CN104130235B - Biodegradable polyester and preparation methods of biodegradable polyester and O-carboxyanhydride monomer - Google Patents
Biodegradable polyester and preparation methods of biodegradable polyester and O-carboxyanhydride monomer Download PDFInfo
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- CN104130235B CN104130235B CN201410258838.0A CN201410258838A CN104130235B CN 104130235 B CN104130235 B CN 104130235B CN 201410258838 A CN201410258838 A CN 201410258838A CN 104130235 B CN104130235 B CN 104130235B
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
- C07D317/32—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- 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
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Abstract
The invention discloses biodegradable polyester and preparation methods of the biodegradable polyester and an O-carboxyanhydride monomer, and belongs to the technical fields of amino acids and polymers. The preparation method of the O-carboxyanhydride monomer comprises the following steps: (1) dissolving an alpha-amino acid in a mixed solvent, to obtain an alpha-amino acid solution; (2) at the temperature of -80 to 15 DEG C, dropwise adding a sodium nitrite aqueous solution into the alpha-amino acid solution, after completion of dropwise adding, continuing to carry out a reaction for 5 min to 4 h at the temperature of -80 to 15 DEG C, then heating up to 10 to 100 DEG C, carrying out the reaction until the solution is clear and transparent, and purifying to obtain an alpha-hydroxy acid; and (3) adding the alpha-hydroxy acid, triphosgene and a catalyst into a reaction device, then adding a solvent to dissolve, carrying out a reaction for 2 h to 3 d at the temperature of 0 to 100 DEG C, and thus obtaining the O-carboxyanhydride monomer. The preparation method of the O-carboxyanhydride monomer has the advantages of mild reaction conditions, strong selectivity, low cost, high yield, and safe and convenient use.
Description
Technical field
The present invention relates to aminoacid and technical field of polymer are and in particular to a kind of Biodegradable polyester and biodegradation gather
Ester and the preparation method of five-membered cyclic carboxylic acid anhydride monomer.
Background technology
Polyester has good biological degradability and biocompatibility, is widely used as Thermosensitive Material Used for Controlled Releasing of Medicine and group weaver
Journey material.Polyester is obtained or is obtained by the ring-opening polymerisation of annular lactone typically by the polycondensation reaction of diacid and glycol.
Diacid and glycol are all the products of petrochemical industry, and oil is non-renewable, price is high, and exhausted at last, so in recent years, from can
The regenerated resources synthesizing polyester that sets out is paid high attention to.
With the development of amino acid monomer, biodegradated polymer materal is prepared based on the aminoacid of biomass source and is subject to
Pay high attention to.In prior art, the method using Amino acid synthesis biodegradable polymer mainly first synthesizes five yuan
Cyclic carboxylic acids acid anhydride (o-carboxyanhydride, oca) monomer, then makes oca monomer be polymerized under catalyst action, obtains height
Molecular material.As bourissou seminar propose a kind of method of polyester synthesis [j.am.chem.soc.2006,128,
16442-16443], first with alpha-hydroxy acid (lactic acid) synthesizing five-membered ring shape carboxylic acid anhydrides (o-carboxyanhydride, oca)
Monomer, recycles DMAP (dmap) catalysis lactic acid oca monomer polymerization, obtains molecular weight and molecular weight distribution is controlled
Polyester.But, the method preparation of phosgene and surpalite is mainly passed through in the preparation of oca monomer, and phosgene is gas, surpalite is liquid
Body, highly volatile and there is severe toxicity, face in the application and be difficult to transport, storage, the problems such as the personal safety of operator, and no
Method carries out industrialization large-scale production.
Lysine is one of essential amino acid, can promote human development, strengthen immunologic function, and is improved maincenter god
Effect through function of organization.Due to some lysine manufacturing enterprises existing, there is a problem of that lysine annual capacity is superfluous, and rely ammonia
Acids macromolecule side chain carries exposed amino, has extensive biomedical applications prospect, so people begin one's study using bad
Propylhomoserin synthesis can give birth to degraded polyester.In prior art, document [j.am.chem.soc.2000,122,6524-6525] reports
A kind of method of polyester of being degraded based on lysine synthesising biological, it adopts 150 DEG C of melt polymerization 3h, and subsequent vacuum polymerization obtains for 5 days
Arrive.But, the molecular weight of polyesters of the method preparation is 3300 it is impossible to reach materials'use rank.
Content of the invention
Present invention aim to address application phosgene, surpalite produce play in the preparation method of oca monomer in prior art
Poison it is difficult to operation, the molecular weight of lysine family macromolecule low it is impossible to the technical problem of practical application, a kind of biodegradation is provided
Polyester and the preparation method of Biodegradable polyester and five-membered cyclic carboxylic acid anhydride monomer.
The preparation method of the five-membered cyclic carboxylic acid anhydride monomer of the present invention, comprises the following steps:
(1) a-amino acid is dissolved in mixed solvent, after stirring, obtains a-amino acid solution；
The solvent that described mixed solvent is mixed with glacial acetic acid for water, or the solvent for water and sulphuric acid mixing；
(2) at -80～15 DEG C, the Deca sodium nitrite in aqueous solution toward in a-amino acid solution, after being added dropwise to complete, continue -
80～15 DEG C of reaction 5min～4h, are then warmed up to 10～100 DEG C, react to solution clear, after purification, obtain α-hydroxyl
Acid；
Described sodium nitrite is (1～3) with the mol ratio of a-amino acid: 1；
(3), after adding alpha-hydroxy acid and triphosgene in reaction unit, solvent dissolving, at 0～100 DEG C, reaction are added
2h-3d, obtains five-membered cyclic carboxylic acid lactone's monomer；
Described triphosgene is (0.5～3) with the mol ratio of alpha-hydroxy acid: 1.
Preferably, in step (1), described a-amino acid is cbz- lysine, Phenylalanine, leucine, isoleucine
Or L-Valine.
Preferably, in step (3), before adding solvent, add catalyst in reaction unit.
Preferably, described catalyst is a kind of or several in activated carbon, triethylamine, pyridine and dimethylformamide (dmf)
Kind, the quality of catalyst is 1 ‰～the 5% of alpha-hydroxy acid quality.
The present invention also provides the preparation method of Biodegradable polyester, comprises the following steps:
(1) cbz- lysine is dissolved in mixed solvent, after stirring, obtains cbz- lysine solution；
The solvent that described mixed solvent is mixed with glacial acetic acid for water, or the solvent for water and sulphuric acid mixing；
(2) at -80～15 DEG C, the Deca sodium nitrite in aqueous solution toward in cbz- lysine solution, after being added dropwise to complete, continues
React 5min～4h at -80～15 DEG C, be then warmed up to 10～100 DEG C, react to solution clear, after purification, obtain
Cbz- lysine hydroxy acid；
Described sodium nitrite is (1～3) with the mol ratio of cbz- lysine: 1；
(3), after adding cbz- lysine hydroxy acid and triphosgene in reaction unit, add solvent dissolving, in 0～100 DEG C
Under, react 2h-3d, after purification, obtain five-membered cyclic carboxylic acid anhydride monomer；
Described triphosgene is (0.5～3) with the mol ratio of cbz- lysine hydroxy acid: 1；
(4) under nitrogen protection, five-membered cyclic carboxylic acid anhydride monomer is dissolved in solvent, adds catalyst and initiator, 10
～100 DEG C of reaction 5min～72h, after purification, obtain polyester；
The catalyst of described step (4), initiator, the mol ratio of five-membered cyclic carboxylic acid anhydride monomer are (13～1000): (13
～1000): 1；
(5) the polyester deprotection obtaining step (4), sedimentation after purification, obtains Biodegradable polyester.
Preferably, in step (3), before adding solvent, add catalyst in reaction unit.
Preferably, described catalyst is one or more in activated carbon, triethylamine, pyridine and dimethylformamide, urges
The quality of agent is 1 ‰～the 5% of cbz- lysine hydroxy acid quality.
Preferably, in step (4), described catalyst is dimethylamino naphthyridine (dmap) or methoxypyridine.
Preferably, in step (4), described initiator is isobutanol, n-butyl alcohol, n-amyl alcohol, isoamyl alcohol, neopentyl alcohol and poly-
Right is one or more of 2～300 poly glycol monomethyl ether.
The Biodegradable polyester of the present invention, structural formula is as shown in formula i:
In formula, n=13～600, r is c4-c10Alkyl orWherein, m=2～300.
Beneficial effects of the present invention:
(1) preparation method of the five-membered cyclic carboxylic acid anhydride monomer of the present invention utilizes Solid triphosgene to prepare oca monomer, has
Reaction condition is gentle, and selectivity is strong, low cost, high income, and safe and convenient to use, the advantage such as low for equipment requirements can be used in
Large-scale industrial production；
(2) Biodegradable polyester of the present invention, molecular weight is high, and achieves living polymerization, can be used in industrial metaplasia
Produce, and be widely used in biomedical materials field.
Brief description
Fig. 1 is the n of the embodiment of the present invention 1 preparationε- cbz- lysine hydroxy acid nmr spectrum (1hmr)；
Fig. 2 be the embodiment of the present invention 1 preparation oca monomer nmr spectrum (1hmr)；
Fig. 3 is the poly- n of the embodiment of the present invention 6 preparationε- cbz- lysine hydroxy acid nuclear magnetic resonance, NMR (1Hmr) spectrogram；
Fig. 4 is the poly- n of the embodiment of the present invention 6 preparationεThe gel permeation chromatography (gpc) of-cbz- lysine hydroxy acid；
Fig. 5 be the embodiment of the present invention 6 preparation Biodegradable polyester nuclear magnetic resonance, NMR (1Hmr) spectrogram.
Specific embodiment
In order to further appreciate that the present invention, with reference to specific embodiment, the preferred embodiments of the invention are retouched
State but it is to be understood that these descriptions are simply to further illustrate the features and advantages of the present invention rather than to patent of the present invention
The restriction requiring.
The preparation method of five-membered cyclic carboxylic acid anhydride monomer, comprises the following steps:
(1) a-amino acid is dissolved in mixed solvent, after stirring, obtains a-amino acid solution；
Wherein, a-amino acid can be in cbz- lysine, Phenylalanine, leucine, isoleucine and L-Valine
Plant or several；
The solvent that mixed solvent is mixed with glacial acetic acid for water, or the solvent for water and sulphuric acid mixing, when mixed solvent is
During the solvent that water is mixed with glacial acetic acid, in mixed solvent, glacial acetic acid concentration is 1～10mol/l, when mixed solvent is water and sulphuric acid
During the solvent of mixing, in mixed solvent, sulfuric acid concentration is 1～1.25mol/l；
Whipping process does not limit, as long as a-amino acid can be dissolved in mixed solvent；
(2) in -80～15 DEG C (consideration preparation costs, preferably 0～5 DEG C), the Deca toward in the a-amino acid solution of step (1)
Sodium nitrite in aqueous solution, after being added dropwise to complete, continues to react 5min～4h at -80～15 DEG C, is then warmed up to 10～100 DEG C, instead
Should be to solution clear, General reactions 12～48h, after purification, obtain alpha-hydroxy acid；
Wherein, the sodium nitrite total amount in the sodium nitrite in aqueous solution of Deca and the a-amino acid in a-amino acid reactant liquor
Mol ratio be (1～3): 1, the concentration of sodium nitrite in aqueous solution does not limit, preferred concentration be 1.5-3mol/l, time for adding
For 30min-2h, drop rate drips/min for 1/s-12；
Above-mentioned alpha-hydroxy acid purge process knows technology for field personnel, generally comprises extraction, washing, drying, filtration, concentrates
And recrystallization, extract can be ethyl acetate, generally adopt in ethyl acetate, ether, oxolane or dichloromethane
Kind, with petroleum ether jointly to the reactant liquor recrystallization containing alpha-hydroxy acid；Present embodiment provides a kind of purification process, but is not limited to
This: add water in reacted solution, be extracted with ethyl acetate repeatedly, concentrated hydrochloric acid washs, organic layer is done with anhydrous sodium sulfate
Dry, filter, concentrated in vacuo, then use ether, petroleum ether (1:3) recrystallization, obtain crystal, i.e. alpha-hydroxy acid；
The reactive chemistry equation of step (2) is as follows:
(3), under nitrogen protection, add the alpha-hydroxy acid that step (2) obtains in reaction unit, and add triphosgene, Ran Houjia
Enter solvent dissolving, at 0～100 DEG C, after reaction 2h-3d, after purification, obtain oca monomer；
Wherein, solvent is thf, toluene, ether, acetonitrile, dioxane, ethyl acetate, dichloromethane or chloroform；Three light
Gas is stable solid, and molten boiling point is high, and volatility is low, stable in properties, and in boiling point, only a small amount of decomposition, has hypotoxicity, three
Phosgene is (0.5～3) with the mol ratio of alpha-hydroxy acid: 1；
Carry out for accelerating reaction, first can also add catalyst, catalysis in reaction unit before adding solvent dissolving
Agent can for activated carbon, triethylamine, pyridine, in dmf one or more, the quality of catalyst be alpha-hydroxy acid quality 1 ‰～
5%；
The purge process of above-mentioned oca monomer for field personnel know technology, generally comprise filtrations, concentration, washing, drying and
Recrystallization, detailed process is: the catalyst (as do not added catalyst can not have this step) in solution after being filtered to remove reaction,
Concentrated in vacuo, obtain hyalomucoid, then washed with anhydrous n-hexane, be dried to obtain solid, then use absolute ether, anhydrous just own
Alkane recrystallization；
The reactive chemistry equation of step (3) is as follows:
The preparation method of the Biodegradable polyester of the present invention, including step (1)-(5), wherein, step (1)-(3) are to prepare
Oca monomer, its preparation method is the preparation method of above-mentioned oca monomer, is the preparation that a-amino acid adopts cbz- lysine
Process, other guide is identical, and here is omitted, and the process of step (4) and (5) is as follows:
(4) under nitrogen protection, oca monomer is dissolved in solvent, adds catalyst and initiator, 10～100 DEG C of reactions
5min～72h, through ether sedimentation, centrifugation, after vacuum drying, obtains polyester；
Wherein, solvent is one or more of dichloromethane (dcm), chloroform and toluene, and catalyst is dmap or methoxy
Yl pyridines, initiator is isobutanol, n-butyl alcohol, n-amyl alcohol, isoamyl alcohol, neopentyl alcohol and polyethyleneglycol that the degree of polymerization is 2～300
One or more of methyl ether, catalyst, initiator, the mol ratio of five-membered cyclic carboxylic acid anhydride monomer are (13～1000): (13～
1000): 1, reaction temperature is preferably 0-60 DEG C.
The reactive chemistry equation of step (4) is as follows:
(5) benzyloxycarbonyl group (cbz) protection sloughed by the polyester obtaining step (4), and sedimentation is after purification, you can to biodegradation
Polyester；
Wherein, deprotection method can be acidolysis under catalytic hydrogenation, or acid condition, and the present invention provides a kind of concrete mistake
Journey, but not limited to this: polyester is dissolved in trifluoroacetic acid, is subsequently adding excessive hbr, at 10 DEG C～50 DEG C reaction 3～
12h.
In the chemical equation of the present invention, r1Represent the side-chain radical of a-amino acid, be those skilled in the art's known technology, by
The species of a-amino acid determines, when preparing Biodegradable polyester, r1For the side-chain radical of lysine, that is,R generation
The alkyl chain of table alcohols initiator, generally c4-c10Alkyl, or representM=2～300.
The Biodegradable polyester of the present invention, structural formula is as shown in formula i:
In formula, n=13～600, r is c4-c10Alkyl orWherein, m=2～300.
With reference to embodiments and accompanying drawing further illustrates the present invention.
Embodiment 1
When a-amino acid is nεDuring-cbz- lysine, the preparation of oca monomer:
(1) take 50ml there-necked flask to dry, add 0.28gn in there-necked flaskε- cbz- lysine, adds 2.5ml
Water and 2.5ml acetic acid, stir, obtain nε- cbz- lysine solution；
(2) ice-water bath keeping temperature 0-5 DEG C, to nεIn-cbz- lysine solution, Deca 1ml sodium nitrite in aqueous solution is (dense
Degree 2mol/l), time for adding is 30min, and after completion of dropping, keeping temperature 0-5 DEG C reacts 30min；Then remove frozen water, 25
DEG C react to solution homogeneous phase transparent, obtain containing nεThe reactant liquor of-cbz- lysine hydroxy acid；
(3) to containing nεAdd 5ml water in the reactant liquor of-cbz- lysine hydroxy acid, extracted three times with 5ml ethyl acetate,
5ml concentrated hydrochloric acid washes twice, organic layer anhydrous sodium sulfate drying, filters, concentrated in vacuo, and adds a small amount of toluene, is spin-dried for residual
Remaining ice glacial acetic acid, obtains yellow oily liquid；It is subsequently adding 1.5ml methanol, 1.5ml water, k2co3Adjust ph=8-9, hydrolyze 3h；
Add 2ml water, be spin-dried for methanol, be extracted twice with 5ml ethyl acetate, leave water layer, water layer adjusts ph=2 with 1m hydrochloric acid, then
Extracted three times with 5ml ethyl acetate, 5ml concentrated hydrochloric acid washes twice, organic layer anhydrous sodium sulfate drying, is spin-dried for, normal hexane is washed
Wash, be dried；Then use ether, petroleum ether (1:3) recrystallization, obtain white crystal 0.15g, yield 52%, i.e. nε- cbz- relies ammonia
Sour hydroxy acid；
(4) take 50ml there-necked flask, add 0.28gn in there-necked flaskε- cbz- lysine hydroxy acid, adds 0.2g solid three
Phosgene, adds 3mg activated carbon and 40ul triethylamine, adds the dissolving of 7ml anhydrous tetrahydro furan, after stirring 5min, 25 DEG C of stirrings
Reaction 24h, obtains the solution containing oca monomer；
(5) it is filtered to remove activated carbon and the triethylamine salt in the solution containing oca monomer, concentrated in vacuo, obtain yellow saturating
Bright mucus, then washed twice with 20ml anhydrous n-hexane, it is dried to obtain pale solid, then use absolute ether, anhydrous just own
Alkane recrystallization (11:2), obtains white benzyloxycarbonyl group lysine hydroxy acid crystal 0.19g, i.e. oca monomer, yield 67%.
Fig. 1 is that the embodiment of the present invention 1 prepares nε- cbz- lysine hydroxy acid nmr spectrum (1hmr)；Fig. 2 is this
The oca monomer of bright embodiment 1 preparation nmr spectrum (1Hmr), can illustrate, the present invention is prepared for by Fig. 1 and Fig. 2
Oca monomer.
Embodiment 2
When a-amino acid is for Phenylalanine, the preparation of oca monomer:
(1) take 50ml there-necked flask to dry, add 0.826g Phenylalanine in there-necked flask, adding 20ml concentration is
The sulphuric acid of 1.25mol/l, stirs, and obtains Phe solution；
(2) ice-water bath keeping temperature 0-5 DEG C, the Deca 5ml sodium nitrite in aqueous solution (concentration in Phe solution
2mol/l), time for adding is 1h, and after completion of dropping, keeping temperature 0-5 DEG C reacts 30min；Then remove frozen water, anti-at 25 DEG C
The reactant liquor containing Phenylalanine hydroxy acid should be obtained to solution homogeneous phase transparent；
(3) add 5ml water in the reactant liquor containing Phenylalanine hydroxy acid, extracted three times with 5ml ethyl acetate, 5ml is dense
Hydrochloric acid washes twice, organic layer anhydrous sodium sulfate drying, filters, concentrated in vacuo, obtains white-yellowish solid, with ethyl acetate,
Petroleum ether (1:2) recrystallization, obtains white crystal 0.61g, i.e. Phenylalanine hydroxy acid, yield 72%；
(4) take 50ml polymerization bottle through evacuating nitrogen charging gas disposal 15min (inflation 3 times) at 80 DEG C, after being cooled to room temperature,
Under nitrogen protection, in there-necked flask, add 0.15g Phenylalanine hydroxy acid, add 0.2g Solid triphosgene, add 40ul pyridine,
Add the dissolving of 7ml anhydrous tetrahydro furan, after stirring 5min, stir 24h at 25 DEG C, obtain the solution containing oca monomer；
(5) it is filtered to remove the pyridiniujm in the solution containing oca monomer, concentrated in vacuo, then washed with anhydrous n-hexane, do
Dry obtain white-yellowish solid, then use oxolane, anhydrous n-hexane recrystallization (1:2), obtain light brown crystalline, that is, oca is mono-
Body, yield is 85%.
Embodiment 3
When a-amino acid is for leucine, the preparation of oca monomer:
(1) take 50ml there-necked flask to dry, add 0.13g leucine in there-necked flask, adding 20ml concentration is
The sulphuric acid of 1mol/l, stirs, and obtains leucine solution；
(2) ice-water bath keeping temperature 5-15 DEG C, the Deca 2ml sodium nitrite in aqueous solution (concentration in leucine solution
1.5mol/l), time for adding is 1.5h, and after completion of dropping, keeping temperature 5-15 DEG C reacts 2h；Then remove frozen water, at 60 DEG C
React to solution homogeneous phase transparent, obtain the reactant liquor containing leucine hydroxy acid；
(3) add 5ml water in the reactant liquor containing leucine hydroxy acid, extracted three times with 5ml ethyl acetate, the dense salt of 5ml
Acid elution twice, organic layer anhydrous sodium sulfate drying, filter, concentrated in vacuo, obtain solid, with ethyl acetate, petroleum ether (1:
2) recrystallization, obtains crystal, i.e. leucine hydroxy acid；
(4) take 50ml polymerization bottle through evacuating nitrogen charging gas disposal 15min (inflation 3 times) at 80 DEG C, after being cooled to room temperature,
Under nitrogen protection, in there-necked flask, add 0.17g leucine hydroxy acid, add 0.38g Solid triphosgene, add 20ul pyridine,
Add the dissolving of 7ml toluene, after stirring 5min, stir 12h at 50 DEG C, obtain the solution containing oca monomer；
(5) it is filtered to remove the pyridiniujm in the solution containing oca monomer, concentrated in vacuo, then washed with anhydrous n-hexane, do
Dry obtain solid, then use oxolane, anhydrous n-hexane recrystallization (1:2), obtain crystal, i.e. oca monomer.
Embodiment 4
When a-amino acid is for isoleucine, the preparation of oca monomer:
(1) take 50ml there-necked flask dry, in there-necked flask add 0.66g isoleucine, add 2.5ml water and
2.5ml acetic acid, stirs, and obtains isoleucine solution；
(2) -10～5 DEG C of ice-water bath keeping temperature, the Deca 5ml sodium nitrite in aqueous solution (concentration in isoleucine solution
1mol/l), time for adding is 1h, after completion of dropping, -10～5 DEG C of reaction 30min of keeping temperature；Then remove frozen water, at 25 DEG C
React to solution homogeneous phase transparent, obtain the reactant liquor containing isoleucine hydroxy acid；
(3) add 5ml water in the reactant liquor containing isoleucine hydroxy acid, extracted three times with 5ml ethyl acetate, 5ml is dense
Hydrochloric acid washes twice, organic layer anhydrous sodium sulfate drying, filters, concentrated in vacuo, obtains solid, with ethyl acetate, petroleum ether
(1:2) recrystallization, obtains crystal, i.e. isoleucine hydroxy acid；
(4) take 50ml polymerization bottle through evacuating nitrogen charging gas disposal 15min (inflation 3 times) at 80 DEG C, after being cooled to room temperature,
Under nitrogen protection, in there-necked flask, add 2g isoleucine hydroxy acid, add 4.1g Solid triphosgene, add 50uldmf, then plus
Enter the dissolving of 7ml toluene, after stirring 5min, stir 12h at 25 DEG C, obtain the solution containing oca monomer；
(5) it is filtered to remove the dmf in the solution containing oca monomer, concentrated in vacuo, then washed with anhydrous n-hexane, it is dried
Obtain solid, then use oxolane, anhydrous n-hexane recrystallization (1:2), obtain crystal, i.e. oca monomer.
Embodiment 5
When a-amino acid is for L-Valine, the preparation of oca monomer:
(1) take 50ml there-necked flask to dry, add 0.234g L-Valine in there-necked flask, adding 20ml concentration is
The sulphuric acid of 1.25mol/l, stirs, and obtains valine solution；
(2) ice-water bath keeping temperature 0-5 DEG C, Deca 1ml sodium nitrite in aqueous solution (concentration 1mol/ in valine solution
L), time for adding is 30min, and after completion of dropping, keeping temperature 0-5 DEG C reacts 30min；Then remove frozen water, react at 40 DEG C
To solution homogeneous phase transparent, obtain the reactant liquor containing L-Valine hydroxy acid；
(3) add 5ml water in the reactant liquor containing L-Valine hydroxy acid, extracted three times with 5ml ethyl acetate, the dense salt of 5ml
Acid elution twice, organic layer anhydrous sodium sulfate drying, filter, concentrated in vacuo, obtain solid, with ethyl acetate, petroleum ether (1:
2) recrystallization, obtains crystal, i.e. L-Valine hydroxy acid；
(4) take 50ml polymerization bottle through evacuating nitrogen charging gas disposal 15min (inflation 3 times) at 80 DEG C, after being cooled to room temperature,
Under nitrogen protection, in there-necked flask, add 1g L-Valine hydroxy acid, add 2.2g Solid triphosgene, add 20ul pyridine, then plus
Enter the dissolving of 7ml toluene, after stirring 5min, stir 12h at 25 DEG C, obtain the solution containing oca monomer；
(5) it is filtered to remove the pyridiniujm in the solution containing oca monomer, concentrated in vacuo, then washed with anhydrous n-hexane, do
Dry obtain solid, then use oxolane, anhydrous n-hexane recrystallization (1:2), obtain crystal, i.e. oca monomer.
Embodiment 6
In conjunction with Fig. 3-5, embodiment 6 is described
The preparation method of Biodegradable polyester:
Take 50ml polymerization bottle through evacuating nitrogen charging gas disposal 15min (inflation 3 times) at 80 DEG C, after being cooled to room temperature, in nitrogen
Under gas shielded, add the cbz lysine oca monomer of 12.3g embodiment 1 preparation.Vacuum is drained, nitrogen displacement 30min.Nitrogen is protected
Add the isobutanol of 51mgdmap and 38ul under shield, be subsequently adding the dissolving of 20ml dichloromethane, after dissolving finishes, be immediately placed in
In 25 DEG C of oil bath pans, its conversion ratio is measured by nuclear-magnetism, treat that its conversion ratio reaches 91% (about 6h), with ether sedimentation, centrifugation point
From (8000r/min, 3min), it is vacuum dried, obtains solid white polymer, i.e. poly- nε- cbz- lysine hydroxy acid.Gpc measures
The number-average molecular weight of solid white polymer is 19.2 × 103.0.5g solid white polymer is dissolved in 3ml trifluoroacetic acid
In, it is subsequently adding 3mlhbr acetum, at 25 DEG C, after reaction 6h, with ether sedimentation, acetone and ether washing, be vacuum dried,
Obtain Biodegradable polyester.
Poly- n to embodiment 6 preparationε- cbz- lysine hydroxy acid carries out gel chromatography detection, testing result such as Fig. 4 and Biao 1
Shown:
Table 1
In table 1, mn is number-average molecular weight, and mw is weight average molecular weight, and mp is summit value, and mz is viscosity-average molecular weight, and mz+1 is z
+ 1 mean molecule quantity, mz/mw is polydispersity index, and mz+1/mw is mz average molecular weight, the wherein list of mn, mw, mp, mz and mz+1
Position is dalton.
Magnetic resonance detection is carried out to the Biodegradable polyester of embodiment 6 preparation, its nuclear magnetic spectrogram is as shown in Figure 5.
Embodiment 7
The preparation method of Biodegradable polyester:
Take 50ml polymerization bottle through evacuating nitrogen charging gas disposal 15min (inflation 3 times) at 80 DEG C, after being cooled to room temperature, in nitrogen
Under gas shielded, add the cbz lysine oca monomer of 30.7g embodiment 1 preparation.Vacuum is drained, nitrogen displacement 30min.Nitrogen is protected
Add the n-amyl alcohol of 100ul methoxypyridine and 91ul under shield, be subsequently adding the dissolving of 30ml dichloromethane, after dissolving finishes,
It is immediately placed in 40 DEG C of oil bath pans, its conversion ratio is measured by nuclear-magnetism, treat that its conversion ratio reaches 91% (about 30min), use ether
Sedimentation, centrifugation (8000r/min, 3min), vacuum drying, obtain solid white polymer.Gpc measures white solid polymerization
The number-average molecular weight of thing is 24.8 × 103.The polymer 2g of gained is dissolved in 10ml trifluoroacetic acid, is subsequently adding
10mlhbr acetum, at 40 DEG C, reacts 4h.With ether sedimentation, acetone and ether washing.Vacuum drying, you can to biological fall
Solution polyester.
Embodiment 8
The preparation method of Biodegradable polyester:
Take 50ml polymerization bottle through evacuating nitrogen charging gas disposal 15min (inflation 3 times) at 80 DEG C, after being cooled to room temperature, in nitrogen
Under gas shielded, add the cbz lysine oca monomer of 21.5g embodiment 1 preparation.Vacuum is drained, nitrogen displacement 30min.Nitrogen is protected
Add the neopentyl alcohol of 42.7mgdmap and 31mg under shield, be subsequently adding the dissolving of 30ml dichloromethane, after dissolving finishes, put immediately
Enter in 25 DEG C of oil bath pans, its conversion ratio is measured by nuclear-magnetism, treat that its conversion ratio reaches 91% (about 6h), with ether sedimentation, centrifugation
Separate (8000r/min, 3min), vacuum drying, obtain solid white polymer.The number that gpc measures solid white polymer is equal
Molecular weight is 44.7 × 103.The polymer 1g of gained is dissolved in 5ml trifluoroacetic acid, is subsequently adding 5mlhbr acetum,
At 30 DEG C, react 3h.With ether sedimentation, acetone and ether washing.Vacuum drying, you can to Biodegradable polyester.
Obviously, the explanation of above example is only intended to help and understands the method for the present invention and its core concept.Should refer to
Go out, for the those of ordinary skill of described technical field, under the premise without departing from the principles of the invention, can also be to this
Bright carry out some improve and modify, these improve and modify also fall in the protection domain of the claims in the present invention.
Claims (6)
1. the preparation method of Biodegradable polyester is it is characterised in that comprise the following steps:
(1) cbz- lysine is dissolved in mixed solvent, after stirring, obtains cbz- lysine solution；
The solvent that described mixed solvent is mixed with glacial acetic acid for water, or the solvent for water and sulphuric acid mixing；
(2) at -80～15 DEG C, the Deca sodium nitrite in aqueous solution toward in cbz- lysine solution, after being added dropwise to complete, continues -80
～15 DEG C of reaction 5min～4h, are then warmed up to 10～100 DEG C, react to solution clear, after purification, obtain cbz- and rely ammonia
Sour hydroxy acid；
Described sodium nitrite is (1～3) with the mol ratio of cbz- lysine: 1；
(3), after adding cbz- lysine hydroxy acid and triphosgene in reaction unit, add solvent dissolving, at 0～100 DEG C,
Reaction 2h-3d, after purification, obtains five-membered cyclic carboxylic acid anhydride monomer；
Described triphosgene is (0.5～3) with the mol ratio of cbz- lysine hydroxy acid: 1.
(4) under nitrogen protection, five-membered cyclic carboxylic acid anhydride monomer is dissolved in solvent, adds catalyst and initiator, 10～100
DEG C reaction 5min～72h, after purification, obtain polyester；
The catalyst of described step (4), initiator, the mol ratio of five-membered cyclic carboxylic acid anhydride monomer are (13～1000): (13～
1000):1；
(5) the polyester deprotection obtaining step (4), sedimentation after purification, obtains Biodegradable polyester.
2. the preparation method of Biodegradable polyester according to claim 1 is it is characterised in that in step (3), molten adding
Before agent, add catalyst in reaction unit.
3. the preparation method of Biodegradable polyester according to claim 2 is it is characterised in that described catalyst is activity
In charcoal, triethylamine, pyridine and dimethylformamide one or more, the quality of catalyst is cbz- lysine hydroxy acid quality
1 ‰～5%.
4. the preparation method of Biodegradable polyester according to claim 1 is it is characterised in that in step (4), described catalysis
Agent is dimethylamino naphthyridine or methoxypyridine.
5. the preparation method of Biodegradable polyester according to claim 1 is it is characterised in that in step (4), described initiation
Agent is in isobutanol, n-butyl alcohol, n-amyl alcohol, isoamyl alcohol, neopentyl alcohol and poly glycol monomethyl ether that the degree of polymerization is 2～300
Plant or several.
6. Biodegradable polyester is it is characterised in that structural formula is as shown in formula i:
In formula, n=13～600, r is c4-c10Alkyl orWherein, m=2～300.
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Non-Patent Citations (3)
| Title |
|---|
| Dynamic Kinetic Resolution via Dual-Function Catalysis of Modified Cinchona Alkaloids: Asymmetric Synthesis of а-hydroxy Carboxylic Acids;Liang Tang et al.;《J. AM. CHEM. SOC.》;20020503;第124卷(第12期);2870-2871 * |
| Functionalized polyesters from organocatalyzed ROP of gluOCA, the O-carboxyanhydride derived from glutamic acid;Olivier Thillaye du Boullay et al.;《Chem. Commun.》;20080317;1787-1788 * |
| N-Heterocyclic Carbenes as Organocatalysts in Controlled/Loving Ring-Opening Polymerization of O-Carboxyanhydrides Derived from L-Lactic Acid and L-Mandelic Acid;Haidong Xia et al.;《Journal of polymer science, part A: polymer chemistry》;20140526;第52卷;2306-2315 * |
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Effective date of registration: 20191231 Address after: Changzhou City, Jiangsu province Hehai road 213000 No. 9 Patentee after: Changzhou Institute of Energy Storage Materials & Devices Address before: 130022 No. 5625 Renmin Street, Changchun, Jilin, Chaoyang District Patentee before: Changchun Institue of Applied Chemistry, Chinese Academy of Sciences |