CN101318950B - Preparation method for couplet benzene ring octadiene system lignans and application thereof - Google Patents

Preparation method for couplet benzene ring octadiene system lignans and application thereof Download PDF

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CN101318950B
CN101318950B CN 200810058702 CN200810058702A CN101318950B CN 101318950 B CN101318950 B CN 101318950B CN 200810058702 CN200810058702 CN 200810058702 CN 200810058702 A CN200810058702 A CN 200810058702A CN 101318950 B CN101318950 B CN 101318950B
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alcohol
alkali
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CN101318950A (en
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刘靖平
孙汉董
张洪彬
肖伟烈
李蓉涛
普建新
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Kunming Institute of Botany of CAS
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Kunming Institute of Botany of CAS
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Abstract

The invention provides a method for preparing dibenzocyclooctadiene lignan as shown in formula (I) and an application of the dibenzocyclooctadiene lignan on anti-HIV-1. The method has readily available raw materials, and simple and easy operation, and the prepared compound has remarkable anti-HIV-1 activity. R1=OH, R2=OCH3 or R1=OCH3.

Description

The preparation method of couplet benzene ring octadiene system lignans and its application
Technical field
The present invention relates to the preparation method of the compound couplet benzene ring octadiene system lignans shown in the structural formula (I), and the application in preparation anti-AIDS (HIV-1) medicine.
R 1=OH, R 2=OCH 3Perhaps R 1=OCH 3, R 2=OH
Background technology
Since Patient With Aids report in 1981, its popular rapid spread is to countries in the world.Ministry of Health's circular shows: end on October 31st, 2006, whole nation accumulative total over the years reports acquired immune deficiency syndrome (AIDS) 183733 examples, wherein AIDS patients 40667 examples; Dead 12464 examples, epidemic status is comparatively serious, and the possibility that further spreads still exists.As 16 great special projects one of, clearly be the most important thing in China development in science and technology with " the serious infectious diseases controls such as acquired immune deficiency syndrome (AIDS) and viral hepatitis " in February, 2006 " National Program for Medium-to Long-term Scientific and Technological Development " issued by the State Council.The present clinical inverase that uses is biotechnological formulation mostly, and these medicines existence treatments are expensive, toxic side effect large, the defectives such as generation loaded down with trivial details, that can not remove body inner virus and multidrug resistant disease strain of taking medicine.Therefore, developing a kind of alternative these biotechnological formulations or the medicine complementary with it is very important.
In recent years, natural product has demonstrated the result who gets a good chance of in treating AIDS.So far finding has the natural product that surpasses 100 kinds to have good HIV (human immunodeficiency virus)-resistant activity, as: glycyrrhizin, hypericin, curcumine, Soyasaponin, camptothecine, lentinan, smallpox albumen etc.Simultaneously, these natural products can be used as lead compound, have the more template of strong biological activity new drug as design.And this compounds of couplet benzene ring octadiene class xylogen has extremely strong restraining effect to hiv integrase, can suppress the reverse transcription process of HIV-1.Because this compounds comes from natural phant, most lignanoids have no side effect to human body cell simultaneously, have the possibility that is developed to as the treatment AIDS-treating medicine, therefore synthetic the seeming of this compounds are necessary very much.
So far, in the prior art there are no the report of couplet benzene ring octadiene class lignin compou nd synthesis method.
Summary of the invention
The purpose of this invention is to provide a kind of preparation method of couplet benzene ring octadiene class lignin compound, another purpose provides the application of above-claimed cpd in anti-HIV-1.
In order to realize above-mentioned purpose of the present invention, the invention provides following technical scheme:
The preparation method of couplet benzene ring octadiene system lignans compound shown in the structural formula (I) is take gallic acid as raw material, through esterification; the phenolic hydroxyl group protection, etherificate is gone protection; etherificate; reduction, halo, nucleophilic substitution; the preparation of Horner-Emmons reagent; the Horner-Emmons reaction, catalytic hydrogenation, oxidative coupling series reaction obtain the compound shown in the structural formula (I)
Figure RE-S200810058702XD00021
R 1=OH, R 2=OCH 3Perhaps R 1=OCH 3, R 2=OH
Described esterification is the esterification of gallic acid carboxyl, adopt methyl esters or ethyl ester or propyl ester, solvent is methyl alcohol or ethanol or propyl alcohol, the acid that catalysis is used is sulfuric acid or sulfur oxychloride, the sulfuric acid consumption is the mol ratio of 5%-10%, the sulfur oxychloride consumption is the mol ratio of 10%-100%, and temperature of reaction is that room temperature is to reflux.
Described phenolic hydroxyl group protection, i.e. previous step esterification products therefrom reacts with ortho-formiate under acid catalysis, protection two phenolic hydroxyl groups wherein; The mol ratio of reaction substrate and ortho-formiate is 1: 2-10, ortho-formiate can be original acid A ester or ethyl orthoformate, the acid of adopting can be tosic acid or acidic resins (Amberlyst) or polynite (Montrollinite), the preferential acidic resins (Amberlyst) that adopt, the solvent that adopts can be benzene or toluene or dimethylbenzene, can be not yet solubilizing agent and take ortho-formiate as solvent in addition.
Described etherificate, namely the previous step phenolic hydroxyl group protects products therefrom under the alkali effect, remaining the 3rd phenolic hydroxyl group of etherificate; Etherifying reagent adopts methyl iodide or methyl-sulfate or bromobenzyl (BnBr) or to methoxyl group bromobenzyl (p-MeOBnBr), consumption is 1-5 with respect to reaction substrate: 1 mol ratio, alkali adopts salt of wormwood or yellow soda ash or sodium hydride or potassium hydride KH or sodium hydroxide or potassium hydroxide or sodium amide, solvent adopts acetone or alcohol or methyl-sulphoxide or water, the preferential acetone that uses, temperature of reaction is that room temperature is to reflux.
Described going protected, and namely previous step etherificate products therefrom goes protection through acidifying, restores two original phenolic hydroxyl groups; Dilute sulphuric acid or dilute hydrochloric acid or dilute phosphoric acid or sulfonic acid are adopted in acid, and consumption is the mol ratio of 10%-100% with respect to reaction substrate, and solvent adopts methyl alcohol or ethanol or acetone.
Described etherificate, namely previous step goes to protect products therefrom under the alkali effect, two phenolic hydroxyl groups of etherificate; Etherifying reagent adopts methyl iodide or methyl-sulfate or methylene iodide or methylene bromide or iodine monobromethane or methyl chlorobromide, consumption is 1-5 with respect to reaction substrate: 1 mol ratio, alkali adopts salt of wormwood or yellow soda ash or sodium hydride or potassium hydride KH or sodium hydroxide or potassium hydroxide or sodium amide, solvent adopts acetone or methyl-sulphoxide (DMSO) or N, dinethylformamide (DMF) or N, N-N,N-DIMETHYLACETAMIDE (DMAC) preferentially uses DMF, and temperature of reaction is room temperature-80 ℃.
Described reduction, namely previous step etherificate products therefrom obtains alcohol through reduction; Reductive agent adopts lithium aluminum hydride (LiAlH 4) or di-isopropyl aluminium hydrogen (Dibal-H) or aluminium hydrogen (AlH 3) or calcium borohydride (CaBH 4) or borine (BH 3) or sodium borohydride-titanium tetrachloride (NaBH 4-TiCl 4), preferentially adopt lithium aluminum hydride (LiAlH 4), consumption is 1: 1 mol ratio with respect to reaction substrate, solvent uses ether or tetrahydrofuran (THF), 0 ℃-80 ℃ of temperature of reaction.
Described halo, i.e. previous step etherificate gained alcohol product and halogenating agent effect gets halides; Halogenating agent adopts PX 3(X=I, Br, Cl) or PPh 3-CX 4Or NXS (X=C, B, I) or HX (X=I, Br, Cl) or X 2(X=I, Br, Cl), consumption is 1-3 with respect to raw material: 1 mol ratio, solvent uses methylene dichloride or 1,2-ethylene dichloride or chloroform, room temperature or illumination reaction.
Described nucleophilic substitution, namely previous step halo products therefrom under the alkali effect with 2-butanone generation nucleophilic substitution reaction; Alkali adopts lithium diisopropylamine (LDA) or the silica-based Lithamide of hexamethyl (LiHMDS) or the silica-based sodium amide of hexamethyl (NaHMDS) or the silica-based potassium amide of hexamethyl (KHMDS) or butyllithium or sodium hydride or potassium hydride KH, preferential LDA or the LiHMDS of adopting, the mol ratio of consumption and 2-butanone reaction substrate is 1.5: 1.5: 1, temperature of reaction-78 ℃-0 ℃, the solvents tetrahydrofurane of use or ether.
Described Horner-Emmons reagent preparation, i.e. previous step nucleophilic substitution products therefrom and phosphite reaction obtains Horner-Emmons reagent; Phosphite adopts methyl phosphite or phosphorous acid ethyl ester, and consumption is 1.5-5 with respect to reaction substrate: 1 mol ratio, do not need other solubilizing agent, and 120 ℃-150 ℃ of temperature of reaction are not until till having low-boiling point liquid to steam.
Described Horner-Emmons reaction namely go up two step nucleophilic substitution products therefroms and Horner-Emmons reagent and is prepared products therefrom and Horner-Emmons occurs under the alkali effect react; The mol ratio of claim 9 products therefrom and claim 10 products therefrom is 1: 1-10, alkali adopts sodium hydride (NaH) or potassium hydride KH (KH) or potassium tert.-butoxide (KO tBu) or butyllithium, solvent uses tetrahydrofuran (THF) or benzene or toluene or dimethylbenzene, preferentially adopts potassium tert.-butoxide (KO tBu) be alkali, toluene is solvent, and temperature of reaction is 80 ℃-120 ℃.
Described catalytic hydrogenation, namely the previous step products therefrom is take transition metal or precious metal as catalyzer, and room temperature is led to hydrogen, catalytic hydrogenation; The preferential catalyzer that adopts of hydrogenation is nickel, palladium or rhodium, and consumption is 0.1%-100% with respect to the reaction substrate weight ratio, solvent adopts alcohol or ester or ether, preferentially adopts methyl alcohol or ethanol or ethyl acetate and composition thereof to be solvent.
Described oxidative coupling, namely previous step catalytic hydrogenation products therefrom oxidative coupling under the oxygenant effect obtains the compound that structural formula is (I); Oxygenant adopts 2,3-, two chloro-5,6-dicyan-Isosorbide-5-Nitrae-benzoquinones (DDQ) or Iron triperchlorate (Fe (ClO 4) 3), corresponding solvent is the mixed solvent of trifluoroacetic acid or trifluoroacetic acid-methylene dichloride, or molybdenum pentachloride (MoCl 5), or methylene dichloride; Preferential molybdenum pentachloride (the MoCl that adopts 5) be oxygenant, consumption is 5-1 with respect to reaction substrate: 1, methylene dichloride is solvent, temperature of reaction is 40 ℃-60 ℃.
The application of compound in preparation anti-AIDS HIV-1 medicine with structural formula (I).
The present invention is compound synthetic that comes implementation structure formula (I) by following steps:
Step 1
Gallic acid (gallic acid) is dissolved in an amount of alcohol, adds acid catalysis, temperature of reaction is in room temperature-100 ℃.A few hours in reaction times were by tens of hours.Boil off remaining alcohol after reacting completely, washing, concentrated, recrystallization can obtain target product.Described alcohol is methyl alcohol, ethanol, and propyl alcohol etc., acid is the vitriol oil, sulfur oxychloride (SOCl 2) etc.The product that obtains when used alcohol is methyl alcohol is compound 1.
Step 2
Figure RE-S200810058702XD00051
In organic solvent, above-mentioned compound 1 and ortho-formiate under heating condition, through acid catalysis, reacted 2-18 hour.Ortho-formiate can be methyl esters, ethyl ester etc.When being ethyl orthoformate, obtain compound 2 when used.Wherein the mol ratio of compound 1 and ortho-formiate is 1: 2-10, organic solvent are benzene, toluene, and dimethylbenzene etc. can not wanted organic solvent to not impact of reaction yet.Described acid is acidic resins (Ameberlyst), polynite (Montmorillonite) etc.
Step 3
In polar solvent and under the room temperature-70 ℃, compound 2 alkali and halohydrocarbons reaction 2-18 hour, obtains target product.R can be methyl (CH 3), benzyls (Bn) etc. are worked as R=CH 3The time, product is compound 3, when R=Bn, product is compound 4.Described polar solvent is acetone, methyl alcohol, and ethanol, methyl-sulphoxide (DMSO) etc., alkali is salt of wormwood (K 2CO 3), yellow soda ash (NaCO 3), sodium hydroxide (NaOH), potassium hydroxide (KOH), sodium hydride (NaH) etc.
Step 4
In alcohol and under the room temperature, above-claimed cpd 3 acidifyings 10 minutes-2 hours obtain compound 5.Described alcohol is methyl alcohol, ethanol, and Virahol etc., acid is dilute hydrochloric acid, dilute sulphuric acid, dilute phosphoric acid etc.
Step 5
Figure RE-S200810058702XD00061
In alcohol or acetone and under the room temperature, above-claimed cpd 4 acidifyings 10 minutes-2 hours obtain compound 6.Described alcohol is methyl alcohol, ethanol, and Virahol etc., acid is dilute hydrochloric acid, dilute sulphuric acid, dilute phosphoric acid, sulfonic acid etc.
Step 6
Figure RE-S200810058702XD00062
In dry polar solvent and under 50 ℃-100 ℃, compound 5, alkali with the dihalo methane reaction, obtains compound 7.Described polar solvent is DMF (DMF), N,N-dimethylacetamide (DMAC) etc., and alkali is salt of wormwood (K 2CO 3), yellow soda ash (NaCO 3), sodium hydride (NaH) etc., the dihalo hydrocarbon is methylene iodide, methylene bromide, 1,1 '-iodine monobromethane, 1,1 '-methyl chlorobromide etc.
Step 7
Figure RE-S200810058702XD00063
In polar solvent and under the room temperature-70 ℃, compound 6, alkali and methylating reagent reaction 2-18 hour obtain compound 8.Described polar solvent is acetone, methyl alcohol, and ethanol, methyl-sulphoxide (DMSO) etc., alkali is salt of wormwood (K 2CO 3), yellow soda ash (NaCO 3), sodium hydroxide (NaOH), potassium hydroxide (KOH), sodium hydride (NaH) etc., methylating reagent is methyl iodide (CH 3I), methyl-sulfate ((CH 3) 2SO 4) etc.
Step 8
In ethers solution, compound 7 obtains compound 9 with the reductive agent effect.Described ethers solution is ether, and tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane etc., reductive agent are tetrahydrochysene lithium aluminium (LiAlH 4), di-isopropyl aluminium hydrogen (Dibal-H), aluminium hydrogen (AlH 3), calcium borohydride (CaBH 4), borine (BH 3), sodium borohydride-titanium tetrachloride (NaBH 4-TiCl 4) etc.
Step 9
In ethers solution, compound 8 obtains compound 10 with the reductive agent effect.Described ethers solution is ether, and tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane etc., reductive agent are tetrahydrochysene lithium aluminium (LiAlH 4), di-isopropyl aluminium hydrogen (Dibal-H), aluminium hydrogen (AlH 3), calcium borohydride (CaBH 4), borine (BH 3), sodium borohydride-titanium tetrachloride (NaBH 4-TiCl 4) etc.
Step 10
Figure RE-S200810058702XD00073
In polar solvent, compound 9 gets target product with the halogenating agent effect.X can be I, Br, Cl.When X=Br, product is compound 11.Described halogenating agent can be PX 3(X=I, Br, Cl), PPh 3-CX 4, NXS (X=C, B, I), HX (X=I, Br, Cl), X 2(X=I, Br, Cl) etc., polar solvent can be methylene dichloride, 1,2-ethylene dichloride, chloroform etc.
Step 11
Compound 8 compound 12X=Br
In polar solvent, compound 10 gets target product with the halogenating agent effect.X can be I, Br, Cl.When X=Br, product is compound 12.Described halogenating agent can be PX 3(X=I, Br, Cl), NXS (X=C, B, I), HX (X=I, Br, Cl), X 2(X=I, Br, Cl) etc., polar solvent can be methylene dichloride, 1,2-ethylene dichloride, chloroform etc.
Step 12
Figure DEST_PATH_GDA0000064135980000012
Compound 11 compounds 13
In aprotic solvent ,-78 ℃-100 ℃, compound 11 and 2-butanone, the alkali effect obtains compound 13.Described aprotic solvent can be tetrahydrofuran (THF) (THF), ether, dioxane, benzene, toluene etc., alkali can be lithium diisopropylamine (LDA), the silica-based Lithamide of hexamethyl (LiHMDS), the silica-based sodium amide of hexamethyl (NaHMDS), the silica-based potassium amide of hexamethyl (KHMDS), butyllithium, sodium hydride, potassium hydride KH etc.
Step 13
Figure DEST_PATH_GDA0000064135980000013
Compound 12 compounds 14
In aprotic solvent ,-78 ℃-100 ℃, compound 12 and 2-butanone, the alkali effect obtains compound 14.Described aprotic solvent can be tetrahydrofuran (THF) (THF), ether, dioxane, benzene, toluene etc., alkali can be lithium diisopropylamine (LDA), the silica-based Lithamide of hexamethyl (LiHMDS), the silica-based sodium amide of hexamethyl (NaHMDS), the silica-based potassium amide of hexamethyl (KHMDS), butyllithium, sodium hydride, potassium hydride KH etc.
Step 14
Figure RE-S200810058702XD00091
The Dean-Stark device is housed, and under greater than 120 ℃ of temperature condition, compound 12 until there is not low-boiling point liquid to generate, namely obtains target product with the phosphite reaction.Described phosphite can be trimethyl phosphite, triethyl-phosphite.When used phosphite is triethyl-phosphite, R=C 2H 5, generating product is compound 16.
Step 15
Figure RE-S200810058702XD00092
The Dean-Stark device is housed, and under greater than 120 ℃ of temperature condition, compound 11 until there is not low-boiling point liquid to generate, namely obtains target product with the phosphite reaction.Described phosphite can be trimethyl phosphite, triethyl-phosphite.When used phosphite is triethyl-phosphite, R=C 2H 5, generating product is compound 18.
Step 16
Figure RE-S200810058702XD00093
In aprotic organic solvent, compound 16 first with alkali effect 10-30 minute then under 80 ℃ of-120 ℃ of temperature, add compound 13, TLC follows the tracks of reaction raw materials and disappears.Described aprotic organic solvent can be tetrahydrofuran (THF) (THF), benzene, toluene, dimethylbenzene etc.Alkali can be sodium hydride (NaH), potassium hydride KH (KH), potassium tert.-butoxide (KO tBu), butyllithium etc.
Step 17
Figure RE-S200810058702XD00101
In aprotic organic solvent, compound 14 first with alkali effect 10-30 minute then under 80 ℃ of-120 ℃ of temperature, add compound 18, TLC follows the tracks of reaction raw materials and disappears.Described aprotic organic solvent can be tetrahydrofuran (THF) (THF), benzene, toluene, dimethylbenzene etc.Alkali can be sodium hydride (NaH), potassium hydride KH (KH), potassium tert.-butoxide (KO tBu), butyllithium etc.
Step 18
Figure RE-S200810058702XD00102
Compound 19 is dissolved in the organic solvent, adds a certain proportion of metal catalyst nickel (Ni) or palladium (Pd) or rhodium (Rh) etc., room temperature is led to hydrogen reaction, can obtain reduzate compound 21 after 10 hours.The organic solvent of described use can be the alcoholic solvents such as methyl alcohol, ethanol, also can be ester class or the ether solvents such as ethyl acetate.
Step 19
Figure RE-S200810058702XD00103
Compound 20 is dissolved in the organic solvent, adds a certain proportion of metal catalyst nickel (Ni) or palladium (Pd) or rhodium (Rh) etc., room temperature is led to hydrogen reaction, can obtain reduzate compound 21 after 10 hours.The organic solvent of described use can be the alcoholic solvents such as methyl alcohol, ethanol, also can be ester class or the ether solvents such as ethyl acetate.
Step 20
Figure RE-S200810058702XD00111
At methylene dichloride (CH 2Cl 2) in, room temperature arrives under the temperature that refluxes, compound 21 and a certain proportion of molybdenum pentachloride (MoCl 5) effect can obtain structural formula and be the target product of (I).
The present invention provides the application of structural formula (I) compound in the medicine of preparation prevention or treatment acquired immune deficiency syndrome (AIDS) HIV-1 simultaneously.
Embodiment:
The following example is illustrating rather than limiting it of the inventive method.The multiple condition that it will be apparent to those skilled in the art and other modifications and the adaptive change of parameter comprise within the spirit and scope of the present invention.
Embodiment 1:
Figure RE-S200810058702XD00112
Get gallic acid 0.1mol and be dissolved among the new steaming methyl alcohol 250mL, slowly splash into vitriol oil 0.01mol, refluxed 17 hours.The fully rear pressure reducing and steaming partial solvent of TLC detection reaction is poured in the 500mL unsaturated carbonate aqueous solutions of potassium, and the adularescent solid is separated out.Tell white solid, (3 * 200mL) extract water with ethyl acetate.Merge organic phase, anhydrous sodium sulfate drying, concentrated, namely be compound 1 after the white solid drying of gained.
The productive rate of this reaction process is 97%.Relevant test data is as follows:
1H-NMR(300MHz，CDCl 3)：δ＝6.82(2H)，3.87(3H).
Embodiment 2
Figure RE-S200810058702XD00121
The Dean-Stark device is housed, get embodiment 1 gained compound 150mmol and be dissolved in the 200mL benzene, add the triethyl orthoformate of 150mmol and the acidic resins Amberlyst 15E of 5mg/mmol, reflux, TLC detects to follow the tracks of and filters after raw material disappears, and column chromatography got compound 2 after filtrate was concentrated.
The productive rate of this reaction process is 98%.Relevant test data is as follows:
1H-NMR(300MHz，CDCl 3)：δ＝7.39(1H)，7.28(1H)，7.06(1H)，3.87(3H)，3.56(2H)，1.2(3H).
Embodiment 3
Figure RE-S200810058702XD00122
Get embodiment 2 gained compound 240mmol and be dissolved among the acetone 200mL, add methyl iodide or bromobenzyl 60mmol, salt of wormwood 60mmol, back flow reaction, TLC detection reaction be rear the filtration fully, and concentrated, column chromatography gets compound 3 or compound 4.
The productive rate of this reaction process is 96%.Relevant test data is as follows:
Compound 3 1H-NMR (300MHz, CDCl 3): δ=7.28 (1H), 7.25 (1H), 7.10 (1H), 3.89 (3H), 3.86 (3H), 3.62 (2H), 1.34 (3H).
Compound 4 1H-NMR (300MHz, CDCl 3): δ=7.21-7.41 (8H), 5.06 (2H), 3.87 (3H), 3.81 (2H), 1.23 (3H).
Embodiment 4
Figure RE-S200810058702XD00131
Getting compound 3 or compound 430mmol is dissolved in an amount of methyl alcohol, the aqueous hydrochloric acid 10mL that adds 3N, the stirring at room reaction, TLC follows the tracks of and boils off solvent after reaction raw materials disappears, add ethyl acetate 200mL, saturated common salt water washing three times, anhydrous sodium sulfate drying concentrates and can obtain corresponding product compound 5 or compound 6.
The productive rate of this reaction process is 99%.Relevant test data is as follows:
Compound 5 1H-NMR (300MHz, CDCl 3): δ=6.91-7.23 (2H), 3.87 (3H), 3.72 (3H).
Compound 6 1H-NMR (300MHz, CDCl 3): δ=7.20-7.41 (7H), 5.01 (2H), 3.87 (3H).
Embodiment 5
Figure RE-S200810058702XD00132
Get embodiment 4 gained compounds 5 20mmol and be dissolved in the 100mL DMF (DMF), add methylene bromide 25mmol and salt of wormwood 50mmol, reaction is 4 hours under 80 ℃ of temperature, the TLC detection reaction is rear the filtration fully, and concentrated, column chromatography obtains compound 7.
The productive rate of this reaction process is 87%.Relevant test data is as follows:
Compound 7 1H-NMR (300MHz, CDCl 3): δ=7.24 (1H), 7.10 (1H), 6.02 (2H), 3.89 (3H), 3.86 (3H).
Embodiment 6
Figure RE-S200810058702XD00141
Get embodiment 4 gained compound 620mmol and be dissolved in the 100mL acetone, add methyl iodide 50mmol and salt of wormwood 50mmol, room temperature reaction filters until the TLC detection reaction is complete, and concentrated, column chromatography gets compound 8.
The productive rate of this reaction process is 93%.Relevant test data is as follows:
Compound 8 1H-NMR (300MHz, CDCl 3): δ=7.41-7.21 (7H), 5.06 (2H), 3.88 (3H), 3.81 (6H).
Embodiment 7
Figure RE-S200810058702XD00142
Get lithium aluminum hydride (LiAlH 4) 10mmol is dissolved in the 50mL tetrahydrofuran (THF), slowly adding is dissolved in the system of compound 7 of 50mL tetrahydrofuran (THF) in advance under 0 ℃ of condition, and TLC follows the tracks of reaction raw materials and disappears, and carefully adds rubble ice (having a large amount of bubbles to overflow) in batches, until without bubble formation, pour in the saturated aqueous ammonium chloride, tell organic layer, (3 * 100mL) extract water with ethyl acetate, merge organic phase, anhydrous sodium sulfate drying, concentrated, column chromatography gets compound 9.
The productive rate of this reaction process is 94%.Relevant test data is as follows:
Compound 9 1H-NMR (300MHz, CDCl 3): δ=6.51 (1H), 6.46 (1H), 5.84 (2H), 4.40 (2H), 3.88 (3H).
Embodiment 8
Figure RE-S200810058702XD00151
Get lithium aluminum hydride (LiAlH 4) 10mmol is dissolved in the 50mL tetrahydrofuran (THF), slowly adding is dissolved in the system of compound 8 of 50mL tetrahydrofuran (THF) in advance under 0 ℃ of condition, and TLC follows the tracks of reaction raw materials and disappears, and carefully adds rubble ice (having a large amount of bubbles to overflow) in batches, until without bubble formation, pour in the saturated aqueous ammonium chloride, tell organic layer, (3 * 100mL) extract water with ethyl acetate, merge organic phase, anhydrous sodium sulfate drying, concentrated, column chromatography gets compound 10.
The productive rate of this reaction process is 92%.Relevant test data is as follows:
Compound 10 1H-NMR (300MHz, CDCl 3): δ=7.40-7.23 (5H), 6.51 (1H), 6.46 (1H), 5.08 (2H), 4.40 (2H), 3.81 (6H), 2.79 (1H).
Embodiment 9
Figure RE-S200810058702XD00152
Get embodiment 7 gained compound 95mmol and be dissolved in the 30mL methylene dichloride, under 0 ℃, splash into phosphorus tribromide (PBr 3) 5mmol, after TLC follows the tracks of the reaction raw materials disappearance, slowly add saturated sodium bicarbonate aqueous solution until without Bubble formation, add suitable quantity of water, tell organic layer, (2 * 50mL) extractions merge organic phase to water with methylene dichloride, anhydrous sodium sulfate drying, concentrated, column chromatography gets compound 11.
The productive rate of this reaction process is 99%.Relevant test data is as follows:
Compound 11 1H-NMR (300MHz, CDCl 3): δ=6.51 (1H), 6.46 (1H), 5.84 (2H), 5.10 (2H), 3.88 (3H).
Embodiment 10
Get embodiment 8 gained compounds 10 5mmol and be dissolved in the 30mL methylene dichloride, under 0 ℃, splash into phosphorus tribromide (PBr 3) 5mmol, after TLC follows the tracks of the reaction raw materials disappearance, slowly add saturated sodium bicarbonate aqueous solution until without Bubble formation, add suitable quantity of water, tell organic layer, (2 * 50mL) extractions merge organic phase to water with methylene dichloride, anhydrous sodium sulfate drying, concentrated, column chromatography gets compound 12.
The productive rate of this reaction process is 97%.Relevant test data is as follows:
Compound 12 1H-NMR (300MHz, CDCl 3): δ=7.39-7.23 (5H), 6.52 (1H), 6.45 (1H), 5.10 (2H), 4.56 (2H), 3.80 (6H).
Embodiment 11
Figure RE-S200810058702XD00162
Getting 2-butanone 15mmol is dissolved in the 20mL tetrahydrofuran (THF), be cooled to-78 ℃, add LDA 15mmol, add compound 11 10mmol that are dissolved in advance the 20mL tetrahydrofuran (THF) after 30 minutes, pour in the saturated aqueous ammonium chloride after the TLC detection reaction is complete, tell organic layer, (3 * 50mL) extractions merge organic phase, drying to water with ethyl acetate, concentrated, column chromatography gets compound 13.
The productive rate of this reaction process is 86%.Relevant test data is as follows:
Compound 13 1H-NMR (300MHz, CDCl 3): δ=6.27 (1H), 6.24 (1H), 5.86 (2H), 3.82 (3H), 2.86-2.68 (2H), 2.36-2.42 (1H), 2.02 (3H), 0.97 (3H).
Embodiment 12
Figure RE-S200810058702XD00171
Getting 2-butanone 15mmol is dissolved in the 20mL tetrahydrofuran (THF), be cooled to-78 ℃, add LDA 15mmol, add compound 12 10mmol that are dissolved in advance the 20mL tetrahydrofuran (THF) after 30 minutes, pour in the saturated aqueous ammonium chloride after the TLC detection reaction is complete, tell organic layer, (3 * 50mL) extractions merge organic phase, drying to water with ethyl acetate, concentrated, column chromatography gets compound 14.
The productive rate of this reaction process is 88%.Relevant test data is as follows:
Compound 14 1H-NMR (300MHz, CDCl 3): δ=7.40-7.23 (5H), 6.50 (1H), 6.43 (1H), 5.08 (2H), 3.82 (6H), 2.86-2.68 (2H), 2.36-2.42 (1H), 2.02 (3H), 0.97 (3H).
Embodiment 13
The Dean-Stark device is housed, gets embodiment 10 gained compounds 12 10mmol and be dissolved in the triethyl orthoformate of 20mmol, 140 ℃ until there is not liquid return, and TLC follows the tracks of raw material and disappears, and column chromatography gets compound 16.
The productive rate of this reaction process is 90%.Relevant test data is as follows:
Compound 16 1H-NMR (300MHz, CDCl 3): δ=7.39-7.20 (5H), 6.51 (1H), 6.45 (1H), 5.08 (2H), 4.41-4.07 (4H), 3.82 (6H), 3.48 (2H), 0.98-1.25 (6H).
Embodiment 14
Figure RE-S200810058702XD00181
The Dean-Stark device is housed, gets embodiment 9 gained compounds 11 10mmol and be dissolved in the triethyl orthoformate of 20mmol, 140 ℃ until there is not liquid return, and TLC follows the tracks of raw material and disappears, and column chromatography gets compound 18.
The productive rate of this reaction process is 92%.Relevant test data is as follows:
Compound 18 1H-NMR (300MHz, CDCl 3): δ=6.27 (1H), 6.24 (1H), 5.87 (2H), 4.41-4.07 (4H), 3.87 (3H), 3.46 (2H), 0.98-1.28 (6H).
Embodiment 15
Figure RE-S200810058702XD00182
Getting embodiment 13 gained compound 168mmol is dissolved in the 20mL toluene, the potassium tert.-butoxide that adds 8mmol, add the compound 13 of 4mmol behind dissolution of solid, be heated to 100 ℃, TLC follows the tracks of and pours in the frozen water after compound 13 disappears, tell organic layer, (2 * 20mL) extractions merge organic phase, drying to water with ethyl acetate, concentrated, column chromatography gets compound 19.
The productive rate of this reaction process is 84%.Relevant test data is as follows:
Compound 19 1H-NMR (300MHz, CDCl 3): δ=7.47-7.31 (5H), 6.44-6.29 (4H), 6.11 (1H), 5.88 (2H), 5.14 (2H), 3.97-3.85 (9H), 2.73-2.69 (1H), 2.55-2.46 (2H), 1.73 (3H), 1.02 (3H).
Embodiment 16
Figure RE-S200810058702XD00191
Getting embodiment 14 gained compound 188mmol is dissolved in the 20mL toluene, the potassium tert.-butoxide that adds 8mmol, add the compound 14 of 4mmol behind dissolution of solid, be heated to 100 ℃, TLC follows the tracks of and pours in the frozen water after compound 14 disappears, tell organic layer, (2 * 20mL) extractions merge organic phase, drying to water with ethyl acetate, concentrated, column chromatography gets compound 20.
The productive rate of this reaction process is 80%.Relevant test data is as follows:
Compound 20 1H-NMR (300MHz, CDCl 3): δ=7.47-7.31 (5H), 6.44-6.29 (4H), 6.11 (1H), 5.88 (2H), 5.14 (2H), 3.97-3.85 (9H), 2.73-2.69 (1H), 2.55-2.46 (2H), 1.73 (3H), 1.02 (3H).
Embodiment 17
Figure RE-S200810058702XD00192
Get embodiment 15 gained compounds 19 or embodiment 16 gained compound 205mmol are dissolved in the 50mL ethyl acetate, add the 10%Pd/C of 0.1mg/mg, at room temperature logical hydrogen reaction, the TLC detection reaction is complete after 12 hours, filter, concentrated, column chromatography gets compound 21.
The productive rate of this reaction process is 96%.Relevant test data is as follows:
Compound 21 1H-NMR (300MHz, CDCl 3): δ=6.45-6.20 (4H), 5.93 (2H), 3.89-3.82 (9H), 2.73-2.23 (4H), 1.80-1.76 (2H), 0.90-0.85 (6H).
Embodiment 18
Figure RE-S200810058702XD00201
Get embodiment 17 gained compounds 21 2mmol and be dissolved in the 10mL methylene dichloride, add 4mmol molybdenum pentachloride (MoCl 5), refluxing 3 hours, TLC follows the tracks of and pours in the frozen water after compound 21 disappears, and tells organic layer, the water methylene dichloride (2 * 10mL) extractions merge organic phase, drying, and concentrated, column chromatography gets the compound of structural formula (I).
The productive rate of this reaction process is 41%.Relevant test data is as follows:
1H-NMR(300MHz，CDCl 3)：δ＝6.66-6.62(1H)，6.51-6.48(1H)，5.96-5.95(2H)，3.94-3.48(9H)，2.52-2.33(4H)，1.89-1.60(2H)，1.01-0.94(3H)，0.88-0.83(3H).MS(70Ev)：m/z(％)：386(100)[M]，299(15)，284(14)，219(14)，165(9).
Embodiment 19
Compound with structural formula (I) has been carried out In Vitro Anti HIV-1 activity experiment, and contrast is the natural product gomisin M 2(Gomisin M 2).The result shows that the compound with structural formula (I) of synthetic has more significant anti-HIV-1 effect (seeing Table 1) equally.
Figure RE-S200810058702XD00202
Table 1 compound vitro cytotoxicity and Anti-HIV-1 Active result
Figure RE-S200810058702XD00211
Embodiment 20:
Making first couplet benzene ring octadiene class lignin compound (I) by embodiment 1-18 step, is that 5: 1 ratio adds vehicle, pelletizing press sheet in itself and vehicle weight ratio.
Embodiment 21:
Make first couplet benzene ring octadiene class lignin compound (I) by embodiment 1-18 step, the injection liquid method for making injects water routinely, the essence filter, and injection liquid is made in the embedding sterilization.

Claims (1)

1. the preparation method of couplet benzene ring octadiene system lignans compound shown in the structure formula I is take gallic acid as raw material, through esterification; the phenolic hydroxyl group protection, etherificate is gone protection; etherificate again; reduction, halo, nucleophilic substitution; the preparation of Horner-Emmons reagent; the Horner-Emmons reaction, catalytic hydrogenation, the oxidative coupling series reaction obtains the compound shown in the structure formula I
Figure FDA0000215729221
It is characterized in that described esterification is the esterification of gallic acid carboxyl, gallic acid gallic acid is dissolved in an amount of alcohol, add acid catalysis, temperature of reaction is in room temperature-100 ℃, and a few hours in reaction times boiled off remaining alcohol by tens of hours after reacting completely, washing, concentrated, recrystallization can obtain target product, and described alcohol is methyl alcohol, ethanol, propyl alcohol, acid are the vitriol oils, sulfur oxychloride SOCl 2, the product that obtains when used alcohol is methyl alcohol is compound 1;
Figure FDA0000215729222
The protection of described phenolic hydroxyl group be with the previous step products therefrom in organic solvent, with ortho-formiate, under heating condition, through acid catalysis, reacted 2-18 hour, ortho-formiate is methyl esters or ethyl ester, when being ethyl orthoformate, obtains compound 2 when used; Wherein the mol ratio of compound 1 and ortho-formiate is 1:2-10, and organic solvent is benzene, toluene, and dimethylbenzene can not wanted organic solvent to not impact of reaction yet, and described acid is acidic resins Ameberlyst or polynite Montmorillonite;
Figure FDA0000215729223
Described etherificate be with previous step hydroxyl protection gained compound 2 in polar solvent and under the room temperature-70 ℃, alkali and halohydrocarbons reaction 2-18 hour, obtain target product, R is methyl CH 3, benzyl Bn works as R=CH 3The time, product is compound 3, and when R=Bn, product is compound 4, and described polar solvent is acetone, methyl alcohol, ethanol, methyl-sulphoxide DMSO, alkali are salt of wormwood K 2CO 3, yellow soda ash NaCO 3, sodium hydroxide NaOH, potassium hydroxide KOH, sodium hydride NaH;
Figure FDA0000215729224
Described go the protection be in alcohol and room temperature under, above-claimed cpd 3 acidifyings 10 minutes-2 hours obtain compound 5; Compound 4 acidifyings 10 minutes-2 hours obtain compound 6, and described alcohol is methyl alcohol, ethanol, and Virahol, acid is dilute hydrochloric acid, dilute sulphuric acid, dilute phosphoric acid;
Figure FDA0000215729225
Figure FDA0000215729226
Described again etherificate be in dry polar solvent and 50 ℃-100 ℃ under, compound 5, alkali with the dihalo methane reaction, obtains compound 7, described polar solvent is DMF DMF, N,N-dimethylacetamide DMAC, alkali are salt of wormwood K 2CO 3, yellow soda ash NaCO 3, sodium hydride NaH, the dihalo hydrocarbon is methylene iodide, methylene bromide, 1,1 '-iodine monobromethane, 1,1 '-methyl chlorobromide;
Figure FDA0000215729227
Described again etherificate be in polar solvent and room temperature-70 ℃ under, compound 6, alkali and methylating reagent reaction 2-18 hour obtain compound 8, described polar solvent is acetone, methyl alcohol, ethanol, methyl-sulphoxide DMSO, alkali are salt of wormwood K 2CO 3, yellow soda ash NaCO 3, sodium hydroxide NaOH, potassium hydroxide KOH, sodium hydride NaH, methylating reagent are methyl iodide CH 3I, methyl-sulfate CH 3) 2SO 4
Figure FDA0000215729228
Described reduction be with previous step again the etherificate products therefrom obtain alcohol through reduction, in ethers solution, compound 7 obtains compound 9 with the reductive agent effect; Compound 8 obtains compound 10 with the reductive agent effect, and described ethers solution is ether, tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane; Reductive agent adopts lithium aluminum hydride LiAlH 4Or di-isopropyl aluminium hydrogen DIBAL-H or aluminium hydrogen or calcium borohydride or borine or sodium borohydride-titanium tetrachloride, consumption is 1: 1 mol ratio with respect to reaction substrate, solvent uses ether or tetrahydrofuran (THF), 0 ℃-80 ℃ of temperature of reaction;
Described halo is that previous step etherificate gained alcohol product compound 9 is got halides with the halogenating agent effect, and halogenating agent adopts PX 3, X=I wherein, Br, Cl, when X=Br, product is compound 11, consumption is 1-3 with respect to raw material: 1 mol ratio, solvent uses methylene dichloride or 1,2-ethylene dichloride or chloroform, room temperature or illumination reaction,
Figure FDA00002157292211
Described halo be with previous step etherificate gained alcohol product compound 10 in polar solvent, get compound 12 with the halogenating agent effect, described halogenating agent adopts PX 3, X is I, Br, and Cl, when X=Br, product is compound 12; Perhaps, halogenating agent adopts NXS, X=C in the formula, B, I or HX, X=I in the formula, Br, Cl or X 2, X=I in the formula, Br, Cl, polar solvent are methylene dichloride, 1,2-ethylene dichloride, chloroform,
Figure FDA00002157292212
Described nucleophilic substitution be with previous step halo products therefrom under the alkali effect with 2-butanone generation nucleophilic substitution reaction, in aprotic solvent ,-78 ℃-100 ℃, compound 11 and 2-butanone, the alkali effect obtains compound 13; Compound 12 and 2-butanone, the alkali effect obtains compound 14, and described aprotic solvent adopts tetrahydrofuran THF, ether, dioxane, benzene, toluene; Described alkali adopts lithium diisopropylamine LDA or the silica-based Lithamide LiHMDS of hexamethyl or the silica-based sodium amide NaHMDS of hexamethyl or the silica-based potassium amide KHMDS of hexamethyl or butyllithium BuLi or sodium hydride NaH or potassium hydride KH KH,
Described Horner-Emmons reagent preparation is that previous step nucleophilic substitution products therefrom and phosphite reaction are obtained Horner-Emmons reagent, phosphite adopts methyl phosphite or phosphorous acid ethyl ester, consumption is the mol ratio of 1.5-5:1 with respect to reaction substrate, do not need other solubilizing agent, 120 ℃-150 ℃ of temperature of reaction, until till not having low-boiling point liquid to steam, when previous step compound 12 and used phosphite are triethyl-phosphite reaction R=C 2H 5The time, generate product compound 16,
Figure FDA00002157292214
Perhaps, at the Dean-Stark device, under 120 ℃ of temperature condition, compound 11 until there is not low-boiling point liquid to generate, namely obtains target product with the phosphite reaction, and described phosphite is trimethyl phosphite, triethyl-phosphite, when used phosphite is triethyl-phosphite, R=C 2H 5The time, generate product compound 18,
Figure FDA00002157292215
Described Horner-Emmons reaction is upper step nucleophilic substitution products therefrom and previous step Horner-Emmons reagent to be prepared products therefrom Horner-Emmons occurs under the alkali effect react, mol ratio is 1:1-10, alkali adopts sodium hydride or potassium hydride KH or potassium tert.-butoxide or sodium tert-butoxide or butyllithium, solvent uses tetrahydrofuran (THF) or benzene or toluene or dimethylbenzene, and temperature of reaction is 80 ℃-120 ℃;
In aprotic organic solvent, compound 16 or compound 14 elder generations and alkali effect under 80 ℃ of-120 ℃ of temperature, added compound 13 or 18, TLC and follow the tracks of the reaction raw materials disappearance after 10-30 minute; Described aprotic organic solvent is tetrahydrofuran THF, benzene, and toluene, dimethylbenzene, alkali are sodium hydride NaH, potassium hydride KH KH, potassium tert.-butoxide KO tBu, butyllithium,
Figure FDA00002157292216
Described catalytic hydrogenation is take transition metal or precious metal as catalyzer with previous step gained Horner-Emmons reaction product, room temperature is led to hydrogen, catalytic hydrogenation, the catalyzer that hydrogenation adopts is nickel, palladium or rhodium, consumption is 0.1-100% with respect to the reaction substrate weight ratio, and solvent adopts alcohol or ester or ether; Compound 19 or 20 is dissolved in the organic solvent, adds a certain proportion of metal catalyst nickel or palladium Pd or rhodium Rh, room temperature is led to hydrogen reaction, can obtain reduzate compound 21 after 10 hours,
Described oxidative coupling is previous step catalytic hydrogenation products therefrom oxidative coupling under the oxygenant effect to be obtained structural formula be the compound of (I), and oxygenant adopts 2,3-, two chloro-5,6-dicyan-1,4-benzoquinones DDQ or Iron triperchlorate, corresponding solvent is trifluoroacetic acid, or molybdenum pentachloride MoCl 5, coordinative solvent is methylene dichloride; Consumption is 5-1:1 with respect to reaction substrate, and temperature of reaction is 40 ℃-60 ℃, at methylene dichloride CH 2Cl 2In, room temperature arrives under the temperature that refluxes, compound 21 and a certain proportion of molybdenum pentachloride MoCl 5Effect can obtain structural formula and be the target product of (I),
Figure FDA00002157292218
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