CN1206211C - Process for synthesis of medical biodegradable material in presence of bionic organic guanidine salt catalyst - Google Patents

Abstract

The present invention relates to a technologic method for synthesizing medicinal biodegradation material by using a bionic organic guanidine salt catalyst, which belongs to the technical field of high polymer chemistry. At present, the synthesis of the medicinal biodegradation material at both home and abroad has the problems that bivalence stannide which is used for polymerization and is generally accepted as an optimal commercial catalyst has cytotoxicity, and the bivalence stannide can not be thoroughly removed from a synthetic polymer after reaction; thus, unsafe hidden dangers are brought to the medicinal biodegradation material. Therefore, the research and development of a new nontoxic catalyst which has high efficiency is an urgent affair. Proved by research, bionic organic guanidine salt has no cytotoxicity and can be used as a main catalyst; the bionic organic guanidine salt can be obtained by using a synthetic method; besides, metal salt (NaCl, KCl, etc.) is used as a cocatalyst. Synthesized polymers which are synthesized by using a mass polymerization method has the advantage of high quality, high productive rate, good color and narrow molecular weight distribution; the synthesized polymers can be controllably polymerized and synthesized into medicinal biodegradation polyester (homopolymers and copolymers) which has required performance. The technologic method has no three waste pollution and has high economic benefits.

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 Chemistry2000, 38, 1673) for the synthesis of PLA, PGA by the melt polycondensation method have cytotoxicity [ cytotoxity, m.okada, prog.tm.sci., 2002, 27, 104 plum blossom red, chamazuron, bear east, danpio, yellow-bore, high molecules, reports, 1999, (3), 24]since they cannot be completely removed from the synthesized Polymer after the polymerization reaction, this class of materials has no potential as human pharmaceutical and medical materials, especially as long-term application materials (carriers for long-term taking 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-R₆each independently is: CH (CH)₃，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 a human body, and living organisms such as arginine, creatine and the like generated in the human body are all guanidine derivatives, and many important medicaments are guanidine derivatives such as antihypertensive medicament guanethidine, broad-spectrum antibiotic streptomycin, hypoglycemic medicament phenformin, anticancer medicament hydroxyguanidine sulfate, antiviral medicament morpholinoguanidine hydrochloride and the like), so that the completely nontoxic metal salt MY which is completely nontoxic to the human body and can participate in metabolism in the 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:

will M₁、M₂、M₁+M₂Or PM₁+PM₂Adding a guanidinium catalyst and a cocatalyst into a reactor according to a molar ratio of (50-40,000)/1.0/(1.0-3.0), vacuumizing to remove air, then filling high-purity nitrogen, repeating the steps for three times, and finally closing the reactor; slowly raising the temperature of the reactor under stirring, and reacting for a certain time of 12-260 hours, preferably 50-200 hours at a constant temperature of 60-260 ℃, preferably 100-200 ℃; and finally stopping the reaction, dissolving the polymer by using acetone, then pouring the solution into deionized water, filtering out a water phase, and drying the precipitate for several days at room temperature to obtain a snow white solid, wherein the synthesis reaction is as follows:

M₁is L-lactide, D, L-lactide or glycolide, M₂Is caprolactone, valerolactone or butyrolactone, R is H or Me, and m is 3, 4 or 5.

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 is controllableIs made at $\stackrel{\‾}{M_W}=1.0~10.0\×{10}^4,$ The molecular weight distribution index (PDI) is 1.04-1.20, the yield is not less than 96%, and the color is snow white.

Example 1

Preparation of guanidine salt 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 by a 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.

And (3) carrying out suction filtration to remove a white solid to obtain a large-sheet crystal, putting the large-sheet crystal into a dryer for drying, recycling, distilling the filtrate at normal pressure to remove solvent tetrahydrofuran to obtain oily liquid with white precipitates, washing the oily liquid with 2M hydrochloric acid to remove excessive amine, layering the solution, and washing the upper layer liquid with distilled water to be neutral 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%)

The dried tetrabutyl urea was dissolved in acetonitrile and stirred at 80 ℃ before adding a solution of phosgene in acetonitrile. 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, and slowly dropping into the systemAdding diisopropylamine, after the dropwise addition of the white solid is finished, 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, and washing a product adsorbed on the solid by acetonitrile.Drying the obtained solid in a vacuum drying oven for one to two days (50 ℃, 10mmHg), extracting and filtering by using dried acetonitrile to remove NaOH and NaCl, distilling the obtained acetonitrile solution under reduced pressure, drying in vacuum, washing the dried solid to be acidic by using a hydrochloric acid solution, removing the solvent, and drying in 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 (3)

1. 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) uses bionic organic guanidine salt GX as main catalyst, and can participate in human bodyIntermetabolized metal salt MY_nIs a cocatalyst, wherein GX ≡ s

R₁-R₆Each independently is: CH (CH)₃，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，

M is K⁺，Na⁺，Ca²⁺，Fe²⁺Or Mg²⁺Y is CH₃COO^-N' is 1 or 2;

(2) the synthesis reaction is as follows:

M₁is L-lactide, D, L-lactide or glycolide, M₂Caprolactone, valerolactone or butyrolactone, R is H or Me, m is 3, 4 or 5;

1) will M₁、M₂、M₁+M₂Or PM₁+PM₂Adding the catalyst, a guanidinium catalyst and a cocatalyst into a reactor according to the molar ratio of 50-40,000: 1-3;

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

3) slowly heating the reactor while stirring, and then reacting for 12-260 h at the temperature of 60-260 ℃;

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

2. The process for synthesizing biodegradable medical material under catalysis of biomimetic guanidine salt as in claim 1, wherein the temperature is 100-200 ℃.

3. The process for synthesizing biodegradable medical material under catalysis of bionic guanidine salt as claimed in claim 1, wherein the reaction time is 50-200 hr.