CN101550126B - Epsilon-caprolactone derivative and polymer thereof - Google Patents
Epsilon-caprolactone derivative and polymer thereof Download PDFInfo
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- CN101550126B CN101550126B CN200910050425.2A CN200910050425A CN101550126B CN 101550126 B CN101550126 B CN 101550126B CN 200910050425 A CN200910050425 A CN 200910050425A CN 101550126 B CN101550126 B CN 101550126B
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Abstract
The invention relates to an epsilon-caprolactone derivative and polymer thereof. The epsilon-caprolactone derivatives have a structure represented by formula I; the polymer is obtained by homopolymerization with compound represented by formula I or copolymerized by caprolactone, lactide and glycolide (number average molecular weight 5000-50000). The polymer is de-protected to obtain the target polymer. Advantages of the invention lie in that by chemical modification of aliphatic polyester compounds, with guidance of reactive groups in main chains, use of the invention in targeting carrier, medical release and tissue engineering is greatly extended; the invention uses simple materials; has low cost and mild reaction conditions. In formula I, R is a chained alkyl or a chained alkyl substituted by arylcycle.
Description
Technical field
The present invention relates to a kind of epsilon-caprolactone derivative and polymkeric substance thereof.
Background technology
Aliphatic polyester, polycaprolactone (PCL) for example, polylactide (PLA), polyglycolic acid (PGA), due to its good biological degradability, biocompatibility and nontoxicity, obtained research widely, yet most aliphatic polyester is hydrophobic in recent two decades, be difficult for degraded, and lack reactable group, greatly limited its application, the preparation of the biodegradable polymer that therefore contains function side group has been a great concern.Now reported the ring-opening polymerization to lactone or lactide and functionalized monomer, and successful hydroxyl, carbonyl, sulfydryl, amino, carboxyl, the groups such as halogen are introduced main polymer chain, and are obtaining application aspect targeting vector, medicine controlled releasing and organizational project.
In order to improve polymer performance, generally adopt the method for copolymerization, thereby by regulating the kind, ratio etc. of comonomer in multipolymer to change wetting ability, the degradation property of polymkeric substance, reactivity.Robert Langer etc. has reported the preparation method (J.Am.Chem.Soc.1993 that introduces reactable amido functional group in aliphatic polyester the earliest; 115; 11010-11011); first synthesize the amino acid monomer with amino protecting group; then with the copolymerization of different ratios rac-Lactide; last deprotection base, obtains amino and connection freely and has gone up biologically active substance RGD, has greatly increased the range of application of material.Nowadays, under the joint efforts of researcher, develop various novel monomerics, and obtained the different polyester copolymer of performance, become the novel biomaterial of a class.
Summary of the invention
The object of the invention is to, a kind of novel epsilon-caprolactone derivative and polymkeric substance thereof (comprising homopolymer and multipolymer) are provided.
The said epsilon-caprolactone derivative of the present invention, it has structure shown in formula I:
In formula I: R is chain-like alkyl or the chain-like alkyl that replaced by aromatic ring yl, said chain-like alkyl comprises straight chain or with the chain-like alkyl of side chain.
Preferred R is C
1~C
6chain-like alkyl or by C
6~C
20the C that aromatic ring yl replaces
1~C
6chain-like alkyl; Preferred R is C
2~C
6chain-like alkyl or by C
6~C
13the C that aromatic ring yl replaces
2~C
6chain-like alkyl; Best R is the tertiary butyl, or by the C of phenyl or fluorenyl (fluorenyl) replacement
2~C
6chain-like alkyl.
A kind of method of preparing epsilon-caprolactone derivative of the present invention, its key step is: take to Trans-4-Amino Cyclohexanol is raw material, after " replacement ", " oxidation " and " lactonizing " reaction, obtain target compound (compound shown in formula I) successively, its synthetic route is as follows:
Wherein: the implication of R is with described identical above, and compound shown in formula A and B is commercially available product.
Epsilon-caprolactone derivative of the present invention (compound shown in formula I) can be through homopolymerization, or after binary, ternary or terpolymer, obtain the modified poly ester with amino (side chain) with monomer shown in formula II, formula III or formula IV, its number-average molecular weight is 5,000~50,000.This modified poly ester all makes moderate progress at aspects such as degree of crystallinity, wetting ability and degradation rates, can be used for the fields such as bio-pharmaceuticals.
Embodiment
A kind of method of preparing epsilon-caprolactone derivative of the present invention, its key step is: will be placed in reactor to compound shown in Trans-4-Amino Cyclohexanol (compound shown in formula A), sodium bicarbonate, formula B and water, 10 ℃~60 ℃ reactions 1~5 hour, through extraction (as ethyl acetate etc.) concentrated and dry compound as shown in formula C;
By compound shown in formula C, through Jones ' reagent, (method for making of said Jones ' reagent is: take 2.6g chromium trioxide and be dissolved in the 2.3mL vitriol oil and 4mL water, be diluted to 10mL) oxidation, through extraction (as ethyl acetate etc.) concentrated and dry compound as shown in formula D;
Compound shown in formula D, m-chloro-benzoic acid peroxide (m-CPBA) and halohydrocarbon (as methylene dichloride etc.) are placed in to reactor, in 10 ℃~50 ℃ stirring reactions at least 24 hours, after washing, dry and recrystallization, obtain target compound (compound shown in formula I).
The copolymerization of compound shown in compound shown in formula I and formula II of take is example, elaboration is with the preparation method of the modified poly ester of amino (side chain), its key step is: by compound shown in formula I (monomer) and compound shown in formula II (monomer) in molar ratio 1: the ratio of (1~20) is mixed, with tin class, zinc class or aluminium metal compound (as: stannous iso caprylate, aluminum isopropylate or zinc ethyl etc.), be catalyzer, in 100 ℃~150 ℃ polyreactions, within 24 hours~72 hours, obtain multipolymer;
The multipolymer of above-mentioned gained is mixed with tetrahydrofuran (THF) (solvent); 25 ℃~50 ℃, catalyzer (Pd/C) exist and atmosphere of hydrogen in; react 24 hours~72 hours (sloughing the protecting group in the polymkeric substance of gained), filtration catalizer, concentrated, in ether, precipitation obtains subject polymer [with the modified poly ester of amino (side chain)].
Superiority of the present invention is: one, by the simple organic reaction of three steps, obtained a class completely newly with the novel 6-caprolactone class monomer of side group protecting group, raw material is simple and easy to get, low price, reaction temperature and, and transformation efficiency is high, is applicable to scale operation; Two, by the simple deprotection reaction of a step, can on side chain, introduce one and can react amino group, greatly expand the application of polyester material in the aspects such as biology, pharmacy; Three, the change of polyester construction, can realize the modification to performances such as this type of polymer crystallization degree, wetting ability and degradation rates.
Below by example, the present invention is further elaborated, and its object is only better to understand content of the present invention.Therefore example does not limit the scope of the invention.
Embodiment 1
The preparation of 4-carboxylamine benzyl ester hexalin:
Trans to Trans-4-Amino Cyclohexanol (10.3g, 89.4mmol), sodium bicarbonate (18.8g, 224mmol) is placed in the round-bottomed flask of 1L, adds 300mL water, stirs, and it is dissolved, and forms a colourless transparent solution.Solution is placed in water-bath, then drips chloroformic acid benzyl ester (16.6mL, 116mmol), continues 10 minutes~20 minutes, starts to be heated to 40 ℃~50 ℃, and keeps 1 hour~2 hours, ethyl acetate and n-butanol extraction for product after dropwising.Merge organic layer, use subsequently hydrochloric acid, sodium chloride solution washing, anhydrous sodium sulfate drying spends the night, and filters, and has been concentrated into crystal and has produced.Product, just in former solvent recrystallization, obtains white needle-like crystal.Productive rate is 80%.
1H?NMR(CDCL
3):δ=1.12-2.15(-(C
H 2 )
2-CH(OH)-(C
H 2 )
2-),3.43(1H,-C
H-NH-),3.58(-C
H-OH-),4.62(-N
H-),5.09(-C
H 2 -Ph),7.30-7.37(5H,-C
6 H 5 ).
The preparation of 4-carboxylamine benzyl ester pimelinketone:
4-carboxylamine benzyl ester hexalin (24.9g, 0.1mol) joins in two mouthfuls of round-bottomed flasks of 500mL, then adds about 300mL~350mL acetone, forms a dispersion system.Round-bottomed flask is placed in ice-water bath, then drips Jones ' reagent (approximately 25mL~30mL), and stirring is spent the night.Filter, collect filtrate, spin off acetone, resistates, is extracted with ethyl acetate to neutral with saturated sodium bicarbonate washing, combining extraction liquid, and sodium-chlor washing, dried over sodium sulfate is spent the night, and filters, and spins off solvent, with ethyl acetate/normal hexane recrystallization.Productive rate is 50%.
1H?NMR(CDCL
3):δ=1.65-2.45(-(C
H 2 )
2-C(O)-(C
H 2 )2-),3.99(-C
H-NH-),4.80(-N
H-),5.14(-C
H 2 -Ph),7.30-7.38(-C
6 H 5 ).
The preparation of 4-carboxylamine benzyl ester-6-caprolactone (target compound):
4-carboxylamine benzyl ester pimelinketone (13.15g, 0.05mol) is placed in 500mL round-bottomed flask, adds 100mL methylene dichloride to dissolve, ice-water bath, (12.99g, 80% content 0.06mol) drop in solution after being dissolved in 200mL methylene dichloride m-CPBA.Under reactant room temperature, continue to stir 14 hours~24 hours.Crude product Sulfothiorine, sodium bicarbonate, sodium-chlor washs respectively three times, and dried over sodium sulfate is spent the night, and filters and spins off solvent, ethyl acetate/normal hexane recrystallization.Productive rate 80%.
1HNMR(CDCL
3):δ=1.52-2.29(-C
H 2 -CH(NH)-C
H 2 -),2.53-2.62(-C(O)-C
H 2 -CH
2-),3.82(-C
H-NH-),4.14-4.31(-O-C
H 2 -CH
2-)4.76(-N
H-),5.09(-C
H 2 -Ph),7.30-7.37(-C
6 H 5 );
13CNMR(CDCL
3):δ=29.5(-CH
2-CH
2-C(O)O-),30.9(-CH
2-CH
2-C(O)O-),36.1(-CH
2-CH
2-O-C(O)),51.5(-CH
2-CH(NH)-CH
2-),66.1(C
6H
5-CH
2-O-C(O)),67.4(-CH
2-CH
2-O-C(O)),128.7,128.8,129.1,136.8(C
6H
5-),156.0(-O-CO-NH-),175.6(-CH
2-CO-O-)。
Embodiment 2
Side chain is with the preparation of amino polycaprolactone:
4-carboxylamine benzyl ester-6-caprolactone and 6-caprolactone mix by different mol ratio example that (mol ratio of 4-carboxylamine benzyl ester-6-caprolactone and 6-caprolactone is respectively 1: 3; 1: 4; 1: 6; 1: 8; 1: 10; 1: 19) mix and to be placed in polymerizing pipe, 1/1000 the stannous iso caprylate of whole monomer molar numbers of take is catalyzer, at 120 ℃~150 ℃, polyreaction 24 hours~48) hour, then cooling, chloroform dissolves, and in methyl alcohol, precipitates, and obtains multipolymer.
Get above-mentioned multipolymer (0.5 gram~1 gram), be dissolved in 10mL~20mL tetrahydrofuran (THF), the Pd/C (catalyzer) that adds 0.3 gram~0.6 gram, repeatedly after hydrogen exchange, at 25 ℃~50 ℃, under atmosphere of hydrogen, react 24 hours~72 hours, reaction finishes rear filtering palladium carbon, spins off tetrahydrofuran (THF), and chloroform dissolves, in ether, precipitate, obtain target multipolymer.The nuclear magnetic data of target multipolymer is as follows:
1HNMR(CDCL
3):δ=1.35-1.41(-COCH
2CH
2C
H 2 CH
2CH
2O-),1.64-1.68(-COCH
2C
H 2 C-H
2C
H 2 CH
2O-),1.79-1.86(-COCH
2C
H 2 CH(NH)C
H 2 CH
2O-),2.29-2.37(-COC
H 2 CH
2CH
2CH
2-CH
2O-),2.38-2.40(-COC
H 2 CH
2CH(NH)CH
2CH
2O-),3.75(-COCH
2CH
2C
H(NH)CH
2CH
2O-),4.04-4.13(-COCH
2CH
2CH
2CH
2C
H 2 O-),4.14-4.23(-COCH
2CH
2CH(NH)CH
2C
H 2 O-)。
Claims (5)
2. epsilon-caprolactone derivative as claimed in claim 1, is characterized in that, wherein R is C
2~C
6chain-like alkyl or by C
6~C
13the C that aromatic ring yl replaces
2~C
6chain-like alkyl.
3. epsilon-caprolactone derivative as claimed in claim 2, is characterized in that, wherein R is by the C of phenyl or fluorenyl replacement
2~C
6chain-like alkyl.
4. a modified poly ester, its by compound shown in formula I through homopolymerization, or with compound copolymerization shown in formula II, formula III or formula IV after obtain, the number-average molecular weight of gained modified poly ester is 5,000~50,000;
The definition of R is described in claim 1 or 2.
5. a modified poly ester, it is characterized in that, said modified poly ester is by compound shown in formula I and compound shown in formula II in molar ratio 1: the ratio of (1~20) is mixed, with tin class, zinc class or aluminium metal compound, it is catalyzer, in 100 ℃~150 ℃ polyreactions, within 24 hours~72 hours, obtain multipolymer, the number-average molecular weight of gained multipolymer is 5,000~50,000;
The definition of R is as described in any one in claim 1~3;
The multipolymer of gained mixes with tetrahydrofuran (THF), 25 ℃~50 ℃, catalyzer exist and atmosphere of hydrogen in, react 24 hours~72 hours, filtration catalizer, concentrated, in ether, precipitation obtains subject polymer, i.e. described modified poly ester.
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CN1560049A (en) * | 2004-03-09 | 2005-01-05 | 华东理工大学 | Lactone monomer of medical macromolecule material with biodegradability and preparation process thereof |
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Non-Patent Citations (2)
Title |
---|
戴炜枫等.新型官能团化聚己内酯的研究进展.《高分子通报》.2008,(第9期),第10-19页. |
新型官能团化聚己内酯的研究进展;戴炜枫等;《高分子通报》;20080930(第9期);第10-19页 * |
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