetate extraction, organic phase is with saturated NaCl solution washing, anhydrous sodium sulfate drying.Reclaim solvent, add the small amount of ethanol recrystallization in the residue, esterification, condensation two-step reaction total recovery 59.7%.
1HNMR(CDCl
3)δ：3.83(s，6H，3，5-OCH
3)，3.90(s，4H，4’-OCH
3)，4.67(s，2H，3’-CH
2)，6.38(t，1H，J＝2.0Hz，4-H)，6.65(d，2H，J＝2.4Hz，2，6-H)，6.69(d，1H，J＝8.4Hz，5-H)，6.92，7.02(d，2H，J＝16.4Hz，α，β-H)，7.43(dd，1H，J＝8.4Hz，J＝2.0Hz，6-H)，7.53(d，2H，J＝2.0Hz，2-H)。
3,4 ', 5-trimethoxy Stilbene-3 '-methylene radical phosphine ester synthetic: add 3 '-chloromethyl-3 of 0.005mol in the 50mL there-necked flask, 4 ', 5-trimethoxy Stilbene, the 0.0075mol triethyl-phosphite, tetrabutylammonium iodide is a small amount of, stir, oil bath is heated to 110-115 ℃, reaction 3-6h.With reactant underpressure distillation below 90 ℃, remove excessive triethyl-phosphite, remaining light golden rod yellow oily matter is product in the bottle, is directly used in next step reaction.
(E)-3 '-((E)-3-methyl-1-butene)-3,4 ', 5-trimethoxy Stilbene synthetic: go up step reaction gained phosphonic acid ester oily matter and be dissolved in the 25mL dry tetrahydrofuran (THF), cryosel is bathed and is cooled to below 0 ℃, stir and add NaH powder (0.0125mol) down rapidly, stirring 30min.Stir the 25mL THF solution that slowly drips the isobutyric aldehyde of 1mL down.Reactant is risen to room temperature (14-25 ℃), stir 6-8h.In reaction solution impouring frozen water, reaction solution is neutralized to slant acidity with 1M HCl solution, with ethyl acetate extraction, organic phase is with saturated NaCl solution washing, anhydrous sodium sulfate drying.Reclaim solvent, residue is a golden yellow oily, non-crystallizable.Separate (Mercker 200-300 order silica gel), elutriant (normal hexane: ethyl acetate=5: 1), obtain golden yellow oily product, productive rate: 65.0% through post.
1HNMR(CDCl
3)δ：1.11(s，3H，CH
3)，1.13(s，3H，CH
3)，2.51(m，1H，3″-CH)，3，81(s，6H，3，5-OCH
3)，3.84(s，4H，4’-OCH
3)，6.25(dd，1H，J＝16.4Hz，J＝6.25Hz，2″-H)，6.37(t，1H，J＝2.0Hz，4-H)，6.65(d，2H，J＝2.0Hz，2，6-H)，6.67(d，1H，J＝16.4Hz，1″-H)，6.82(d，1H，J＝8.4Hz，6-H)，6.92，7.04(d，2H，J＝16.4Hz，α，β-H)，7.31(dd，1H，J＝8.4Hz，J＝2.0Hz，5′-H)，7.58(d，2H，J＝2.0Hz，2′-H)。
(E)-3 '-((E)-3-methyl-1-butene)-2,4 ', the synthesis condition of 5-trimethoxy Stilbene is the same substantially, post separate golden yellow oily matter.
1HNMR(CDCl
3)δ：1.11(s，3H，CH
3)，1.13(s，3H，CH
3)，2.51(m，1H，3″-CH)，3,81(s，3H，5-OCH
3)，3.84(s，3H，2-OCH
3)，3.85(s，3H，4-OCH
3)，6.26(dd，J＝16.0Hz，J＝6.8Hz，2″-H)，6.67(d，1H，J＝16.0Hz，1″-H)，6.76(dd，1H，J＝9.0Hz，J＝2.8Hz，4-H)，6.82(d，1H，J＝9.0Hz，3-H)，6.82(d，1H，J＝8.4Hz，6-H)，7.14(d，1H，J＝2.8Hz，6-H)，7.05，7.32(d，2H，J＝16.4Hz，α，β-H)，7.31(dd，1H，J＝8.4Hz，J＝2.0Hz，5-H)，7.59(d，1H，J＝2.0Hz，2-H)。
(E)-3 '-((E)-3-methyl-1-butene)-4,4 '-synthesis condition of dimethoxy Stilbene is the same substantially, uses ethanol/CH
2Cl
2Recrystallization gets the milk yellow powder.
1HNMR(CDCl
3)δ：1.11(s，3H，CH
3)，1.13(s，3H，CH
3)，2.51(m，1H，3″-CH)，3,83(s，3H，4-OCH
3)，3.86(s，3H，4-OCH
3)，6.25(dd，J＝16.0Hz，J＝6.8Hz，2″-H)，6.67(d，1H，J＝16.0Hz，1″-H)，6.89(d，2H，J＝8.8Hz，3′，5′-H)，7.44(d，2H，J＝8.8Hz，2′，6′-H)，6.83(d，1H，J＝8.4Hz，6-H)，6.92，6.97(d，2H，J＝16.0Hz，α，β-H)，7.31(dd，1H，J＝8.4Hz，J＝2.0Hz，5-H)，7.57(d，2H，J＝2.0Hz，2-H)。
Claims (4)
1, a kind ofly have a substituent polyhydroxy stilbenes compound, it is characterized in that this compounds has following general structure (I):
In the general formula (I):
When the X=N atomic time,
R
1＝O；
R
2-R
10=identical or different H, OH, OR
1, C
1-C
8Alkyl, C
2-C
8Thiazolinyl, C
2-C
8Alkynyl, C
3-C
9Cycloalkyl, phenyl, benzyl or by 1-3 phenyl or benzyl that replaces by Y;
R
1=C
1-C
6Alkyl, C
2-C
6Thiazolinyl, C
2-C
6Alkynyl, C
3-C
7Cycloalkyl, phenyl, benzyl or 1-3 phenyl or benzyl that is replaced by Y;
Y=C
1-C
3Alkyl, C
2-C
4Thiazolinyl, halogen, CN or NO
2
When the X=C atomic time,
R
1-R
10=identical or different H, OH, OR
1, C
1-C
8Alkyl, C
2-C
8Thiazolinyl, C
2-C
8Alkynyl, C
3-C
9Cycloalkyl, phenyl, benzyl or by 1-3 phenyl or benzyl that replaces by Y;
R
1=C
1-C
6Alkyl, C
2-C
6Thiazolinyl, C
2-C
6Alkynyl, C
3-C
7Cycloalkyl, phenyl, benzyl or 1-3 phenyl or benzyl that is replaced by Y;
Y=C
1-C
3Alkyl, C
2-C
4Thiazolinyl, halogen, CN or NO
2
2, polyhydroxy stilbenes compound according to claim 1, its feature in preferred 14 compounds is:
(1) (E)-and 2-[2-(2, the 5-dihydroxy phenyl) vinyl]-3, the 4-dihydroxy-pyridine;
(2) (E)-and 2-[2-(3, the 5-dihydroxy phenyl) vinyl]-3, the 4-dihydroxy-pyridine;
(3) (E)-and 2-[2-(2, the 5-dihydroxy phenyl) vinyl]-3,5-dimethyl-4-pyridone;
(4) (E)-and 2-[2-(4-hydroxy phenyl) vinyl]-3,5-dimethyl-4-pyridone;
(5) (E)-and 2-[2-(3, the 5-dihydroxy phenyl) vinyl]-3,5-dimethyl-4-pyridone;
(6) (E)-and 5-[2-(3, the 5-dihydroxy phenyl) vinyl]-1, the 3-dihydroxy-benzene;
(7) (E)-and 4-[2-(3, the 5-dihydroxy phenyl) vinyl]-1, the 3-dihydroxy-benzene;
(8) (E)-and 2-[2-(3, the 5-dihydroxy phenyl) vinyl]-1, the 3-dihydroxy-benzene;
(9) (E)-and 4-[2-(4-hydroxy phenyl) vinyl]-1, the 3-dihydroxy-benzene;
(10) (E)-and 4-[2-(2, the 4-dihydroxy phenyl) vinyl]-1, the 3-dihydroxy-benzene;
(11) (E)-and 4-[2-(2, the 5-Dimethoxyphenyl) vinyl]-1, the 3-dihydroxy-benzene;
(12) (E)-and 5-[2-(4-methoxyl group-3-((E)-3-methyl-1-butene base) phenyl) vinyl]-1, the 3-dimethoxy benzene;
(13) (E)-and 4-[2-(4-hydroxy phenyl) vinyl]-2 ((E)-3-methyl-butenyl) phenol;
(14) (E)-and 2-[2-(4-methoxyl group-3-((E)-3-methyl-1-butene base) phenyl)] vinyl]-1, the 4-dimethoxy benzene.
3,, it is characterized in that this method is according to the preparation method of the described polyhydroxy stilbenes compound of claim 1:
At first, will have benzyl chloride or the bromide and the triethyl-phosphite of alkoxy substituent, in molar ratio 1: the ratio of 1.5-15 is added in the reactor, in the presence of a small amount of tetrabutylammonium iodide,, stir 6-18h in 95-125 ℃, then, excessive triethyl-phosphite is removed in underpressure distillation, gets phosphonic acid ester and is dissolved in the dry tetrahydrofuran (THF), be cooled to below 0 ℃, stir the rapid down 60%NaH of adding, stir, and under agitation slowly drip the THF solution of the alkoxy benzene formaldehyde of replacement; Drip, reaction mixture is risen to room temperature, stir 8-16h.Be chilled to 0 ℃, slowly drip water 10ml, cancellation excessive N aH.Reaction solution is neutralized to pH4-6 with HCl solution.With saturated NaCl solution washing, anhydrous sodium sulfate drying reclaims solvent with ethyl acetate extraction, organic phase, and the residue recrystallization gets purified alkoxyl group stilbenes compound; To make with extra care the alkoxyl group stilbenes compound and dissolve with anhydrous methylene chloride, and be cooled to below 0 ℃, the inflated with nitrogen protection is stirred and is slowly dripped BBr down
3Anhydrous methylene chloride solution 20ml, dropwise, rise to 25-28 ℃, stir 3-6h, in reaction solution impouring frozen water, stir, add NaHCO
3Saturated solution is adjusted to about pH7, the micro emulsion yellow mercury oxide occurs, and directly suction filtration can obtain product, and useable solvents is carried out recrystallization.
4, according to the purposes of the described polyhydroxy stilbenes compound of claim 1, it is characterized in that containing the polyhydroxystilbene compounds of 0.001-50% (wt) active ingredient and the composition of one or more medicine inert matters or assistant agent formation, be used for suppressing and killing sars coronavirus.
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