CN101328270B - Synthetic method of non-linear structure polycaprolactone-block-polyethyleneglycol - Google Patents
Synthetic method of non-linear structure polycaprolactone-block-polyethyleneglycol Download PDFInfo
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- CN101328270B CN101328270B CN2008100412082A CN200810041208A CN101328270B CN 101328270 B CN101328270 B CN 101328270B CN 2008100412082 A CN2008100412082 A CN 2008100412082A CN 200810041208 A CN200810041208 A CN 200810041208A CN 101328270 B CN101328270 B CN 101328270B
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- polyoxyethylene glycol
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Abstract
The invention discloses a method for synthesizing polycaprolactone-block-polyethylene glycol with a non-linear structure in the chemical technical field, which is finished through a one-step click chemical reaction, namely the method is finished by polycaprolactone with an acetylene terminated sector structure and polyethylene glycol with an azido-terminated linear structure through a click chemical reaction, and the reaction takes cuprous bromide and pentamethyldiethylenetriamine as a co-catalyst and is performed in a N, N-dimethylformamide solution. The method provides a simple and effective approach for the preparation of degradable amphiphilic biomedical polymers with non-linear structures, and provides a theoretical evidence for obtaining a novel polymer drug carrier with controllable degradation rate and drug release rate.
Description
Technical field
The present invention relates to a kind of method of chemical technology field, specifically, what relate to is a kind of synthetic method of non-linear structure polycaprolactone-block-polyethyleneglycol.
Background technology
Biodegradable polymer polycaprolactone and multipolymer thereof are subjected to extensive studies in fields such as controlled drug delivery system, organizational project, biological nano technology in recent years.Yet, because the biological activity of strong-hydrophobicity, poor, the uppity material degradation of cell adhesion and medicine controlled releasing speed and shortage inducing cell, tissue or neomorph has hindered the further application of biodegradable polymer in clinical.Therefore, design has controlled degradation and drug release rate, bioactive functions and intelligent biodegradable polymer will provide valid approach for addressing this problem, and has important significance for theories and wide application prospect.Click chemistry (Click Chemistry) is development in recent years get up synthetic method efficiently, and it is synthetic in organic synthesis, medicine, the finishing of carbon nanotube and inorganic nanocrystal, be subjected to extensive concern especially in Polymer Synthesizing and materials chemistry thereof.But, utilize the method for click chemistry and ring-opening polymerization, do not see bibliographical information as yet about design, the control study on the synthesis of (line style-fan type, fan type-line style-fan type) amphiphilic biodegradable polymer of nonlinear organization.
Find through literature search prior art,
Deng " Combination of Ring-OpeningPolymerization and " Click " the Chemistry Towards Functionalization andGrafting of Poly (ε-caprolactone) " that on " Macromolecules " (macromole) in 2007 the 40th volume 796-803 page or leaf, deliver (" ring-opening polymerization " and " click chemistry " integrated process are used for the functionalization and the graft reaction of polycaprolactone), this article proposes ring-opening polymerization and the azido reaction by the alpha-chloro caprolactone, linear main chain azide polycaprolactone, pass through " click chemistry " again, can prepare the polycaprolactone-grafting-polyoxyethylene glycol of linear structure.Its weak point is: 1. the document does not provide the preparation method of the polycaprolactone-block-polyoxyethylene glycol of non-linearity topological framework (fan type-line style and fan type-line style-fan type).2. the document only is used for polycaprolactone-grafting-polyoxyethylene glycol synthetic of linear structure, can not carry out the functionalization again of material, and, the degraded and the medicine controlled releasing performance that are difficult to regulate multipolymer.3. when the document prepares the alpha-chloro caprolactone, need to use peroxy acid reagent, it is restricted in laboratory and industrial production.
Summary of the invention
The objective of the invention is to overcome the deficiencies in the prior art, a kind of synthetic method of non-linear structure polycaprolactone-block-polyethyleneglycol is provided, the present invention provides a kind of simple valid approach for the amphiphilic biomedical polymer of degradable of preparation non-linearity structure, provide theoretical foundation for obtaining degraded and the controlled novel high polymer pharmaceutical carrier of drug release rate, reasonable in design, easy to operate.
The objective of the invention is to be achieved through the following technical solutions, the present invention is finished by a step " click chemistry " reaction, promptly by the polycaprolactone (Dm-PCL) of Terminal Acetylenes base sector structure and the polyoxyethylene glycol (PEO-N of end azido-linear structure
3), finish by the click chemistry reaction, be co-catalyst with cuprous bromide (CuBr) and PMDETA (PMDETA), at N, carry out in dinethylformamide (DMF) solution.
Polycaprolactone-the block of described non-linearity structure-polyoxyethylene glycol comprises fan type-line style polycaprolactone-block-polyoxyethylene glycol and fan type-line style-fan type polycaprolactone-block-polyoxyethylene glycol.
Described click chemistry reaction is carried out under 35 ℃ of following mild conditionss.
When the polyoxyethylene glycol of described end azido-linear structure contained the single-end azido-, obtained was the polycaprolactone-block-polyoxyethylene glycol of fan type-linear structure.At this moment, the click chemistry reaction times is 24 hours.The polyoxyethylene glycol of single-end azido-linear structure is 1.1: 1 with the mole dosage ratio of the polycaprolactone of Terminal Acetylenes base sector structure.The mole dosage ratio of the polycaprolactone of the polyoxyethylene glycol of described end azido-linear structure, Terminal Acetylenes base sector structure, cuprous bromide, PMDETA is 1.1: 1: 1.1: 1.1.
When the polyoxyethylene glycol of described end azido-linear structure contained two end azido-s, obtained was the polycaprolactone-block-polyoxyethylene glycol of fan type-line style-sector structure.At this moment, the click chemistry reaction times is 36 hours, and the polyoxyethylene glycol of two end azido-linear structures is 1: 2.2 with the mole dosage ratio of the polycaprolactone of Terminal Acetylenes base sector structure.The mole dosage ratio of the polycaprolactone of the polyoxyethylene glycol of described end azido-linear structure, Terminal Acetylenes base sector structure, cuprous bromide, PMDETA is 1: 2.2: 2.2: 2.2.
The synthetic route of aforesaid method of the present invention is as follows:
The present invention has following advantage: the 1) synthetic method of the polycaprolactone-block-polyoxyethylene glycol of non-linearity (fan type-line style and fan type-line style-fan type) structure, to finish by a step " click chemistry " reaction, and step is simple; 2) topological framework of non-linearity (fan type-line style and fan type-line style-fan type) is by the polycaprolactone (Dm-PCL) of Terminal Acetylenes base sector structure and the polyoxyethylene glycol (PEO-N of end azido-linear structure
3) common control, easy to operate; 3) the amphiphilic biomedical polymer of degradable for preparation non-linearity structure provides a kind of simple valid approach, is applicable to suitability for industrialized production.
Embodiment
Below in conjunction with accompanying drawing embodiments of the invention are elaborated: present embodiment is being to implement under the prerequisite with the technical solution of the present invention, provided detailed embodiment and concrete operating process, but protection scope of the present invention is not limited to following embodiment.
Embodiment 1
The synthetic method of the polycaprolactone-block of fan type-linear structure-polyoxyethylene glycol
Polyoxyethylene glycol (the PEO-N of end azido-linear structure
3) with a step " click chemistry " reaction of the alkynyl polycaprolactone (Dm-PCL) of linear structure: the polyoxyethylene glycol PEO-N that takes by weighing end azido-linear structure
3(110.0mg, 0.219mmol) and the alkynyl polycaprolactone Dm-PCL (118.1mg of linear structure, 0.199mmol alkynyl) add 25mL eggplant shaped reaction bottle, be dissolved in fully among the 2mL DMF, under nitrogen, add cuprous bromide (CuBr, 3.1mg, 0.0219mmol) and PMDETA (PMDETA, 5 μ L, 0.0219mmol), 35 ℃ were reacted 24 hours.The sedimentation in a large amount of ether of reaction post polymerization thing solution, and with the purification of 10mL cold methanol (about 10 ℃) solvent extration, to remove excessive PEO-N fully
3Product in 40 ℃ of vacuum-dryings, is obtained the polycaprolactone-block-polyoxyethylene glycol (productive rate is 69.5%) of 158.5mg fan type-linear structure.
Embodiment 2
The synthetic method of the polycaprolactone-block of fan type-line style-sector structure-polyoxyethylene glycol
Polyoxyethylene glycol (the N of both-end azido-linear structure
3-PEO-N
3) with a step " click chemistry " reaction of the alkynyl polycaprolactone (Dm-PCL) of linear structure: the polyoxyethylene glycol N that takes by weighing both-end azido-linear structure
3-PEO-N
3(50.0mg, 0.0123mmol) and the alkynyl polycaprolactone Dm-PCL (131.6mg of linear structure, 0.0272mmol alkynyl) add 25mL eggplant shaped reaction bottle, be dissolved in fully among the 1.5mL DMF, under nitrogen, add cuprous bromide (CuBr, 3.9mg, 0.0272mmol) and PMDETA (PMDETA, 6 μ L, 0.0272mmol), 35 ℃ were reacted 36 hours.The sedimentation in a large amount of ether of reaction post polymerization thing solution.Adopt solvent extration, the mixing solutions (10mL, benzene: normal hexane=0.7: 1, volume ratio) of using benzene and normal hexane is to remove excessive Dm-PCL fully.Product in 40 ℃ of vacuum-dryings, is obtained the polycaprolactone-block-polyoxyethylene glycol (productive rate is 74.8%) of 135.8mg fan type-line style-sector structure.
Claims (6)
1. the synthetic method of a non-linear structure polycaprolactone-block-polyethyleneglycol, it is characterized in that, hitting chemical reaction by a beans-and bullets shooter finishes, promptly by the polycaprolactone of Terminal Acetylenes base sector structure and the polyoxyethylene glycol of end azido-linear structure, finish by the click chemistry reaction, with cuprous bromide and PMDETA is co-catalyst, at N, carries out in the dinethylformamide solution;
When the polyoxyethylene glycol of described end azido-linear structure contained the single-end azido-, the mole dosage ratio of the polyoxyethylene glycol of end azido-linear structure, the polycaprolactone of Terminal Acetylenes base sector structure, cuprous bromide, PMDETA was 1.1: 1: 1.1: 1.1;
When the polyoxyethylene glycol of described end azido-linear structure contained two end azido-s, the mole dosage ratio of the polyoxyethylene glycol of end azido-linear structure, the polycaprolactone of Terminal Acetylenes base sector structure, cuprous bromide, PMDETA was 1: 2.2: 2.2: 2.2.
2. according to the synthetic method of the described non-linear structure polycaprolactone-block-polyethyleneglycol of claim 1, it is characterized in that described click chemistry is reflected under 35 ℃ and carries out.
3. according to the synthetic method of the described non-linear structure polycaprolactone-block-polyethyleneglycol of claim 1, it is characterized in that when the polyoxyethylene glycol of described end azido-linear structure contained the single-end azido-, the click chemistry reaction times was 24 hours.
4. according to the synthetic method of the described non-linear structure polycaprolactone-block-polyethyleneglycol of claim 1, it is characterized in that when the polyoxyethylene glycol of described end azido-linear structure contained two end azido-s, the click chemistry reaction times was 36 hours.
5. according to the synthetic method of the described non-linear structure polycaprolactone-block-polyethyleneglycol of claim 1, it is characterized in that, when the polyoxyethylene glycol of described end azido-linear structure contained the single-end azido-, obtained was the polycaprolactone-block-polyoxyethylene glycol of fan type-linear structure.
6. according to the synthetic method of the described non-linear structure polycaprolactone-block-polyethyleneglycol of claim 1, it is characterized in that, when the polyoxyethylene glycol of described end azido-linear structure contained two end azido-s, obtained was the polycaprolactone-block-polyoxyethylene glycol of fan type-line style-sector structure.
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| CN101787135B (en) * | 2010-02-10 | 2013-01-02 | 东南大学 | Reticular polymer gel based on polyethylene glycol and preparation method thereof |
| CN102276817B (en) * | 2011-04-22 | 2012-07-11 | 武汉大学 | Arborescent graft polycaprolactone |
| CN102532502B (en) * | 2011-12-13 | 2013-09-04 | 暨南大学 | Biological functionalization degradable polyester and preparation method thereof |
| CN103656755A (en) * | 2013-12-12 | 2014-03-26 | 华南理工大学 | Preparation method of polymer-bioglass hybrid material for bone repair |
| CN105037737B (en) * | 2015-06-18 | 2017-09-26 | 西安理工大学 | A kind of free radical nanometer capture material and preparation method thereof |
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| CN1425706A (en) * | 2003-01-14 | 2003-06-25 | 天津大学 | Polyglycol block modified polyhexanolactone and its preparing method |
| CN1812764A (en) * | 2003-06-27 | 2006-08-02 | 株式会社太平洋 | Self-assembled polymeric nanoparticles containing physiologically active ingredients and external application containing the nanoparticles |
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