CN102718696A - Preparation method and anti-AIDS purpose of Baculiferin L and analog thereof - Google Patents

Preparation method and anti-AIDS purpose of Baculiferin L and analog thereof Download PDF

Info

Publication number
CN102718696A
CN102718696A CN2011100779568A CN201110077956A CN102718696A CN 102718696 A CN102718696 A CN 102718696A CN 2011100779568 A CN2011100779568 A CN 2011100779568A CN 201110077956 A CN201110077956 A CN 201110077956A CN 102718696 A CN102718696 A CN 102718696A
Authority
CN
China
Prior art keywords
preferred
product
reaction
hiv
organic solvent
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN2011100779568A
Other languages
Chinese (zh)
Inventor
范爱丽
林文翰
贾彦兴
徐岷涓
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Peking University
Original Assignee
Peking University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Peking University filed Critical Peking University
Priority to CN2011100779568A priority Critical patent/CN102718696A/en
Publication of CN102718696A publication Critical patent/CN102718696A/en
Pending legal-status Critical Current

Links

Landscapes

  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention discloses a preparation method of Baculiferin L and analogs (see the following formula) thereof. I is prepared under protection of inert gas by a substituted phenylacetaldehyde and an amino compound or ammonia gas; II is obtained through a reaction between I and 2-bromo-2-(3,4-dimethoxy benzyl) acetic acid trichloroethyl alcohol ester under an condition of acidic alumina; III is obtained through a reaction among II and zinc dust and an ammonium acetate solution; IV is obtained through a reaction among III and potassium acetate and acetic anhydride; V is obtained through a reaction in an organic solvent between IV and a sodium hydroxide solution; Baculiferin L and analogs thereof are obtained under protection of inert gas by V and boron tribromide in the presence of organic solvent. The method is characterized by fewer steps, simple process, and high yield; and precious metal catalysts are not needed. The method saves energy, reduces emission, and has high efficiency. The invention also discloses the anti-AIDS related applications of Baculiferin L and analogs thereof aiming at AIDS key targets like Vif, APOBEC3G, pg41, and the like.

Description

The preparation method of Baculiferin L and analogue thereof and anti-AIDS purposes
Technical field
The present invention relates to a kind of preparation method who prepares marine natural product baculiferin L and analogue thereof and as the purposes of anti-hiv agent.
Background technology
Baculiferin L (formula as follows) is by the Chinese scholar sheet spiral shell chlorins compound of isolation identification from sponge Iotrochota baculifera first in 2010.It is reported, this compound have the target of anti-HIV-1 active (Wenhan Lin, et al.Bioorg.& Med.Chem., 2010,18,5466-5474).The structure hypotype of sheet spiral shell chlorins compound is numerous, and the tool different subtype is also different with the target spot effect of HIV-1.Part of compounds through the more existing bibliographical informations of complete synthesis preparation (Chem.Rev., 2008,108,264-287).Because the sheet spiral shell chlorins compound that this patent relates to system obtains from the ocean, the scale preparation technology becomes the technical bottleneck of going deep into study of pharmacy.This patent reported first baculiferin L and analogue thereof synthetic.
Figure BSA00000462577200011
Summary of the invention
One of the object of the invention provides that a kind of manual work is synthetic in a large number to prepare the baculiferin L method of (comprising baculiferin L analogue), and baculiferin L and part analogue thereof be formula as follows:
Figure BSA00000462577200012
Figure BSA00000462577200021
Its synthetic intermediate:
Figure BSA00000462577200022
Two of the object of the invention provides the pharmaceutical composition that comprises above-claimed cpd.
Another object of the present invention provides the purposes of above-claimed cpd as the anti HIV-1 virus agent.Baculiferin L Alkaloid compound of the present invention has good avidity to HIV virus vif, gp41 albumen and the intravital APOBEC 3G of people albumen, has HIV-resistant activity.
Specifically, the invention provides following formula I, II compound, perhaps the salt of its pharmaceutical acceptable acid or alkali, the perhaps compound method of solvolyte:
Figure BSA00000462577200031
Wherein, R 3Can be hydrogen or alkyl or aryl, preferred-CH 2COOMe or-CH 2COOH or-H
R 2Can for give electron substituent group (like-OMe ,-Oi-Pr ,-OBn or-OH etc.) or H, preferred-OMe or-OH
R 1Can for give electron substituent group (like-OMe ,-Oi-Pr ,-OBn or-OH etc.) or H, preferred-OMe or-OH
R 4Can be multiple group, preferred-OMe or-OH
R 5Can be multiple group, preferred-OMe or-OH
The method of synthetic baculiferin L provided by the invention, baculiferin L methyl esters comprises the steps:
1) under protection of inert gas, 3, the hydrochloride of 4-dimethoxy hyacinthin and glycine methyl ester stirring reaction in anhydrous organic solvent adds silver acetate and sodium acetate after 30 minutes, and reacting by heating obtains product I (compound 13);
2) in anhydrous organic solvent, said product I and 2-bromo-2-(3, the 4-Dimethoxyphenyl) acetate ethapon ester are reacted under acid aluminium sesquioxide condition, obtain product II;
3) under protection of inert gas, said product II is dissolved in the organic solvent reacts with zinc powder and Spirit of Mindererus, obtain product III;
4) under protection of inert gas, said product III, Potassium ethanoate and acetic anhydride backflow are reacted, obtain product IV (compound 3);
5) said product IV and sodium hydroxide solution are reacted in organic solvent, obtain product V (compound 4);
6) in the presence of protection of inert gas and tetrahydrobenzene, said product V and boron tribromide are reacted in organic solvent, obtain said baculiferin L (compound 1) and methyl esters (compound 2) thereof.
In the step 1) of this method, said 3, the amount ratio of 4-dimethoxy hyacinthin and glycine methyl ester hydrochloride is 2: 1～1: 5, preferred 1: 1; The consumption of said silver acetate and sodium acetate is 3,1～5 times of 4-dimethoxy hyacinthin consumption, preferred 3 times; Said rare gas element is nitrogen or argon gas; Said temperature of reaction is 0～100 ℃, preferred 60 ℃; Said reaction solvent is Na-K alloy exsiccant THF or hydrolith exsiccant methylene dichloride or ethylene dichloride or ether or toluene etc., preferred THF;
Said step 2) in, the amount ratio of said product I and said 2-bromo-2-(3, the 4-Dimethoxyphenyl) acetate ethapon ester is 2: 1～1: 5, preferred 1: 2.5; The temperature of reaction is 0～150 ℃, preferred 60 ℃; Reaction medium is Na-K alloy exsiccant THF or hydrolith exsiccant methylene dichloride or ether or ethylene dichloride or toluene etc., preferred methylene dichloride;
In the said step 3), the amount ratio of said product II, zinc powder and Spirit of Mindererus is 1: 1: 1～1: 50: 50, preferred 1: 40: 4; The temperature of reaction is 0～150 ℃, preferred room temperature; Said rare gas element is nitrogen or argon gas; Said organic solvent is THF or methylene dichloride or ether or toluene, preferred THF;
In the said step 4), said rare gas element is nitrogen or argon gas; The amount ratio of said product III and said Potassium ethanoate is 2: 1～1: 5, preferred 1: 2.6; The temperature of reaction is 0～200 ℃, preferred 155 ℃;
In the said step 5), said sodium hydroxide solution is the aqueous solution of sodium hydroxide, preferred 5% aqueous sodium hydroxide solution; The temperature of reaction is 0～100 ℃, preferred room temperature; Said organic solvent is THF or methylene dichloride or ether or toluene or methyl alcohol, particular methanol;
In the said step 6), said rare gas element is nitrogen or argon gas; The amount ratio of said product V and said boron tribromide is 1: 5～1: 50, preferred 1: 20; Preferred-78 ℃～room temperature of the temperature of reaction; Said organic solvent is Na-K alloy exsiccant THF or hydrolith exsiccant methylene dichloride or ether or ethylene dichloride or toluene etc., preferred hydrolith exsiccant methylene dichloride; Method of purification is that anti-phase ODS column chromatography is separated (MeOH/H 2O).
In the aforesaid method, the concentration of reactant in solvent in each step except that aforementioned special qualification, is only required that solvent can dissolve reactant fully to get final product.The reaction times of each step is detected by TLC and confirms to get final product.The method of purified product is conventional column chromatography separation in every step except that specified otherwise.
The present invention has synthesized compound b aculiferin L, baculiferin L methyl esters and analogue 8 thereof first.The required step of this method is few, and technology is easy, and production cost is lower, and productive rate is higher, and nuclear-magnetism and mass spectrometric detection are confirmed to utilize this method products therefrom to be target compound baculiferin L, baculiferin L methyl esters and analogue 8 thereof.
In addition, the compound method of above-claimed cpd provided by the present invention can also be synthesized more compounds with following general formula more:
Figure BSA00000462577200041
Formula I formula II
Wherein, R 3Can be hydrogen or alkyl or aryl, preferred-CH 2COOMe or-CH 2COOH or-H
R 2Can for give electron substituent group (like-OMe ,-Oi-Pr ,-OBn or-OH etc.) or H, preferred-OMe or-OH
R 1Can for give electron substituent group (like-OMe ,-Oi-Pr ,-OBn or-OH etc.) or H, preferred-OMe or-OH
R 4Can be multiple group, preferred-OMe or-OH
R 5Can be multiple group, preferred-OMe or-OH
Comprise the steps:
1) under protection of inert gas, substituted phenylacetic aldehyde and amine or ammonium salt or ammonia stirring reaction in anhydrous organic solvent adds silver acetate and sodium acetate after 30 minutes, and reacting by heating obtains product I;
2) in anhydrous organic solvent, said product I and 2-bromo-2-(substituted phenyl) acetate ethapon ester are reacted under acid aluminium sesquioxide condition, obtain product II;
3) under protection of inert gas, said product II is dissolved in the organic solvent reacts with zinc powder and Spirit of Mindererus, obtain product III;
4) under protection of inert gas, said product III, Potassium ethanoate and acetic anhydride backflow are reacted, obtain product IV, i.e. analogue among the formula I;
5) said product IV and sodium hydroxide solution are reacted in organic solvent, obtain product V;
6) in the presence of protection of inert gas and tetrahydrobenzene, said product V and boron tribromide are reacted in organic solvent, obtain said baculiferin L analogue.
In the step 1) of this method, said substituted benzene acetaldehyde and amine or ammonium salt or the amount ratio of ammonia are 2: 1～1: 5, preferred 1: 1; The consumption of said silver acetate and sodium acetate is 1～5 times of substituted benzene acetaldehyde consumption, preferred 2 times; Said rare gas element is nitrogen or argon gas; Said temperature of reaction is 0～100 ℃, preferred 60 ℃; Said reaction solvent is Na-K alloy exsiccant THF or hydrolith exsiccant methylene dichloride or ether or ethylene dichloride or toluene etc., preferred Na-K alloy exsiccant THF;
Said step 2) in, the amount ratio of said product I and said 2-bromo-2-(substituted phenyl) acetate ethapon ester is 2: 1～1: 5, preferred 1: 2.5; The temperature of reaction is 0～150 ℃, preferred 60 ℃; Reaction medium is Na-K alloy exsiccant THF or hydrolith exsiccant methylene dichloride or ether or ethylene dichloride or toluene etc., preferred hydrolith exsiccant methylene dichloride;
In the said step 3), the amount ratio of said product II, zinc powder and Spirit of Mindererus is 1: 40: 4; The temperature of reaction is a room temperature; Said rare gas element is nitrogen or argon gas; Said organic solvent is THF or methylene dichloride or ether or ethylene dichloride or toluene etc., preferred THF; Need not separate, get product III bullion after the extraction;
In the said step 4), said rare gas element is nitrogen or argon gas; The amount ratio of said product III and said Potassium ethanoate is 2: 1～1: 5, preferred 1: 2.6; The temperature of reaction is 0～200 ℃, preferred 155 ℃;
In the said step 5), said sodium hydroxide solution is the aqueous solution of sodium hydroxide, preferred 5% aqueous sodium hydroxide solution; The temperature of reaction is room temperature～100 ℃, preferred room temperature; Said organic solvent is THF or methylene dichloride or ether or ethylene dichloride or toluene or methyl alcohol etc., particular methanol;
In the said step 6), said rare gas element is nitrogen or argon gas; The amount ratio of said product V and said boron tribromide is 1: 1～1: 50, preferred 1: 20; The temperature of preferred reaction is-78 a ℃～room temperature; Said organic solvent is Na-K alloy exsiccant THF or hydrolith exsiccant methylene dichloride or ether or ethylene dichloride or toluene etc., preferred hydrolith exsiccant methylene dichloride; Method of purification is that anti-phase ODS column chromatography is separated (MeOH/H 2O).
In the aforesaid method, the concentration of reactant in solvent in each step except that aforementioned special qualification, is only required that solvent can dissolve reactant fully to get final product.The reaction times of each step is detected by TLC and confirms to get final product.The method of purified product is conventional column chromatography separation in every step except that specified otherwise.
The invention provides a kind of pharmaceutical composition that comprises the invention described above compound.In this pharmaceutical composition, the content of The compounds of this invention is 0.001-99.99 weight %.As required, pharmaceutical composition of the present invention can be made into oral prepns, non-gastrointestinal formulations, topical preparation, for example tablet, capsule, granule, ointment, emulsifiable paste, injection etc.
Through experiment confirm, baculiferin L, its analogue and the synthetic precursor compound thereof of the present invention's preparation has good avidity to the APOBEC 3G of HIV virus gp41 and vif albumen and human body, therefore can be used as anti-hiv agent.
Synthetic baculiferin L of the present invention, its analogue and synthetic intermediate thereof can be processed anti-hiv agent through adding medicine or reagent acceptable auxiliary or solution, are used for treatment or the chemicobiology research of HIV.When in chemicobiology research, being used as the low molecular probe that suppresses HIV virus gp41 and vif proteolytic enzyme, compound of the present invention dissolves in DMSO 99.8MIN., methyl alcohol, aqueous methanol or the water and uses.
Embodiment
Below in conjunction with specific embodiment the present invention is further specified, but the present invention is not limited to following examples.These embodiment are illustrative fully, and they only are used for the present invention is carried out concrete description, are not to be understood that to be limitation of the present invention.
Embodiment 1
Baculiferin L's is complete synthesis
The method for preparing baculiferin L and analogue thereof provided by the invention, its concrete preparation flow is as follows:
Embodiment 1, preparation baculiferin L
2.0g 3,4-dimethoxy hyacinthin and 1.4g glycine methyl ester hydrochloride are dissolved in anhydrous tetrahydro furan under argon shield; Stirring at room adds 0.57g Silver monoacetate and 0.28g sodium-acetate after 30 minutes, 60 ℃ of heated overnight are after the TLC detection reaction is complete; Suction filtration, the gained filtrate decompression is revolved dried, gets crude product I; Gained crude product I through silica gel column chromatography P.E.: Acetone (2: 1) separate product I (compound 12), productive rate is 62%.0.9g product I and 2.4g 2-bromo-2-(3, the 4-Dimethoxyphenyl) acetate ethapon ester are dissolved in anhydrous methylene chloride in the presence of the acid alchlor of 9.6g; 60 ℃ of backflows are spent the night, and after the TLC detection reaction is complete, filter the aluminum chloride solid; Filtrating is revolved dried; Silica gel column chromatography P.E.: Acetone (1: 1) separates, and gets product II, and productive rate is 86%.Under argon shield, the room temperature condition, 1.5g product II, 4.7g zinc powder and 1M Spirit of Mindererus 5.8mL reacted in THF 1.5 hours, after the TLC detection reaction is complete, and the filtering zinc powder, filtrating is revolved dried, gets crude product III0.98g, and productive rate is 84%.140.0mg crude product III under argon shield, refluxed in acetic anhydride 1.5 hours with the 45mg Potassium ethanoate, after reacting completely; Reaction solution is poured in the water, with saturated sodium hydrogen carbonate solution neutralization, ethyl acetate extraction; Revolve do after; Separate through silica gel column chromatography DCM: EA (10: 1), get product IV (compound 3), productive rate is 81%.47mg product IV and 5% sodium hydroxide solution react half a hour in methyl alcohol, after reacting completely, neutralize with 5% hydrochloric acid; Ethyl acetate extraction, decompression separate PE.: Acetone (1: 1) through silica gel column chromatography after revolving and doing; Get 28mg product V (compound 4), productive rate is 70%.Product V is an alkali with a hydronium(ion) oxidation lithium in the mixed solvent of THF and water (1: 1), and hydrolysis generates product VI (compound 5).Under argon shield, 28mg product V is dissolved in the anhydrous methylene chloride, adds tetrahydrobenzene; Cool to-78 ℃, dropwise add the dichloromethane solution 0.8mL of 1M boron tribromide, slowly be warming up to room temperature; Reacted two days, and added shrend and go out, separate through anti-phase ODS post; The 45%MeOH wash-out gets end product BaculiferinL (1), baculiferin L methyl esters (2) and analogue 8 thereof.
Figure BSA00000462577200081
Nuclear-magnetism and the high resolution mass spectrum result of Baculiferin L (compound 1) are following:
1H?NMR(400MHz，MeOD)δ7.89(s，2H)，7.44(s，2H)，6.77(d，J＝8.0Hz，2H)，6.63(s，2H)，6.52(d，J＝8.0Hz，2H)，3.59(s，2H)；? 13C?NMR(100MHz，MeOD)δ185.7，171.7，155.7，150.1，149.0，146.6，146.3，131.6，126.1，125.4，124.8，123.5，119.0，118.7，116.5，115.0，114.2，48.1；HRMS(ESI)：m/z?calcd?forC 34H 22NO 12(M+H) +636.11365；found?636.1141.
The nuclear-magnetism of compound 2 and high resolution mass spectrum result are following:
Figure BSA00000462577200082
1H?NMR(400MHz，MeOD)δ7.90(s，2H)，7.43(s，2H)，6.76(d，J＝8.0Hz，2H)，6.54(s，2H)，6.45(d，J＝8.0Hz，2H)，3.66(s，2H)，3.44(s，3H)； 13C?NMR(100MHz，MeOD)δ185.8，170.5，154.9，150.4，149.2，146.7，146.4，131.4，126.0，125.3，124.8，123.6，119.1，118.7，116.3，115.0，114.2，52.6，48.1；HRMS(ESI)：m/z?calcd?for?C 35H 24NO 12(M+H) +650.12930；found?650.12993.
The nuclear-magnetism of compound 8 and high resolution mass spectrum result are following:
1H?NMR(400MHz，MeOD)δ7.89(s，2H)，7.50(s，2H)，6.84(d，J＝1.6Hz，2H)，6.81(d，J＝8.0Hz，2H)，6.70(d，J＝8.0Hz，2H)； 13C?NMR(100Hz，MeOD)δ184.3，152.9，150.0，148.9，146.6，146.61，146.58，130.1，126.7，125.3，124.8，123.0，118.5，116.7，116.6，115.7，114.3；HRMS(ESI)m/z?calcd?forC 32H 20NO 10(M+H) +578.10817；found?578.10867.
The nuclear-magnetism of compound 13 and high resolution mass spectrum result are following:
Figure BSA00000462577200091
1H?NMR(400MHz，CDCl 3)δ6.8(dd，J＝8.4Hz，1.6Hz，2H)，6.78(d，J＝8.4Hz，2H)，6.74(d，J＝1.6Hz，2H)，4.65(s，2H)，3.85(s，6H)，3.79(s，3H)，3.67(s，6H)； 13C?NMR(100Hz，CDCl 3)δ168.9，148.3，147.2，128.3，123.8，120.5，112.2，111.0，55.8，55.6，52.5，50.8；HRMS(ESI)m/z?calcd?for?C 23H 26NO 6(M+H) +412.17546；found412.17560.
Synthesizing of embodiment 2, baculiferin L analogue 6,7,8
Under the argon shield, 3, the 4-dimethoxy hyacinthin is dissolved in anhydrous tetrahydro furan; Feed ammonia, stirring at room adds Silver monoacetate and sodium-acetate, 60 ℃ of heated overnight after 30 minutes; After the TLC detection reaction is complete, suction filtration, the gained filtrate decompression is revolved dried; Get crude product I, gained crude product I separates through silica gel column chromatography P.E.: Acetone (2: 1), gets product I.Product I and 2-bromo-2-(3, the 4-Dimethoxyphenyl) acetate ethapon ester is dissolved in anhydrous methylene chloride in the presence of acid alchlor; 60 ℃ of backflows are spent the night; After the TLC detection reaction is complete, filter the aluminum chloride solid, filtrating is revolved dried; Silica gel column chromatography P.E.: Acetone (1: 1) separates, and gets product II.Under argon shield, the room temperature condition, product II, zinc powder and 1M Spirit of Mindererus reacted in THF 1.5 hours, after the TLC detection reaction is complete, and the filtering zinc powder, filtrating is revolved dried, gets crude product III.Crude product III refluxed in acetic anhydride 1.5 hours with Potassium ethanoate, after reacting completely under argon shield; Reaction solution is poured in the water, with saturated sodium hydrogen carbonate solution neutralization, ethyl acetate extraction; Revolve do after, separate through silica gel column chromatography DCM: EA (10: 1), product IV (compound 6).Product IV and 5% sodium hydroxide solution react half a hour in methyl alcohol, after reacting completely, and with the neutralization of 5% hydrochloric acid, ethyl acetate extraction, decompression separates PE.: Acetone (1: 1) through silica gel column chromatography after revolving and doing, and gets product V (compound 7).Under argon shield, product V is dissolved in the anhydrous methylene chloride, adds tetrahydrobenzene, cools to-78 ℃; The dichloromethane solution that dropwise adds the 1M boron tribromide slowly is warming up to room temperature, reacts two days, adds shrend and goes out; Separate through anti-phase ODS post, the 45%MeOH wash-out gets compound 8.
The nuclear-magnetism of compound 6 and high resolution mass spectrum detected result are following:
1H?NMR(400MHz，CDCl 3)δ8.364(s，1H)，8.355(s，2H)，7.29(s，2H)，7.09(dd，J＝8.4Hz，1.6Hz，2H)，7.05(d，J＝1.6Hz，2H)，6.98(d，J＝8.4Hz，2H)，4.06(s，6H)，4.04(s，6H)，3.96(s，6H)，3.86(s，6H)，2.23(s，6H)； 13C?NMR(100Hz，CDCl 3)δ169.4，149.4，149.2，149.0，148.1，141.0，134.7，126.0，124.1，121.9，118.9，116.9，115.5，112.8，111.7，106.7，102.4，56.5，56.0，55.92，55.88，20.7；HRMS(ESI)m/z?calcd?for?C 44H 42NO 12(M+H) +776.27015，found?776.26827；calcd?for?C 44H 41NNaO 12(M+Na) +798.25210；found?798.25042.
Compound 7 nuclear-magnetisms and high resolution mass spectrum detected result are following:
Figure BSA00000462577200101
1H?NMR(400MHz，CDCl 3)δ7.91(s，2H)，7.73(s，2H)，7.39(s，1H)，7.02(d，J＝2.0Hz，2H)，6.97(dd，J＝8.4Hz，2.0Hz，2H)，6.90(d，J＝8.4Hz，2H)，4.02(s，6H)，3.90(s，12H)，3.88(s，3H)； 13C?NMR(100Hz，CDCl 3)δ181.9，151.2，151.0，150.6，149.2，149.1，129.0，126.5，124.8，124.0，122.3，115.0，113.5，111.3，110.3，108.8，56.6，56.2，55.9；HRMS(ESI)m/zcalcd?for?C 40H 36NO 10(M+H) +690.23337；found?690.23177.
Compound 8 nuclear-magnetisms and high resolution mass spectrum detected result are seen instance 1.
Synthesizing of embodiment 3, baculiferin L analogue 9,10,11
4-anisole acetaldehyde and glycine methyl ester hydrochloride are dissolved in anhydrous tetrahydro furan under argon shield, stirring at room adds Silver monoacetate and sodium-acetate after 30 minutes; 60 ℃ of heated overnight, after the TLC detection reaction is complete, suction filtration; The gained filtrate decompression is revolved dried; Get crude product I, gained crude product I separates through silica gel column chromatography P.E.: Acetone (2: 1), gets product I (compound 13).Product I and 2-bromo-2-(3, the 4-Dimethoxyphenyl) acetate ethapon ester is dissolved in anhydrous methylene chloride in the presence of acid alchlor; 60 ℃ of backflows are spent the night; After the TLC detection reaction is complete, filter the aluminum chloride solid, filtrating is revolved dried; Silica gel column chromatography P.E.: Acetone (1: 1) separates, and gets product II.Under argon shield, the room temperature condition, product II, zinc powder and 1M Spirit of Mindererus reacted in THF 1.5 hours, after the TLC detection reaction is complete, and the filtering zinc powder, filtrating is revolved dried, gets crude product III.Crude product III refluxed in acetic anhydride 1.5 hours with Potassium ethanoate, after reacting completely under argon shield; Reaction solution is poured in the water, with saturated sodium hydrogen carbonate solution neutralization, ethyl acetate extraction; Revolve do after, separate through silica gel column chromatography DCM: EA (10: 1), product IV.Product IV and 5% sodium hydroxide solution react half a hour in methyl alcohol, after reacting completely, and with the neutralization of 5% hydrochloric acid, ethyl acetate extraction, decompression separates PE.: Acetone (1: 1) through silica gel column chromatography after revolving and doing, and gets product V (compound 9).Under argon shield, product V is dissolved in the anhydrous methylene chloride, adds tetrahydrobenzene, cools to-78 ℃; The dichloromethane solution that dropwise adds the 1M boron tribromide slowly is warming up to room temperature, reacts two days, adds shrend and goes out; Separate through anti-phase ODS post, the 45%MeOH wash-out gets product 10,11.
Compound 9 nuclear-magnetisms and high resolution mass spectrum detected result are following:
Figure BSA00000462577200102
1H?NMR(400MHz，CDCl 3)δ?8.36(d，J＝8.0Hz，2H)，7.69(s，2H)，7.09(d，J＝8.0Hz，2H)，6.86(d，J＝7.2Hz，2H)，6.76(m，4H)，3.93(s，6H)，3.89(s，6H)，3.84(s，6H)，3.74(s，2H)，3.38(s，3H)；? 13C?NMR(100Hz，CDCl 3)δ183.9，161.2，153.7，149.1，148.8，133.0，129.8，128.1，124.9，123.3，123.1，118.9，117.7，114.0，111.0，?110.9，55.9，55.8，55.7，51.6，47.27；HRMS(ESI)m/z?calcd?forC 41H 36NO 10(M+H) +702.23337；found?702.23229.
Synthesizing of embodiment 4, baculiferin L analogue 12
Under the argon shield, 3, the 4-dimethoxy hyacinthin is dissolved in anhydrous tetrahydro furan; Add the Beta-alanine methyl ester hydrochloride, stirring at room adds Silver monoacetate and sodium-acetate, 60 ℃ of heated overnight after 30 minutes; After the TLC detection reaction is complete, suction filtration, the gained filtrate decompression is revolved dried; Get crude product I, gained crude product I separates through silica gel column chromatography P.E.: Acetone (2: 1), gets product I (compound 15).Product I and 2-bromo-2-(3, the 4-Dimethoxyphenyl) acetate ethapon ester is dissolved in anhydrous methylene chloride in the presence of acid alchlor; 60 ℃ of backflows are spent the night; After the TLC detection reaction is complete, filter the aluminum chloride solid, filtrating is revolved dried; Silica gel column chromatography P.E.: Acetone (1: 1) separates, and gets product II.Under argon shield, the room temperature condition, product II, zinc powder and 1M Spirit of Mindererus reacted in THF 1.5 hours, after the TLC detection reaction is complete, and the filtering zinc powder, filtrating is revolved dried, gets crude product III.Crude product III refluxed in acetic anhydride 1.5 hours with Potassium ethanoate, after reacting completely under argon shield; Reaction solution is poured in the water, with saturated sodium hydrogen carbonate solution neutralization, ethyl acetate extraction; Revolve do after, separate through silica gel column chromatography DCM: EA (10: 1), product IV.Product IV and 5% sodium hydroxide solution react half a hour in methyl alcohol, after reacting completely, and with the neutralization of 5% hydrochloric acid, ethyl acetate extraction, decompression separates PE.: Acetone (1: 1) through silica gel column chromatography after revolving and doing, and gets product V (compound 12).
Compound 12 nuclear-magnetisms and high resolution mass spectrum detected result are following:
Figure BSA00000462577200111
1H?NMR(400MHz，CDCl 3)δ7.89(s，2H)，7.68(s，2H)，6.89(m，6H)，4.00(s，6H)，3.89(s，6H)，3.87(s，6H)，3.86(s，6H)，3.31(s，3H)，3.13(t，J＝6.8Hz，2H)，2.03(t，J＝6.8Hz，2H)； 13C?NMR(100Hz，CDCl 3)δ183.0，170.3，153.5，151.15，151.10，149.1，148.7，131.0，126.2，125.1，124.0，123.4，117.5，113.9，110.9，109.8，108.7，56.5，56.1，55.84，55.81，51.4，41.0，32.6；HRMS(ESI)m/zcalcd?for?C 44H 42NO 12(M+H) +776.27105；found?776.26981
Compound 15 nuclear-magnetisms and high resolution mass spectrum detected result are following:
Figure BSA00000462577200112
1H?NMR(400?MHz，CDCl 3)δ6.79(m，8H)，4.23(t，J＝6.8Hz，2H)，3.86(s，6H)，3.72(s，3H)，3.68(s，6H)，2.86(t，J＝6.8Hz，2H)； 13CNMR(100Hz，CDCl 3)δ171.4，148.5，147.2，128.7，123.3，120.5，119.5，112.3，111.2，55.9，55.6，51.9，45.0，36.1；HRMS(ESI)m/z?calcd?for?C 24H 28NO 6(M+H) +426.19111；found?426.19109.calcd?forC 24H 27NNaO 6(M+H) +448.17306；found?448.17314.
Experimental example 5, compound anti-HIV-1 pseudovirus activity
(1) material:
Cell: MAGI test (Multinuclear Activation of Galactosidase Indicator writes a Chinese character in simplified form) claims Single Life Cycle again, and used cell is HeLa-CD4-LTR-β-gal.Beijing University of Technology's life science and biotechnology institute cultivate and preserve.
Pseudovirus: skeleton plasmid is 11051; The coating plasmid is 11035
Compound: compound 1,2,4,5,6,7 to be determined, 8.
(2) method: MAGI test.
This law can quantitatively determined HIV titre, to calculate the inhibiting rate of medicine to virus.
(3) result:
Measuring gets, the IC of compound 1 50Value is 1.24 μ g/mL, the IC of compound 2 50Value is 3.02 μ g/mL, the IC of compound 8 50Value is 3.47 μ g/mL.
The inhibition HIV-1 NL4_3 virus activity test in the 293T cell of experimental example 6, each sample
(1) material:
Cell: the 293T cell, the Magi cell is cultivated preservation by Jilin University.
Strain: HIV-1 NL4_3, Jilin University cultivate and preserve.
Medicine: compound 3,4,13 to be determined
(2) method:
Each testing sample dissolves with DMSO, to final concentration 10mM.
1. toxotest: H9 cell counting, 1.0 * 106/mL.Be laid on 24 orifice plates.The 1mL/ hole.Every hole adds testing sample respectively, and final concentration is 50uM.The blank equal-volume DMSO that adds.Cell cultures 24h, counting.Calculating is with respect to the barren survival rate.
2. viral inhibiting rate test: 293T cell bed board, cultivate 24h.With HIV-1 NL4_3 and A3G cotransfection, change liquid behind the 6h.Add medicine when changing liquid simultaneously, final concentration 50uM.Cultivate 48h, infect the Magi cell, detect infectious behind the 48h.
(3) compound inhibition NL4 3 virus activity results are following:
Figure BSA00000462577200121
The result can know thus, and the cytotoxicity of compound 3,4,12 is lower, and can obviously reduce the cell infection rate, has shown stronger HIV-resistant activity.

Claims (5)

1. a formula I or formula II compound, the perhaps salt of its pharmaceutical acceptable acid or alkali, perhaps solvolyte or pharmaceutical composition:
Figure FSA00000462577100011
Wherein, R 3Can be hydrogen or alkyl or aryl, preferred-CH 2COOMe or-CH 2COOH or-H
R 2Can for give electron substituent group (like-OMe ,-Oi-Pr ,-OBn or-OH etc.) or H, preferred-OMe or-OH
R 1Can for give electron substituent group (like-OMe ,-Oi-Pr ,-OBn or-OH etc.) or H, preferred-OMe or-OH
R 4Can be multiple group, preferred-OMe or-OH
R 5Can be multiple group, preferred-OMe or-OH.
2. a method for preparing Baculiferin L and analogue thereof comprises the steps:
1) under protection of inert gas, substituted phenylacetic aldehyde and amides or ammonia stirring reaction in anhydrous organic solvent adds silver acetate and sodium acetate after 30 minutes, and reacting by heating obtains product I;
2) in anhydrous organic solvent, said product I and 2-bromo-2-(3, the 4-Dimethoxyphenyl) acetate ethapon ester are reacted under acid aluminium sesquioxide condition, obtain product II;
3) under protection of inert gas, said product II is dissolved in the organic solvent reacts with zinc powder and Spirit of Mindererus, obtain product III;
4) under protection of inert gas, said product III, Potassium ethanoate and acetic anhydride backflow are reacted, obtain product IV;
5) said product IV and sodium hydroxide solution are reacted in organic solvent, obtain product V;
6) in the presence of protection of inert gas and tetrahydrobenzene, said product V and boron tribromide are reacted in organic solvent, obtain said baculiferin L, its methyl esters and analogue thereof.
3. method according to claim 1 is characterized in that:
In the described step 1) of this method, said substituted benzene acetaldehyde and amine or ammonium salt or the amount ratio of ammonia are 2: 1～1: 5, preferred 1: 1; The consumption of said silver acetate and sodium acetate is 1～5 times of substituted benzene acetaldehyde consumption, preferred 2～3 times; Said rare gas element is nitrogen or argon gas; Said temperature of reaction is 0～100 ℃, preferred 60 ℃; Said reaction solvent is Na-K alloy exsiccant THF or hydrolith exsiccant methylene dichloride or ether or ethylene dichloride or toluene etc., preferred Na-K alloy exsiccant THF;
Said step 2) in, the amount ratio of said product I and said 2-bromo-2-(substituted phenyl) acetate ethapon ester is 2: 1～1: 5, preferred 1: 2.5; The temperature of reaction is 0～150 ℃, preferred 60 ℃; Reaction medium is Na-K alloy exsiccant THF or hydrolith exsiccant methylene dichloride or ether or ethylene dichloride or toluene etc., preferred hydrolith exsiccant methylene dichloride;
In the said step 3), the amount ratio of said product II, zinc powder and Spirit of Mindererus is 1: 40: 4; The temperature of reaction is a room temperature; Said rare gas element is nitrogen or argon gas; Said organic solvent is THF or methylene dichloride or ether or ethylene dichloride or toluene etc., preferred THF; Need not separate, get product III bullion after the extraction;
In the said step 4), said rare gas element is nitrogen or argon gas; The amount ratio of said product III and said Potassium ethanoate is 2: 1～1: 5, preferred 1: 2.6; The temperature of reaction is 0～200 ℃, preferred 155 ℃;
In the said step 5), said sodium hydroxide solution is the aqueous solution of sodium hydroxide, preferred 5% aqueous sodium hydroxide solution; The temperature of reaction is room temperature～100 ℃, preferred room temperature; Said organic solvent is THF or methylene dichloride or ether or ethylene dichloride or toluene or methyl alcohol etc., particular methanol;
In the said step 6), said rare gas element is nitrogen or argon gas; The amount ratio of said product V and said boron tribromide is 1: 1～1: 50, preferred 1: 20; The temperature of preferred reaction is-78 a ℃～room temperature; Said organic solvent is Na-K alloy exsiccant THF or hydrolith exsiccant methylene dichloride or ether or ethylene dichloride or toluene etc., preferred hydrolith exsiccant methylene dichloride; Method of purification is that anti-phase ODS column chromatography is separated.
4. compound according to claim 1 or compsn are as the purposes of anti-HIV-1 preparation.
According to the requirement of right 3, prepared compound and compsn thereof have following characteristics:
1) action target spot of its anti-HIV-1 is the inhibition infectant vif of HIV-1;
2) action target spot of its anti-HIV-1 is that inducing of HIV-1 produces anti-vif factors A POBEC3G;
3) action target spot of its anti-HIV-1 is the inhibition HIV-1 fusion rotein GP41 of HIV-1;
4) effect of its anti-HIV-1 suppresses the IIIB virus of HIB-1;
5) effect of its anti-HIV-1 suppresses the NL-43 virus of HIB-1.
5. the salt of the said compound of arbitrary claim or its pharmaceutical acceptable acid or alkali in the claim 1, the perhaps medicine that catches at preparation treatment HIV of solvolyte or the application in the reagent.
CN2011100779568A 2011-03-30 2011-03-30 Preparation method and anti-AIDS purpose of Baculiferin L and analog thereof Pending CN102718696A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN2011100779568A CN102718696A (en) 2011-03-30 2011-03-30 Preparation method and anti-AIDS purpose of Baculiferin L and analog thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN2011100779568A CN102718696A (en) 2011-03-30 2011-03-30 Preparation method and anti-AIDS purpose of Baculiferin L and analog thereof

Publications (1)

Publication Number Publication Date
CN102718696A true CN102718696A (en) 2012-10-10

Family

ID=46944601

Family Applications (1)

Application Number Title Priority Date Filing Date
CN2011100779568A Pending CN102718696A (en) 2011-03-30 2011-03-30 Preparation method and anti-AIDS purpose of Baculiferin L and analog thereof

Country Status (1)

Country Link
CN (1) CN102718696A (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107602439A (en) * 2017-09-14 2018-01-19 浙江工业大学 A kind of synthetic method for preparing marine alkaloids Baculiferin L intermediates

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
QINGJIANG LI ET AL: "One-Pot AgOAc-Mediated Synthesis of Polysubstituted Pyrroles from Primary Amines and Aldehydes: Application to the Total Synthesis of Purpurone", 《ORGANIC LETTERS》 *
贾彦兴: "一锅串联反应在天然产物合成中的应用", 《中国化学会第八届天然有机化学学术研讨会论文集》 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107602439A (en) * 2017-09-14 2018-01-19 浙江工业大学 A kind of synthetic method for preparing marine alkaloids Baculiferin L intermediates
CN107602439B (en) * 2017-09-14 2020-06-23 浙江工业大学 Synthetic method for preparing marine alkaloid Baculiferin-L intermediate

Similar Documents

Publication Publication Date Title
CN104903334A (en) Tenofovir prodrug and pharmaceutical uses thereof
Bhattacharya et al. Diversity-oriented synthesis of α-aminophosphonates: A new class of potential anticancer agents
WO2021037077A1 (en) Patentiflorin a analogs as antiviral agents
CN103333942A (en) A synthetic method for (R)-praziquantel
CN101148418B (en) Alpine yarrow herb ketoacid derivatives and applications thereof
JP7123417B2 (en) Anxiolytic deuterium compound and its medicinal use
CN102617442B (en) Preparation method and use of 3,3'-methylenebis(1H-Indole)
CN103254075B (en) Preparation method of flurbiprofen axetil
CN112409183B (en) Zanthoxylum bungeanum ketene and derivative thereof, and preparation method and application thereof
CN102180914A (en) Preparation method of 2-deoxidizing-D-glucose
CN102718696A (en) Preparation method and anti-AIDS purpose of Baculiferin L and analog thereof
CN107266404A (en) A kind of neuraminidase inhibitor zanamivir derivative and preparation method thereof
CN101844970B (en) Dibenzocyclooctene lignin derivatives with bioactivity
CN101671376B (en) Alkannin acetyl glucose and preparation method and application thereof
CN104774171B (en) The methylol Oxoindole of 3 amino 3, the methylol oxoindole derivative of 3 hydroxyl 3 and its preparation method and application
CN107235853B (en) A kind of synthetic method being used to prepare Canton love-pea vine A prime and its isomers
CN102276615B (en) Method for preparing (-)-5-N-formalardeemin
CN105859823A (en) Application of ilicis routundae cortex acid ester derivatives in preparation of anti-tumor drugs
CN101284811B (en) Synthetic method for chiral carbocyclic ring intermediate of abacavir
CN104288133A (en) 3,5-diisoamylene, 2,4,4'-trihydroxyl chalcone as well as use and preparation method of derivative of the 3,5-diisoamylene, 2,4,4'-trihydroxyl chalcone
CN109206389B (en) Isoalantolactone derivatives, pharmaceutical compositions thereof and uses thereof
CN109745309B (en) Mitsuma as antiviral agent
CN102399228B (en) Preparation method of N-alkyl polyhydroxypiperidine derivative
WO2022135136A1 (en) Tuberculatin analogs as antiviral agents
CN113387934B (en) Polyaryl substituted imidazole derivative and preparation method and application thereof

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C02 Deemed withdrawal of patent application after publication (patent law 2001)
WD01 Invention patent application deemed withdrawn after publication

Application publication date: 20121010