CN111004373A

CN111004373A - A kind of preparation method of medical multi-arm polycaprolactone

Info

Publication number: CN111004373A
Application number: CN201911374386.1A
Authority: CN
Inventors: 赵春华; 苏红清; 王栋; 李建; 袁文博
Original assignee: Shandong Guyuchun Biotechnology Technology Co ltd
Current assignee: Shandong Guyuchun Biotechnology Technology Co ltd
Priority date: 2019-12-27
Filing date: 2019-12-27
Publication date: 2020-04-14

Abstract

The invention belongs to the technical field of organic polymer synthesis, and particularly relates to a preparation method of medical multi-arm polycaprolactone.

Description

Preparation method of medical multi-arm polycaprolactone

Technical Field

Background

Biodegradable polyesters have become a hotspot in biomaterial research in recent years due to their excellent biodegradability and biocompatibility. Wherein polycaprolactone [ poly (epsilon-caprolactone), PCL ] is used as an auxiliary material approved by the Food and Drug Administration (FDA) of the United states and can be used as a drug carrier, has excellent biocompatibility and good drug permeability, and has become one of the commonly used carrier materials. However, the linear PCL has higher crystallinity and hydrophobicity, so that the biodegradation speed is slower, and the application of the linear PCL is limited.

The polycaprolactone series products produced commercially at present are basically polycaprolactone (linear polymer), polycaprolactone polyol, caprolactone and other ester copolymers, wherein the alcohol in the polycaprolactone polyol is dihydroxy or trihydroxy alcohol.

The preparation method of polycaprolactone is most commonly characterized in that epsilon-caprolactone is used as a main raw material, alcohols are used as an initiator, and ring-opening polymerization is carried out under the action of a catalyst (as shown in the following formula).

Polymerization catalytic systems can be divided into: an active hydrogen catalytic system; a cationic catalytic system; an anionic catalytic system; metal compound coordination catalytic system. Compared with other polymerization methods, the metal compound coordination catalyst system has the advantages of high monomer conversion rate, mild reaction conditions, high molecular weight, narrow distribution and strong catalyst designability, and is the most applied method at present. Stannous octoate is the most widely used organometallic catalyst.

The polycaprolactone has higher crystallinity and hydrophobicity, so that the biodegradation speed is lower, and compared with the traditional linear polycaprolactone, the polymer with a multi-arm dendritic and star-shaped structure has a plurality of excellent characteristics, such as: multiple surface functionality, good intramolecular environment, low crystallization property and the like. The synthesis of the material with the special structure can increase the efficiency of controlled release of the drugs and genes to some extent.

As a medical degradable material, a tin salt metal catalyst such as stannous octoate is used in the synthesis process of polycaprolactone, although the dosage is small, the neurotoxicity of polycaprolactone has a stimulating effect on eyes, skin, mucous membrane and upper respiratory tract, and whether the polycaprolactone can be safely used in a human body for a long time is still to be examined, so that the application of polycaprolactone in the medical field is limited.

Disclosure of Invention

Aiming at the problems in the prior art, the invention provides a preparation method of multi-arm polycaprolactone, which adopts a bulk melt polymerization method, is simple to operate, takes a compound of a metal element required by human health as a catalyst and polyol as an initiator, and has the advantages of high reaction rate, mild conditions, high yield of the obtained product, narrow molecular weight distribution, good molecular weight controllability and no cytotoxicity.

The preparation method of the multi-arm polycaprolactone takes epsilon-caprolactone monomer as a raw material for melt polymerization, and adopts an organic metal compound as a catalyst; the organic metal compound is a metal compound of magnesium, calcium, zinc, iron or titanium.

The method comprises the following specific steps: adding an epsilon-caprolactone monomer into a reactor under the protection of nitrogen, then adding a mixture of a catalyst and an initiator, reacting for 2-8h at 90-200 ℃, and obtaining a crude product after the reaction is finished; and dissolving the crude product in a benign solvent, precipitating the crude product with a poor solvent and drying the crude product in vacuum to obtain the multi-arm polycaprolactone.

The invention can react for 2-8 hours under the protection of nitrogen. The invention preferably reacts for 3 to 7 hours at a temperature of between 100 and 160 ℃ under the protection of nitrogen. The invention particularly preferably has the reaction temperature of 110-140 ℃ and the reaction time of 3-5 hours.

The catalyst is a metal compound with strong coordination capacity, and zinc lactate, magnesium caprylate or ferric acetylacetonate are preferred. The mole ratio of the epsilon-caprolactone monomer to the catalyst is 8000-18000.

The initiator is glycerol or pentaerythritol or dipentaerythritol or glucose or xylitol.

The mole ratio of the epsilon-caprolactone monomer to the initiator is 100-1600.

After the reaction, the mixed system contains polycaprolactone, residual catalyst and initiator, and the dissolving and precipitating are adopted to remove unreacted catalyst, initiator and low molecular weight polycaprolactone, so that the molecular weight distribution of polycaprolactone is narrow and the performance is more excellent. The benign solvent is selected from toluene or xylene or tetrahydrofuran or chloroform or dichloromethane or dichloroethane. The mass volume ratio of the epsilon-caprolactone monomer to the benign solvent is 1 kg/2L. After the addition of the benign solvent, the crude product was completely dissolved, and then a poor solvent was added dropwise thereto until no precipitation occurred upon delamination. Separating supernatant, dissolving the lower precipitate with benign solvent, precipitating with poor solvent, separating, and repeating the steps. And finally, drying the precipitate in vacuum to obtain the multi-arm polycaprolactone. The poor solvent is selected from methanol, ethanol, diethyl ether, petroleum ether or n-hexane.

The invention takes the compound of metal elements required by human health as the catalyst and the polyalcohol as the initiator, has fast reaction rate, mild conditions, high yield of the obtained product, narrow molecular weight distribution, good molecular weight controllability and no cytotoxicity, can effectively improve the biological safety of the PCL and has wider application range.

Detailed Description

Example 1

Weighing 200g of epsilon-caprolactone monomer, pouring into a three-neck flask, weighing 0.053g of zinc lactate (8000 of monomer and molar ratio thereof) and 0.48g of pentaerythritol (500 of monomer and molar ratio thereof), mixing a catalyst and an initiator, injecting into the three-neck flask, installing a nitrogen guide pipe, a mercury thermometer, a stirrer and the like, introducing nitrogen, starting a stirring device, heating after the system is sealed, controlling the temperature of liquid in the three-neck flask to be 140 ℃, discharging after reacting for 5 hours, wherein the product is pure white, dissolving a crude product by 400ml of toluene, precipitating for four times by methanol, and drying in vacuum to constant weight to obtain a finished product. The molecular weight and molecular weight distribution index were measured by GPC gel chromatography, and the weight average molecular weight of the obtained product was 43225, and the molecular weight distribution index was 1.42.

Example 2

Weighing 200g of epsilon-caprolactone monomer, pouring into a three-neck flask, 0.061g of magnesium octoate (the molar ratio of the monomer to the monomer is 10000) and 0.52g of glucose (the molar ratio of the monomer to the initiator is 600), mixing a catalyst and an initiator, injecting into the three-neck flask, installing a nitrogen guide pipe, a mercury thermometer, a stirrer and the like, introducing nitrogen, starting a stirring device, heating after the system is sealed, controlling the temperature of liquid in the three-neck flask to be 110 ℃, reacting for 5 hours, then discharging a product which is pure white in color, dissolving a crude product by using 400ml of tetrahydrofuran, precipitating by using diethyl ether for four times, and drying in vacuum to constant weight to obtain a finished product. The molecular weight and molecular weight distribution index were measured by GPC gel chromatography, and the weight average molecular weight of the obtained product was 55049, and the molecular weight distribution index was 1.40.

Example 3

Weighing 200g of epsilon-caprolactone monomer, pouring into a three-neck flask, weighing 0.052g of iron acetylacetonate (the molar ratio of the monomer to the monomer is 12000) and 0.26g of xylitol (the molar ratio of the monomer to the monomer is 1000), mixing a catalyst and an initiator, injecting into the three-neck flask, installing a nitrogen guide pipe, a mercury thermometer, a stirrer and the like, introducing nitrogen, starting a stirring device, heating an oil bath after determining that a system is sealed, controlling the temperature of liquid in the three-neck flask to be 200 ℃, reacting for 3 hours, discharging, wherein the product is pure white in color, dissolving a crude product by using 400ml of dichloromethane, precipitating by using n-hexane for four times, and drying in vacuum to constant weight to obtain a finished product. The molecular weight and the molecular weight distribution index were measured by GPC gel chromatography, and the weight average molecular weight of the obtained product was 66769, and the molecular weight distribution index was 1.37.

Example 4

Weighing 200g of epsilon-caprolactone monomer, pouring into a three-neck flask, 0.085g of magnesium octoate (monomer and molar ratio of 14000) and 0.096g of pentaerythritol (monomer and molar ratio of 100), mixing a catalyst and an initiator, injecting into the three-neck flask, installing a nitrogen guide pipe, a mercury thermometer, a stirrer and the like, introducing nitrogen, starting a stirring device, heating after the system is sealed, controlling the temperature of liquid in the three-neck flask to be 90 ℃, reacting for 8 hours, discharging a product with pure white color, dissolving a crude product by 400ml of dimethylbenzene, precipitating for four times by methanol, and vacuum drying to constant weight to obtain a finished product. The molecular weight and the molecular weight distribution index are measured by GPC gel chromatography, and the weight average molecular weight of the obtained product is 20125, and the molecular weight distribution index is 1.42.

Example 5

Weighing 200g of epsilon-caprolactone monomer, pouring into a three-neck flask, 0.119g of zinc lactate (the molar ratio of the monomer to the caprolactone monomer is 18000) and 1.38g of glucose (the molar ratio of the monomer to the caprolactone monomer is 1600), mixing a catalyst and an initiator, injecting into the three-neck flask, installing a nitrogen guide pipe, a mercury thermometer, a stirrer and the like, introducing nitrogen, starting a stirring device, heating after the system is sealed, controlling the temperature of liquid in the three-neck flask to be 200 ℃, reacting for 2 hours, then discharging a product which is pure white in color, dissolving a crude product by using 400ml of tetrahydrofuran, precipitating for four times by using methanol, and drying in vacuum to constant weight to obtain a finished product. The molecular weight and molecular weight distribution index were measured by GPC gel chromatography, and the weight average molecular weight of the obtained product was 79413, and the molecular weight distribution index was 1.39.

Example 6

Weighing 200g of epsilon-caprolactone monomer, pouring into a three-neck flask, 0.078g of iron acetylacetonate (the molar ratio of the monomer to the monomer is 10000), 0.21g of xylitol (the molar ratio of the monomer to the monomer is 800), mixing a catalyst and an initiator, injecting into the three-neck flask, installing a nitrogen guide pipe, a mercury thermometer, a stirrer and the like, introducing nitrogen, starting a stirring device, heating after determining that a system is sealed, controlling the temperature of liquid in the three-neck flask to be 200 ℃, reacting for 2 hours, then discharging a product which is pure white in color, dissolving a crude product by using 400ml of chloroform, precipitating by using diethyl ether for four times, and drying in vacuum to constant weight to obtain a finished product. The molecular weight and the molecular weight distribution index were measured by GPC gel chromatography, and the weight average molecular weight of the obtained product was 60317 and the molecular weight distribution index was 1.43.

Claims

1. a preparation method of multi-arm polycaprolactone, takes ε-caprolactone monomer as raw material melt polymerization, is characterized in that, adopts organometallic compound to be catalyzer; Described organometallic compound is magnesium or calcium or zinc Or metal compounds of iron or titanium.

2. the preparation method of a kind of multi-arm polycaprolactone according to claim 1, is characterized in that, concrete steps are: under nitrogen protection, add ε-caprolactone monomer in the reactor, then add catalyzer and The mixture of initiators is reacted at 90-200 DEG C for 2-8 hours. After the reaction is completed, a crude product is obtained; the crude product is dissolved in a benign solvent, precipitated in a poor solvent and dried in vacuum to obtain a multi-arm polycaprolactone.

3. the preparation method of a kind of multi-arm polycaprolactone according to claim 1, is characterized in that, described catalyst is zinc lactate or magnesium octoate or iron acetylacetonate.

4 . The method for preparing a multi-arm polycaprolactone according to claim 1 , wherein the molar ratio of the ε-caprolactone monomer to the catalyst is 8000-18000. 5 .

5. the preparation method of a kind of multi-arm polycaprolactone according to claim 2, is characterized in that, described initiator is glycerol or pentaerythritol or dipentaerythritol or glucose or xylitol.

6 . The method for preparing a multi-arm polycaprolactone according to claim 2 , wherein the molar ratio of the ε-caprolactone monomer to the initiator is 100-1600. 7 .

7 . The preparation method of a multi-arm polycaprolactone according to claim 2 , wherein the benign solvent is selected from toluene or xylene or tetrahydrofuran or chloroform or dichloromethane or dichloroethane. 8 .

8 . The preparation method of a multi-arm polycaprolactone according to claim 2 , wherein the mass-volume ratio of the ε-caprolactone monomer to the benign solvent is 1kg/2L. 9 .

9. the preparation method of a kind of multi-arm polycaprolactone according to claim 2, is characterized in that, described poor solvent is selected from methanol or ethanol or ether or petroleum ether or n-hexane.