CN100999515B - Synthesizing process and use of unsaturation cyclic aliphatic carbonate monomer - Google Patents
Synthesizing process and use of unsaturation cyclic aliphatic carbonate monomer Download PDFInfo
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Abstract
The invention relates to a cyclic aliphatic carbonate monomer with a triple bond side group, a preparation method and use thereof. 2-methyl-2-propargyl oxygen carbonyl trimethylene carbonate is synthesized from 2,2-dimethylolpropionic acid. The monomer can be used for ring-opening polymerization or ring-opening copolymerization with aliphatic cyclic ester monomer to obtain the aliphatic polycarbonate with triple bond side group or the copolymers of aliphatic polyester-carbonic ester. The polymers have advantages of the aliphatic polyester and carbonic ester, can be biodegradated. The degradation product is non-toxic. The polymers can be used for biomedical material.
Description
The synthetic method of unsaturation cyclic aliphatic carbonate monomer and purposes the present invention relates to the synthetic method and the purposes of unsaturation cyclic aliphatic carbonate monomer and polymkeric substance thereof.Be specifically related to side group and contain annular aliphatic carbonate monomer and polymkeric substance and the method for making and the purposes of two keys and/or three key, belong to field of biomedical polymer materials.
Background technology
In recent decades, along with advancing by leaps and bounds of developing rapidly of polymer science and modern pharmacy, biology and engineering science, the research of biological medical polymer material has obtained developing rapidly.Biodegradable Polymers wherein owing to after implanting, do not need second operation to take out, thereby at operating sutures, artificial skin, artificial blood vessel, bone is fixing and repair and fields such as medicine sustained release have obtained widespread use.Biodegradable synthetic macromolecule mainly comprises aliphatic polyester, polyamino acid, poly phosphate, poly-acid anhydrides, poe, polycarbonate etc.Aliphatic polyester, polylactide (PLA) for example, poly-glycollide (PGA), poly-epsilon-caprolactone (PCL) has low immunogenicity and favorable biological degradability and biocompatibility, has been widely used in biomedicine and field of medicaments, as fracture fixation, operating sutures, tissue engineering bracket, the carrier of medicament slow release etc.
Recently, the research of introducing functional group on the molecular chain of polymkeric substance is particularly active, because it is significant in practice to have the polymkeric substance of functional group.For example, on these functional groups, connect various medicines and form the polymer prodrug, can realize that the position-controllable of medicine discharges or lasting release; Connect molecule such as antibody and polysaccharide, can make polymkeric substance and micella thereof, capsule have target function with target function; Connection has other bioactive molecule, can improve the biocompatibility and the biological activity of material; By the introducing of functional group can also change polymkeric substance degradation rate, physical and mechanical properties, hydrophilic and hydrophobic can etc., thereby have the research of aliphatic polyester of functional group and the very big interest that application has caused people.
Valuable function side group comprises carboxyl (COOH), amino (NH
2), hydroxyl (OH), sulfydryl (SH) etc.Wanting the polymkeric substance of these function side groups of anamorphic zone, generally is the monomer that first anamorphic zone has functional group, carries out polymerization or copolymerization then.But because unnecessary even deleterious side reaction is often followed in the existence of functional group in polymerization process, so above functional group at first will protect deprotection again after the polymerization.
Be used for function monomer with the copolymerization of aliphatics cyclic ester at present, glycollide derivative, epsilon-caprolactone derivative, morpholine diketone derivative, N-carbonyl-alpha-amino group acid anhydrides (NCA) and dioxane derovatives etc. are arranged.Synthesizing of having in them is very difficult, yield is very low, cost is very high, and the polymerization activity that has is very low, and molecular weight of copolymer is low, and the function monomer that can introduce is limited, thereby has been difficult to practical use.Comparatively speaking, functional cyclic aliphatic carbonate monomer raw material is easy to get, and synthetic ratio is easier to, and polymerization efficiency is higher, and the molecular weight of resulting polymers is also than higher.Chinese patent CN1323795A has disclosed the synthetic method of 5-benzyloxy one trimethylene carbonate, and Chinese patent CN1335330A has disclosed poly-(5-benzyloxy-trimethylene carbonate) and preparation method thereof and purposes.Summarizing in fact, is exactly synthetic 5-benzyloxy-trimethylene carbonate, with they polymerizations, obtains polymkeric substance with pendant hydroxyl group by hydro-reduction again.This series of patents only limits to this monomeric homopolymer, and well known fact is that the aliphatic acid ester carbonate of homopolymerization is unsatisfactory at the intravital biodegradability of people, thereby its application aspect bio-medical will be limited.In this patent through overprotection and these two steps of deprotection.Thereby the building-up process complexity, cost is higher.Chinese patent 200510107434.2 has improved the biocompatibility and the biological degradability of polymkeric substance with above-mentioned cyclic carbonate monomer and the copolymerization of aliphatics cyclic ester monomer, but still adopts the method for protection and deprotection to synthesize.
Summary of the invention
In order to solve the shortcoming and defect that above-mentioned polymkeric substance exists, one of purpose of the present invention provides unsaturation cyclic aliphatic carbonate monomer; Two of purpose of the present invention provides the method for preparing unsaturation cyclic aliphatic carbonate monomer; Three of purpose of the present invention is that described unsaturation cyclic aliphatic carbonate monomer is carried out ring-opening polymerization, obtains their homopolymer or multipolymer; Four of purpose of the present invention is that above-mentioned unsaturation cyclic aliphatic carbonate monomer and aliphatics cyclic ester monomer are carried out ring-opening copolymerization, obtains the multipolymer of they and aliphatics cyclic ester monomer; Five of purpose of the present invention provides multipolymer or the multipolymer of annular aliphatic carbonate and aliphatics cyclic ester and the segmented copolymer of polyoxyethylene glycol of the homopolymer of above-mentioned unsaturation cyclic aliphatic carbonate, above-mentioned unsaturation cyclic aliphatic carbonate; Six of purpose of the present invention provides the purposes of the above-mentioned various polymkeric substance of unsaturation cyclic aliphatic carbonate.
1). unsaturation cyclic aliphatic carbonate monomer provided by the invention is: the annular aliphatic carbonate monomer 2-methyl-2-alkynes third oxygen carbonyl trimethylene carbonate (hereinafter to be referred as monomers B) of the annular aliphatic carbonate monomer 2-methyl-2-allyloxycarbonyl trimethylene carbonate (hereinafter to be referred as monomer A) of band double-bond lateral group and band three bond lateral group.Their structural formula is respectively following (A) and (B):
Their characteristics are that two keys and three key are in respectively in allyl group and the propargyl, and link to each other with the carbonic ether ring by the ester bridge.
2). the preparation method of unsaturation cyclic aliphatic carbonate monomer provided by the invention, promptly be with two keys and the annular aliphatic carbonate monomer A of three bond lateral group or the preparation method of monomers B, its step and condition are as follows:
(1), 2, the reaction of 2-dimethylol propionic acid and sodium hydroxide generates 2,2-dimethylol propionic acid salt; 100 ℃ of temperature of reaction, reaction times 1～2h, solvent are DMF.
(2), 2,2-dimethylol propionic acid salt reacts with 3-bromopropylene or 3-propargyl bromide respectively, the eternal pressure dropping funnel of 3-bromopropylene or 3-propargyl bromide slowly is added drop-wise in (1) gained salts solution, 24 hours reaction times, 30～40 ℃ of temperature of reaction, obtain 2-methyl-2-allyloxycarbonyl-1, ammediol or 2-methyl-2-alkynes third oxygen carbonyl-1, ammediol
(3), 2-methyl-2-allyloxycarbonyl-1, ammediol or 2-methyl-2-alkynes third oxygen carbonyl-1, ammediol and Vinyl chloroformate reaction, catalysts is a triethylamine, solvent is a tetrahydrofuran (THF), 0 ℃ of temperature of reaction, reaction times 2～12h obtains 2-methyl-2-allyloxycarbonyl trimethylene carbonate (being monomer A) or 2-methyl-2-alkynes third oxygen carbonyl trimethylene carbonate (being monomers B).
More than three the step available following reaction equation represent:
The structure of resulting 2-methyl-2-allyloxycarbonyl trimethylene carbonate or 2-methyl-2-alkynes third oxygen carbonyl trimethylene carbonate by proton NMR spectrum (
1H NMR) confirms.(referring to Fig. 1 and 2)
3). the invention provides unsaturation cyclic aliphatic carbonate homopolymer or multipolymer; Described unsaturation cyclic aliphatic carbonate monomer is the annular aliphatic carbonate monomer A of band double-bond lateral group and/or the annular aliphatic carbonate monomer B of band three bond lateral group.
Unsaturation cyclic aliphatic carbonate monomer carries out the method that ring-opening polymerization prepares its homopolymer or multipolymer, and concrete steps and condition are as follows:
Under the condition of anhydrous and oxygen-free, the zinc ethyl that adds monomer total mass 1/100～1/1000 in monomer A, monomers B or the mixture of the two is made initiator, polymerization 1～10h under 40～100 ℃ of heating and stirring condition, and, obtain the homopolymer or the multipolymer of cyclic carbonate with product precipitation, filtration, washing, vacuum-drying;
(4). the invention provides the multipolymer of unsaturation cyclic aliphatic carbonate monomer and aliphatics cyclic ester monomer, be that above-mentioned unsaturation cyclic aliphatic carbonate monomer and aliphatics cyclic ester monomer are carried out ring-opening copolymerization, obtain the multipolymer of unsaturation cyclic aliphatic carbonate monomer and aliphatics cyclic ester monomer.
Described unsaturation cyclic aliphatic carbonate monomer is the annular aliphatic carbonate monomer A of band double-bond lateral group and/or the annular aliphatic carbonate monomer B of band three bond lateral group.
Described aliphatics cyclic ester monomer can be a kind of, two or three the mixture in rac-Lactide (LA), glycollide (GA) and the 6-caprolactone (CL); Ratio between them is not limit.
Total mol ratio of described unsaturation cyclic aliphatic carbonate monomer and aliphatics cyclic ester monomer is 1: 99～50: 50.
Described unsaturation cyclic aliphatic carbonate monomer and aliphatics cyclic ester monomer carry out the method for ring-opening copolymerization, and its concrete steps and condition are as follows:
Under the condition of anhydrous and oxygen-free, by proportioning annular aliphatic carbonate monomer and aliphatics cyclic ester monomer are added in the reactor, the initiator zinc ethyl that adds monomer total mass 1/100～1/1000, under heating and stirring condition, carry out polymerization, polymerization time is 1～10h, temperature is 40～100 ℃, and product is through precipitation, filtration, washing, vacuum-drying, the unsaturated multipolymer that obtains annular aliphatic carbonate monomer and aliphatics cyclic ester monomer.
Five of purpose of the present invention provides the segmented copolymer of above-mentioned unsaturation cyclic aliphatic carbonate monomer and aliphatics cyclic ester monomer and polyoxyethylene glycol, it is characterized in that described comonomer is that unsaturation cyclic aliphatic carbonate monomer is the annular aliphatic carbonate monomer 2-methyl-2-allyloxycarbonyl trimethylene carbonate of band double-bond lateral group, the annular aliphatic carbonate monomer 2-methyl-2-alkynes third oxygen carbonyl trimethylene carbonate and/or the aliphatics cyclic ester monomer of band three bond lateral group; The molecular weight of described polyoxyethylene glycol block is 400～5000.
The preparation method of this segmented copolymer: under the condition of anhydrous and oxygen-free, with molecular weight is that 400～5000 one-ended hydroxy polyoxyethylene glycol is as macromole evocating agent, the zinc ethyl that adds monomer total mass 1/100～1/1000 is made initiator, polymerization 1～10h under 40～100 ℃ of heating and stirring condition, and with product precipitation, filtration, washing, vacuum-drying.
Six of purpose of the present invention provides the purposes of the above-mentioned various polymkeric substance of unsaturation cyclic aliphatic carbonate, promptly utilize allyl group and/or propargyl on its molecular chain, directly and drug molecule, polypeptide or protein molecule, monose or polysaccharide molecule or drug molecule through modifying, polypeptide or protein molecule, monose or polysaccharide molecule reaction, make the high molecule bonding thing of these materials, perhaps they are converted into the carboxyl that can react, amino, hydroxyl, sulfydryl, epoxide group, and then and drug molecule, polypeptide or protein molecule, monose or polysaccharide molecule or drug molecule through modifying, polypeptide or protein molecule, monose or polysaccharide molecule react, and make the high molecule bonding thing of these materials.These key compounds are mainly used in the orientation of medicine and carry and sustained release, particularly polymer prodrug, also as the separating and purifying of cell recognition and adhesion, immunoassay, antigen/antibody, and tissue engineering bracket material etc.
Described drug molecule be taxol, Zorubicin and other can with the drug molecule of two keys, three key, carboxyl, amino, hydroxyl, sulfydryl, epoxide group reaction; Small peptide is the small peptide NH that contains the RGD aminoacid sequence
2-RGD-CONH
2, GRGDY-I
2, GRGDSY-I
2, GRGDS and RGDS or other can with the small peptide of two keys, three key, carboxyl, amino, hydroxyl, sulfydryl, epoxide group reaction; Carbohydrate be glucose, lactose and semi-lactosi or other can with the glycan molecule of two keys, three key, carboxyl, amino, hydroxyl, sulfydryl, epoxide group reaction; Protein comprises antigen, antibody, enzyme, virus and vaccine; Other biologically active substance comprises vitamin H (biotin), vitamin H conjugated protein (Avidin) and folic acid (folic acid) etc.
If treat the bonding molecule or through modification treat the bonding molecule can be directly with above-mentioned annular aliphatic carbonate polymkeric substance in two keys or three key react, then can directly carry out this reaction.For example when treating that the bonding molecule contains nitrine or sulfydryl, they can react with side three key or the two keys of side of polymkeric substance:
Wherein azido group can be transformed by hydroxyl or amino, as hydroxyl in polypeptide or the protein or amino.This is the reaction that people know.Nitrine and triple-linked annulation can carry out in the aqueous systems medium, and about 4 ℃ of temperature also can be carried out in polar organic solvent, are catalyzer with cuprous sulfate or cuprous chloride.
If treat the bonding molecule or through modification treat the bonding molecule can not be directly with above-mentioned annular aliphatic carbonate polymkeric substance in two keys or three key react, then can be earlier with the two keys in the annular aliphatic carbonate polymkeric substance or three key be converted into can with the group of their reactions, as carboxyl, amino, hydroxyl, sulfydryl, epoxide group, so with treat the bonding molecule or treat the bonding molecular reaction through what modify.These conversion reactions have:
(A) Michael (Michae1) reaction: of the present invention described polymkeric substance that will the two keys of band side and Thiovanic acid or end group are that other compound of sulfydryl reacts, solvent for use is methylene dichloride or tetrahydrofuran (THF), temperature of reaction is a room temperature, in 48～72 hours reaction times, side chain then is converted into carboxyl or other group.Wherein two representational reaction equations are
(B) side allyl silicaneization: will with the of the present invention described polymer dissolution of the two keys of side in chloroform or tetrahydrofuran (THF), carry out the addition reaction of hydrogen silicon, and corresponding reactive group be introduced side group, as NH with silylating reagent
2, SH, epoxy etc.The representative reactions equation is
(C) side double bond epoxidation: will add oxygenant with the of the present invention described polymer dissolution of the two keys of side in chloroform, and react 4～8 hours under the condition that chloroform refluxes, two keys are oxidized fully and do not have the main chain degraded and a side reaction generation of polymkeric substance.Reaction equation is as follows:
(D) the two key hydroxylations of side: will be dissolved in tetrahydrofuran (THF) with the of the present invention described polymkeric substance of the two keys of side, and add tetrahydrofuran solution, distilled water, sodium hydroxide solution and the hydrogen peroxide of borine successively, 0 ℃ of temperature of reaction, reaction times 1～2h.The equation of reaction is as follows:
Below all belong to high molecular weight reactive, reactive activity and selectivity are all than higher, and relevant functional group does not need protection and deprotection.
More than the carboxyl, amino, hydroxyl, sulfydryl and the epoxide group that change into by the two keys of the side of polymkeric substance, can react with drug molecule, polypeptide or protein molecule, monose or polysaccharide molecule or drug molecule, polypeptide or the protein molecule modified with process, monose or polysaccharide molecule, make the high molecule bonding thing of these materials.But should select corresponding polymer functional group, linked reaction and catalyzer according to the reactive functionality for the treatment of that the bonding molecule is had.Be exemplified below:
(1) treats that the bonding molecule contains hydroxyl, then the two keys of the side of described polymkeric substance of the present invention are converted into carboxyl, perhaps conversely, when treating that the bonding molecule contains carboxyl, then the two keys of the side of polymkeric substance being converted into hydroxyl, is that dewatering agent carries out esterification with dicyclohexylcarbodiimide (DCC) then.Concrete reaction conditions is: reaction solvent is methylene dichloride, N, dinethylformamide, methyl-sulphoxide or their mixed solvent, and the amount of DCC is polymkeric substance hydroxyl or carboxyl molar weight 1～5 times, 0～25 ℃ of temperature of reaction, reaction times 10～48h.
(2) with the method for small peptide molecular linkage: the homopolymer of the carbonic ether of the band pendant hydroxyl group that the present invention is obtained or the multipolymer and the biologically active substance of carbonic ether and aliphatics cyclic ester are dissolved in methylene chloride, N, in dinethylformamide, methyl-sulphoxide or their mixture, be that catalyzer reacts with dicyclohexylcarbodiimide (DCC).The amount of DCC is 1～5 times of described polymkeric substance hydroxyl molar weight of the present invention, 0～25 ℃ of temperature of reaction, reaction times 10～48h.
(3) with the bonding of protein molecule: when treating that the bonding molecule contains free amino group, then the two keys of the side of described polymkeric substance of the present invention are converted into carboxyl, perhaps conversely, when treating that the bonding molecule contains carboxyl, then the two keys of the side of polymkeric substance are converted into primary amino, then with N-hydroxy-succinamide (NHS) or 1,1 '-carbonyl dimidazoles (CDI) activated carboxyl, at last, with the primary amino condensation for the treatment of bonding, form amido linkage.Reaction equation is as follows:
Useful effect of the present invention is as follows:
The present invention is from 2, and the 2-dimethylol propionic acid synthesizing carbonate ester monomer that sets out is compared with other carbonate monomer synthetic route, and cost of material is cheap; Building-up reactions had only for two steps, and per step productive rate is all higher; The easy purifying of product obtains highly purified cyclic carbonate monomer.
The polymerization activity height of synthetic cyclic carbonate monomer A of institute of the present invention and B both can homopolymerization, again can copolymerization, can also with the copolymerization of aliphatics cyclic ester monomer, the polymerisation conversion height can obtain high molecular weight polymers.
The introducing of two keys of the side on the institute of the present invention synthetic polymkeric substance or side three key, and they are converted into the reaction of hydroxyl, carboxyl, amino, epoxy etc., do not require and protect and deprotection, do not cause the degraded of main polymer chain.This is rare advantage concerning the chemical modification of aliphatic polyester.
Two keys of side on the institute of the present invention synthetic polymkeric substance or three key, be on allyl group or the propargyl, and link to each other with main polymer chain by an ester bridge, thereby has a high reaction activity and high, follow-up connection or the group that changes into, and all there is quite long spacer between main polymer chain, thereby has high reaction activity and high.
Description of drawings
Fig. 1: the nuclear magnetic spectrogram of 2-methyl-2-allyloxycarbonyl trimethylene carbonate and ownership (embodiment 3) thereof;
Fig. 2: the nuclear magnetic spectrogram of 2-methyl-2-alkynes third oxygen carbonyl trimethylene carbonate and ownership (embodiment 4) thereof;
Fig. 3: the nuclear magnetic spectrogram of 2-methyl-2-allyloxycarbonyl trimethylene carbonate and lactic acid copolymer and ownership thereof (embodiment 6);
Fig. 4: the nuclear magnetic spectrogram of 2-methyl-2-alkynes third oxygen carbonyl trimethylene carbonate and lactic acid copolymer and ownership (embodiment 6) thereof;
Embodiment
Embodiment 1:2-methyl-2-allyloxycarbonyl-1, ammediol synthetic
With 2 of 9.00g, the potassium hydroxide of 2-dimethylol propionic acid and 4.30g is dissolved in 50ml N, in the dinethylformamide.Under 100 ℃, vigorous stirring 1h makes it form 2,2-dimethylol propionic acid sylvite.Then the propylene bromine is joined in the above-mentioned solution, under 100 ℃, vigorous stirring 15h again.Steam solvent, residue is dissolved in the 200ml ether, uses 50ml distilled water wash three times, obtains 2-methyl-2-allyloxycarbonyl-1 with the toluene recrystallization at last, ammediol 7.9 grams, and productive rate is 68%.Its structure is confirmed by proton NMR spectrum.
The embodiment 2:2-methyl-2-alkynes third oxygen carbonyl-1, ammediol synthetic
With 2 of 9.00g, the potassium hydroxide of 2-dimethylol propionic acid and 4.30g is dissolved in 50ml N, in the dinethylformamide.Under 100 ℃, vigorous stirring 1h makes it form 2,2-dimethylol propionic acid sylvite.Then the propine bromine is joined in the above-mentioned solution, under 100 ℃, vigorous stirring 15h again.Steam solvent, residue is dissolved in the 200ml ether, uses 50ml distilled water wash three times, obtains 2-methyl-2-alkynes third oxygen carbonyl-1 with the toluene recrystallization at last, ammediol 8 grams, and productive rate is 70%.Its structure is confirmed by proton NMR spectrum.
Synthesizing of embodiment 3:2-methyl-2-allyloxycarbonyl trimethylene carbonate (monomer A)
With 10g 2-first-2-allyloxycarbonyl-1, ammediol and 28.5g chloro ethyl formate are dissolved in the 600ml tetrahydrofuran (THF), cool off with ice-water bath.The 28g triethylamine is slowly joined in the above-mentioned solution, the maintenance system is about 0 ℃ in the adition process again.Then at room temperature reaction 10h.Filter out throw out, filtrate decompression concentrates, and residue obtains white crystal 9.2g, productive rate 80% with tetrahydrofuran (THF) and ether recrystallization.Its structure is confirmed by proton NMR spectrum, sees accompanying drawing 1.
Synthesizing of embodiment 4:2-methyl-2-alkynes third oxygen carbonyl trimethylene carbonate (monomers B)
With 10g 2-first-2-alkynes third oxygen carbonyl-1, ammediol and 28.5g chloro ethyl formate are dissolved in the 600ml tetrahydrofuran (THF), cool off with ice-water bath.The 28g triethylamine is slowly joined in the above-mentioned solution, the maintenance system is about 0 ℃ in the adition process again.Then at room temperature reaction 10h.Filter out throw out, filtrate decompression concentrates, and residue obtains white crystal 9.4g, productive rate 82% with tetrahydrofuran (THF) and ether recrystallization.Its structure is confirmed by proton NMR spectrum, sees accompanying drawing 2.
Embodiment 5: carbonate polymer synthetic
Under the condition of anhydrous and oxygen-free, the 1mol carbonate monomer is joined in the polyreaction bottle, adding gives the zinc ethyl of certainty ratio as initiator again, react 2h down at 60 ℃, product dissolves with trichloromethane, methanol extraction, filter, washing, 35 ℃ of following vacuum-dryings promptly obtain carbonate polymer to constant weight.Wherein, each time polymeric monomer ratio, zinc ethyl consumption and product yield, molecular weight are listed in the table 1.
Table 1. cyclic carbonate monomer aggregated data
| Sequence number | Monomer A/monomers B (mol ratio) | Zinc ethyl/monomer total amount (mol ratio) | Weight yield (%) | Molecular weight (10 4) | |
| 1 | 100/0 | 1/200 | 79 | 1.02 | 1.23 |
| 2 | 100/0 | 1/500 | 82 | 0.89 | 1.30 |
| 3 | 75/25 | 1/200 | 81 | 1.26 | 1.24 |
| 4 | 50/50 | 1/500 | 86 | 1.50 | 1.21 |
| 5 | 25/75 | 1/200 | 80 | 1.56 | 1.32 |
| 6 | 0/100 | 1/800 | 78 | 1.41 | 1.26 |
| 7 | 0/100 | 1/100 | 80 | 0.75 | 1.20 |
Embodiment 6: the multipolymer of monomer A, B and lactic acid synthetic
Under the condition of anhydrous and oxygen-free, get monomer A and the monomers B and the lactide monomer of different ratios, 1/200 the zinc ethyl that adds the monomer total mass is as initiator, and at 60 ℃ of following stirring reaction 2h, product dissolves with trichloromethane, methanol extraction, filter washing, 35 ℃ of following vacuum-drying 24h, the calculating productive rate of weighing obtains the multipolymer of monomer A, B and the lactic acid of different ratios.The gained polymerization result sees Table 2.
The copolymerization of table 2. monomer A, B and lactic acid
| Sequence number | Monomer A (mole %) | Monomers B (mole %) | Rac-Lactide (mole %) | Zinc ethyl/monomer total amount (mole) | Weight yield (%) | Mw(10 4) | |
| 1 | 10 | 0 | 90 | 1/200 | 78 | 1.28 | 1.21 |
| 2 | 0 | 20 | 80 | 1/200 | 89 | 1.56 | 1.15 |
Embodiment 7: the copolymerization of monomer A, B and lactic acid in the presence of polyoxyethylene glycol
Under the condition of anhydrous and oxygen-free, with molecular weight is that 5000 methoxy poly (ethylene glycol) (PEG) is a macromole evocating agent, gets the monomer and the lactide monomer of different ratios, and 1/200 the zinc ethyl that adds the monomer total mass is as initiator, at 60 ℃ of following stirring reaction 2h, product dissolves with trichloromethane, and methanol extraction filters, washing, 35 ℃ of following vacuum-drying 24h, the calculating productive rate of weighing obtains the monomer of different ratios and the multipolymer of lactic acid.The gained polymerization result sees Table 3.
The copolymerization of table 3. monomer A, B and lactic acid in the presence of polyoxyethylene glycol
| Sequence number | Monomer A (mole) | Monomers B (mole) | Rac-Lactide (mole) | Weight yield (%) | Mw(10 4) | |
| 1 | 0.10 | 0 | 0.90 | 89 | 2.04 | 1.18 |
| 2 | 0 | 0.10 | 0.90 | 85 | 1.60 | 1.17 |
Embodiment 8: the multipolymer of carbonic ether and 6-caprolactone synthetic
Under the condition of anhydrous and oxygen-free, 0.1mol cyclic carbonate monomer and 0.5mol 6-caprolactone monomer are joined in the polyreaction bottle, 1/800 the zinc ethyl that adds the monomer total amount again is as initiator, react 2h down at 60 ℃, product dissolves with trichloromethane, methanol extraction, filter, washing, 35 ℃ of following vacuum-dryings promptly obtain the multipolymer of carbonic ether and 6-caprolactone to constant weight.Related data sees Table 4.
The copolymerization of table 4. monomer A, B and 6-caprolactone
| Sequence number | Monomer A (mole) | Monomers B (mole) | 6-caprolactone (mole) | Weight yield (%) | Mw(10 4) | |
| 1 | 0.1 | 0 | 0.5 | 85 | 0.70 | 1.23 |
| 2 | 0 | 0.1 | 0.5 | 81 | 0.81 | 1.20 |
Embodiment 9: the multipolymer of carbonic ether and rac-Lactide, glycollide synthetic
Under the condition of anhydrous and oxygen-free, by the proportioning in the table 5 cyclic carbonate monomer and rac-Lactide, glycolide monomer are joined in the polyreaction bottle, 1/1000 the zinc ethyl that adds the monomer total amount again is as initiator, react 2h down at 140 ℃, product dissolves with trichloromethane, methanol extraction, filter, washing, 35 ℃ of following vacuum-dryings promptly obtain the multipolymer of carbonic ether and rac-Lactide, glycollide to constant weight.Related data sees Table 5.
The copolymerization of table 5. monomer A and B and rac-Lactide, glycollide
| Sequence number | Monomer A (mole) | Monomers B (mole) | Rac-Lactide (mole) | Glycollide (mole) | Weight yield (%) | Mw(10 4) | |
| 1 | 0.1 | 0 | 0.8 | 0.2 | 87 | 1.30 | 1.24 |
| 2 | 0 | 0.1 | 0.7 | 0.3 | 88 | 0.89 | 1.20 |
Embodiment 10: the multipolymer of carbonic ether and rac-Lactide, glycollide, 6-caprolactone synthetic
Under the condition of anhydrous and oxygen-free, by the proportioning in the table 6 cyclic carbonate monomer and rac-Lactide, glycollide, 6-caprolactone monomer are joined in the polyreaction bottle, 1/1000 the zinc ethyl that adds the monomer total amount again is as initiator, react 2h down at 140 ℃, product dissolves with trichloromethane, methanol extraction, filter, washing, 35 ℃ of following vacuum-dryings promptly obtain the multipolymer of carbonic ether and rac-Lactide, glycollide, 6-caprolactone to constant weight.Related data sees Table 6.
The copolymerization of table 6. monomer A and B and rac-Lactide, glycollide, 6-caprolactone
| Sequence number | Monomer A (mole) | Monomers B (mole) | Rac-Lactide (mole) | Glycollide (mole) | 6-caprolactone (mole) | Yield (%) | Mw (10 4) | |
| 1 | 0.1 | 0 | 0.8 | 0.1 | 0.1 | 83 | 1.01 | 1.2 |
| 2 | 0 | 0.1 | 0.7 | 0.2 | 0.1 | 82 | 1.5 | 1.3 |
Embodiment 11: the two key hydroxylations of side
Polymkeric substance (multipolymer of carbonic ether and the rac-Lactide) 2.7g (0.13 mmol) of the two keys of band side is dissolved in 300ml THF at 0 ℃, and to the tetrahydrofuran solution 3mmol that wherein adds borine, 0 ℃ was reacted 2 hours.Add 25ml water then, 25ml NaOH solution (3N) and 25ml H
2O
2(30%).After reaction is carried out 1 hour, add 300m1 water again, the solvent rotary evaporation is removed, and polymkeric substance is precipitated out in water, removes and anhydrates, and 25 ℃ of following vacuum-dryings obtain the polymer powder of white to constant weight.
Embodiment 12: the reaction of two keys of side and sulfydryl
Polymkeric substance (multipolymer of carbonic ether and the rac-Lactide) 0.5g (0.025mmol) of the two keys of band side is dissolved in the 20ml methylene dichloride, to wherein adding equimolar Thiovanic acid, reaction was at room temperature carried out 48 hours, vacuum concentration, settle out with a large amount of ether, and with methanol wash three times, 25 ℃ of following vacuum-dryings obtain the polymkeric substance that side chain contains carboxyl to constant weight.
Embodiment 13: the hydroxyl polymkeric substance multipolymer of rac-Lactide (carbonic ether with) is connected with vitamin H (biotin's)
The polymkeric substance that 0.32g (0.016 mmol) embodiment 11 is obtained is dissolved in 10ml N, dinethylformamide, solution cools off with frozen water, adds the vitamin H of 22mg (0.09 mmol) then, adds 21mg (0.1mmol) dicyclohexylcarbodiimide (DCC) again, at 0 ℃ of stirring reaction 48h, filter out insolubles, vacuum concentration settles out with a large amount of ether, and with methanol wash three times, 25 ℃ of following vacuum-dryings are to constant weight.
Embodiment 14: the polymkeric substance (multipolymer of carbonic ether and 6-caprolactone) of band carboxyl is with paclitaxel bonded
The polymer dissolution that 0.6g (0.03 mmol) band embodiment 12 is obtained, makes it to cool off with ice/water-bath in the dinethylformamide at 20ml N, the triethylamine and the dicyclohexylcarbodiimide (DCC) that add equivalent then, at 0 ℃ of stirring reaction 24h, add the 20mg taxol then, room temperature reaction 24h, filter out insolubles, vacuum concentration settles out with a large amount of ether, and uses N, dinethylformamide washing three times, 25 ℃ of following vacuum-dryings are to constant weight.
Embodiment 15: the hydroxyl polymkeric substance multipolymer of 6-caprolactone (carbonic ether with) is connected with folic acid (folicacid's)
The polymkeric substance that 0.40g (0.020 mmol) embodiment 11 is obtained is dissolved in 10ml N, dinethylformamide, solution cools off with frozen water, adds the folic acid of 32mg (0.074 mmol) then, adds 21mg (0.1mmol) dicyclohexylcarbodiimide (DCC) subsequently, at 0 ℃ of stirring reaction 24h, filter out insolubles, vacuum concentration settles out with a large amount of ether, and with methanol wash three times, 25 ℃ of following vacuum-dryings are to constant weight.
Embodiment 16: the polymkeric substance multipolymer of rac-Lactide (carbonic ether with) of band carboxyl is connected with small peptide RGD's
The polymer dissolution that 0.5g (0.025 mmol) embodiment 12 is obtained in the dinethylformamide, makes it cooling with ice/water-bath at 20ml N, the triethylamine and the nitrobenzyl chloroformate ester that add equivalent then, at 0 ℃ of stirring reaction 24h, add 20mg (0.058 mmol) RGD then, room temperature reaction 24h, filter out insolubles, vacuum concentration settles out with a large amount of ether, and uses N, dinethylformamide washing three times, 25 ℃ of following vacuum-dryings are to constant weight.
Embodiment 17: the polymkeric substance multipolymer of rac-Lactide (carbonic ether with) of band carboxyl is connected with glucose
The polymkeric substance (28.6 μ mol COOH) that 0.1g embodiment 12 is obtained is dissolved in 2ml DMSO, add and contain in the DMSO solution of 6.5mg CDI, 60 ℃ add amino functional after down stirring 24h glucose (16.9mg, 57.1 μ mol) and 2ml DMSO mixing solutions, 60 ℃ are stirred 24h down, are cooled to room temperature then, vacuum concentration, use a large amount of methanol extractions, product is given a baby a bath on the third day after its birth inferior with ethanol, and 25 ℃ of following vacuum-dryings are to constant weight.
Embodiment 18: the polymkeric substance multipolymer of rac-Lactide (carbonic ether with) of band carboxyl is connected with lactose
The polymkeric substance (30 μ mol COOH) that 0.5g embodiment 12 is obtained is dissolved in 2ml DMSO, poly-adding contains in the DMSO solution of 68mg CDI, after stirring 24 under 60 ℃, add amino functional lactose (20mg) and 2ml DMSO mixing solutions, 60 ℃ of stirring 24h down are cooled to room temperature then, vacuum concentration, use a large amount of methanol extractions, product is given a baby a bath on the third day after its birth inferior with ethanol, and 25 ℃ of following vacuum-dryings are to constant weight.
Claims (3)
1. be with the annular aliphatic carbonate monomer 2-methyl-2-alkynes third oxygen carbonyl trimethylene carbonate of three bond lateral group, its structural formula is:
2. the preparation method of the annular aliphatic carbonate monomer of band three bond lateral group as claimed in claim 1 is characterized in that, step and condition are as follows:
(1) 2,2-dimethylol propionic acid and potassium hydroxide reaction generate 2,2-dimethylol propionic acid salt; 100 ℃ of temperature of reaction, reaction times 1～2h, solvent are DMF;
(2) 2,2-dimethylol propionic acid salt and the reaction of 3-propargyl bromide, the 3-propargyl bromide is added drop-wise in (1) gained salts solution with constant pressure funnel, reacts 24 hours, and 30～40 ℃ of temperature of reaction obtain 2-methyl-2-alkynes third oxygen carbonyl-1, ammediol;
(3) 2-methyl-2-alkynes third oxygen carbonyl-1, ammediol and Vinyl chloroformate reaction, catalysts is a triethylamine, solvent is a tetrahydrofuran (THF), 0 ℃ of temperature of reaction, reaction times 2～12h obtains 2-methyl-2-alkynes third oxygen carbonyl trimethylene carbonate.
3. monomeric according to claim 1 application is characterized in that, this monomer carry out ring-opening polymerization or with the ring-opening polymerization of aliphatics cyclic ester monomer, obtain the multipolymer of monomeric multipolymer or monomer and aliphatics cyclic ester monomer.
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| CN105542143B (en) * | 2015-12-24 | 2017-07-18 | 常州南京大学高新技术研究院 | Fatty poly-ester carbonate containing epoxide group and preparation method thereof |
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