CN1401633A

CN1401633A - Process for synthesis of medical biodegradable material in presence of bionic organic guanidine salt catalyst

Info

Publication number: CN1401633A
Application number: CN02131195A
Authority: CN
Inventors: 李弘�; 王晨宏; 吴军; 岳进
Original assignee: Nankai University
Current assignee: Nankai University
Priority date: 2002-10-17
Filing date: 2002-10-17
Publication date: 2003-03-12
Anticipated expiration: 2022-10-17
Also published as: CN1206211C

Abstract

A process for synthesizing the biodegradable medical material is characterized by that the bionic organic guanidine salt without cytotoxity is used as main catalyst of bulk polymerization method and the metal salt (NaCl, KCl, etc) is used as co-catalyst. Its advantages are no cytotoxity, and no environmental pollution.

Description

Process for synthesizing medical biodegradable material by bionic organic guanidine salt catalyst

Technical Field

The invention relates to the research and development of artificially synthesized medical biodegradable materials, uses organic guanidine salt as a catalyst, and belongs to the technical field of polymer chemistry.

Background

In recent years, with the rapid development of medicine and biological tissue engineering science, the international demand for medical biodegradable materials is increasing. The most important attention is paid to the artificial synthesis of medical biodegradable materials by aliphatic polyesters (such as polylactic acid (PLA), polyglycolic acid (PGA) and copolymers thereof), and the materials have excellent biodegradability, biocompatibility (no organism rejection effect) and biological safety (degradation products can participate in sugar metabolism in human bodies and have no residues), so the materials can be widely applied to the following fields: (1) controlled release drug carriers (such as anticancer drug carriers, targeted drug carriers, etc.); (2) absorbable, implantable biological tissue engineering materials (surgical sutures; soft and hard tissue repair, replacement materials such as: implantable bone joints, fixation materials, artificial ligaments, tendons, blood vessels, ureters) etc. (g.schwach, j.coudane, r.engel, m.vert, poly.bull, 1992, 32, 617; m.c.tanzi, p.verderio, m.g.lampugnani, m.dejana, e.e.sturani, j.mater.sci.mater.med., 1994, 5, 393). A relatively serious problem exists in the synthesis of the materials at home and abroad at present: commercial catalysts used in polymerization reactions are tin (ii) compounds that are recognized by the market as having the best catalytic efficiency [ e.g.: the commercial catalysts stannous chloride and stannous chloride-p-toluenesulfonic acid (s.i. moon, c.w.lee, m.miyamoto, y.kimura j.polym.sci.: Part a: polymer chemistry 2000, 38, 1673), which are used in the synthesis of PLA, PGA by the ring-opening polymerization method, have cytotoxicity [ cytotoxity, m.oka, prog.polym.sci., 2002, 27, 104 plum blossom red, champion, bear east, danpion, yellow-bore, high molecules, 1999, (3), 24], and thus, since they cannot be completely removed from the synthesized polymer after the polymerization reaction, they pose no potential problems for the use of such materials as human pharmaceutical and medical materials, particularly for longer-term application materials (carriers for long-term taking of drugs, implantable medical materials, etc.). Therefore, research and development of novel nontoxic and efficient polymerization catalysts for synthesizing medical biodegradable materials with high biosafety have become the focus of current scientists engaged in medical polymer material research in various countries around the world and urgent needs for solution. The polymer research institute of southern Kai university and the national emphasis laboratory for adsorbing and separating functional polymer materials, Li Hong professor, under the support of national science foundation (No.20074016), initiatively adopted a bionic organic guanidinium catalyst method to synthesize biodegradable polymers at home and abroad, and the synthesis is successful.

Disclosure of Invention

The research and development of a novel non-toxic and high-efficiency polymerization reaction catalyst is one of the purposes of the invention; the research shows that the bionic organic guanidine salt (GX) is the non-toxic catalyst required by us, and the molecular structural formula of the bionic organic guanidine salt is as follows:R₁-R₆：CH₃，C₂H₅，C₃H₇，(CH₃)₂CH，(CH₃)₃C，C₅H₁₁，C₆H₁₃，(C₄H₉)(C₂H₅)CH，C₆H₁₁，...X：Cl，I，HCO₃，HS，HSO₄，H₂PO₄，CH₃COO，C₂H₅COO，C₃H₇COO，CH₃COCOO，NH₂CH₂COO，HSCH₂COO，...

secondly, by adopting a new synthesis method, the bionic organic guanidine salt catalyst is obtained, and the technical scheme is as follows: organic amine is used as raw material to react with solid phosgene to prepare tetraalkyl urea, then the tetraalkyl urea reacts with phosgene to prepare tetraalkyl chloroamidine, and finally the tetraalkyl chloroamidine reacts with amine to prepare the guanidine salt catalyst.

The catalyst is completely nontoxic, so that the synthesized biodegradable polymer has high biological safety.

The completely nontoxic bionic organic guanidine salt originated at home and abroad is used as a main catalyst (guanidine is a substance existing in human bodies, and biological substances such as arginine, creatine and the like generated in the human bodies are guanidine derivatives; many important medicaments are guanidine derivatives, such as antihypertensive medicamentsGuanethidine, broad-spectrum antibiotic streptomycin, hypoglycemic drug phenformin, anticancer drug hydroxyguanidine sulfate, antiviral drug morpholinoguanidine hydrochloride, etc.) so as to be completely nontoxic to human body and participate in metabolism in human body_n(M＝K⁺，Na⁺，Ca²⁺，Fe²⁺，Mg²⁺…) as a cocatalyst, and lactide (DLLA, LLA), Glycolide (GA), Caprolactone (CL) and the like as monomers, and a high-organism-safety medical biodegradable material (PDLLA, PLLA, PGA, PLLA-PGA and the like) can be synthesized by a bulk ring-opening polymerization method.

The yield of the medical biodegradable polymer synthesized by the method is high (more than or equal to 96 percent, and the yield of the stannous octoate catalysis method is less than or equal to 85 percent); good polymer quality (white color) and narrow molecular weight distribution: PDI is less than or equal to 1.20); has the characteristic of active polymerization reaction, and can be used for synthesizing a block copolymer with controlled composition; the process adopts bulk polymerization, and no environmental pollutants are generated.

Detailed Description

1. At present, the bivalent tin catalyst for synthesizing the commercial biodegradable polymer material can be replaced by the bionic organic guanidine salt, so that the medical biodegradable material with high biological safety is obtained.

2. The synthesis process of the bionic guanidine salt catalyst comprises the following steps:

organic amine is used as a raw material to react with solid phosgene to prepare tetraalkyl urea, then the tetraalkyl urea reacts with phosgene to prepare tetraalkyl chloroamidine, and finally the tetraalkyl chloroamidine reacts with amine to prepare a novel bionic guanidine salt catalyst:

the synthesis reaction can be carried out at normal temperature.

3. The synthesis process of the medical biodegradable material comprises the following steps:

putting L-lactide (L-LA), a guanidinium catalyst and a cocatalyst intoa reactor according to a molar ratio of (50-40,000)/1.0/(1.0-3.0), vacuumizing to remove air, filling high-purity nitrogen, repeating the steps for three times, and finally closing the reactor;the reactor was slowly warmed up with stirring and then at a constant temperatureAt 60-260 ℃, preferably 100-; and finally stopping the reaction, dissolving the polymer by using acetone, pouring the solution into deionized water, filtering out a water phase, and drying the precipitate at room temperature for a plurality of days to obtain a snow-white solid, wherein the synthetic reaction is as follows:

^*M₁，M₂＝L-LA，DL-LA，GA，ω-CL，δ-VL，β-BL，… R＝H，Me，

the molecular weight of the polymer was determined on a Waters-410 GPC spectrometer at room temperature using tetrahydrofuran as solvent, a μ -Styragel packed column, (monodisperse polystyrene as standard and corrected for universal values). The molecular weight of the synthesized polymer can be controlled in

1.0-10.0 × 104, molecular weight distribution index (PDI) of 1.04-1.20, yield of more than or equal to 96 percent, and white color. Example 1 preparation of guanidinium catalyst:

adding di-n-butylamine and 100ml of anhydrous tetrahydrofuran into a three-necked bottle at room temperature, wherein the molar ratio of triphosgene to di-n-butylamine is 1: 4, beginning to dropwise add 25ml of anhydrous tetrahydrofuran solution dissolved with about 1g of triphosgene under stirring, wherein the dropwise adding speed is slow at the beginning, white precipitate is generated immediately and is accompanied bya large amount of white fog, and after about half an hour, the solution is dropwise added, the upper layer has light yellow oily substances, and continuously stirring for 6 hours.

Filtering, removing white solid to obtain large-flake crystal, drying in a dryer, recovering, reusing, distilling the filtrate under normal pressure to remove solvent tetrahydrofuran to obtain oily liquid with white precipitate, washing with 2M hydrochloric acid to remove excessive amine, demixing the solution, and washing the upper layer liquid with distilled water to neutrality to remove residual hydrochloric acid and ammonium salt. Residual water in tetrabutyl urea was distilled off under reduced pressure to give tetrabutyl urea as pale yellow oil, which was dried in a desiccator (yield: 95%)

Dissolving dried tetrabutyl urea in acetonitrile, stirring at 80 deg.C, and stirringAdding acetonitrile solution dissolved with solid phosgene. After 2-3 hours, the color of the reaction system gradually changed from light yellow to dark brown, and the reaction mixture was heated to N₂The reaction is continued for 5-6 hours at 80 ℃ under protection. At this time, the power-on of N is stopped₂The absence of bubbles in the bubbler indicates that the reaction is complete (i.e., decarboxylation is complete.). A portion of the acetonitrile was distilled off under reduced pressure to remove unreacted phosgene. System is N₂Stirring at room temperature under protection, slowly dropwise adding diisopropylamine into the system, after the dropwise addition of white solid is generated, continuously refluxing the system for 1-2 hours to obtain a liquid-solid mixed system, wherein the precipitated solid is amine salt, performing suction filtration to remove the amine salt, washing a product adsorbed on the solid with acetonitrile, performing reduced pressure distillation on the obtained acetonitrile solution to obtain a mixture of the amine salt and the product, treating the mixture with a mixed solution of excessive sodium hydroxide and sodium chloride (the amount of NaCl is far greater than that of NaOH), performing reduced pressure distillation on the obtained aqueous solution to remove water and amine, drying the obtained solid for one to two days (50 ℃, 10mmHg) in a vacuum drying oven, and drying the obtained solid by using a drierThe acetonitrile obtained was distilled under reduced pressure to remove NaOH and NaCl, dried under vacuum, the solid obtained after drying was washed with hydrochloric acid solution to acidity, the solvent was removed, and dried under vacuum example 2

Synthesis of biodegradable polylactic acid:

according to the reaction conditions of 1/200 (proportioning) at 120 ℃ for 72 hours, the method comprises the following steps:

cleaning and drying the sealed tube, filling about 1g of lactide, adding a proper amount of toluene solution of guanidine salt and toluene solution of potassium acetate according to the concentration of the required catalyst, cutting off a funnel at the top end of the sealed tube, and connecting the sealed tube to a vacuum system. Vacuumizing, replacing with nitrogen for three times, vacuumizing, sealing with alcohol burner, and vertically putting the sealed tube into oil bath with regulated temperature. And taking out the sealed tube when the reaction is finished, cooling and then breaking the sealed tube to obtain the PLA product. Dissolving the obtained PLA in acetone, pouring into deionized water, filtering to remove water phase, vacuum drying at 50 deg.C for 24 hr to obtain white powder solid with yield of 99% and weight average molecular weight of 2.0 × 10 determined by GPC⁴And PDI is 1.20.

Claims

1. A bionic organic guanidine salt hasa molecular structural formula:

R₁-R₆：CH₃，C₂H₅，C₃H₇，(CH₃)₂CH，(CH₃)₃C，C₅H₁₁，C₆H₁₃，(C₄H₉)(C₂H₅)CH，C₆H₁₁，...

X：Cl，I，HCO₃，HS，HSO₄，H₂PO₄，CH₃COO，C₂H₅COO，C₃H₇COO，CH₃COCOO，NH₂CH₂COO，HSCH₂COO，...

the method is characterized in that: can be used as a catalyst for synthesizing nontoxic medical biodegradable materials: PDLLA, PLLA, PGA, PLLA-PGA.

2. A synthesis process of a bionic organic guanidine salt catalyst uses a polar organic solvent and phosgene for synthesis, and is characterized in that: organic amine is used as a raw material to react with solid phosgene to prepare tetraalkyl urea, then the tetraalkyl urea reacts with phosgene to prepare tetraalkyl chloroamidine, and finally the tetraalkyl chloroamidine reacts with amine to prepare the guanidine salt catalyst:the molecular structural formula is as follows:

3. the process of claim 2, wherein the synthesis reaction is carried out at room temperature.

4. A technological method for synthesizing medical biodegradable material by biomimetic guanidine salt catalysis uses a main catalyst and a cocatalyst, and is characterized in that:

(1) metal salt MX using bionic organic guanidine salt GX as main catalyst and capable of participating in metabolism in human body_n(M＝K⁺，Na⁺，Ca²⁺，Fe²⁺，Mg²⁺…) as cocatalyst;

(2) the synthesis reaction is as follows: M₁，M₂＝L-LA，DL-LA，GA，ω-CL，δ-VL，β-BL，… R＝H，Me，

1) putting L-lactide (L-LA), a guanidinium catalyst and a cocatalyst into a reactor according to the molar ratio of (50-40,000) to 1 to (1-3);

2) vacuumizing to remove air, filling high-purity nitrogen, and closing the reactor under vacuum;

3) slowly raising the temperature of the reactor under stirring, and then reacting for a certain time (12-260 hours) at a constant temperature (60-260 ℃);

4) after the reaction was stopped, the polymer was dissolved in acetone, poured into deionized water, the aqueous phase was filtered off, precipitated and dried at room temperature for several days.

5. The process for synthesizing biodegradable materials under the catalysis of biomimetic guanidinium according to claim 4, wherein said constant temperature is preferably 100-200 ℃.

6. The process for synthesizing biodegradable medical material catalyzed by biomimetic guanidine salt according to claim 4, characterized in that the reaction time is preferably 50-200 h.