CN100395276C - 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 PDFInfo
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Abstract
The present invention relates to a catalytic synthesis method of medical biodegradability polyester, which adopts a carboxylic acid creatinine guanidine compound whose structure is showed by CRCA, wherein the R is a single compound independently selected from CH3-, CH3 CH2-and CH3 CH2 CH2- as a catalyst. The active body ring-opening polymerization reaction of L-lactide (LLA) or D, L-lactide (DLLA) or (3S)-3-benzyloxymethyl-(6S)-6-methyl-morpholine diketone (serine morpholine diketone) (BMD) is catalyzed. Poly-L-lactide (PLLA), poly-D, L-lactide (PDLLA) and polyserine morpholine diketone (PBMD) with specified molecular weight and narrow molecular weight distribution are synthesized. The polymer has high biological safety. PBMD can be used for synthesizing L-serine-L-lactic acid alternating copolymer (P (LSE-LLA)).
Description
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.
Carboxylic acid creatinine guanidine provided by the invention (CRCA) has following structure:
CRCA
In the formula: R=CH
3, CH
3CH
2, CH
3CH
2CH
2
The synthetic method of above-mentioned carboxylic acid creatinine guanidine (CRCA) is, and is synthetic by creatinine and carboxylic acid direct reaction,
CR CA CRCA
In the formula: R=CH
3, CH
3CH
2, CH
3CH
2CH
2
This building-up reactions is that creatinine is added in the Schlenk flask, behind the air, adds carboxylic acid under the nitrogen atmosphere in the strict expeling flask, the mol ratio of creatinine and carboxylic acid is: 1/3, in 25-120 ℃ of reaction 2-3 hour, nitrogen atmosphere decompression down steamed carboxylic acid, obtains the product carboxylic acid creatinine guanidine; Wherein, described carboxylic acid is acetic acid or propionic acid or butanic acid.
Preferably in 90 ℃ of reactions 2.5 hours, productive rate can reach more than 98% reaction conditions under this reaction conditions.
A kind of above-mentioned application of carboxylic acid creatinine guanidine in the medical degradation property polylactide of catalysis synthesising biological: with carboxylic acid creatinine guanidine (CRCA) is catalyzer, carries out cyclic ester class monomer rac-Lactide (M
1) the active open loop catalytic polymerization of body, synthetic have a polylactide of specifying molecular weight and narrow molecular weight distributions,
M in the formula
1Independently be selected from: LLA, DLLA; Its building-up process comprises:
The first, with monomer rac-Lactide (M
1) and single carboxylic acid creatinine guanidine compound be added in the reactor, the mol ratio of monomer and carboxylic acid creatinine guanidine is: 50/1～400/1, after three vacuum-applying argon gas operations, in 110～180 ℃ the reaction 24～96 hours after, with small amount of acetone dissolving rac-Lactide polymerization reaction system, solution is slowly dripped in the distilled water to be settled out polymkeric substance;
The second, filter after with throw out 40 ℃ of following vacuum-dryings 24 hours, obtain the polylactide of different number-average molecular weights and molecular weight heterogeneity index PDI=1.07-1.20;
Wherein, described rac-Lactide is L-rac-Lactide (LLA), or D, L-rac-Lactide (DLLA); Polylactide is poly-L-rac-Lactide (PLLA), or poly-D, L-rac-Lactide (PDLLA).
Polymeric reaction condition preferably 130～160 ℃ the reaction 96 hours, productive rate can reach more than 90%.
The another kind of above-mentioned application of carboxylic acid creatinine guanidine in the medical degradation property PBMD of catalysis synthesising biological (PBMD): with carboxylic acid creatinine guanidine (CRCA) is catalyzer, carrying out cyclic ester class monomer (3S)-3-benzyloxymethyl-(6S)-6-methyl-morpholine diketone is the active open loop catalytic polymerization of body of serine morpheline-2,5-dione (BMD), synthetic PBMD (PBMD) with appointment molecular weight and narrow molecular weight distributions
M in the formula
2Independently be selected from: BMD; Its building-up process comprises:
The first, with monomer serine morpheline-2,5-dione (BMD) (M
2) and single carboxylic acid creatinine guanidine compound be added in the reactor, the mol ratio of monomer and carboxylic acid creatinine guanidine is: 50/1～400/1, after three vacuum one are filled the hydrogen operation, in 110～180 ℃ the reaction 24～96 hours after, use N, dinethylformamide dissolving serine morpheline-2,5-dione polymerization reaction system slowly drips in the ether solution to be settled out polymkeric substance;
The second, filter after with throw out 40 ℃ of following vacuum-dryings 24 hours, obtain the PBMD (PBMD) of different number-average molecular weights and molecular weight heterogeneity index PDI=1.07-1.20.
Polymeric reaction condition preferably 130～160 ℃ the reaction 96 hours, productive rate can reach more than 90%.
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 (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: 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 (7)
1. carboxylic acid creatinine guanidine CRCA, it is characterized in that: this carboxylic acid creatinine guanidine has following structure:
In the formula: R=CH
3, CH
3CH
2, CH
3CH
2CH
2
2. the synthetic method of the described carboxylic acid creatinine guanidine CRCA of claim 1 is characterized in that: synthetic by creatinine and carboxylic acid direct reaction,
In the formula: R=CH
3, CH
3CH
2, CH
3CH
2CH
2
This building-up reactions is that creatinine is added in the Schlenk flask, behind the air, adds carboxylic acid under the nitrogen atmosphere in the strict expeling flask, the mol ratio of creatinine and carboxylic acid is: 1/3, in 25-120 ℃ of reaction 2-3 hour, nitrogen atmosphere decompression down steamed carboxylic acid, obtains the product carboxylic acid creatinine guanidine; Wherein, described carboxylic acid is acetic acid or propionic acid or butanic acid.
3. the synthetic method of carboxylic acid creatinine guanidine CRCA according to claim 2 is characterized in that: reaction conditions is that productive rate can reach more than 98% under this reaction conditions in 90 ℃ of reactions 2.5 hours.
4. the application of the described carboxylic acid creatinine guanidine of claim 1 in the medical degradation property polylactide of catalysis synthesising biological, it is characterized in that: with carboxylic acid creatinine guanidine CRCA is catalyzer, carries out cyclic ester class monomer rac-Lactide M
1The active open loop catalytic polymerization of body, synthetic have a polylactide of specifying molecular weight and narrow molecular weight distributions,
M in the formula
1Independently be selected from: LLA, DLLA; Its building-up process comprises:
The first, with monomer rac-Lactide M
1And single carboxylic acid creatinine guanidine compound is added in the reactor, the mol ratio of monomer and carboxylic acid creatinine guanidine is: 50/1～400/1, after three vacuum-applying argon gas operations, in 110～180 ℃ the reaction 24～96 hours after, with small amount of acetone dissolving rac-Lactide polymerization reaction system, solution is slowly dripped in the distilled water to be settled out polymkeric substance;
The second, filter after with throw out 40 ℃ of following vacuum-dryings 24 hours, obtain the polylactide of different number-average molecular weights and molecular weight heterogeneity index PDI=1.07-1.20;
Wherein, described rac-Lactide is L-rac-Lactide LLA, or D, L-rac-Lactide DLLA; Polylactide is poly-L-rac-Lactide PLLA, or poly-D, L-rac-Lactide PDLLA.
5. application according to claim 4 is characterized in that: polymeric reaction condition is 130～160 ℃ of reactions 96 hours, and productive rate can reach more than 90%.
6. the application of the described carboxylic acid creatinine guanidine of claim 1 in the medical degradation property PBMD of catalysis synthesising biological PBMD, it is characterized in that: with carboxylic acid creatinine guanidine CRCA is catalyzer, carrying out cyclic ester class monomer (3S)-3-benzyloxymethyl-(6S)-6-methyl-morpholine diketone is the active open loop catalytic polymerization of body of serine morpheline-2,5-dione BMD, synthetic PBMD PBMD with appointment molecular weight and narrow molecular weight distributions
M in the formula
2Independently be selected from: BMD; Its building-up process comprises:
The first, with monomer serine morpheline-2,5-dione BMD M
2And single carboxylic acid creatinine guanidine compound is added in the reactor, the mol ratio of monomer and carboxylic acid creatinine guanidine is: 50/1～400/1, after three vacuum one are filled the hydrogen operation, in 110～180 ℃ the reaction 24～96 hours after, use N, dinethylformamide dissolving serine morpheline-2,5-dione polymerization reaction system slowly drips in the ether solution to be settled out polymkeric substance;
The second, filter after with throw out 40 ℃ of following vacuum-dryings 24 hours, obtain the PBMD PBMD of different number-average molecular weights and molecular weight heterogeneity index PDI=1.07-1.20.
7. application according to claim 6 is characterized in that: polymeric reaction condition is 130～160 ℃ of reactions 96 hours, and productive rate can reach more than 90%.
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| 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 |
| CN102443166B (en) * | 2011-10-14 | 2013-03-20 | 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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| JP2003064174A (en) * | 2001-08-24 | 2003-03-05 | Nagoya Industrial Science Research Inst | Lactone ring-opening polymerization catalyst, method for producing polyester, and method for producing block copolymer |
| JP2003313282A (en) * | 2002-04-19 | 2003-11-06 | National Institute Of Advanced Industrial & Technology | Method for manufacturing polyester by rare earth metal compound catalyst |
| CN1556128A (en) * | 2004-01-08 | 2004-12-22 | 南开大学 | Technological method of catalytic synthesizing medical biodegradable material with biomass organic guanidine compound |
| CN1560109A (en) * | 2004-03-02 | 2005-01-05 | 南开大学 | Process of snthesizing medical biological degradative material by acetic acid organic guanidine as catalast |
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| JP2003064174A (en) * | 2001-08-24 | 2003-03-05 | Nagoya Industrial Science Research Inst | Lactone ring-opening polymerization catalyst, method for producing polyester, and method for producing block copolymer |
| JP2003313282A (en) * | 2002-04-19 | 2003-11-06 | National Institute Of Advanced Industrial & Technology | Method for manufacturing polyester by rare earth metal compound catalyst |
| CN1556128A (en) * | 2004-01-08 | 2004-12-22 | 南开大学 | Technological method of catalytic synthesizing medical biodegradable material with biomass organic guanidine compound |
| CN1560109A (en) * | 2004-03-02 | 2005-01-05 | 南开大学 | Process of snthesizing medical biological degradative material by acetic acid organic guanidine as catalast |
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