CN101318960B - Process for synthesizing acetate bicyclo guanidine and catalysis synthesis for poly-lactide and poly-serine morpholine diketone - Google Patents
Process for synthesizing acetate bicyclo guanidine and catalysis synthesis for poly-lactide and poly-serine morpholine diketone Download PDFInfo
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- CN101318960B CN101318960B CN2008100539134A CN200810053913A CN101318960B CN 101318960 B CN101318960 B CN 101318960B CN 2008100539134 A CN2008100539134 A CN 2008100539134A CN 200810053913 A CN200810053913 A CN 200810053913A CN 101318960 B CN101318960 B CN 101318960B
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- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 title claims abstract description 133
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 title claims abstract description 69
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 title claims abstract description 69
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 title claims abstract description 54
- 238000006555 catalytic reaction Methods 0.000 title claims abstract description 17
- 238000000034 method Methods 0.000 title claims abstract description 11
- JJTUDXZGHPGLLC-UHFFFAOYSA-N lactide Chemical compound CC1OC(=O)C(C)OC1=O JJTUDXZGHPGLLC-UHFFFAOYSA-N 0.000 title claims description 8
- 230000015572 biosynthetic process Effects 0.000 title abstract description 4
- 238000003786 synthesis reaction Methods 0.000 title abstract description 4
- 230000002194 synthesizing effect Effects 0.000 title abstract description 4
- 108010000222 polyserine Proteins 0.000 title abstract 3
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Natural products C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 title 1
- 238000006243 chemical reaction Methods 0.000 claims abstract description 40
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 36
- 229920000747 poly(lactic acid) Polymers 0.000 claims abstract description 16
- 238000006116 polymerization reaction Methods 0.000 claims abstract description 11
- 229920001432 poly(L-lactide) Polymers 0.000 claims abstract description 8
- 238000009826 distribution Methods 0.000 claims abstract description 5
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 27
- 239000000126 substance Substances 0.000 claims description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 20
- 239000012153 distilled water Substances 0.000 claims description 19
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 18
- 229910052786 argon Inorganic materials 0.000 claims description 18
- 238000001291 vacuum drying Methods 0.000 claims description 17
- 239000007787 solid Substances 0.000 claims description 16
- 239000000178 monomer Substances 0.000 claims description 15
- 239000007789 gas Substances 0.000 claims description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 12
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 claims description 11
- -1 cyclic ester Chemical class 0.000 claims description 10
- 229920000642 polymer Polymers 0.000 claims description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 8
- JVTAAEKCZFNVCJ-REOHCLBHSA-N L-lactic acid Chemical compound C[C@H](O)C(O)=O JVTAAEKCZFNVCJ-REOHCLBHSA-N 0.000 claims description 6
- 229920001244 Poly(D,L-lactide) Polymers 0.000 claims description 6
- 230000015556 catabolic process Effects 0.000 claims description 5
- 238000006731 degradation reaction Methods 0.000 claims description 5
- 238000004821 distillation Methods 0.000 claims description 5
- 230000003197 catalytic effect Effects 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 238000010189 synthetic method Methods 0.000 claims description 2
- 239000012300 argon atmosphere Substances 0.000 claims 1
- 239000003054 catalyst Substances 0.000 abstract description 7
- 231100000252 nontoxic Toxicity 0.000 abstract description 4
- 230000003000 nontoxic effect Effects 0.000 abstract description 4
- 238000007151 ring opening polymerisation reaction Methods 0.000 abstract description 4
- 229920001577 copolymer Polymers 0.000 abstract description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 125000002619 bicyclic group Chemical group 0.000 abstract 5
- JJTUDXZGHPGLLC-IMJSIDKUSA-N 4511-42-6 Chemical compound C[C@@H]1OC(=O)[C@H](C)OC1=O JJTUDXZGHPGLLC-IMJSIDKUSA-N 0.000 abstract 4
- MENOBBYDZHOWLE-UHFFFAOYSA-N morpholine-2,3-dione Chemical compound O=C1NCCOC1=O MENOBBYDZHOWLE-UHFFFAOYSA-N 0.000 abstract 2
- LOWGKFCSJQKCCF-YUZLPWPTSA-N (5S)-2-methyl-5-(phenylmethoxymethyl)morpholine Chemical compound C(C1=CC=CC=C1)OC[C@@H]1NCC(OC1)C LOWGKFCSJQKCCF-YUZLPWPTSA-N 0.000 abstract 1
- 239000007864 aqueous solution Substances 0.000 abstract 1
- 229920002988 biodegradable polymer Polymers 0.000 abstract 1
- 239000004621 biodegradable polymer Substances 0.000 abstract 1
- 230000000694 effects Effects 0.000 abstract 1
- 150000002894 organic compounds Chemical class 0.000 abstract 1
- 238000011112 process operation Methods 0.000 abstract 1
- 229960001153 serine Drugs 0.000 description 9
- 238000005303 weighing Methods 0.000 description 9
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 8
- 239000003814 drug Substances 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 239000000463 material Substances 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 238000012662 bulk polymerization Methods 0.000 description 2
- 239000004310 lactic acid Substances 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 150000005846 sugar alcohols Polymers 0.000 description 2
- KSBAEPSJVUENNK-UHFFFAOYSA-L tin(ii) 2-ethylhexanoate Chemical compound [Sn+2].CCCCC(CC)C([O-])=O.CCCCC(CC)C([O-])=O KSBAEPSJVUENNK-UHFFFAOYSA-L 0.000 description 2
- OBETXYAYXDNJHR-SSDOTTSWSA-M (2r)-2-ethylhexanoate Chemical compound CCCC[C@@H](CC)C([O-])=O OBETXYAYXDNJHR-SSDOTTSWSA-M 0.000 description 1
- FVKFHMNJTHKMRX-UHFFFAOYSA-N 3,4,6,7,8,9-hexahydro-2H-pyrimido[1,2-a]pyrimidine Chemical compound C1CCN2CCCNC2=N1 FVKFHMNJTHKMRX-UHFFFAOYSA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N Lactic Acid Natural products CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 1
- 229920000954 Polyglycolide Polymers 0.000 description 1
- 239000004793 Polystyrene Substances 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- VJMAITQRABEEKP-UHFFFAOYSA-N [6-(phenylmethoxymethyl)-1,4-dioxan-2-yl]methyl acetate Chemical compound O1C(COC(=O)C)COCC1COCC1=CC=CC=C1 VJMAITQRABEEKP-UHFFFAOYSA-N 0.000 description 1
- OBETXYAYXDNJHR-UHFFFAOYSA-N alpha-ethylcaproic acid Natural products CCCCC(CC)C(O)=O OBETXYAYXDNJHR-UHFFFAOYSA-N 0.000 description 1
- 229920005603 alternating copolymer Polymers 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 239000003519 biomedical and dental material Substances 0.000 description 1
- 238000007036 catalytic synthesis reaction Methods 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 150000002357 guanidines Chemical class 0.000 description 1
- 238000007327 hydrogenolysis reaction Methods 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000012567 medical material Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000004633 polyglycolic acid Substances 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 125000002924 primary amino group Chemical class [H]N([H])* 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 238000003672 processing method Methods 0.000 description 1
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Abstract
The invention relates to an acetate bicyclic guanidine, a synthesizing method thereof and a synthesis of a polylactide and a polyserine morpholine dione by catalysis. The acetate bicyclic guanidine has the above structure and is synthesized by a direct reaction of bicyclic guanidine and acetic acid in a catalyst-free aqueous solution. In the invention, the acetate bicyclic guanidine is adopted asa catalyst to catalyze a bulk activity of L-lactide (LLA), D,L-lactide (DLLA) or (3S)-3- benzyloxymethyl-6-methyl-morpholine dione (BMMD) to perform ring opening polymerization reaction , thereby synthesizing a poly L-lactide (PLLA) and a poly D,L-lactide (PDLLA) with a number average degree of polymerization of between 120 and 280 and narrow molecular weight distribution and polyserine morpholine dione with a number average degree of polymerization of between 120 and 150. PBMMD can be used for preparing a lactic acid-serine copolymer. The acetate bicyclic guanidine as the catalyst is a nonmetallic and nontoxic organic compound; the method has low production cost, simple process operation, no pollution, a high product yield of more than or equal to 95 percent and a high product purity ofmore than or equal to 98 percent; and a synthesized biodegradable polymer has high biological safety.
Description
[technical field]
The invention belongs to the medical biodegradable material technical field, relate to the process for catalytic synthesis of medical use biological degradable polymkeric substance.
[background technology]
In recent years, along with the fast development of medicine and biomedical science, both at home and abroad to the demand of medical biodegradable material with good biocompatibility and biological safety in sharp increase.The synthetic use catalyzer that needs of biological degradation polyalcohol (poly(lactic acid), polyglycolic acid, lactic acid amino acid copolymer etc.), the synthetic employing stannous octoate (2 ethyl hexanoic acid tin) of commercialization medicine degradation polymer is a catalyzer.In recent years, countries in the world scientist's research proves that fully stannous octoate has cytotoxicity, owing to tin-containing catalyst thoroughly can't be removed after the polyreaction, thereby stay security hidden danger when giving this type of biological degradation polyalcohol as human pharmaceutical use, medical material from polymkeric substance.Therefore, research and development Wuxi, non-toxic compound have become a new challenge in the synthetic field of bio-medical material as catalyzer.Inst. of High-Molecular Chemistry, Nankai Univ. and " functional high molecule material key lab of the Ministry of Education " Li Hong professor and laboratory member thereof are under the subsidy of state natural sciences fund (No20474030), designed and synthesized a kind of nontoxic first in both at home and abroad, the acetate bicyclo guanidine catalyst (TBDA) of no metal, be used for catalysis rac-Lactide [L-rac-Lactide (LLA), D, L-rac-Lactide (DLLA)] and the active ring-opening polymerization synthesis of medical biodegradable polylactide (PLLA of serine morpheline-2,5-dione (BMMD), PDLLA also claims poly(lactic acid)) and PBMD (PBMMD).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 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 acetate bicyclo guanidine compound and the synthetic method thereof that the purpose of this invention is to provide a kind of nontoxic, no metal, and the processing method of using synthetic polylactide of acetate bicyclo guanidine catalysis and PBMD.
Acetate bicyclo guanidine TBDA provided by the invention has following structure:
TBDA 。
Acetate bicyclo guanidine of the present invention is synthetic with acetic acid (english abbreviation AA) direct reaction by bicyclo guanidine (formal name used at school: 1,5,7-three nitrogen dicyclos [4,4,0]-5-decene, English name: 1,5,7-triazabicyclo[4,4,0] dec-5-ene, english abbreviation TBD).
The concrete implementation route of catalyst acetic acid bicyclo guanidine (TBDA) synthetic is:
TBD AA TBDA
Its preparation process is: a certain amount of bicyclo guanidine (TBD) is added in the Schlenk flask, behind the strict air of driving away in the flask, adding entry under argon atmospher is solvent, and the acetic acid (AA) of adding and bicyclo guanidine equimolar amount reacted 2-12 hour in 25-100 ℃ again.Be chilled to room temperature after the reaction, underpressure distillation removes and anhydrates, and in room temperature vacuum-drying 12-60 hour, the solid that obtains white was acetate bicyclo guanidine (TBDA) product with the gained solid.Preferred reaction conditions is that in 80 ℃ of reactions 8 hours, productive rate reached more than 95% under this reaction conditions.
Its representative preparation technology is: bicyclo guanidine (TBD) 0.5127g (3.69mmol) is placed reactor, repeat to vacuumize-applying argon gas three times after, in argon atmospher downhill reaction device, add 3ml distilled water, after bicyclo guanidine dissolves fully under the room temperature, in reactor, add 0.21mL (3.69mmol) acetic acid, reacted 8 hours down at 80 ± 1 ℃.After being chilled to room temperature, moisture content is removed in underpressure distillation, and solid drying under vacuum obtained the white solid acetate bicyclo guanidine, productive rate 95%, product purity 〉=98% in 24 hours.
It is catalyzer that the present invention adopts acetate bicyclo guanidine (TBDA), carry out cyclic ester class monomer L-rac-Lactide (LLA), D shown in structural formula, the active ring-opening polymerization of L-rac-Lactide (DLLA) and (3S)-3-benzyloxymethyl-6-methyl-morpholine diketone (serine morpheline-2,5-dione) catalyst body (BMMD), synthetic number-average degree of polymerization be 120-280 and narrow molecular weight distributions the medical use biological degradable polylactide (PLLA, PDLLA) or number-average degree of polymerization be the PBMD (PBMD) of 120-150.
LLA DLLA BMMD
PLLA is synthesized in acetate bicyclo guanidine catalysis, and PDLLA, PBMD chemical equation are as follows:
In the formula, M
1Independently be selected from rac-Lactide: LLA or DLLA, n is 120-280;
M
2Independently be selected from: BMMD, n are 120-150.
Polylactide (PLLA, concrete building-up process PDLLA) comprises:
The first, with monomer rac-Lactide M
1And the acetate bicyclo guanidine compound is added in the reactor, the mol ratio of monomer and acetate bicyclo guanidine is: 50/1～200/1, after three vacuum-applying argon gas operations, in under the vacuum 95～150 ℃ the reaction 3～60 minutes after, polymkeric substance with acetone solution generates slowly drips to solution in the distilled water to be settled out polymkeric substance again;
The second, upward after the throw out filtration that the step obtains, 40 ℃ of following vacuum-dryings 24 hours, obtaining number-average degree of polymerization was the polylactide of 120-280 and molecular weight heterogeneity index PDI=1.10-1.30 with throw out;
Wherein, polylactide is poly-L-rac-Lactide PLLA or poly-D, L-rac-Lactide PDLLA.
Preferred polymeric reaction condition is 95～100 ℃ of reactions 25-45 minute, and polymer yield can reach 96%.
The concrete building-up process of PBMD comprises:
The first, with monomer serine morpheline-2,5-dione M
2And the acetate bicyclo guanidine compound is added in the reactor, the mol ratio of monomer and acetate bicyclo guanidine is: 100/1, after vacuumizing-fill the hydrogen operation for three times, under vacuum, reach 130～150 ℃ of reactions 3～10 minutes, polymkeric substance with the methylene dichloride dissolving generates 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, obtaining number-average degree of polymerization is the PBMD PBMMD of 120-150 and molecular weight heterogeneity index PDI=1.20-1.33.
Preferred polymeric reaction condition is that Serine reacted 5-10 minute down at 140～150 ℃, and polymer yield can reach 93%.
The polymer molecule quantity measuring method: 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.
Advantage of the present invention and beneficial effect: 1. direct synthesis technique in the synthetic employing catalyst-free of polymerisation catalysts acetate bicyclo guanidine (TBDA), the water solvent, technological operation is easy, and is pollution-free; 2. the acetate bicyclo guanidine production cost is low, product yield is high (〉=95%), product purity height (〉=98%); 3. the acetic acid synthesized bicyclo guanidine of institute (TBDA) has high catalytic activity to rac-Lactide (LLA, DLLA) and serine morpheline-2,5-dione monomer (BMMD) body ring-opening polymerization., can reach in 60 minutes 100 ℃ of reactions and finish (monomer conversion 〉=96%) when monomer/TBDA initial molar ratio is 100/1 the rac-Lactide bulk polymerization; Can reach in 10 minutes 140 ℃ of reactions the serine morpheline-2,5-dione bulk polymerization and to finish (monomer conversion 〉=93%); 4. synthetic resulting polymers has the biological safety of height; 5. polymericular weight can design according to demand, and narrow molecular weight distribution (molecular weight heterogeneity index PDI:1.10-1.33).
[embodiment]
The preparation of embodiment 1 acetate bicyclo guanidine
Bicyclo guanidine (TBD) 0.5127g (3.69mmol) is placed reactor, repeat to vacuumize-applying argon gas three times after, in argon atmospher downhill reaction device, add 3ml distilled water, after treating under the room temperature that bicyclo guanidine dissolves fully, in reactor, add 0.21mL (3.69mmol) acetic acid, reacted 9 hours down at 80 ℃.Stopped reaction is chilled to room temperature, and underpressure distillation removes and anhydrates, and vacuum-drying obtained the white solid acetate bicyclo guanidine in 24 hours, and productive rate is 88.0%, product purity 〉=98%.
The preparation of embodiment 2 acetate bicyclo guanidines
Bicyclo guanidine (TBD) 0.5026g (3.61mmol) is placed reactor, repeat to vacuumize-applying argon gas three times after, in argon atmospher downhill reaction device, add 3ml distilled water, after treating under the room temperature that bicyclo guanidine dissolves fully, in reactor, add 0.20mL (3.61mmol) acetic acid, reacted 7 hours down at 80 ℃.Stopped reaction is chilled to room temperature, and underpressure distillation removes and anhydrates, and vacuum-drying obtained the white solid acetate bicyclo guanidine in 24 hours, and productive rate is 90.5%, product purity 〉=98%.
The synthetic L-rac-Lactide (reaction conditions of this example and following synthetic polylactide is suitable equally to PBMD, gives an example no longer separately, down together) that gathers of embodiment 3 acetate bicyclo guanidine catalysis
Take by weighing 1.000g (6.90mmol) L-rac-Lactide respectively and acetate bicyclo guanidine 0.0138g (0.0690mmol) places reactor, sealed reactor after three vacuum-argon gas operations places 100 ℃ of oil baths to react 50min reactor.Reaction back is with 3mL acetone solution polymkeric substance, slowly drips in the distilled water with the polymkeric substance that settles out, and removes by filter distilled water, 40 ℃ of following vacuum-dryings of gained solid 24 hours.Productive rate: 87.09%, Mn=3.9 * 10
4, PDI=1.15.
The synthetic poly-L-rac-Lactide of embodiment 4 acetate bicyclo guanidine catalysis
Take by weighing 1.000g (6.90mmol) L-rac-Lactide respectively and acetate bicyclo guanidine 0.0138g (0.0690mmol) places reactor, sealed reactor after three vacuum-argon gas operations places 110 ℃ of oil baths to react 45min reactor.Reaction back is with 3mL acetone solution polymkeric substance, slowly drips in the distilled water with the polymkeric substance that settles out, and removes by filter distilled water, 40 ℃ of following vacuum-dryings of gained solid 24 hours.Productive rate: 96.1%, Mn=2.3 * 10
4, PDI=1.10.
The synthetic poly-L-rac-Lactide of embodiment 5 acetate bicyclo guanidine catalysis
Take by weighing 1.000g (6.90mmol) L-rac-Lactide respectively and acetate bicyclo guanidine 0.0276g (0.1389mmol) places reactor, sealed reactor after three vacuum-argon gas operations places 110 ℃ of oil baths to react 20min reactor.Reaction back is with 3mL acetone solution polymkeric substance, slowly drips in the distilled water with the polymkeric substance that settles out, and removes by filter distilled water, 40 ℃ of following vacuum-dryings of gained solid 24 hours.Productive rate: 90.8%, Mn=1.9 * 10
4, PDI=1.15.
The synthetic poly-L-rac-Lactide of embodiment 6 acetate bicyclo guanidine catalysis
Take by weighing 1.000g (6.90mmol) L-rac-Lactide respectively and acetate bicyclo guanidine 0.0069g (0.0347mmol) places reactor, sealed reactor after three vacuum-argon gas operations places 100 ℃ of oil baths to react 45min reactor.Reaction back is with 3mL acetone solution polymkeric substance, slowly drips in the distilled water with the polymkeric substance that settles out, and removes by filter distilled water, 40 ℃ of following vacuum-dryings of gained solid 24 hours.Productive rate: 93.6%, Mn=3.4 * 10
4, PDI=1.20.
The synthetic poly-L-rac-Lactide of embodiment 7 acetate bicyclo guanidine catalysis
Take by weighing 1.000g (6.90mmol) L-rac-Lactide respectively and acetate bicyclo guanidine 0.0138g (0.0690mmol) places reactor, sealed reactor after three vacuum-argon gas operations places 100 ℃ of oil baths to react 25min reactor.Reaction back is with 3mL acetone solution polymkeric substance, slowly drips in the distilled water with the polymkeric substance that settles out, and removes by filter distilled water, 40 ℃ of following vacuum-dryings of gained solid 24 hours.Productive rate: 92.8%, Mn=2.7 * 10
4, PDI=1.11.
The synthetic poly-D of embodiment 8 acetate bicyclo guanidine catalysis, the L-rac-Lactide
Take by weighing 1.000g (6.90mmol) D respectively, L-rac-Lactide and acetate bicyclo guanidine 0.0138g (0.0690mmol) place reactor, and sealed reactor after three vacuum-argon gas operations places 110 ℃ of oil baths to react 45min reactor.Reaction back is with 3mL acetone solution polymkeric substance, slowly drips in the distilled water with the polymkeric substance that settles out, and removes by filter distilled water, 40 ℃ of following vacuum-dryings of gained solid 24 hours.Productive rate: 90.2%, M
n=2.4 * 10
4, PDI=1.14.
The synthetic poly-D of embodiment 9 acetate bicyclo guanidine catalysis, the L-rac-Lactide
Take by weighing 1.000g (6.90mmol) D respectively, L-rac-Lactide and acetate bicyclo guanidine 0.0138g (0.0690mmol) place reactor, and sealed reactor after three vacuum-argon gas operations places 130 ℃ of oil baths to react 25min reactor.Reaction back is with 3mL acetone solution polymkeric substance, slowly drips in the distilled water with the polymkeric substance that settles out, and removes by filter distilled water, 40 ℃ of following vacuum-dryings of gained solid 24 hours.Productive rate: 93.4%, Mn=3.2 * 10
4, PDI=1.30.
PBMD (reaction conditions of this example and following synthetic PBMD is suitable equally to polylactide, gives an example no longer separately, down together) is synthesized in embodiment 10 acetate bicyclo guanidine catalysis
Take by weighing serine morpheline-2,5-dione (BMMD) 0.4000g (1.61mmol) respectively and acetate bicyclo guanidine 3.20mg (0.0160mmol) places reactor,, place 150 ℃ of oil baths to react 15 minutes through three vacuum-argon gas operation back sealed reactors.Reaction back is with 1mL methylene dichloride dissolve polymer, slowly drips in the ether with the polymkeric substance that settles out, and removes by filter ether, and 40 ℃ of following vacuum-dryings of gained solid promptly got product PBMD (PBMMD) in 24 hours.Productive rate: 92.0%, Mn=3.2 * 10
4, PDI=1.33.
PBMD is synthesized in embodiment 11 acetate bicyclo guanidine catalysis
Take by weighing serine morpheline-2,5-dione (BMMD) 0.4000g (1.61mmol) respectively and acetate bicyclo guanidine 3.20mg (0.0160mmol) places reactor, sealed reactor after three vacuum-argon gas operations places 150 ℃ of oil baths to react 3min.Reaction back is with 1mL methylene dichloride dissolve polymer, slowly drips in the ether with the polymkeric substance that settles out, and removes by filter ether, and 40 ℃ of following vacuum-dryings of institute's gained solid promptly got product PBMD (PBMMD) in 24 hours.Productive rate: 93.7%, Mn=3.3 * 10
4.PDI=1.22.
Claims (6)
1. acetate bicyclo guanidine TBDA has following structure:
2. the synthetic method of the described acetate bicyclo guanidine of claim 1 is characterized in that: described acetate bicyclo guanidine is synthetic by bicyclo guanidine and acetic acid direct reaction,
This building-up reactions is that bicyclo guanidine is added in the Schlenk flask, behind the strict air of driving away in the flask, adding entry under the argon atmosphere is solvent, add acetic acid again with the bicyclo guanidine equimolar amount, in 25-100 ℃ of reaction 2-12 hour, be chilled to room temperature again, underpressure distillation removes and anhydrates, vacuum-drying under the solid room temperature is promptly obtained the product acetate bicyclo guanidine, productive rate 85%-95%.
3. the application of the described acetate bicyclo guanidine of claim 1 in the medical degradation property polylactide of catalysis synthesising biological is characterized in that: be catalyzer with the acetate bicyclo guanidine, carry out cyclic ester class monomer rac-Lactide M
1The active open loop catalytic polymerization of body, synthetic number-average degree of polymerization is the polylactide of 120-280 and narrow molecular weight distributions,
M in the formula
1Independently be selected from: L-rac-Lactide, D, L-rac-Lactide, n=120-280; Concrete building-up process comprises: the first, with monomer rac-Lactide M
1And the acetate bicyclo guanidine compound is added in the reactor, the mol ratio of monomer and acetate bicyclo guanidine is: 50/1～200/1, after three vacuum-applying argon gas operations, in under the vacuum 95～150 ℃ the reaction 3～60 minutes after, polymkeric substance with acetone solution generates slowly drips to solution in the distilled water to be settled out polymkeric substance again;
The second, upward after the throw out filtration that the step obtains, 40 ℃ of following vacuum-dryings 24 hours, obtaining number-average degree of polymerization was the polylactide of 120-280 and molecular weight heterogeneity index PDI=1.10-1.30 with throw out;
Wherein, polylactide is poly-L-rac-Lactide PLLA or poly-D, L-rac-Lactide PDLLA.
4. application according to claim 3 is characterized in that: polymeric reaction condition is 95～100 ℃ of reactions 25-45 minute, and polymer yield can reach 96%.
5. the application of the described acetate bicyclo guanidine of claim 1 in the medical degradation property PBMD of catalysis synthesising biological PBMMD, it is characterized in that: be catalyzer with the acetate bicyclo guanidine, carrying out cyclic ester amides monomer (3S)-3-benzyloxymethyl-6-methyl-morpholine diketone is the active open loop catalytic polymerization of body of serine morpheline-2,5-dione, synthetic PBMD PBMMD with appointment molecular weight and narrow molecular weight distributions
M in the formula
2Independently be selected from: serine morpheline-2,5-dione; N=120-150; Its concrete building-up process comprises:
The first, with monomer serine morpheline-2,5-dione M
2And the acetate bicyclo guanidine compound is added in the reactor, the mol ratio of monomer and acetate bicyclo guanidine is: 100/1, after vacuumizing-fill the hydrogen operation for three times, under vacuum, reach 130～150 ℃ of reactions 3～10 minutes, polymkeric substance with the methylene dichloride dissolving generates 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, obtaining number-average degree of polymerization is the PBMD PBMMD of 120-150 and molecular weight heterogeneity index PDI=1.20-1.33.
6. application according to claim 5 is characterized in that: polymeric reaction condition is to react 5-10 minute down at 140～150 ℃, and polymer yield can reach more than 93%.
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| 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 |
| CN102757433A (en) * | 2012-07-06 | 2012-10-31 | 南开大学 | Synthesis of lactic bicyclic guanidine and technique for catalyzing ring-opening polymerization synthesis of degradable polymers by using lactic bicyclic guanidine |
| CN102757432A (en) * | 2012-07-06 | 2012-10-31 | 南开大学 | Synthesis of glycollic bicyclic guanidine and technique for catalyzing ring-opening polymerization synthesis of degradable polymers by using glycollic bicyclic guanidine |
| CN102850531B (en) * | 2012-10-16 | 2014-03-19 | 南京大学 | Technical method for synthesizing medical biodegradable polylactic acid by catalyzing condensation polymerization of lactic acid through chlorinated bicyclic guanidine |
| CN104892916B (en) * | 2015-06-11 | 2017-01-11 | 南京大学 | Technology for controlled synthesis of polylactic acid through lactide activity ring-opening polymerization under catalytic action of organic guanidine-nontoxic alcohol |
| CN105131259B (en) * | 2015-09-14 | 2017-05-31 | 南京大学 | Biological guanidine compound system catalytic fusion solid phase synthesizes high-molecular-weight poly alpha-hydroxy acid |
| CN105367763B (en) * | 2015-12-14 | 2018-07-06 | 南京工业大学 | A kind of method that ring-opening polymerisation prepares polyester |
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| CN101215374A (en) * | 2007-12-27 | 2008-07-09 | 南开大学 | Preparation of cyclic esters ring-opening polymerization catalyst phosphoric acid creatinine guanidine |
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