CN101550126A - Epsilon-caprolactone derivative and polymer thereof - Google Patents
Epsilon-caprolactone derivative and polymer thereof Download PDFInfo
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- CN101550126A CN101550126A CNA2009100504252A CN200910050425A CN101550126A CN 101550126 A CN101550126 A CN 101550126A CN A2009100504252 A CNA2009100504252 A CN A2009100504252A CN 200910050425 A CN200910050425 A CN 200910050425A CN 101550126 A CN101550126 A CN 101550126A
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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), because its favorable biological degradability, biocompatibility and nontoxicity have obtained extensive studies in recent two decades, yet most aliphatic polyester is hydrophobic, be difficult for degraded, and lack the reactable group, greatly limited it and used, the preparation that therefore contains the biodegradable polymer of function side group has received great concern.Now reported ring-opening polymerization to lactone or lactide and functionalized monomer, and successful hydroxyl, carbonyl, sulfydryl, amino, carboxyl, groups such as halogen are introduced main polymer chain, and are obtaining application aspect targeting vector, medicine controlled releasing and the organizational project.
In order to improve polymer performance, generally adopt the method for copolymerization, thereby the kind by regulating comonomer in the multipolymer, ratio etc. 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 the reactable amido functional group in aliphatic polyester the earliest; 115; 11010-11011); the promptly synthetic earlier amino acid monomer that has amino protecting group; then with the copolymerization of different ratios rac-Lactide; remove protecting group at last, obtain amino freely and connect having gone up biologically active substance RGD, greatly increased the range of application of material.Nowadays, under the joint efforts of researcher, developed various novel monomerics, and obtained the different polyester copolymer of performance, made it become the novel biomaterial of a class.
Summary of the invention
The objective 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 the formula I:
Among the formula I: R is chain-like alkyl or the chain-like alkyl that replaced by aromatic ring yl, and said chain-like alkyl comprises straight chain or has 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 for preparing epsilon-caprolactone derivative of the present invention, its key step is: being raw material to Trans-4-Amino Cyclohexanol, obtain target compound (compound shown in the formula I) successively after " replacement ", " oxidation " and " lactonizing " reaction, its synthetic route is as follows:
Wherein: the implication of R is described identical with preamble, and compound shown in formula A and the B is a commercially available product.
Epsilon-caprolactone derivative of the present invention (compound shown in the formula I) can be through homopolymerization, or after binary, ternary or terpolymer, obtain having the modified poly ester of amino (side chain) with monomer shown in formula II, formula III or the 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 fields such as bio-pharmaceuticals.
Embodiment
A kind of method for preparing epsilon-caprolactone derivative of the present invention, its key step is: will place reactor to compound shown in Trans-4-Amino Cyclohexanol (compound shown in the formula A), sodium bicarbonate, the formula B and water, 10 ℃～60 ℃ reactions 1～5 hour, through extraction (as ethyl acetate etc.) concentrate and dry formula C shown in compound;
(method for making of said Jones ' reagent is: take by weighing the 2.6g chromium trioxide and be dissolved in the 2.3mL vitriol oil and the 4mL water through Jones ' reagent with compound shown in the formula C, being diluted to 10mL gets final product) oxidation, through extraction (as ethyl acetate etc.) concentrate and dry formula D shown in compound;
Compound shown in the formula D, m-chloro-benzoic acid peroxide (m-CPBA) and halohydrocarbon (as methylene dichloride etc.) are placed reactor,, behind washing, drying and recrystallization, obtain target compound (compound shown in the formula I) in 10 ℃～50 ℃ stirring reactions at least 24 hours.
Copolymerization with compound shown in compound shown in the formula I and the formula II is an example, elaboration has the preparation method of the modified poly ester of amino (side chain), its key step is: with compound (monomer) shown in compound shown in the formula I (monomer) and the formula II in molar ratio 1: the mixed of (1～20), with tin class, zinc class or aluminium metal compound (as: stannous iso caprylate, aluminum isopropylate or zinc ethyl etc.) is catalyzer, gets multipolymer in 24 hours～72 hours in 100 ℃～150 ℃ polyreactions;
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, concentrate, precipitation obtains subject polymer [modified poly ester that has amino (side chain)] in ether.
Superiority of the present invention is: one, obtained the novel 6-caprolactone class monomer that a class completely newly has the side group protecting group by three simple organic reactions of step, raw material is simple and easy to, low price, reaction temperature and, and transformation efficiency height is fit to scale operation; Two, can on side chain, introduce one by simple deprotection reaction of a step and can react amino group, enlarge the application of polyester material on aspects such as biology, pharmacy greatly; 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.
The present invention is further elaborated below by example, and its purpose only is better to understand content of the present invention.Therefore give an actual example and do not limit protection scope of the present invention.
Embodiment 1
The preparation of 4-carboxylamine benzyl ester hexalin:
It is trans that (10.3g, 89.4mmol), (18.8g 224mmol) places the round-bottomed flask of 1L to sodium bicarbonate, adds 300mL water, stirs, and makes its dissolving, forms a colourless transparent solution to Trans-4-Amino Cyclohexanol.Solution places water-bath, and (16.6mL 116mmol), continues 10 minutes～20 minutes, begins to be heated to 40 ℃～50 ℃ after dropwising, and keeps 1 hour～2 hours, product ethyl acetate and n-butanol extraction to drip chloroformic acid benzyl ester then.Merge organic layer, use hydrochloric acid subsequently, the sodium chloride solution washing, anhydrous sodium sulfate drying spends the night, and filters, and has been concentrated into crystal and has produced.Product obtains the needle-like crystal of white just in former solvent recrystallization.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:
(24.9g 0.1mol) joins in two mouthfuls of round-bottomed flasks of 500mL 4-carboxylamine benzyl ester hexalin, adds about 300mL～350mL acetone then, forms a dispersion system.Round-bottomed flask places ice-water bath, and (approximately 25mL～30mL), stirring is spent the night to drip Jones ' reagent then.Filter, collect filtrate, spin off acetone, resistates to neutral, is used ethyl acetate extraction with the saturated sodium bicarbonate washing, combining extraction liquid, and the 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) places the 500mL round-bottomed flask, adds the dissolving of 100mL methylene dichloride, ice-water bath, and (12.99g, 80% content 0.06mol) drop in the solution after being dissolved in the 200mL methylene dichloride m-CPBA.Continue under the reactant room temperature to stir 14 hours～24 hours.Crude product Sulfothiorine, sodium bicarbonate, sodium-chlor wash respectively three times, and dried over sodium sulfate is spent the night, and filter to spin 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 has the preparation of amino polycaprolactone:
4-carboxylamine benzyl ester-6-caprolactone and 6-caprolactone mix by the different mol ratio example that (mol ratio of 4-carboxylamine benzyl ester-6-caprolactone and 6-caprolactone was respectively 1: 3; 1: 4; 1: 6; 1: 8; 1: 10; 1: 19) mix and to be placed in the polymerizing pipe, be catalyzer with 1/1000 stannous iso caprylate of whole monomer molar numbers, 120 ℃～150 ℃ following polyreactions 24 hours～48) hour, cooling then, the chloroform dissolving precipitates in methyl alcohol, 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 is repeatedly behind the hydrogen exchange, at 25 ℃～50 ℃, reaction is 24 hours～72 hours under the atmosphere of hydrogen, reaction finishes back filtering palladium carbon, spins off tetrahydrofuran (THF), the chloroform dissolving, in ether, precipitate, obtain the 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)
1, a kind of epsilon-caprolactone derivative, it has structure shown in the formula I:
Among the formula I: 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.
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 the tertiary butyl, or by the C of phenyl or fluorenyl replacement
2～C
6Chain-like alkyl.
4, a kind of modified poly ester, its by compound shown in the formula I through homopolymerization, or with compound copolymerization shown in formula II, formula III or the formula IV after obtain, the number-average molecular weight of gained modified poly ester is 5,000～50,000;
5, as modified poly ester as described in the claim 4, it is characterized in that, said modified poly ester is by compound shown in compound shown in the formula I and the formula II in molar ratio 1: the mixed of (1～20), with tin class, zinc class or aluminium metal compound is catalyzer, gets multipolymer in 24 hours～72 hours in 100 ℃～150 ℃ polyreactions;
The multipolymer of gained mixes with tetrahydrofuran (THF), 25 ℃～50 ℃, catalyzer exist and atmosphere of hydrogen in, react 24 hours～72 hours, filtration catalizer, concentrate, in ether, precipitate and obtain subject polymer.
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|---|---|---|---|
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|---|---|
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| CN101550126B CN101550126B (en) | 2014-02-19 |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102782008A (en) * | 2010-05-26 | 2012-11-14 | 日本合成化学工业株式会社 | Polyester resin, process for production of polyester resin, and aqueous fluid that contains polyester resin |
| CN107298673A (en) * | 2016-04-15 | 2017-10-27 | 华东理工大学 | Epsilon-caprolactone derivative and its preparation method and application |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
-
2009
- 2009-04-30 CN CN200910050425.2A patent/CN101550126B/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Non-Patent Citations (1)
| 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》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102782008A (en) * | 2010-05-26 | 2012-11-14 | 日本合成化学工业株式会社 | Polyester resin, process for production of polyester resin, and aqueous fluid that contains polyester resin |
| CN107298673A (en) * | 2016-04-15 | 2017-10-27 | 华东理工大学 | Epsilon-caprolactone derivative and its preparation method and application |
| CN107298673B (en) * | 2016-04-15 | 2020-06-12 | 华东理工大学 | Epsilon-caprolactone derivative and preparation method and application thereof |
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|---|---|
| CN101550126B (en) | 2014-02-19 |
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