CN113388097A - Synthesis method of high-stability polyglycolide - Google Patents
Synthesis method of high-stability polyglycolide Download PDFInfo
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- 229920000954 Polyglycolide Polymers 0.000 title claims abstract description 129
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Polymers OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 title claims abstract description 123
- 238000001308 synthesis method Methods 0.000 title claims description 15
- 238000006243 chemical reaction Methods 0.000 claims abstract description 96
- 238000000034 method Methods 0.000 claims abstract description 41
- 239000003054 catalyst Substances 0.000 claims abstract description 39
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 36
- 239000004970 Chain extender Substances 0.000 claims abstract description 32
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 26
- RKDVKSZUMVYZHH-UHFFFAOYSA-N 1,4-dioxane-2,5-dione Chemical compound O=C1COC(=O)CO1 RKDVKSZUMVYZHH-UHFFFAOYSA-N 0.000 claims abstract description 21
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 16
- 239000000178 monomer Substances 0.000 claims abstract description 16
- 125000003504 2-oxazolinyl group Chemical group O1C(=NCC1)* 0.000 claims abstract description 9
- JVTAAEKCZFNVCJ-REOHCLBHSA-N L-lactic acid Chemical group C[C@H](O)C(O)=O JVTAAEKCZFNVCJ-REOHCLBHSA-N 0.000 claims description 34
- 239000011261 inert gas Substances 0.000 claims description 31
- KSBAEPSJVUENNK-UHFFFAOYSA-L tin(ii) 2-ethylhexanoate Chemical compound [Sn+2].CCCCC(CC)C([O-])=O.CCCCC(CC)C([O-])=O KSBAEPSJVUENNK-UHFFFAOYSA-L 0.000 claims description 28
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 26
- 229930182843 D-Lactic acid Natural products 0.000 claims description 15
- JVTAAEKCZFNVCJ-UWTATZPHSA-N D-lactic acid Chemical compound C[C@@H](O)C(O)=O JVTAAEKCZFNVCJ-UWTATZPHSA-N 0.000 claims description 15
- 229940022769 d- lactic acid Drugs 0.000 claims description 15
- KKKKCPPTESQGQH-UHFFFAOYSA-N 2-(4,5-dihydro-1,3-oxazol-2-yl)-4,5-dihydro-1,3-oxazole Chemical group O1CCN=C1C1=NCCO1 KKKKCPPTESQGQH-UHFFFAOYSA-N 0.000 claims description 14
- 239000007795 chemical reaction product Substances 0.000 claims description 12
- 229960000448 lactic acid Drugs 0.000 claims description 12
- 238000002156 mixing Methods 0.000 claims description 12
- 239000003153 chemical reaction reagent Substances 0.000 claims description 8
- HMOZDINWBHMBSQ-UHFFFAOYSA-N 2-[3-(4,5-dihydro-1,3-oxazol-2-yl)phenyl]-4,5-dihydro-1,3-oxazole Chemical compound O1CCN=C1C1=CC=CC(C=2OCCN=2)=C1 HMOZDINWBHMBSQ-UHFFFAOYSA-N 0.000 claims description 7
- 239000002981 blocking agent Substances 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 6
- UKLDJPRMSDWDSL-UHFFFAOYSA-L [dibutyl(dodecanoyloxy)stannyl] dodecanoate Chemical group CCCCCCCCCCCC(=O)O[Sn](CCCC)(CCCC)OC(=O)CCCCCCCCCCC UKLDJPRMSDWDSL-UHFFFAOYSA-L 0.000 claims description 4
- 239000012975 dibutyltin dilaurate Substances 0.000 claims description 4
- CANRESZKMUPMAE-UHFFFAOYSA-L Zinc lactate Chemical compound [Zn+2].CC(O)C([O-])=O.CC(O)C([O-])=O CANRESZKMUPMAE-UHFFFAOYSA-L 0.000 claims description 3
- ISKQADXMHQSTHK-UHFFFAOYSA-N [4-(aminomethyl)phenyl]methanamine Chemical compound NCC1=CC=C(CN)C=C1 ISKQADXMHQSTHK-UHFFFAOYSA-N 0.000 claims description 3
- 229940050168 zinc lactate Drugs 0.000 claims description 3
- 235000000193 zinc lactate Nutrition 0.000 claims description 3
- 239000011576 zinc lactate Substances 0.000 claims description 3
- 230000007062 hydrolysis Effects 0.000 abstract description 4
- 238000006460 hydrolysis reaction Methods 0.000 abstract description 4
- 230000009286 beneficial effect Effects 0.000 abstract description 2
- 239000000126 substance Substances 0.000 abstract description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 56
- 229910052757 nitrogen Inorganic materials 0.000 description 28
- 230000000052 comparative effect Effects 0.000 description 18
- 238000011049 filling Methods 0.000 description 17
- 239000000047 product Substances 0.000 description 15
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 14
- 238000010438 heat treatment Methods 0.000 description 13
- 229920000642 polymer Polymers 0.000 description 12
- 239000000463 material Substances 0.000 description 8
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 7
- 239000007853 buffer solution Substances 0.000 description 7
- 238000001816 cooling Methods 0.000 description 6
- 238000002844 melting Methods 0.000 description 6
- 230000008018 melting Effects 0.000 description 6
- 238000005303 weighing Methods 0.000 description 6
- 230000000903 blocking effect Effects 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 238000006068 polycondensation reaction Methods 0.000 description 5
- 238000006116 polymerization reaction Methods 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- 230000015556 catabolic process Effects 0.000 description 4
- 238000006731 degradation reaction Methods 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 230000003197 catalytic effect Effects 0.000 description 3
- 238000009826 distribution Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 229920000747 poly(lactic acid) Polymers 0.000 description 3
- 238000007151 ring opening polymerisation reaction Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000007790 solid phase Substances 0.000 description 3
- 239000000375 suspending agent Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 229910052786 argon Inorganic materials 0.000 description 2
- 239000012620 biological material Substances 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 229920001577 copolymer Polymers 0.000 description 2
- 238000006073 displacement reaction Methods 0.000 description 2
- KPKCMLNDHOXMLT-UHFFFAOYSA-N lithium amino(phenyl)azanide Chemical group NN(C1=CC=CC=C1)[Li] KPKCMLNDHOXMLT-UHFFFAOYSA-N 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 150000001335 aliphatic alkanes Chemical group 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 238000010539 anionic addition polymerization reaction Methods 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 229920001400 block copolymer Polymers 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 239000007822 coupling agent Substances 0.000 description 1
- LQZZUXJYWNFBMV-UHFFFAOYSA-N dodecan-1-ol Chemical compound CCCCCCCCCCCCO LQZZUXJYWNFBMV-UHFFFAOYSA-N 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 230000009477 glass transition Effects 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 229920002643 polyglutamic acid Polymers 0.000 description 1
- 239000004633 polyglycolic acid Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000011265 semifinished product Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000001360 synchronised effect Effects 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
- C08G63/68—Polyesters containing atoms other than carbon, hydrogen and oxygen
- C08G63/685—Polyesters containing atoms other than carbon, hydrogen and oxygen containing nitrogen
- C08G63/6852—Polyesters containing atoms other than carbon, hydrogen and oxygen containing nitrogen derived from hydroxy carboxylic acids
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
- C08G63/78—Preparation processes
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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicinal Chemistry (AREA)
- Polymers & Plastics (AREA)
- Organic Chemistry (AREA)
- Polyesters Or Polycarbonates (AREA)
Abstract
The invention provides a method for synthesizing high-stability polyglycolide, which comprises the following steps: end capping glycolide monomers by end capping reaction, and chain extending by chain extending reaction to obtain high-stability polyglycolide; the end capping reaction and the chain extension reaction both contain catalysts. The invention has the beneficial effects that: the method for synthesizing the high-stability polyglycolide further modifies the polyglycolide on the basis of end capping through a two-step method, synthesizes the modified polyglycolide in a chain extension mode, combines the end capping reaction and the chain extension reaction, converts the single linear structure polyglycolide prepared by the one-step method in the prior art into more stable polyglycolide with a net structure, and uses the carboxyl end capping agent and the oxazoline chain extender in a matching way, so that the prepared polyglycolide with the net structure (body structure) has more excellent chemical stability, thermal stability and hydrolysis resistance, and the application range of the polyglycolide in the industry is improved.
Description
Technical Field
The invention relates to the technical field of preparation of biological materials, in particular to the technical field of synthesis of high-molecular biological materials, and particularly relates to a method for synthesizing high-stability polyglycolide.
Background
Polyglycolide (PGA), also known as polyglycolic acid, is a highly crystalline, biodegradable aliphatic polymer with a high degradation rate, and is mainly used in the fields of surgical sutures and the like. The prior preparation method of polyglycolide is mainly carried out by methods such as polycondensation reaction, ring-opening polymerization of glycolide and the like.
At present, the polyglycolide products on the market cannot be applied in large scale in industry due to the molecular structure of the polyglycolide. The main reason is that polyglycolide prepared by the two methods is a linear structure by adopting a synthesis process of solid-phase tackifying or a preparation process of end-capping modification, the molecular weight is large, but the thermal stability is extremely poor, the thermal degradation phenomenon is very serious in the material processing process, the degradation is generally over 50 percent, the product performance is seriously influenced, and meanwhile, the finished product is easy to degrade. After the end capping modification, although the thermal degradation phenomenon is relieved, the requirements of most industrial products cannot be met.
Solid phase tackifying, also called solid phase polycondensation, is a polycondensation reaction carried out in a solid state, solid polymer particles with a certain molecular weight are heated to a temperature above the glass transition temperature (usually between about 10 ℃ and 40 ℃ below the melting point) of the solid polymer particles, and small molecular products are taken away by vacuum or inert gas protection (generally using high-purity nitrogen), so that the polycondensation reaction is continued, the viscosity is further increased,
patent publication No. CN104497280A describes "a method for preparing polyglycolide", which comprises mixing a catalyst, an organic solvent and glycolide, carrying out ring-opening polymerization reaction under the conditions of no water and no oxygen and under the protection of inert gas, and treating the reactant after the reaction to obtain polyglycolide; the catalyst is an amino anilino lithium compound; the organic solvent is one or two of hexane, toluene and cyclohexane; the main technical purpose is to provide an amino anilino lithium compound as a catalyst for ring-opening polymerization reaction, and to improve the catalytic activity.
Patent publication No. CN105885021A describes "a method for synthesizing polyglycolide" by placing glycolide, stannous octoate (catalyst) and lauryl alcohol in a reaction kettle for reaction, but does not describe the principle, and the ultimate purpose is to realize mass production of polyglycolide and to improve the conversion rate and relative molecular mass.
Patent publication No. CN101343354A describes "preparation methods of polylactide, polyglycolide and their copolymers", which comprises a method for preparing polyglycolide by mixing glycolide with a suspending agent and stannous octoate as a catalyst, and also defines that the suspending agent is alkane with a boiling point of more than 90 ℃, and the polymerization temperature is higher than the melting point of the monomer and lower than the boiling point of the suspending agent; the main technical purpose is to provide a preparation method of polyglycolide which has low production cost, high product purity and high molecular weight and can be produced in a large scale.
However, in the prior art, a single-step reaction is adopted, so that the polyglycolide cannot be completely modified, and finally obtained polyglycolide products are polymers with linear structures.
Chain extension refers to the process of growing the polymer backbone, chain extension being an important method of synthesizing block copolymers. There are mainly four methods, including: 1. condensation between living end polymers; 2. condensing with low molecular coupling agent; 3. utilizing a chain exchange reaction in a polycondensation reaction; 4. living anionic chain initiated anionic polymerization.
Disclosure of Invention
The present invention aims at overcoming the demerits of available technology, and provides the synthesis process of high stability polyglycolide with two-step process, i.e., carboxyl end capping and oxazoline chain extender.
In order to achieve the purpose, the technical scheme provided by the invention is as follows: the synthesis method of the high-stability polyglycolide comprises the following steps: end capping glycolide monomers by end capping reaction, and chain extending by chain extending reaction to obtain high-stability polyglycolide; the end capping reaction and the chain extension reaction both contain catalysts.
Further, in the method for synthesizing the high-stability polyglycolide, the end-capping reaction is to cap the glycolide monomer with an end-capping agent, the end-capping agent is a carboxyl end-capping agent, and the end-capping reaction product is low-molecular-weight double-end carboxyl polyglycolide with a molecular weight of less than 120000.
Further, in the method for synthesizing the high-stability polyglycolide, the chain extension reaction is to extend the chain of the end-capped reaction product by using a chain extender, the chain extender is an oxazoline chain extender, and the chain extension reaction product is the high-stability polyglycolide with the molecular weight of 120000-250000 and the high molecular structure of three-dimensional structure.
In the first step, a glycolide monomer is blocked by a carboxyl blocking agent to obtain low-molecular-weight double-terminal carboxyl polyglycolide, the polyglycolide is still in a linear structure at the moment, but the blocked double-terminal carboxyl polyglycolide temporarily stops the polymerization reaction due to the addition of the blocking agent, and simultaneously the tail end of the semi-finished product polyglycolide has a potential reactive group; and secondly, carrying out chain extension polymerization reaction on the semi-finished polyglycolide under the action of an oxazoline chain extender through a reactive group at the tail end and a reactive group of the polyglycolide, wherein the chain extension polymerization reaction is carried out at the moment, and finally, the brand-new high-molecular-weight and high-stability polyglycolide with a three-dimensional (reticular) structure is obtained because the two reactive groups react simultaneously.
Further, in the method for synthesizing the high-stability polyglycolide, the catalyst is dibutyltin dilaurate, stannous octoate, dibutyltin diacetate and/or zinc lactate, and stannous octoate is preferred.
The catalyst selected in the technology is a metal catalyst which contains metal zinc or tin, wherein stannous octoate has better catalytic activity, dibutyltin dilaurate and stannous octoate can be used jointly, and the catalytic activity of the catalyst is better than that of the stannous octoate which is used alone.
Further, in the above method for synthesizing polyglycolide with high stability, the end-capping reagent is L-lactic acid, D-lactic acid or DL-lactic acid mixed with both in the end-capping reaction; in the DL-lactic acid, the mixing ratio of the L-lactic acid and the D-lactic acid is (1:9) - (9:1) according to the weight ratio; preferably (4:6) - (6: 4).
D-lactic acid is D-lactic acid, L-lactic acid is L-lactic acid, DL-lactic acid is racemic lactic acid, D-lactic acid and L-lactic acid are optical isomers, and DL-lactic acid is a mixture of the D-lactic acid and the L-lactic acid. In the end capping reaction, any one of the three lactic acids can produce the end capping effect, but the L-lactic acid has the fastest end capping speed and the best efficiency, so the L-lactic acid is selected as the optimal choice of the end capping agent in the technology.
Further, in the synthesis method of the high-stability polyglycolide, in the end-capping reaction, the usage amounts of the glycolide monomer, the catalyst and the end-capping agent are 1: (1/1000-1/20000): (1/10-1/20000); preferably 1: (1/2000-1/15000): (1/50-1/10000); the reaction temperature of the end-capping reaction is 140 ℃ and 170 ℃, and preferably 160 ℃; the reaction time is 180-300min, preferably 240 min.
Further, in the above method for synthesizing high-stability polyglycolide, in the chain extension reaction, the chain extender is 2,2 '-bis (2-oxazoline) or 2,2' - (1, 3-phenylene) -bisoxazoline; 2,2' -bis (2-oxazoline) is preferred.
The chain extender is selected from oxazoline chain extenders, wherein two of the chain extenders with better effects are 2,2 '-bis (2-oxazoline) and 2,2' - (1, 3-phenylene) -bisoxazoline, and after practical verification, the 2,2 '-bis (2-oxazoline) has better chain extension effect and moderate chain extension speed and can be well matched with end capping reaction, so that the 2,2' -bis (2-oxazoline) is the optimal choice for the chain extender in the technology.
Further, in the method for synthesizing polyglycolide with high stability, the end-capping reaction product, the catalyst and the chain extender are used in an amount of 1: (1/100-1/10000): (1/10-1/20000); preferably 1 (1/300-1/1000) to 1/50-1/10000); the reaction temperature of the chain extension reaction is 200-230 ℃, and preferably 210 ℃; the reaction time is 60-90min, preferably 75 min.
Further, in the above method for synthesizing polyglycolide with high stability, the reaction atmosphere of the end-capping reaction and the chain extension reaction is: reacting for 3 times in an inert gas atmosphere to remove air by replacement; the inert gas is preferably nitrogen or argon; preferably nitrogen.
The second invention of the invention provides a high-stability polyglycolide, which is synthesized by the above synthesis method; the intrinsic viscosity of the high-stability polyglycolide is 0.1 to 2.5dl/g, and preferably 1.0 to 1.8 dl/g.
The invention has the beneficial effects that: the method for synthesizing the high-stability polyglycolide further modifies the polyglycolide on the basis of end capping through a two-step method, synthesizes the modified polyglycolide in a chain extension manner, combines the end capping reaction and the chain extension reaction, and converts the single linear structure polyglycolide prepared by the one-step method in the prior art into more stable network structure polyglycolide, thereby effectively improving the thermal stability and the hydrolysis resistance of the polyglycolide.
In the two-step method, the first step is to prepare low molecular weight double-end carboxyl polyglycolide, the second step is to react terminal carboxyl with oxazoline chain extenders to generate carboxylic acid amide ester, amide ester bonds are added in the molecular structure, the molecular structure of the polyglycolide is changed while the molecular weight of the polyglycolide is increased, and the carboxyl end capping reagent and the oxazoline chain extenders are matched for use, so that the synchronous proceeding of the end capping reaction and the chain extending reaction can be ensured, the matching degree of the two reactions is fully increased, the prepared polyglycolide with a reticular structure (body structure) has more excellent chemical stability, thermal stability and hydrolytic resistance, and the application range of the polyglycolide in the industry is improved.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1:
the synthesis method of the high-stability polyglycolide comprises the following steps: end capping glycolide monomers by end capping reaction, and chain extending by chain extending reaction to obtain high-stability polyglycolide; both the end-capping reaction and the chain extension reaction contain a catalyst.
In the synthesis method, the blocking reaction is to block glycolide monomers by using a blocking agent, wherein the blocking agent is a carboxyl blocking agent, and the blocking reaction product is low-molecular-weight double-end carboxyl polyglycolide with the molecular weight of less than 120000; the end capping agent is L-lactic acid, D-lactic acid or DL-lactic acid mixed with the L-lactic acid and the D-lactic acid in the carboxyl end capping agent; in the DL-lactic acid, the mixing ratio of the L-lactic acid and the D-lactic acid is (1:9) - (9:1) according to the weight ratio, and can be selected from 2:8,3:7,4:6,5:5,6:4,7:3,8: 2; the weight ratio in the end capping reaction is as follows: 1 part of glycolide monomer, 1/1000-1/20000 parts of catalyst, optionally 1/2000 parts, 1/3000 parts, 1/5000 parts, 1/7000 parts, 1/9000 parts, 1/11000 parts, 1/13000 parts, 1/15000 parts, 1/17000 parts, 1/19000 parts of end capping agent 1/10-1/20000 parts, optionally 1/10 parts, 1/50 parts, 1/100 parts, 1/1000 parts, 1/3000 parts, 1/5000 parts, 1/7000 parts, 1/9000 parts, 1/11000 parts, 1/13000 parts, 1/15000 parts, 1/17000 parts and 1/19000 parts; the reaction temperature of the end-capping reaction is 140-170 ℃, and can be selected from 145 ℃,150 ℃,155 ℃,160 ℃ and 165 ℃; the reaction time is 180-300min, and can be selected from 200min,220min,240min,260min and 280 min.
In the synthesis method, in the chain extension reaction, a chain extender is used for chain extension of the end-capped reaction product, the chain extender is an oxazoline chain extender, preferably 2,2' -bis (2-oxazoline) or 2,2' - (1, 3-phenylene) -bisoxazoline, most preferably 2,2' -bis (2-oxazoline), and the chain extension reaction product is high-stability polyglycolide with the molecular weight of 120000-250000 and the high molecular structure of the three-dimensional structure; the molecular weight may be chosen to be 140000,160000,180000,200000,220000,240000.
In the synthesis method, the catalyst is dibutyltin dilaurate, stannous octoate, dibutyltin diacetate and/or zinc lactate, and stannous octoate is preferred.
In the synthesis method, the weight ratio of the chain extension reaction is that 1 part of end capping reaction product, 1/100-1/10000 parts of catalyst, optionally 1/500 parts, 1/1000 parts, 1/3000 parts, 1/5000 parts, 1/7000 parts, 1/9000 parts, 1/10-1/20000 parts of chain extender, optionally 1/10 parts, 1/50 parts, 1/100 parts, 1/1000 parts, 1/3000 parts, 1/5000 parts, 1/7000 parts, 1/9000 parts, 1/11000 parts, 1/13000 parts, 1/15000 parts, 1/17000 parts and 1/19000 parts; the reaction temperature of the chain extension reaction is 200-; the reaction time is 60-90min, and can be selected from 65min,70min,75min,80min, and 85 min.
Further, in the above method for synthesizing polyglycolide with high stability, the reaction atmosphere of the end-capping reaction and the chain extension reaction is: reacting for 3 times in an inert gas atmosphere to remove air by replacement; the inert gas is preferably nitrogen or argon; preferably nitrogen.
Example 2:
a method for synthesizing high-stability polyglycolide comprises the following steps:
s1, mixing glycolide monomers, a catalyst and a carboxyl end-capping reagent, reacting for 3 times in an inert gas atmosphere to remove air by displacement, and heating to continue the reaction to obtain low-molecular-weight double-end carboxyl polyglycolide;
wherein the catalyst is stannous octoate, the carboxyl end-capping agent is L-lactic acid, and the inert gas is nitrogen;
the specific operation is as follows:
weighing 1 part of glycolide monomer, 1/5000 parts of stannous octoate and 1/10 parts of L-lactic acid, adding into a reaction kettle, vacuumizing, filling inert gas (nitrogen), reacting for 3 times to replace air, heating to 160 ℃, reacting for 300min, cooling, and taking out the material to obtain low-molecular-weight double-end carboxyl polyglycolide, wherein the intrinsic viscosity is as follows: 0.1 to 0.2 dl/g;
s2, mixing low-molecular-weight double-end carboxyl polyglycolide, a catalyst and a chain extender, reacting in an inert gas atmosphere, and quickly heating for reaction to obtain the high-stability polyglycolide;
wherein the catalyst is stannous octoate, the chain extender is 2,2' - (1, 3-phenylene) -bisoxazoline, and the inert gas is nitrogen;
the specific operation is as follows:
weighing 1 part of low-molecular-weight double-end carboxyl polyglycolide, 1/10 parts of 2,2' - (1, 3-phenylene) -bisoxazoline and 1/5000 parts of stannous octoate, adding into a reaction kettle, vacuumizing, filling inert gas (nitrogen), filling nitrogen for 3 times to replace and remove air, quickly heating to 200 ℃, reacting for 60min, cooling, and taking out the material to obtain chain extension polyglycolide (modified), wherein the intrinsic viscosity of the chain extension polyglycolide is as follows: 0.1-2.5dl/g, preferably 1.0-1.8dl/g, molecular weight 120000-250000; the polymer structure is a body structure.
The reaction formula of the synthetic route is shown as follows:
1. end capping reaction:
in the blocking reaction, the catalyst is stannous octoate Sn (Oct)2The end-capping reagent is L-lactic acid, n is 1, m is 1, and the low molecular weight double-end carboxyl polyglycolide is obtained after the end-capping reaction;
2. chain extension reaction:
in the chain extension reaction, the catalyst is stannous octoate Sn (Oct)2The chain extender is 2,2' - (1, 3-phenylene) -bisoxazoline, n is 1, m is 1, a is not less than 4, and the high-stability polyglycolide (modified) is obtained after chain extension reaction.
Example 3:
a method for synthesizing high-stability polyglycolide comprises the following steps:
s1, mixing glycolide monomers, a catalyst and a carboxyl end-capping reagent, reacting for 3 times in an inert gas atmosphere to remove air by displacement, and heating to continue the reaction to obtain low-molecular-weight double-end carboxyl polyglycolide;
wherein, the catalyst is stannous octoate, the carboxyl end-capping agent is D-lactic acid, and the inert gas is nitrogen;
the specific operation is as follows:
weighing 1 part of glycolide, 1/10000 parts of stannous octoate and 1/20 parts of D lactic acid, adding the materials into a reaction kettle, vacuumizing, filling inert gas (nitrogen), filling the nitrogen for 3 times to replace and remove air, heating the inert gas atmosphere to 170 ℃, reacting for 180min, cooling, and taking out the materials to obtain the low-molecular-weight double-end carboxyl polyglycolide, wherein the intrinsic viscosity is as follows: 0.1 to 0.2 dl/g;
s2, mixing low-molecular-weight double-end carboxyl polyglycolide, a catalyst and a chain extender, vacuumizing and filling inert gas (nitrogen), filling nitrogen for 3 times to replace and remove air, and quickly heating to react in an inert gas atmosphere to obtain the high-stability polyglycolide;
wherein the catalyst is stannous octoate, the chain extender is 2,2' -bis (2-oxazoline), and the inert gas is nitrogen;
the specific operation is as follows:
weighing 1 part of low-molecular-weight double-end carboxyl polyglycolide, 1/20 parts of 2,2' -bis (2-oxazoline) and 1/10000 parts of stannous octoate, adding into a reaction kettle, vacuumizing and filling inert gas (nitrogen), filling the nitrogen for 3 times to replace and remove air, quickly heating to 210 ℃ in the atmosphere of the inert gas, reacting for 75min, cooling, and taking out the material to obtain chain extension polyglycolide (modified), wherein the intrinsic viscosity is as follows: 0.2-2.0dl/g, preferably 1.1-1.6 dl/g, molecular weight of 130000-; the polymer structure is a body structure.
The reaction formula of the synthetic route is shown as follows:
1. end capping reaction:
in the blocking reaction, the catalyst is stannous octoate Sn (Oct)2The end-capping reagent is D-lactic acid, n is 1, m is 1, and the low molecular weight double-end carboxyl polyglycolide is obtained after the end-capping reaction;
2. chain extension reaction:
in the chain extension reaction, the catalyst is stannous octoate Sn (Oct)2The chain extender is 2,2' -bis (2-oxazoline), n is 1, m is 1, a is not less than 4, and the high-stability polyglycolide (modified) is obtained after chain extension reaction.
Example 4:
a method for synthesizing high-stability polyglycolide comprises the following steps:
s1, mixing glycolide monomers, a catalyst and a carboxyl end-capping reagent, vacuumizing, filling inert gas (nitrogen), filling nitrogen for 3 times to replace and remove air, heating in an inert gas atmosphere, and continuing to react to obtain low-molecular-weight double-end carboxyl polyglycolide;
wherein the catalyst is stannous octoate, the carboxyl end-capping agent is DL-lactic acid, and the inert gas is nitrogen; the mixing ratio of the L-lactic acid and the D-lactic acid in the DL-lactic acid is (1:9) - (9:1) according to the weight ratio; preferably (4:6) - (6: 4);
the specific operation is as follows:
weighing 1 part of glycolide, 1/6000 parts of stannous octoate and 1/15 parts of DL-lactic acid, adding into a reaction kettle, vacuumizing, filling inert gas (nitrogen), filling nitrogen for 3 times to replace air, heating to 140 ℃, reacting for 240min, cooling, and taking out the material to obtain low-molecular-weight double-end carboxyl polyglycolide, wherein the intrinsic viscosity is as follows: 0.1 to 0.3 dl/g;
s2, mixing low-molecular-weight double-end carboxyl polyglycolide, a catalyst and a chain extender, vacuumizing and filling inert gas (nitrogen), filling nitrogen for 3 times to replace and remove air, and quickly heating to react in an inert gas atmosphere to obtain the high-stability polyglycolide;
wherein the catalyst is stannous octoate, the chain extender is 2,2' -bis (2-oxazoline), and the inert gas is nitrogen;
the specific operation is as follows:
weighing 1 part of low-molecular-weight double-end carboxyl polyglycolide, 1/15 parts of 2,2' -bis (2-oxazoline) and 1/6000 parts of stannous octoate, adding into a reaction kettle, vacuumizing and filling inert gas (nitrogen), filling the nitrogen for 3 times to replace and remove air, quickly heating to 230 ℃ in the atmosphere of the inert gas, reacting for 90min, cooling, and taking out the material to obtain chain extension polyglycolide (modified), wherein the intrinsic viscosity is as follows: 0.2 to 2.1dl/g, preferably 0.9 to 1.5 dl/g; molecular weight is 100000-160000; the polymer structure is a body structure.
The reaction formula of the synthetic route is shown as follows:
1. end capping reaction:
in the blocking reaction, the catalyst is stannous octoate Sn (Oct)2The end capping agent is DL-lactic acid, n is 1, m is 1,obtaining low molecular weight double-end carboxyl polyglycolide after end-capping reaction;
2. chain extension reaction:
in the chain extension reaction, the catalyst is stannous octoate Sn (Oct)2The chain extender is 2,2' -bis (2-oxazoline), n is 1, m is 1, a is not less than 4, and the high-stability polyglycolide (modified) is obtained after chain extension reaction.
Comparative example 1:
polyglycolide obtained by the method for producing polyglycolide described in patent publication No. CN 104497280A.
Comparative example 2:
polyglycolide obtained by the method for synthesizing polyglycolide described in patent publication No. CN 105885021A.
Comparative example 3:
polyglycolide obtained by the method for producing polylactide, polyglycolide and a copolymer of polylactide and polyglycolide described in patent publication No. CN 101343354A.
Results of comparison of examples 2 to 4 with comparative examples 1 to 3:
the intrinsic viscosity can indicate the molecular weight of the polymer to a certain extent, and generally, the higher the intrinsic viscosity of the polymer is, the larger the molecular weight is, so that the control of the range of the intrinsic viscosity is an important criterion for indicating whether the molecular weight (polymerization degree) is controllable, that is, whether the polymer product is stable in the art.
Table 1 shows the physical properties of the high stability polyglycolide obtained by the synthesis method of examples 2 to 4 of the present invention compared with those of the polyglycolide prepared in comparative examples 1 to 3.
TABLE 1
As can be seen from Table 1, the polyglycolide prepared according to the technical schemes of the patent documents listed in the comparative examples 1 to 3 has large difference and can not be accurately controlled, the minimum is 0.1dl/g, the maximum can reach 4.0dl/g, the stability of the polyglycolide production process is difficult to realize, while the intrinsic viscosity of the examples 2 to 4 of the invention is about 0.1 to 2.2dl/g, and the error between different batches can be controlled; in addition, the polyglycolide prepared according to comparative example 1 has a relatively low molecular weight distribution of about 1.3 and a relatively low melting point of about 225 ℃, but comparative examples 2 and 3 have a relatively high molecular weight distribution and a relatively high melting point, and compared with examples 2 to 4 of the present invention, even the lowest comparative example 1 has a molecular weight distribution higher than that of the examples of the present invention, and the modified polyglycolide prepared according to the examples of the present invention has a relatively low melting point.
Table 2 shows the thermal stability of the high stability polyglycolide obtained by the synthesis method of examples 2 to 4 of the present invention compared with the polyglycolide prepared by comparative examples 1 to 3.
TABLE 2
As can be seen from Table 2, under the same conditions (at 240 ℃ C., 5 minutes of heating and melting), the intrinsic viscosities of comparative examples 1-3 were respectively reduced by 40% -50%, and the intrinsic viscosities of inventive examples 2-4 were reduced by only 5% -10%, so that it can be seen that the stability of the modified polyglycolide provided by the present invention is significantly better than that of the prior art of comparative examples 1-3 in the heated state.
Table 3 shows the hydrolysis resistance of the high stability polyglycolide obtained by the synthesis method of examples 2 to 4 of the present invention compared to the polyglycolide prepared by comparative examples 1 to 3.
TABLE 3
| Product name | Resistance to hydrolysis |
| Comparative example 1 | PGA product (2 mm diameter bar) was broken in a phosphoric acid buffer solution at 37 ℃ and pH 7.4 for 6 days |
| Comparative example 2 | PGA product (2 mm diameter bar) was broken in a phosphoric acid buffer solution at 37 ℃ and pH 7.4 for 6 days |
| Comparative example 3 | PGA product (2 mm diameter bar) was broken in a phosphoric acid buffer solution at 37 ℃ and pH 7.4 for 5 days |
| Example 2 | PGA product (2 mm diameter bar) was broken in a phosphoric acid buffer solution at 37 ℃ and pH 7.4 for 12 days |
| Example 3 | PGA product (2 mm diameter bar) was broken in a phosphoric acid buffer solution at 37 ℃ and pH 7.4 for 15 days |
| Example 4 | PGA product (2 mm diameter bar) was broken in a phosphoric acid buffer solution at 37 ℃ and pH 7.4 for 14 days |
As can be seen from Table 3, under the same conditions (37 ℃ C., pH 7.4 phosphoric acid buffer solution), the polyglycolides of comparative examples 1 to 3 were fractured within 5 to 6 days, the polyglycolides prepared in examples 2 to 4 of the present invention were fractured within 12 to 14 days, and the fracture time was prolonged by 2 to 3 times, so that it can be seen that the modified polyglycolides provided by the present invention have stability significantly better than the prior art of comparative examples 1 to 3 under the same conditions.
Finally, it should be noted that: the above embodiments are only used to illustrate the technical solution of the present invention, and not to limit the same; while the invention has been described in detail and with reference to the foregoing embodiments, it will be understood by those skilled in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some or all of the technical features may be equivalently replaced; and the modifications or the substitutions do not make the essence of the corresponding technical solutions depart from the scope of the technical solutions of the embodiments of the present invention.
Claims (10)
1. The synthesis method of the high-stability polyglycolide is characterized by comprising the following steps: end capping glycolide monomers by end capping reaction, and chain extending by chain extending reaction to obtain high-stability polyglycolide; the end capping reaction and the chain extension reaction both contain catalysts.
2. The method for synthesizing polyglycolide with high stability according to claim 1, wherein the end-capping reaction is performed by end-capping glycolide monomers with an end-capping agent, the end-capping agent is a carboxyl end-capping agent, and the end-capping reaction product is low molecular weight double-end carboxyl polyglycolide with a molecular weight of less than 120000.
3. The method for synthesizing high-stability polyglycolide according to claim 1, wherein the chain extension reaction is to extend the chain of the end-capped reaction product with a chain extender, the chain extender is an oxazoline chain extender, and the chain extension reaction product is high-stability polyglycolide with a molecular weight of 120000-250000 and a high molecular structure of three-dimensional structure.
4. The method for synthesizing polyglycolide with high stability according to claim 1, wherein the catalyst is dibutyl tin dilaurate, stannous octoate, dibutyl tin diacetate and/or zinc lactate.
5. The method for synthesizing polyglycolide with high stability according to any of claims 1 to 4, wherein the end-capping reagent is L-lactic acid, D-lactic acid or DL-lactic acid mixed with both; in the DL-lactic acid, the mixing ratio of the L-lactic acid and the D-lactic acid is (1:9) - (9:1) according to the weight ratio.
6. The method for synthesizing polyglycolide with high stability according to claim 5, wherein the amount of glycolide monomer, catalyst and blocking agent is 1: (1/1000-1/20000): (1/10-1/20000); the reaction temperature of the end-capping reaction is 140-170 ℃, and the reaction time is 180-300 min.
7. The method for synthesizing high-stability polyglycolide according to any one of claims 1 to 4, wherein the chain extender is 2,2 '-bis (2-oxazoline) or 2,2' - (1, 3-phenylene) -bisoxazoline in the chain extension reaction.
8. The method for synthesizing polyglycolide with high stability according to claim 7, wherein the amount of the capping reaction product, the catalyst and the chain extender is 1: (1/100-1/10000): (1/10-1/20000); the reaction temperature of the chain extension reaction is 200-230 ℃; the reaction time is 60-90 min.
9. The method for synthesizing polyglycolide with high stability according to claim 6 or 8, wherein the reaction atmosphere of the end-capping reaction and the chain-extending reaction is an inert gas atmosphere.
10. A high stability polyglycolide synthesized according to the synthesis method of claims 1 to 4 or 6 or 8 or 9; the intrinsic viscosity of the high-stability polyglycolide is 0.1-2.5 dl/g.
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| CN101321829A (en) * | 2005-12-02 | 2008-12-10 | 株式会社吴羽 | Polyglycolic acid resin composition |
| CN105348501A (en) * | 2015-08-17 | 2016-02-24 | 宁波天益医疗器械有限公司 | Bisoxazoline chain-extending polylactic acid polyhydric alcohol with low-acid value and preparation method for bisoxazoline chain-extending polylactic acid polyhydric alcohol with low-acid value |
| CN110283305A (en) * | 2019-06-12 | 2019-09-27 | 山东谷雨春生物科技有限公司 | A kind of preparation method of pharmaceutical Biodegradable polymer material poly (glycolide-lactide) |
| CN110684179A (en) * | 2019-11-11 | 2020-01-14 | 上海汉禾生物新材料科技有限公司 | Preparation method of high-molecular-weight polylactic acid |
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|---|---|---|---|---|
| CN101321829A (en) * | 2005-12-02 | 2008-12-10 | 株式会社吴羽 | Polyglycolic acid resin composition |
| CN105348501A (en) * | 2015-08-17 | 2016-02-24 | 宁波天益医疗器械有限公司 | Bisoxazoline chain-extending polylactic acid polyhydric alcohol with low-acid value and preparation method for bisoxazoline chain-extending polylactic acid polyhydric alcohol with low-acid value |
| CN110283305A (en) * | 2019-06-12 | 2019-09-27 | 山东谷雨春生物科技有限公司 | A kind of preparation method of pharmaceutical Biodegradable polymer material poly (glycolide-lactide) |
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