WO2008017247A1

WO2008017247A1 - A biodegradable polyester containing phosphatidylcholine groups and its preparation

Info

Publication number: WO2008017247A1
Application number: PCT/CN2007/002316
Authority: WO
Inventors: Xianglin Luo; Lijian Wang; Juan Luo; Xiaobei Zhou
Original assignee: Sichuan University
Priority date: 2006-08-02
Filing date: 2007-08-01
Publication date: 2008-02-14
Also published as: CN1903909A; CN100540585C

Abstract

A biodegradable polyester containing phosphatidylcholine groups, its main chain is biodegradable polyester, the phosphatidylcholine groups are positioned on the end groups and side chains of polyester main chain or on the side chains of polyester main chain. Its preparation method includes the following steps: (1) use phosphatidylcholine containing two hydroxyl groups to ring-open cyclic esters (lactide) so as to obtain biodegradable polyester whose single side-chain contains phosphatidylcholine group; then said polyester can be used for preparing biodegradable polyester whose multi side-chains contain phosphatidylcholine groups by adding diisocyanate and chain extender; and (2) use the above-mentioned prepared biodegradable polyester whose single side-chain or multi side-chains contain(s) phosphatidylcholine group(s) to react with 2-chloro-2-oxo-1,3,2-dioxaphosphacyclopentane to obtain intermediate compound, then use trimethylamine to ring-open said obtained intermediate so as to obtain a biodegradable polyester whose end groups and single side-chain or multi side-chains contain phosphatidylcholine groups. These biodegradable polyesters can be used as biodegradable materials, especially medicaments sustained-releasing materials and tissue engineering materials.

Description

Biodegradable polyester containing phosphatidylcholine group and preparation method thereof

The invention belongs to the technical field of biodegradable polymer materials and preparation thereof, and particularly relates to a biodegradable polyester containing a phosphatidylcholine group and a preparation method thereof. The phosphatidylcholine group-containing biodegradable polyester prepared by the invention can be used as a drug controlled release carrier material, a medical polymer material and a tissue engineering material, and can also be used as a coating for existing medical polymer materials and products. Layer material. Background technique

Polyester and its copolymers are the most widely studied biodegradable polymers in drug controlled release, tissue engineering research and use. However, due to the structure of the polyester itself and the local acidity generated upon degradation, the desired biocompatibility cannot be obtained. Therefore, the introduction of other molecules in polyester, such as polyethylene glycol (PEG), is a research topic that scientists and technicians all over the world have been working on in the past decade. However, PEG also has some defects, for example, it is a non-biodegradable material itself, and there is no complete research result on its toxicity and in vivo discharge efficiency; PEG may cause dark oxidation to produce intermediates and peroxides that cause nucleic acids, not Injury and oxidative inactivation of saturated fatty acids, peptides, proteins, etc.

The introduction of phospholipids such as phosphatidylcholine into polymers to polymerize peg-like molecules in biological tissues to obtain highly biocompatible materials has attracted great attention in the biomedical field. 2-(methacryloyloxy)ethyl-2'-(trimethylamino)ethyl phosphate (MPC) synthesized by Japanese Tadao Nakaya (BP, phosphatidylcholine-containing acrylate) and Its copolymer exhibits excellent anticoagulant properties, reduced protein adsorption and denaturation properties (Toshikazu Yoneyama, Ken-ichi Sug ihara, Kazuhiko Ishihara, Yasuhiko Iwasaki, Nobuo Nakabayashi. Biomaterials 23 (2002) 1455 - 1459), but these materials Not degradable. Nakabayashi et al. conducted a preliminary study in 2003 on the introduction of phosphatidylcholine groups in degradable polyester molecules to improve the biocompatibility of materials (Yasuh iko Iwasaki, Yoko Tojo, Tomoyuki Kurosaki, Nobuo Nakabayashi. J Biomed Mater Res, 2003, 65A: 164- 169 ), they initiated the polymerization of lactide ring with glycerylphosphorylcholine (L-α-Glycerophosphorylchol ine) to obtain polylactic acid with only one phosphatidylcholine in the side chain. Molecule: Hi lborn et al. reacted with 2-chloro-2-oxo-1,3,2-dioxaphospholane on the side of the polycaprolactone side and obtained a pity with one end of the trimethylamine oxime ring. The acyl base group is composed of Fredrik Nederberg, Tim Bowden, and Joins Hi lborn. Macromolecules 2004, 37, 954-965) o Domestically, in the "phospholipid biodegradable polyester and its preparation method" of the patent application No. 200410093122. 6, the introduction of phosphatidylcholine at the end group of the polyester is disclosed. Group and its preparation method. However, the phosphatidylcholine groups introduced in these published documents or patents have a limited number in the polymer chain of the polyester, and thus have a limited contribution to the properties of the entire material, and cannot be obtained to meet the needs of different drug controlled release and tissue engineering. Different materials with good biocompatibility. Summary of the invention

It is an object of the present invention to provide a biodegradable polyester containing a phosphatidylcholine group in view of the deficiencies of the prior art.

Another object of the present invention is to provide a process for preparing the above phosphatidylcholine group-containing biodegradable polyester.

The phosphatidylcholine group-containing biodegradable polyester provided by the present invention, the biodegradable polyester is a main chain thereof, and the phosphatidylcholine group is located at the terminal group and the side chain or the side chain of the polyester main chain. , its molecular structure is as follows:

(II)

People o

,

(III)

Where: OH or

Pc represents P— O— CH ₂ — CH ₂ — N ⁺ (CH ₃ ) ₃

Z represents the following structure: the structure after the reaction of the diisocyanate with the terminal hydroxyl group of the biodegradable phosphatidylcholine polyester, or the reaction of the diisocyanate with the terminal hydroxyl group of the biodegradable phosphatidylcholine polyester and the hydroxyl or amino group of the chain extender a structure, or a structure in which a diisocyanate is reacted with a hydroxyl group or an amino group of a chain extender (ie, a diisocyanate is reacted through an isocyanate group at both ends to form a urethane bond, and the polyester and the polyester or the polyester and the chain extender are expanded. The chain agent and the chain extender are linked together, the overall result is to increase the molecular weight of the biodegradable phosphatidylcholine polyester); the functional group reactive with diisocyanate may be the hydroxyl group, amino group of the polyester and/or chain extender. Carboxyl; n is a natural number of ^.

The phosphatidylcholine group-containing biodegradable polyester provided by the present invention can be confirmed by infrared spectroscopy and hydrogen nuclear magnetic resonance spectroscopy, and they can clearly show characteristic absorption peaks of phosphatidylcholine groups. 1 and 2 are infrared and nuclear magnetic spectra of a phosphatidylcholine group-containing biodegradable polyester having a polyester unit of polylactic acid as an example. In the infrared spectrum, the absorption peak of the triammonium-N+ (CH ₃ ) ₃ characteristic absorption peak and the phosphoester bond at ~ 1235 cnf' in the fingerprint region 969 cm - ', the phosphatidylcholine group can be seen in the nuclear magnetic spectrum. One N ⁺ (CH ₃ ) ₃ characteristic single peak ( δ = 3. 25 ), — 0P0CH ₂ proton peak ( δ = 3. 43 ) and - N ⁺ C3⁄4 proton peak ( δ = 4. 3).

The biodegradable polyester containing the pitiylcholine group of the present invention, when the molecule contains a poly-side chain phosphatidylcholine group, that is, the end of the diisocyanate and the biodegradable phosphatidylcholine polyester is used. Hydroxyl reaction, with or without the addition of a chain extender, a characteristic absorption peak of carbamate-Hff- appears in the infrared spectrum, which is represented by a nitrogen bond in the carbamate. Absorption spectrum. The band, 1581 _C m_' is the deformation vibration of the carbamate-NH bond, 1623 cm- ¹ is the carbonyl vibration in the carbamate, and the -CO stretching vibration of the carbamate occurs at 1267 cm-'. Figure 3 shows that the polyester unit is polylactic acid and the diisocyanate is hexamethylene. The diisocyanate, the infrared spectrum of the reacted phosphatidylcholine group-containing biodegradable polyester is taken as an example to confirm the claimed compound. The present invention provides various structures of phosphatidylcholine group-containing biodegradable polyesters having an average molecular weight of 500 to 2,000,000, a number of phosphatidylcholine groups of 1 to 200, and an effective number of phospholipids. The phosphatidylcholine group is related to the molecular weight of the biodegradable polyester, and is also related to its use. Those skilled in the art can adjust the molecular weight of the polyester and contain the phosphatidyl group according to the purpose of use and the properties of the phosphatidylcholine polyester. The number of choline groups.

The method for preparing the above phosphatidylcholine group-containing biodegradable polyester provided by the present invention, wherein the preparation method of the phosphatidylcholine group-containing biodegradable polyester having the molecular formula (I) is:

01〜5%的催化剂之间。 The catalyst is 0. 01~5% of the catalyst is 0. 01~5% by weight of the cyclic lactone. Mixing, drying at a vacuum of 0.01 to 100 mmHg, room temperature to 100 ° C for 1 to 24 hours, vacuum sealing at 100 to 180 ° C for 1 to 120 hours, after purification to obtain a unilateral chain containing phosphatidylcholine Group of biodegradable polyester; after drying 1~50 parts, dissolve in 1~100 parts of dry organic solvent, add 1~100 parts of alkaline reagent, and cool the system to -50~0 °C And the molar ratio of the biodegradable polyester is 1~1. 3 times of 2-chloro-2-oxo-1,3,2-dioxaphospholane is dissolved in 1~100 parts of dry organic solvent. , adding dropwise to the reaction system, the dropwise addition time is 0. 25~10 hours; after the completion of the dropwise addition, the reaction is carried out at a temperature of 10 to 100 ° C for 1 to 72 hours; the precipitate is removed by filtration, the solvent is removed; and the dry organic solvent is added to the middle. The product is dissolved, and transferred to a pressure bottle, and then added 0. 05~25 parts of trimethylamine, heated to 30~100 ° C, reaction 2 72 hours; the system was cooled to room temperature, and the solvent was heated purge trimethylamine, i.e., to obtain purified phosphatidylcholine-containing group as the molecular structure of formula (I) are biodegradable polyesters;

Method for preparing phosphatidylcholine group-containing polyester having molecular structure formula (U)

01〜5%的催化剂之间。 The catalyst is 0. 01~5% of the catalyst is 0. 01~5% by weight of the cyclic lactone. Mixing, drying at a vacuum of 0.01 to 100 mmHg, room temperature to 100 ° C for 1 to 24 hours, vacuum sealing at 100 to 180 ° C for 1 to 120 hours, after purification to obtain a unilateral chain containing phosphatidylcholine The biodegradable polyester of the group; after drying 1~50 parts, it is dissolved in 10~100 parts of dry organic solvent, then adding 1~50 parts of diisocyanate, 0~50 parts of chain extender, at temperature 0~ 100 ° C reaction 0. 1~50 hours, purification to obtain a multi-side chain phosphatidylcholine group biodegradable polyester (II);

Method for preparing phosphatidylcholine group-containing polyester having molecular structure formula (ΙΠ)

0. 01~10 parts of phosphatidylcholine with two hydroxyl groups and 10~100 parts of purified cyclic lactone are mixed and dried After drying, the catalyst is mixed with 0. 01~5% by weight of the cyclic lactone, and dried at a vacuum of 0.11~100mmHg, room temperature ~ 100 °C for 1~24 hours, and vacuum sealed at 100~ The reaction is carried out at 180 ° C for 1 to 120 hours, and after purification, a biodegradable polyester containing a phosphatidylcholine group in a single side chain is obtained; after drying 1 to 50 parts, it is dissolved in 10 to 100 parts of a dry organic solvent. Further, adding 1 to 50 parts of diisocyanate, 0 to 50 parts of a chain extender, and reacting at a temperature of 0 to 100 ° C for 0.1 to 50 hours, purifying the multi-side chain phosphatidylcholine group biodegradable polyester; After drying from 1 to 50 parts, it is dissolved in 1 to 100 parts of a dry organic solvent; 1 to 100 parts of an alkaline reagent is further added, and the system is cooled to -50 to (TC; then the molar ratio is polyester ~ 1 The galvanic addition time is 0. 25 times. ~10 hours; after the completion of the dropwise addition, the reaction is carried out at a temperature of 10 to 100 ° C for 1 to 72 hours: the precipitate is removed by filtration, and the solvent is removed; a dry organic solvent is added until the intermediate product is dissolved, and Transfer to a pressure bottle, then add 0. 05~25 parts of trimethylamine, heat to 30~100 ° C, reaction for 2~72 hours; reduce the system to room temperature, heat off the trimethylamine and solvent, and purify to obtain the molecular structure (III) a phosphatidylcholine group-containing biodegradable polyester;

Unless otherwise specified, the above materials are all parts by weight.

The purification method used in the above method is a method generally used for purifying polyester. The intermediate product is transferred to a pressure bottle so that the low-boiling trimethylamine does not rapidly evaporate from the reaction system after heating, so that the reaction proceeds smoothly.

The cyclic lactone used in the above method is at least one of glycolide, lactide, and caprolactone.

The catalyst used in the above method is at least one of tin, zinc, aluminum, magnesium, or an inorganic salt thereof, an organic salt, and/or an oxide thereof.

The organic solvents used in the above methods are dichloromethane, trichloromethane, chloroacetam, 1,2-dichloroethane, 1,1,1-trichloroacetamidine, 1,1,2-trichloro Ethane, 1 , 1 , 1 , 2-tetrachloroethane, L, 1 , 2, 2-tetrachloroethane, acetone, ethyl acetate, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N At least one of N-dimethylacetamide, 1, 4-dioxane, and ethyl acetate. The selection principle is either a good solvent for all the raw materials in the homogeneous reaction system or a good suspending agent in the heterogeneous reaction system. The diisocyanate used in the above method is isophorone diisocyanate, toluene diisocyanate, phenyldimethylene diisocyanate, methylcyclohexyl diisocyanate, 4,4'-methylenebiscyclohexylmethane diisocyanate, six Any of methyl diisocyanate.

The chain extender used in the above method is any one of two functional groups containing a hydroxyl group or an amino group, such as ethylene glycol, aminoethanol, 1,3-propanediol, 1,4-butanediol, glycerol. , pentaerythritol, 1,6-hexanediol, ethylenediamine, 1, 4-butanediamine, 1,6-hexanediamine, 1, 10-decanediamine, diethylene glycol, diethylene glycol Glycol, tricondensate Tetraethylene glycol, phenylenediamine, benzenediol.

The alkaline agent used in the above method is any one of ruthenium, osmium, iridium, Ν'-tetramethylethylenediamine, pyridine, triethylamine, (Ν, Ν-dimethylamino)pyridine. The purpose is to remove the HC1 which is evolved during the reaction to form a salt which is insoluble in the organic solvent.

The phosphatidylcholine having two hydroxyl groups used in the present invention may be commercially available, such as glycerol phosphatidylcholine, or may be synthesized by those skilled in the art based on the knowledge of organic chemistry. The general method for synthesizing phosphatidylcholine with two hydroxyl groups is to use difunctional or trifunctional molecules such as alcohols with double bonds (propenol, 3-butenol, etc.), glycerol, 2-methyl-2- Amino-1, 3-propanediol, etc., by protecting some of these functional groups, after introduction of the phosphatidylcholine functional group, the deprotection is introduced to introduce two hydroxyl groups. For example, 3-butenol is reacted with 2-chloro-2-oxo-1,3,2-dioxaphospholane after protecting the double bond, and then ring-opened with trimethylamine. The method is similar to the literature. Pre-synthesis of 2-methacryloyloxyethyl-2'-trimethylamine ethyl phosphate with 2-hydroxyethyl methacrylate, oxidizing the double bond to 3-butene phosphatidylcholine Glycol; if glycerol is used as the starting molecule, benzaldehyde is used to protect the two hydroxyl groups in the ortho position, and the third hydroxyl group is used with 2-chloro-2-oxo-1,3,2-dioxaphosphol. The alkane is reacted, then ring-opened with trimethylamine, and the protecting group benzaldehyde is removed with aqueous ammonia. The invention has the following advantages:

1. The phosphatidylcholine group-containing biodegradable polyester provided by the present invention has both a single or multi-chain biodegradable polyester containing a phosphatidylcholine group, and a single side chain and a terminal group. Biodegradable polyesters each containing a phosphatidylcholine group and a multi-side chain and a terminal group containing a phosphatidylcholine group, thereby adding to the family of biodegradable polyester materials containing phosphatidylcholine groups The new variety also offers a wider range of choices for different biocompatible materials for different drug controlled release and tissue engineering needs.

2. The phosphatidylcholine group-containing biodegradable polyester provided by the present invention has both a side chain containing a phosphatidylcholine group-containing biodegradable polyester, and a single side chain and a terminal group. a phosphatidylcholine group and a biodegradable polyester containing a phosphatidylcholine group in both the side chain and the terminal group, so that the number of the introduced phosphatidylcholine group is greatly increased in the polymer chain of the polyester, and thus The contribution of the overall material properties is greatly enhanced, resulting in better biocompatibility, suitable hydrophilicity and biodegradability.

3. Since the polyester backbone length and the density of the phosphatidylcholine side chain can be adjusted by the preparation method provided by the present invention to adjust mechanical properties, crystallinity, hydrophilicity, and biodegradability, Drug controlled release system materials, medical product materials and tissue engineering materials, and a variety of applications that can be used as coating materials Way.

4. The method provided by the invention is simple and the process is easy to control. DRAWINGS

Figure 1 is an infrared spectrum of a polylactic acid polymer containing a phosphatidylcholine group.

Figure 2 is a 'Η-gang R' map of a polylactic acid polymer containing a phosphatidylcholine group.

Figure 3 is an infrared spectrum of a polylactic acid polymer containing a poly-side chain phosphatidylcholine group. detailed description

The invention will now be described in detail by way of examples. It is to be noted that the following examples are merely illustrative of the present invention and are not to be construed as limiting the scope of the present invention, and those skilled in the art will make some non-essential improvements and adjustments based on the above-described aspects of the present invention. It still falls within the scope of protection of the present invention.

It should also be noted that the parts of the materials in the following examples are all parts by weight unless otherwise specified.

Example 1

0. 01 parts of glycerol phosphatidylcholine was mixed with 10 parts of recrystallized purified lactide, dried, and then added with a metal zinc powder catalyst of 1% by weight of lactide, at a vacuum of 100 mmHg, temperature. Drying at 50 ° C for 24 hours, vacuum sealing tube at 150 ° C for 20 hours, to obtain a biodegradable polyester containing phosphatidylcholine groups in a single side chain; 6 parts of which are dried and dissolved in 10 parts of dry Dichloromethane solvent, and added to a three-necked flask equipped with a dropping funnel and a stirrer, adding 5 parts of pyridine, and cooling the system to -20 ° C; then equimolar number of 2-chloro-2-oxo- 1, 3, 2-dioxaphospholane is dissolved in 30 parts of dry chloroform solvent, added dropwise to the reaction system, and the dropping time is 2 hours; after the completion of the dropwise addition, the reaction is carried out at a temperature of 10 ° C. Hour; remove the precipitate by filtration, remove the solvent by rotary evaporation under reduced pressure; dissolve the intermediate product by adding 5 parts of dry chloroform, transfer it to a pressure bottle, add 10 parts of dry trimethylamine, heat to 50 Torr, reaction 40 Hours; lower the system to room temperature, slowly open the plug, Heat to 70 Torr, the residual trimethylamine was driven into concentrated sulfuric acid, and the solvent was removed, dissolved in tetrahydrofuran, precipitated with diethyl ether, filtered, washed with ethanol, and dried in vacuo to obtain purified phosphatidylcholine in both the terminal group and the unilateral chain. Group of biodegradable polyesters (1).

Example 2

10.5 parts of 2-methyl-2-amino-1,3-propanediol was dissolved in 50 parts of water, and then 50 parts of 1,4-dioxane was added, and then 26 parts of t-butoxy carbonate was added thereto, and reacted at room temperature. After 24 hours, the water and solvent were removed by rotary evaporation under reduced pressure. The residue was dissolved in diethyl ether and purified by petroleum ether. 25 parts of triethylamine, after cooling to 0 ° C, slowly add 14. 5 parts of acetyl chloride, and after completion of the dropwise addition, react at room temperature for 3 hours, remove the precipitate by filtration, remove the solvent by rotary evaporation under reduced pressure, and purify by column chromatography; The aliquots were dissolved in 50 parts of hydrazine, hydrazine-dimethylformamide and 200 parts of tetrahydrofuran, and 4. 6 parts of three were added. Ethylamine, hydrazine-hydroxybenzotriazole and 5.3 parts of 10-hydroxy decanoic acid, cooled to 0 ° C in an ice bath, and then added 6.4 parts of dicyclohexylcarbodiimide, reacted for 24 hours, and filtered to remove precipitates. , the column was purified by column chromatography; the solution was dissolved in 100 parts of anhydrous diethyl ether and 50 parts of acetonitrile, the system was cooled to -20 ° C, and 1.73 parts of triethylamine was added slowly. -Chloro-2-oxo-1,3,2-dioxaphospholidine, after completion of the dropwise addition, reacted at -10 ° C for 3 hours, at room temperature for 1 hour, filtered to remove the precipitate, and added 50 parts of anhydrous acetonitrile. Transfer it to a pressure bottle, add excess dry trimethylamine in an ice bath, seal, heat to 55 ° C, react for 15 hours, and remove the solvent by rotary evaporation under reduced pressure. Was dissolved in ethanol, ammonia water hydrolysis, purified by reverse phase silica gel to give phosphatidylcholine having two hydroxyl groups.

1% of the above phosphatidylcholine is mixed with 10 parts of the re-purified purified caprolactone, and then added with 0.01% of the stannous octoate catalyst in a vacuum degree of 10 mmHg, room temperature. After drying for 24 hours, vacuum sealing tube was reacted at 100 ° C for 120 hours to obtain a biodegradable polyester containing a phosphatidylcholine group in a single side chain; 6 parts of it was dried and dissolved in 10 parts of dry dichloro Methyl hydrazine solvent, and added to a three-necked flask equipped with a dropping funnel and a stirrer, adding 5 parts of pyridine, and cooling the system to -20 ° C; and then equimolar number of 2-chloro-2-oxo-1, 3,2-dioxaphospholane is dissolved in 30 parts of dry dichloromethane solvent, added dropwise to the reaction system, and the dropwise addition time is 2 hours; after completion of the dropwise addition, the reaction is carried out at temperature 10 for 30 hours; Precipitate, remove the solvent by rotary evaporation under reduced pressure; add 5 parts of dry dichloromethane solvent to dissolve the intermediate product, transfer it to a pressure bottle, add 10 parts of dry trimethylamine, heat to 60 ° C, reaction for 30 hours Reduce the system to room temperature, slowly open the plug, heat to 70残余 The residual trimethylamine is driven into concentrated sulfuric acid, and the solvent is removed, dissolved in tetrahydrofuran, precipitated with diethyl ether, filtered, washed with ethanol, and dried in vacuo to obtain a purified bisphosphonylcholine group. Biodegradable polyester (1).

Example 3

0.1 parts of glycerol phosphatidylcholine was mixed with 10 parts of recrystallized purified lactide and glycolide, and then mixed with 5% aluminum isopropoxide catalyst by weight of lactide. Vacuum degree 0. 01 Hg, drying at 100"C for 1 hour, vacuum sealing tube at 180T for 1 hour, the product was dissolved in dichloromethane, precipitated in anhydrous ether, and dried in vacuo to give a single side chain. a biodegradable polyester of phosphatidylcholine group, which is dried in 8 parts, dissolved in 10 parts of dry dichloromethane solvent, and added to a three-necked flask equipped with a dropping funnel and a stirrer; 5 parts of pyridine, and the system is cooled to -2CTC; then the equivalent mole of 2-chloro-2-oxo-1,3,2-dioxaphospholane of the polyester is dissolved in 30 parts of dry trichloromethane. In a solvent, dropwise added to the reaction system, the dropping time is 2 hours; after the completion of the dropwise addition, the reaction is carried out at a temperature of 10 ° C for 72 hours; the precipitate is removed by filtration, and the solvent is removed by rotary evaporation under reduced pressure; 5 parts of dry chloroform is added. The intermediate product was dissolved and transferred to a pressure bottle, 10 parts of dry trimethylamine was added, heated to 60 Torr, and reacted for 30 hours; the system was cooled to room temperature, the stopper was slowly opened, and the residual trimethylamine was heated to 70 ° C. Into the concentrated sulfuric acid, and the solvent is removed, dissolved in tetrahydrofuran, precipitated with diethyl ether, filtered, washed with ethanol, and dried in vacuo to obtain a biodegradable poly(phosphoacylcholine group) containing purified phosphatidylcholine groups. Ester (1).

Example 4

Mixing 0.1 part of phosphatidylcholine of Example 1 with 100 parts of recrystallized purified glycolide, drying, and then adding 2% of zinc stearate catalyst by weight of glycolide, mixed in vacuum Degree lmmHg, temperature 80 ° C drying for 15 hours, vacuum sealing tube reaction at 120 ° C for 40 hours, the product was dissolved in acetone, precipitated with anhydrous ether, vacuum drying, to obtain a unilateral chain containing phosphatidylcholine groups Biodegradable polyester; 20 parts of it is dried and dissolved in 20 parts of dry methylene chloride solvent, and added to a three-necked flask equipped with a dropping funnel and a stirrer; then 50 parts of mash, Ν, Ν' , Ν'-tetramethylethylenediamine, and the system is cooled to -40 ° C; then the number of moles of the polyester is 1. 3 times of 2 - chloro-2-methoxy - 1, 3, 2-diphosphorane The cyclopentane was dissolved in 50 parts of dry acetonitrile solvent and added dropwise to the reaction system for 6 hours; after completion of the dropwise addition, the reaction was carried out at a temperature of 60 T for 1 hour; the precipitate was removed by filtration, and the solvent was removed by rotary evaporation under reduced pressure: 5 parts of dry chloroform dissolved the intermediate product and transferred it to the pressure bottle, then added 15 parts Dry trimethylamine, heat to 45 ° C, reaction for 60 hours: Reduce the system to room temperature, slowly open the plug, heat to 70 ° C to transfer residual trimethylamine into concentrated sulfuric acid, and remove the solvent, then dissolve with tetrahydrofuran, ether Precipitation, filtration, ethanol washing, and vacuum drying, to obtain a biodegradable polyester (1) containing a phosphatidylcholine group and a purified terminal group and a single side chain.

Example 5

Mixing 5 parts of glycerol phosphatidylcholine with 80 parts of recrystallized purified caprolactone, drying, and then adding 4% of 1:1 of stannous chloride and stannous octoate mixed catalyst based on the weight of caprolactone Drying at a vacuum of 3 mmHg at 50 ° C for 20 hours, vacuum sealing at 11 (TC for 100 hours, to obtain a biodegradable polyester containing a phosphatidylcholine group in a single side chain, and drying 20 parts thereof Dissolve in 10 parts of dry dichloromethane solvent, and add to a three-necked flask equipped with a dropping funnel and a stirrer; add 5 parts of pyridine, and cool the system to -20 Ό; then it will be polyester (I) equimolar The number of 2-chloro-2-oxo-1,3,2-dioxaphospholane is dissolved in 30 parts of dry tetrahydrofuran solvent, added dropwise to the reaction system, and the dropping time is 2 hours; After reacting at a temperature of 25" C for 40 hours; The solvent was removed by rotary evaporation under reduced pressure; the intermediate was dissolved by adding 5 parts of dry 1,1,2,2-tetrachloroethane, and transferred to a pressure bottle, and then 10 parts of dry trimethylamine was added and heated. To 100 ° C, the reaction was carried out for 2 hours; the system was cooled to room temperature, the plug was slowly opened, heated to 70 Torr, the residual trimethylamine was transferred to concentrated sulfuric acid, and the solvent was removed, dissolved in tetrahydrofuran, precipitated with diethyl ether, filtered, washed with ethanol, vacuum Drying, that is, obtaining a biodegradable polyester (1) containing a phosphatidylcholine group in both a purified terminal group and a single side chain.

Example 6

5%的含含镁催化剂混合混合,在真空度。 The 0.5 parts of the glycerol phosphatidylcholine was mixed with 90 parts of the recrystallized purified lactide, and then added, based on the weight of lactide, 0.5% n-butyl magnesium catalyst mixed, in vacuum 50 hidden Hg, dried at 70 ° C for 22 hours, and vacuum sealed at 160 for 4 hours to obtain a biodegradable polyester containing a phosphatidylcholine group in a single side chain, and 50 parts of it was dried and dissolved in 10 In a dry tetrahydrofuran solvent, 1 part of isophorone diisocyanate, 0.5 parts of 1,4-butanediol chain extender, and reacted at 0 ° C for 50 hours to obtain a multi-side chain phosphatidyl group A biodegradable polyester (11) of a choline group.

Example 7

1% of the stannous octoate catalyst is mixed, in a vacuum degree of 10raraHg, room temperature, after mixing 1 part of the glycerol phosphatidylcholine with 10 parts of the recrystallized purified caprolactone, and then adding, by weight of caprolactone. After drying for 24 hours, vacuum sealing tube was reacted at 100 C for 120 hours to obtain a biodegradable polyester containing a phosphatidylcholine group in a single side chain; 8 parts of the dried unilateral chain containing a phosphatidylcholine group After drying the biodegradable polyester, it is dissolved in 10 parts of dry tetrahydrofuran solvent, and then added 1 part of isophorone diisocyanate, 0.5 part of 1,4-butanediol chain extender, and reacted at temperature 0Έ50 In hours, a biodegradable polyester (11) containing a phosphatidylcholine group in a multi-side chain is obtained.

Example 8

0. 01 parts of glycerol phosphatidylcholine was mixed with 10 parts of recrystallized purified lactide, dried, and then added with a metal zinc powder catalyst of 1% by weight of lactide, at a vacuum of 100 mmHg, temperature. Drying at 50 ° C for 24 hours, vacuum sealing tube at 150 ° C for 20 hours, to obtain a biodegradable polyester containing a phosphatidylcholine group in a single side chain; 5 parts of which are dried and dissolved in 50 parts of dry 2小时得到得到多多。 In the dichloromethane solvent, the addition of 2 parts of 4, 4 '-methylene biscyclohexyl carbaryl diisocyanate, 1 part of hexamethylene diamine chain extender, at a temperature of 100 reaction 0. 1 hour, that is more A biodegradable polyester (Π) containing a phosphatidylcholine group in a side chain.

Example 9

Mixing 5 parts of glycerol phosphatidylcholine with 80 parts of re-purified purified caprolactone, drying, and then adding 4% of 1:1 of stannous chloride and stannous octoate mixed catalyst based on the weight of caprolactone , under vacuum 3 _m mHg, 50"C After drying for 20 hours, the vacuum sealed tube was reacted at 10 ° C for 100 hours to obtain a biodegradable polyester containing a phosphatidylcholine group in a single side chain, and 70 parts of it was dried and dissolved in 100 parts of dry trichlorochloride. In the solvent of formazan and ethyl acetate (4:1), 50 parts of hexamethylene diisocyanate and 0.05 parts of glycerol chain extender were added, and the reaction was carried out at a temperature of 20 ° C for 40 hours to obtain a multi-side chain. Biodegradable polyester (11) containing a phosphatidylcholine group.

Example 10

0.1 part of glycerophosphatidylcholine is mixed with 100 parts of recrystallized purified glycolide, dried, and then added with 2% of zinc stearate catalyst by weight of glycolide, mixed at a vacuum of 1 mmHg, The mixture was dried at 80 ° C for 15 hours, and vacuum-sealed at 120 ° C for 40 hours. The product was dissolved in acetone, precipitated with anhydrous diethyl ether, and dried in vacuo to obtain a flavonoid-containing group containing phosphatidylcholine groups. Degrading the polyester; drying 60 parts and dissolving in 20 parts of dry acetone solvent, adding 45 parts of methylcyclohexylmethane diisocyanate, 50 parts of triethylene glycol chain extender, reacting at 80 ° C At 10 hours, a biodegradable polyester (11) containing a phosphatidylcholine group in a multi-side chain was obtained.

Example 11

0.1 parts of glycerophosphatidylcholine was mixed with 10 parts of the re-purified purified caprolactone and the recrystallized purified lactide, and then added with a metal zinc powder catalyst of 1% by weight of the lactide. Mixing, drying at a vacuum of 100 mmHg, temperature of 50 ° C for 24 hours, vacuum sealing at 150 for 20 hours, to obtain a biodegradable polyester containing a phosphatidylcholine group in a single side chain; Soluble in 50 parts of dry dichloromethane solvent, add 1 part of 4, 4 '-methylenebiscyclohexylmethane diisocyanate, react at temperature 80 ° C for 5 hours, then obtain multi-side chain phosphatidylcholine Base group of biodegradable polyester (11).

Example 12

5%的含含镁催化剂混合混合,在真空度。 The 0.5 parts of the glycerol phosphatidylcholine was mixed with 90 parts of the recrystallized purified lactide, and then added, based on the weight of lactide, 0.5% n-butyl magnesium catalyst mixed, in vacuum 50% Hg, dried at 70"C for 22 hours, and vacuum sealed at 160T for 4 hours to obtain a biodegradable polyester containing a phosphatidylcholine group in a single side chain, and 50 parts of it is dried and dissolved in 10 a portion of dry methylene chloride solvent, and added to a three-necked flask equipped with a dropping funnel and a stirrer; add 5 parts of pyridine, and cool the system to -20 Torr; 2- Oxo- 1, 3, 2-dioxaphospholane is dissolved in 30 parts of dry chloroform solvent, added dropwise to the reaction system, and the dropping time is 2 hours; after the completion of the dropwise addition, the temperature is 10 The reaction was carried out at ° C for 30 hours; the precipitate was removed by filtration, and the solvent was removed by rotary evaporation under reduced pressure; the intermediate was dissolved by adding 5 portions of dry trichloromethane, and transferred to a pressure bottle, and then 10 parts of dry trimethylamine was added and heated. React to 60 ° C, 30 hours; lower the system to room temperature, slowly open the stopper, The residual trimethylamine was heated to 70 ° C, and the residual trimethylamine was charged into concentrated sulfuric acid, and the solvent was removed, dissolved in tetrahydrofuran, precipitated with diethyl ether, filtered, washed with ethanol, and dried in vacuo to obtain a purified bisphosphonyl group and a unilateral chain. A biodegradable polyester (1) of a choline group.

Example 13

0.1 part of glycerophosphatidylcholine is mixed with 100 parts of recrystallized purified glycolide, dried, and then added with 2% of zinc stearate catalyst by weight of glycolide, mixed at a vacuum of 1 mmHg, The mixture was dried at 80 ° C for 15 hours, and vacuum-sealed at 120 T for 40 hours. The product was dissolved in acetone, precipitated with anhydrous diethyl ether, and dried in vacuo to obtain a biodegradable poly(polyphosphoryl) group containing a phosphatidylcholine group. Ester; 60 parts of it is dried and dissolved in 100 parts of dry dichloromethane solution, and then 10 parts of 4,4 '-methylenebiscyclohexylformamidine diisocyanate is added and reacted at 80 ° C for 5 hours. , that is, obtaining a biodegradable polyester containing a phosphatidylcholine group in a multi-side chain; 20 parts of the biodegradable polyester having a poly side chain containing a phosphatidylcholine group is dried and dissolved in 20 parts of a dry acetone solvent, And added to a three-necked flask equipped with a dropping funnel and a stirrer; add 50 parts of hydrazine, hydrazine, hydrazine, Ν'-tetramethylethylenediamine, and allow the system to cool to -4 CTC; then polyester (I a molar ratio of 1. 3 times of 2-chloro-2-oxo-1,3,2-dioxaphospholane 50 parts of the dry acetonitrile solvent was added dropwise to the reaction system, the dropping time was 6 hours; after the completion of the dropwise addition, the reaction was carried out at a temperature of 60 Torr for 1 hour; the precipitate was removed by filtration, and the solvent was removed by rotary evaporation under reduced pressure; 5 parts of dry three were added; Chloroformam dissolved the intermediate product and transferred it to a pressure bottle, then added 15 parts of dry trimethylamine, heated to 45 V, and reacted for 60 hours; the system was cooled to room temperature, the plug was slowly opened, and heated to 70 Ό to remnant The trimethylamine is transferred to concentrated sulfuric acid, and the solvent is removed, dissolved in tetrahydrofuran, precipitated with diethyl ether, filtered, washed with ethanol, and dried in vacuo to obtain a purified phosphatidylcholine group containing both terminal and multi-side chains. Degradation of polyester (111).

Example 14

5%的含含镁催化剂混合混合,在真空度。 The 0.5 parts of the glycerol phosphatidylcholine was mixed with 90 parts of the recrystallized purified lactide, and then added, based on the weight of lactide, 0.5% n-butyl magnesium catalyst mixed, in vacuum 50 hidden Hg, dried at 70 ° C for 22 hours, vacuum sealed at 160 ° C for 4 hours, the product was dissolved in acetone, precipitated with anhydrous ether, and dried under vacuum to obtain a unilateral chain containing phosphatidylcholine Group of biodegradable polyester; 30 parts of it is dried and dissolved in 20 parts of dry tetrahydrofuran solvent, and added to a three-necked flask equipped with a dropping funnel and a stirrer; 30 parts of triethylamine is added, and the system is cooled. To -1CTC; further dissolve the polyester mole number of 1.05 times of 2-chloro-2-oxo-1,3,2-dioxaphospholane in 10 parts of dry dichloromethane solvent, Adding to the reaction system, the dropping time is 1 hour; after the completion of the dropwise addition, the reaction is carried out at a temperature of 40 ° C for 4 hours; the precipitate is removed by filtration, and the solvent is removed by rotary evaporation under reduced pressure; the intermediate product is dissolved by adding 10 parts of dry acetonitrile, and 0份干燥的三甲胺, At 35 ° C, the reaction was carried out for 50 hours; the system was cooled to room temperature, the plug was slowly opened, and the residual trimethylamine was transferred to concentrated sulfuric acid by heating to 70 ° C, and the solvent was removed, dissolved in tetrahydrofuran, precipitated with diethyl ether, filtered, and dried in vacuo. That is, a biodegradable polyester (ΠΙ) containing a phosphatidylcholine group in both the purified terminal group and the multi-side chain is obtained.

Example 15

The 5 parts of the multi-side chain phosphatidylcholine group-containing biodegradable polyester prepared in Example 11 was dried, and dissolved in 30 parts of dry tetrahydrofuran and N,N-dimethylformamide (1:1). The mixture of the organic solvent was added to a three-necked flask equipped with a dropping funnel and a stirrer; 1 part of triethylamine was added, and the system was cooled to -50 ° C; Chloro-2-oxo-1,3,2-dioxaphospholane is dissolved in 20 parts of dry tetrahydrofuran solvent, added dropwise to the reaction system, and the dropping time is 1 hour; after the completion of the dropwise addition, the temperature is 70. The reaction was carried out for 20 hours at ° C; the precipitate was removed by filtration, and the solvent was removed by rotary evaporation under reduced pressure; the intermediate product was dissolved by adding 10 parts of dry acetonitrile, and transferred to a pressure bottle, and then 5 parts of dry trimethylamine was added thereto, and the mixture was heated to 80 Torr. The reaction was allowed to stand for 25 hours; the system was cooled to room temperature, the plug was slowly smashed, heated to 80 ° C, the residual trimethylamine was charged into concentrated sulfuric acid, and the solvent was removed by rotary evaporation, dissolved in dichloromethane, precipitated with diethyl ether, filtered and dried in vacuo. That is to obtain purified both terminal groups and multiple side chains Biodegradable polyester (111) containing a phosphatidylcholine group.

Example 16

1 part of the multi-side chain type phosphatidylcholine group-containing biodegradable polyester prepared by the method of Example 9 is dried, dissolved in 1 part of dry hydrazine, hydrazine-dimethylacetamide solvent, and added In the three-necked flask of the dropping funnel and the agitator; 2 parts of (Ν, Ν-dimethylamino) pyridine were added, and the system was cooled to -17 Torr; then the mole of the polyester was 1.1 times 2-chloro-2. The lapsed time is 0.25 hours. The dropwise addition time is 0.25 hours. The dropwise addition time is 0.25 hours. The iodine is added to the reaction system. After the completion of the dropwise addition, the reaction was carried out at a temperature of 50 ° C for 72 hours; the precipitate was removed by filtration, and the solvent was removed by rotary evaporation under reduced pressure; the intermediate product was dissolved by adding 10 parts of dry acetonitrile, and transferred to a pressure bottle, and then 8 parts of dryness was added. Trimethylamine, heated to 100 ° C, reaction for 2 hours; the system was cooled to room temperature, slowly open the plug, heated to 70 ° C, the residual trimethylamine was driven into concentrated sulfuric acid, and the solvent was removed, dissolved in tetrahydrofuran, diethyl ether precipitated , filtration, ethanol washing, vacuum drying, to obtain purified two-end and multi-side Inclusive phosphatidylcholine group biodegradable polyester (111).

Example 17

The 50 parts of the multi-chain phosphatidylcholine group biodegradable polyester prepared by the method of Example 10 was dried, dissolved in 100 parts of dry tetrahydrofuran solvent, and added to a three-necked flask equipped with a dropping funnel and a stirrer. Adding 100 parts of triethylamine and cooling the system to 0 ° C _; then adding 1.03 times the mole of polyester to 2-chloro-2-oxo-1,3,2- Dioxophosphonium is dissolved in 100 parts of dry acetonitrile solvent, added dropwise to the reaction system, and the dropping time is 10 hours; after the completion of the dropwise addition, the reaction is carried out at a temperature of 100 ° C for 1 hour; the precipitate is removed by filtration, and the pressure is reduced. The solvent was removed by rotary evaporation; the intermediate was dissolved by adding 10 parts of dry acetonitrile, and transferred to a pressure bottle, and 25 parts of dry trimethylamine was added thereto, and heated to 30 ° C for 72 hours; the system was cooled to room temperature. Slowly smash the stopper, heat to 8CTC, drive the residual trimethylamine into concentrated sulfuric acid, remove the solvent by rotary evaporation, dissolve it with dichloromethane, precipitate the petroleum ether, filter and vacuum dry, then obtain the purified two-end and multi-side chains. Biodegradable polyester (111) each containing a phosphatidylcholine group.

Claims

Rights request

A biodegradable polyester containing a phosphatidylcholine group having a backbone of a phosphatidylcholine group on the terminal group and a side chain or a side chain of the polyester backbone.

The phosphatidylcholine group-containing biodegradable polyester according to claim 1, which has an average molecular weight of 500 to 2,000,000 and a number of phosphatidylcholine groups of 1 to 200.

3. The phosphatidylcholine group-containing biodegradable polyester according to claim 1 or 2, which has the molecular structural formula as follows:

(I)

o

II

Pc represents O-CH ₂ — CH ₂ — N ⁺ (CH ₃ ) ₃

Z represents the following structure: the structure after the reaction of the diisocyanate with the terminal hydroxyl group of the biodegradable phosphatidylcholine polyester, or the reaction of the diisocyanate with the terminal hydroxyl group of the biodegradable phosphatidylcholine polyester and the hydroxyl or amino group of the chain extender Structure, or a structure in which a diisocyanate reacts with a hydroxyl group or an amino group of a chain extender; 0 is a natural number ≥1.

The method for preparing a phosphatidylcholine group-containing biodegradable polyester according to claim 3, wherein the preparation method of the phosphatidylcholine group-containing biodegradable polyester having the molecular formula (I) comprises: The phosphatidylcholine having two hydroxyl groups is reacted with a cyclic lactone to react with 2-chloro-2-oxo-1,3,2-dioxaphospholane to obtain an intermediate product, which is opened with trimethylamine. Thereby obtaining a biodegradable polyester containing a phosphatidylcholine group having a molecular structure of (I); the preparation method of the biodegradable polyester containing a phosphatidylcholine group having a molecular structure of (Π) comprises: After reacting a hydroxyphosphatidylcholine with a cyclic lactone, a diisocyanate and a chain extender are added to carry out a reaction, thereby obtaining a multi-side chain phosphatidylcholine group biodegradable polyester (II);

The preparation method of the biodegradable polyester containing a phosphatidylcholine group having a molecular structure of (ΠΙ) includes: reacting a phosphatidylcholine having two hydroxyl groups with a cyclic lactone, and adding a diisocyanate and a chain extender The reaction is carried out to obtain a multi-side chain phosphatidylcholine group-containing biodegradable polyester, and then reacted with 2-chloro-2-oxo-1,3,2-dioxaphospholane to obtain an intermediate product. The trimethylamine is opened to obtain a phosphatidylcholine group-containing biodegradable polyester having a molecular structure of (ΠΙ).

The process according to claim 4, characterized in that the cyclic lactone used in the process is at least one of glycolide, lactide and caprolactone.

6. Process according to claim 4 or 5, characterized in that the catalyst used in the process is at least one of tin, zinc, aluminum, magnesium, or an inorganic salt thereof, an organic salt and/or an oxide thereof.

The process according to claim 4 or 5, characterized in that the organic solvent used in the process is methylene chloride, trichloromethane, chloroacetam, 1,2-dichloroethane, 1, 1, 1 -trichloroethane, 1,1,2-trichloroethane, 1, 1, 1, 2-tetrachloroethane, 1, 1, 2, 2-tetrachloroethane, acetone, ethyl acetate, tetrahydrofuran And at least one of acetonitrile, hydrazine, hydrazine-dimethylformamide, and hydrazine, hydrazine-dimethylacetamide.

The process according to claim 6, wherein the organic solvent used in the process is dichloromethane, chloroform, chloroacetam, 1,2-dichloroethane, 1, 1, 1-trichloro Acetyl, 1,1,2-trichloroacetamidine, 1, 1, 1, 2-tetrachloroacetamidine, 1, 1, 2, 2-tetrachloroacetamidine, acetone, ethyl acetate, tetrahydrofuran, acetonitrile, At least one of hydrazine, hydrazine-dimethylformamide, hydrazine, hydrazine-dimethylacetamide, and 1,4-dioxane.

The process according to claim 4 or 5, characterized in that the diisocyanate used in the process is isophorone diisocyanate, toluene diisocyanate, benzene dimethylene diisocyanate, methylcyclohexyl diisocyanate, 4, Any of 4'-methylenebiscyclohexylmethane diisocyanate or hexamethylene diisocyanate.

The process according to claim 8, characterized in that the diisocyanate used in the process is isophorone diisocyanate, toluene diisocyanate, benzene dimethylene diisocyanate, methylcyclohexyl diisocyanate, 4, 4 ' Any one of methylene bicyclohexylformamidine diisocyanate and hexamethylene diisocyanate.

1 . The production method according to claim 4 or 5, wherein the chain extender used in the method is any one of two functional groups containing a hydroxyl group or an amino group; and the alkaline reagent used is ruthenium, osmium, iridium. ', Ν'-tetramethylethylenediamine, pyridine, triethylamine, (Ν, Ν-dimethylamino) pyridine.

The process according to claim 8, wherein the chain extender used in the method is any one of two functional groups containing a hydroxyl group or an amino group; and the alkaline agent used is ruthenium, osmium, iridium, Ν '-tetramethylethylenediamine, pyridine, triethylamine, (Ν, Ν-dimethylamino)pyridine.