CN101817920B - Aliphatic poly(ester-carbonate) with triple bond side group and preparation method thereof - Google Patents

Abstract

The invention relates to aliphatic poly(ester-carbonate) with triple bond side groups and a preparation method thereof, belonging to the field of biomedical polymer materials. Using 2-methyl-2-propargyloxycarbonyl trimethylene carbonate as a monomer with a triple bond side group, copolymerized with a cyclic ester monomer such as lactide, glycolide or ε-caprolactone to obtain a Aliphatic poly(ester-carbonate) with triple bond side groups. This type of polymer combines the advantages of aliphatic polyester and carbonate, is biodegradable, and the degradation products are non-toxic. Utilizing the reactivity of the triple bond side group, drugs, active short peptides or other biologically active molecules can be linked to the polymer to improve the biocompatibility and biological activity of the polymer, so it may be used in drug controlled release, high Fields such as molecular prodrugs and tissue engineering have gained practical applications.

Description

Aliphatic poly(ester-carbonate) with triple bond side group and preparation method thereof

technical field

The invention relates to aliphatic poly(ester-carbonate) with triple bond side groups and a preparation method thereof, belonging to the field of biomedical polymer materials. the

Background technique

In recent decades, with the rapid development of polymer science and the rapid development of modern pharmacy, biology and engineering, the research on biomedical polymer materials has developed rapidly. Among them, biodegradable polymer materials have been widely used in the fields of surgical sutures, artificial skin, artificial blood vessels, bone fixation and repair, and controlled release of drugs because they do not require secondary surgery to remove after implantation. Biodegradable synthetic polymers mainly include aliphatic polyesters, polyamino acids, polyphosphates, polyanhydrides, polyorthoesters, polycarbonates, and the like. Aliphatic polyesters, such as polylactide (PLA), polyglycolide (PGA), polyε-caprolactone (PCL), have low immunogenicity and good biodegradability and biocompatibility, and have been It is widely used in the fields of biomedicine and medicine, such as fracture fixation, surgical sutures, tissue engineering scaffolds, drug sustained-release carriers, etc. the

Recently, the introduction of functional groups into the molecular chains of polymers has been particularly active, because polymers with functional groups are of great significance in practice. For example, linking various drugs to these functional groups to form polymer prodrugs can realize position-controlled release or sustained release of drugs; linking molecules with targeting functions such as antibodies and polysaccharides can make polymers and their micelles , Capsules have targeting function; connecting molecules with other biological activities can improve the biocompatibility and biological activity of materials; the introduction of functional groups can also change the degradation rate, physical and mechanical properties, hydrophilic and hydrophobic properties of polymers etc. Therefore, the research and application of aliphatic polyesters with functional groups has aroused great interest. the

Valuable functional side groups include carboxyl (COOH), amino ( _NH2 ), hydroxyl (OH), mercapto (SH) and the like. To synthesize polymers with these functional side groups, generally, monomers with functional groups are synthesized first, and then polymerized or copolymerized. However, due to the existence of functional groups, the polymerization process is often accompanied by unnecessary or even harmful side reactions, so the above functional groups must be protected first, and then deprotected after polymerization.

The functional monomers currently used for copolymerization with aliphatic cyclic esters include glycolide derivatives, ε-caprolactone derivatives, morpholine dione derivatives, N-carbonyl-α-amino acid anhydride (NCA) and dioxygen Hexacyclic diketone derivatives, etc. Some of them are very difficult to synthesize, the yield is very low, and the cost is high, and some of them have very low polymerization activity, low molecular weight of the copolymer, and limited functional monomers that can be introduced, so it is difficult to have practical applications. Relatively speaking, functional cyclic aliphatic carbonate monomer raw materials are easy to obtain, the synthesis is relatively easy, the polymerization efficiency is high, and the molecular weight of the obtained polymer is relatively high. Chinese patent CN1323795A discloses a synthesis method of 5-benzyloxy-trimethylene carbonate, and Chinese patent CN1335330A discloses poly(5-benzyloxy-trimethylene carbonate) and its preparation method and application. In a nutshell, it is to synthesize 5-benzyloxy-trimethylene carbonate, polymerize them, and then obtain a polymer with a side hydroxyl group by hydrogenation reduction. This series of patents is limited to the homopolymer of this monomer. It is a well-known fact that the biodegradability of homopolymerized aliphatic carbonate in the human body is not ideal, so its application in biomedicine will be limited. There are two steps of protection and deprotection in this patent. Therefore, the synthesis process is complicated and the cost is high. Chinese patent 200510107434.2 copolymerizes the above-mentioned cyclic carbonate monomer and aliphatic cyclic ester monomer to improve the biocompatibility and biodegradability of the polymer, but still adopts the method of protection and deprotection for synthesis. the

Contents of the invention

In order to solve the shortcomings and deficiencies of the above-mentioned polymers, the present invention provides aliphatic poly(ester-carbonate) with triple bond side groups and a preparation method thereof. the

The aliphatic poly(ester-carbonate) with a triple bond side group provided by the present invention adopts the copolymerization of the aliphatic cyclic carbonate monomer with a propargyl group and the cyclic ester monomer, and introduces the triple bond side group into the polymer, Specifically, it includes the following two kinds of aliphatic poly(ester-carbonate) with triple bonds:

1. an aliphatic poly(ester-carbonate) with a triple bond side group is characterized in that the polymer molecular chain contains a propargyloxycarbonyl side group; it is obtained by monomer A and aliphatic cyclic ester monomer The product of ring-opening copolymerization; the aliphatic cyclic ester monomer is a mixture of one, two or three of lactide, glycolide and ε-caprolactone, and the ratio between them is different. limit; the total molar ratio of the monomer A to the aliphatic cyclic ester monomer is 1:99～50:50;

Described monomer A is 2-methyl-2-propargyloxycarbonyl trimethylene carbonate, and its molecular structural formula is:

The molecular chain structure of the aliphatic poly(ester-carbonate) with a triple bond side group is expressed as follows by taking the polymerization product of monomer A and lactide as an example:

2. A polyethylene glycol-aliphatic poly(ester-carbonate) block copolymer with a triple bond side group is characterized in that the polymer molecular chain contains a propargyloxycarbonyl side group; Polyethylene glycol is an initiator, and the product of ring-opening copolymerization of the above monomer A and aliphatic cyclic ester monomer; the number average molecular weight of the polyethylene glycol is 400 to 5000; the aliphatic ring The ester monomer is a mixture of one, two or three of lactide, glycolide and ε-caprolactone, and the ratio between them is not limited; the monomer A and the aliphatic cyclic ester monomer The total molar ratio of the body is 1:99～50:50. the

A molecular chain structure of a poly(ethylene glycol)-aliphatic poly(ester-carbonate) block copolymer with a triple bond side group is expressed as follows with the polymerization product of monomer A and lactide as an example:

The present invention prepares the above two kinds of polymers by ring-opening copolymerization of related monomers. The reaction steps and operating conditions are: under anhydrous and oxygen-free conditions, monomer A and aliphatic cyclic ester monomers are added according to the ratio In the reactor, add the catalyst ethylzinc of 1/100-1/1000 of the total mass of the monomer, and carry out polymerization under the condition of heating and stirring. The polymerization time is 1-10 hours, and the temperature is 40-100°C. Filtration, washing, and vacuum drying give the corresponding aliphatic poly(ester-carbonate) with triple bond side groups. the

Wherein, the aliphatic cyclic ester monomer is a mixture of one, two or three of lactide, glycolide and ε-caprolactone, and the ratio between them is not limited;

The above-mentioned 2nd kind of polymer is the aliphatic poly(ester-carbonate) with polyethylene glycol block, and the introduction of polyethylene glycol block is by splitting the cyclic carbonate monomer and the cyclic ester monomer. The ring copolymerization is realized by using hydroxyl-terminated polyethylene glycol as a polymerization initiator. The number-average molecular weight of the hydroxyl-terminated polyethylene glycol used is 400 to 5000, so that it can be excreted through the kidneys when used in the body. the

The copolymers of cyclic carbonate monomers and cyclic ester monomers prepared by the present invention all have propargyloxycarbonyl side groups, so the main purposes of these polymers are to utilize the reactivity of these triple bonds to interact with drugs Molecules, polypeptide or protein molecules, monosaccharide or polysaccharide molecules or modified drug molecules, polypeptide or protein molecules, monosaccharide or polysaccharide molecules react to form polymer bonds of these substances. These bonds are mainly used for the directional delivery and controlled release of drugs, especially polymer prodrugs, and are also used for cell recognition and adhesion, immune analysis, antigen/antibody separation and purification, and tissue engineering scaffold materials. the

A typical reaction of the above triple bond is the 2+3 addition ring formation reaction with azide:

Wherein N ₃ -R represents an azide compound, which is an azide product of a drug molecule, polypeptide or protein molecule, monosaccharide or polysaccharide molecule or a modified drug molecule, polypeptide or protein molecule, monosaccharide or polysaccharide molecule. The ring-forming reaction of azide and triple bond can be carried out in water system medium at a temperature of about 4°C, or in a polar organic solvent, using cuprous sulfate or cuprous chloride as a catalyst. The reaction conditions are mild, the efficiency is high, the by-products are few, and the separation and purification are easy.

Beneficial effects: the introduction of side triple bonds on the polymer synthesized by the invention does not require protection and deprotection, and does not cause degradation of the main chain of the polymer. This is a rare advantage for the chemical modification of aliphatic polyesters. the

The side triple bond on the synthesized polymer of the present invention is on the propargyl group, and is connected to the main chain of the polymer through an ester bridge, so it has higher reactivity, and the subsequent connection or conversion into the group, and the polymerization There is a relatively long spacer between the main chains of the substance, so it has high reactivity. the

Description of drawings

Fig. 1: NMR spectrum of 2-methyl-2-propargyloxycarbonyl trimethylene carbonate and lactic acid copolymer and its attribution (polymer of embodiment 3). the

Detailed ways

Embodiment 1: the synthesis of 2-methyl-2-propargyloxycarbonyl-1,3-propanediol

9.00 g of 2,2-dimethylolpropionic acid and 4.30 g of potassium hydroxide were dissolved in 50 ml of N,N-dimethylformamide. Stir vigorously for 1 h at 100°C to form potassium salt of 2,2-dimethylolpropionate. Then propargyl bromide was added to the above solution, and stirred vigorously at 100°C for 15h. The solvent was distilled off, the residue was dissolved in 200 ml of ether, washed three times with 50 ml of distilled water, and finally recrystallized with toluene to obtain 8 g of 2-methyl-2-propargyloxycarbonyl-1,3-propanediol with a yield of 70%. Its structure was confirmed by proton NMR spectroscopy. the

Embodiment 2: the synthesis of 2-methyl-2-propargyloxycarbonyl trimethylene carbonate (monomer A)

10g of 2-methyl-2-propargyloxycarbonyl-1,3-propanediol and 28.5g of ethyl chloroformate were dissolved in 600ml of tetrahydrofuran and cooled in an ice-water bath. Then slowly add 28g of triethylamine into the above solution, and keep the system at about 0°C during the addition. Then react at room temperature for 10h. The precipitate was filtered off, the filtrate was concentrated under reduced pressure, and the residue was recrystallized from tetrahydrofuran and diethyl ether to obtain 9.4 g of white crystals with a yield of 82%. Its structure was confirmed by proton NMR spectroscopy. the

Embodiment 3: the synthesis of the copolymer of monomer A and lactic acid

Under anhydrous and oxygen-free conditions, add 0.2 mole of monomer A and 0.8 mole of lactide monomer into the polymerization reaction bottle, and then add ethyl zinc of 1/200 of the total mass of the monomer as an initiator, at 60 The reaction was stirred at ℃ for 2 hours, the product was dissolved in chloroform, precipitated in methanol, filtered, washed, dried in vacuum at 35 ℃ for 24 hours, and the yield was calculated by weighing to obtain a copolymer of monomer A and lactic acid. The weight yield is 89%, the weight average molecular weight is 1.56×10 ⁴ , and the molecular weight distribution index is 1.15.

Example 4: Copolymerization of monomer A and lactic acid in the presence of polyethylene glycol

Under anhydrous and oxygen-free conditions, methoxypolyethylene glycol (PEG) with a molecular weight of 5000 was used as a macroinitiator, 0.1 mole of monomer A and 0.9 mole of lactide monomer were added, and the total mass of monomer was added 1/200 of ethyl zinc was used as an initiator, stirred and reacted at 60°C for 2h, the product was dissolved in chloroform, precipitated with methanol, filtered, washed, dried in vacuo at 35°C for 24h, weighed to calculate the yield, and obtained Alcohol initiated copolymer of monomer A with lactic acid. The weight yield is 85%, the weight average molecular weight is 1.6×10 ⁴ , and the molecular weight distribution index is 1.17.

Embodiment 5: the synthesis of the copolymer of monomer A and ε-caprolactone

Under anhydrous and oxygen-free conditions, add 0.1 mol monomer A and 0.5 mol ε-caprolactone monomer into the polymerization reaction bottle, and then add 1/800 of the total monomer amount of ethyl zinc as an initiator, React at 60°C for 2 hours, dissolve the product in chloroform, precipitate with methanol, filter, wash, and vacuum-dry at 35°C to constant weight to obtain a copolymer of carbonate and ε-caprolactone. The weight yield is 81%, the weight average molecular weight is 0.81×10 ⁴ , and the molecular weight distribution index is 1.20.

Embodiment 6: the synthesis of the copolymer of monomer A and lactide, glycolide

Under anhydrous and oxygen-free conditions, add 0.1 mole of monomer A, 0.7 mole of lactide, and 0.3 mole of glycolide monomer into the polymerization reaction bottle, and then add 1/1000 of the total amount of monomer Ethyl zinc was used as an initiator, reacted at 140°C for 2 hours, the product was dissolved in chloroform, precipitated with methanol, filtered, washed, and vacuum-dried at 35°C to constant weight to obtain a mixture of carbonate, lactide, and glycolide copolymer. The weight yield is 88%, the weight average molecular weight is 0.89×10 ⁴ , and the molecular weight distribution index is 1.20.

Embodiment 7: the synthesis of the copolymer of monomer A and lactide, glycolide, ε-caprolactone

Under anhydrous and oxygen-free conditions, add 0.1 mole of monomer A, 0.7 mole of lactide, 0.2 mole of glycolide, and 0.1 mole of ε-caprolactone monomer into the polymerization reaction bottle, and then add the monomer total 1/1000 of the amount of ethyl zinc was used as an initiator, reacted at 140°C for 2 hours, and the product was dissolved in chloroform, precipitated with methanol, filtered, washed, and dried in vacuum at 35°C to constant weight to obtain monomers A and C Copolymer of lactide, glycolide, ε-caprolactone. The weight yield is 82%, the weight average molecular weight is 1.5×10 ⁴ , and the molecular weight distribution index is 1.3.

Claims (4)

1. an aliphatic poly(ester-carbonate) with a triple bond side group is characterized in that the polymer molecular chain contains a propargyloxycarbonyl side group; it is obtained by monomer A and aliphatic cyclic ester monomer The product of ring-opening copolymerization; the aliphatic cyclic ester monomer is a mixture of one, two or three of lactide, glycolide and ε-caprolactone, and the ratio between them is different. limit; the total molar ratio of the monomer A to the aliphatic cyclic ester monomer is 1:99～50:50; Described monomer A is 2-methyl-2-propargyloxycarbonyl trimethylene carbonate, and its molecular structural formula is: 2. A polyethylene glycol-aliphatic poly(ester-carbonate) block copolymer with a triple bond side group is characterized in that the polymer molecular chain contains a propargyloxycarbonyl side group; Hydroxypolyethylene glycol is an initiator, and is a product of ring-opening copolymerization of monomer A and aliphatic cyclic ester monomer; the number average molecular weight of the polyethylene glycol is 400 to 5000; the aliphatic cyclic ester The monomer is a mixture of one, two or three of lactide, glycolide and ε-caprolactone, and the ratio between them is not limited; the monomer A and the aliphatic cyclic ester monomer The total molar ratio is 1:99～50:50; Described monomer A is 2-methyl-2-propargyloxycarbonyl trimethylene carbonate monomer, and its molecular structural formula is:

3. the preparation method of the aliphatic poly(ester-carbonate) of band triple bond side group as claimed in claim 1, its steps and condition are: under anhydrous and oxygen-free condition, monomer A and The aliphatic cyclic ester monomer is added to the reactor, the catalyst ethyl zinc of 1/100~1/1000 of the total mass of the monomer is added, and the polymerization is carried out under the condition of heating and stirring, the polymerization time is 1~10h, and the temperature is 40~ At 100°C, the product was precipitated, filtered, washed, and vacuum-dried to obtain an aliphatic poly(ester-carbonate) with triple bond side groups. 4. the preparation method of the polyethylene glycol-aliphatic poly(ester-carbonate) block copolymer of band triple bond side group as claimed in claim 2, its steps and condition are: in anhydrous and oxygen-free condition Next, add polyethylene glycol, monomer A and aliphatic cyclic ester monomer into the reactor according to the ratio, add the catalyst ethylzinc of 1/100 to 1/1000 of the total mass of the monomer, under the condition of heating and stirring Carry out polymerization, the polymerization time is 1 ~ 10h, the temperature is 40 ~ 100 ° C, the product is precipitated, filtered, washed, and vacuum dried to obtain polyethylene glycol-aliphatic poly(ester-carbonate) embedded poly(ester-carbonate) with triple bond side group segment copolymers.

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