WO2023208121A1

WO2023208121A1 - Method of preparing methoxy poly(ethylene glycol)-b-poly(l-lactide) block copolymer

Info

Publication number: WO2023208121A1
Application number: PCT/CN2023/091215
Authority: WO
Inventors: 李睿智; 张堃; 许凯; 宋大伟
Original assignee: 爱美客技术发展股份有限公司
Priority date: 2022-04-29
Filing date: 2023-04-27
Publication date: 2023-11-02
Also published as: CN117003997A

Abstract

A method of preparing a methoxy poly(ethylene glycol)-b-poly(L-lactide) (mPEG-PLLA) block copolymer is disclosed. During preparation of lactide, a mixture of antimony trioxide and phosphoric acid is used as a catalyst; at the same time, by also using a deep hydrolysis process, the optical purity of the lactide is increased; while the lactide and methoxy poly(ethylene glycol) are subjected to ring-opening polymerization to generate an mPEG-PLLA block copolymer, a solution polymerization reaction system is combined with a composite aluminum catalyst, and with colloid hierarchical purification and other processes to accurately control the molecular weight of the finished mPEG-PLLA block copolymer product. The invention allows for an increased finished product yield, as well as elimination of the toxic side effects on the human body that the high levels of tin residues in current mPEG-PLLA block copolymer processes can cause.

Description

Preparation method of polyethylene glycol monomethyl ether-polylactic acid block copolymer

Technical field

The invention belongs to the field of polymer material synthesis, and specifically relates to a preparation method of polyethylene glycol monomethyl ether-polylactic acid block copolymer.

Background technique

In recent years, the cosmetic micro-plastic surgery market has developed rapidly, and injectable fillers have occupied the main force in the industry. Polyethylene glycol monomethyl ether-polylactic acid block copolymer (mPEG-PLLA) has good biocompatibility and biodegradability. Favored by the industry for its amphiphilic nature.

In the currently disclosed preparation process of polyethylene glycol monomethyl ether-polylactic acid block copolymer, most of them start with purchased lactide, stannous octoate is used as a catalyst, bulk polymerization is performed, and the molecular weight of the product is controlled by adding a polymerization inhibitor. The reaction temperature in the later stage of the process is as high as about 180°C, and the reaction time exceeds 4 hours. At the same time, the introduction of impurities in lactide and the addition of polymerization inhibitors aggravate side reactions, making it difficult to accurately control the molecular weight of the polymer, with a wide molecular weight distribution and optical rotation. Problems such as degree deviation and difficulty in removing polymerization inhibitor and catalyst residues. Although the finished product refining process can narrow the molecular weight distribution and reduce the residue of polymerization inhibitor, the finished product yield is less than 40%, resulting in high production costs. At the same time, the problems of precise control of molecular weight, optical rotation deviation, and tin residue have not yet been solved. .

For example, Chinese patent CN201510593332. Due to the susceptibility of human skin to sensitization, the production of injectable fillers requires high-purity raw materials and strict control of heavy metals, chemical reagents and other residues to ensure the clinical application of the product; at the same time, in the production of the product, the molecular weight and dispersion of poly-L-lactic acid must be The coefficient directly determines the yield of the product, so qualified raw materials for injection fillers need to have: poly-L-lactic acid block copolymer with high purity, low residue, controllable molecular weight, and narrow molecular weight distribution.

Chinese patent CN 104892909 discloses the use of polyethylene glycol monomethyl ether and D, L-lactide as reaction raw materials, stannous octoate as catalyst, prepared by melt polycondensation method, and after the reaction is completed, 1 to 4 times of dichloromethane are used to dissolve - The finished product is obtained by crystallizing diethyl ether. This method is a commonly used method for preparation. The reaction time of this method is as long as 12 to 14 hours, and the molecular weight of the product is low. The long-term reaction produces transesterification, resulting in poor optical purity of the finished product. The yield of the finished product is <80%. .

Chinese patent CN 1111253A discloses using triisobutylaluminum as a catalyst under nitrogen protection. 60-220℃, initiate bulk or solution copolymerization of lactone (or lactide) and polyether glycol, and use a fatty alcohol with 12-24 carbon atoms as a molecular weight regulator to control the molecular weight. This process avoids heavy metals The residual tin can better control the molecular weight of the polymerized product polyD,L-lactide. However, the addition of fatty alcohol terminates the polymerization reaction in advance, resulting in a broad molecular weight distribution. At the same time, the fatty alcohol chain is introduced, which increases the residual amount in the polymer. things.

Chinese patent CN 106995528 A discloses that polyethylene glycol monomethyl ether-polylactic acid block copolymer (mPEG-PDLLA) is refined through a stepwise cooling method to narrow the molecular weight distribution of the polymer and prepare a polymer glue. The particle size of the bundle is small and uniform, the freeze-dried powder has excellent stability and good reconstitution effect. However, the yield of this process is less than 40%, the material loss is large, and the production cost is high.

In addition, most of the production methods of the above-mentioned patented polyethylene glycol monomethyl ether-polylactic acid block copolymers start with lactide. Commercially available L-lactide is basically an industrial product, and does not pay attention to the high optical purity and high optical purity required for medical use. Low residue, the adverse impact of this defect on the finished product of polyethylene glycol monomethyl ether-polylactic acid block copolymer is difficult to make up for in the later stage.

Contents of the invention

The present invention starts with lactic acid, and through process implantation and integration, first produces high-purity lactide, and then completes liquid phase polymerization using a composite aluminum catalyst at a mild reaction temperature (lower than 145°C, reaction time shorter than 1 hour) , the polymerized colloid is refined to obtain polyethylene glycol monomethyl ether-polylactic acid block copolymer with high optical purity and controllable molecular weight.

The invention provides a preparation method of polyethylene glycol monomethyl ether-polylactic acid block copolymer, which specifically includes the following steps:

Step 1: Under the catalysis of a composite aluminum catalyst, lactide and polyethylene glycol monomethyl ether undergo a ring-opening polymerization reaction to generate a polyethylene glycol monomethyl ether-polylactic acid block copolymer colloid;

Step 2: The polyethylene glycol monomethyl ether-polylactic acid block copolymer is colloidally refined to obtain the finished polyethylene glycol monomethyl ether-polylactic acid block copolymer.

Preferably, the preparation process of lactide in step 1 includes the following steps:

Step 1), dehydrate lactic acid to obtain oligomeric lactic acid. First, under certain temperature and negative pressure conditions, the free water in the lactic acid is removed, and then under the conditions of a catalyst, the bound water in the lactic acid is removed by gradually heating up and reducing the pressure.

Preferably, the temperature for removing free water is 70°C to 90°C, and further preferably the temperature is 75°C to 85°C, such as 75°C, 78°C, 80°C, 82°C, and 85°C.

Preferably, the negative pressure for removing free water is -0.090~-0.097MPa, and further preferably the negative pressure is -0.093~-0.097MPa, such as -0.093MPa, -0.094MPa, -0.095MPa, -0.096MPa, -0.097MPa .

Preferably, the catalyst for removing bound water in lactic acid is a mixture of antimony trioxide and phosphoric acid. Compared with using antimony trioxide alone as a catalyst, the mixed catalyst can better reduce the cyclization of lactic acid oligomers into racemic lactide. Or conversion to D-lactide, thereby improving the optical purity of L-lactide.

Preferably, in the mixed catalyst, the amount of antimony trioxide added is 0.75-0.85% of the mass of lactic acid, more preferably 0.75-0.80%, such as 0.75%, 0.76%, 0.77%, 0.78%, 0.79%, 0.80%.

Preferably, in the mixed catalyst, the added amount of phosphoric acid is 0.2% to 0.4% of the mass of lactic acid, more preferably 0.25% to 0.4%, such as 0.25%, 0.28%, 0.30%, 0.35%, 0.38%, 0.40 %.

Preferably, the starting temperature for removing bound water in lactic acid is 120 to 160°C, more preferably 140 to 160°C, such as 140°C, 145°C, 150°C, 155°C, and 160°C.

Preferably, in the process of removing lactic acid-bound water, the heating and pressure reduction methods are stepwise, and the temperature of each step is 2 to 5°C, such as 2°C, 3°C, 4°C, and 5°C. The pressure of each stage is -0.01~-0.03MPa, such as -0.01MPa, -0.02MPa, -0.03MPa.

Preferably, the final temperature for removing lactic acid bound water is 180-190°C, and the vacuum degree is ultimate vacuum.

Step 2), oligolactic acid is cleaved and cyclized to generate lactide. After the dehydration of lactic acid is completed, first use inert gas to replace the reaction vessel to normal pressure, then remove the aqueous solution, then add the catalyst, and crack and cyclize it at a temperature above 200°C and a negative pressure below -0.095MP to prepare block propylene. Lactide.

Preferably, the inert gas is selected from at least one of nitrogen, argon or helium, and is further preferably nitrogen.

Preferably, the catalyst is antimony trioxide and glycerol.

Preferably, the amount of antimony trioxide added is 0.15% to 0.25% of the initial lactic acid mass. It is further preferred that the amount of antimony trioxide added is 0.15% to 0.2% of the initial lactic acid mass, such as 0.15%, 0.16%, 0.17%. , 0.18%, 0.19%, 0.20%.

Preferably, the amount of glycerol added is 3% to 8% of the initial lactic acid mass, more preferably 5% to 8%, For example, 5%, 5.5%, 6.0%, 6.5%, 7.0%, 7.5%, 8.0%.

Preferably, the temperature above 200°C is 200°C to 260°C, more preferably 220°C to 250°C, more preferably 220°C to 240°C, such as 220°C, 225°C, 230°C, 235°C, and 240°C.

In the existing lactide synthesis process, the cleavage and cyclization of oligolactic acid into lactide requires a long-term and high-temperature reaction, which inevitably leads to side reactions of transesterification, forming part of meso-lactide, and affecting the properties of lactide. Optical rotation and late polymerization. Therefore, it is crucial to reduce transesterification side reactions during synthesis and completely eliminate meso-lactide during lactide purification.

The present invention uses a composite high-efficiency catalytic system of antimony trioxide + phosphoric acid, antimony trioxide + glycerol, and adds it in stages. The first stage catalyst accelerates the dehydration and polycondensation of lactic acid. The introduction of phosphoric acid can increase the stability of the system reaction, forming The molecular weight distribution of oligomeric lactic acid is narrower, which is beneficial to the later cleavage and cyclization reaction. The addition of the second stage catalyst increases the activation energy of the reaction system, and at the same time introduces glycerol with a high boiling point, which makes the heat transfer of the reaction system more complete, reduces side reactions caused by local ultra-high temperatures, and facilitates the distillation of the product lactide. . Furthermore, at the same temperature, the reaction rate of the entire lactide synthesis process is accelerated, and the change in optical rotation due to transesterification caused by continued high temperature is reduced, so that the lactide in the crude lactide that changes the optical rotation is reduced, improving the Optical purity and yield of L-lactide.

Step 3), subject the lactide prepared in step 2) to water extraction. Add lump lactide and water together according to the preset mass ratio, stir and mix evenly, let stand and then filter out the aqueous solution.

Preferably, the mass ratio of bulk lactide to water is 1:1 to 1:3, more preferably 1:1.5 to 1:2.5, such as 1:1.5, 1:1.75, 1:2, 1:2.25, 1:2.5.

Step 4), hydrolyze the lactide after water extraction. Add the water-extracted lactide to warm water for deep hydrolysis.

Preferably, the mass ratio of lactide to warm water after water extraction is 1:2-4, more preferably 1:2-3, such as 1:2, 1:2.3, 1:2.5, 1:2.7, 1: 3.

Preferably, the temperature of the warm water is 45-55°C, more preferably 48-53°C, such as 48°C, 49°C, 50°C, 51°C, 52°C, 53°C.

Preferably, the hydrolysis time is 2 to 5 h, more preferably 2.5 to 5 h, such as 2.5 h, 3.0 h, 3.5 h, 4.0 h, 4.5 h, 5.0 h.

Through deep hydrolysis of lactide, the present invention completely eliminates meso-lactide in crude lactide, improves the optical purity of L-lactide, and obtains high-purity monomers, thereby further preparing high-optical-purity polyester. milk acid.

Step 5): The hydrolyzed lactide is sequentially filtered to remove water, filtered and washed with an organic solvent, and dried to obtain crude lactide.

Preferably, the organic solvent is selected from any one of ethanol, diethyl ether, and propanol, and is further preferably ethanol.

Preferably, the drying method is air drying or oven drying, and the drying temperature is preferably 65°C or lower, and more preferably 60°C or lower.

Step 6), purify and refine the crude lactide. The prepared crude lactide and absolute ethanol are added into a crystallization purification vessel, dissolved and filtered, and the filtrate is crystallized overnight, and then solid-liquid separation is performed to obtain lactide crystals, which are then vacuum dried to obtain primary purification of lactide. Then, ethyl acetate is used to purify and crystallize the once-purified lactide to obtain refined lactide.

Preferably, the mass ratio of crude lactide to absolute ethanol is 1:1 to 2, more preferably 1:1 to 1:1.5, such as 1:1, 1:1.05, 1:1.1, 1:1.15 , 1:1.2, 1:1.25, 1:1.3, 1:1.35, 1:1.4, 1:1.45, 1:1.5.

Preferably, the mass ratio of primary lactide to ethyl acetate is 1:0.7-1.5, more preferably 1:0.7-1.2, such as 1:0.7, 1:0.75, 1:0.8, 1:0.85, 1 :0.9, 1:0.95, 1:1.0, 1:1.05, 1:1.1, 1:1.15, 1:1.2.

Preferably, the dissolution temperature is 70 to 85°C, more preferably 70 to 80°C, such as 70°C, 72°C, 74°C, 76°C, 78°C, or 80°C.

Preferably, the crystallization temperature of the filtrate is 10 to 35°C, more preferably 10 to 30°C, such as 10°C, 15°C, 20°C, 25°C, or 30°C.

Preferably, the vacuum drying temperature is 45-60°C, more preferably 45-55°C, such as 45°C, 47°C, 50°C, 53°C, 55°C.

The present invention adopts a multi-solvent alternating recrystallization purification process and utilizes the different solubilities of solvents to effectively remove insoluble impurities and soluble impurities, including the removal of free acids and moisture, and can improve the crystallinity of lactide to prepare low-residue High-purity lactide lays a solid foundation for the later polymerization reaction to be stable and sufficient.

In one embodiment of the present invention, the preparation process of polyethylene glycol monomethyl ether-polylactic acid block copolymer colloid in step 1 includes the following steps:

Step 1-1, add the refined lactide and polyethylene glycol monomethyl ether prepared through the above step 6) into the polyethylene glycol monomethyl ether. In the combined reaction vessel, after vacuum drying, replace with inert gas to remove moisture in the reaction system.

Preferably, in the mixture of refined lactide and polyethylene glycol monomethyl ether, the mass fraction of lactide is 97 to 99.5%, more preferably 97.5 to 99.5%, such as 97.5%, 98%, 98.5%, 99 %, 99.5%.

Preferably, the vacuum drying temperature is 45 to 60°C, more preferably 45 to 55°C, such as 45°C, 47°C, 50°C, 53°C, and 55°C.

Preferably, the inert gas is selected from at least one of helium, argon, and nitrogen, and is further preferably argon.

Preferably, the number of substitutions of the inert gas is 2 to 5 times, more preferably 3 to 5 times, such as 3 times, 4 times, or 5 times.

Step 1-2: Add anhydrous xylene to the reaction system treated in step 1-1, heat it up to dissolve, then add a catalyst, and heat up the reaction to obtain a polyethylene glycol monomethyl ether-polylactic acid block copolymer colloid.

Preferably, the mass ratio of anhydrous xylene to monomer is 1.5 to 2.5:1, more preferably 2.0 to 2.5:1, such as 2.0:1, 2.1:1, 2.2:1, 2.3:1, 2.4:1, 2.5:1.

Preferably, the temperature of the elevated temperature dissolution is controlled below 130°C, more preferably below 120°C.

Preferably, the catalyst is a composite aluminum catalyst, further preferably the catalyst includes triisobutylaluminum, and more preferably, the catalyst includes triisobutylaluminum, isobutylene and xylene. More preferably, the mass ratio of triisobutylaluminum, isobutylene and xylene is 1:2.5~3.0:0.1~0.2.

Preferably, based on the total mass of lactide and polyethylene glycol monomethyl ether, and calculated based on pure triisobutylaluminum, the added amount of the composite aluminum catalyst is 0.15 to 2.0%, more preferably 0.15 to 2.0%. 1.0%, such as 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.42%, 0.45%, 0.5%, 0.75%, 1.0%.

The present invention adopts a self-developed high-activity composite aluminum catalyst, which has higher catalytic activity than the commonly used stannous octoate, resulting in lower reaction temperature and faster reaction rate. Ordinary aluminum-based catalysts are easily decomposed or reacted with trace amounts of water and oxygen during use, resulting in reduced activity. By combining isobutylene, xylene and aluminum-based catalysts, the present invention can prevent aluminum-based catalysts from interacting with trace amounts of water. Reacts with oxygen to maintain the high activity of the aluminum catalyst and make the entire process proceed steadily before, during and after the polymerization reaction.

Preferably, the temperature of the ring-opening polymerization reaction is 110 to 145°C, more preferably 115 to 140°C, more preferably 120 to 140°C, such as 120°C, 125°C, 130°C, 135°C, and 140°C.

Preferably, the ring-opening polymerization reaction time is 0.5 to 1.5h, more preferably 0.5 to 1.0h, such as 0.5h, 0.75h, 0.8h, 1.0h.

Preferably, polyethylene glycol monomethyl ether, refined lactide and anhydrous xylene constitute the solution polymerization reaction system of the ring-opening polymerization reaction,

Preferably, the anhydrous solvent is selected from at least one of anhydrous xylene, decalin or diphenyl ether, and is further preferably anhydrous xylene.

Preferably, the mass ratio of the total mass of refined lactide and polyethylene glycol monomethyl ether to anhydrous xylene is 1:1.5 to 2.5. More preferably, the mass ratio of refined lactide and polyethylene glycol monomethyl ether is The mass ratio of the total mass to anhydrous xylene is 1:1.5~2.2, such as 1:1.5, 1:1.8, 1:2.0, 1:2.1, 1:2.2.

In another embodiment of the present invention, the process of colloid refining the polyethylene glycol monomethyl ether-polylactic acid block copolymer in step 2 to obtain the finished polyethylene glycol monomethyl ether-polylactic acid block copolymer includes the following steps:

Step 2-1, classification treatment of polyethylene glycol monomethyl ether-polylactic acid block copolymer colloid.

First, add the polyethylene glycol monomethyl ether-polylactic acid block copolymer colloid and methylene chloride obtained in step 1-2 into the purification reaction vessel, stir and dissolve, add absolute ethanol, and continue stirring until the polyethylene glycol monomethyl ether is dissolved. After the methyl ether-polylactic acid block copolymer is completely dissolved, slowly add absolute ethanol dropwise. Stop when a large amount of soft colloids appear in the solution, let it stand for clarification, and remove the supernatant.

Preferably, the mass ratio of polyethylene glycol monomethyl ether-polylactic acid block copolymer to methylene chloride is 1:4-8, more preferably 1:5-7, such as 1:5, 1:5.5, 1 :6, 1:6.5, 1:7.

Preferably, the added volume of absolute ethanol is the same as the volume of methylene chloride.

Step 2-2, purification of polyethylene glycol monomethyl ether-polylactic acid block copolymer soft colloid.

First, add an appropriate amount of absolute ethanol to the polyethylene glycol monomethyl ether-polylactic acid block copolymer soft colloid that has been classified in step 2-1, stir and precipitate, separate the solid and liquid, and dry the precipitate to obtain polyethylene glycol. A pure product of monomethyl ether-polylactic acid block copolymer.

Add the primary product of polyethylene glycol monomethyl ether-polylactic acid block copolymer and methylene chloride into the purification container, and stir to dissolve. Then filter it into a purification container in a class 10,000 clean area, add an appropriate amount of absolute ethanol to precipitate under stirring, separate the solid and liquid, dry and sieve the precipitate, and then vacuum-dry the fine powder to obtain polyethylene glycol monomethyl ether-polymer Finished lactic acid block copolymer.

Preferably, the filtration is 0.2 micron pressure filtration.

Preferably, the temperature for vacuum drying of the fine powder is 45-60°C, more preferably 45-55°C, for example Such as 45℃, 47℃, 50℃, 53℃, 55℃.

The hierarchical purification process of the present invention can remove low molecular weight polymers and make the molecular weight distribution of the finished product narrower. The classification operation method in this process is organically combined with the conventional purification process of polylactic acid, which effectively saves production costs on the basis of achieving results.

Beneficial effects of the present invention:

1. In the preparation process of lactide, the present invention uses antimony trioxide and phosphoric acid, antimony trioxide and glycerol as catalysts respectively, and the catalysts are added in batches in two stages. The first stage catalyst accelerates the production of lactic acid. Dehydration and polycondensation, the introduction of phosphoric acid can increase the stability of the system reaction, so that the molecular chain of the formed oligolactic acid is shorter, the molecular weight distribution is narrower, and it is easy to crack and cyclize; the addition of the second stage catalyst increases the activation energy of the reaction system, and at the same time The introduction of glycerol with a high boiling point makes the heat transfer of the reaction system more complete, reduces side reactions caused by local ultra-high temperatures, and facilitates the distillation of the product lactide; at the same time, the change in optical rotation of lactide is reduced, and the L - Optical purity and yield of lactide.

2. In the preparation process of lactide, the present invention adopts a unique deep hydrolysis process to eliminate meso-lactide and further improve the optical purity of L-lactide.

3. In the refining process of lactide, the present invention adopts a multi-solvent alternating recrystallization purification process to effectively remove impurities (such as free acid and moisture), improve the crystallinity of lactide, and further improve the crystallinity of L-lactide. purity.

4. The residual amount of lactide prepared by the present invention is less than 10PPM. The medical industry standard YY/T0661-2017 limits it to ≤3%; after verification, the lactide residue of medical polylactic acid sold by Corbion, an internationally renowned polylactic acid manufacturer, is <0.1%. The residual amount of lactide prepared by the present invention is low, which avoids the problem of unstable mechanical properties caused by internal cracks in injection molded parts during subsequent processing, and also reduces the risk of aseptic inflammation caused by acidic release caused by rapid hydrolysis of lactide in clinical applications. risks of.

5. The present invention first prepares high-purity monomers, and then with the support of a solution polymerization system and a composite aluminum catalyst, the oxidative decomposition of triisobutylaluminum can be inhibited by introducing isobutylene into the composite aluminum catalyst, so that low-concentration composite aluminum The catalyst can achieve efficient catalytic reactions. The low-concentration catalyst reaction system can be rapidly dispersed and uniform. At a suitable reaction temperature, coordination polymerization can go hand in hand, and the energy exchange of the solution reaction system is sufficient, thus achieving a reaction time of less than 145°C. The polymerization reaction is completed under reaction conditions of less than 1 hour, which effectively avoids side reactions such as transesterification caused by high temperatures and long-term reactions in traditional processes, and produces polymers with high optical purity. At the same time, the low-concentration solution reaction system can still effectively maintain intermolecular motion during the later polymerization. This ensures sufficient monomer conversion, effectively reduces lactide residue, and increases the polymer yield.

6. During the ring-opening polymerization reaction, the present invention adopts a solution polymerization system, which makes the reaction more complete, lowers the reaction temperature, and shortens the reaction time. It effectively avoids side reactions such as transesterification caused by high temperature and long-term reactions in traditional processes, improves the optical purity of polyethylene glycol monomethyl ether-polylactic acid block copolymer, and makes high optical purity L-polylactic acid and polyethylene glycol Alcohol monomethyl ether copolymer has a smooth metabolic pathway, thereby improving biocompatibility; and a unique composite aluminum catalyst is used to replace stannous octoate and ordinary aluminum catalysts, which improves reaction activity and eliminates the use of existing technologies. Problems such as excessive tin residue caused by stannous octoate and easy oxidation of aluminum catalysts eliminate the toxic side effects of tin on the human body and effectively solve the shortcomings of mPEG-PLLA in medical applications.

7. In the colloid purification process of polyethylene glycol monomethyl ether-polylactic acid block copolymer, the present invention adopts a hierarchical purification process to remove low molecular weight polymers, making the molecular weight distribution of the finished product narrower. At the same time, through precise control of polyethylene Glycol monomethyl ether-polylactic acid block copolymer has a narrow molecular weight and molecular weight distribution. In downstream processing applications, its mechanical properties are more stable and the yield of downstream finished products is higher. Furthermore, no polymerization inhibitor and molecular weight regulator are added in the present invention, which reduces side reactions caused by polymerization inhibitors and high temperatures and narrows the molecular weight distribution of the product.

Description of the drawings

Figure 1 is the infrared spectrum of the sample of Example 4;

Figure 2 is the NMR spectrum of the sample of Example 4.

Detailed ways

The technical solution of the present invention will be further described below in conjunction with the embodiments. The advantages and features of the present invention will become clearer with the description. However, it should be understood that the embodiments are only exemplary and do not limit the scope of the present invention.

Example 1: Preparation of L-Lactide Sample 1

1.1. L-lactic acid dehydration

Add 1.25kg of 80% L-lactic acid into the L-lactide synthesis reaction kettle, maintain it at 80°C and -0.095MPa for 1.5h, remove the free water in L-lactic acid, then turn off the vacuum and add dioxide 8.5g of antimony and 1.5mL of phosphoric acid, with a starting temperature of 160°C and -0.03MPa, reacted for 0.5h, and then increased in steps of 5°C and -0.02MPa, adjusting every 0.5h until treated under ultimate vacuum at 180°C for 1h. Then use nitrogen to replace the pressure to normal pressure, remove the aqueous solution, and remove the bound water in L-lactic acid to obtain the oligomeric L-lactic acid reaction material.

1.2. Cleavage and cyclization of oligomeric L-lactic acid to generate L-lactide

Add 1.5g of antimony trioxide and 50mL of glycerin to the reaction material, and then react under extreme vacuum at 220°C. The temperature increases by 5°C every 1 hour until about 70mL of the reaction material remains. Stop the reaction to obtain block L- Lactide.

1.3. Water extraction treatment of bulk L-lactide

Add 1.4 to 1.5L of purified water to the reaction kettle, stir and break up the lumps of L-lactide, thoroughly mix the L-lactide and purified water, and then filter out the aqueous solution.

1.4. Deep hydrolysis of L-lactide

Pour the water-extracted L-lactide into the stirring kettle, add 2L of 50°C purified water, and hydrolyze it for 3 hours under stirring at 500 rpm.

1.5. Preparation of crude L-lactide

The aqueous solution in the hydrolyzate was removed by filtration, then 0.25L of absolute ethanol was added to filter and wash, and then air-dried at 60°C to obtain crude L-lactide.

1.6. Purification and refining of crude L-lactide

Add 800g of crude L-lactide and 1.15L of absolute ethanol into a crystallization purification tank, stir, dissolve and filter at 80°C. The filtrate crystallizes at room temperature overnight, and solid-liquid separation is performed to obtain L-lactide crystals. It is then vacuum dried at 50°C to obtain primary purified L-lactide. Then add 600g of purified L-lactide and 0.7L of anhydrous ethyl acetate into the crystallization and purification tank, dissolve at 80°C and crystallize at room temperature overnight, solid-liquid separation to obtain L-lactide crystals, and vacuum drying at 50°C to obtain the refined product L-lactide sample 1. After testing, the purity of L-lactide is as high as 99.95%.

Example 2: Preparation of L-Lactide Sample 2

2.1 L-lactic acid dehydration:

Add 1.25kg of 80% L-lactic acid into the L-lactide synthesis reaction kettle, maintain it at 80°C and -0.095MPa for 1.5h, remove the free water in L-lactic acid, then turn off the vacuum and add dioxide trioxide 7.5g of antimony and 1.5mL of phosphoric acid, with a starting temperature of 160°C and -0.03MPa, react for 0.5h, and then proceed with each step of 5°C and -0.02MPa, adjusting every 0.5h until treated under ultimate vacuum at 180°C for 1h. Then use nitrogen to replace the pressure to normal pressure, remove the aqueous solution, and remove the bound water in L-lactic acid to obtain the oligomeric L-lactic acid reaction material.

2.2 Cleavage and cyclization of oligomeric L-lactic acid to generate L-lactide:

Add 2.5g of antimony trioxide and 50mL of glycerin to the reaction material, and then react under extreme vacuum at 220°C. The temperature increases by 5°C every 1 hour until about 70mL of the reaction material remains. Stop the reaction to obtain block L- Lactide.

Other subsequent steps are the same as in Example 1. The purity of L-lactide sample 2 was finally detected to be 99.9%.

Comparative Example 1: Preparation of L-lactide Comparative Sample 1

The experimental process was the same as that in Example 1, the only difference being that no phosphoric acid was added to the catalyst for dehydration of L-lactic acid. The purity of L-lactide comparative sample 1 was finally measured to be 97.5%.

Comparative Example 2: Preparation of L-lactide Comparative Sample 2

The experimental process is the same as that of Example 1. The only difference is that the catalyst antimony trioxide added in both the dehydration of L-lactic acid and the cleavage and cyclization of oligomeric L-lactic acid is adjusted to add antimony trioxide all at once during the dehydration of L-lactic acid. Antimony 10g.

Comparative Example 3: Preparation of L-lactide Comparative Sample 3

The experimental process is the same as that in Example 1. The only difference is that there is no deep hydrolysis process of L-lactide. Instead, the water-extracted L-lactide is poured into a stirring tank, and 2L of purified water is added for purification and crushing. ,filter. Then enter the preparation step of crude L-lactide.

Comparative example A:

1.1. L-lactic acid dehydration

Add 1.25kg of 80% L-lactic acid into the L-lactide synthesis reaction kettle, maintain it at 80°C and -0.095MPa for 1.5h, remove the free water in L-lactic acid, then turn off the vacuum and add dioxide 8.5g of antimony and 50mL of glycerol, the starting temperature is 160℃, -0.03MPa, react for 0.5h, then proceed with each step of 5℃, -0.02MPa, adjust every 0.5h, until treated at 180℃ ultimate vacuum for 1h . Then use nitrogen to replace the pressure to normal pressure, remove the aqueous solution, and remove the bound water in L-lactic acid to obtain the oligomeric L-lactic acid reaction material.

1.2. Cleavage and cyclization of oligomeric L-lactic acid to generate L-lactide

Add 1.5g of antimony trioxide and 1.5mL of phosphoric acid to the reaction material, and then react under extreme vacuum at 220°C. The temperature increases by 5°C every 1 hour until the reaction material remains about 200mL. It does not decrease for 0.5 hours and there is no distillation in the receiving pipe. substance, stop the reaction, and obtain block L-lactide.

Other steps are the same as Example 1.

Example 3: Determination of L-lactide sample

3.1. Determination of specific optical rotation of L-lactide sample

According to the General Chapter 0621 of the 2020 edition of the "Pharmacopoeia of the People's Republic of China (Part IV)" - Optical Rotation Determination Method, the L-lactide sample prepared in the Example and the L-lactide comparison sample prepared in the Comparative Example were measured. The measurement results are shown in Table 1.

Table 1

It can be seen from Table 1 that the specific optical rotation of the L-lactide sample prepared in the Example is lower than that of the Comparative Example sample, indicating that compared with the existing process (Comparative Example process), the process of the present invention can improve Optical purity of L-lactide. The improvement of the optical purity of L-lactide lays a technical foundation for improving the quality of polyethylene glycol monomethyl ether-poly-L-lactic acid block copolymer.

3.2. Determination of free acid in L-lactide samples

3.2.1. Free acid determination method:

A. Calibration of sodium methoxide standard solution: Accurately weigh about 50 mg of benzoic acid into a 100 mL Erlenmeyer flask, add 25 mL of anhydrous methanol and two drops of 0.2% α-naphthol phthalol solution, slowly add dry N ₂ and start stirring. Dissolve the sample (about 5 minutes), and then drop the anhydrous methanol solution of about 0.02mol/L sodium methoxide to be calibrated to the light blue end point. The concentration of this sodium methoxide solution is calculated according to the following formula:

In the formula:

c-Concentration of sodium methoxide standard solution (mol/L);

V-the volume of sodium methoxide standard solution consumed in titrating the sample (mL);

m _B - mass of benzoic acid (mg);

122.1-Molecular weight of benzoic acid.

B. Accurately weigh 1.8~2.0gL-lactide sample into a 100mL Erlenmeyer flask, and titrate with the calibrated sodium methoxide solution according to the calibration procedures of the sodium methoxide standard solution. The free acid content is calculated as follows:

In the formula:

c-Concentration of sodium methoxide standard solution (mol/L);

m-sample mass (mg);

90.08-L-lactic acid molecular weight.

3.2.2. Determination of free acid content in L-lactide

The free acid content in the L-lactide sample prepared in the Example and the L-lactide comparison sample was measured according to the method in 3.2.1. The results are shown in Table 2.

Table 2

As can be seen from Table 2, the free acid content in the L-lactide sample prepared in the Example is significantly lower than the free acid content in the L-lactide comparison sample. It shows that compared with the prior art (comparative example process), the process of the present invention can significantly reduce the residual amount of free acid in L-lactide. The reduction in the residual amount of free acid indicates the improvement of the purity of L-lactide, thus laying a technical foundation for improving the quality of polyethylene glycol monomethyl ether-poly-L-lactic acid block copolymer.

Example 4: Preparation of mPEG-PLLA Sample 1

The target molecular weight of this sample is designed to be Mw=95,000. The specific preparation process is as follows:

4.1. Removal of moisture

Weigh 300g of the L-lactide sample of Example 1 and 3.16g of polyethylene glycol monomethyl ether, add them to the polymerization reaction kettle, dry them under vacuum at 50°C, and then replace them with argon three times to remove the moisture in the reaction system. .

4.2. Ring-opening polymerization reaction

Add 0.75L of anhydrous xylene to the reaction kettle, mix and stir, and raise the temperature to 120°C. Stir at 120°C to obtain an anhydrous xylene solution of L-lactide and polyethylene glycol monomethyl ether. Then add 0.8M composite aluminum catalyst (the mass ratio of the three components of the catalyst is: triisobutylaluminum:isobutylene:xylene=1:2.8:0.14) 8.0mL (which contains 1.2693g triisobutylaluminum) , raise the temperature to 140°C and react for 0.5h to obtain mPEG-PLLA colloid.

4.3. Grading of mPEG-PLLA colloids

Add all the mPEG-PLLA colloid prepared in step 4.2 and 1.2L of dichloromethane into the purification kettle, stir and dissolve, then add 1.2L of absolute ethanol, stir until completely dissolved, then slowly add absolute ethanol dropwise again until a large amount of soft colloid appears in the solution Stop, let it stand for clarification and pour the supernatant to complete the classification.

4.4. Purification of mPEG-PLLA soft colloid

Add an appropriate amount of absolute ethanol to the graded soft colloid under stirring to precipitate into fine powder, and separate the solid and liquid. Separate and air-dry to obtain the primary purified mPEG-PLLA; add 285g of the primary purified mPEG-PLLA and 1.5L of methylene chloride into the purification kettle, stir and dissolve, filter with 0.2 micron pressure into the purification kettle in the 10,000-level clean area, and stir under stirring Add an appropriate amount of absolute ethanol to precipitate into a fine powder, separate the solid and liquid, air-dry, sieve, and dry under vacuum at 55°C for 24 hours to obtain 275g of mPEG-PLLA finished product.

Example 5: Preparation of mPEG-PLLA Sample 2

The target molecular weight of this sample is designed to be Mw=135,000. The specific preparation process is as follows:

5.1. Removal of moisture

Weigh 300g of the L-lactide sample of Example 1 and 2.23g of polyethylene glycol monomethyl ether, add them to the polymerization reaction kettle, dry them under vacuum at 50°C, and then replace them with argon three times to remove the moisture in the reaction system. .

5.2. Ring-opening polymerization reaction

Add 0.7 L of anhydrous xylene to the reaction kettle, mix and stir, and raise the temperature to 120°C. Stir at 120°C to obtain an anhydrous xylene solution of L-lactide and polyethylene glycol monomethyl ether. Then add 0.8M composite aluminum catalyst (the mass ratio of the three components of the catalyst is: triisobutylaluminum:isobutylene:xylene=1:2.8:0.14) 5.0mL (which contains 0.7933g triisobutylaluminum) , raise the temperature to 140°C and react for 45 minutes to obtain mPEG-PLLA colloid.

5.3. Grading of mPEG-PLLA colloids

Add all the mPEG-PLLA colloid prepared in step 5.2 and 1.4L of methylene chloride into the purification kettle, stir and dissolve, then add 1.4L of absolute ethanol, stir until completely dissolved, then slowly add absolute ethanol dropwise again until a large amount of soft colloid appears in the solution Stop, let it stand for clarification and pour the supernatant to complete the classification.

5.4. Purification of mPEG-PLLA soft colloid

Add an appropriate amount of absolute ethanol to the graded soft colloid under stirring to precipitate into fine powder, separate the solid and liquid, and air-dry to obtain a primary purified product of mPEG-PLLA; add 287.5g of a primary purified product of mPEG-PLLA and 1.7L of methylene chloride for purification Stir and dissolve in the kettle, filter with 0.2 micron pressure into a purification kettle in a class 10,000 clean area, add an appropriate amount of absolute ethanol under stirring to precipitate into a fine powder, separate the solid and liquid, air-dry, sieve, and dry under vacuum at 55°C for 24 hours to prepare 275.6g of mPEG-PLLA finished product was obtained.

Example 6: Preparation of mPEG-PLLA Sample 3

The target molecular weight of this sample is designed to be Mw=165,000. The specific preparation process is as follows:

6.1. Removal of moisture.

Weigh 300g of the L-lactide sample of Example 1 and 1.82g of polyethylene glycol monomethyl ether, add polymerization reaction place in the kettle, dry under vacuum at 50°C, and then replace with argon three times to remove moisture in the reaction system.

6.2. Ring-opening polymerization reaction.

Add 0.65L of anhydrous xylene to the reaction kettle, mix and stir, and raise the temperature to 120°C. Stir at 120°C to obtain an anhydrous xylene solution of L-lactide and polyethylene glycol monomethyl ether. Then add 0.8M composite aluminum catalyst (the mass ratio of the three components of the catalyst is: triisobutylaluminum:isobutylene:xylene=1:2.8:0.14) 3.6mL (which contains 0.5712g triisobutylaluminum) , raise the temperature to 140°C and react for 50 minutes to obtain mPEG-PLLA colloid.

6.3. Grading of mPEG-PLLA colloid.

Add all the mPEG-PLLA colloid prepared in step 6.2 and 1.6L of dichloromethane into the purification kettle, stir and dissolve, then add 1.6L of absolute ethanol, stir until completely dissolved, then slowly add absolute ethanol dropwise again until a large amount of soft colloid appears in the solution Stop, let it stand for clarification and pour the supernatant to complete the classification.

6.4. Purification of mPEG-PLLA soft colloid.

Add an appropriate amount of absolute ethanol to the graded soft colloid under stirring to precipitate into fine powder, separate the solid and liquid, and air-dry to obtain the mPEG-PLLA primary purified product; add 283.9g of the mPEG-PLLA primary purified product and 1.9L of methylene chloride for purification Stir and dissolve in the kettle, filter with 0.2 micron pressure into a purification kettle in a class 10,000 clean area, add an appropriate amount of absolute ethanol under stirring to precipitate into a fine powder, separate the solid and liquid, air-dry, sieve, and dry under vacuum at 55°C for 24 hours to prepare 273.1g of mPEG-PLLA finished product was obtained.

Example 7: Preparation of mPEG-PLLA Sample 4

The experimental process is the same as Example 4, the only difference is:

In the ring-opening polymerization reaction step, 7.1 mL of 0.9M composite aluminum catalyst was added, and the mass ratio of the three components of the catalyst was: triisobutylaluminum:isobutylene:xylene=1:2.5:0.1 (which contains Triisobutylaluminum (1.2673g). Finally, 276g of mPEG-PLLA finished product was obtained.

Example 8: Preparation of mPEG-PLLA Sample 5

The experimental process is the same as that in Example 4, the only difference is that after adding composite aluminum series catalytic addition to the reactor, the temperature is raised to 135°C and reacted for 50 minutes to obtain mPEG-PLLA colloid. Finally, 273.75g of mPEG-PLLA finished product was obtained.

Comparative Example 4: Preparation of mPEG-PLLA Comparative Sample 1

The experimental process is the same as that of Example 4, the only difference is that the mass ratio of the catalyst components in 8.0 mL of the 0.8M aluminum catalyst is: triisobutylaluminum:xylene=1:4.4 (which contains triisobutylaluminum Total 1.2693g). Finally, 253.1g of mPEG-PLLA finished product was obtained.

Comparative Example 5: Preparation of mPEG-PLLA Sample 2

The experimental process is the same as that of Example 4, the only difference is:

In the ring-opening polymerization reaction step, no anhydrous xylene was added, bulk polymerization was adopted, and the monomers of L-lactide and polyethylene glycol monomethyl ether were completely melted by stirring at 120°C. Then the temperature was raised to 140°C, 0.98g of stannous octoate was added, the temperature was raised to 160°C and the reaction was carried out for 12 hours to obtain 244.6g of mPEG-PLLA.

Comparative Example 6: Preparation of mPEG-PLLA Sample 3

1). Removal of moisture.

Weigh 300g of L-lactide Example 1 sample, 3.16g of polyethylene glycol monomethyl ether and 0.6g of molecular regulator lauryl alcohol, add them to the polymerization reaction kettle, dry them under vacuum at 50°C, and then replace them with argon gas three times. Remove moisture from the reaction system.

2), Ring-opening polymerization reaction.

Mix and stir and raise the temperature to 120°C. Stir at 120°C to completely melt the monomers of L-lactide, polyethylene glycol monomethyl ether, and lauryl alcohol. Then the temperature was raised to 140°C, 0.63g of stannous octoate was added, and the temperature was raised to 160°C and reacted for 12 hours to obtain mPEG-PLLA.

3), Purification of mPEG-PLLA.

Add 1.4L of methylene chloride to the reaction kettle, stir and dissolve, and then discharge it into the purification kettle. Add an appropriate amount of absolute ethanol under stirring to precipitate into fine powder, separate the solid and liquid, and air-dry to obtain a primary purified product of mPEG-PLLA. Add 260.5g of the primary purification product of mPEG-PLLA and 1.4L of methylene chloride into the purification kettle, stir and dissolve, filter with 0.2 micron pressure into the purification kettle in a class 10,000 clean area, add an appropriate amount of absolute ethanol under stirring to precipitate into a fine powder. Solid-liquid separation, air drying, sieving, and drying under vacuum at 55°C for 24 hours produced 227.4g of mPEG-PLLA finished product.

Example 9: Determination of mPEG-PLLA samples

9.1. Determination of mPEG-PLLA samples by infrared spectroscopy

The mPEG-PLLA sample 1 prepared in Example 4 was measured according to General Chapter 0402-Infrared Spectroscopy of the 2020 Edition of the "Pharmacopoeia of the People's Republic of China (Part IV)". The results are shown in Table 3 and Figure 1.

table 3

The results in Table 3 and Figure 1 represent the radical and infrared spectra of Sample 1 prepared in Example 4.

9.2. Determination of mPEG-PLLA samples by hydrogen nuclear magnetic resonance method

The sample 1 prepared in mPEG-PLLA Example 4 was measured according to the nuclear magnetic resonance spectroscopy method of General Chapter 0441 of the 2020 edition of the "Pharmacopoeia of the People's Republic of China (Part IV)". Deuterated chloroform was used as the deuterated solvent. The results are shown in Figure 2.

The results in Figure 2 show that the characteristic peaks are: 5.1-5.3(-CH-), 3.5-3.8(-CH ₂ -), 1.4-1.7(-CH ₃ ). The NMR spectrum shows that polyethylene glycol monomethyl ether and L mPEG-PLLA block copolymer was successfully prepared from -lactide. The relatively small peak area of 3.5-3.8 (-CH ₂ -) in the figure also confirms the proportion of polyethylene glycol monomethyl ether in the copolymer. Less, and there are no impurity peaks except the solvent peak, which shows that the copolymer has high purity. Combined with the infrared spectrum in Figure 1, it further shows that the copolymer is mPEG-PLLA.

9.3. Determination of specific optical rotation of mPEG-PLLA sample

According to the Optical Rotation Determination Method in General Chapter 0621 of the 2020 edition of the "Pharmacopoeia of the People's Republic of China (Part IV)", the solvent is chloroform, a solution with a concentration of 0.01g/mL is prepared, and the mPEG-PLLA Example and Comparative Example samples are measured. The results are shown in Table 4.

Table 4

It can be seen from the results in Table 4 that the specific optical rotation of the mPEG-PLLA example samples using the process of the present invention is lower than -155° and higher than -160°, which complies with YY/T 0661-2017 "Surgical Implant Semi-finals". The standard for crystalline poly-L-lactide polymers and copolymer resins requires specific optical rotation of mPEG-PLLA products (-155°~-160°), and the reaction conditions are mild. However, the specific optical rotation of the mPEG-PLLA comparative samples using the existing process are all higher than -155°. Continuing high temperature for a long time causes transesterification and changes the optical rotation, making the final product not in compliance with the mPEG-PLLA standard in YY/T 0661-2017. PLLA product specific optical rotation requirements. Explain the invention The purity of mPEG-PLLA products prepared by this process is higher than that of mPEG-PLLA products prepared by existing processes.

It should be noted that the molar content of polyethylene glycol monomethyl ether in the copolymer of the present invention is less than 3%, and polyethylene glycol monomethyl ether is an achiral compound, so polyethylene glycol monomethyl ether-poly L-lactic acid block copolymer The material can still be based on poly-L-lactide standards.

9.4. Detection of polymerization ring-opening reaction catalyst residues in mPEG-PLLA samples

Take 0.25g of mPEG-PLLA sample, place it in a polytetrafluoroethylene digestion tank, add 6.0 mL of nitric acid and 2.0 mL of concentrated hydrogen peroxide solution, cover the inner cover, tighten the outer cover, and place it in a microwave digestion instrument for digestion. After the digestion is complete, remove the digestion tank and place it on an electric hot plate to slowly heat it until the red-brown gas evaporates. Carefully transfer the digestion solution in the tank to a 100mL volumetric flask with ultrapure water and dilute it to the mark. Shake well to use as the test solution. Prepare reagent blank solution in the same way. The residual amount of tin or aluminum in the samples of the Examples and Comparative Examples was determined according to General Chapter 0412 of the 2020 edition of the "Pharmacopoeia of the People's Republic of China (Part IV)" by inductively coupled plasma mass spectrometry. The measurement results are shown in Table 5.

table 5

As can be seen from Table 5, the tin residues in the samples of Comparative Examples 5 and 6 are relatively high, significantly exceeding the limit requirement of catalyst residual Sn <150ppm in the YY/T0661-2017 standard. The tin in the samples of the embodiments of the present invention is all 0 ppm, and the residual amount of aluminum is less than 10 ppm. It shows that the process of the present invention does not have the problem of tin residue in mPEG-PLLA. At the same time, because trace amounts of aluminum can be excreted by the kidneys through normal metabolism of the human body, the safe clinical application of mPEG-PLLA is ensured.

9.5. Determination of L-lactide residue in mPEG-PLLA

9.5.1. Determination method of L-lactide residue

Take an appropriate amount of butyl acetate, weigh it accurately, add methylene chloride to dissolve it, and make it into a mixture containing approximately 0.125 mg per 1 mL. The solution is used as the internal standard solution; take about 0.1g of the measurement sample, weigh it accurately, place it in a 10mL measuring bottle, add 2mL of the internal standard solution, dissolve it with methylene chloride, dilute to the mark, shake well, and use it as the test sample Solution; take another appropriate amount of L-lactide, accurately add an appropriate amount of internal standard solution, dissolve it in dichloromethane and make a solution containing approximately 100 μg of L-lactide and 25 μg of butyl acetate per 1 mL, as a control solution. Determined in accordance with General Chapter 0521-Gas Chromatography of the 2020 edition of the "Pharmacopoeia of the People's Republic of China (Part IV)". For a chromatographic column with 5% phenyl-methylpolysiloxane (or similar polarity) as the stationary liquid, the column temperature is 135°C, the inlet temperature is 250°C, and the detector temperature is 300°C. Take 3 μL each of the test solution and the control solution and inject them into the gas chromatograph respectively. Calculate the residual amount of L-lactide based on the peak area according to the internal standard method.

9.5.2. Determination of L-lactide residue

The L-lactide in the mPEG-PLLA Example and Comparative Example samples was measured according to the measurement method in 9.5.1. The results are shown in Table 6.

Table 6

As can be seen from Table 6, the L-lactide residues of the mPEG-PLLA comparative samples prepared using the existing technology are all higher than 10 ppm, and the L-lactide residues of Comparative Example 6 are as high as 23 ppm. The L-lactide content of the mPEG-PLLA example samples prepared by the process of the present invention is less than 3 ppm. It shows that the process of the present invention can significantly reduce the residual amount of L-lactide in the preparation process of mPEG-PLLA.

9.6. Determination of molecular weight of mPEG-PLLA sample

9.6.1. Determination method of molecular weight and distribution

Take an appropriate amount of the sample, weigh it accurately, add tetrahydrofuran to dissolve it and make a solution containing about 3 mg per 1 mL, shake it, and leave it at room temperature overnight to serve as the test solution. Take an appropriate amount of another 5 polystyrene molecular weight reference substances (the molecular weight range should include the molecular weight of the test sample), add tetrahydrofuran to dissolve and make a solution containing approximately 3 mg per 1 mL, shake, and use it as a reference solution. Determined in accordance with General Chapter 0514 of the 2020 edition of the "Pharmacopoeia of the People's Republic of China (Part IV)" - size exclusion chromatography, using a gel chromatography column, tetrahydrofuran as the mobile phase, and a differential refractive index detector; the detector temperature is 35°C. Take 20 μL of acetonitrile and inject it into the liquid chromatograph, record the chromatogram, and the number of theoretical plates should be no less than 10,000 based on the acetonitrile peak. Take 20 μL of each of the above reference solutions and inject them into the liquid chromatograph, record the chromatogram, and calculate the regression equation using GPC software. Take 20 μL of the test solution and measure it in the same way. Use GPC software to calculate the weight average molecular weight, number average molecular weight and molecular weight distribution of the test product.

9.6.2. Determine the molecular weight of mPEG-PLLA sample

The molecular weights of the mPEG-PLLA Example and Comparative Example samples were measured according to the method in 9.6.1. The results are shown in Table 7.

Table 7

It can be seen from Table 7 that the difference between the actual measured molecular weight of the mPEG-PLLA example samples prepared by the process of the present invention and the target molecular weight is small, the deviations are both less than 2%, and the dispersion coefficients are all <2.0. When compared with the target molecular weight range, the actual measured molecular weight of the mPEG-PLLA comparative sample prepared using the existing process was low, with a deviation of about 10%, and the dispersion coefficient was all >2.0. It shows that the process of the present invention can accurately control the molecular weight of mPEG-PLLA. The reason is that the use of composite aluminum catalyst makes the liquid phase polymerization process more uniform and controllable, effectively avoiding the occurrence of side reactions, and the yield of finished products is as high as more than 90%. The yield is much higher than that of the comparative example; at the same time, with the help of the composite aluminum catalyst, the controllability of the molecular weight of the target product is improved, making the molecular weight of the target product more concentrated; at the same time, with the help of fractional purification technology, the mPEG-PLLA colloid can effectively remove low molecular weight polymer, resulting in a narrower molecular weight distribution of the finished product.

In order to examine the effect of the molecular weight regulator, the present invention conducted an experiment in Comparative Example 6. The results show that compared with Comparative Example 5, the addition of the molecular weight regulator lauryl alcohol can reduce the molecular weight and achieve the effect of molecular weight regulation. However, the mPEG-PLLA sample The molecular weight dispersion coefficient is large, which affects the application of mPEG-PLLA, and there is a risk of lauryl alcohol residues in the product.

In addition, the molecular weight and molecular weight dispersion coefficient of the mPEG-PLLA example sample have small deviations and good data parallelism, indicating that the process of the present invention has excellent reproducibility and stability.

9.7. Statistics of finished product yield of mPEG-PLLA samples

The finished product yields of the mPEG-PLLA Examples and Comparative Example samples were statistically calculated. The results are shown in Table 8.

Table 8

It can be seen from Table 8 that the yields of mPEG-PLLA samples prepared by the process of the present invention are all higher than 90.0%, and the yield of finished products is high. The yield of the comparative sample prepared using the existing technology is about 80%, and the yield of Comparative Example 6 in which a molecular weight regulator is added is only 75%. It shows that using the process of the present invention can significantly increase the yield of mPEG-PLLA finished products and improve the quality of mPEG-PLLA samples.

The above are only preferred embodiments of the present invention, and are not intended to limit the present invention. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the foregoing embodiments. Modify the recorded technical solutions, or make equivalent substitutions for some of the technical features. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention shall be included in the protection scope of the present invention.

Claims

A preparation method of polyethylene glycol monomethyl ether-polylactic acid block copolymer, characterized in that: the preparation method includes:

Step 1: Under the catalysis of a composite aluminum catalyst, lactide and polyethylene glycol monomethyl ether undergo a ring-opening polymerization reaction to generate a polyethylene glycol monomethyl ether-polylactic acid block copolymer colloid;

Step 2: The polyethylene glycol monomethyl ether-polylactic acid block copolymer is colloidally refined to obtain the finished polyethylene glycol monomethyl ether-polylactic acid block copolymer.
The preparation method according to claim 1, characterized in that: the composite aluminum catalyst includes triisobutylaluminum, isobutylene and xylene;

Preferably, the mass ratio of triisobutylaluminum, isobutylene and xylene is 1:2.5~3.0:0.1~0.2; based on triisobutylaluminum, the added amount of the composite aluminum catalyst is the lactide and the 0.15-2.0% of the total mass of polyethylene glycol monomethyl ether.
The preparation method according to claim 1, characterized in that: the step 1 includes dissolving the lactide and the polyethylene glycol monomethyl ether in an anhydrous solvent to perform a ring-opening polymerization reaction;

Preferably, the solvent is selected from at least one of anhydrous xylene, decalin or diphenyl ether, more preferably anhydrous xylene;

Preferably, the mass ratio of the total mass of lactide and polyethylene glycol monomethyl ether to anhydrous xylene is 1:1.5 to 2.5.
The preparation method according to claim 3, characterized in that: in the lactide and polyethylene glycol monomethyl ether, the mass fraction of lactide is 97 to 99.5%.
The preparation method according to claim 3, characterized in that: the temperature of the ring-opening polymerization reaction is 110-145°C, preferably 120-140°C;

The reaction time is 0.5-1.5h, preferably 0.5-1h.
The preparation method according to claim 1, characterized in that: the preparation method of lactide in step 1 includes the following steps:

Step 1), dehydrate lactic acid to obtain oligomeric lactic acid;

Step 2), oligolactic acid is cleaved and cyclized to generate lactide;

Step 3), subjecting the lactide prepared in step 2) to water extraction;

Step 4), hydrolyze the lactide after water extraction;

Step 5), sequentially filter the hydrolyzed lactide to remove water, filter and wash with organic solvents, and dry to obtain crude lactide;

Step 6), purify and refine the crude lactide.
The preparation method according to claim 6, characterized in that: in step 4), lactide is added to water at 45 to 55°C, and the hydrolysis reaction is carried out for 2 to 4 hours;

Preferably, the mass ratio of lactide to water is 1:2-4.
The preparation method according to claim 6, characterized in that: the catalyst in step 1) is antimony trioxide and phosphoric acid;

Preferably, the mass of antimony trioxide is 0.75-0.85% of the mass of lactic acid, and the mass of phosphoric acid is 0.2-0.4% of the mass of lactic acid.
The preparation method according to claim 6, characterized in that: the catalyst in step 2) is antimony trioxide and glycerol;

Preferably, the mass of antimony trioxide is 0.15-0.25% of the mass of lactic acid.
The preparation method according to claim 1, characterized in that in step 2, it includes a fractional purification process of the polyethylene glycol monomethyl ether-polylactic acid block copolymer colloid.
The polyethylene glycol monomethyl ether-polylactic acid block copolymer obtained according to the preparation method according to any one of claims 1 to 10.