CN108976237B - Preparation method and application of perylene acid drug molecule with anti-tumor activity - Google Patents
Preparation method and application of perylene acid drug molecule with anti-tumor activity Download PDFInfo
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Abstract
The invention discloses a preparation method and application of a perylene acid drug molecule with anti-tumor activity, and belongs to the technical field of medicine synthesis. The technical scheme provided by the invention has the key points that: a perylene acid drug molecule with anti-tumor activity has a structural formula as follows:
Description
Technical Field
The invention belongs to the technical field of synthesis of antitumor drugs, and particularly relates to a preparation method and application of a perylene acid drug molecule with antitumor activity.
Background
The perylene compound is a planar, rigid and conjugated condensed ring macromolecular compound, has good photochemical stability and strong fluorescence property, is always used as a reducing dye for dyeing cotton fibers and fabrics, and has extremely high application fastness, so scientists develop the perylene compound into a series of high-performance organic dyes; at present, more than ten varieties of such dyes registered by the "dye index" are mainly red, such as c.i. pigment red 123, 149, 178, 179, 190, 224 and c.i. pigment violet 29, and newly developed black perylene pigment c.i. pigment black 31 and 32, and therefore, the dyes are mainly used as pigments or dyes in the early research of perylene compounds. In recent years, with the development of science and technology, perylene compounds are found to be good organic semiconductor materials, the photoelectric and electrooptical properties and the luminescence properties of the perylene compounds are remarkable, and research reports on the functional aspects of organic photoconductors, organic energy conversion, organic photoelectric molecular devices, cell fluorescent probes and the like are extremely active. The research of the perylene formic acid compound as the organic photosensitive conductor is an important aspect of the application and development of the organic photosensitive conductor, for example, the perylene tetracarboxylic acid compound is applied to the organic photoconductor electrostatic copying technology by utilizing the good photosensitive conductivity of the perylene tetracarboxylic acid compound; the photoelectric conversion rate of the solid solar cell formed by the perylene tetracarboxylic compound can reach 2 percent; in addition, the photosensitive molecular switch which performs light operation by reversible electron transfer reaction by utilizing the two-photon selective reduction characteristic of the perylene tetracarboxylic acid body is utilized, and a plurality of microelectronic devices of organic molecular level are developed.
Perylene compounds also have wide applications in the biomedical field. Perylene is modified from perylene "imide" sites. Langhals et al introduce some solubilizing groups, such as long chain aliphatic primary amines and aromatic primary amines, etc., from the perylene core "imide" site. Particularly, when the N substituent is a tert-butyl benzene ring, the solubility of perylene imide is greatly influenced. The synthesis method mostly adopts quinoline, imidazole and nitrogen methyl pyrrolidone as solvents and carries out reflux reaction at higher temperature. The synthesis strategy well maintains the flat, rigid and conjugated plane of the perylene chromophore, and a series of designed and synthesized perylene imides are often used for research on self-assembly. Seybold and colleagues find that the perylene nucleus is distorted due to the space tension of the substituent after the substituent is introduced into the position of the 'sea island', the distortion can inhibit the intermolecular accumulation, and the entropy value is increased in the dissolving process to improve the solubility of the perylene imide. The perylene derivatives are generated by affinity substitution reaction of dibromo perylene imide or tetrabromo perylene imide intermediates and various substituent groups, so that the planarity of perylene nucleus is distorted to a certain extent, the fluorescence emission of perylene imide is greatly red-shifted, and the application of the perylene imide in the field of biomedicine is expanded.
Compared with chromophores such as cyanine dyes, partial cyanine dyes and fluorescein, the perylene compounds have high light and chemical stability and fluorescence quantum yield due to the stable polycyclic aromatic hydrocarbon conjugated structure. The modified asymmetric perylene compound shows the characteristics of wide absorption and narrow emission, the maximum fluorescence emission wavelength is adjustable (more than 525nm), the modified asymmetric perylene compound can be obviously separated from a cell background fluorescence signal (395 nm-479 nm), and the modified asymmetric perylene compound can continuously and stably provide a fluorescence signal, and is suitable for being applied to the research in the aspect of biological fluorescence probes. Fluorescent dyes used in these fields satisfy at least the following points: 1. sufficient water solubility and sufficient fluorescence signal in aqueous solution; 2. secondly, functional groups which have the function of reacting with biomolecules; 3. finally, the fluorescent dye molecules do not affect the function of the biomolecules. The perylene compounds meeting the above conditions can effectively enter cells and act on corresponding proteins to form fluorescent probes, and based on the effects, the perylene compounds are subjected to structural modification, so that the perylene compounds have an anti-tumor effect and have very significant significance.
Disclosure of Invention
The technical problem to be solved by the invention is to symmetrically modify perylene groups, and the invention provides a preparation method of perylene drug molecules with anti-tumor activity, which has the advantages of simple synthesis method, low raw material price, novel structure, good water solubility and no influence on the functions of biomolecules.
The invention adopts the following technical scheme for solving the technical problems, and the perylene medicine molecule with the anti-tumor activity comprises the following specific steps:
A. adding acenaphthene into glacial acetic acid, adding a certain amount of oxidant, stirring uniformly at room temperature, slowly heating to 80 ℃, keeping the temperature for reaction until TLC monitors that the raw materials react completely, pouring the reaction liquid into ice water while the reaction liquid is hot, stirring, separating out solids, filtering the reaction liquid, and drying a filter cake to obtain 1, 8-naphthalic anhydride; the oxidant is potassium dichromate, sodium dichromate dihydrate, periodic acid or potassium permanganate; the feeding amount molar ratio of the acenaphthene to the oxidant is 1: 1.5-3.
B. Adding 1, 8-naphthalic anhydride into saturated ammonia water, stirring at room temperature to obtain yellow mixed liquid, slowly heating to a certain temperature, keeping the temperature for reaction until TLC monitors that the raw materials completely react, stopping heating, slowly cooling to room temperature, separating out solids, filtering the reaction liquid, washing a filter cake to be neutral by using water, and then drying to obtain 1, 8-naphthalic diamide; the certain temperature is 50-80 ℃.
C. Adding a certain amount of hydroxide and anhydrous sodium acetate into a stainless steel reaction kettle with stirring, heating to a certain temperature under a vacuum condition, keeping the temperature and stirring for a period of time, adding 1, 8-naphthalene diimide under the protection of nitrogen, continuously heating to 300 ℃ after the addition, reacting for a period of time, cooling to 200 ℃ again, adding a certain amount of water, pouring the reaction liquid into water after stirring, stirring for a period of time at room temperature, separating out a large amount of solids, filtering the reaction liquid, washing a filter cake with water, adding the filter cake into a saturated hydrochloric acid solution, heating to 75 ℃, stirring and reacting for a period of time, filtering the reaction liquid again, and drying the filter cake at 80 ℃ to obtain a crude product of 3,4,9, 10-perylene tetracarboxylic diimide; adding the crude 3,4,9, 10-perylenetetracarboxylic diimide hydrochloride into concentrated sulfuric acid, slowly heating to 80 ℃, completely dissolving the crude product, slowly dropwise adding a certain amount of sulfuric acid with the concentration of 50%, heating to 100 ℃ after dropwise adding, continuously reacting for a period of time, cooling to room temperature, separating out a large amount of solids, filtering the reaction solution, washing a filter cake with a sulfuric acid solution with the concentration of 78%, and drying at 80 ℃ to obtain a pure 3,4,9, 10-perylenetetracarboxylic diimide; the hydroxide is sodium hydroxide, potassium hydroxide or barium hydroxide; the feeding amount molar ratio of the 1, 8-naphthalene diimide to the hydroxide is 1: 20-40; the certain temperature is 150-350 ℃.
D. Slowly adding 3,4,9, 10-perylenetetracarboxylic diimide into concentrated sulfuric acid at room temperature, slowly heating to 220 ℃ after the 3,4,9, 10-perylenetetracarboxylic diimide is added, keeping the temperature for reaction for a period of time, slowly cooling to room temperature, separating out a large amount of solids during cooling, filtering reaction liquid, washing a filter cake to be neutral by using water, and drying the filter cake at 80 ℃ to obtain a crude product of the 3,4,9, 10-peryleneglycoside; under the condition of keeping out of the sun, completely adding the obtained crude product into a mixed solution of water and a potassium hydroxide solution, slowly heating to 90 ℃ under the protection of nitrogen, keeping the temperature, stirring for reaction for a period of time, cooling to room temperature, separating out a large amount of solids, carrying out vacuum filtration on the reaction solution, and washing a filter cake with water; under the conditions of nitrogen protection and light shielding, adding potassium hydroxide and activated carbon into the filtrate, stirring at room temperature, adding metal salt ions and water, keeping the room temperature, stirring for reacting for a period of time, filtering the reaction solution, adding a saturated hydrochloric acid solution into the filtrate, heating to 80-90 ℃, stirring until a large amount of solids appear, cooling to room temperature, filtering the reaction solution, and drying a filter cake to obtain 3,4,9, 10-perylene tetracarboxylic anhydride; the metal salt ions are ferric sulfate, ferric chloride or copper chloride.
E. Adding 3,4,9, 10-perylenetetracarboxylic anhydride into a potassium hydroxide saturated aqueous solution, uniformly stirring, heating to 90 ℃, then transferring the reaction liquid into an autoclave, sealing the autoclave, slowly heating to a certain temperature to ensure that the pressure in the autoclave is 0.2-0.4 MPa, carrying out heat preservation reaction for a period of time, cooling to room temperature, adjusting the pH of the reaction liquid to 8-9 by using a 10% hydrochloric acid solution, filtering the reaction liquid, continuously adjusting the pH of the filtrate to 2-3 by using a 10% hydrochloric acid solution, separating out a large amount of solids, filtering the reaction liquid, washing a filter cake for multiple times by using a saturated sodium chloride solution, and drying the filter cake to obtain 3, 9-perylenedioic acid; the feeding amount molar ratio of the 3,4,9, 10-perylene tetracarboxylic anhydride to the potassium hydroxide is 1: 5-8; the certain temperature is 150-250 ℃.
F. Adding 3, 9-perylene diacid into thionyl chloride, heating and reacting at 60 ℃ under the protection of nitrogen until the raw materials react completely, and evaporating the thionyl chloride as a solvent to obtain 3, 9-perylene diacid chloride; adding 3, 9-perylene dichloride into a potassium hydroxide aqueous solution, dropwise adding liquid bromine at room temperature under the protection of nitrogen, heating to 60 ℃ after dropwise adding, reacting until the raw materials react completely, pouring the reaction liquid into dilute hydrochloric acid, filtering the reaction liquid, adding the solid into a sodium hydroxide solution for complete dissolution, adjusting the pH of the reaction liquid to be neutral by using the dilute hydrochloric acid solution, filtering the reaction liquid again, washing a filter cake for multiple times by using ice water, and drying the filter cake to obtain the 3, 9-dicarboxyl-4, 10-dibromo perylene.
G. Adding 3, 9-dicarboxyl-4, 10-dibromoperylene and potassium thiocyanate into acetonitrile, dropwise adding thionyl chloride under the protection of nitrogen at room temperature, heating to 50 ℃ after dropwise adding, reacting until the raw materials react completely, pouring the reaction liquid into ice water, adjusting the reaction liquid for multiple times by using a saturated sodium chloride solution, filtering the reaction liquid again, extracting the filtrate for multiple times by using chloroform, combining organic phases, and concentrating to obtain the 3, 9-dimethyl isothiocyanate-4, 10-dibromoperylene.
H. Adding 3, 9-dimethylisothiocyanate-4, 10-dibromoperylene, cuprous iodide, 2-quinolinecarboxylic acid-N-oxide and cesium carbonate into dimethyl sulfoxide, heating to 50 ℃, dropwise adding the dimethyl sulfoxide dissolved with an amination reagent, heating to 80 ℃ after dropwise adding, reacting until the raw materials completely react, adding a certain amount of water and ethyl acetate into the reaction liquid, stirring uniformly, filtering the reaction liquid, separating an organic phase, extracting the water phase with ethyl acetate for three times, combining the organic phases, drying with anhydrous sodium sulfate, concentrating, and recrystallizing with a mixed solution of ethanol and acetone to obtain 3, 9-dimethylisothiocyanate-4, 10-diaminoperylene; the amination reagent is urea or thiourea; the feeding amount molar ratio of the 3, 9-dimethyl isothiocyanate-4, 10-dibromoperylene to the amination reagent is 1: 1.2-2.
I. Adding 3, 9-dimethyl isothiocyanate-4, 10-diaminoperylene and TBAB into anhydrous acetonitrile in a reaction bottle, uniformly stirring at room temperature, heating for reflux reaction until the raw materials react completely, evaporating the acetonitrile solvent under reduced pressure, adding the concentrate into a mixed solution of water and ethanol, heating to 60 ℃, uniformly stirring, filtering the reaction solution, washing a filter cake with THF for multiple times, and drying to obtain the compound
The invention adopts the following technical scheme for solving the technical problems, and the preparation method of the perylene medicine molecule with the anti-tumor activity comprises the following specific steps:
Detailed Description
The present invention is described in further detail below with reference to examples, but it should not be construed that the scope of the above subject matter of the present invention is limited to the following examples, and that all the technologies realized based on the above subject matter of the present invention belong to the scope of the present invention.
Example 1
In a reaction bottle, adding 15g of acenaphthene into 500mL of glacial acetic acid, adding 55g of sodium dichromate dihydrate, stirring uniformly at room temperature, slowly heating to 80 ℃, keeping the temperature for reaction for 6h, monitoring the reaction completion of raw materials by TLC, pouring the reaction liquid into 2000mL of ice water while the reaction liquid is hot, separating out solids, filtering the reaction liquid, drying a filter cake to obtain 16g of 1, 8-naphthalic anhydride,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。
example 2
In a reaction bottle, adding 15g of acenaphthene into 500mL of glacial acetic acid, adding 59g of potassium dichromate, stirring uniformly at room temperature, slowly heating to 80 ℃, keeping the temperature for reaction for 6h, monitoring the reaction of raw materials by TLC, pouring the reaction liquid into 2000mL of ice water while the reaction liquid is hot, separating out solids, filtering the reaction liquid, drying a filter cake to obtain 18g of 1, 8-naphthalic anhydride,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。
example 3
In the reactionIn a bottle, adding 15g of acenaphthene into 500mL of glacial acetic acid, adding 46g of periodic acid dihydrate, stirring uniformly at room temperature, slowly heating to 80 ℃, keeping the temperature for reaction for 6h, monitoring the reaction of the raw materials by TLC, pouring the reaction liquid into 2000mL of ice water while the reaction liquid is hot, separating out solids, filtering the reaction liquid, drying the filter cake to obtain 13g of 1, 8-naphthalic anhydride,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。
example 4
In a reaction bottle, adding 15g of acenaphthylene into 500mL of glacial acetic acid, adding 35g of periodic acid dihydrate, stirring uniformly at room temperature, slowly heating to 80 ℃, keeping the temperature for reaction for 6h, monitoring the reaction completion of raw materials by TLC, pouring the reaction liquid into 2000mL of ice water while the reaction liquid is hot, separating out solids, filtering the reaction liquid, drying the filter cake to obtain 9g of 1, 8-naphthalic anhydride,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。
example 5
In a reaction bottle, adding 15g of acenaphthene into 500mL of glacial acetic acid, adding 69g of periodic acid dihydrate, stirring uniformly at room temperature, slowly heating to 80 ℃, keeping the temperature for reaction for 6h, monitoring the reaction completion of raw materials by TLC, pouring the reaction liquid into 2000mL of ice water while the reaction liquid is hot, separating out solids, filtering the reaction liquid, drying a filter cake to obtain 17g of 1, 8-naphthalic anhydride,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。
example 6
In a reaction bottle, adding 15g of acenaphthene into 500mL of glacial acetic acid, adding 48g of potassium permanganate, stirring uniformly at room temperature, slowly heating to 80 ℃, keeping the temperature for reaction for 6h, monitoring the reaction of the raw materials by TLC, pouring the reaction liquid into 2000mL of ice water while the reaction liquid is hot, separating out solids, filtering the reaction liquid, drying the filter cake to obtain 16.4g of 1, 8-naphthalic anhydride,1H NMR(400MHz,DMSO-d6):δ8.55(dd,J1＝8.0Hz,J1＝4.0Hz,4H),7.93(t,J1＝4.0Hz,J2＝8.0Hz,2H)；13C NMR(400MHz,DMSO-d6):161.19,135.86,132.93,130.22,128.03,119.54。
example 7
Adding 50g of 1, 8-naphthalic anhydride into 1000mL of saturated ammonia water in a reaction flask, stirring for 10min at room temperature to obtain yellow mixed liquid, slowly heating to 50 ℃, keeping the temperature for reaction for 90min, stopping heating after TLC monitors that raw materials completely react, slowly cooling to room temperature, separating out a solid, filtering the reaction liquid, washing a filter cake to be neutral by 500mL of water, drying at 60 ℃ to obtain 31g of 1, 8-naphthalamide,1H NMR(400MHz,DMSO-d6):δ8.42(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。
example 8
Adding 50g of 1, 8-naphthalic anhydride into 1000mL of saturated ammonia water in a reaction flask, stirring for 10min at room temperature to obtain yellow mixed liquid, slowly heating to 60 ℃, keeping the temperature for reaction for 90min, stopping heating after TLC monitors that raw materials completely react, slowly cooling to room temperature, separating out a solid, filtering the reaction liquid, washing a filter cake to be neutral by 500mL of water, drying at 60 ℃ to obtain 37g of 1, 8-naphthalamide,1H NMR(400MHz,DMSO-d6):δ8.42(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。
example 9
Adding 50g of 1, 8-naphthalic anhydride into 1000mL of saturated ammonia water in a reaction flask, stirring for 10min at room temperature to obtain yellow mixed liquid, slowly heating to 70 ℃, keeping the temperature for reaction for 90min, stopping heating after TLC monitors that raw materials completely react, slowly cooling to room temperature, separating out a solid, filtering the reaction liquid, washing a filter cake to be neutral by 500mL of water, drying at 60 ℃ to obtain 44g of 1, 8-naphthalamide,1H NMR(400MHz,DMSO-d6):δ8.42(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。
example 10
Adding 50g of 1, 8-naphthalic anhydride into 1000mL of saturated ammonia water in a reaction flask, stirring for 10min at room temperature to obtain yellow mixed liquid, slowly heating to 80 ℃, keeping the temperature for reacting for 90min, stopping heating after TLC monitors that the raw materials completely react, slowly cooling to room temperature,separating out solid, filtering reaction liquid, washing a filter cake to be neutral by 500mL of water, drying at 60 ℃ to obtain 42g of 1, 8-naphthalene diamide,1H NMR(400MHz,DMSO-d6):δ8.42(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。
example 11
In a reaction bottle, 400g (content: 85%) of potassium hydroxide and 20g of anhydrous sodium acetate are added into a stainless steel reaction kettle with a stirrer, the mixture is heated to 300 ℃ under vacuum condition, the temperature is kept for stirring for 2h, and 25g of water is distilled off; then cooling to 200 ℃, adding 50g of 1, 8-naphthalene diimide under the protection of nitrogen, continuing to heat to 300 ℃ after the addition is finished, reacting for 6 hours, cooling to 200 ℃ again, adding 500mL of water, stirring for 10 minutes, pouring the reaction solution into 2000mL of water, stirring for 3 hours at room temperature, separating out a large amount of solid, filtering the reaction solution, washing a filter cake with water, adding the filter cake into a saturated hydrochloric acid solution, heating to 75 ℃, stirring for reacting for 1 hour, filtering the reaction solution again, and drying the filter cake at 80 ℃ to obtain a crude product of 3,4,9, 10-perylene tetracarboxylic diimide; adding the crude product of 3,4,9, 10-perylenetetracarboxylic diimide hydrochloride into 1000g of concentrated sulfuric acid, slowly heating to 80 ℃, completely dissolving the crude product, slowly dropwise adding 600g of 50% sulfuric acid, completely dropwise adding for about 1h, heating to 100 ℃, continuously reacting for 30min, cooling to room temperature, separating out a large amount of solid, filtering the reaction solution, washing the filter cake with 78% sulfuric acid solution, and drying at 80 ℃ to obtain 45g of pure 3,4,9, 10-perylenetetracarboxylic diimide product, anal24H10N2O4:C,73.85；H,2.58；N,7.18.Found:C,73.66；H,2.52；N,7.13。
Example 12
Adding 240g of sodium hydroxide and 20g of anhydrous sodium acetate into a stainless steel reaction kettle with stirring in a reaction bottle, heating to 200 ℃ under a vacuum condition, adding 50g of 1, 8-naphthalene diimide under the protection of nitrogen, continuously heating to 300 ℃ after the addition, reacting for 6 hours, cooling to 200 ℃, adding 300mL of water, stirring for 10 minutes, pouring the reaction solution into 1500mL of water, stirring for 3 hours at room temperature, separating out a large amount of solids, filtering the reaction solution, washing a filter cake with water, adding the filter cake into a saturated hydrochloric acid solution, heating to 75 ℃, stirring, reacting for 1 hour, filtering the reaction solution again, and drying the filter cake at 80 ℃ to obtain a crude product of the 3,4,9, 10-perylene tetracarboxylic diimide; adding the crude product of 3,4,9, 10-perylenetetracarboxylic diimide hydrochloride into 1000g of concentrated sulfuric acid, slowly heating to 80 ℃, completely dissolving the crude product, slowly dropwise adding 600g of 50% sulfuric acid, completely dropwise adding for about 1h, heating to 100 ℃, continuously reacting for 30min, cooling to room temperature, separating out a large amount of solid, filtering the reaction solution, washing the filter cake with 78% sulfuric acid solution, and drying at 80 ℃ to obtain 27g of pure 3,4,9, 10-perylenetetracarboxylic diimide product, anal24H10N2O4:C,73.85；H,2.58；N,7.18.Found:C,73.66；H,2.52；N,7.13。
Example 13
In a reaction bottle, adding 500g of barium hydroxide and 20g of anhydrous sodium acetate into a stainless steel reaction kettle with stirring, heating to 200 ℃ under a vacuum condition, adding 50g of 1, 8-naphthalene diimide under the protection of nitrogen, continuing to heat to 300 ℃ after the addition, reacting for 6 hours, cooling to 200 ℃, adding 500mL of water, stirring for 10 minutes, pouring the reaction solution into 2000mL of water, stirring for 3 hours at room temperature, separating out a large amount of solids, filtering the reaction solution, washing a filter cake with water, adding the filter cake into a saturated hydrochloric acid solution, heating to 75 ℃, stirring, reacting for 1 hour, filtering the reaction solution again, and drying the filter cake at 80 ℃ to obtain a crude product of the 3,4,9, 10-perylene tetracarboxylic diimide; adding the crude 3,4,9, 10-perylenetetracarboxylic diimide hydrochloride into concentrated sulfuric acidIn 1000g, slowly heating to 80 ℃, completely dissolving the crude product, slowly dripping 600g of 50% sulfuric acid, completely dripping for about 1h, heating to 100 ℃, filtering the reaction solution while hot, continuously stirring the filtrate for 30min, cooling to room temperature, separating out a large amount of solids, filtering the reaction solution, washing a filter cake with 78% sulfuric acid solution, and drying at 80 ℃ to obtain 47g of a pure 3,4,9, 10-perylene tetracarboxylic diimide product; call for C24H10N2O4:C,73.85；H,2.58；N,7.18.Found:C,73.66；H,2.52；N,7.13。
Example 14
Slowly adding 200g of 3,4,9, 10-perylenetetracarboxylic diimide into 800g (content: 95%) of concentrated sulfuric acid in a reaction bottle at room temperature, slowly heating to 220 ℃ after adding, keeping the temperature for reaction for 2 hours, slowly cooling to room temperature, separating out a large amount of solids in the cooling process, filtering the reaction solution, washing a filter cake to be neutral by using water, and drying the filter cake at 80 ℃ to obtain a crude product of the 3,4,9, 10-peryleneglycoside; under the condition of keeping out of the sun, completely adding the obtained crude product into a mixed solution of 6000mL of water and 140g (the content is 85%) of potassium hydroxide, slowly heating to 90 ℃ under the protection of nitrogen, keeping the temperature, stirring for reaction for 1 hour, cooling to room temperature, separating out a large amount of solid, carrying out vacuum filtration on the reaction solution, and washing a filter cake with 100mL of water; adding 60g (content: 85%) of potassium hydroxide and 60g of activated carbon into the filtrate under the conditions of nitrogen protection and light shielding, stirring for 30min at room temperature, adding 60g of ferric sulfate and 600mL of water, stirring and reacting for 30min at room temperature, filtering the reaction solution, adding 600g of saturated hydrochloric acid solution into the filtrate, heating to 80-90 ℃, stirring for 1h, allowing a large amount of solids to appear, cooling to room temperature, filtering the reaction solution, and drying the filter cake to obtain 162g of 3,4,9, 10-perylenetetracarboxylic anhydride.
Example 15
Slowly adding 200g of 3,4,9, 10-perylenetetracarboxylic diimide into 500g (content: 95%) of concentrated sulfuric acid in a reaction bottle at room temperature, slowly heating to 220 ℃ after adding, keeping the temperature for reaction for 2 hours, slowly cooling to room temperature, separating out a large amount of solids in the cooling process, filtering the reaction solution, washing a filter cake to be neutral by using water, and drying the filter cake at 80 ℃ to obtain a crude product of the 3,4,9, 10-peryleneglycoside; under the condition of keeping out of the sun, completely adding the obtained crude product into a mixed solution of 6000mL of water and 140g (the content is 85%) of potassium hydroxide, slowly heating to 90 ℃ under the protection of nitrogen, keeping the temperature, stirring for reaction for 1 hour, cooling to room temperature, separating out a large amount of solid, carrying out vacuum filtration on the reaction solution, and washing a filter cake with 100mL of water; adding 60g (content: 85%) of potassium hydroxide and 60g of activated carbon into the filtrate under the conditions of nitrogen protection and light shielding, stirring for 30min at room temperature, adding 60g of ferric sulfate and 600mL of water, stirring and reacting for 30min at room temperature, filtering the reaction solution, adding 600g of saturated hydrochloric acid solution into the filtrate, heating to 80-90 ℃, stirring for 1h, allowing a large amount of solids to appear, cooling to room temperature, filtering the reaction solution, and drying the filter cake to obtain 107g of 3,4,9, 10-perylenetetracarboxylic anhydride.
Example 16
Slowly adding 200g of 3,4,9, 10-perylenetetracarboxylic diimide into 600g (content: 95%) of concentrated sulfuric acid in a reaction bottle at room temperature, slowly heating to 220 ℃ after adding, keeping the temperature for reaction for 2 hours, then slowly cooling to room temperature, separating out a large amount of solids in the cooling process, filtering the reaction solution, washing a filter cake to be neutral by using water, and drying the filter cake at 80 ℃ to obtain a crude product of the 3,4,9, 10-peryleneglycoside; under the condition of keeping out of the sun, completely adding the obtained crude product into a mixed solution of 6000mL of water and 140g (the content is 85%) of potassium hydroxide, slowly heating to 90 ℃ under the protection of nitrogen, keeping the temperature, stirring for reaction for 1 hour, cooling to room temperature, separating out a large amount of solid, carrying out vacuum filtration on the reaction solution, and washing a filter cake with 100mL of water; adding 60g (content: 85%) of potassium hydroxide and 60g of activated carbon into the filtrate under the conditions of nitrogen protection and light shielding, stirring for 30min at room temperature, adding 60g of ferric sulfate and 600mL of water, stirring and reacting for 30min at room temperature, filtering the reaction solution, adding 600g of saturated hydrochloric acid solution into the filtrate, heating to 80-90 ℃, stirring for 1h, allowing a large amount of solids to appear, cooling to room temperature, filtering the reaction solution, and drying the filter cake to obtain 134g of 3,4,9, 10-perylenetetracarboxylic anhydride.
Example 17
Slowly adding 200g of 3,4,9, 10-perylenetetracarboxylic diimide into 700g (content: 95%) of concentrated sulfuric acid in a reaction bottle at room temperature, slowly heating to 220 ℃ after adding, keeping the temperature for reaction for 2 hours, then slowly cooling to room temperature, separating out a large amount of solids in the cooling process, filtering the reaction solution, washing a filter cake to be neutral by using water, and drying the filter cake at 80 ℃ to obtain a crude product of the 3,4,9, 10-peryleneglycoside; under the condition of keeping out of the sun, completely adding the obtained crude product into a mixed solution of 6000mL of water and 140g (the content is 85%) of potassium hydroxide, slowly heating to 90 ℃ under the protection of nitrogen, keeping the temperature, stirring for reaction for 1 hour, cooling to room temperature, separating out a large amount of solid, carrying out vacuum filtration on the reaction solution, and washing a filter cake with 100mL of water; adding 60g (content: 85%) of potassium hydroxide and 60g of activated carbon into the filtrate under the conditions of nitrogen protection and light shielding, stirring for 30min at room temperature, adding 60g of ferric sulfate and 600mL of water, stirring and reacting for 30min at room temperature, filtering the reaction solution, adding 600g of saturated hydrochloric acid solution into the filtrate, heating to 80-90 ℃, stirring for 1h, allowing a large amount of solids to appear, cooling to room temperature, filtering the reaction solution, and drying the filter cake to obtain 166g of 3,4,9, 10-perylenetetracarboxylic anhydride.
Example 18
Slowly adding 200g of 3,4,9, 10-perylenetetracarboxylic diimide into 700g (content: 95%) of concentrated sulfuric acid in a reaction bottle at room temperature, slowly heating to 220 ℃ after adding, keeping the temperature for reaction for 2 hours, then slowly cooling to room temperature, separating out a large amount of solids in the cooling process, filtering the reaction solution, washing a filter cake to be neutral by using water, and drying the filter cake at 80 ℃ to obtain a crude product of the 3,4,9, 10-peryleneglycoside; under the condition of keeping out of the sun, completely adding the obtained crude product into a mixed solution of 6000mL of water and 140g (the content is 85%) of potassium hydroxide, slowly heating to 90 ℃ under the protection of nitrogen, keeping the temperature, stirring for reaction for 1 hour, cooling to room temperature, separating out a large amount of solid, carrying out vacuum filtration on the reaction solution, and washing a filter cake with 100mL of water; adding 60g (content: 85%) of potassium hydroxide and 60g of activated carbon into the filtrate under the conditions of nitrogen protection and light shielding, stirring for 30min at room temperature, adding 60g of ferric chloride and 600mL of water, stirring and reacting for 30min at room temperature, filtering the reaction solution, adding 600g of saturated hydrochloric acid solution into the filtrate, heating to 80-90 ℃, stirring for 1h, allowing a large amount of solids to appear, cooling to room temperature, filtering the reaction solution, and drying the filter cake to obtain 175g of 3,4,9, 10-perylenetetracarboxylic anhydride.
Example 19
Slowly adding 200g of 3,4,9, 10-perylenetetracarboxylic diimide into 700g (content: 95%) of concentrated sulfuric acid in a reaction bottle at room temperature, slowly heating to 220 ℃ after adding, keeping the temperature for reaction for 2 hours, then slowly cooling to room temperature, separating out a large amount of solids in the cooling process, filtering the reaction solution, washing a filter cake to be neutral by using water, and drying the filter cake at 80 ℃ to obtain a crude product of the 3,4,9, 10-peryleneglycoside; under the condition of keeping out of the sun, completely adding the obtained crude product into a mixed solution of 6000mL of water and 140g (the content is 85%) of potassium hydroxide, slowly heating to 90 ℃ under the protection of nitrogen, keeping the temperature, stirring for reaction for 1 hour, cooling to room temperature, separating out a large amount of solid, carrying out vacuum filtration on the reaction solution, and washing a filter cake with 100mL of water; adding 60g (content: 85%) of potassium hydroxide and 60g of activated carbon into the filtrate under the conditions of nitrogen protection and light shielding, stirring for 30min at room temperature, adding 60g of copper chloride and 600mL of water, stirring and reacting for 30min at room temperature, filtering the reaction solution, adding 600g of saturated hydrochloric acid solution into the filtrate, heating to 80-90 ℃, stirring for 1h, allowing a large amount of solids to appear, cooling to room temperature, filtering the reaction solution, and drying the filter cake to obtain 141g of 3,4,9, 10-perylenetetracarboxylic anhydride.
Example 20
Adding 40g of 3,4,9, 10-perylene tetracarboxylic anhydride into 200mL of aqueous solution containing 33.5g of potassium hydroxide in a reaction bottle, uniformly stirring, heating to 90 ℃, transferring the reaction liquid into an autoclave, sealing the autoclave, slowly heating to 250 ℃, and using for about 3 hours, wherein the pressure in the autoclave is 0.3-0.4 MPa, carrying out heat preservation reaction for 20 hours, cooling to room temperature, adjusting the pH of the reaction liquid to 8-9 by using 10% hydrochloric acid solution, filtering the reaction liquid, continuously adjusting the pH of the filtrate to 2-3 by using 10% hydrochloric acid solution, separating out a large amount of solids, filtering the reaction liquid, washing a filter cake twice by using 200mL of saturated sodium chloride solution, and drying the filter cake to obtain 22g of 3, 9-perylene diacid;1H NMR(400MHz,DMSO-d6):δ8.90-8.81(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。
example 21
Adding 40g of 3,4,9, 10-perylene tetracarboxylic anhydride into 200mL of aqueous solution containing 33.5g of potassium hydroxide in a reaction bottle, uniformly stirring, heating to 90 ℃, transferring the reaction liquid into an autoclave, sealing the autoclave, slowly heating to 200 ℃, and using for about 3 hours, wherein the pressure in the autoclave is 0.2-0.3 MPa, carrying out heat preservation reaction for 20 hours, cooling to room temperature, adjusting the pH of the reaction liquid to 8-9 by using 10% hydrochloric acid solution, filtering the reaction liquid, continuously adjusting the pH of the filtrate to 2-3 by using 10% hydrochloric acid solution, separating out a large amount of solids, filtering the reaction liquid, washing a filter cake twice by using 200mL of saturated sodium chloride solution, and drying the filter cake to obtain 26g of 3, 9-perylene diacid;1H NMR(400MHz,DMSO-d6):δ8.90-8.81(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。
example 22
Adding 40g of 3,4,9, 10-perylene tetracarboxylic anhydride into 200mL of aqueous solution containing 40g of potassium hydroxide in a reaction bottle, uniformly stirring, heating to 90 ℃, then transferring the reaction liquid into an autoclave, sealing the autoclave, slowly heating to 200 ℃, and taking the reaction liquid for about 3 hours, wherein the pressure in the autoclave is 0.2-0.3 MPa, carrying out heat preservation reaction for 20 hours, cooling to room temperature, adjusting the pH of the reaction liquid to 8-9 by using 10% hydrochloric acid solution, filtering the reaction liquid, continuously adjusting the pH of the filtrate to 2-3 by using 10% hydrochloric acid solution, separating out a large amount of solid, filtering the reaction liquid, washing a filter cake twice by using 200mL of saturated sodium chloride solution, and drying the filter cake to obtain 31g of 3, 9-perylene diacid;1H NMR(400MHz,DMSO-d6):δ8.90-8.81(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。
example 23
Adding 40g of 3,4,9, 10-perylene tetracarboxylic anhydride into 200mL of aqueous solution containing 45g of potassium hydroxide in a reaction bottle, uniformly stirring, heating to 90 ℃, then transferring the reaction solution into a high-pressure kettle, sealing the high-pressure kettle, slowly heating to 200 ℃, using for about 3 hours, controlling the pressure in the kettle to be 0.2-0.3 MPa, carrying out heat preservation reaction for 20 hours, cooling to room temperature, adjusting the pH of the reaction solution to be 8-9 by using 10% hydrochloric acid solution, filtering the reaction solution, continuously adjusting the pH of the filtrate to be 2-3 by using 10% hydrochloric acid solution, separating out a large amount of solids, filtering the reaction solution, washing a filter cake twice by using 200mL of saturated sodium chloride solution,drying the filter cake to obtain 27g of 3, 9-perylene diacid;1H NMR(400MHz,DMSO-d6):δ8.90-8.81(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。
example 24
Adding 34g of 3, 9-perylene diacid into 350mL of thionyl chloride in a reaction bottle, heating and reacting for 1h at 60 ℃ under the protection of nitrogen, monitoring the complete reaction of raw materials by TLC, evaporating the thionyl chloride serving as a solvent, adding into 100mL of aqueous solution containing 28g of potassium hydroxide, dropwise adding 30g of liquid bromine under the protection of nitrogen at room temperature, heating to 60 ℃ after dropwise adding, reacting for 5h, monitoring the complete reaction of the raw materials by TLC, pouring the reaction liquid into dilute hydrochloric acid until solids appear, filtering the reaction liquid, adding the solids into sodium hydroxide solution for complete dissolution, adjusting the pH of the reaction liquid to be neutral by using the dilute hydrochloric acid solution, filtering the reaction liquid again, washing a filter cake for multiple times by using ice water, and drying the filter cake to obtain 42g of 3, 9-dicarboxyl-4, 10-dibromo perylene.
Example 25
Adding 5g of 3, 9-dicarboxyl-4, 10-dibromoperylene and 2.8g of potassium thiocyanate into 15mL of acetonitrile in a reaction bottle, dropwise adding 10mL of thionyl chloride under the protection of nitrogen at room temperature, heating to 50 ℃ after dropwise adding, reacting for 1h, monitoring the complete reaction of raw materials by TLC, pouring the reaction liquid into ice water, adjusting the reaction liquid by using a saturated sodium chloride solution for multiple times, filtering the reaction liquid again, extracting the filtrate by using chloroform for multiple times, combining organic phases, and concentrating to obtain 5g of 3, 9-dimethylisothiocyanate-4, 10-dibromoperylene;1H NMR(400MHz,DMSO-d6):δ7.89(d,J＝8.0Hz,2H),7.73(d,J＝8.0Hz,2H),7.61-7.60(m,2H),7.46(d,J＝8.0Hz,2H)；HRMS(ESI):578.8419[M+H]+；Anal.Calcd for C24H8Br2N2O2S2:C,49.68；H,1.39；N,4.83.Found:C,49.58；H,1.43；N,4.81。
example 26
Adding 29g of 3, 9-dimethyl isothiocyanate-4, 10-dibromoperylene, 0.4g of cuprous iodide, 0.9g of 2-quinolinecarboxylic acid-N-oxide and 8g of cesium carbonate into 100mL of dimethyl sulfoxide in a reaction bottle, heating to 50 ℃, dropwise adding dimethyl sulfoxide dissolved with 4.8g of urea, heating to 80 ℃ after dropwise adding, reacting for 2 hours, monitoring the complete reaction of raw materials by TLC (thin layer chromatography), adding certain amount of water and ethyl acetate into the reaction solution, stirring for 10 minutes, filtering the reaction solution, separating out an organic phase, extracting the water phase for three times by using ethyl acetate, combining the organic phases, drying by using anhydrous sodium sulfate, concentrating, and recrystallizing by using a mixed solution of ethanol and acetone to obtain 21g of 3, 9-dimethyl isothiocyanate-4, 10-diaminoperylene;1H NMR(400MHz,DMSO-d6):δ8.16-8.15(m,2H),7.69(d,J＝8.0Hz,2H),7.47(d,J＝12.0Hz,2H),7.11(d,J＝12.0Hz,2H),6.57-6.55(m,4H)；13C NMR(400MHz,DMSO-d6):δ165.5,142.1,139.5,129.4,128.0,126.9,117.7,116.2,115.3,108.8,101.4,97.3。
example 27
Adding 29g of 3, 9-dimethylisothiocyanate-4, 10-dibromoperylene, 0.4g of cuprous iodide, 0.9g of 2-quinolinecarboxylic acid-N-oxide and 8g of cesium carbonate into 100mL of dimethyl sulfoxide in a reaction bottle, heating to 50 ℃, dropwise adding 30mL of dimethyl sulfoxide dissolved with 7.6g of thiourea, heating to 80 ℃ after dropwise adding, reacting for 2h, monitoring the complete reaction of raw materials by TLC, adding certain amount of water and ethyl acetate into the reaction solution, stirring for 10min, filtering the reaction solution, separating out an organic phase, extracting an aqueous phase with ethyl acetate for three times, combining the organic phases, drying with anhydrous sodium sulfate,after concentration, the mixed solution of ethanol and acetone is recrystallized to obtain 19g of 3, 9-dimethyl isothiocyanate-4, 10-diaminoperylene;1H NMR(400MHz,DMSO-d6):δ8.16-8.15(m,2H),7.69(d,J＝8.0Hz,2H),7.47(d,J＝12.0Hz,2H),7.11(d,J＝12.0Hz,2H),6.57-6.55(m,4H)；13C NMR(400MHz,DMSO-d6):δ165.5,142.1,139.5,129.4,128.0,126.9,117.7,116.2,115.3,108.8,101.4,97.3。
example 28
Adding 29g of 3, 9-dimethyl isothiocyanate-4, 10-dibromoperylene, 0.4g of cuprous iodide, 0.9g of 2-quinolinecarboxylic acid-N-oxide and 8g of cesium carbonate into 100mL of dimethyl sulfoxide in a reaction bottle, heating to 50 ℃, dropwise adding 20mL of dimethyl sulfoxide dissolved with 6g of urea, heating to 80 ℃ after dropwise adding, reacting for 2 hours, monitoring the complete reaction of raw materials by TLC, adding certain amount of water and ethyl acetate into the reaction solution, stirring for 10 minutes, filtering the reaction solution, separating out an organic phase, extracting the water phase for three times by using ethyl acetate, combining the organic phases, drying by using anhydrous sodium sulfate, concentrating, and recrystallizing by using a mixed solution of ethanol and acetone to obtain 20g of 3, 9-dimethyl isothiocyanate-4, 10-diaminoperylene;1H NMR(400MHz,DMSO-d6):δ8.16-8.15(m,2H),7.69(d,J＝8.0Hz,2H),7.47(d,J＝12.0Hz,2H),7.11(d,J＝12.0Hz,2H),6.57-6.55(m,4H)；13C NMR(400MHz,DMSO-d6):δ165.5,142.1,139.5,129.4,128.0,126.9,117.7,116.2,115.3,108.8,101.4,97.3。
example 29
Adding 9g of 3, 9-dimethyl isothiocyanate-4, 10-diaminoperylene and 0.4g of tetrabutylammonium bromide into 50mL of anhydrous acetonitrile in a reaction flask, stirring for 10min at room temperature, heating and refluxing for 2h, monitoring the reaction completion of raw materials by TLC, evaporating the acetonitrile solvent under reduced pressure, adding the concentrate into a mixture of 30mL of water and 20mL of ethanolHeating the mixed solution to 60 ℃, stirring for 30min, filtering the reaction solution, washing the filter cake with THF for multiple times, and drying to obtain the final product
7.9g；1H NMR(400MHz,DMSO-d6):δ9.37(s,2H),8.25(d,J＝12.4Hz,2H),7.99(d,J＝12.4Hz,2H),7.65-7.63(m,2H),7.16-7.14(m,2H),4.22(s,2H)；13C NMR(400MHz,DMSO-d6):δ172.3,161.9,135.1,127.8,125.5,124.9,123.7,117.8,112.4,109.1,106.3,102.5；HRMS(ESI):453.0471[M+H]+；Anal.Calcd for C24H12N4O2S2:C,63.70；H,2.67；N,12.38.Found:C,63.51；H,2.72；N,12.33。
Example 30
Biological activity assay
Taking three tumor cells of human cervical cancer Hela cells, human breast cancer MDA-MB-231 cells and human liver cancer HepG2 cells in a growth period, culturing the three tumor cells at 37 ℃ and 5% CO2 by using a DMEM culture medium containing 10% fetal calf serum, digesting the three tumor cells by using 0.25% pancreatin-0.02% EDTA, carrying out passage, collecting the cells with vigorous proliferation and good state, suspending the cells by using a cell culture solution, counting the tumor cells, and adjusting the concentration of the tumor cells to be that the number of the cells contained in the suspension is 5000-10000; inoculating the tumor cell suspension into a 96-well plate, wherein each well is 200 mu L, carrying out adherent culture for 4h after cell inoculation, then adding medicament DMSO solutions with different concentrations, the medicament is provided with four concentrations of 5, 10, 50 and 100 mu mol/L, each concentration is provided with 5 parallel multiple wells, continuously culturing for 48h in a cell culture box, adding 10 mu L of CCK-8 reagent, incubating for 2h at 37 ℃, measuring 490nm optical density, and simultaneously setting the tumor cells and the medicament as a control. Calculating the inhibition rate of the drug on the corresponding tumor cells according to the measured optical density value, wherein the inhibition rate is (1-experimental group OD value/control group OD value) × 100%
Example 31
Cytotoxicity assays
The CCK-8 method is used for detecting the influence of the target compounds with different concentrations on the survival rate of human fibroblasts, and the results show that the target compounds with different concentrations are cultured with cells respectively, and compared with a negative control group, the difference has no statistical significance, and the target compounds have safety on the human fibroblasts.
The foregoing embodiments illustrate the principles, principal features and advantages of the invention, and it will be understood by those skilled in the art that the invention is not limited to the foregoing embodiments, which are merely illustrative of the principles of the invention, and that various changes and modifications may be made therein without departing from the scope of the principles of the invention.
Claims (9)
1. A perylene acid drug molecule with anti-tumor activity is characterized in that the structure of the perylene acid drug molecule is as follows:
。
2. the preparation method of the peryleneic acid drug molecule with the antitumor activity according to claim 1, which is characterized by comprising the following specific steps:
A. adding acenaphthene into glacial acetic acid, adding a certain amount of oxidant, stirring uniformly at room temperature, slowly heating to 80 ℃, keeping the temperature for reaction until TLC monitors that the raw materials react completely, pouring the reaction liquid into ice water while the reaction liquid is hot, stirring, separating out solids, filtering the reaction liquid, and drying a filter cake to obtain 1, 8-naphthalic anhydride;
B. adding 1, 8-naphthalic anhydride into saturated ammonia water, stirring at room temperature to obtain yellow mixed liquid, slowly heating to a certain temperature, keeping the temperature for reaction until the raw materials completely react, stopping heating, slowly cooling to room temperature, separating out solids, filtering the reaction liquid, washing a filter cake to be neutral by using water, and then drying to obtain 1, 8-naphthalic diamide;
C. adding a certain amount of hydroxide and anhydrous sodium acetate into a stainless steel reaction kettle with stirring, heating to a certain temperature under a vacuum condition, keeping the temperature and stirring for a period of time, adding 1, 8-naphthalene diimide under the protection of nitrogen, continuously heating to 300 ℃ after the addition, reacting for a period of time, cooling to 200 ℃ again, adding a certain amount of water, pouring the reaction liquid into water after stirring, stirring for a period of time at room temperature, separating out a large amount of solids, filtering the reaction liquid, washing a filter cake with water, adding the filter cake into a saturated hydrochloric acid solution, heating to 75 ℃, stirring and reacting for a period of time, filtering the reaction liquid again, and drying the filter cake at 80 ℃ to obtain a crude product of 3,4,9, 10-perylene tetracarboxylic diimide; adding the crude 3,4,9, 10-perylenetetracarboxylic diimide hydrochloride into concentrated sulfuric acid, slowly heating to 80 ℃, completely dissolving the crude product, slowly dropwise adding a certain amount of sulfuric acid with the concentration of 50%, heating to 100 ℃ after dropwise adding, continuously reacting for a period of time, cooling to room temperature, separating out a large amount of solids, filtering the reaction solution, washing a filter cake with a sulfuric acid solution with the concentration of 78%, and drying at 80 ℃ to obtain a pure 3,4,9, 10-perylenetetracarboxylic diimide;
D. slowly adding 3,4,9, 10-perylenetetracarboxylic diimide into concentrated sulfuric acid at room temperature, slowly heating to 220 ℃ after the 3,4,9, 10-perylenetetracarboxylic diimide is added, keeping the temperature for reaction for a period of time, slowly cooling to room temperature, separating out a large amount of solids during cooling, filtering reaction liquid, washing a filter cake to be neutral by using water, and drying the filter cake at 80 ℃ to obtain a crude product of the 3,4,9, 10-peryleneglycoside; under the condition of keeping out of the sun, completely adding the obtained crude product into a mixed solution of water and a potassium hydroxide solution, slowly heating to 90 ℃ under the protection of nitrogen, keeping the temperature, stirring for reaction for a period of time, cooling to room temperature, separating out a large amount of solids, carrying out vacuum filtration on the reaction solution, and washing a filter cake with water; under the conditions of nitrogen protection and light shielding, adding potassium hydroxide and activated carbon into the filtrate, stirring at room temperature, adding metal salt ions and water, keeping the room temperature, stirring for reacting for a period of time, filtering the reaction solution, adding a saturated hydrochloric acid solution into the filtrate, heating to 80-90 ℃, stirring until a large amount of solids appear, cooling to room temperature, filtering the reaction solution, and drying a filter cake to obtain 3,4,9, 10-perylene tetracarboxylic anhydride;
E. adding 3,4,9, 10-perylenetetracarboxylic anhydride into a potassium hydroxide saturated aqueous solution, uniformly stirring, heating to 90 ℃, then transferring the reaction liquid into an autoclave, sealing the autoclave, slowly heating to a certain temperature to ensure that the pressure in the autoclave is 0.2-0.4 MPa, carrying out heat preservation reaction for a period of time, cooling to room temperature, adjusting the pH of the reaction liquid to 8-9 by using a 10% hydrochloric acid solution, filtering the reaction liquid, continuously adjusting the pH of the filtrate to 2-3 by using a 10% hydrochloric acid solution, separating out a large amount of solids, filtering the reaction liquid, washing a filter cake for multiple times by using a saturated sodium chloride solution, and drying the filter cake to obtain 3, 9-perylenedioic acid;
F. adding 3, 9-perylene diacid into thionyl chloride, heating and reacting at 60 ℃ under the protection of nitrogen until the raw materials react completely, and evaporating the thionyl chloride as a solvent to obtain 3, 9-perylene diacid chloride; adding 3, 9-perylene dichloride into a potassium hydroxide aqueous solution, dropwise adding liquid bromine at room temperature under the protection of nitrogen, heating to 60 ℃ after dropwise adding, reacting until the raw materials react completely, pouring the reaction liquid into dilute hydrochloric acid, filtering the reaction liquid, adding the solid into a sodium hydroxide solution for complete dissolution, adjusting the pH of the reaction liquid to be neutral by using the dilute hydrochloric acid solution, filtering the reaction liquid again, washing a filter cake for multiple times by using ice water, and drying the filter cake to obtain 3, 9-dicarboxyl-4, 10-dibromo perylene;
G. adding 3, 9-dicarboxyl-4, 10-dibromoperylene and potassium thiocyanate into acetonitrile, dropwise adding thionyl chloride under the protection of nitrogen at room temperature, heating to 50 ℃ after dropwise adding, reacting until the raw materials react completely, pouring the reaction liquid into ice water, adjusting the reaction liquid for multiple times by using a saturated sodium chloride solution, filtering the reaction liquid again, extracting the filtrate for multiple times by using chloroform, combining organic phases, and concentrating to obtain 3, 9-dimethyl isothiocyanate-4, 10-dibromoperylene;
H. adding 3, 9-dimethylisothiocyanate-4, 10-dibromoperylene, cuprous iodide, 2-quinolinecarboxylic acid-N-oxide and cesium carbonate into dimethyl sulfoxide, heating to 50 ℃, dropwise adding the dimethyl sulfoxide dissolved with an amination reagent, heating to 80 ℃ after dropwise adding, reacting until the raw materials completely react, adding a certain amount of water and ethyl acetate into the reaction liquid, stirring uniformly, filtering the reaction liquid, separating an organic phase, extracting the water phase with ethyl acetate for three times, combining the organic phases, drying with anhydrous sodium sulfate, concentrating, and recrystallizing with a mixed solution of ethanol and acetone to obtain 3, 9-dimethylisothiocyanate-4, 10-diaminoperylene;
I. adding 3, 9-dimethyl isothiocyanate-4, 10-diaminoperylene and TBAB into anhydrous acetonitrile in a reaction bottle, uniformly stirring at room temperature, heating for reflux reaction until the raw materials react completely, evaporating the acetonitrile solvent under reduced pressure, adding the concentrate into a mixed solution of water and ethanol, heating to 60 ℃, uniformly stirring, filtering the reaction solution, washing a filter cake with THF for multiple times, and drying to obtain the compound
。
3. The method of preparing peryleneic acid drug molecules with anti-tumor activity according to claim 2, wherein: the oxidant in the step A is potassium dichromate, sodium dichromate dihydrate, periodic acid or potassium permanganate; the feeding amount molar ratio of the acenaphthene to the oxidant is 1: 1.5-3.
4. The method of preparing peryleneic acid drug molecules with anti-tumor activity according to claim 2, wherein: the certain temperature in the step B is 50-80 ℃.
5. The method of preparing peryleneic acid drug molecules with anti-tumor activity according to claim 2, wherein: the hydroxide in the step C is sodium hydroxide, potassium hydroxide or barium hydroxide; the feeding amount molar ratio of the 1, 8-naphthalene diimide to the hydroxide is 1: 20-40; the certain temperature is 150-350 ℃.
6. The method of preparing peryleneic acid drug molecules with anti-tumor activity according to claim 2, wherein: and D, the metal salt ions in the step D are ferric sulfate, ferric chloride or copper chloride.
7. The method of preparing peryleneic acid drug molecules with anti-tumor activity according to claim 2, wherein: the feeding amount molar ratio of the 3,4,9, 10-perylene tetracarboxylic anhydride to the potassium hydroxide in the step E is 1: 5-8; the certain temperature is 150-250 ℃.
8. The method of preparing peryleneic acid drug molecules with anti-tumor activity according to claim 2, wherein: the amination reagent in the step H is urea or thiourea; the feeding amount molar ratio of the 3, 9-dimethyl isothiocyanate-4, 10-dibromoperylene to the amination reagent is 1: 1.2-2.
9. The use of the peryleneic acid drug molecule of claim 1 with anti-tumor activity for the preparation of an anti-tumor drug.
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