CN108676067B - A kind of noval chemical compound and preparation method thereof of pre- preventing HIV infection - Google Patents
A kind of noval chemical compound and preparation method thereof of pre- preventing HIV infection Download PDFInfo
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Abstract
The invention discloses a kind of general structure compounds as shown in formula (I), and the compound being prepared using compound shown in formula (I) for raw material, shown in general structure such as formula (III).The invention also discloses a kind of general structure compounds as shown in formula (II), and the compound being prepared using compound shown in formula (II) for raw material, shown in general structure such as formula (IV).Meanwhile the invention also discloses the preparation methods of compound shown in formula (I)~(IV).It is provided by the invention as formula (III) and formula (IV) compound represented can effective pre- preventing HIV infection, have HIV-resistant activity high, the advantages that preparation cost is low, and preparation method is simple and high income, can be mass-produced and apply.
Description
Technical field
The invention belongs to technical field of chemical medicine, and in particular to a kind of noval chemical compound of pre- preventing HIV infection and its preparation
Method.
Background technique
Human immunodeficiency virus (Human Immunodeficiency Virus, HIV) belongs to retrovirus, is a kind of
The slow virus for infecting human immune system's cell, can cause human immune system's defect, human body is made to lose resistance, be also easy to produce each
Kind disease even cancer.The helper T lymphocyte system of HIV primary challenge human body, once intrusion body cell, virus will be with
Cellular integration is difficult to eliminate throughout one's life together.Its blood for being widely present in the infected, sperm, vaginal fluid, milk, brain ridge
Liquid has in the brain tissue liquid of nervous symptoms, wherein with concentration highest in blood, sperm, vaginal fluid；The infected's incubation period
Long, death rate height.Its caused disease-AIDS without effective therapy, has mortality so far.
Patent ZL02807728.8 discloses a kind of medicament for preventing and treating sexually transmitted disease-I in the prior art, is used for
It kills vagina microorganism and is propagated with its is prevented, it is anti-with wide spectrum such as HIV, BV (Bacterial vaginosis, BV) etc.
Virus activity.The committed step for synthesizing the medicament can be briefly summarized are as follows: the trifluoroacetate of L-lysine dendritic
With end-capping group R in the presence of condensing agent PyBOP and organic base diisopropylethylamine, reacts and complete in DMF solvent, increasing amount
Water dilution is purified using sodium form ion exchange resin column chromatography after filtering, is collected product, filtering, and be lyophilized, is obtained
Product.The preparation method has the disadvantages that (1) condensing agent PyBOP (1H- benzotriazole -1- base oxygen tripyrrole alkyl hexafluoro
Phosphate) it is not only expensive, and it can also be increased burden using the segment of introducing to purifying；(2) it is handed over using expensive ion
Resin column chromatography is changed to be purified；(3) product is dried using the mode of freeze-drying, energy consumption is very high.Therefore, condensing agent
At high cost, the factors such as energy consumption of freeze drying height and column chromatographic runs are unfavorable for industrialized production.
Summary of the invention
Based on this, a kind of compound is provided it is an object of the invention to overcome above-mentioned the deficiencies in the prior art place, it can
It is used to prepare the noval chemical compound of pre- preventing HIV infection.
To achieve the above object, the technical scheme adopted by the invention is as follows: a kind of compound, the general structure of the compound
As shown in formula (I):
Wherein, n is the integer of 1≤n≤5.
The present invention also provides the preparation methods of compound shown in formula (I), comprising the following steps: is dissolved in bromacyl bromide
Organic solvent is simultaneously cooled to -60~0 DEG C, is slowly added to alkali, then adds catalyst DMAP, obtains bromacyl bromide/alkali/DMAP
Organic solvent system；Take BHA-Lys-Lys2-Lys4-Lys8- 16TFA is dissolved in the solution of organic solvent, it is cooled to -40 in advance~-
It after 20 DEG C, is added dropwise in bromacyl bromide/alkali/DMAP organic solvent system, is to slowly warm up to -10~10 DEG C of reactions；Detect body
Without BHA-Lys-Lys in system2-Lys4-Lys8After -16TFA is remaining, saturated salt solution quenching reaction is slowly added dropwise into system, stirs
It mixes, liquid separation, separates organic solvent layer, respectively washed for the first time, removed under reduced pressure with 0.5mol/L dilute hydrochloric acid and saturated salt solution respectively
Organic solvent is to get compound shown in formula (I).
Preferably, bromacyl bromide is dissolved in organic solvent and is cooled to -40~-20 DEG C, be slowly added to alkali；The bromo
Acylbromide, alkali, DMAP and BHA-Lys-Lys2-Lys4-Lys8The molar ratio of -16TFA is (16~32): (32~64): 0.1:1；It is excellent
Selection of land, the bromacyl bromide, alkali, DMAP and BHA-Lys-Lys2-Lys4-Lys8The molar ratio of -16TFA is (19~24): (35
~40): 0.1:1；The organic solvent is selected from methylene chloride, chloroform, ethyl acetate, isopropyl acetate, toluene or diformazan
Benzene；The alkali is selected from sodium bicarbonate, sodium carbonate, sodium hydride, sodium methoxide, sodium ethoxide, sodium tert-butoxide, triethylamine, diisopropyl second
Amine or pyridine.
The present invention also provides a kind of compound, shown in the structural formula of the compound such as formula (III):
Wherein, n is the integer of 1≤n≤5；
R5 is expressed as follows group:
Compound shown in formula (III) is prepared using compound shown in formula (I) as raw material；Shown in formula (I)
In compound structure general formula when n=1, n=2, n=3, n=4 and n=5, n in general structure shown in formula (III) is prepared respectively
=1, the compound of n=2, n=3, n=4 and n=5.
The present invention also provides the preparation methods of compound shown in formula (III), comprising the following steps:
(1) compound shown in formula (I) is prepared according to the method；
(2) alkali and 3,6- sodium disulfonate -1- is added in compound shown in the formula (I) with the acquisition of anhydrous DMSO dissolving step (1)
Naphthols is warming up to 40~90 DEG C, is stirred to react；Reaction terminates, and is filtered to remove insoluble matter, and filtrate is slowly added dropwise into organic solvent
In, solid precipitating, filtering is precipitated；Filtering obtained solid is recrystallized using the mixed solvent of C1, C2 or C3 alcohol and water, i.e.,
It obtains such as formula (III) compound represented.
Preferably, the molar ratio of alkali and 3 in the step (2), 6- sodium disulfonate -1- naphthols is (16~32): (16~
32), it is preferable that the alkali and 3, the molar ratio of 6- sodium disulfonate -1- naphthols are (19~24): (17.6~20.8)；The alkali
50~70 DEG C are warming up to 3,6- sodium disulfonate -1- naphthols, is stirred to react；The alkali be selected from sodium hydride, sodium methoxide, sodium ethoxide or
Sodium tert-butoxide；The organic solvent is selected from ethyl acetate, isopropyl acetate, acetonitrile, acetone, tetrahydrofuran or isopropanol；It is described
Alcohol is selected from methanol, ethyl alcohol, normal propyl alcohol or isopropanol.
The present invention also provides a kind of compound, shown in the general structure of the compound such as formula (II):
Wherein, n is the integer of 0≤n≤4.
The present invention also provides the preparation methods of compound shown in formula (II), comprising the following steps: dissolves bromacyl bromide
In organic solvent and be cooled to -60~0 DEG C, be slowly added to alkali, then add catalyst DMAP, obtain bromacyl bromide/alkali/
The organic solvent system of DMAP, it is spare；Take BHA-Lys-Lys2-Lys4-Lys8-Lys16- 32TFA is dissolved in the molten of organic solvent
Liquid after being cooled to -40~-20 DEG C in advance, is added dropwise in bromacyl bromide/alkali/DMAP organic solvent system, it is to slowly warm up to -10~
10 DEG C of reactions；Without BHA-Lys-Lys in detection architecture2-Lys4-Lys8-Lys16After -32TFA is remaining, slowly it is added dropwise into system
Saturated salt solution quenching reaction, stirring, liquid separation separate organic solvent layer, use 0.5mol/L dilute hydrochloric acid and saturated salt solution respectively
Each washing for the first time, removes organic solvent under reduced pressure to get formula (II) compound represented.
Preferably, bromacyl bromide 2 is dissolved in organic solvent and is cooled to -40~-20 DEG C, be slowly added to alkali；The bromine
For acylbromide 2, alkali, DMAP and BHA-Lys-Lys2-Lys4-Lys8-Lys16The molar ratio of -32TFA is (32~64): (64~
128): 0.1:1；Preferably, the bromacyl bromide, alkali, DMAP and BHA-Lys-Lys2-Lys4-Lys8-Lys16- 32TFA's rubs
You are than being (38.4~48): (70.4~80): 0.1:1；The organic solvent be selected from methylene chloride, chloroform, ethyl acetate,
Isopropyl acetate, toluene or dimethylbenzene；The alkali is selected from sodium bicarbonate, sodium carbonate, sodium hydride, sodium methoxide, sodium ethoxide, the tert-butyl alcohol
Sodium, triethylamine, diisopropylethylamine or pyridine.
Preferably, the BHA-Lys-Lys2-Lys4-Lys8-Lys16The same patent of the preparation method of -32TFA
ZL02807728.8。
The present invention also provides a kind of compound, shown in the structural formula of the compound such as formula (IV):
Wherein, n is the integer of 0≤n≤4；
R5 is expressed as follows group:
Compound shown in formula (IV) is prepared using compound shown in formula (II) as raw material；Shown in formula (II)
In compound structure general formula when n=0, n=1, n=2, n=3 and n=4, n in general structure shown in formula (IV) is prepared respectively
=0, the compound of n=1, n=2, n=3 and n=4.
The present invention also provides the preparation methods of compound shown in formula (IV), comprising the following steps:
(1) compound shown in formula (II) is prepared according to the method；
(2) alkali and 3,6- sodium disulfonate-is added in compound shown in the formula (II) with the acquisition of anhydrous DMSO dissolving step (1)
1- naphthols is warming up to 40~90 DEG C, is stirred to react；Reaction terminates, and is filtered to remove insoluble matter, and filtrate is slowly added dropwise into organic molten
In agent, solid precipitating, filtering is precipitated；Filtering obtained solid is recrystallized using the mixed solvent of alcohol and water to get such as formula
(IV) compound represented.
Preferably, step (2) alkali and 3, the molar ratio of 6- sodium disulfonate -1- naphthols are (32~64): (32~64),
Preferably, the alkali and 3, the molar ratio of 6- sodium disulfonate -1- naphthols are (38~48): (35.2~41.6)；The alkali and 3,
6- sodium disulfonate -1- naphthols is warming up to 50~70 DEG C, is stirred to react；The alkali is selected from sodium bicarbonate, sodium carbonate, sodium hydride, first
Sodium alkoxide, sodium ethoxide, sodium tert-butoxide, triethylamine, diisopropylethylamine or pyridine；The organic solvent is selected from ethyl acetate, acetic acid
Isopropyl ester, acetonitrile, acetone, tetrahydrofuran or isopropanol；The alcohol is selected from methanol, ethyl alcohol, normal propyl alcohol or isopropanol.
The present invention also provides use of the compound in the drug for preparing pre- preventing HIV infection shown in formula (III) or formula (IV)
On the way.
Compound shown in formula (III) provided by the invention or formula (IV) can be used for preparing the drug of pre- preventing HIV infection.
The present invention also provides a kind of drug of pre- preventing HIV infection, the drug includes formula (III) or formula (IV) shownization
Close object and pharmaceutically acceptable carrier.
The compound provided by the invention as shown in formula (III) or formula (IV) is the prevention disclosed in patent ZL02807728.8
Be transformed in the medicament SPL7013 structure basis of sexual transmitted diseases-I made of analog；It improves SPL7013
Crucial synthesis technology is at high cost, purifies the unfavorable conditions such as cumbersome and energy consumption of freeze drying height, so that new process is more conducive to industrialize.
The preparation method of compound shown in formula (III) or formula (IV) is two-step method, wherein chemical combination shown in formula (III)
Object preparation method specifically includes that (1) L-lysine dendritic BHA-Lys-Lys2-Lys4-Lys8In alkali and catalyst
It in the presence of DMAP (4-dimethylaminopyridine), in organic solvent, is reacted with bromo acid bromide RCOBr R4, the polymerization of L-lysine dendroid
Object BHA-Lys-Lys2-Lys4-Lys8Exposed total 16 amino of outermost are acylated to obtain by the acylbromide of bromo acid bromide RCOBr R4
Amide compound BHA-Lys-Lys2-Lys4-Lys8- R4 (16), is simply washed and the intermediate for meeting purity requirement can be obtained
Compound；(2) end ε-bromine that the amide compound contains, in the presence of a base, by 3,6- sodium disulfonate -1- in organic solvent
The phenolic hydroxyl group negative oxygen ion attack of naphthols replaces, and generates ehter bond, is simply post-processed and target compound can be obtained in recrystallization
BHA-Lys-Lys2-Lys4-Lys8-R2(16)。
Its chemical equation is as follows:
Compounds process for production thereof shown in formula (IV) specifically includes that (1) L-lysine dendritic BHA-Lys-Lys2-
Lys4-Lys8-Lys16In the presence of alkali and catalyst DMAP (4-dimethylaminopyridine), in organic solvent, with bromo acyl group
Bromine R3 reaction, L-lysine dendritic BHA-Lys-Lys2-Lys4-Lys8-Lys16Exposed total 32 ammonia of outermost
Base is acylated to obtain amide compound BHA-Lys-Lys by the acylbromide of bromo acid bromide RCOBr R32-Lys4-Lys8-Lys16- R3 (32),
It is simply washed and the midbody compound for meeting purity requirement can be obtained；(2) α-bromine that the amide compound contains, is deposited in alkali
Under, replaced in organic solvent by the phenolic hydroxyl group negative oxygen ion attack of 3,6- sodium disulfonate -1- naphthols, ehter bond is generated, through letter
Target compound BHA-Lys-Lys can be obtained in single post-processing and recrystallization2-Lys4-Lys8-Lys16-R1(32)。
Its chemical equation is as follows:
Wherein, end-capping group R1, R2 are respectively represented such as flowering structure:
Corresponding bromacyl bromide R3 and R4 is respectively represented such as flowering structure:
Compared with the existing technology, the invention has the benefit that (1) the present invention provides a kind of the new of pre- preventing HIV infection
Compound, can effectively pre- preventing HIV infection, HIV-resistant activity it is high；(2) the compounds of this invention preparation cost is low, and preparation method is simple,
Acylbromide activity is high, is swift in response thoroughly with amino, generates hydrogen bromide by Alkali absorption, post-processes simple and high income；And END CAPPED GROUP
Group's segment 3,6- sodium disulfonate -1- naphthols replace α-bromine or ε-bromine atom reaction mild, only generate hydrogen bromide, no condensing agent introduces
Extra segment, post-processing is simple, can be obtained high-purity object using the method for recrystallization purifying, without using column layer
Analysis, is very suitable to industrial amplification production.
Specific embodiment
To better illustrate the object, technical solutions and advantages of the present invention, below in conjunction with specific embodiment to the present invention
It is described further.
Embodiment 1
The present embodiment provides when n=1, a kind of preparation method of compound shown in formula (I) and formula (III), including following step
It is rapid:
(1) 16mmol 3- bromopropionyl bromide is dissolved in methylene chloride and is cooled to -60 DEG C, be slowly added to the carbon of 32mmol
Then sour hydrogen sodium adds the catalyst DMAP of 0.1mmol, obtain 3- bromopropionyl bromide/sodium bicarbonate/DMAP methylene chloride body
System；It synthesizes to obtain BHA-Lys-Lys according to patent ZL02807728.8 the method2-Lys4-Lys8- 16TFA takes 1mmol's
BHA-Lys-Lys2-Lys4-Lys8- 16TFA is dissolved in the solution of methylene chloride, after being cooled to -40 DEG C in advance, is added dropwise to 3- bromine propionyl
In bromine/sodium bicarbonate/DMAP dichloromethane system, it is to slowly warm up to -10 DEG C of reactions；Without BHA-Lys- in detection architecture
Lys2-Lys4-Lys8After -16TFA is remaining, saturated salt solution quenching reaction, stirring are slowly added dropwise into system, liquid separation separates two
Chloromethanes layer is respectively washed for the first time with 0.5mol/L dilute hydrochloric acid and saturated salt solution respectively, removes methylene chloride under reduced pressure to get n
=1 formula (I) compound represented, is denoted as compound 1；
(2) with anhydrous DMSO dissolving step (1) obtain formula (I) shown in compound, be added 16mmol sodium methoxide and
3, the 6- sodium disulfonate -1- naphthols of 16mmol, is warming up to 40 DEG C, is stirred to react；Reaction terminates, and is filtered to remove insoluble matter, will filter
Liquid is slowly added dropwise in ethyl acetate, and solid precipitating, filtering is precipitated；Obtained solid will be filtered and use the mixed solvent of methanol and water
Compound shown in the formula (III) to get n=1 is recrystallized, compound 11 is denoted as.
Embodiment 2
The present embodiment provides when n=2, a kind of preparation method of compound shown in formula (I) and formula (III), including following step
It is rapid:
(1) the 4- bromine butyryl bromide of 32mmol is dissolved in chloroform and is cooled to 0 DEG C, be slowly added to the carbonic acid of 64mmol
Then sodium adds the catalyst DMAP of 0.1mmol, obtain 4- bromine butyryl bromide/sodium carbonate/DMAP chloroform system；Root
It synthesizes to obtain BHA-Lys-Lys according to patent ZL02807728.8 the method2-Lys4-Lys8- 16TFA takes the BHA- of 1mmol
Lys-Lys2-Lys4-Lys8- 16TFA is dissolved in the solution of chloroform, after being cooled to -20 DEG C in advance, is added dropwise to 4- bromine butyryl bromide/carbon
In the organic solvent system of sour sodium/DMAP, it is to slowly warm up to 10 DEG C of reactions；Without BHA-Lys-Lys in detection architecture2-Lys4-
Lys8After -16TFA is remaining, saturated salt solution quenching reaction, stirring are slowly added dropwise into system, liquid separation separates chloroform layer,
It is respectively washed for the first time with 0.5mol/L dilute hydrochloric acid and saturated salt solution respectively, removes chloroform under reduced pressure to get the formula (I) of n=2
Shown compound is denoted as compound 2；
(2) with anhydrous DMSO dissolving step (1) obtain formula (I) shown in compound, be added 32mmol sodium hydride and
3, the 6- sodium disulfonate -1- naphthols of 32mmol, is warming up to 90 DEG C, is stirred to react；Reaction terminates, and is filtered to remove insoluble matter, will filter
Liquid is slowly added dropwise in isopropyl acetate, and solid precipitating, filtering is precipitated；It is molten using the mixing of ethyl alcohol and water that obtained solid will be filtered
Agent is recrystallized compound shown in the formula (III) to get n=2, is denoted as compound 12.
Embodiment 3
The present embodiment provides when n=3, a kind of preparation method of compound shown in formula (I) and formula (III), including following step
It is rapid:
(1) the 5- bromine bromine pivaloyl of 19mmol is dissolved in ethyl acetate and is cooled to -40 DEG C, be slowly added to the hydrogen of 35mmol
Change sodium, then adds the catalyst DMAP of 0.1mmol, obtain 5- bromine bromine pivaloyl/sodium hydride/DMAP ethyl acetate system；
It synthesizes to obtain BHA-Lys-Lys according to patent ZL02807728.8 the method2-Lys4-Lys8- 16TFA takes the BHA- of 1mmol
Lys-Lys2-Lys4-Lys8- 16TFA is dissolved in the solution of ethyl acetate, after being cooled to -30 DEG C in advance, is added dropwise to 5- bromine bromine pivaloyl/hydrogen
Change in sodium/DMAP ethyl acetate system, is to slowly warm up to -5 DEG C of reactions；Without BHA-Lys-Lys in detection architecture2-Lys4-
Lys8After -16TFA is remaining, saturated salt solution quenching reaction, stirring are slowly added dropwise into system, liquid separation separates ethyl acetate layer,
It is respectively washed for the first time with 0.5mol/L dilute hydrochloric acid and saturated salt solution respectively, removes ethyl acetate under reduced pressure to get the formula (I) of n=3
Shown compound is denoted as compound 3；
(2) with anhydrous DMSO dissolving step (1) obtain formula (I) shown in compound, be added 19mmol sodium ethoxide and
3, the 6- sodium disulfonate -1- naphthols of 17.6mmol, is warming up to 50 DEG C, is stirred to react；Reaction terminates, and is filtered to remove insoluble matter, will
Filtrate is slowly added dropwise in acetonitrile, and solid precipitating, filtering is precipitated；Obtained solid will be filtered and use the mixed solvent of normal propyl alcohol and water
Compound shown in the formula (III) to get n=3 is recrystallized, compound 13 is denoted as.
Embodiment 4
The present embodiment provides when n=4, a kind of preparation method of compound shown in formula (I) and formula (III), including following step
It is rapid:
(1) the 6- bromine hexanoyl bromide of 24mmol is dissolved in isopropyl acetate and is cooled to -20 DEG C, be slowly added to 40mmol's
Then sodium carbonate adds the catalyst DMAP of 0.1mmol, obtain 6- bromine hexanoyl bromide/sodium carbonate/DMAP isopropyl acetate body
System；It synthesizes to obtain BHA-Lys-Lys according to patent ZL02807728.8 the method2-Lys4-Lys8- 16TFA takes 1mmol's
BHA-Lys-Lys2-Lys4-Lys8- 16TFA is dissolved in the solution of isopropyl acetate, after being cooled to -35 DEG C in advance, be added dropwise to 6- bromine oneself
In acylbromide/sodium carbonate/DMAP isopropyl acetate system, it is to slowly warm up to 0 DEG C of reaction；Without BHA-Lys- in detection architecture
Lys2-Lys4-Lys8After -16TFA is remaining, saturated salt solution quenching reaction, stirring are slowly added dropwise into system, liquid separation separates second
Isopropyl propionate layer is respectively washed for the first time with 0.5mol/L dilute hydrochloric acid and saturated salt solution respectively, removes isopropyl acetate under reduced pressure, i.e.,
Compound shown in the formula (I) of n=4 is obtained, compound 4 is denoted as；
(2) with anhydrous DMSO dissolving step (1) obtain formula (I) shown in compound, be added 24mmol sodium tert-butoxide and
3, the 6- sodium disulfonate -1- naphthols of 20.8mmol, is warming up to 70 DEG C, is stirred to react；Reaction terminates, and is filtered to remove insoluble matter, will
Filtrate is slowly added dropwise in acetone, and solid precipitating, filtering is precipitated；Obtained solid will be filtered and use the mixed solvent of isopropanol and water
Compound shown in the formula (III) to get n=4 is recrystallized, compound 14 is denoted as.
Embodiment 5
The present embodiment provides when n=5, a kind of preparation method of compound shown in formula (I) and formula (III), including following step
It is rapid:
(1) the 7- bromine heptanoyl bromide of 30mmol is dissolved in isopropyl acetate and is cooled to -30 DEG C, be slowly added to 45mmol's
Then sodium carbonate adds the catalyst DMAP of 0.1mmol, obtain 7- bromine heptanoyl bromide/sodium carbonate/DMAP isopropyl acetate body
System；It synthesizes to obtain BHA-Lys-Lys according to patent ZL02807728.8 the method2-Lys4-Lys8- 16TFA takes 1mmol's
BHA-Lys-Lys2-Lys4-Lys8- 16TFA is dissolved in the solution of isopropyl acetate, after being cooled to -30 DEG C in advance, is added dropwise to 7- bromine heptan
In acylbromide/sodium carbonate/DMAP isopropyl acetate system, it is to slowly warm up to 5 DEG C of reactions；Without BHA-Lys- in detection architecture
Lys2-Lys4-Lys8After -16TFA is remaining, saturated salt solution quenching reaction, stirring are slowly added dropwise into system, liquid separation separates second
Isopropyl propionate layer is respectively washed for the first time with 0.5mol/L dilute hydrochloric acid and saturated salt solution respectively, removes isopropyl acetate under reduced pressure, i.e.,
Compound shown in the formula (I) of formula n=5 is obtained, compound 5 is denoted as；
(2) with anhydrous DMSO dissolving step (1) obtain formula (I) shown in compound, be added 30mmol sodium hydride and
3, the 6- sodium disulfonate -1- naphthols of 25mmol, is warming up to 80 DEG C, is stirred to react；Reaction terminates, and is filtered to remove insoluble matter, will filter
Liquid is slowly added dropwise in acetone, and solid precipitating, filtering is precipitated；To filter obtained solid using isopropanol and water mixed solvent into
Compound shown in formula (III) of the row recrystallization to get n=5, is denoted as compound 15.
Embodiment 6
The present embodiment provides when n=0, a kind of preparation method of compound shown in formula (II) and formula (VI), including following step
It is rapid:
(1) 2 bromo propionyl bromide of 32mmol is dissolved in toluene and is cooled to -60 DEG C, be slowly added to three second of 64mmol
Then amine adds the catalyst DMAP of 0.1mmol, obtain 2 bromo propionyl bromide/triethylamine/DMAP toluene system, spare；Root
It synthesizes to obtain BHA-Lys-Lys according to patent ZL02807728.8 the method2-Lys4-Lys8-Lys16- 32TFA takes 1mmol's
BHA-Lys-Lys2-Lys4-Lys8-Lys16- 32TFA is dissolved in the solution of toluene, after being cooled to -40 DEG C in advance, is added dropwise to 2- bromine propionyl
In bromine/triethylamine/DMAP toluene system, it is to slowly warm up to -10 DEG C of reactions；Without BHA-Lys-Lys in detection architecture2-Lys4-
Lys8-Lys16After -32TFA is remaining, saturated salt solution quenching reaction, stirring are slowly added dropwise into system, liquid separation separates toluene
Layer is respectively washed for the first time with 0.5mol/L dilute hydrochloric acid and saturated salt solution respectively, removes toluene under reduced pressure to get the formula (II) of n=0
Shown compound is denoted as compound 6；
(2) with anhydrous DMSO dissolving step (1) obtain formula (II) shown in compound, be added 32mmol sodium carbonate and
3, the 6- sodium disulfonate -1- naphthols of 32mmol, is warming up to 40 DEG C, is stirred to react；Reaction terminates, and is filtered to remove insoluble matter, will filter
Liquid is slowly added dropwise in tetrahydrofuran, and solid precipitating, filtering is precipitated；Obtained solid will be filtered and use the mixed solvent of methanol and water
Compound shown in the formula (VI) to get n=0 is recrystallized, compound 16 is denoted as.
Embodiment 7
The present embodiment provides when n=1, a kind of preparation method of compound shown in formula (II) and formula (VI), including following step
It is rapid:
(1) the 2- bromine butyryl bromide of 64mmol is dissolved in dimethylbenzene and is cooled to 0 DEG C, be slowly added to the two of 128mmol
Then wopropyl ethyl amine adds the catalyst DMAP of 0.1mmol, obtain 2- bromine butyryl bromide/diisopropylethylamine/DMAP two
Toluene system, it is spare；It synthesizes to obtain BHA-Lys-Lys according to patent ZL02807728.8 the method2-Lys4-Lys8-Lys16-
32TFA takes the BHA-Lys-Lys of 1mmol2-Lys4-Lys8-Lys16- 32TFA is dissolved in the solution of dimethylbenzene, is cooled to -20 DEG C in advance
Afterwards, it is added dropwise in 2- bromine butyryl bromide/diisopropylethylamine/DMAP dimethylbenzene system, is to slowly warm up to 10 DEG C of reactions；Detect body
Without BHA-Lys-Lys in system2-Lys4-Lys8-Lys16After -32TFA is remaining, saturated salt solution is slowly added dropwise into system and is quenched instead
It answers, stirs, liquid separation separates diformazan benzene layer, is respectively washed for the first time with 0.5mol/L dilute hydrochloric acid and saturated salt solution respectively, decompression is steamed
Except compound shown in formula (II) of the dimethylbenzene to get n=1, it is denoted as compound 7；
(2) with anhydrous DMSO dissolving step (1) obtain formula (II) shown in compound, be added 64mmol sodium carbonate and
3, the 6- sodium disulfonate -1- naphthols of 64mmol, is warming up to 90 DEG C, is stirred to react；Reaction terminates, and is filtered to remove insoluble matter, will filter
Liquid is slowly added dropwise in isopropanol, and solid precipitating, filtering is precipitated；To filter obtained solid using ethyl alcohol and water mixed solvent into
Compound shown in formula (VI) of the row recrystallization to get n=1, is denoted as compound 17.
Embodiment 8
The present embodiment provides when n=2, a kind of preparation method of compound shown in formula (II) and formula (VI), including following step
It is rapid:
(1) the 2- bromine bromine pivaloyl of 38.4mmol is dissolved in toluene and is cooled to -40 DEG C, be slowly added to 70.4 pyrrole
Then pyridine adds the catalyst DMAP of 0.1mmol, obtain 2- bromine bromine pivaloyl/pyridine/DMAP toluene system, spare；According to
Patent ZL02807728.8 the method synthesizes to obtain BHA-Lys-Lys2-Lys4-Lys8-Lys16- 32TFA takes 1mmol's
BHA-Lys-Lys2-Lys4-Lys8-Lys16- 32TFA is dissolved in the solution of toluene, after being cooled to -35 DEG C in advance, is added dropwise to 2- bromine valeryl
In bromine/pyridine/DMAP toluene system, it is to slowly warm up to -5 DEG C of reactions；Without BHA-Lys-Lys in detection architecture2-Lys4-
Lys8-Lys16After -32TFA is remaining, saturated salt solution quenching reaction, stirring are slowly added dropwise into system, liquid separation separates toluene
Layer is respectively washed for the first time with 0.5mol/L dilute hydrochloric acid and saturated salt solution respectively, removes toluene under reduced pressure to get the formula (II) of n=2
Shown compound is denoted as compound 8；
(2) with anhydrous DMSO dissolving step (1) obtain formula (II) shown in compound, be added 38mmol sodium bicarbonate and
3, the 6- sodium disulfonate -1- naphthols of 35.2mmol, is warming up to 55 DEG C, is stirred to react；Reaction terminates, and is filtered to remove insoluble matter, will
Filtrate is slowly added dropwise in ethyl acetate, and solid precipitating, filtering is precipitated；Obtained solid will be filtered and use the mixing of normal propyl alcohol and water
Solvent is recrystallized compound shown in the formula (VI) to get n=2, is denoted as compound 18.
Embodiment 9
The present embodiment provides when n=3, a kind of preparation method of compound shown in formula (II) and formula (VI), including following step
It is rapid:
(1) the 2- bromine hexanoyl bromide of 48mmol is dissolved in dimethylbenzene and is cooled to -20 DEG C, be slowly added to the three of 80mmol
Then ethamine adds the catalyst DMAP of 0.1mmol, obtain 2- bromine hexanoyl bromide/triethylamine/DMAP dimethylbenzene system, standby
With；It synthesizes to obtain BHA-Lys-Lys according to patent ZL02807728.8 the method2-Lys4-Lys8-Lys16- 32TFA takes
The BHA-Lys-Lys of 1mmol2-Lys4-Lys8-Lys16- 32TFA is dissolved in the solution of dimethylbenzene, after being cooled to -30 DEG C in advance, is added dropwise
Enter in 2- bromine hexanoyl bromide/triethylamine/DMAP dimethylbenzene system, is to slowly warm up to 5 DEG C of reactions；Without BHA-Lys- in detection architecture
Lys2-Lys4-Lys8-Lys16After -32TFA is remaining, saturated salt solution quenching reaction is slowly added dropwise into system, stirs, liquid separation,
Separate diformazan benzene layer, respectively with 0.5mol/L dilute hydrochloric acid and saturated salt solution respectively wash for the first time, remove under reduced pressure dimethylbenzene to get
Compound shown in the formula (II) of n=3, is denoted as compound 9；
(2) with anhydrous DMSO dissolving step (1) obtain formula (II) shown in compound, be added 48mmol sodium carbonate and
3, the 6- sodium disulfonate -1- naphthols of 41.6mmol, is warming up to 75 DEG C, is stirred to react；Reaction terminates, and is filtered to remove insoluble matter, will
Filtrate is slowly added dropwise in isopropyl acetate, and solid precipitating, filtering is precipitated；Obtained solid will be filtered and use the mixed of isopropanol and water
Bonding solvent is recrystallized compound shown in the formula (VI) to get n=3, is denoted as compound 19.
Embodiment 10
The present embodiment provides when n=4, a kind of preparation method of compound shown in formula (II) and formula (VI), including following step
It is rapid:
(1) the 2- bromine heptanoyl bromide of 40mmol is dissolved in dimethylbenzene and is cooled to -10 DEG C, be slowly added to the three of 90mmol
Then ethamine adds the catalyst DMAP of 0.1mmol, obtain 2- bromine heptanoyl bromide/triethylamine/DMAP dimethylbenzene system, standby
With；It synthesizes to obtain BHA-Lys-Lys according to patent ZL02807728.8 the method2-Lys4-Lys8-Lys16- 32TFA takes
The BHA-Lys-Lys of 1mmol2-Lys4-Lys8-Lys16- 32TFA is dissolved in the solution of dimethylbenzene, after being cooled to -25 DEG C in advance, is added dropwise
Enter in 2- bromine heptanoyl bromide/triethylamine/DMAP dimethylbenzene system, is to slowly warm up to 3 DEG C of reactions；Without BHA-Lys- in detection architecture
Lys2-Lys4-Lys8-Lys16After -32TFA is remaining, saturated salt solution quenching reaction is slowly added dropwise into system, stirs, liquid separation,
Separate diformazan benzene layer, respectively with 0.5mol/L dilute hydrochloric acid and saturated salt solution respectively wash for the first time, remove under reduced pressure dimethylbenzene to get
Compound shown in the formula (II) of n=4, is denoted as compound 10；
(2) with anhydrous DMSO dissolving step (1) obtain formula (II) shown in compound, be added 60mmol sodium carbonate and
3, the 6- sodium disulfonate -1- naphthols of 60mmol, is warming up to 65 DEG C, is stirred to react；Reaction terminates, and is filtered to remove insoluble matter, will filter
Liquid is slowly added dropwise in isopropyl acetate, and solid precipitating, filtering is precipitated；Obtained solid will be filtered and use the mixing of isopropanol and water
Solvent is recrystallized compound shown in the formula (VI) to get n=4, is denoted as compound 20.
Embodiment 11
The present embodiment detects the yield of compound 1~10 and compound 11~20 in Examples 1 to 10.
1, yield detection method
The relative molar mass (unit are as follows: g/mol) of compound 1~20 is denoted as respectively: M1、M2、M3、M4、M5、M6、M7、M8、
M9、M10、M11、M12、M13、M14、M15、M16、M17、M18、M19And M20；
Weight (the unit are as follows: g) be denoted as respectively: W of the compound 1~20 actually obtained in embodiment1、W2、W3、W4、W5、
W6、W7、W8、W9、W10、W11、W12、W13、W14、W15、W16、W17、W18、W19And W20。
Weight data table 1 compound relative molecular mass and actually obtained
Compound 1-10 yield universal calculation equation=[W/ (M*0.001)] * 100%
1 yield of compound=(3.839/4.265) * 100%=90%
2 yield of compound=(4.131/4.490) * 100%=92%
3 yield of compound=(4.478/4.714) * 100%=95%
4 yield of compound=(4.642/4.938) * 100%=94%
5 yield of compound=(4.853/5.163) * 100%=94%
6 yield of compound=(7.628/8.475) * 100%=90%
7 yield of compound=(8.032/8.924) * 100%=90%
8 yield of compound=(8.717/9.373) * 100%=93%
9 yield of compound=(9.331/9.822) * 100%=95%
10 yield of compound=(9.552/10.271) * 100%=93%
Compound 11-20 yield calculation formula difference is as follows:
11 yield of compound=[W11/(M11* 0.90*0.001)] * 100%=(6.612/7.689) * 100%=86%
12 yield of compound=[W12/(M12* 0.92*0.001)] * 100%=(7.098/8.066) * 100%=88%
13 yield of compound=[W13/(M13* 0.95*0.001)] * 100%=(7.602/8.542) * 100%=89%
14 yield of compound=[W14/(M14* 0.94*0.001)] * 100%=(7.450/8.663) * 100%=86%
15 yield of compound=[W15/(M15* 0.94*0.001)] * 100%=(8.164/8.874) * 100%=92%
16 yield of compound=[W16/(M16* 0.90*0.001)] * 100%=(13.028/15.327) * 100%=
85%
17 yield of compound=[W17/(M17* 0.9*0.001)] * 100%=(14.158/15.731) * 100%=90%
18 yield of compound=[W18/(M18* 0.93*0.001)] * 100%=(15.673/16.673) * 100%=
94%
19 yield of compound=[W19/(M19* 0.95*0.001)] * 100%=(16.585/17.458) * 100%=
95%
20 yield of compound=[W20/(M20* 0.93*0.001)] * 100%=(16.282/17.508) * 100%=
93%
2, testing result
The yield testing result of compound 1~10 and compound 11~20 that Examples 1 to 10 is prepared such as 2 institute of table
Show:
2 yield testing result of table
By above-mentioned testing result it is found that the yield that the method for the present invention acylation reaction obtains compound 1~10 is 90-
95%；The yield that substitution reaction obtains compound 11~20 is 85-95%；Total yield is 76.5%-90%, and patent
The yield of preparation method is 75% in ZL02807728.8, illustrates that comprehensive yield of the present invention is higher than the prior art.And system of the present invention
Preparation Method reagent cost is low, easy to operate.
Embodiment 12
The HIV-resistant activity for the compound 11~20 that the present embodiment research Examples 1 to 10 is prepared.
1, detection method
The detection method of referenced patent ZL02807728.8, the inhibition of HIV strain type used be HIV-1IIIB, in parallel into
Row anti-retroviral activity and cytotoxicity assay.These tests are based on being then exposed to various concentration by HIV infection
The survival of the MT-4 cell of test compound.After MT-4 cell Proliferation 5 days, by bromination 3- based on tetrazole colorimetric (4,
5- dimethylthiazole -2- base) -2,5- dimethyl tetrazole (MTT) method, the number of quantifying live cells on 96 hole microplates.
In all these detections, virus input (virus infection plural number MOI) is 50% cell culture infective dose
(CCID50) 0.01 or 100 times.50% antiviral effective concentration EC50The cell of 50% virus infection of protection is defined as to disease-resistant
Compound concentration required for the cytopathogenicity of poison.50% cytotoxic concentration CC50It is defined as the cell of simulated infection
Compound concentration required for survival reduces 50%." > ", indicates the maximum concentration it has been found that the test of no cytotoxicity compound.3
The average EC of secondary independent experiment50And CC50Value is as defined above to be indicated.SI is defined as antiviral selectivity index (SI=CC50/
EC50)。
2, testing result
The testing result of the HIV-resistant activity of the compounds of this invention 11~20 is as shown in table 3:
3 HIV-resistant activity testing result of table
It, can be effective by above-mentioned testing result it is found that compound provided by the invention 11~20 has good HIV-resistant activity
Pre- preventing HIV infection.
Finally, it should be noted that the above embodiments are merely illustrative of the technical solutions of the present invention rather than protects to the present invention
The limitation of range is protected, although the invention is described in detail with reference to the preferred embodiments, those skilled in the art should
Understand, it can be with modification or equivalent replacement of the technical solution of the present invention are made, without departing from the essence of technical solution of the present invention
And range.
Claims (10)
1. a kind of compound, which is characterized in that shown in the general structure of the compound such as formula (I):
Wherein, n is the integer of 1≤n≤5.
2. a kind of preparation method of compound as described in claim 1, which comprises the following steps: by bromo acyl
Bromine is dissolved in organic solvent and is cooled to -60~0 DEG C, is slowly added to alkali, then adds catalyst DMAP, obtains bromo acyl
Bromine/alkali/DMAP organic solvent system；Take BHA-Lys-Lys2-Lys4-Lys8- 16TFA is dissolved in the solution of organic solvent, in advance
It after being cooled to -40~-20 DEG C, is added dropwise in bromacyl bromide/alkali/DMAP organic solvent system, is to slowly warm up to -10~10 DEG C instead
It answers；Without BHA-Lys-Lys in detection architecture2-Lys4-Lys8After -16TFA is remaining, saturated common salt water quenching is slowly added dropwise into system
It goes out reaction, stirring, liquid separation separates organic solvent layer, it is respectively washed for the first time with 0.5mol/L dilute hydrochloric acid and saturated salt solution respectively,
Organic solvent is removed under reduced pressure to get compound shown in formula (I)；Wherein, the organic solvent be selected from methylene chloride, chloroform,
Ethyl acetate, isopropyl acetate, toluene or dimethylbenzene.
3. preparation method as claimed in claim 2, which is characterized in that bromacyl bromide is dissolved in organic solvent and be cooled to-
40~-20 DEG C, it is slowly added to alkali；The bromacyl bromide, alkali, DMAP and BHA-Lys-Lys2-Lys4-Lys8Mole of -16TFA
Than for 16~32:32~64:0.1:1；The alkali is selected from sodium bicarbonate, sodium carbonate, sodium hydride, sodium methoxide, sodium ethoxide, the tert-butyl alcohol
Sodium, triethylamine, diisopropylethylamine or pyridine.
4. preparation method as claimed in claim 3, which is characterized in that the bromacyl bromide, alkali, DMAP and BHA-Lys-Lys2-
Lys4-Lys8The molar ratio of -16TFA is 19~24:35~40:0.1:1.
5. a kind of compound, which is characterized in that shown in the structural formula of the compound such as formula (III):
Wherein, n is the integer of 1≤n≤5；
R5It is expressed as follows group:
6. a kind of preparation method of compound as claimed in claim 5, which comprises the following steps:
(1) compound shown in formula (I) is prepared according to Claims 2 or 3 the method；
(2) alkali and 3,6- sodium disulfonate -1- naphthalene is added in compound shown in the formula (I) with the acquisition of anhydrous DMSO dissolving step (1)
Phenol is warming up to 40~90 DEG C, is stirred to react；Reaction terminates, and is filtered to remove insoluble matter, and filtrate is slowly added dropwise into organic solvent
In, solid precipitating, filtering is precipitated；Filtering obtained solid is recrystallized using the mixed solvent of C1, C2 or C3 alcohol and water, i.e.,
It obtains such as formula (III) compound represented；Wherein, the organic solvent is selected from ethyl acetate, isopropyl acetate, acetonitrile, acetone, four
Hydrogen furans or isopropanol.
7. preparation method as claimed in claim 6, which is characterized in that alkali and 3 in the step (2), 6- sodium disulfonate -1- naphthalene
The molar ratio of phenol is 16~32:16~32；The alkali and 3,6- sodium disulfonate -1- naphthols are warming up to 50~70 DEG C, are stirred to react；
The alkali is selected from sodium hydride, sodium methoxide, sodium ethoxide or sodium tert-butoxide；The alcohol is selected from methanol, ethyl alcohol, normal propyl alcohol or isopropanol.
8. preparation method as claimed in claim 7, which is characterized in that alkali and 3 in the step (2), 6- sodium disulfonate -1- naphthalene
The molar ratio of phenol is 19~24:17.6~20.8.
9. purposes of the compound described in claim 5 in the drug for preparing pre- preventing HIV infection.
10. a kind of drug of pre- preventing HIV infection, which is characterized in that the drug includes compound and medicine described in claim 5
The acceptable carrier of object.
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