CN109796472A - The preparation method and application of biologically active novel class drug molecule - Google Patents
The preparation method and application of biologically active novel class drug molecule Download PDFInfo
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Abstract
The invention discloses a kind of preparation method and applications of biologically active novel class drug molecule, belong to medical synthesis technical field.Technical solution of the present invention main points are as follows: a kind of biologically active class drug molecule, structural formula are as follows:
Description
Technical field
The invention belongs to medical synthesis technical fields, and in particular to a kind of biologically active novel class drug molecule
Preparation method and application.
Background technique
Based compound is the condensed ring macromolecular class compound of a kind of plane, rigidity, conjugation, has good photochemistry steady
Qualitative and stronger fluorescence property, wherein acid imide is important based compound.Imide derivative substantial amounts, function
It can be numerous and functional.Although acid imide be all nuance using core as parent, in structure in nature
It can show the difference of difference, especially fluorescence quantum yield and the variation of ultraviolet/fluorescence spectrum.Good rigidity itself
Planes of molecules assigns its stabilization, excellent fluorescence property, it is made to have great application prospect in terms of fluorescent chromophore；But
Also the electron conjugated structure just because of big plane, rigidity makes intermolecular pi-pi accumulation effect very strong, has biggish crystalline substance
Lattice energy, the driving force of intermolecular interaction are easy to make dye aggregation.Acid imide intermolecular aggregation can not only cause fluorescence to subtract
It is weak or even be quenched, but also the problems such as its dissolubility in most of organic and inorganic solvents is very poor, and there are the separation of product difficulty,
Limit imido development and application.Although some insoluble and dystectic derivative can by with it is numerous
Fatty amine, aromatic amine, which directly react, to be obtained, but in practical application with greater need for be soluble dye.In order to break through synthesis and answer
Bottleneck, H.Langhals et al. introduces some solubilizing groups from core " acid imide " position, such as long-chain fat primary amine and fragrance
Class primary amine etc..Especially when N substituent group is tert-butyl phenyl ring, there is large effect to imido dissolubility.This conjunction
Mostly use quinoline, imidazoles, N-methyl pyrrolidones as solvent at method, at a higher temperature back flow reaction.This synthesis
Strategy has been effectively maintained the smooth of chromophore itself, rigidity, conjugate planes, designs a series of acid imides of synthesis usually
It is used for the research in terms of self assembly.G.Seybold and his colleague have found that " island " position introduces meeting after substituent group under study for action
Core is set to be distorted because of substituent group steric strain, distortion can inhibit intermolecular accumulation, entropy during dissolution
Increase and improves imido solubility.They are using dibromo acid imide or tetrabromo acid imide intermediate and each substitution
Group nucleophilic substitution reaction generates corresponding derivative, can distort to a certain extent the flatness of core, but can make simultaneously
The significantly red shift of imido fluorescent emission extends them in the application of biomedicine field.
Compared to chromophories such as cyanine dye, merocyanine dye, fluoresceins, class compound is total because of its stable condensed-nuclei aromatics
Yoke structure has high light, chemical stability, fluorescence quantum yield.Width is shown by the asymmetric class compound of modification
The characteristics of absorption, narrow transmitting, maximum emission wavelength is adjustable (being greater than 525nm), apparent can believe with cellular context fluorescence
Number (395nm~479nm) is distinguished, and offer fluorescence signal that can be continual and steady, in terms of being suitably applied biological fluorescent labeling
Research.And the fluorescent dye for being applied to these fields at least meets the following: 1, enough water solubilitys, and in aqueous solution
In have enough fluorescence signals；2, secondly have and the functional group of biomolecule action；3, last luminescent dye molecule not shadow
Ring the function of biomolecule.
Summary of the invention
Present invention solves the technical problem that be group on carried out symmetrical modification, provide a kind of letter of synthetic method
Single, low in raw material price, structure novel, and it is water-soluble preferable, the biologically active of the function of biomolecule is not influenced
The preparation method and application of novel class drug molecule.
The present invention adopts the following technical scheme that solve above-mentioned technical problem, a kind of biologically active novel class medicine
Object molecule, it is characterised in that specific steps are as follows:
A, acenaphthene is added in glacial acetic acid, adds a certain amount of potassium bichromate, at room temperature after mixing evenly
80 DEG C are to slowly warm up to, thermotonus is kept to monitor raw material fully reacting to TLC, reaction solution is poured into ice water stirring while hot, had
Solid is precipitated, and filters reaction solution, 1,8- naphthalene dicarboxylic anhydride is obtained after filter cake is dried；
B, 1,8- naphthalene diacid glycosides is added in the ammonium hydroxide of saturation, stirs to get the mixed liquor of yellow at room temperature
Body, then 70 DEG C are heated slowly to, stop heating after keeping the thermotonus to monitor raw material fully reacting to TLC, is slowly dropped to room
Temperature has solid precipitation, filtering reacting liquid, and filter cake is washed with water to neutrality, then obtains 1,8- naphthalene diamides in drying；
C, a certain amount of barium hydroxide and anhydrous sodium acetate are added in the stainless steel cauldron with stirring, in vacuum item
It is heated to certain temperature under part, is kept for temperature stirring a period of time, 1,8- benzene-naphthalene diimide is added under nitrogen protection, after adding
300 DEG C of reaction a period of times are continuously heating to, 200 DEG C is cooled to again, a certain amount of water is added, reaction solution is poured into after stirring
In water, at room temperature stirring a period of time, there are a large amount of solids to be precipitated, filter reaction solution, filter cake is added to after being washed with water
In the hydrochloric acid solution of saturation, it is heated to 75 DEG C and is stirred to react a period of time, filtering reacting liquid, filter cake dry under the conditions of 80 DEG C again
It is dry to obtain 3,4,9,10- tetracarboxylic acid diimide crude product；3,4,9,10- tetracarboxylic acid diimide hydrochloride, crude is added
Into the concentrated sulfuric acid, 80 DEG C are to slowly warm up to, crude product is completely dissolved, and sulfuric acid of a certain amount of concentration for 50%, drop is being slowly added dropwise
It is warming up to 100 DEG C after adding, is down to room temperature after the reaction was continued a period of time, there are a large amount of solids to be precipitated, filtering reacting liquid, filter cake is used
Drying obtains 3,4,9,10- tetracarboxylic acid diimide sterling under the conditions of 80 DEG C again after the sulfuric acid solution washing that concentration is 78%；
D, under room temperature, 3,4,9,10- tetracarboxylic acid diimides are slowly added into the concentrated sulfuric acid, after adding slowly
220 DEG C are warming up to, thermotonus is kept for a period of time, is then slowly dropped to room temperature, there are a large amount of solids to be precipitated in temperature-fall period, mistake
Reaction solution is filtered, filter cake is washed with water to neutrality, dries filter cake under the conditions of 80 DEG C and obtains 3,4,9,10- glycosides crude products；It is being protected from light
Under the conditions of, obtained crude product is all added in the mixed solution of water and potassium hydroxide solution, under nitrogen protection, is slowly added
Heat is down to room temperature after keeping temperature to be stirred to react a period of time to 90 DEG C, has a large amount of solids to be precipitated, and reaction solution, filter is filtered by vacuum
Cake is washed with water；Under the conditions of nitrogen protection is with being protected from light, potassium hydroxide and active carbon are added into filtrate, stirs at room temperature
Iron chloride and water are added after mixing, holding room temperature condition is stirred to react for a period of time, filtering reacting liquid, and the salt of saturation is added in filtrate
Acid solution is heated to 80~90 DEG C of stirrings to there is a large amount of solids to occur, is cooled to room temperature filtering reacting liquid, and drying filter cake obtains 3,
4,9,10- tetracid glycosides；
E, 3,4,9,10- tetra- acid anhydrides are added in potassium hydroxide saturated aqueous solution, are warming up to 90 DEG C after mixing evenly, so
Reaction solution is moved into autoclave afterwards, enclosed high pressure kettle is to slowly warm up to certain temperature, make in kettle pressure reach 0.2~
0.3MPa, insulation reaction are cooled to room temperature afterwards for a period of time, and adjusting reaction solution pH with 10% hydrochloric acid solution is 8~9, and filtering is anti-
Liquid is answered, continues to adjust filtrate pH with 10% hydrochloric acid solution to be 2~3, there are a large amount of solids to be precipitated at this time, filtering reacting liquid, filter cake
It is washed twice with saturated sodium chloride solution 200mL, drying filter cake obtains 3,9- diacid；Tetra- acid anhydrides of 3,4,9,10-
Inventory molar ratio with potassium hydroxide is 1:5~8；The reaction temperature is 150~250 DEG C；
F, 3,9- diacid is added in thionyl chloride, 1h is reacted in 60 DEG C of heating under nitrogen protection, and it is anti-that TLC monitors raw material
Should solvent thionyl chloride be divided exactly and obtain 3,9- diacid chloride completely；3,9- diacid chloride is added in potassium hydroxide aqueous solution,
Under nitrogen protection under room temperature, bromine is added dropwise, 60 DEG C of reactions are warming up to after dripping to raw material fully reacting, reaction solution is fallen
Enter in dilute hydrochloric acid, there is solid appearance, filtering reacting liquid solid is added in sodium hydroxide solution and is completely dissolved, then uses dilute hydrochloric acid
It is neutrality that solution, which adjusts reaction solution pH, filtering reacting liquid again, and it is multiple with ice water wash filter cake, dries filter cake and obtains 3,9-
Dicarboxyl -4,10- dibromo；
G, 3,9- dicarboxyl -4,10- dibromo is dissolved in n,N-Dimethylformamide, at room temperature, stirring is equal
It is even, a certain amount of hydrazine hydrate is slowly added dropwise, 70 DEG C are warming up to after dripping, is stirred to react a period of time, reaction solution is fallen while hot
Enter in ice water, there are a large amount of solids to be precipitated, filter reaction solution, filter cake is washed repeatedly with cold methanol, and drying filter cake obtains 3,9-, bis- acyl
Base hydrazine -4,10- dibromo；
H, 3,9- diacyl hydrazide -4,10- dibromo and potassium hydroxide are added in dehydrated alcohol, under nitrogen protection,
It is to slowly warm up to flow back, at reflux, carbon disulfide is slowly added dropwise, after dripping, confined reaction liquid is warming up to 100 DEG C,
Reaction system pressure increases, and keeps thermotonus 2h, divides exactly reaction dissolvent ethyl alcohol, and the DMF added dissolved with hydrazine class compound is molten
Liquid is warming up to 130 DEG C after dripping, react 30min, and TLC monitors raw material fully reacting, is cooled to 70 DEG C, reaction solution is poured into
In ice water, there are a large amount of solids to be precipitated, filter reaction solution, filter cake is washed repeatedly with dehydrated alcohol, and drying filter cake obtainsThe hydrazine class compound is hydrazine hydrochloride or hydrazine hydrate；
I, in reaction flask,Cuprous iodide, 2- quinoline carboxylic acid-N- oxide and cesium carbonate are added two
In methyl sulfoxide, it is heated to 80 DEG C reacting to raw material fully reacting, a certain amount of water and ethyl acetate is added into reaction solution,
It stirs evenly, filtering reacting liquid, separates organic phase, water phase is extracted with ethyl acetate three times again, merges organic phase, use anhydrous slufuric acid
After sodium is dry, it is recrystallized to give after concentration through ethyl alcohol and acetone mixture
J, handleIt is added in carbon tetrachloride with Cob altporphyrin, under nitrogen protection, a certain amount of triethylamine is added, until
In -10 DEG C of environment, phosgene is slowly added dropwise, after dripping, is to slowly warm up to 0 DEG C, TLC monitors raw material fully reacting, after of continuing rising
Temperature excludes nitrogen and takes the complete phosgene of unreacted out of, saturated sodium chloride solution is added into reaction solution to 25 DEG C, filters after stirring anti-
Answer liquid, separate organic phase, water phase again with carbon tetrachloride extraction three times, merge organic phase, with anhydrous sodium sulfate it is dry after, after concentration
It is recrystallized to give through ethyl alcohol and acetone mixture
The present invention adopts the following technical scheme that solve above-mentioned technical problem, a kind of biologically active novel class medicine
The preparation method of object molecule, it is characterised in that specific steps are as follows:
Specific embodiment
Above content of the invention is described in further details by the following examples, but this should not be interpreted as to this
The range for inventing above-mentioned theme is only limitted to embodiment below, and all technologies realized based on above content of the present invention belong to this hair
Bright range.
Embodiment 1
In reaction flask, acenaphthene 15g is added in glacial acetic acid 500mL, potassium bichromate 59g is added, in room temperature condition
Under be to slowly warm up to 80 DEG C after mixing evenly, keep thermotonus 6h, TLC to monitor raw material fully reacting, reaction solution is fallen while hot
Enter in ice water 2000mL, there is solid precipitation, filters reaction solution, 1,8- naphthalene dicarboxylic anhydride 18g is obtained after filter cake is dried,1H NMR
(400MHz,DMSO-d6):δ8.55(dd,J1=8.0Hz, J1=4.0Hz, 4H), 7.93 (t, J1=4.0Hz, J1=8.0Hz,
2H)；13C NMR(400MHz,DMSO-d6):161.19,135.86,132.93,130.22,128.03,119.54。
Embodiment 2
In reaction flask, 1,8- naphthalene diacid glycosides 50g is added in the ammonium hydroxide 1000mL of saturation, is stirred at room temperature
10min obtains the mixing liquid of yellow, is heated slowly to 70 DEG C, keeps thermotonus 90min, and TLC monitoring raw material has reacted
Stop heating after complete, be slowly dropped to room temperature, there is a solid precipitation, filtering reacting liquid, filter cake is washed with water 500mL to neutrality, then
Drying obtains 1,8- naphthalene diamides 44g under the conditions of 60 DEG C；1H NMR(400MHz,DMSO-d6): δ 8.42 (d, J=4.0Hz,
4H),7.83(t,J1=8.0Hz, J2=4.0Hz, 2H)；13C NMR(400MHz,DMSO-d6):164.56,134.78,
132.03,130.42,127.53,122.93。
Embodiment 3
In reaction flask, barium hydroxide 500g and anhydrous sodium acetate 20g is added in the stainless steel cauldron with stirring,
It is heated to 200 DEG C under vacuum conditions, 1,8- benzene-naphthalene diimide 50g is added under nitrogen protection, is continuously heating to 300 after adding
DEG C reaction 6h, is cooled to 200 DEG C again, water 500mL is added, reaction solution is poured into water 2000mL after stirring 10min, in room temperature
Under the conditions of stir 3h, there are a large amount of solids to be precipitated, filter reaction solution, filter cake is added in the hydrochloric acid solution of saturation after being washed with water,
It is heated to 75 DEG C and is stirred to react 1h, again filtering reacting liquid, filter cake dries under the conditions of 80 DEG C and obtains 3,4,9,10- tetrabasic carboxylic acids
Imidodicarbonic diamide crude product；3,4,9,10- tetracarboxylic acid diimide hydrochloride, crudes are added in concentrated sulfuric acid 1000g, are slowly risen
To 80 DEG C, crude product is completely dissolved temperature, and sulfuric acid 600g of the concentration for 50% is being slowly added dropwise, and about 1h is added dropwise completely, is warming up to 100
DEG C, filtering reacting liquid, filtrate continue to be cooled to room temperature after stirring 30min while hot, and there are a large amount of solids to be precipitated, filtering reacting liquid, filter
Cake dries that obtain 3,4,9,10- tetracarboxylic acid diimide pure under the conditions of 80 DEG C again after wash with the sulfuric acid solution that concentration is 78%
Product 47g；Anal.Calcd for C24H10N2O4:C,73.85；H,2.58；N,7.18.Found:C,73.66；H,2.52；N,
7.13。
Embodiment 4
In reaction flask, under room temperature, 3,4,9,10- tetracarboxylic acid diimide 200g are slowly added into the concentrated sulfuric acid
In 700g (content 95%), it is to slowly warm up to 220 DEG C after adding, keeps thermotonus 2h, is then slowly dropped to room temperature, cooled down
The a large amount of solids of Cheng Zhongyou are precipitated, filtering reacting liquid, and filter cake is washed with water to neutrality, dries filter cake under the conditions of 80 DEG C and obtains 3,4,
9,10- glycosides crude product；Under the conditions of being protected from light, obtained crude product is all added to water 6000mL and potassium hydroxide 140g (content
85%) in mixed solution, under nitrogen protection, 90 DEG C are slowly heated to, are down to room temperature after keeping temperature to be stirred to react 1h, have
A large amount of solids are precipitated, and reaction solution is filtered by vacuum, and filter cake is washed with water 100mL；Under the conditions of nitrogen protection is with being protected from light, into filtrate
Potassium hydroxide 60g (content 85%) and active carbon 60g is added, iron chloride 60g and water is added after stirring 30min at room temperature
600mL keeps room temperature condition to be stirred to react 30min, filtering reacting liquid, and the hydrochloric acid solution 600g of saturation, heating are added in filtrate
To 80~90 DEG C of stirring 1h, there are a large amount of solids to occur, be cooled to room temperature filtering reacting liquid, drying filter cake obtains 3,4,9,10-
Tetracid glycosides 175g.
Embodiment 5
In reaction flask, 3,4,9,10- tetra- acid anhydrides 40g are added in the aqueous solution 200mL containing potassium hydroxide 40g,
It is warming up to 90 DEG C after mixing evenly, then reaction solution is moved into autoclave, enclosed high pressure kettle is to slowly warm up to 200 DEG C, about
Used time 3h, pressure is 0.2~0.3MPa in kettle at this time, is cooled to room temperature after insulation reaction 20h, is adjusted with 10% hydrochloric acid solution
Reaction solution pH is 8~9, filtering reacting liquid, continues to adjust filtrate pH with 10% hydrochloric acid solution to be 2~3, there is a large amount of solids at this time
It is precipitated, filtering reacting liquid, filter cake is washed twice with saturated sodium chloride solution 200mL, and drying filter cake obtains 3,9- diacid 31g；H
NMR(400MHz,DMSO-d6): δ 8.90-8.81 (m, 2H), 8.55-8.42 (m, 4H), 8.16 (d, J=4.0Hz, 2H), 7.72
(dd, J=8.0Hz, J=8.0Hz, 2H)；13C NMR(400MHz,DMSO-d6):168.90,133.79,132.45,130.93,
128.68,128.34,126.38,122.20,121.68,120.98,99.98。
Embodiment 6
In reaction flask, 3,9- diacid 34g is added in thionyl chloride 350mL, 60 DEG C of heating are anti-under nitrogen protection
It answers 1h, TLC to monitor raw material fully reacting, is added in the aqueous solution 100mL of the 28g containing potassium hydroxide after dividing exactly solvent thionyl chloride,
Under nitrogen protection under room temperature, bromine 30g is added dropwise, 60 DEG C of reaction 5h, TLC monitoring raw materials are warming up to after dripping and have been reacted
Entirely, reaction solution is poured into dilute hydrochloric acid, there is solid appearance, filtering reacting liquid is added solid completely molten in sodium hydroxide solution
Solution, then adjusting reaction solution pH with dilute hydrochloric acid solution is neutral, filtering reacting liquid again, and multiple, baking of with ice water wash filter cake
Dry filter cake obtains 3,9- dicarboxyl -4,10- dibromo 42g.
Embodiment 7
In reaction flask, 3,9- diacid 34g is added in thionyl chloride 350mL, 60 DEG C of heating are anti-under nitrogen protection
It answers 1h, TLC to monitor raw material fully reacting, is added in the aqueous solution 100mL of the 28g containing potassium hydroxide after dividing exactly solvent thionyl chloride,
Under nitrogen protection under room temperature, bromine 25g is added dropwise, 60 DEG C of reaction 5h, TLC monitoring raw materials are warming up to after dripping and have been reacted
Entirely, reaction solution is poured into dilute hydrochloric acid, there is solid appearance, filtering reacting liquid is added solid completely molten in sodium hydroxide solution
Solution, then adjusting reaction solution pH with dilute hydrochloric acid solution is neutral, filtering reacting liquid again, and multiple, baking of with ice water wash filter cake
Dry filter cake obtains 3,9- dicarboxyl -4,10- dibromo 29g.
Embodiment 8
In reaction flask, 3,9- diacid 34g (0.1mol) is added in thionyl chloride 350mL, under nitrogen protection 60
DEG C heating reaction 1h, TLC monitor raw material fully reacting, divide exactly the aqueous solution that the 28g containing potassium hydroxide is added after solvent thionyl chloride
In 100mL, under nitrogen protection under room temperature, bromine 45g is added dropwise, it is former that 60 DEG C of reaction 5h, TLC monitoring are warming up to after dripping
Expect fully reacting, reaction solution is poured into dilute hydrochloric acid, there is solid appearance, sodium hydroxide solution is added in solid by filtering reacting liquid
In be completely dissolved, then adjusting reaction solution pH with dilute hydrochloric acid solution is neutral, filtering reacting liquid again, and washs filter cake with ice water
Repeatedly, drying filter cake obtains 3,9- dicarboxyl -4,10- dibromo 39g.
Embodiment 9
3,9- dicarboxyl -4,10- dibromo 50g is dissolved in n,N-Dimethylformamide 400mL, at room temperature,
It stirs evenly, hydrazine hydrate 20g is slowly added dropwise, 70 DEG C are warming up to after dripping, be stirred to react 30min, reaction solution is poured into while hot
In ice water, there are a large amount of solids to be precipitated, filter reaction solution, filter cake is washed repeatedly with cold methanol, and drying filter cake obtains 3,9- diacyl
Hydrazine -4,10- dibromo 49g；HR MS(ESI):524.9531[M+H]+；Anal.Calcd for C22H14Br2N4O2:C,
50.22；H,2.68；N,10.65.Found:C,50.35；H,2.72；N,10.71.
Embodiment 10
3,9- diacyl hydrazide -4,10- dibromo 52g and anhydrous potassium hydroxide 22g are added in dehydrated alcohol 500mL,
Under nitrogen protection, it is to slowly warm up to flow back, at reflux, carbon disulfide 23g is slowly added dropwise, it is closed anti-after dripping
Answer liquid, be warming up to 100 DEG C, reaction system pressure increases, and keeps thermotonus 2h, divides exactly reaction dissolvent ethyl alcohol, add dissolved with
The n,N-Dimethylformamide solution of hydrazine hydrochloride 20g is warming up to 130 DEG C after dripping, react 30min, and TLC monitors raw material reaction
Completely, 70 DEG C are cooled to, reaction solution is poured into ice water, there are a large amount of solids to be precipitated, filters reaction solution, filter cake is washed with dehydrated alcohol
It washs repeatedly, drying filter cake obtains53g；1H NMR(400MHz,DMSO-d6):δ13.66-13.65(m,2H),
7.97-7.96 (m, 2H), 7.76 (d, J=4.0Hz, 2H), 7.72-7.81 (m, 2H), 7.55 (d, J=4.0Hz, 2H), 5.32-
5.30(m,4H)；13C NMR(400MHz,DMSO-d6):δ163.7,152.4,126.3,124.9,121.6,120.1,117.5,
116.4,146.1,109.8,107.1,102.2。
Embodiment 11
3,9- diacyl hydrazide -4,10- dibromo 52g and potassium hydroxide 11g are added in dehydrated alcohol 500mL, in nitrogen
It under gas shielded, is to slowly warm up to flow back, at reflux, carbon disulfide 23g is slowly added dropwise, after dripping, confined reaction liquid,
100 DEG C are warming up to, reaction system pressure increases, and thermotonus 2h is kept, divides exactly reaction dissolvent ethyl alcohol, then hydrazine hydrate 10g is added dropwise,
It is warming up to 130 DEG C after dripping, reacts 30min, TLC monitors raw material fully reacting, is cooled to 70 DEG C, reaction solution is poured into ice water
In, there are a large amount of solids to be precipitated, filter reaction solution, filter cake is washed repeatedly with dehydrated alcohol, and drying filter cake obtains
41g；1H NMR(400MHz,DMSO-d6): δ 13.66-13.65 (m, 2H), 7.97-7.96 (m, 2H), 7.76 (d, J=4.0Hz,
2H), 7.72-7.81 (m, 2H), 7.55 (d, J=4.0Hz, 2H), 5.32-5.30 (m, 4H)；13C NMR(400MHz,DMSO-
d6):δ163.7,152.4,126.3,124.9,121.6,120.1,117.5,116.4,146.1,109.8,107.1,102.2。
Embodiment 12
In reaction flask,32g, cuprous iodide 0.8g, 2- quinoline carboxylic acid-N- oxide 1.8g and carbon
Sour caesium 16g is added in dimethyl sulfoxide 100mL, is heated to 80 DEG C of reaction 2h, TLC monitors raw material fully reacting, to reaction solution
The middle water and ethyl acetate for being added certain, stirs 10min, and filtering reacting liquid separates organic phase, and water phase is extracted with ethyl acetate again
It takes three times, merges organic phase, after anhydrous sodium sulfate drying, be recrystallized to give after concentration through ethyl alcohol and acetone mixture22g；1H NMR(400MHz,CDCl3): δ 12.78 (s, 2H), 7.91 (d, J=8.4Hz, 2H), 7.83-7.82
(m, 2H), 7.57 (d, J=8.4Hz, 2H), 6.57-6.56 (m, 2H)；13C NMR(400MHz,CDCl3):δ131.4,129.7,
128.6,127.1,124.6,123.3,116.4,115.7,106.8,104.6,101.3,97.4；HRMS(ESI):477.0623
[M+H]+；Anal.Calcd for C24H12N8S2:C,60.49；H,2.54；N,23.51.Found:C,60.69；H,2.71；N,
23.74。
Embodiment 13
In reaction flask,47g and Cob altporphyrin 2.5g is added in carbon tetrachloride 250mL, under nitrogen protection,
Triethylamine 30g is added, phosgene 20g is slowly added dropwise as in -10 DEG C of environment, after dripping, is to slowly warm up to 0 DEG C, TLC monitoring
Raw material fully reacting is continuously heating to 25 DEG C, excludes nitrogen and takes the complete phosgene of unreacted out of, and saturation chlorination is added into reaction solution
Sodium solution stirs 10min, and filtering reacting liquid separates organic phase, water phase again with carbon tetrachloride extraction three times, merge organic phase, use
After anhydrous sodium sulfate is dry, it is recrystallized to give after concentration through ethyl alcohol and acetone mixture45g；1H NMR
(400MHz,DMSO-d6):δ7.87(dd,J1=8.0Hz, J1=8.0Hz, 4H), 7.32 (dd, J1=8.0Hz, J1=8.0Hz,
4H)；13C NMR(400MHz,DMSO-d6):δ162.7,150.3,127.9,126.6,122.5,121.1,120.8,120.2,
119.1,117.5,116.7,114.1,112.7；HRMS(ESI):529.0233[M+H]+；Anal.Calcd for
C26H8N8S2O2:C,59.08；H,1.53；N,21.20.Found:C,59.21；H,1.57；N,21.29.
Embodiment 14
In reaction flask,47g and Cob altporphyrin 2.5g is added in carbon tetrachloride 250mL, under nitrogen protection,
Triethylamine 30g is added to drip as the carbon tetrachloride 200mL solution in 0 DEG C of environment, being slowly added dropwise dissolved with triphosgene 60g
Afterwards, TLC monitors raw material fully reacting, is continuously heating to 25 DEG C, excludes nitrogen and takes the complete phosgene of unreacted out of, adds into reaction solution
Enter saturated sodium chloride solution, stir 10min, filtering reacting liquid separates organic phase, water phase again with carbon tetrachloride extraction three times, close
And organic phase is recrystallized to give after concentration through ethyl alcohol and acetone mixture after anhydrous sodium sulfate drying
37g；1H NMR(400MHz,DMSO-d6):δ7.87(dd,J1=8.0Hz, J1=8.0Hz, 4H), 7.32 (dd, J1=8.0Hz,
J1=8.0Hz, 4H)；13C NMR(400MHz,DMSO-d6):δ162.7,150.3,127.9,126.6,122.5,121.1,
120.8,120.2,119.1,117.5,116.7,114.1,112.7；HRMS(ESI):529.0233[M+H]+；Anal.Calcd
for C26H8N8S2O2:C,59.08；H,1.53；N,21.20.Found:C,59.21；H,1.57；N,21.29.
Embodiment 15
In reaction flask,47g and Cob altporphyrin 2.5g is added in carbon tetrachloride 250mL, under nitrogen protection,
Triethylamine 30g is added, thiophosgene 25g is slowly added dropwise as in -10 DEG C of environment, after dripping, is to slowly warm up to 0 DEG C, TLC prison
Raw material fully reacting is controlled, is continuously heating to 25 DEG C, nitrogen is excluded and takes the complete phosgene of unreacted out of, saturation chlorine is added into reaction solution
Change sodium solution, stir 10min, filtering reacting liquid separates organic phase, water phase again with carbon tetrachloride extraction three times, merge organic phase,
After anhydrous sodium sulfate drying, it is recrystallized to give after concentration through ethyl alcohol and acetone mixture49g；1H NMR
(400MHz,DMSO-d6):δ7.92(dd,J1=8.0Hz, J1=8.0Hz, 4H), 7.37 (dd, J1=8.0Hz, J1=8.0Hz,
4H)；13C NMR(400MHz,DMSO-d6):δ167.4,159.8,131.5,127.6,125.7,124.3,123.1,122.6,
120.7,119.8,118.4,115.1,113.9；HRMS(ESI):560.9871[M+H]+；Anal.Calcd for
C26H8N8S4:C,55.70；H,1.44；N,19.99.Found:C,55.82；H,1.52；N,19.86.
Embodiment 16
Biological activity determination
Take human cervical carcinoma Hela cell, human breast carcinoma MDA-MB-231 cell and three kinds of human hepatoma HepG2 cell in life
Long-term tumour cell, with the DMEM culture medium containing 10% fetal calf serum, in 37 DEG C, 5%CO2 is cultivated, with 0.25% pancreatin-
Molecular marker for increased proliferation, cell in good condition are collected in 0.02%EDTA digestion, passage, and after being suspended with cell culture fluid, it is thin to count tumour
Born of the same parents, adjustment tumour cell concentration are that containing cell number in suspension is 5000~10000；Tumor cell suspension is inoculated into 96 orifice plates
In, then every 200 μ L of hole, adhere-wall culture 4h after cell inoculation are added the drug DMSO solution of various concentration, drug is equipped with 5,
10,50,100 μm of ol/L, tetra- kinds of concentration, each concentration are equipped with 5 parallel multiple holes, and cell incubator continues to be added 10 after cultivating 48h
The CCK-8 reagent of μ L, 37 DEG C of incubation 2h measure 490nm optical density, while setting with tumour cell and drug as control.Pass through survey
The OD value obtained, calculates drug to the inhibiting rate of corresponding tumour cell, inhibiting rate=(1- experimental group OD value/control group OD
Value) × 100%
Embodiment 17
Cytotoxicity detection
Influence of the target compound of various concentration to human fibroblasts survival rate is detected by CCK-8 method, as a result table
Bright, the target compound of various concentration is respectively with cell co-culture, and each concentration group is compared with negative control group compared with difference is without system
Meter learns meaning, and target compound has certain safety, mesh to human fibroblasts in the case where concentration is less than 5 μ g/mL
Between mark compound for comparison, the toxicity of compound of R=S is less than the compound of R=O.
Embodiment above describes basic principles and main features of the invention and advantage, the technical staff of the industry should
Understand, the present invention is not limited to the above embodiments, and the above embodiments and description only describe originals of the invention
Reason, under the range for not departing from the principle of the invention, various changes and improvements may be made to the invention, these changes and improvements are each fallen within
In the scope of protection of the invention.
Claims (5)
1. the preparation method and application of biologically active novel class drug molecule, it is characterised in that the acid drug molecule
Structure are as follows:Wherein R is O or S.
2. the preparation method of biologically active novel class drug molecule according to claim 1, it is characterised in that
Specific steps are as follows:
A, acenaphthene is added in glacial acetic acid, adds a certain amount of potassium bichromate, at room temperature after mixing evenly slowly
80 DEG C are warming up to, thermotonus is kept to monitor raw material fully reacting to TLC, reaction solution is poured into ice water stirring while hot, there is solid
It is precipitated, filters reaction solution, 1,8- naphthalene dicarboxylic anhydride is obtained after filter cake is dried；
B, 1,8- naphthalene diacid glycosides is added in the ammonium hydroxide of saturation, stirs to get the mixing liquid of yellow at room temperature, then
70 DEG C are heated slowly to, stops heating after keeping the thermotonus to monitor raw material fully reacting to TLC, is slowly dropped to room temperature, has
Solid is precipitated, and filtering reacting liquid, filter cake is washed with water to neutrality, then obtains 1,8- naphthalene diamides in drying；
C, a certain amount of barium hydroxide and anhydrous sodium acetate are added in the stainless steel cauldron with stirring, under vacuum conditions
It is heated to certain temperature, is kept for temperature stirring a period of time, 1,8- benzene-naphthalene diimide is added under nitrogen protection, continues after adding
300 DEG C of reaction a period of times are warming up to, 200 DEG C is cooled to again, a certain amount of water is added, reaction solution is poured into water after stirring
In, at room temperature stirring a period of time, there are a large amount of solids to be precipitated, filters reaction solution, filter cake is added to full after being washed with water
In the hydrochloric acid solution of sum, it is heated to 75 DEG C and is stirred to react a period of time, filtering reacting liquid, filter cake are dried under the conditions of 80 DEG C again
Obtain 3,4,9,10- tetracarboxylic acid diimide crude product；3,4,9,10- tetracarboxylic acid diimide hydrochloride, crude is added to
In the concentrated sulfuric acid, 80 DEG C are to slowly warm up to, crude product is completely dissolved, and sulfuric acid of a certain amount of concentration for 50% is being slowly added dropwise, is being added dropwise
It is warming up to 100 DEG C after complete, is down to room temperature after the reaction was continued a period of time, there are a large amount of solids to be precipitated, filtering reacting liquid, filter cake is with dense
Degree is drying obtains 3,4,9,10- tetracarboxylic acid diimide sterling under the conditions of 80 DEG C again after 78% sulfuric acid solution washing；
D, under room temperature, 3,4,9,10- tetracarboxylic acid diimides are slowly added into the concentrated sulfuric acid, slowly heating after adding
It to 220 DEG C, keeps thermotonus for a period of time, is then slowly dropped to room temperature, there are a large amount of solids to be precipitated in temperature-fall period, filtering is anti-
Liquid is answered, filter cake is washed with water to neutrality, dries filter cake under the conditions of 80 DEG C and obtains 3,4,9,10- glycosides crude products；It is being protected from light condition
Under, obtained crude product is all added in the mixed solution of water and potassium hydroxide solution, under nitrogen protection, is slowly heated to
90 DEG C, it is down to room temperature after keeping temperature to be stirred to react a period of time, there are a large amount of solids to be precipitated, reaction solution is filtered by vacuum, filter cake is used
Water washing；Under the conditions of nitrogen protection is with being protected from light, potassium hydroxide and active carbon are added into filtrate, after stirring at room temperature
Iron chloride and water is added, holding room temperature condition is stirred to react for a period of time, filtering reacting liquid, and the hydrochloric acid that saturation is added in filtrate is molten
Liquid is heated to 80~90 DEG C of stirrings to there is a large amount of solids to occur, is cooled to room temperature filtering reacting liquid, and drying filter cake obtains 3,4,9,
10- tetracid glycosides；
E, 3,4,9,10- tetra- acid anhydrides be added potassium hydroxide saturated aqueous solution in, be warming up to 90 DEG C after mixing evenly, then
Reaction solution moves into autoclave, and enclosed high pressure kettle is to slowly warm up to certain temperature, and pressure in kettle is made to reach 0.2~0.3MPa, protects
Temperature is cooled to room temperature after reaction a period of time, and adjusting reaction solution pH with 10% hydrochloric acid solution is 8~9, and filtering reacting liquid continues
Adjusting filtrate pH with 10% hydrochloric acid solution is 2~3, has a large amount of solids to be precipitated at this time, filtering reacting liquid, filter cake saturation chlorination
Sodium solution 200mL is washed twice, and drying filter cake obtains 3,9- diacid；
F, 3,9- diacid is added in thionyl chloride, 1h is reacted in 60 DEG C of heating under nitrogen protection, and TLC monitoring raw material has reacted
Entirely, divide exactly solvent thionyl chloride and obtain 3,9- diacid chloride；3,9- diacid chloride is added in potassium hydroxide aqueous solution, in nitrogen
Under protection under room temperature, bromine is added dropwise, 60 DEG C of reactions are warming up to after dripping to raw material fully reacting, reaction solution are poured into dilute
In hydrochloric acid, there is solid appearance, filtering reacting liquid solid is added in sodium hydroxide solution and is completely dissolved, then uses dilute hydrochloric acid solution
Adjusting reaction solution pH is neutrality, filtering reacting liquid again, and it is multiple with ice water wash filter cake, dries filter cake and obtains 3,9- dicarboxyl
Base -4,10- dibromo；
G, 3,9- dicarboxyl -4,10- dibromo is dissolved in n,N-Dimethylformamide, at room temperature, is stirred evenly, delayed
Slowly a certain amount of hydrazine hydrate is added dropwise, 70 DEG C are warming up to after dripping, is stirred to react a period of time, reaction solution is poured into ice water while hot
In, there are a large amount of solids to be precipitated, filters reaction solution, filter cake is washed repeatedly with cold methanol, and drying filter cake obtains diacyl hydrazide -4 3,9-,
10- dibromo；
H, 3,9- diacyl hydrazide -4,10- dibromo and potassium hydroxide are added in dehydrated alcohol, under nitrogen protection, slowly
It is warming up to reflux, at reflux, carbon disulfide is slowly added dropwise, after dripping, confined reaction liquid is warming up to 100 DEG C, reaction
System pressure increases, and keeps thermotonus 2h, divides exactly reaction dissolvent ethyl alcohol, add the N dissolved with hydrazine class compound, N- dimethyl
Formamide is warming up to 130 DEG C after dripping, reaction to raw material fully reacting is cooled to 70 DEG C, reaction solution is poured into ice water,
There are a large amount of solids to be precipitated, filter reaction solution, filter cake is washed repeatedly with dehydrated alcohol, and drying filter cake obtains
I, in reaction flask,Dimethyl is added in cuprous iodide, 2- quinoline carboxylic acid-N- oxide and cesium carbonate
In sulfoxide, it is heated to that a certain amount of water and ethyl acetate are added into reaction solution, stirs to 80 DEG C of reactions to raw material fully reacting
Uniformly, filtering reacting liquid separates organic phase, and water phase is extracted with ethyl acetate three times again, merges organic phase, dry with anhydrous sodium sulfate
After dry, it is recrystallized to give after concentration through ethyl alcohol and acetone mixture
J, handleIt is added in carbon tetrachloride with Cob altporphyrin, under nitrogen protection, a certain amount of triethylamine is added, as-
In 10 DEG C of environment, phosgene is slowly added dropwise, after dripping, is to slowly warm up to 0 DEG C, TLC monitors raw material fully reacting, is continuously heating to
It 25 DEG C, excludes nitrogen and takes the complete phosgene of unreacted out of, saturated sodium chloride solution is added into reaction solution, reaction is filtered after stirring
Liquid, separates organic phase, water phase again with carbon tetrachloride extraction three times, merge organic phase, with anhydrous sodium sulfate it is dry after, passed through after concentration
Ethyl alcohol and acetone mixture are recrystallized to give
3. the preparation method of biologically active novel class drug molecule according to claim 2, it is characterised in that:
In step E；The inventory molar ratio of tetra- acid anhydrides of 3,4,9,10- and potassium hydroxide is 1:5~8；The reaction temperature
Degree is 150~250 DEG C.
4. the preparation method of biologically active novel class drug molecule according to claim 2, it is characterised in that:
Hydrazine class compound described in step H is hydrazine hydrochloride or hydrazine hydrate.
5. as described in claim 1 a kind of biologically active novel class drug molecule is in the preparation of antitumor drugs
Using.
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