CN1556128A - Technological method of catalytic synthesizing medical biodegradable material with biomass organic guanidine compound - Google Patents
Technological method of catalytic synthesizing medical biodegradable material with biomass organic guanidine compound Download PDFInfo
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- CN1556128A CN1556128A CNA2004100186030A CN200410018603A CN1556128A CN 1556128 A CN1556128 A CN 1556128A CN A2004100186030 A CNA2004100186030 A CN A2004100186030A CN 200410018603 A CN200410018603 A CN 200410018603A CN 1556128 A CN1556128 A CN 1556128A
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Abstract
A process for catalytically synthesizing the medical biodegradable material features that the non-toxic non-metal biologic organic guanidine compound (bio-GD), such as creatine, creatinine, and guanidinoacetic acid, is used as catalyst for the open-loop polymerizing reaction of cycloester monomers (L-lactide, glycolide, etc). Its advantage is no environmental pollution.
Description
Technical Field
The invention relates to a medical biodegradable material, in particular to a novel process method for synthesizing a polyester polymer, which uses biomass organic guanidine compounds bio-GD (creatine, creatinine and guanidinoacetic acid) as a catalyst to carry out ring-opening polymerization on cyclic ester (lactide and lactone) monomers, and belongs to the technical field of high polymer chemistry.
Background
In recent years, the demand for biodegradable materials for medical use has been rapidly increasing at home and abroad, most of which is the rapid development of medicine and biological tissue engineering science worldwide. In the artificially synthesized medical biodegradable material, aliphatic polyester (such as: poly-L-lactic acid P (L-LA), poly-D, L-lactic acid P (D, L-LA), polyglycolic acid PGA, polycaprolactone PCL and copolymers thereof have been most important. Because of excellent biocompatibility and biosafety, the material has been widely and importantly applied in the medical and pharmaceutical fields, such as (1) being used as a controlled release drug carrier (such as an anticancer and anti-AIDS targeting drug carrier); (2) the implantable absorbable tissue engineering material (such as operation suture, bone jointing and fixing material, artificial cartilage, ligament, tendon, blood vessel, ureter supporting material and the like). At present, a more serious problem exists in the biodegradation and synthesis of polyester materials at home and abroad: the commercial catalyst stannous compound (such as the commercial catalysts stannous chloride and stannous chloride-p-toluenesulfonic acid synthesized by a melt polycondensation method and the commercial catalysts stannous octoate synthesized by polylactic acid and polyglycolic acid synthesized by a ring-opening polymerization method) used for polymerization reaction and known to have the best catalytic efficiency has cytotoxicity, and the tin-containing catalyst cannot be completely removed from the synthesized polymer after the polymerization reaction, so that the material can be used as a human medicinal and medical material, and particularly, the material for long-term application (a carrier for taking the medicine for a long time, an implantable medical material for a long time and the like) has no safety hazard. Therefore, research and development of novel nontoxic and efficient polymerization catalysts for synthesizing medical biodegradable materials with high biological safety have become the focus of current scientists engaged in medical polymer material research in various countries in the world and urgent needs to be solved. The polymer research institute of southern Kai university and the national emphasis laboratory for adsorbing and separating functional polymer materials, Li Hongyo professor, under the support of national science foundation (No.20074016), initiatively adopts a biomass organic guanidine compound (creatine, creatinine and guanidinoacetic acid) catalyst method to synthesize the biomedical degradable polyester polymer material and succeeds. The biomass organic guanidine compound is a completely nontoxic compound naturally generated in the human body in the metabolic process (arginine metabolism, energy storage and transduction process). Therefore, the medical biodegradable polymer synthesized by using the catalyst of biomass organic guanidine is highly safe to organisms.
Disclosure of Invention
The present invention utilizes a commercial biomass organoguanidine (bio-GD) reagent: creatine, creatinine and guanidinoacetic acid are used as catalysts, and cyclic esters (lactide such as L-lactide L-LA, D, L-lactide D, L-LA, glycolide GA and lactones such as epsilon-caprolactone epsilon-CL and the like) are used as monomers to synthesize the medical biodegradable polyester material through ring-opening polymerization.
The commercial biomass organoguanidinium catalyst (bio-GD) has the following structure and chemical name:
creatine guanidinoacetate (N-methyl guanidinoacetic acid) creatinine
The process method for synthesizing the medical biodegradable polymer is characterized in that: the yield is high (more than or equal to 96 percent), and the polymer quality is good: mn of 1.0 to 2.0X 104The molecular weight distribution index PDI is 1.20-1.50, and the color is as follows: snow white, suitable for use as a controlled release drug carrier. The process adopts a bulk polymerization method, is simple and does not generate environmental pollutants.
Detailed Description
1. Creatine, creatinine and guanidinoacetic acid are respectively used as catalysts, cyclic ester (L-lactide L-LA, D, L-lactide D, L-LA, glycolide GA, epsilon-caprolactone epsilon-CL and the like) is used as a monomer, and the high-biosafety medical biodegradable polyester material is synthesized through a bulk ring-opening polymerization reaction.
2. The synthesis process of the medical biodegradable polyester material comprises the following steps: cyclic ester monomers (such as L-LA) and biomass organic guanidine catalysts are mixed according to a molar ratio of (50-40, 00): 1.0, putting into a reactor, vacuumizing to remove air, then filling high-purity nitrogen, repeating the steps for three times, and finally closing the reactor under vacuum. Slowly raising the temperature of the reactor under stirring, and then reacting for a certain time (48-96 hours, preferably 72 hours) at a constant temperature of 120-200 ℃ (preferably 130-150 ℃). And after the reaction is stopped, dissolving the polymer by using acetone, then pouring the solution into deionized water for precipitation, filtering out a water phase, and drying the precipitate at room temperature for 24-72 hours to obtain a snow-white solid, namely the synthesized biodegradable polymer. The synthesis reaction formula of the medical biodegradablepolymer is as follows:
R＝H，CH3m＝3，4，5
M1，M2independently selected from: LLA, DLLA, GA, ε -CL,
bio-GD is independently selected from: creatine, creatinine and guanidinoacetic acid
The molecular weight of the synthesized polymer was determined by a Waters-410 gel chromatograph using tetrahydrofuran as a solvent and a. mu. -Styragel packed column (using monodisperse polystyrene as a standard and corrected for a universal value). The molecular weight of the synthesized polymer can be controlled inMw＝1.0～2.0×104The molecular weight distribution index (PDI) is 1.20-1.50, the yield is not less than 96%, and the product is snow white in color.
Example 1
144 g of lactide were charged into a reaction kettle, and 119 mg of creatine were added in a molar ratio of monomer to catalyst of 1000: 1. Vacuumizing the reaction kettle, replacing the reaction kettle with nitrogen, repeating the operation for three times, closing the reaction kettle under vacuum, slowly heating the reaction kettle, and reacting the reaction kettle at a constant temperature (150 ℃) for a certain time of 72 hours. After the reaction was stopped, the reaction vessel was cooled to room temperature, and acetone was then added to dissolve the polymer in the vessel. Deionized water was then added to precipitate the polymer. The aqueous phase was filtered off and finally the precipitate was placed in a vacuum oven and dried in vacuo at 50 ℃ for 24 hours togive a white powdery solid with a yield of 97%. The molecular weight of the polymer is 1.0-2.0 x 104，PDI≤1.40。
Example 2
144 g of lactide were charged into a reaction vessel and 113 mg of creatinine was added in a molar ratio of monomer to catalyst of 1000: 1. Vacuumizing the reaction kettle, and thenThe operation was repeated three times with nitrogen displacement, the reactor was closed under vacuum, the reactor was slowly heated and reacted at constant temperature (130 ℃) for a certain period of 72 hours. After the reaction was stopped, the reaction vessel was cooled to room temperature, and acetone was then added to dissolve the polymer in the vessel. Deionized water was then added to precipitate the polymer. The aqueous phase was filtered off and finally the precipitate was placed in a vacuum oven and dried under vacuum at 50 ℃ for 24 hours to give a white powdery solid with a yield of 98.5%. The molecular weight of the polymer is 1.0-2.0 x 104，PDI≤1.30。
Example 3
144 g of lactide were charged into a reaction vessel, and 105 mg of guanidinoacetic acid were added in a molar ratio of monomer to catalyst of 1000: 1. Vacuumizing the reaction kettle, replacing the reaction kettle with nitrogen, repeating the operation for three times, closing the reaction kettle under vacuum, slowly heating the reaction kettle, and reacting the reaction kettle at a constant temperature (150 ℃) for a certain time of 72 hours. After the reaction was stopped, the reaction vessel was cooled to room temperature, and acetone was then added to dissolve the polymer in the vessel. Deionized water was then added to precipitate the polymer. The aqueous phase was filtered off and finally the precipitate was placed in a vacuum oven and dried under vacuum at 50 ℃ for 24 hours to give a white powdery solid with a yield of 96.5%. The molecular weight of the polymer is 1.0-2.0 x 104，PDI≤1.40。
Claims (1)
1. A process method for synthesizing medical biodegradable material by catalyzing biomass organic guanidine compounds is characterized by comprising the following steps: with biomass organoguanidinium (bio-GD): creatine, creatinine and guanidinoacetic acid are used as catalysts to carry out the bulk ring-opening polymerization reaction of cyclic ester monomers (D, L-lactide D, L-LA, L-lactide L-LA, glycolide GA, epsilon-caprolactone epsilon-CL and the like) to synthesize the medical biodegradable polyester material without metal and with high biological safety. The synthetic chemical reaction formula is as follows:
R＝H，CH3m＝3，4，5
M1，M2independently selected from: LLA, DLLA, GA, ε -CL,
bio-GD is independently selected from: creatine, creatinine and guanidinoacetic acid
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Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100393753C (en) * | 2005-07-04 | 2008-06-11 | 南开大学 | Polymerization method of in-situ catalyzing atom transfer free radical by metal-guanidine complex |
| CN100395276C (en) * | 2005-12-19 | 2008-06-18 | 南开大学 | Catalyzing synthesis of polylactide and polyserine morphodilone from carboxylic acid creatinine guanidine |
| CN100500729C (en) * | 2006-01-27 | 2009-06-17 | 中国人民解放军军事医学科学院毒物药物研究所 | Use of nucleic acid base compound in preparing medicinal biodegradation material and method of preparing medicinal biodegradation material |
| CN101037500B (en) * | 2006-01-27 | 2010-05-26 | 中国人民解放军军事医学科学院毒物药物研究所 | Usage of amidocyanogen containing small molecule compound and method for preparing biodegradable materials |
| CN102161752A (en) * | 2011-03-14 | 2011-08-24 | 南京大学 | Process method for synthesizing medical biodegradable polylactic acid by polycondensation of lactic acid in presence of creatinine catalyst |
| CN102295765A (en) * | 2011-06-30 | 2011-12-28 | 南京大学 | Copolycondensation synthesized polylactic acid-glycollic acid catalyzed by biomass creatinine |
| CN102702487A (en) * | 2012-07-02 | 2012-10-03 | 南京大学 | Process for synthesizing poly D-lactic acid with high biosafety by catalyzing and condensing poly D-lactic acid with creatinine |
| WO2013000226A1 (en) * | 2011-06-30 | 2013-01-03 | 南京大学 | High molecular weight polylactic acid synthesized by using method for synthesizing and catalytically-polycondensing bionic creatinine guanidinium chloride |
| GB2496227A (en) * | 2011-11-03 | 2013-05-08 | Nanjing University | Process for synthesizing medical biodegradable polylactic acid by creatinine catalysed lactic acid condensation |
| CN104448261A (en) * | 2014-12-12 | 2015-03-25 | 南京大学 | Synthesis process of high-performance and high-molecular-weight poly-L-lactic acid |
| CN107090079A (en) * | 2017-05-26 | 2017-08-25 | 南京大学 | A kind of polylactic acid poly glycol monoethyl ether diblock copolymer and preparation method thereof |
| CN113582965A (en) * | 2021-08-23 | 2021-11-02 | 扬州惠通科技股份有限公司 | Method for preparing high-purity lactide based on catalytic cracking of organic guanidine complex |
-
2004
- 2004-01-08 CN CN 200410018603 patent/CN1234750C/en not_active Expired - Fee Related
Cited By (23)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100393753C (en) * | 2005-07-04 | 2008-06-11 | 南开大学 | Polymerization method of in-situ catalyzing atom transfer free radical by metal-guanidine complex |
| CN100395276C (en) * | 2005-12-19 | 2008-06-18 | 南开大学 | Catalyzing synthesis of polylactide and polyserine morphodilone from carboxylic acid creatinine guanidine |
| CN100500729C (en) * | 2006-01-27 | 2009-06-17 | 中国人民解放军军事医学科学院毒物药物研究所 | Use of nucleic acid base compound in preparing medicinal biodegradation material and method of preparing medicinal biodegradation material |
| CN101037500B (en) * | 2006-01-27 | 2010-05-26 | 中国人民解放军军事医学科学院毒物药物研究所 | Usage of amidocyanogen containing small molecule compound and method for preparing biodegradable materials |
| CN102161752A (en) * | 2011-03-14 | 2011-08-24 | 南京大学 | Process method for synthesizing medical biodegradable polylactic acid by polycondensation of lactic acid in presence of creatinine catalyst |
| CN102161752B (en) * | 2011-03-14 | 2013-02-27 | 南京大学 | Process method for synthesizing medical biodegradable polylactic acid by polycondensation of lactic acid in presence of creatinine catalyst |
| WO2012122807A1 (en) * | 2011-03-14 | 2012-09-20 | 南京大学 | Process for synthesizing medical biodegradable polylactic acid by creatinine catalysed lactic acid condensation |
| WO2013000227A1 (en) * | 2011-06-30 | 2013-01-03 | 南京大学 | Synthesized poly(lactic-co-glycolic acid) from biomass creatinine-catalyzed copolycondensation of lactic acid and glycolic acid |
| US9062159B2 (en) | 2011-06-30 | 2015-06-23 | Nanjing University | Poly(lactic-co-glycolic acid) synthesized via copolycondensation catalyzed by biomass creatinine |
| WO2013000226A1 (en) * | 2011-06-30 | 2013-01-03 | 南京大学 | High molecular weight polylactic acid synthesized by using method for synthesizing and catalytically-polycondensing bionic creatinine guanidinium chloride |
| US9062006B2 (en) | 2011-06-30 | 2015-06-23 | Nanjing University | High molecular weight polylactic acid synthesized via polycondensation catalyzed by bionic creatinine guanidinium chloride |
| CN102295765A (en) * | 2011-06-30 | 2011-12-28 | 南京大学 | Copolycondensation synthesized polylactic acid-glycollic acid catalyzed by biomass creatinine |
| CN102295765B (en) * | 2011-06-30 | 2012-11-28 | 南京大学 | Copolycondensation synthesized polylactic acid-glycollic acid catalyzed by biomass creatinine |
| GB2496227A (en) * | 2011-11-03 | 2013-05-08 | Nanjing University | Process for synthesizing medical biodegradable polylactic acid by creatinine catalysed lactic acid condensation |
| GB2496227B (en) * | 2011-11-03 | 2015-11-04 | Nanjing University | Polycondensation of lactic acid for medical biodegradable polylactic acid catalyzed by creatinine |
| CN102702487A (en) * | 2012-07-02 | 2012-10-03 | 南京大学 | Process for synthesizing poly D-lactic acid with high biosafety by catalyzing and condensing poly D-lactic acid with creatinine |
| CN104448261A (en) * | 2014-12-12 | 2015-03-25 | 南京大学 | Synthesis process of high-performance and high-molecular-weight poly-L-lactic acid |
| US20160168316A1 (en) * | 2014-12-12 | 2016-06-16 | Nanjing University | Method for preparing high molecular weight poly-l-lactic acid |
| JP2017507229A (en) * | 2014-12-12 | 2017-03-16 | 南京大学 | High performance high molecular weight poly L-lactic acid synthesis process |
| US9845377B2 (en) * | 2014-12-12 | 2017-12-19 | Nanjing University | Method for preparing high molecular weight poly-L-lactic acid |
| CN107090079A (en) * | 2017-05-26 | 2017-08-25 | 南京大学 | A kind of polylactic acid poly glycol monoethyl ether diblock copolymer and preparation method thereof |
| CN113582965A (en) * | 2021-08-23 | 2021-11-02 | 扬州惠通科技股份有限公司 | Method for preparing high-purity lactide based on catalytic cracking of organic guanidine complex |
| CN113582965B (en) * | 2021-08-23 | 2022-04-26 | 扬州惠通科技股份有限公司 | Method for preparing lactide based on catalytic cracking of organic guanidine complex |
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