CN113651739B - Oligo-ethylene glycol fluorinated aromatic ring organic small molecule and preparation method and application thereof - Google Patents
Oligo-ethylene glycol fluorinated aromatic ring organic small molecule and preparation method and application thereof Download PDFInfo
- Publication number
- CN113651739B CN113651739B CN202110947944.XA CN202110947944A CN113651739B CN 113651739 B CN113651739 B CN 113651739B CN 202110947944 A CN202110947944 A CN 202110947944A CN 113651739 B CN113651739 B CN 113651739B
- Authority
- CN
- China
- Prior art keywords
- fluorinated aromatic
- gold
- oligo
- aromatic ring
- small molecule
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/10—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C323/11—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
- C07C323/12—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
- A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers
- A61K9/1273—Polymersomes; Liposomes with polymerisable or polymerised bilayer-forming substances
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/02—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of thiols
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C327/00—Thiocarboxylic acids
- C07C327/20—Esters of monothiocarboxylic acids
- C07C327/22—Esters of monothiocarboxylic acids having carbon atoms of esterified thiocarboxyl groups bound to hydrogen atoms or to acyclic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/16—Preparation of ethers by reaction of esters of mineral or organic acids with hydroxy or O-metal groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Engineering & Computer Science (AREA)
- Inorganic Chemistry (AREA)
- Dispersion Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses an oligo-polyethylene glycol fluorinated aromatic ring micromolecule ligand, a preparation method and application thereof, and the oligo-polyethylene glycol fluorinated aromatic ring micromolecule ligand has the following structure:
formula (I), wherein m and n are both positive integers, and m =1-6, n =1-8. The ligand and the gold nanoparticles can be self-assembled into a gold nanoparticle vesicle structure with a plasma resonance characteristic in a solution, and the maximum absorption peak of an ultraviolet absorption spectrum of the gold nanoparticle vesicle shows a larger red shift than that of the dispersed gold nanoparticles, so that the gold nanoparticle vesicle shows excellent optical performance and has wide application prospects in the fields of medicines and materials.
Description
Technical Field
The invention relates to the field of organic synthesis, in particular to an oligo-polyethylene glycol fluorinated aromatic ring organic small molecule and a preparation method and application thereof.
Background
The information disclosed in this background section is only for enhancement of understanding of the general background of the invention and is not necessarily to be construed as an admission or any form of suggestion that this information forms the prior art that is already known to a person of ordinary skill in the art.
The gold nanoparticles are widely concerned due to unique optical properties, the modified gold nanoparticles can be self-assembled into one-dimensional, two-dimensional and three-dimensional structures under certain conditions, and ultraviolet absorption has red shift characteristics due to strong plasma coupling among the gold nanoparticles in the self-assembled body, so that the gold nanoparticles have wide potential application in aspects of biosensing, detection and the like. Plasma coupling among the gold nanoparticles depends on the size and the number of the gold nanoparticles and the distance between the gold nanoparticles, and the three-dimensional hollow gold nanoparticle vesicles have attracted much attention due to unique optical properties.
The preparation of the gold nanoparticle vesicles is mostly based on amphiphilic block copolymer modified gold nanoparticle templated self-assembly, but the gold nanoparticle vesicles in the form have the following defects: (1) When the nano-gold nanoparticle is applied to a drug transfer process, the size of a carrier is critical, generally, the size is smaller than 100nm, the transmission efficiency is higher, but the nano-particles can hardly overcome the interfacial energy of the nano-emulsion droplets, so that only a nano-gold vesicle structure with the micron-sized particle size can be obtained, and the application in cell transfer is limited; (2) The amphiphilic block copolymer is relatively long, and in addition, the internal space of the gold nano vesicle formed by templated self-assembly contains more free high molecular polymers, so that the internal effective load space is reduced, and the amphiphilic block copolymer cannot be efficiently applied to the related fields of biological detection, high biosensing and the like.
In addition, it is worth noting that the formation of the gold nano vesicle is not an easy process, and the templated self-assembly method of the gold nano particle modified by the block copolymer is mostly adopted in the prior art, because the gold nano particle can be tightly coated by the ligand molecule thereof, the binding force can be improved, and the stability is enhanced, but the defect that the gold nano particle is difficult to fully act with other substances and the application of the gold nano particle is influenced exists, therefore, the high stability and the high coupling of the gold nano vesicle are realized, and the gold nano vesicle can be successfully prepared only when the interaction between the vesicle wall and the gold nano particle is in a relatively balanced state, and then the relevant performance indexes of the stability, the coupling degree and the like can be considered.
However, the self-assembly of gold nano-particles into gold nano-vesicles based on the participation of novel organic small molecular ligands is reported, so that the research on the nano-vesicles with high stability, high coupling and excellent plasma resonance characteristics is of great significance.
Disclosure of Invention
In order to overcome the problems, the invention designs the oligo-polyethylene glycol fluorinated aromatic ring organic micromolecule which can be self-assembled with the gold nanoparticles to form a gold nanoparticle vesicle structure with hollow and plasma resonance characteristics, compared with a high molecular polymer, the short organic micromolecule can shorten the distance between the gold nanoparticles, so that strong plasma coupling between the gold nanoparticles is caused, the ultraviolet absorption spectrum of the gold nanoparticles is enabled to absorb red shift maximally, and the spectrum red shift phenomenon has wide application in the fields of biological detection, high-performance biological sensing and the like.
Based on the research results, the present disclosure provides the following technical solutions:
in a first aspect of the present disclosure, a novel oligo-polyethylene glycol fluorinated aromatic ring small molecule ligand is provided, which has a structure shown in formula (I):
In a second aspect of the present disclosure, a method for preparing a novel oligo-polyethylene glycol fluorinated aromatic ring small molecule ligand is provided, which comprises the following steps:
(1) Fluorinated aromatic bisphenol is taken as a raw material and undergoes nucleophilic substitution with 11-bromoundecene to obtain mono-substituted undecene fluorinated aromatic phenol;
(2) Carrying out nucleophilic substitution reaction on mono-substituted undecylene fluorinated aromatic phenol and p-toluenesulfonyl mono-protected oligo-polyethylene glycol to obtain undecylene fluorinated aromatic phenol with the tail end of the oligo-polyethylene glycol;
(3) The undecylene fluorinated aromatic phenol with the tail end of the oligoethylene glycol and thioacetic acid are subjected to click reaction to obtain a thioacetic acid undecylene fluorinated aromatic ring micromolecule ligand with the tail end of the oligoethylene glycol;
(4) The small molecular ligand of the fluorinated aromatic ring of the thioacetic acid undecyl ester with the tail end of the oligoethylene glycol is subjected to alcoholysis or acidolysis to obtain the small molecular ligand of the fluorinated aromatic ring of the oligoethylene glycol.
In a third aspect of the disclosure, a gold nanovesicle is provided, wherein the gold nanovesicle is formed by self-assembling gold nanoparticles and the above-mentioned oligo-ethylene glycol fluorinated aromatic ring organic small molecule ligand.
The fourth aspect of the present disclosure provides a method for preparing a gold nanovesicle, comprising: and uniformly mixing the concentrated gold nanoparticles with a solution of the oligoethylene glycol fluorinated aromatic ring organic micromolecule ligand, and standing to obtain the gold nano vesicle.
In a fifth aspect of the present disclosure, applications of the above oligo-ethylene glycol fluorinated aromatic ring organic small molecule ligand or gold nano-vesicle in biocatalysis, biological diagnosis, micro-reactor construction and drug delivery are provided.
One or more specific embodiments of the present disclosure achieve at least the following technical effects:
(1) The hollow gold nanoparticle vesicle structure with the diameter of 50-200nm can be prepared, the structure is regular, the appearance is good, the distance between the gold nanoparticles can be shortened by the small-molecular ligand size, the number of the gold nanoparticles on the surface is increased, the surface plasma coupling effect between the gold nanoparticles is enhanced, and compared with monodisperse gold nanoparticles, the absorption of the gold nanoparticle vesicle is obviously red shifted.
(2) The gold nano vesicle prepared by the method can fully utilize the good biocompatibility of the gold nano particles, and meanwhile, the gold nano vesicle has a cavity structure, and is expected to load drugs in the hollow part of the gold nano vesicle to realize the cooperative treatment of tumors.
(3) The preparation method disclosed by the invention is simple, has strong practicability, and has wide application prospects in the related fields of biocatalysis, biological diagnosis, microreactor construction, drug transportation and the like.
Drawings
The accompanying drawings, which are included to provide a further understanding of the disclosure, illustrate embodiments of the disclosure and together with the description serve to explain the disclosure and are not to limit the disclosure.
FIG. 1 shows the NMR spectrum of intermediate 1 prepared in example 1 of the present invention;
FIG. 2 is a nuclear magnetic resonance hydrogen spectrum of intermediate 2a prepared in example 2 of the present invention;
FIG. 3 is a NMR chart of intermediate 2b prepared in example 3 of the present invention;
FIG. 4 is a NMR chart of intermediate 2c prepared in example 4 of the present invention;
FIG. 5 is a NMR chart of intermediate 3a prepared in example 5 of the present invention;
FIG. 6 is a NMR chart of intermediate 3b prepared in example 6 of the present invention;
FIG. 7 shows the NMR spectrum of intermediate 3c prepared in example 7 of the present invention;
FIG. 8 is a NMR chart of target 4a prepared in example 8 of the present invention;
FIG. 9 is a NMR chart of target 4b prepared in example 9 of the present invention;
FIG. 10 is a NMR chart of target 4c prepared in example 10 of the present invention;
FIG. 11 is a high-resolution transmission electron microscope image of gold nanovesicles prepared in example 11 of the present invention;
FIG. 12 is a high-resolution transmission electron micrograph of gold nanovesicles prepared in example 12 of the present invention;
FIG. 13 is a high-resolution transmission electron micrograph of gold nanovesicles prepared in example 13 of the present invention;
FIG. 14 is a UV absorption spectrum of gold nanovesicles and monodisperse gold nanoparticles prepared in example 11 of the present invention;
FIG. 15 is a UV absorption spectrum of the gold nanovesicles and monodisperse gold nanoparticles prepared in example 12 of the present invention;
fig. 16 is a uv absorption spectrum of the gold nanovesicle and the monodisperse gold nanoparticle prepared in example 13 of the present invention.
Detailed Description
It should be noted that the following detailed description is exemplary and is intended to provide further explanation of the disclosure. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.
It is noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of example embodiments according to the present disclosure. As used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, and it should be understood that when the terms "comprises" and/or "comprising" are used in this specification, they specify the presence of stated features, steps, operations, devices, components, and/or combinations thereof, unless the context clearly indicates otherwise.
As introduced in the background art, the existing gold nano vesicles are large in size, poor in plasma coupling performance and poor in stability, and reports are provided for the self-assembly of gold nano vesicles by gold nano particles participated by novel organic small molecular ligands. Therefore, the disclosure provides a novel oligo-polyethylene glycol fluorinated aromatic ring small molecule ligand, which can be self-assembled with gold nanoparticles to form a gold nanoparticle vesicle structure with hollow and strong plasmon resonance coupling characteristics.
In a first aspect of the present disclosure, a novel oligo-polyethylene glycol fluorinated aromatic ring small molecule ligand is provided, which has a structure shown in formula (I):
In a second aspect of the present disclosure, a method for preparing a novel oligo-polyethylene glycol fluorinated aromatic ring small molecule ligand is provided, which comprises the following steps:
(1) Fluorinated aromatic bisphenol is taken as a raw material and undergoes nucleophilic substitution with 11-bromoundecenyl to obtain mono-substituted undecene fluorinated aromatic phenol;
(2) Mono-substituted undecylene fluorinated aromatic phenol and oligo-polyethylene glycol mono-protected by p-toluenesulfonyl are subjected to nucleophilic substitution reaction to obtain undecylene fluorinated aromatic phenol with the tail end being the oligo-polyethylene glycol;
(3) The undecylene fluorinated aromatic phenol with the tail end of the oligoethylene glycol and thioacetic acid are subjected to click reaction to obtain a thioacetic acid undecylene fluorinated aromatic ring micromolecule ligand with the tail end of the oligoethylene glycol;
(4) The small molecular ligand of the aryl fluoride ring with the tail end of the oligoethylene glycol is obtained by alcoholysis or acidolysis of the small molecular ligand of the aryl fluoride ring with the tail end of the oligoethylene glycol.
In a typical embodiment, in step (1), the reaction conditions are alkaline conditions, preferably, the base is one of potassium carbonate, sodium hydroxide or potassium hydroxide, and more preferably, the base is potassium carbonate.
In a typical embodiment, in the step (1), the solvent is one of N, N-dimethylformamide, dimethyl sulfoxide and acetone, and preferably, the solvent is N, N-dimethylformamide, which can produce a good dispersing effect on the raw materials and improve the yield.
In one exemplary embodiment, in step (1), the solvent, fluorinated aromatic bisphenol, base, and 11-bromoundecene are present in a ratio of (10-25) mL: (0.4-1.2) g: (0.3-1.0) g: (0.6-1.3) g, preferably 20mL:1g:0.42g:1g.
In a typical embodiment, in step (1), the reaction temperature is 50-100 ℃.
In a typical embodiment, in step (2), the reaction conditions are alkaline conditions, preferably, the base is one of potassium carbonate, sodium hydroxide or potassium hydroxide, and more preferably, the base is potassium carbonate.
In a typical embodiment, in the step (2), the solvent is one of N, N-dimethylformamide, dimethyl sulfoxide and acetone, and preferably, the solvent is N, N-dimethylformamide, which can produce a good dispersing effect on the raw materials and improve the yield.
In a typical embodiment, in step (2), the solvent, intermediate 1, base and p-toluenesulfonyl mono-protected oligoethylene glycol are in a ratio of (8-20) mL: (0.4-0.8) g: (0.1-0.3) g: (0.4-0.6) g, preferably 15mL:0.75g:0.22g:0.54g.
In a typical embodiment, in step (2), the reaction temperature is 50-100 ℃.
In a typical embodiment, in step (3), the radical initiator is azobisisobutyronitrile or benzoyl peroxide, preferably azobisisobutyronitrile, which can improve the reaction efficiency.
In a typical embodiment, in the step (3), the solvent is one of tetrahydrofuran, dioxane and methyltetrahydrofuran, and preferably, the solvent is tetrahydrofuran, which can produce a good dispersion effect on the raw materials and improve the yield.
In one exemplary embodiment, in step (3), the solvent, intermediate 2, thioacetic acid and initiator are in a ratio of (5-10) mL: (0.3-0.6) g: (0.2-0.6) g: (0.1-0.3) g, preferably 9mL:0.43g:0.44g:0.13g.
In a typical embodiment, in the step (3), the reaction temperature is 60-80 ℃ and the reaction time is 16-24h, preferably, the reaction temperature is 65-70 ℃ and the reaction time is 19-20h, so that the reaction can be more complete and more efficient.
In a typical embodiment, in step (4), the alcoholysis reagent is sodium methoxide methanol solution, sodium ethoxide ethanol solution or sodium hydroxide solution, and preferably, the alcoholysis reagent is sodium methoxide methanol solution, so that the reaction effect is more excellent.
In a typical embodiment, in step (4), the alcoholysis reaction is carried out under the following conditions: the alkali is sodium methoxide methanol solution, the reaction temperature is 0-30 ℃, and the reaction time is 12-24h. When the reaction temperature is 20-30 ℃, the reaction efficiency is higher; when the reaction time is 16-18h, the reaction is more complete.
In one exemplary embodiment, in step (4), the acidolysis reaction conditions are: the acid is concentrated hydrochloric acid, the reaction temperature is 30-75 ℃, and the reaction time is 12-24h. When the reaction temperature is 60-75 ℃, the reaction efficiency is higher. When the reaction time is 18-24h, the reaction is more complete.
In an exemplary embodiment, in step (4), when alcoholysis is used, the ratio of methanol to intermediate 3 to sodium methoxide is as follows: (1-3) mL: (0.1-0.5) g (0.2-0.6) g, preferably 1mL: 0.22g.
Or when acidolysis is adopted, the proportion relation of the methanol, the intermediate 3 and the concentrated hydrochloric acid is as follows: (5-7) mL: (0.1-0.5) g: (0.2-0.4) g, preferably 6.7mL:0.4g:0.33mL.
The disclosure preferably discloses a preparation method of an organic micromolecule of fluorinated aromatic ring of oligo-polyethylene glycol, taking octafluoro-4, 4' -biphenol as an example, and the steps are as follows:
(1) Adding octafluoro-4, 4' -biphenol raw material into an organic solvent, adding alkali and 11-bromoundecene under stirring at room temperature, and heating to react to obtain an intermediate 1;
(2) Adding the intermediate 1 obtained in the step (1) into an organic solvent, adding alkali and oligoethylene glycol mono-p-methylbenzenesulfonate, heating and stirring to react to obtain an intermediate 2;
(3) Dissolving the intermediate 2 obtained in the step (2) in an organic solvent, adding thioacetic acid and an initiator, and heating and stirring to react to obtain an intermediate 3;
(4) And (4) dissolving the intermediate 3 obtained in the step (3) in an organic solvent, adding alkali or acid, and reacting at room temperature to obtain the organic micromolecule ligand of which the tail end of the target compound is the oligoethylene glycol octafluoro-4, 4' -biphenol.
The synthesis process is shown as the following formula:
wherein, the intermediate 1 is undecylene octafluoro-4, 4' -biphenol, the intermediate 2 is undecylene octafluoro-4, 4' -biphenol with the end of oligoethylene glycol, the intermediate 3 is a thioacetic acid undecyl ester fluorinated aromatic ring intermediate with the end of oligoethylene glycol, and the target is oligoethylene glycol octafluoro-4, 4' -biphenol organic micromolecule ligand.
In a third aspect of the disclosure, a gold nanovesicle is provided, wherein the gold nanovesicle is formed by self-assembling gold nanoparticles and the above-mentioned oligo-ethylene glycol fluorinated aromatic ring organic small molecule ligand.
In a fourth aspect of the present disclosure, a method for preparing a gold nanovesicle is provided, including: and uniformly mixing the concentrated gold nanoparticles with a solution of the oligoethylene glycol fluorinated aromatic ring organic micromolecule ligand, and standing to obtain the gold nano vesicle.
In a typical embodiment, the size of the gold nanoparticles is 5-20nm, and the gold nanovesicles obtained by self-assembling the gold nanoparticles and the organic small molecule ligand in the size range can have a larger absorption wavelength in an ultraviolet absorption spectrum.
In one exemplary embodiment, the concentrated gold nanoparticles are prepared by: and (3) after the gold nanoparticle sol is centrifuged, removing the supernatant to obtain the gold nanoparticle sol, wherein the centrifugation speed is 10000-14800rpm, and the centrifugation time is 25-60min.
In a typical embodiment, the solvent of the organic small molecular ligand is THF, the standing time is 1.5-3.5h, the gold nanoparticles can be better dispersed, and the preparation of the gold nanoparticle vesicles with uniform distribution and strong plasma resonance coupling performance is facilitated.
In a fifth aspect of the present disclosure, applications of the above oligo-ethylene glycol fluorinated aromatic ring organic small molecule ligand or gold nano-vesicle in biocatalysis, biological diagnosis, micro-reactor construction and drug delivery are provided.
In order to make the technical solutions of the present disclosure more clearly understood by those skilled in the art, the technical solutions of the present disclosure will be described in detail below with reference to specific examples and comparative examples.
Example 1 (m = 2):
to a 100mL round-bottom flask were added 20mL of N, N-dimethylformamide, 1g of octafluoro-4, 4' -biphenol, and 0.42g of K 2 CO 3 Stirring was carried out for 0.5 hour, 1.0g of 11-bromoundecene was added dropwise, and the system was slowly warmed to 85 ℃. Distilling under reduced pressure to remove organic solvent, and performing column chromatography to obtain intermediate1, yield 36.3%, its nuclear magnetic resonance hydrogen spectrum is shown in figure 1.
Example 2 (n = 1):
to a 50mL round-bottom flask were added 10mL of N, N-dimethylformamide, 0.53g of intermediate 1, and 0.15g of K 2 CO 3 Stirring for 0.5h, adding 0.49g of mono-4-methyl benzenesulfonic acid diethylene glycol ester, and slowly heating the system to 85 ℃. The organic solvent was removed by rotary evaporation under reduced pressure, and column chromatography was carried out to obtain intermediate 2a with a yield of 52.4%, whose nuclear magnetic resonance hydrogen spectrum is shown in FIG. 2.
Example 3 (n = 2):
to a 50mL round-bottomed flask were added 10mL of N, N-dimethylformamide, 0.50g of intermediate 1, and 0.14g of K 2 CO 3 Stirring for 0.5h, adding 0.52g of triethylene glycol mono-4-methylbenzenesulfonate, and slowly heating the system to 85 ℃. The organic solvent was removed by rotary evaporation under reduced pressure, and column chromatography was carried out to obtain intermediate 2b in 35.9% yield, whose nuclear magnetic resonance hydrogen spectrum is shown in FIG. 3.
Example 4 (n = 3):
to a 50mL round bottom flask was added 15mL N, N-dimethylformamide, 0.75g intermediate 1, 0.22g K 2 CO 3 Stirring for 0.5h, adding 0.54g of mono-4-methylbenzenesulfonic acid tetraethylene glycol ester, and slowly heating the system to 85 ℃. The organic solvent was removed by rotary evaporation under reduced pressure, and the intermediate 2c was obtained by column chromatography in 53.9% yield with a nuclear magnetic resonance hydrogen spectrum as shown in fig. 4.
Example 5:
a25 mL round bottom flask was charged with 9mL tetrahydrofuran, 0.43g intermediate 2a, 0.44g thioacetic acid, and 0.13g initiator azobisisobutyronitrile and refluxed at 70 ℃ for 20h under nitrogen. The organic solvent was removed, and column chromatography was carried out to obtain intermediate 3a with a yield of 80.0%, whose nuclear magnetic resonance hydrogen spectrum is shown in fig. 5.
Example 6:
a25 mL round bottom flask was charged with 6.5mL tetrahydrofuran, 0.37g intermediate 2b, 0.22g thioacetic acid, and 0.11g initiator azobisisobutyronitrile and refluxed at 70 ℃ for 20h under nitrogen. The organic solvent was removed, and column chromatography was performed to obtain intermediate 3b in 38.6% yield, whose nuclear magnetic resonance hydrogen spectrum is shown in fig. 6.
Example 7:
a25 mL round bottom flask was charged with 8.9mL tetrahydrofuran, 0.50g intermediate 2c, 0.57g thioacetic acid, and 0.25g initiator azobisisobutyronitrile and refluxed at 70 ℃ for 20h under nitrogen. The organic solvent was removed, and column chromatography was performed to obtain intermediate 3c with a yield of 65.1%, whose nuclear magnetic resonance hydrogen spectrum is shown in fig. 7.
Example 8:
a25 mL round-bottomed flask was charged with 2.7mL of methanol, 0.39g of intermediate 3a, and 0.57g of sodium methoxide methanol solution, and reacted at 25 ℃ for 17 hours. The organic solvent was removed, and column chromatography was performed to obtain the target 4a in 74.9% yield, whose hydrogen nuclear magnetic resonance spectrum is shown in FIG. 8.
Example 9:
a25 mL round bottom flask was charged with 1mL of methanol, 0.16g of intermediate 3b, and 0.22g of sodium methoxide methanol solution, and reacted at 25 ℃ for 17h. The organic solvent was removed, and column chromatography was performed to obtain the objective 4b with a yield of 79.9%, whose nuclear magnetic resonance hydrogen spectrum is shown in fig. 9.
Example 10:
a25 mL round bottom flask was charged with 6.7mL of methanol, 0.40g of intermediate 3c, and 0.33mL of concentrated HCl and reacted at 70 ℃ under reflux for 24h. The organic solvent was removed, and column chromatography was performed to obtain the objective 4c with a yield of 60.5%, and its nmr hydrogen spectrum is shown in fig. 10.
Example 11:
and (3) centrifuging the 10nm gold nanoparticle sol at a high speed of 12000rpm for 30min, removing a supernatant, uniformly mixing the concentrated gold nanoparticles with a THF (tetrahydrofuran) solution containing a target 4a, and standing for 2h to obtain a gold nanoparticle vesicle solution.
Example 12:
and (3) centrifuging the 10nm gold nanoparticle sol at a high speed of 12000rpm for 30min, removing a supernatant, uniformly mixing the concentrated gold nanoparticles with a THF (tetrahydrofuran) solution containing a target 4b, and standing for 2h to obtain a gold nanoparticle vesicle solution.
Example 13:
and (3) centrifuging the 10nm gold nanoparticle sol at a high speed of 12000rpm for 30min, removing a supernatant, uniformly mixing the concentrated gold nanoparticles with a THF (tetrahydrofuran) solution containing a target 4c, and standing for 2h to obtain a gold nanoparticle vesicle solution.
The TEM spectra of the gold nanovesicles prepared in examples 11 to 13 are shown in fig. 11 to 13, and it can be seen that the diameter of the prepared spherical gold nanovesicles is 50 to 200nm, the gold nanoparticles are uniformly and densely distributed on the surface of the vesicles, which proves that the gold nanovesicles are formed, and from the ultraviolet-visible spectrum, as shown in fig. 14 to 16, the maximum absorption wavelength of the gold nanoparticles is 520nm, and the maximum absorption wavelength is red-shifted to 570nm after the gold nanovesicles are formed, which is because the distance between the gold nanoparticles is reduced, so that the ultraviolet absorption spectrum is red-shifted, which fully proves that the gold nanovesicles with strong plasmon resonance coupling characteristics are successfully prepared, and the plasmon analysis technology is a high-sensitivity detection technology and widely applied to various biochemical detection technology fields, so the disclosure has great utility value. Meanwhile, the vesicle has a unique cavity structure and has important application value in various aspects such as drug transportation, artificial cell models, biological microreactors and the like.
Although the present invention has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that changes may be made in the embodiments and/or equivalents thereof without departing from the spirit and scope of the invention. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (18)
1. An oligo (ethylene glycol) fluorinated aromatic ring small molecule ligand, characterized by the following structure:
wherein m and n are both positive integers, and m =2, n =1, 2 or 3.
2. The method for preparing an oligo (ethylene glycol) fluorinated aromatic ring small molecule ligand according to claim 1, comprising the steps of:
(1) Fluorinated aromatic bisphenol is taken as a raw material and undergoes nucleophilic substitution with 11-bromoundecenyl to obtain mono-substituted undecene fluorinated aromatic phenol;
(2) Mono-substituted undecylene fluorinated aromatic phenol and oligo-polyethylene glycol mono-protected by p-toluenesulfonyl are subjected to nucleophilic substitution reaction to obtain undecylene fluorinated aromatic phenol with the tail end being the oligo-polyethylene glycol;
(3) The undecylene fluorinated aromatic phenol with the tail end of the oligo-polyethylene glycol and thioacetic acid have click reaction to obtain a thioacetic acid undecylene fluorinated aromatic ring micromolecule ligand with the tail end of the oligo-polyethylene glycol;
(4) The small molecular ligand of the fluorinated aromatic ring of the thioacetic acid undecyl ester with the tail end of the oligoethylene glycol is subjected to alcoholysis or acidolysis to obtain the small molecular ligand of the fluorinated aromatic ring of the oligoethylene glycol.
3. The preparation method according to claim 2, wherein in the steps (1) and (2), the reaction conditions are alkaline conditions, and the adopted base is one of potassium carbonate, sodium hydroxide or potassium hydroxide;
the solvent is one of N, N-dimethylformamide, dimethyl sulfoxide and acetone;
the reaction temperature is 50-100 ℃.
4. The method according to claim 3, wherein in the steps (1) and (2), the base used is potassium carbonate; the solvent is N, N-dimethylformamide.
5. The method according to claim 2, wherein in the step (1), the solvent, the fluorinated aromatic bisphenol, the base and the 11-bromoundecene are used in a ratio of (10 to 25) mL: (0.4-1.2) g: (0.3-1.0) g: (0.6-1.3) g.
6. The method according to claim 5, wherein in the step (1), the solvent, the fluorinated aromatic bisphenol, the base and the 11-bromoundecene are used in a ratio of 20mL:1g:0.42g:1g of the total weight of the composition.
7. The method according to claim 5, wherein in the step (1), the solvent, the fluorinated aromatic bisphenol, the base and the 11-bromoundecen are used in a ratio of 20mL:1g:0.42g:1g.
8. The method according to claim 7, wherein in the step (2), the solvent, the intermediate 1, the base and the p-toluenesulfonyl group mono-protected oligoethylene glycol are used in a ratio of 15mL:0.75g:0.22g:0.54g.
9. The production method according to claim 2,
in the step (3), the free radical initiator is azobisisobutyronitrile or benzoyl peroxide;
the reaction temperature is 60-80 ℃, and the reaction time is 16-24h.
10. The production method according to claim 9, wherein in the step (3), the radical initiator is azobisisobutyronitrile; the reaction temperature is 65-70 ℃ and the reaction time is 19-20h.
11. The method according to claim 2, wherein in the step (4), the alcoholysis reagent is selected from the group consisting of a sodium methoxide methanol solution, a sodium ethoxide ethanol solution, and a sodium hydroxide solution.
12. The method according to claim 11, wherein in step (4), the alcoholysis reagent is sodium methoxide methanol solution.
13. A gold nanovesicle, wherein the gold nanovesicle is formed by self-assembly of gold nanoparticles and the oligo (ethylene glycol) fluorinated aromatic ring organic small molecule ligand according to claim 1.
14. A preparation method of gold nano vesicles is characterized by comprising the following steps: and (3) uniformly mixing the concentrated gold nanoparticles with the solution of the oligo-polyethylene glycol fluorinated aromatic ring organic small molecule ligand according to claim 1, and standing to obtain the gold nano-vesicles.
15. The method of claim 14, wherein the gold nanoparticles are 5-20nm in size.
16. The method according to claim 14, wherein the concentrated gold nanoparticles are prepared by: and (3) after the gold nanoparticle sol is centrifuged, removing the supernatant to obtain the gold nanoparticle sol, wherein the centrifugation speed is 10000-14800rpm, and the centrifugation time is 25-60min.
17. The preparation method of claim 14, wherein the solvent of the organic small molecule ligand is THF, and the standing time is 1.5-3.5h.
18. Use of the oligoethylene glycol fluorinated aromatic ring organic small molecule ligand of claim 1 or the gold nanovesicle of claim 13 in the preparation of biocatalytic reagents, biological diagnostic reagents, drug delivery reagents and construction of microreactors.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110947944.XA CN113651739B (en) | 2021-08-18 | 2021-08-18 | Oligo-ethylene glycol fluorinated aromatic ring organic small molecule and preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110947944.XA CN113651739B (en) | 2021-08-18 | 2021-08-18 | Oligo-ethylene glycol fluorinated aromatic ring organic small molecule and preparation method and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN113651739A CN113651739A (en) | 2021-11-16 |
| CN113651739B true CN113651739B (en) | 2023-01-03 |
Family
ID=78480877
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110947944.XA Active CN113651739B (en) | 2021-08-18 | 2021-08-18 | Oligo-ethylene glycol fluorinated aromatic ring organic small molecule and preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113651739B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114671897B (en) * | 2022-04-15 | 2024-07-02 | 山东师范大学 | Preparation method of size-separated double-layer-like gold nano vesicles |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104127875A (en) * | 2014-03-11 | 2014-11-05 | 常州碳宇纳米科技有限公司 | Gene carrier of small size gold nanoparticle vesicle structure and preparation method thereof |
| CN108498461A (en) * | 2017-02-24 | 2018-09-07 | 国家纳米科学中心 | Gold nano-liposome composite nanometer particle and its pharmaceutical composition and application |
| CN108498460A (en) * | 2017-02-24 | 2018-09-07 | 国家纳米科学中心 | Gold nanoclusters-liposome composite particles and its preparation method and application |
| CN109986090A (en) * | 2019-03-22 | 2019-07-09 | 华南理工大学 | A kind of double ligand gold nanoparticle aqueous solutions and its preparation method and application |
-
2021
- 2021-08-18 CN CN202110947944.XA patent/CN113651739B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104127875A (en) * | 2014-03-11 | 2014-11-05 | 常州碳宇纳米科技有限公司 | Gene carrier of small size gold nanoparticle vesicle structure and preparation method thereof |
| CN108498461A (en) * | 2017-02-24 | 2018-09-07 | 国家纳米科学中心 | Gold nano-liposome composite nanometer particle and its pharmaceutical composition and application |
| CN108498460A (en) * | 2017-02-24 | 2018-09-07 | 国家纳米科学中心 | Gold nanoclusters-liposome composite particles and its preparation method and application |
| CN109986090A (en) * | 2019-03-22 | 2019-07-09 | 华南理工大学 | A kind of double ligand gold nanoparticle aqueous solutions and its preparation method and application |
Also Published As
| Publication number | Publication date |
|---|---|
| CN113651739A (en) | 2021-11-16 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Müllner et al. | Template-directed mild synthesis of anatase hybrid nanotubes within cylindrical core–shell–corona polymer brushes | |
| CN112079684B (en) | Pillar aromatic hydrocarbon and pillar-like aromatic hydrocarbon compound with aggregation-induced emission effect and preparation method and application thereof | |
| CN113651739B (en) | Oligo-ethylene glycol fluorinated aromatic ring organic small molecule and preparation method and application thereof | |
| CN112098391B (en) | Preparation method of surface-enhanced Raman spectrum substrate and surface-enhanced Raman detection method | |
| EP1476753A2 (en) | Functionalized compositions for improved immobilization | |
| CN102660270A (en) | Method for preparing fluorescent graphene quantum dots by solvothermal method | |
| CN1908033A (en) | Crosslinking poly(organophosphazenes) microsphere and preparation method thereof | |
| Njikang et al. | Tadpoles from the intramolecular photo-cross-linking of diblock copolymers | |
| CN101092484A (en) | Surface modified microballons of containing phosphazene, and preparation method | |
| CN100398614C (en) | Solvent-free inorganic nano particle fluid and preparation method thereof | |
| CN1966534A (en) | Inorganic-organic core-shell type rare earth high polymer material and its preparation method | |
| WO2011162366A1 (en) | Water-soluble polymer and water-soluble nanoparticle composite | |
| CN100535022C (en) | Method for preparing polymetallic oxo cluster hybrid polymer microspheres | |
| CN1831079A (en) | Fluorescent, magnetic, multi-functional nanometer material and its prepn. method | |
| CN102751067A (en) | Multifunctional magnetic nano complex and preparation method and applications thereof | |
| CN108164712B (en) | Polyphosphazene high-molecular fluorescent microsphere and preparation method thereof | |
| CN114621159B (en) | Diazosulfide-based fluorescent material, fluorescent polymer, fluorescent nanoparticles, and preparation method and application thereof | |
| CN1289628C (en) | Multifunctional fluorescent, magnetic nano material and preparation method | |
| US20130324738A1 (en) | Compositions and methods for making and using multifunctional polymerized liposomes | |
| Yang et al. | CuS-poly (N-isopropylacrylamide-co-acrylic acid) composite microspheres with patterned surface structures: Preparation and characterization | |
| US8153729B2 (en) | Highly efficient agents for dispersion of nanoparticles in matrix materials | |
| CN1966586A (en) | Reactive, monodispersed surface modified silver nanoparticle and its preparation method | |
| CN114671780B (en) | Covalent organic polymer based on column arene and application thereof | |
| CN1298791C (en) | Superparamagnetic Fe3O4 nanometer particle with synthetic polymer modification from one-step method | |
| CN110426377B (en) | Molecularly imprinted polymer material, preparation and application in aspect of detecting epinephrine |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |