CN1786042A - Catalyzing synthesis of polylactide and polyserine morphodilone from carboxylic acid creatinine guanidine - Google Patents

Catalyzing synthesis of polylactide and polyserine morphodilone from carboxylic acid creatinine guanidine Download PDF

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CN1786042A
CN1786042A CN 200510122436 CN200510122436A CN1786042A CN 1786042 A CN1786042 A CN 1786042A CN 200510122436 CN200510122436 CN 200510122436 CN 200510122436 A CN200510122436 A CN 200510122436A CN 1786042 A CN1786042 A CN 1786042A
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guanidine
creatinine
lactide
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pbmd
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CN100395276C (en
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李弘�
何培茹
李金玲
赵晓娜
白峰
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Nankai University
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Abstract

本发明涉及医用生物降解性聚酯的催化合成方法。采用结构如CRCA所示的羧酸肌酐胍化合物，式中R独立选自CH3－，CH3CH2－，CH3CH2CH2－中的单一化合物为催化剂，催化L－丙交酯(LLA)或D，L－丙交酯(DLLA)或(3S)－3－苄氧甲基－(6S)－6－甲基－吗啉二酮(丝氨酸吗啉二酮)(BMD)的本体活性开环聚合反应，合成指定分子量和窄分子量分布的聚L－丙交酯(PLLA)、聚D，L－丙交酯(PDLLA)和聚丝氨酸吗啉二酮(PBMD)，聚合物具有高度的生物安全性。PBMD可用于合成L－丝氨酸－L－乳酸交替共聚物(P(LSE－LLA))。

Figure 200510122436

The invention relates to a catalytic synthesis method of medical biodegradable polyester. The carboxylic acid creatinine guanidine compound with the structure shown in CRCA is used, where R is independently selected from CH 3 -, CH 3 CH 2 -, CH 3 CH 2 CH 2 - as a catalyst, and catalyzes L-lactide ( LLA) or D, L-lactide (DLLA) or the body of (3S)-3-benzyloxymethyl-(6S)-6-methyl-morpholine dione (serine morpholine dione) (BMD) Living ring-opening polymerization to synthesize poly-L-lactide (PLLA), poly-D, L-lactide (PDLLA) and polyserine morpholine dione (PBMD) with specified molecular weight and narrow molecular weight distribution. The polymer has a high biosafety. PBMD can be used to synthesize L-serine-L-lactic acid alternating copolymer (P(LSE-LLA)).

Figure 200510122436

Description

Synthetic polylactide of carboxylic acid creatinine guanidine catalysis and PBMD
Technical field
The present invention relates to the process for catalytic synthesis of medical use biological degradable polyester.
Background technology
In recent years, along with the fast development of medicine and bioengineered tissue science, both at home and abroad to the demand of medical biodegradable material with good biocompatibility and biological safety in sharp increase.Paid attention to most with aliphatic polyester (mainly be the polylactide class also claims polylactic acid-based), polyamino acid and their multipolymer aspect the synthetic medical biodegradable material, this type of material has excellent biodegradability, biocompatibility (not producing body rejection effect) and biological safety, and (degraded product can participate in body metabolism, noresidue), thereby biomedical, field of pharmacology has extensively, important use, as (1) controlled release drug carrier (as: anticancer and anti-AIDS target medicine carrier); (2) property implanted absorbable tissue engineering materials (as: operating sutures, bone engagement, immobilization material, artificial cartilage, ligament, tendon, blood vessel, ureter propping material etc.).At present both at home and abroad existing a more serious problem at this type of material aspect synthetic is: the inferior tin of octoate catalyst that is widely used in polyreaction has cytotoxicity.Because can't be after the polyreaction with tin-containing catalyst by thoroughly removing in institute's synthetic polymer, this just gives this type of material as human pharmaceutical use, medical material, particularly longer-term Material Used (taking the carrier of medicine for a long time, the longer-term property implanted medical material etc.) brings insecurity hidden danger.Therefore, research and develop novel nontoxic, high-efficiency polymerization catalysts and have a task of top priority that height biological safety medical biodegradable material becomes the focus that the scientists of being engaged in medical macromolecular materials research in the our times various countries pays close attention to and appeals to solve with synthetic.Polymer institute of Nankai University and " functional high molecule material key lab of the Ministry of Education " Li Hong professor and research department thereof are under state natural sciences fund (No.20474030) is subsidized, designed and synthesized nontoxic, no metal, biomimetic type carboxylic acid creatinine guanidine (acetic acid creatinine guanidine, the propionic acid creatinine guanidine, the butanic acid creatinine guanidine) compound, and with carboxylic acid creatinine guanidine (acetic acid creatinine guanidine, the propionic acid creatinine guanidine, the butanic acid creatinine guanidine) compound is a catalyst rac-Lactide [L-rac-Lactide (LLA), D, L-rac-Lactide (DLLA)] and the active ring-opening polymerization of serine morpheline-2,5-dione (BMD) synthesized medical use biological degradable polylactide (PLLA, PDLLA also claims poly(lactic acid)) and PBMD (PBMD).PBMD can be made into L-lactic acid-L-Serine alternating copolymer [english abbreviation: P (LLA-LSE)] after catalytic hydrogenolysis, this amino acid-lactic acid copolymer is having important use (as being used as: the carrier of bioactive species such as cell, the carrier of peptide medicament etc.) aspect organizational project and the medicine controlled releasing.
Summary of the invention
The invention provides the method for synthetic polylactide of catalysis ring-opening polymerization and PBMD, and as nontoxic, the no metal biomimetic type carboxylic acid creatinine guanidine compound and the synthetic method thereof of polymerisation catalysts.
It is catalyzer that the present invention adopts carboxylic acid creatinine guanidine (CRCA), carry out as structural formula (LLA), (DLLA) and cyclic ester class monomer L-rac-Lactide (LLA), the D (BMD), L-rac-Lactide (DLLA) and (3S)-3-benzyloxymethyl-(6S)-the active open loop catalytic polymerization of 6-methyl-morpholine diketone (serine morpheline-2,5-dione) body (BMD)
Figure A20051012243600041
Synthetic have the medical use biological degradable polylactide of specifying molecular weight and narrow molecular weight distributions (PLLA, PDLLA) and PBMD (PBMD).
PLLA is synthesized in carboxylic acid creatinine guanidine catalysis, and PDLLA, PBMD chemical equation are as follows:
M in the formula 1Independently be selected from: LLA, D, L-LA M 2Independently be selected from: BMD
The carboxylic acid creatinine guanidine catalytic polymerization is to be added in the reactor behind monomer rac-Lactide (LLA or DLLA) or serine morpheline-2,5-dione (BMD) and the carboxylic acid creatinine guanidine weighing, monomer/carboxylic acid creatinine guanidine mol ratio is: 50/1-400/1, through vacuumize for three times-the applying argon gas operation after, sealed reactor.In 110-180 ℃ of reaction 24-96 hour.With the reacted rac-Lactide polymerization reaction system of small amount of acetone solvent polymerization, solution is slowly dripped to the polymkeric substance that settles out in the distilled water after the polyreaction.Use N, dinethylformamide dissolving serine morpheline-2,5-dione polymerization reaction system, solution is slowly dripped to the polymkeric substance that settles out in the ether, after the filtration with throw out 40 ℃ of following vacuum-dryings 24 hours, the solid that obtains is polylactide (PLLA or PDLLA) or the PBMD (PBMD) of different number-average molecular weights and molecular weight heterogeneity index PDI=1.07-1.20.
Preferred carboxylic acid creatinine guanidine catalytic polymerization condition is 130-160 ℃ of reaction 96 hours, and productive rate can reach more than 90% under preferred reaction conditions.
Molecular weight determination: with DMF is solvent, and μ-Styragel packed column measures institute's synthetic polymer molecule amount (be with the monodisperse polystyrene standard specimen and proofread and correct through pervasive value) with Waters-410 gel permeation chromatograph (GPC) under the room temperature.
The invention provides a kind of new ring-opening polymerization catalyzer carboxylic acid creatinine guanidine, its molecular structure is shown in CRCA, and substituent R can be methyl, ethyl and propyl group in the formula, corresponding to acetic acid creatinine guanidine, propionic acid creatinine guanidine and butanic acid creatinine guanidine;
Figure A20051012243600052
In the formula: R=CH 3-(acetic acid creatinine guanidine), CH 3CH 2-(propionic acid creatinine guanidine), CH 3CH 2CH 2-(butanic acid creatinine guanidine).
The synthetic of carboxylic acid creatinine guanidine of the present invention is that a certain amount of creatinine is added in the Schlenk flask, behind the air, adds the carboxylic acid (acetic acid, propionic acid, butanic acid) of three times of molar weights under the nitrogen atmosphere, in 25-120 ℃ of reaction 2-3 hour in the strict expeling flask.Nitrogen atmosphere decompression down steams carboxylic acid, can obtain the product carboxylic acid creatinine guanidine after the vacuum-drying, as catalyzer kept dry under the room temperature oxygen free condition.
Preferred carboxylic acid creatinine guanidine synthetic reaction condition is in 90 ℃ of reactions 2.5 hours, and productive rate can reach more than 98% under preferred reaction conditions.
Can be made into poly-(lactic acid-Serine) (lactic acid-Serine alternating copolymer) (P (LLA-LSE)) by PBMD through palladium/carbon catalytic hydrogenolytic cleavage:
Lactic acid is that a certain amount of PBMD (PBMD) is dissolved among the 10mlTHF with the preparation of silk amino acid alternating copolymer [P (LLA-LSE)], adds palladium/carbon (Pd/C) catalyzer of an amount of 10%, stirs to blast H down in mixed solution 255 ℃ were reacted 22 hours down, reaction finishes back filtering Pd/C catalyzer, filtrate is added drop-wise in 20 times of excessive ether/normal hexanes (2: 1 volume ratios) mixing solutions is settled out polymkeric substance, after the filtration solid put into vacuum drying oven in 40 ℃ dry 24 hours down, promptly obtain a lactic acid and a silk amino acid alternating copolymer (P (LLA-LSE)).
The invention has the beneficial effects as follows: (1) adopts nontoxic carboxylic acid creatinine guanidine compound is the biological safety that polymkeric substance that catalyzer carries out rac-Lactide (LLA, DLLA) and serine morpheline-2,5-dione monomer (BMD) mass polymerization gained has height; (2) polyreaction productive rate height, wherein the effect of acetic acid creatinine guanidine catalyzed polymerization is best, productive rate 〉=90% (stannous octoate catalysis method productive rate≤85%); (3) polymericular weight can design according to demand, and narrow molecular weight distribution (molecular weight heterogeneity index PDI:1.07-1.20); (4) PBMD can be used for the alternating copolymer of synthesizing lactic acid and Serine; (5) adopt bulk polymerization, technology is simple, and the non-environmental-pollution thing generates.
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Embodiment
Polyreaction be with monomer rac-Lactide (LLA or DLLA) or (3S)-3-benzyloxymethyl-(6S)-6-methyl-morpholine diketone (serine morpheline-2,5-dione) (BMD) and be added to behind the carboxylic acid creatinine guanidine weighing that (monomer/carboxylic acid creatinine guanidine mol ratio is: 50/1-400/1) in the reactor, after three vacuum-applying argon gas operations, sealed reactor.In 110-180 ℃ of reaction 24-96 hour, preferred 130-160 ℃ of reaction 96 hours.Dissolve the rac-Lactide polymerization reaction system with small amount of acetone after the polyreaction, solution is slowly dripped to the polymkeric substance that settles out in the distilled water, use N, dinethylformamide dissolving serine morpheline-2,5-dione polymerization reaction system, solution is slowly dripped to the polymkeric substance that settles out in the ether, after the filtration with throw out in 40 ℃ of following vacuum 24 hours, the solid that obtains is polylactide (PLLA or PDLLA) or PBMD (PBMD).With DMF is solvent, and μ-Styragel packed column measures institute's synthetic polymer molecule amount (be with the monodisperse polystyrene standard specimen and proofread and correct through pervasive value) with Waters-410 gel permeation chromatograph (GPC) under the room temperature
Lactic acid is that a certain amount of PBMD (PBMD) is dissolved among the 10mlTHF with the preparation of silk amino acid alternating copolymer (P (LLA-LSE)), adds palladium/carbon (Pd/C) catalyzer of an amount of 10%, stirs to blast H down in mixed solution 2, 55 ℃ were reacted 22 hours down.Reaction finishes back filtering Pd/C catalyzer, filtrate is added drop-wise in 20 times of excessive ether/normal hexanes (2: 1 volume ratios) mixing solutions to be settled out polymkeric substance, after the filtration precipitation put into vacuum drying oven in 40 ℃ dry 24 hours down, promptly obtain a lactic acid and a silk amino acid alternating copolymer (P (LLA-LSE)).
Carboxylic acid creatinine guanidine is synthetic to be that a certain amount of creatinine is added in the Schlenk flask, behind the air, adds the carboxylic acid (acetic acid, propionic acid, butanic acid) of three times of molar weights under the nitrogen atmosphere in the strict expeling flask, and in 25-120 ℃, preferably 90 ℃ were reacted 2.5 hours.Nitrogen atmosphere decompression down steams carboxylic acid, can obtain carboxylic acid creatinine guanidine (productive rate can reach more than 98% under preferred reaction conditions) after the vacuum-drying.Products obtained therefrom is kept dry under the room temperature oxygen free condition.
The synthetic poly-L-rac-Lactide of embodiment 1 acetic acid creatinine guanidine catalysis
Weigh 1.728g (0.012mol) L-rac-Lactide respectively and acetic acid creatinine guanidine 0.0069g (0.00004mol) places reactor,, place 110 ℃ of oil baths to react 96 hours reactor through three vacuum-argon gas operation back sealed reactors.The small amount of acetone dissolve polymer is used in reaction back, slowly drips in the distilled water with the polymkeric substance that settles out, and removes by filter distilled water, gained solid vacuum-drying 24 hours.Productive rate: 94.0%, Mn=4.0 * 10 4, PDI=1.08.
The synthetic poly-L-rac-Lactide of embodiment 2 acetic acid creatinine guanidine catalysis
Weigh 1.728g (0.012mol) L-rac-Lactide respectively and acetic acid creatinine guanidine 0.0069g (0.00004mol) places reactor,, place 150 ℃ of oil baths to react 96 hours reactor through three vacuum-argon gas operation back sealed reactors.The small amount of acetone dissolve polymer is used in reaction back, slowly drips in the distilled water with the polymkeric substance that settles out, and removes by filter distilled water, gained solid vacuum-drying 24 hours.Productive rate: 96.1%, Mn=4.2 * 10 4, PDI=1.10.
The synthetic poly-L-rac-Lactide of embodiment 3 acetic acid creatinine guanidine catalysis
Weigh 1.728g (0.012mol) L-rac-Lactide respectively and acetic acid creatinine guanidine 0.0069g (0.00004mol) places reactor,, place 180 ℃ of oil baths to react 96 hours reactor through three vacuum-argon gas operation back sealed reactors.The small amount of acetone dissolve polymer is used in reaction back, slowly drips in the distilled water with the polymkeric substance that settles out, and removes by filter distilled water, gained solid vacuum-drying 24 hours.Productive rate: 92.8%, Mn=4.0 * 10 4, PDI=1.19.
The synthetic poly-D of embodiment 4 acetic acid creatinine guanidine catalysis, the L-rac-Lactide
Weigh 1.728g (0.012mol) D respectively, L-rac-Lactide and acetic acid creatinine guanidine 0.0069g (0.00004mol) place reactor, and sealed reactor after three vacuum-argon gas operations places 110 ℃ of oil bath reactions 96 hours with reactor.The small amount of acetone dissolve polymer is used in reaction back, slowly drips in the distilled water with the polymkeric substance that settles out, and removes by filter distilled water, gained solid vacuum-drying 24 hours.Productive rate: 90.2%, Mn=3.9 * 10 4, PDI=1.08.
The synthetic poly-D of embodiment 5 acetic acid creatinine guanidine catalysis, the L-rac-Lactide
Weigh 1.728g (0.012mol) D respectively, L-rac-Lactide and acetic acid creatinine guanidine 0.0069g (0.00004mol) place reactor, and sealed reactor after three vacuum-argon gas operations places 150 ℃ of oil bath reactions 96 hours with reactor.The small amount of acetone dissolve polymer is used in reaction back, slowly drips in the distilled water with the polymkeric substance that settles out, and removes by filter distilled water, gained solid vacuum-drying 24 hours.Productive rate: 93.4%, Mn=4.0 * 10 4, PDI=1.10.
The synthetic poly-D of embodiment 6 acetic acid creatinine guanidine catalysis, the L-rac-Lactide
Weigh 1.728g (0.012mol) D respectively, L-rac-Lactide and acetic acid creatinine guanidine 0.0069g (0.00004mol) place reactor, and sealed reactor after three vacuum-argon gas operations places 180 ℃ of oil bath reactions 96 hours with reactor.The small amount of acetone dissolve polymer is used in reaction back, slowly drips in the distilled water with the polymkeric substance that settles out, and removes by filter distilled water, gained solid vacuum-drying 24 hours.Productive rate: 90.5%, Mn=3.7 * 10 4, PDI=1.20.
The synthetic poly-L-rac-Lactide of embodiment 7 acetic acid creatinine guanidine catalysis
Weigh 1.728g (0.012mol) L-rac-Lactide respectively and acetic acid creatinine guanidine 0.0414g (0.00024mol) places reactor,, place 150 ℃ of oil baths to react 96 hours reactor through three vacuum-argon gas operation back sealed reactors.The small amount of acetone dissolve polymer is used in reaction back, slowly drips in the distilled water with the polymkeric substance that settles out, and removes by filter distilled water, gained solid vacuum-drying 24 hours.Productive rate: 91.7%, Mn=6.6 * 10 3, PDI=1.10.
The synthetic poly-L-rac-Lactide of embodiment 8 acetic acid creatinine guanidine catalysis
Weigh 1.728g (0.012mol) L-rac-Lactide respectively and acetic acid creatinine guanidine 0.0138g (0.00008mol) places reactor,, place 150 ℃ of oil baths to react 96 hours reactor through three vacuum-argon gas operation back sealed reactors.The small amount of acetone dissolve polymer is used in reaction back, slowly drips in the distilled water with the polymkeric substance that settles out, and removes by filter distilled water, gained solid vacuum-drying 24 hours.Productive rate: 93.1%, Mn=2.0 * 10 4, PDI=1.08.
The synthetic poly-L-rac-Lactide of embodiment 9 acetic acid creatinine guanidine catalysis
Weigh 1.728g (0.012mol) L-rac-Lactide respectively and acetic acid creatinine guanidine 0.0052g (0.00003mol) places reactor,, place 150 ℃ of oil baths to react 96 hours reactor through three vacuum-argon gas operation back sealed reactors.The small amount of acetone dissolve polymer is used in reaction back, slowly drips in the distilled water with the polymkeric substance that settles out, and removes by filter distilled water, gained solid vacuum-drying 24 hours.Productive rate: 91.6%, Mn=5.3 * 10 4, PDI=1.15.
The synthetic poly-L-rac-Lactide of embodiment 10 propionic acid creatinine guanidine catalysis
Weigh 1.728g (0.012mol) L-rac-Lactide respectively and propionic acid creatinine guanidine 0.0075g (0.00004mol) places reactor,, place 110 ℃ of oil baths to react 96 hours reactor through three vacuum-argon gas operation back sealed reactors.The small amount of acetone dissolve polymer is used in reaction back, slowly drips in the distilled water with the polymkeric substance that settles out, and removes by filter distilled water, gained solid vacuum-drying 24 hours.Productive rate: 87.6%, Mn=3.8 * 10 4, PDI=1.09.
The synthetic poly-L-rac-Lactide of embodiment 11 propionic acid creatinine guanidine catalysis
Weigh 1.728g (0.012mol) L-rac-Lactide respectively and propionic acid creatinine guanidine 0.0075g (0.00004mol) places reactor,, place 150 ℃ of oil baths to react 96 hours reactor through three vacuum-argon gas operation back sealed reactors.The small amount of acetone dissolve polymer is used in reaction back, slowly drips in the distilled water with the polymkeric substance that settles out, and removes by filter distilled water, gained solid vacuum-drying 24 hours.Productive rate: 90.1%, Mn=3.9 * 10 4, PDI=1.08.
The synthetic poly-L-rac-Lactide of embodiment 12 propionic acid creatinine guanidine catalysis
Weigh 1.728g (0.012mol) L-rac-Lactide respectively and propionic acid creatinine guanidine 0.0075g (0.00004mol) places reactor,, place 180 ℃ of oil baths to react 96 hours reactor through three vacuum-argon gas operation back sealed reactors.The small amount of acetone dissolve polymer is used in reaction back, slowly drips in the distilled water with the polymkeric substance that settles out, and removes by filter distilled water, gained solid vacuum-drying 24 hours.Productive rate: 85.7%, Mn=3.7 * 10 4, PDI=1.20.
The synthetic poly-D of embodiment 13 propionic acid creatinine guanidine catalysis, the L-rac-Lactide
Weigh 1.728g (0.012mol) D respectively, L-rac-Lactide and propionic acid creatinine guanidine 0.0075g (0.00004mol) place reactor, and sealed reactor after three vacuum-argon gas operations places 110 ℃ of oil bath reactions 96 hours with reactor.The small amount of acetone dissolve polymer is used in reaction back, slowly drips in the distilled water with the polymkeric substance that settles out, and removes by filter distilled water, gained solid vacuum-drying 24 hours.Productive rate: 86.2%, Mn=3.7 * 10 4, PDI=1.09.
The synthetic poly-D of embodiment 14 propionic acid creatinine guanidine catalysis, the L-rac-Lactide
Weigh 1.728g (0.012mol) D respectively, L-rac-Lactide and propionic acid creatinine guanidine 0.0075g (0.00004mol) place reactor, and sealed reactor after three vacuum-argon gas operations places 150 ℃ of oil bath reactions 96 hours with reactor.The small amount of acetone dissolve polymer is used in reaction back, slowly drips in the distilled water with the polymkeric substance that settles out, and removes by filter distilled water, gained solid vacuum-drying 24 hours.Productive rate: 88.7%, Mn=3.8 * 10 4, PDI=1.09.
The synthetic poly-D of embodiment 15 propionic acid creatinine guanidine catalysis, the L-rac-Lactide
Weigh 1.728g (0.012mol) D respectively, L-rac-Lactide and propionic acid creatinine guanidine 0.0075g (000004mol) place reactor, and sealed reactor after three vacuum-argon gas operations places 180 ℃ of oil bath reactions 96 hours with reactor.The small amount of acetone dissolve polymer is used in reaction back, slowly drips in the distilled water with the polymkeric substance that settles out, and removes by filter distilled water, gained solid vacuum-drying 24 hours.Productive rate: productive rate: 85.0%, Mn=3.7 * 10 4, PDI=1.18.
The synthetic poly-L-rac-Lactide of embodiment 16 butanic acid creatinine guanidine catalysis
Weigh 1.728g (0.012mol) L-rac-Lactide respectively and butanic acid creatinine guanidine 0.0080g (0.00004mol) places reactor,, place 110 ℃ of oil baths to react 96 hours reactor through three vacuum-argon gas operation back sealed reactors.The small amount of acetone dissolve polymer is used in reaction back, slowly drips in the distilled water with the polymkeric substance that settles out, and removes by filter distilled water, gained solid vacuum-drying 24 hours.Productive rate: 85.4%, Mn=3.7 * 10 4, PDI=1.11.
The synthetic poly-L-rac-Lactide of embodiment 17 butanic acid creatinine guanidine catalysis
Weigh 1.728g (0.012mol) L-rac-Lactide respectively and butanic acid creatinine guanidine 0.0080g (0.00004mol) places reactor,, place 150 ℃ of oil baths to react 96 hours reactor through three vacuum-argon gas operation back sealed reactors.The small amount of acetone dissolve polymer is used in reaction back, slowly drips in the distilled water with the polymkeric substance that settles out, and removes by filter distilled water, gained solid vacuum-drying 24 hours.Productive rate: 86.5%, Mn=3.7 * 10 4, PDI=1.12.
The synthetic poly-L-rac-Lactide of embodiment 18 butanic acid creatinine guanidine catalysis
Weigh 1.728g (0.012mol) L-rac-Lactide respectively and butanic acid creatinine guanidine 0.0080g (0.00004mol) places reactor,, place 180 ℃ of oil baths to react 96 hours reactor through three vacuum-argon gas operation back sealed reactors.The small amount of acetone dissolve polymer is used in reaction back, slowly drips in the distilled water with the polymkeric substance that settles out, and removes by filter distilled water, gained solid vacuum-drying 24 hours.Productive rate: 85.3%, Mn=3.6 * 10 4, PDI=1.20.
The synthetic poly-D of embodiment 19 butanic acid creatinine guanidine catalysis, the L-rac-Lactide
Weigh 1.728g (0.012mol) D respectively, L-rac-Lactide and butanic acid creatinine guanidine 0.0080g (0.00004mol) place reactor, and sealed reactor after three vacuum-argon gas operations places 110 ℃ of oil bath reactions 96 hours with reactor.The small amount of acetone dissolve polymer is used in reaction back, slowly drips in the distilled water with the polymkeric substance that settles out, and removes by filter distilled water, gained solid vacuum-drying 24 hours.Productive rate: 84.6%, Mn=3.7 * 10 4, PDI=1.12.
The synthetic poly-D of embodiment 20 butanic acid creatinine guanidine catalysis, the L-rac-Lactide
Weigh 1.728g (0.012mol) D respectively, L-rac-Lactide and butanic acid creatinine guanidine 0.0080g (0.00004mol) place reactor, and sealed reactor after three vacuum-argon gas operations places 150 ℃ of oil bath reactions 96 hours with reactor.The small amount of acetone dissolve polymer is used in reaction back, slowly drips in the distilled water with the polymkeric substance that settles out, and removes by filter distilled water, gained solid vacuum-drying 24 hours.Productive rate: 87.1%, Mn=3.8 * 10 4, PDI=1.12.
The synthetic poly-D of embodiment 21 butanic acid creatinine guanidine catalysis, the L-rac-Lactide
Weigh 1.728g (0.012mol) D respectively, L-rac-Lactide and butanic acid creatinine guanidine 0.0080g (0.00004mol) place reactor, and sealed reactor after three vacuum-argon gas operations places 180 ℃ of oil bath reactions 96 hours with reactor.The small amount of acetone dissolve polymer is used in reaction back, slowly drips in the distilled water with the polymkeric substance that settles out, and removes by filter distilled water, gained solid vacuum-drying 24 hours.Productive rate: 83.9%, Mn=3.6 * 10 4, PDI=1.19.
PBMD is synthesized in embodiment 22 acetic acid creatinine guanidine catalysis
Weigh serine morpheline-2,5-dione (BMD) 0.498g (0.002mol) respectively and acetic acid creatinine guanidine 0.0017g (0.00001mol) places reactor,, place 110 ℃ of oil baths to react 96 hours through three vacuum-argon gas operation back sealed reactors.Small amount of N is used in reaction back, and the dinethylformamide dissolve polymer slowly drips in the ether with the polymkeric substance that settles out, and removes by filter ether, and the vacuum-drying of gained solid promptly got product PBMD (PBMD) in 24 hours.Productive rate: 92.0%, Mn=4.6 * 10 4, PDI=1.14.
PBMD is synthesized in embodiment 23 acetic acid creatinine guanidine catalysis
Weigh serine morpheline-2,5-dione (BMD) 0.498g (0.002mol) respectively and acetic acid creatinine guanidine 0.0017g (0.00001mol) places reactor,, place 150 ℃ of oil baths to react 96 hours through three vacuum-argon gas operation back sealed reactors.Small amount of N is used in reaction back, and the dinethylformamide dissolve polymer slowly drips in the ether with the polymkeric substance that settles out, and removes by filter ether, and the vacuum-drying of gained solid promptly got product PBMD (PBMD) in 24 hours.Productive rate: 93.7%, Mn=4.7 * 10 4, PDI=1.07.
PBMD is synthesized in embodiment 24 acetic acid creatinine guanidine catalysis
Weigh serine morpheline-2,5-dione (BMD) 0.498g (0.002mol) respectively and acetic acid creatinine guanidine 0.0017g (0.00001mol) places reactor,, place 180 ℃ of oil baths to react 96 hours through three vacuum-argon gas operation back sealed reactors.Small amount of N is used in reaction back, and the dinethylformamide dissolve polymer slowly drips in the ether with the polymkeric substance that settles out, and removes by filter ether, and the vacuum-drying of gained solid promptly got product PBMD (PBMD) in 24 hours.Productive rate: 91.5%, Mn=4.6 * 10 4, PDI=1.19.
PBMD is synthesized in embodiment 25 propionic acid creatinine guanidine catalysis
Weigh serine morpheline-2,5-dione (BMD) 0.996g (0.004mol) respectively and propionic acid creatinine guanidine 0.0037g (0.00002mol) places reactor,, place 110 ℃ of oil baths to react 96 hours through three vacuum-argon gas operation back sealed reactors.Small amount of N is used in reaction back, and the dinethylformamide dissolve polymer slowly drips in the ether with the polymkeric substance that settles out, and removes by filter ether, and the vacuum-drying of gained solid promptly got product PBMD (PBMD) in 24 hours.Productive rate: 88.6%, Mn=4.4 * 10 4, PDI=1.12.
PBMD is synthesized in embodiment 26 propionic acid creatinine guanidine catalysis
Weigh serine morpheline-2,5-dione (BMD) 0.996g (0.004mol) respectively and propionic acid creatinine guanidine 0.0037g (0.00002mol) places reactor,, place 150 ℃ of oil baths to react 96 hours through three vacuum-argon gas operation back sealed reactors.Small amount of N is used in reaction back, and the dinethylformamide dissolve polymer slowly drips in the ether with the polymkeric substance that settles out, and removes by filter ether, and the vacuum-drying of gained solid promptly got product PBMD (PBMD) in 24 hours.Productive rate: 89.6%, Mn=4.5 * 10 4, PDI=1.09.
PBMD is synthesized in embodiment 27 propionic acid creatinine guanidine catalysis
Weigh serine morpheline-2,5-dione (BMD) 0.996g (0.004mol) respectively and propionic acid creatinine guanidine 0.0037g (0.00002mol) places reactor,, place 180 ℃ of oil baths to react 96 hours through three vacuum-argon gas operation back sealed reactors.Small amount of N is used in reaction back, and the dinethylformamide dissolve polymer slowly drips in the ether with the polymkeric substance that settles out, and removes by filter ether, and the vacuum-drying of gained solid promptly got product PBMD (PBMD) in 24 hours.Productive rate: 87.1%, Mn=4.3 * 10 4, PDI=1.18.
PBMD is synthesized in embodiment 28 butanic acid creatinine guanidine catalysis
Weigh serine morpheline-2,5-dione (BMD) 0.996g (0.004mol) respectively and butanic acid creatinine guanidine 0.0040g (0.00002mol) places reactor,, place 110 ℃ of oil baths to react 96 hours through three vacuum-argon gas operation back sealed reactors.Small amount of N is used in reaction back, and the dinethylformamide dissolve polymer slowly drips in the ether with the polymkeric substance that settles out, and removes by filter ether, and the vacuum-drying of gained solid promptly got product PBMD (PBMD) in 24 hours.Productive rate: 86.2%, Mn=4.3 * 10 4, PDI=1.13.
PBMD is synthesized in embodiment 29 butanic acid creatinine guanidine catalysis
Weigh serine morpheline-2,5-dione (BMD) 0.996g (0.004mol) respectively and butanic acid creatinine guanidine 0.0040g (0.00002mol) places reactor,, place 150 ℃ of oil baths to react 96 hours through three vacuum-argon gas operation back sealed reactors.Small amount of N is used in reaction back, and the dinethylformamide dissolve polymer slowly drips in the ether with the polymkeric substance that settles out, and removes by filter ether, and the vacuum-drying of gained solid promptly got product PBMD (PBMD) in 24 hours.Productive rate: 88.3%, Mn=4.4 * 10 4, PDI=1.09.
PBMD is synthesized in embodiment 30 butanic acid creatinine guanidine catalysis
Weigh serine morpheline-2,5-dione (BMD) 0.996g (0.004mol) respectively and butanic acid creatinine guanidine 0.0040g (0.00002mol) places reactor,, place 180 ℃ of oil baths to react 96 hours through three vacuum-argon gas operation back sealed reactors.Small amount of N is used in reaction back, and the dinethylformamide dissolve polymer slowly drips in the ether with the polymkeric substance that settles out, and removes by filter ether, and the vacuum-drying of gained solid promptly got product PBMD (PBMD) in 24 hours.Productive rate: 85.7%, Mn=4.3 * 10 4, PDI=1.17.
Synthesizing of embodiment 31 acetic acid creatinine guanidines
2.26 gram (0.02mol) creatinines and 3.4mL (0.06mol) acetic acid are placed the Schlenk flask, under the nitrogen atmosphere in 40 ℃ of stirring reactions 2.5 hours.Volatile dry promptly gets the acetic acid creatinine guanidine under nitrogen atmosphere and the room temperature, and product is a faint yellow solid, preserves in moisture eliminator under the anhydrous and oxygen-free.Productive rate: 65.2%
Synthesizing of embodiment 32 acetic acid creatinine guanidines
2.26 gram (0.02mol) creatinines and 3.4mL (0.06mol) acetic acid are placed the Schlenk flask, under the nitrogen atmosphere in 70 ℃ of stirring reactions 2.5 hours.Volatile dry promptly gets the acetic acid creatinine guanidine under nitrogen atmosphere and the room temperature, and product is a faint yellow solid, preserves in moisture eliminator under the anhydrous and oxygen-free.Productive rate 80.6%.
Synthesizing of embodiment 33 acetic acid creatinine guanidines
2.26 gram (0.02mol) creatinines and 3.4mL (0.06mol) acetic acid are placed the Schlenk flask, under the nitrogen atmosphere in 90 ℃ of stirring reactions 2.5 hours.Volatile dry promptly gets the acetic acid creatinine guanidine under nitrogen atmosphere and the room temperature, and product is a faint yellow solid, preserves in moisture eliminator under the anhydrous and oxygen-free.Productive rate: 99.4%
Synthesizing of embodiment 34 propionic acid creatinine guanidines
0.565g creatinine (0.005mol) and 1.1ml (0.015mol) propionic acid are placed the Schlenk flask, and in 40 ℃ of stirring reactions 2.5 hours, decompression steamed the gained solid with remaining propionic acid and is the propionic acid creatinine guanidine under the nitrogen atmosphere.Product is pale brown look solid, preserves in moisture eliminator under the anhydrous and oxygen-free.Productive rate: 56.0%
Synthesizing of embodiment 35 propionic acid creatinine guanidines
0.565g creatinine (0.005mol) and 1.1ml (0.015mol) propionic acid are placed the Schlenk flask, and in 70 ℃ of stirring reactions 2.5 hours, decompression steamed the gained solid with remaining propionic acid and is the propionic acid creatinine guanidine under the nitrogen atmosphere.Product is pale brown look solid, preserves in moisture eliminator under the anhydrous and oxygen-free.Productive rate 80.7%.
Synthesizing of embodiment 36 propionic acid creatinine guanidines
0.565g creatinine (0.005mol) and 1.1ml (0.015mol) propionic acid are placed the Schlenk flask, and in 90 ℃ of stirring reactions 2.5 hours, decompression steamed the gained solid with remaining propionic acid and is the propionic acid creatinine guanidine under the nitrogen atmosphere.Product is pale brown look solid, preserves in moisture eliminator under the anhydrous and oxygen-free.Productive rate: 98.9%
Synthesizing of embodiment 37 butanic acids acid creatinine guanidine
0.565g creatinine (0.005mol) and 1.4ml (0.015mol) butanic acid are placed the Schlenk flask, and in 40 ℃ of stirring reactions 2.5 hours, decompression steamed the gained solid with remaining butanic acid and is the butanic acid creatinine guanidine under the nitrogen atmosphere.Product is pale brown look solid, preserves in moisture eliminator under the anhydrous and oxygen-free.Productive rate: 45.5%
Synthesizing of embodiment 38 butanic acids acid creatinine guanidine
0.565g creatinine (0.005mol) and 1.4ml (0.015mol) butanic acid are placed the Schlenk flask, and in 70 ℃ of stirring reactions 2.5 hours, decompression steamed the gained solid with remaining butanic acid and is the butanic acid creatinine guanidine under the nitrogen atmosphere.Product is pale brown look solid, preserves in moisture eliminator under the anhydrous and oxygen-free.Productive rate: 78.6%
Synthesizing of embodiment 39 butanic acids acid creatinine guanidine
0.565g creatinine (0.005mol) and 1.4ml (0.015mol) butanic acid are placed the Schlenk flask, and in 90 ℃ of stirring reactions 2.5 hours, decompression steamed the gained solid with remaining butanic acid and is the butanic acid creatinine guanidine under the nitrogen atmosphere.Product is pale brown look solid, preserves in moisture eliminator under the anhydrous and oxygen-free.Productive rate: 98.7%
L-silk amino acid-L-lactic acid alternating copolymer is synthesized in embodiment 40 PBMD catalysis
0.5 gram PBMD (PBMD) is dissolved among the 10mlTHF, palladium/carbon (Pd/C) catalyzer that adds 250 milligram 10%, stir and in mixed solution, blast hydrogen down, 55 ℃ were reacted 22 hours down, reaction finishes after-filtration and removes the Pd/C catalyzer, filtrate is added drop-wise in 20 times of excessive ether/normal hexanes (2: 1 volume ratios) mixing solutions with the polymkeric substance that settles out, filters the back solid, promptly obtain a lactic acid and a silk amino acid alternating copolymer (P (LLA-LSE)) in 40 ℃ in vacuum dry 24 hours down.

Claims (6)

1、催化合成生物医用降解性聚L-丙交酯(PLLA)、聚D，L-丙交酯(PDLLA)、聚丝氨酸吗啉二酮(PBMD)的方法，其特征在于：以羧酸肌酐胍(CRCA)为催化剂，进行如结构式(LLA)、(DLLA)和(BMD)1. The method of catalytically synthesizing biomedical degradable poly L-lactide (PLLA), poly D, L-lactide (PDLLA), polyserine morpholine dione (PBMD), is characterized in that: with carboxylic creatinine Guanidine (CRCA) is a catalyst, such as structural formula (LLA), (DLLA) and (BMD) 所示的环酯类单体L-丙交酯(LLA)、D，L-丙交酯(DLLA)和(3S)-3-苄氧甲基-(6S)-6-甲基-吗啉二酮(丝氨酸吗啉二酮)(BMD)的本体活性开环催化聚合反应，合成具有指定分子量和窄分子量分布的聚L-丙交酯(PLLA)、聚D，L-丙交酯(PDLLA)和聚丝氨酸吗啉二酮(PBMD)；The cyclic ester monomers shown are L-lactide (LLA), D,L-lactide (DLLA) and (3S)-3-benzyloxymethyl-(6S)-6-methyl-morpholine Bulk active ring-opening catalyzed polymerization of diketone (serine morpholine dione) (BMD) to synthesize poly-L-lactide (PLLA), poly-D,L-lactide (PDLLA) with specified molecular weight and narrow molecular weight distribution ) and polyserine morpholine dione (PBMD); 式中M1独立选自：LLA、DLLA；M2独立选自：BMD。In the formula, M 1 is independently selected from: LLA, DLLA; M 2 is independently selected from: BMD. 2、根据权利要求1所述羧酸肌酐胍(CRCA)催化合成PLLA，PDLLA和PBMD的方法，其特征在于：聚合反应是将单体LLA、DLLA或BMD及单一羧酸肌酐胍化合物加到反应釜中，单体/羧酸肌酐胍摩尔比为：50/1-400/1，经三次真空-充氩气操作后，于110-180℃反应24-96小时后，用少量丙酮溶解丙交酯聚合反应体系，将溶液缓慢滴到蒸馏水中以沉出聚合物；用N，N-二甲基甲酰胺溶解丝氨酸吗啉二酮聚合反应体系，将溶液缓慢滴到乙醚中以沉出聚合物；过滤后将沉淀物在40℃下真空干燥24小时，得到不同数均分子量和分子量多分散性指数PDI＝1.07-1.20的PLLA，PDLLA或PBMD。2, according to claim 1 said carboxy-creatinine guanidine (CRCA) catalytic synthesis PLLA, the method for PDLLA and PBMD is characterized in that: polymerization reaction is that monomer LLA, DLLA or BMD and single carboxy-creatinine guanidine compound are added to reaction In the kettle, the molar ratio of monomer/carboxylated creatinine and guanidine is: 50/1-400/1. After three times of vacuum-filling with argon, after reacting at 110-180°C for 24-96 hours, dissolve the lactate with a small amount of acetone Ester polymerization reaction system, slowly drop the solution into distilled water to precipitate the polymer; dissolve serine morpholine dione polymerization reaction system with N,N-dimethylformamide, slowly drop the solution into ether to precipitate the polymer ; After filtration, the precipitate was vacuum-dried at 40° C. for 24 hours to obtain PLLA, PDLLA or PBMD with different number-average molecular weights and molecular weight polydispersity index PDI=1.07-1.20. 3、根据权利要求2所述羧酸肌酐胍(CRCA)催化合成PLLA，PDLLA和PBMD的方法，其特征在于：优选的聚合反应条件是130-160℃反应96小时，产率在优选的反应条件下可达到90％以上。3, according to claim 2 said carboxycreatinine guanidine (CRCA) catalyzes the method for synthesizing PLLA, PDLLA and PBMD, it is characterized in that: preferred polymerization reaction condition is 130-160 ℃ of reaction 96 hours, productive rate is in preferred reaction condition It can reach more than 90%. 4、权利要求1所述羧酸肌酐胍(CRCA)催化合成PLLA，PDLLA和PBMD的方法，其特征在于：羧酸肌酐胍结构如(CRCA)所示：4. The method for catalyzed synthesis of PLLA, PDLLA and PBMD by carboxy-creatinine guanidine (CRCA) according to claim 1 is characterized in that: carboxy-creatinine guanidine structure is as shown in (CRCA):
Figure A2005101224360002C5
Figure A2005101224360002C5
 式中：R＝CH3-(醋酸肌酐胍)，CH3CH2-(丙酸肌酐胍)，CH3CH2CH2-(正丁酸肌酐胍)。In the formula: R=CH 3 - (guanidine creatinine acetate), CH 3 CH 2 - (guanidine creatinine propionate), CH 3 CH 2 CH 2 - (guanidine creatinine n-butyrate). 5、根据权利要求4所述羧酸肌酐胍(CRCA)的合成方法，其特征在于：由肌酐(CR)与羧酸(CA)直接反应合成，5, according to the synthetic method of carboxylic creatinine guanidine (CRCA) described in claim 4, it is characterized in that: by creatinine (CR) and carboxylic acid (CA) direct reaction synthesis,
Figure A2005101224360003C1
Figure A2005101224360003C1
 式中：R＝CH3-(醋酸肌酐胍)，CH3CH2-(丙酸肌酐胍)，CH3CH2CH2-(正丁酸肌酐胍)；合成反应是将一定量的肌酐加到Schlenk烧瓶中，严格驱除烧瓶中空气后，在氮氛下加入醋酸或丙酸或正丁酸，肌酐/羧酸摩尔比为：1/3，于25-120℃反应2-3小时，氮氛下减压将羧酸蒸出，得到产物羧酸肌酐胍。In the formula: R=CH 3 - (guanidine creatinine acetate), CH 3 CH 2 - (guanidine creatinine propionate), CH 3 CH 2 CH 2 - (guanidine creatinine n-butyrate); the synthesis reaction is to add a certain amount of creatinine Put it into the Schlenk flask, after strictly removing the air in the flask, add acetic acid or propionic acid or n-butyric acid under nitrogen atmosphere, the molar ratio of creatinine/carboxylic acid is: 1/3, react at 25-120°C for 2-3 hours, nitrogen Distill the carboxylic acid under reduced pressure under the atmosphere to obtain the product carboxylated creatinine guanidine. 6、根据权利要求5所述羧酸肌酐胍的合成方法，其特征在于：优选反应条件是于90℃反应2.5小时，在优选的反应条件下产率可达98％以上。6. The method for synthesizing guanidine carboxycreatinine according to claim 5, characterized in that: the preferred reaction condition is to react at 90°C for 2.5 hours, and the yield can reach more than 98% under the preferred reaction condition.
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CN100434424C (en) * 2007-01-16 2008-11-19 南开大学 Preparation of guanidine glycolate and creatinine lactate as catalysts for ring-opening polymerization of cyclic esters
CN102329269A (en) * 2011-06-30 2012-01-25 南京大学 Synthesis of bionic creatininium chloride and catalytic polycondensation method for synthesizing high-molecular-weight polylactic acid
CN102443166A (en) * 2011-10-14 2012-05-09 南开大学 Process for synthesizing lactic acid-serine copolymer by catalyzing and carrying out ring-opening copolymerization on acetate bicyclo guanidine

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JP4770092B2 (en) * 2001-08-24 2011-09-07 財団法人名古屋産業科学研究所 A catalyst for ring-opening polymerization of a lactone, a method for producing a polyester, and a method for producing a block copolymer.
JP3665819B2 (en) * 2002-04-19 2005-06-29 独立行政法人産業技術総合研究所 Method for producing polyester using rare earth metal compound catalyst
CN1234750C (en) * 2004-01-08 2006-01-04 南开大学 Technological method of catalytic synthesizing medical biodegradable material with biomass organic guanidine compound
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CN100434424C (en) * 2007-01-16 2008-11-19 南开大学 Preparation of guanidine glycolate and creatinine lactate as catalysts for ring-opening polymerization of cyclic esters
CN102329269A (en) * 2011-06-30 2012-01-25 南京大学 Synthesis of bionic creatininium chloride and catalytic polycondensation method for synthesizing high-molecular-weight polylactic acid
WO2013000226A1 (en) * 2011-06-30 2013-01-03 南京大学 High molecular weight polylactic acid synthesized by using method for synthesizing and catalytically-polycondensing bionic creatinine guanidinium chloride
CN102329269B (en) * 2011-06-30 2013-07-17 南京大学 Synthesis of bionic creatininium chloride and catalytic polycondensation method for synthesizing high-molecular-weight polylactic acid
US9062006B2 (en) 2011-06-30 2015-06-23 Nanjing University High molecular weight polylactic acid synthesized via polycondensation catalyzed by bionic creatinine guanidinium chloride
CN102443166A (en) * 2011-10-14 2012-05-09 南开大学 Process for synthesizing lactic acid-serine copolymer by catalyzing and carrying out ring-opening copolymerization on acetate bicyclo guanidine

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