CN113773514A - Polyethylene glycol monomethyl ether-polylactic acid block copolymer and preparation method and application thereof - Google Patents
Polyethylene glycol monomethyl ether-polylactic acid block copolymer and preparation method and application thereof Download PDFInfo
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- CN113773514A CN113773514A CN202111032094.7A CN202111032094A CN113773514A CN 113773514 A CN113773514 A CN 113773514A CN 202111032094 A CN202111032094 A CN 202111032094A CN 113773514 A CN113773514 A CN 113773514A
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Abstract
The invention relates to the technical field of pharmaceutical chemicals, and particularly discloses a polyethylene glycol monomethyl ether-polylactic acid block copolymer, and a preparation method and application thereof. In the method for preparing the polyethylene glycol monomethyl ether-polylactic acid segmented copolymer, the polyethylene glycol monomethyl ether-polylactic acid segmented copolymer is prepared by the reaction of polyethylene glycol monomethyl ether and lactide under the catalysis of stannous octoate, and after the reaction, the method comprises the step of after-treatment of a crude product, wherein the step of after-treatment of the crude product comprises the following steps: (1) crystallizing by using a first crystallization solvent, wherein the first crystallization solvent is a mixture of n-hexane and anhydrous ether; (2) washing with water; (3) and crystallizing by using a second crystallization solvent, wherein the second crystallization solvent is diethyl ether. The preparation method can effectively improve the uniformity of the molecular weight distribution of the polymer, has high yield, and can effectively reduce the content of impurities such as tin, lactic acid, lactide and the like.
Description
Technical Field
The invention relates to the technical field of pharmaceutical chemicals, in particular to a polyethylene glycol monomethyl ether-polylactic acid block copolymer, a preparation method and application thereof.
Background
The polyethylene glycol monomethyl ether-polylactic acid block copolymer (mPEG-PLA) is amphiphilicThe biodegradable material has good biocompatibility, no toxic or side effect, biodegradability and extremely high application value in the aspect of carriers of hydrophobic drugs. The Korean Samyang corporation introduced nano-micelle preparation in 2006
The preparation is prepared by wrapping paclitaxel with polymer mPEG-PLA, and is approved by FDA to enter clinical research in 2002. The preparation has good biocompatibility in vitro and in vivo of animals, the micelle is rapidly dissociated after entering the body to release the drug, and the polymer can be degraded in 15 hours in vivo. The mPEG-PLA copolymer with the average molecular weight of 3000-5000-.
Chinese patent CN102219892 discloses that mPEG-PLA containing the molecular weight is prepared by a solvent polycondensation method (solvents such as isopropanol, xylene and dimethylformamide), but the boiling point of the solvents is high, so that solvent residues are easily caused, and the safety of the further prepared drug polymer micelle is influenced. At present, the melt polycondensation method without using a solvent is the most common method, such as the method disclosed in preparation example 1 of chinese patent CN1214818C specification, but the obtained mPEG-PLA has a wide molecular weight distribution, is hygroscopic and easy to agglomerate, and generates large impurities in the process of preparing paclitaxel polymer micelle with paclitaxel, so the improvement of the preparation method is necessary to improve the product quality. For example, in CN104892909, a melt polycondensation method is disclosed, and then pure water is used to wash the crude product dissolved in dichloromethane, which effectively removes water-soluble oligomers, reduces the molecular weight distribution of the product, and improves the hygroscopicity.
However, in the preparation process of the polymer, a large amount of tin is introduced due to the addition of the catalyst, and the polymer is used as a pharmaceutical adjuvant, so that the requirement on quality, particularly heavy metal, is high, and the post-treatment effect of a crude product is still to be improved in order to ensure that the product quality can better meet the pharmaceutical standard. In addition, in the method, the product preparation link is polymerization in an inert atmosphere environment, the requirement on the moisture of the starting material is high, the reaction system is troublesome in water removal, and the method is not beneficial to industrial operation.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a preparation method and application of a methoxy polyethylene glycol-polylactic acid block copolymer, which can effectively remove impurities in a crude product, has high yield, simple and convenient preparation process and ideal reaction effect.
In order to achieve the purpose, the technical scheme of the invention is as follows:
a method for preparing a polyethylene glycol monomethyl ether-polylactic acid block copolymer is characterized in that the polyethylene glycol monomethyl ether-polylactic acid block copolymer is prepared by the reaction of polyethylene glycol monomethyl ether and lactide under the catalysis of stannous octoate, and after the reaction is finished, the method comprises a crude product post-treatment step, wherein the crude product post-treatment step comprises the following steps:
(1) crystallizing by using a first crystallization solvent, wherein the first crystallization solvent is a mixture of n-hexane and anhydrous ether;
(2) washing with water;
(3) and crystallizing by using a second crystallization solvent, wherein the second crystallization solvent is diethyl ether.
In the invention, the structure of the polyethylene glycol monomethyl ether-polylactic acid block copolymer is as follows:
wherein m is 44 and n is 30-36.
A preferred synthesis route of the polyethylene glycol monomethyl ether-polylactic acid block copolymer is as follows:
wherein mPEG2K is polyethylene glycol monomethyl ether with the average molecular weight of 2000, and mPEG with the molecular weight Mn of 1000-5000 can also be used in the invention. DL-LA is lactide.
According to research, the invention discovers that in the preparation process of the polyethylene glycol monomethyl ether-polylactic acid segmented copolymer with stannous octoate as a catalyst, the post-treatment method can greatly reduce the content of lactide, lactic acid and stannic impurities in the product on the premise of ensuring high yield, improve the quality of the final product and enable the final product to better meet the medicinal standard.
In the invention, in the first crystallization solvent, the volume ratio of n-hexane to anhydrous ether is (0.8-1.5): 1, preferably 1:1, to match with the subsequent steps, and better give consideration to both yield and impurity removal effect.
In the invention, the crystallization in the steps (1) and (3) is carried out at the temperature of-20 ℃ to-12 ℃, preferably-16 ℃ to obtain better crystallization and impurity removal effects.
The temperature of the first crystallization solvent and the second crystallization solvent used in the invention is-20 ℃ to-12 ℃ so as to ensure that the whole crystallization process is at the expected temperature.
In the invention, during the crystallization in the step (1) and the step (3), the product to be crystallized is dissolved by dichloromethane, and then the dichloromethane solution of the product to be crystallized is added into the crystallization solvent under stirring, wherein the stirring speed is 200-600rpm, so as to ensure the yield and the impurity removal effect; when washing in the step (2), dissolving a product to be washed with water with dichloromethane, and then adding water for washing;
in each crystallization step (steps 1 and 3), the amount of dichloromethane added is preferably such that the product to be crystallized can be completely dissolved, and specifically, the amount of dichloromethane added can be 0.5 to 1.5 volume equivalents of the theoretical yield of the product to be crystallized, i.e., 0.5 to 1.5mL of dichloromethane is added per gram of product to be crystallized.
In the water washing step (step 2), the amount of dichloromethane added is preferably such that the product to be washed is sufficiently dissolved and dispersed, and specifically may be 2 to 2.5 volume equivalents of the theoretical yield of the product to be washed, i.e. 2 to 2.5mL of dichloromethane is added per gram of the product to be washed.
Preferably, in the step (1), the first crystallization solvent is used in an amount of 20 times the volume of the dichloromethane used in the step (1);
and/or, during the water washing, the using amount of the water is 0.8-1.1 times, preferably 1 time, of the volume of the dichloromethane used in the step (2), so as to match with the front and rear crystallization steps to ensure the impurity removal effect;
and/or the second crystallization solvent is used in an amount of 15 to 20 times the volume of the dichloromethane used in the step (3).
In the invention, when the polyethylene glycol monomethyl ether-polylactic acid segmented copolymer is prepared, polyethylene glycol monomethyl ether, lactide and stannous octoate are added into a reactor at the same time, air is continuously pumped at room temperature to keep the system vacuum, then the temperature is raised to 50-85 ℃, the vacuum pumping is continuously carried out under the stirring condition, the temperature is raised to 110-120 ℃, the vacuum pumping is stopped and the stirring is maintained, and finally the temperature is raised to the temperature for the polymerization reaction.
In the invention, when the polyethylene glycol monomethyl ether-polylactic acid segmented copolymer is prepared, the room temperature air extraction time is 2-6h, the vacuum pumping time is 20-60min under stirring, and the vacuum pumping is stopped to maintain the stirring time for 15-25 min.
According to the invention, the preparation link of the polyethylene glycol monomethyl ether-polylactic acid segmented copolymer is researched, and through a specific air pumping step, reactants can be subjected to a melting reaction in a vacuum system through a one-pot method, so that a target product with ideal molecular weight distribution and high yield is prepared.
The method has loose requirement on the moisture of the starting material, the moisture content does not exceed 1 percent, the reaction starting material does not need to be refined, the solvent introduced in the refining process can be avoided, and after one-step feeding, the influence of vacuumizing on the total amount of the original material can be avoided while the moisture in the raw material is fully and efficiently removed through the specific air-extracting flow of the method. The influence of system moisture on the reaction is reduced, and the problem of poor air tightness which may occur is avoided due to the increase of the air tightness of the reaction system.
As a preferable preparation mode, the polyethylene glycol monomethyl ether, the lactide and the stannous octoate are added into a reactor at the same time, the air suction is continued for 2 hours at room temperature, then the temperature is raised to 85 ℃, the vacuum pumping is carried out for 20 minutes under the stirring condition, the temperature is raised to 120 ℃, the vacuum pumping is stopped, the stirring is maintained for 20 minutes, and finally the temperature is raised to the temperature for the polymerization reaction.
In the invention, the feeding mass ratio of the polyethylene glycol monomethyl ether to the lactide is 1: (1.15-1.25), the temperature of the polymerization reaction is 130-145 ℃, and the time of the polymerization reaction is 24-40 h;
preferably, the feeding mass ratio of the polyethylene glycol monomethyl ether to the lactide is 1: 1.2, the temperature of the polymerization reaction is 135 ℃, and the time of the polymerization reaction is 40h, so as to obtain the ideal yield and polymer product.
The invention also provides a polyethylene glycol monomethyl ether-polylactic acid block copolymer which is prepared by the method.
The invention also provides application of the polyethylene glycol monomethyl ether-polylactic acid segmented copolymer as a hydrophobic drug carrier.
The invention has the beneficial effects that:
the invention can improve the effect of removing oligomer, catalyst and element impurities under the condition of ensuring high yield, so that the product better meets the medicinal standard. And during the preparation reaction, the polyethylene glycol monomethyl ether-polylactic acid block copolymer can be prepared by a one-pot method through a specific air extraction mode and vacuum melting, and the starting material does not need to be refined (the requirement on the moisture of the starting material is loose), so that the preparation operation process is simplified, the influence of water on the reaction can be effectively avoided, the obtained product is washed by water and crystallized, the contents of lactide, lactic acid and tin are obviously reduced, and the product quality is improved.
Detailed Description
Preferred embodiments of the present invention will be described in detail with reference to the following examples. It is to be understood that the following examples are given for illustrative purposes only and are not intended to limit the scope of the present invention. Various modifications and alterations of this invention will become apparent to those skilled in the art without departing from the spirit and scope of this invention.
The experimental procedures used in the following examples are all conventional procedures unless otherwise specified. Materials, reagents and the like used in the following examples are commercially available unless otherwise specified.
Example 1
The present embodiment provides a methoxy polyethylene glycol-polylactic acid block copolymer and a preparation method thereof.
The method specifically comprises the following steps:
400g mPEG (average molecular weight 2000), 480g lactide (DL-LA) and 2.0g stannous octoate (Sn (Oct))2) Are added together to the reactor. The system was kept under vacuum by evacuating at room temperature for 2 h. The temperature was raised to 85 ℃, stirring was started (stirring rate 100rpm) and vacuum was applied for 20 min. Then, the temperature was raised to 120 ℃ and the vacuum was stopped, and the stirring was continued for 20min while maintaining the system vacuum (stirring rate 500 rpm). Finally, the temperature is raised to 135 ℃ for polymerization reaction for 40 h. After the reaction is finished, cooling the reaction system to obtain a crude product of the polyethylene glycol monomethyl ether-polylactic acid segmented copolymer.
And (3) refining the crude product:
(1) the product to be crystallized (crude product) was dissolved in dichloromethane of 0.5V in theoretical yield (V is the equivalent volume of theoretical yield, and 0.5mL of dichloromethane was added per gram of product to be crystallized), and then the dichloromethane solution with the product dissolved therein was gradually added to a first crystallization solvent of-16 ℃ with stirring (stirring speed 600rpm) (the volume of the first crystallization solvent is 10 times the volume of dichloromethane, and the first crystallization solvent consists of n-hexane and anhydrous ether in a volume ratio of 1: 1), and precipitated while maintaining at-16 ℃, and crude white solid was collected by filtration.
(2) Dissolving the white solid crude product in dichloromethane (2V) (adding 2mL of dichloromethane per gram of the white solid crude product), adding 1V of sterile water for injection (namely, adding water with the volume being 1 time of that of dichloromethane), stirring for 40min, demixing, separating out an organic phase, and rotationally evaporating the solvent.
(3) Adding dichloromethane with the theoretical yield of 0.5V (namely, adding 0.5mL of dichloromethane per gram of crude product) into the crude product obtained in the step (2), then gradually adding the dichloromethane into a second crystallization solvent, namely anhydrous ether with the volume of 20 times that of dichloromethane, at the temperature of-16 ℃ under stirring (the stirring speed is 600rpm), maintaining the temperature for crystallization at the temperature of-16 ℃, and filtering.
(4) And (4) drying the filtered product in the step (3) in vacuum at 30 ℃ to obtain a final product.
Example 2
The present embodiment provides a methoxy polyethylene glycol-polylactic acid block copolymer and a preparation method thereof.
The method specifically comprises the following steps:
the crude polyethylene glycol monomethyl ether-polylactic acid block copolymer was prepared in the same manner as in example 1. The refining process is as follows:
(1) a methylene chloride dissolved product with a theoretical yield of 0.5V of a product to be crystallized (crude product) was charged into a reactor, and then a methylene chloride solution in which the product was dissolved was gradually added to a first crystallization solvent at-12 ℃ with stirring (stirring speed 600rpm) (the composition and the amount of the first crystallization solvent were the same as those in example 1), and the mixture was allowed to stand at-12 ℃ for precipitation, and a crude white solid was collected by filtration.
(2) Dissolving the white solid crude product in dichloromethane (2V), adding 1V sterile water for injection in terms of the volume of the dichloromethane, stirring for 40min, demixing, separating an organic phase, and performing rotary evaporation on the solvent.
(3) The product obtained in the above step (2) was dissolved in dichloromethane (0.5V) (i.e., 0.5mL of dichloromethane was added per gram of the above product), and then the dichloromethane solution in which the above product was dissolved was gradually added to anhydrous ether at-12 ℃ with stirring (stirring speed 600rpm) (the same amount as in example 1), and the precipitate was maintained at-12 ℃, and the product was collected by filtration as a white solid.
(4) And (4) drying the product obtained in the step (3) in vacuum at 30 ℃ to obtain a final product.
Example 3
The present embodiment provides a methoxy polyethylene glycol-polylactic acid block copolymer and a preparation method thereof.
The method specifically comprises the following steps:
the crude polyethylene glycol monomethyl ether-polylactic acid block copolymer was prepared in the same manner as in example 1. The refining process is as follows:
(1) a methylene chloride dissolved product with a theoretical yield of 0.5V of a product to be crystallized (crude product) was charged into a reactor, and then a methylene chloride solution in which the product was dissolved was gradually added to a first crystallization solvent at-20 ℃ with stirring (stirring speed 200rpm) (the composition and amount of the first crystallization solvent were the same as those in example 1), and the mixture was allowed to stand at-20 ℃ for precipitation, and a crude white solid was collected by filtration.
(2) Dissolving the white solid crude product in dichloromethane (2V), adding 1V sterile water for injection in terms of the volume of the dichloromethane, stirring for 40min, demixing, separating an organic phase, and performing rotary evaporation on the solvent.
(3) The product obtained in the above step (2) was dissolved in methylene chloride (0.5V), and then the methylene chloride solution in which the product was dissolved was gradually added to anhydrous ether at-20 ℃ with stirring (stirring speed 200rpm) (the same amount as in example 1), and the product was precipitated while maintaining-20 ℃, and collected by filtration as a white solid.
(4) And (4) drying the product obtained in the step (3) in vacuum at 30 ℃ to obtain a final product.
Example 4
The present embodiment provides a methoxy polyethylene glycol-polylactic acid block copolymer and a preparation method thereof.
The method specifically comprises the following steps:
the crude polyethylene glycol monomethyl ether-polylactic acid block copolymer was prepared in the same manner as in example 1. The refining process is as follows:
(1) adding a dichloromethane dissolved product with a theoretical yield of 0.5V of a product to be crystallized (crude product) into a reactor, then gradually adding a dichloromethane solution with the dissolved product into a first crystallization solvent at the temperature of-16 ℃ under stirring (the stirring speed is 600rpm), keeping the temperature of-16 ℃ for precipitation, and filtering to collect a white solid crude product, wherein the volume of the first crystallization solvent is 10 times that of the dichloromethane, and the first crystallization solvent consists of n-hexane and anhydrous ether in a volume ratio of 0.8: 1.
(2) Dissolving the white solid crude product in dichloromethane (2V), adding 1V sterile water for injection in terms of the volume of the dichloromethane, stirring for 40min, demixing, separating an organic phase, and performing rotary evaporation on the solvent.
(3) The product obtained in the above step (2) was dissolved in methylene chloride (0.5V), and then the methylene chloride solution in which the product was dissolved was gradually added to anhydrous ether at-16 ℃ with stirring (stirring speed 600rpm) (the same amount as in example 1), and precipitated while maintaining at-16 ℃, and the product was collected by filtration as a white solid.
(4) And (4) drying the product obtained in the step (3) in vacuum at 30 ℃ to obtain a final product.
Example 5
The present embodiment provides a methoxy polyethylene glycol-polylactic acid block copolymer and a preparation method thereof.
The method specifically comprises the following steps:
the crude polyethylene glycol monomethyl ether-polylactic acid block copolymer was prepared in the same manner as in example 1. The refining process is as follows:
(1) adding a dichloromethane dissolved product with a theoretical yield of 0.5V of a product to be crystallized (crude product) into a reactor, then gradually adding a dichloromethane solution with the dissolved product into a first crystallization solvent at the temperature of-16 ℃ under stirring (the stirring speed is 600rpm), keeping the temperature of-16 ℃ for precipitation, and filtering to collect a white solid crude product, wherein the volume of the first crystallization solvent is 10 times that of dichloromethane, and the first crystallization solvent consists of n-hexane and anhydrous ether in a volume ratio of 1.5: 1.
(2) Dissolving the white solid crude product in dichloromethane (2V), adding 1V sterile water for injection in terms of the volume of the dichloromethane, stirring for 40min, demixing, separating an organic phase, and performing rotary evaporation on the solvent.
(3) The product obtained in the above step (2) was dissolved in methylene chloride (0.5V), and then the methylene chloride solution in which the product was dissolved was gradually added to anhydrous ether at-16 ℃ with stirring (stirring speed 600rpm) (the same amount as in example 1), and precipitated while maintaining at-16 ℃, and the product was collected by filtration as a white solid.
(4) And (4) drying the product obtained in the step (3) in vacuum at 30 ℃ to obtain a final product.
Example 6
The present embodiment provides a methoxy polyethylene glycol-polylactic acid block copolymer and a preparation method thereof.
The method specifically comprises the following steps:
the crude polyethylene glycol monomethyl ether-polylactic acid block copolymer was prepared in the same manner as in example 1. The refining process is as follows:
(1) the methylene chloride dissolved product of theoretical yield 0.5V of the product to be crystallized (crude product) was charged into the reactor, and then the methylene chloride solution in which the product was dissolved was gradually added to the first crystallization solvent at-16 ℃ with stirring (stirring speed 600rpm) (the composition and amount of the first crystallization solvent were the same as in example 1), and the mixture was allowed to stand at-16 ℃ for precipitation, and the crude white solid was collected by filtration.
(2) Dissolving the white solid crude product in dichloromethane (2V), adding sterile water for injection with volume of 0.8V based on dichloromethane, stirring for 40min, demixing, separating organic phase, and rotary evaporating solvent.
(3) The product obtained in the above step (2) was dissolved in methylene chloride (0.5V), and then the methylene chloride solution in which the product was dissolved was gradually added to anhydrous ether at-16 ℃ with stirring (stirring speed 600rpm) (the same amount as in example 1), and precipitated while maintaining at-16 ℃, and the product was collected by filtration as a white solid.
(4) And (4) drying the product obtained in the step (3) in vacuum at 30 ℃ to obtain a final product.
Example 7
The present embodiment provides a methoxy polyethylene glycol-polylactic acid block copolymer and a preparation method thereof.
The method specifically comprises the following steps:
400g mPEG (average molecular weight 2000), 480g lactide (DL-LA) and 2.0g stannous octoate (Sn (Oct))2) Are added together to the reactor. The system was kept under vacuum by evacuating at room temperature for 2 h. The temperature was raised to 50 ℃, stirring was started (stirring rate 100rpm) and vacuum was applied for 60 min. Then, the temperature was raised to 120 ℃ and the vacuum was stopped, and the stirring was continued for 15min while maintaining the system vacuum (stirring rate 500 rpm). Finally, the temperature is raised to 135 ℃ for polymerization reaction for 40 h. After the reaction is finished, cooling the reaction system to obtain a crude product of the polyethylene glycol monomethyl ether-polylactic acid segmented copolymer.
The purification process was the same as in example 1.
Example 8
The present embodiment provides a methoxy polyethylene glycol-polylactic acid block copolymer and a preparation method thereof.
The method specifically comprises the following steps:
400g mPEG (average molecular weight 2000), 480g lactide (DL-LA) and 2.0g stannous octoate (Sn (Oct))2) Together withIs added into the reactor. The system was kept under vacuum by evacuating at room temperature for 2 h. The temperature was raised to 85 ℃, stirring was started (stirring rate 100rpm) and vacuum was applied for 20 min. Then, the temperature was raised to 120 ℃ and the vacuum was stopped, and the stirring was continued for 25min while maintaining the system vacuum (stirring rate 500 rpm). Finally, the temperature is raised to 135 ℃ for polymerization reaction for 40 h. After the reaction is finished, cooling the reaction system to obtain a crude product of the polyethylene glycol monomethyl ether-polylactic acid segmented copolymer.
The purification process was the same as in example 1.
Example 9
The present embodiment provides a methoxy polyethylene glycol-polylactic acid block copolymer and a preparation method thereof.
The method specifically comprises the following steps:
400g mPEG (average molecular weight 2000), 480g lactide (DL-LA) and 2.0g stannous octoate (Sn (Oct))2) Are added together to the reactor. The system was kept under vacuum by evacuating at room temperature for 2 h. The temperature was raised to 85 ℃, stirring was started (stirring rate 100rpm) and vacuum was applied for 20 min. Then, the temperature was raised to 120 ℃ and the vacuum was stopped, and the stirring was continued for 20min while maintaining the system vacuum (stirring rate 500 rpm). Finally, the temperature is raised to 135 ℃ for polymerization reaction for 24 hours. After the reaction is finished, cooling the reaction system to obtain a crude product of the polyethylene glycol monomethyl ether-polylactic acid segmented copolymer.
The purification process was the same as in example 1.
Example 10
The present embodiment provides a methoxy polyethylene glycol-polylactic acid block copolymer and a preparation method thereof.
The method specifically comprises the following steps:
400g mPEG (average molecular weight 2000), 480g lactide (DL-LA) and 2.0g stannous octoate (Sn (Oct))2) Are added together to the reactor. The system was kept under vacuum by evacuating at room temperature for 2 h. The temperature was raised to 85 ℃, stirring was started (stirring rate 100rpm) and vacuum was applied for 20 min. Then, the temperature was raised to 120 ℃ and the vacuum was stopped, and the stirring was continued for 20min while maintaining the system vacuum (stirring rate 500 rpm). Finally, the temperature is raised to 130 ℃ for polymerization reaction for 40 h. After the reaction is finished, cooling the reaction system to obtain polymerEthylene glycol monomethyl ether-polylactic acid block copolymer crude product.
The purification process was the same as in example 1.
Example 11
The present embodiment provides a methoxy polyethylene glycol-polylactic acid block copolymer and a preparation method thereof.
The method specifically comprises the following steps:
400g mPEG (average molecular weight 2000), 480g lactide (DL-LA) and 2.0g stannous octoate (Sn (Oct))2) Are added together to the reactor. The system was kept under vacuum by evacuating at room temperature for 2 h. The temperature was raised to 85 ℃, stirring was started (stirring rate 100rpm) and vacuum was applied for 20 min. Then, the temperature was raised to 120 ℃ and the vacuum was stopped, and the stirring was continued for 20min while maintaining the system vacuum (stirring rate 500 rpm). Finally, the temperature is raised to 145 ℃ for polymerization reaction for 40 h. After the reaction is finished, cooling the reaction system to obtain a crude product of the polyethylene glycol monomethyl ether-polylactic acid segmented copolymer.
The purification process was the same as in example 1.
Example 12
The present embodiment provides a methoxy polyethylene glycol-polylactic acid block copolymer and a preparation method thereof.
The method specifically comprises the following steps:
400g mPEG (average molecular weight 2000), 460g lactide (DL-LA) and 2.0g stannous octoate (Sn (Oct))2) Are added together to the reactor. The system was kept under vacuum by evacuating at room temperature for 2 h. The temperature was raised to 85 ℃, stirring was started (stirring rate 100rpm) and vacuum was applied for 20 min. Then, the temperature was raised to 120 ℃ and the vacuum was stopped, and the stirring was continued for 20min while maintaining the system vacuum (stirring rate 500 rpm). Finally, the temperature is raised to 135 ℃ for polymerization reaction for 40 h. After the reaction is finished, cooling the reaction system to obtain a crude product of the polyethylene glycol monomethyl ether-polylactic acid segmented copolymer.
The purification process was the same as in example 1.
Example 13
The present embodiment provides a methoxy polyethylene glycol-polylactic acid block copolymer and a preparation method thereof.
The method specifically comprises the following steps:
400g mPEG (average molecular weight 2000), 500g lactide (DL-LA) and 2.0g stannous octoate (Sn (Oct))2) Are added together to the reactor. The system was kept under vacuum by evacuating at room temperature for 2 h. The temperature was raised to 85 ℃, stirring was started (stirring rate 100rpm) and vacuum was applied for 20 min. Then, the temperature was raised to 120 ℃ and the vacuum was stopped, and the stirring was continued for 20min while maintaining the system vacuum (stirring rate 500 rpm). Finally, the temperature is raised to 135 ℃ for polymerization reaction for 40 h. After the reaction is finished, cooling the reaction system to obtain a crude product of the polyethylene glycol monomethyl ether-polylactic acid segmented copolymer.
The purification process was the same as in example 1.
Comparative example 1
This comparative example provides a methoxy polyethylene glycol-polylactic acid block copolymer and a method for preparing the same as in example 1, except that, during the purification: the first crystallization solvent selected in the step (1) is n-hexane. The observation shows that the product after the first crystallization has high viscosity and is filtered out along with the solvent during the suction filtration.
Comparative example 2
This comparative example provides a methoxy polyethylene glycol-polylactic acid block copolymer and a method for preparing the same as in example 1, except that, during the purification: the first crystallization solvent selected in the step (1) is diethyl ether.
Comparative example 3
This comparative example provides a methoxy polyethylene glycol-polylactic acid block copolymer and a method for preparing the same as in example 1, except that, during the purification: in the step (1), the first crystallization solvent consists of ethanol and anhydrous ether in a volume ratio of 1: 1.
Comparative example 4
This comparative example provides a methoxy polyethylene glycol-polylactic acid block copolymer and a method for preparing the same as in example 1, except that, during the purification: in the step (1), the first crystallization solvent consists of n-hexane and anhydrous ether in a volume ratio of 2: 1. The product was observed to be slightly viscous after the first crystallization.
Comparative example 5
This comparative example provides a methoxy polyethylene glycol-polylactic acid block copolymer and a method for preparing the same as in example 1, except that, during the purification: the amount of water used in step (2) is 2 volume equivalents based on the volume of dichloromethane.
Comparative example 6
This comparative example provides a methoxy polyethylene glycol-polylactic acid block copolymer and a method for preparing the same as in example 1, except that, during the purification: step (2) was repeated, i.e. 2 total identical water washing steps were performed.
Comparative example 7
This comparative example provides a methoxy polyethylene glycol-polylactic acid block copolymer and a method for preparing the same as in example 1, except that, during the purification: the crystallization temperature in the step (1) and the step (3) was 0 ℃.
Comparative example 8
This comparative example provides a methoxy polyethylene glycol-polylactic acid block copolymer and a method for preparing the same as in example 1, except that, during the purification: the amount of water used in step (2) was 0.5 volume equivalents based on the volume of dichloromethane.
Comparative example 9
This comparative example provides a methoxy polyethylene glycol-polylactic acid block copolymer and a method for preparing the same as in example 1, except that, during the purification: the purification was carried out by only two crystallizations without carrying out the step (2).
Comparative example 10
This comparative example provides a methoxy polyethylene glycol-polylactic acid block copolymer and a method for preparing the same as in example 1, except that, during the purification: the crystallization stirring speed in the step (1) and the step (3) was 100 rpm.
Comparative example 11
This comparative example provides a methoxy polyethylene glycol-polylactic acid block copolymer and a method for preparing the same as in example 1, except that 400g of mPEG (average molecular weight) was used in the preparation of a crude productAmounts 2000), 480g lactide (DL-LA) and 2.0g stannous octoate (Sn (Oct)2) Are added together to the reactor. Vacuum-pumping at 100 deg.C for 40min to remove water. Then, the temperature was raised to 135 ℃ to carry out polymerization for 40 hours. After the reaction is finished, cooling the reaction system to obtain a crude product of the polyethylene glycol monomethyl ether-polylactic acid segmented copolymer.
The purification process was the same as in example 1.
Comparative example 12
This comparative example provides a methoxy polyethylene glycol-polylactic acid block copolymer and a method for preparing the same as example 1 except that the polymerization time was 15 hours when preparing a crude product.
Comparative example 13
The comparative example provides a polyethylene glycol monomethyl ether-polylactic acid block copolymer and a preparation method thereof, the preparation method is the same as that in example 1, and the difference is that mPEG and stannous octoate are added into a reaction bottle, the temperature is raised to 120 ℃, the vacuum pumping is carried out for 20min, then DL-LA is added, and the vacuum pumping is carried out for 20 min. Then, the temperature was further increased to carry out the polymerization reaction.
Experimental example 1
In this experimental example, the finished products obtained in each example and comparative example were examined.
The test method is as follows:
the yield was calculated as: actual/theoretical yield.
The GPC (PD) test method is determined by size exclusion chromatography (general rule 0541) as follows:
test solution: taking a proper amount of the product, precisely weighing, adding tetrahydrofuran, dissolving to prepare a solution containing about 2mg of tetrahydrofuran in each 1mL, uniformly mixing, and filtering to obtain a test solution.
Control solution: taking appropriate amount of polystyrene molecular weight control (molecular weight 1920, 2790, 4750, 6660, and 12980), adding tetrahydrofuran to dissolve, making into solution containing about 2mg per 1mL, and shaking to give control solution.
Chromatographic conditions are as follows: using a gel chromatography column (Waters Styragel)
Guard HT 3 THF 4.0*6.0mm、Waters Styragel
HT 3 THF 7.8 × 300mm, 500A and Waters Styragel
HT 5 DMF 7.8 × 300mm, 500A in series), tetrahydrofuran as the mobile phase, differential refractive detector; the detector temperature is 35 ℃, the column temperature is 30 ℃, the sample injection volume is 100 mu L, the flow rate is 1.0mL/min, and the refractive index detector is shown.
The determination method comprises the following steps: and (3) injecting the reference substance solution into a liquid chromatograph, recording a chromatogram, and calculating a regression equation by GPC software, wherein the linear correlation coefficient R should be not less than 0.99. And (3) taking the test sample solution, measuring by the same method, and calculating the weight average molecular weight and the molecular weight distribution of the test sample according to a regression equation. The polyethylene glycol monomethyl ether used in the embodiments of the present invention has a molecular weight of 2000; after the polymerization, the Mn value measured by the above-mentioned GPC method is a suitable value of 5500. + -. 500.
The lactide is measured by high liquid chromatography (general rule 0512), which is as follows:
control solution: taking about 25mg of lactide, precisely weighing, placing in a 50mL measuring flask, adding acetonitrile to dissolve and dilute to a scale, and shaking up; precisely measuring 3mL, placing in a 10mL measuring flask, adding acetonitrile to dilute to scale, shaking up, and filtering to obtain a reference solution.
Test solution: taking about 100mg of the product, accurately weighing, placing in a 10mL measuring flask, adding acetonitrile to dissolve and dilute to a scale, shaking uniformly, and filtering to obtain a test solution.
Chromatographic conditions are as follows: octadecylsilane chemically bonded silica is used as filler (such as Waters Xbridge C184.6mm × 150mm, 5 μm or other chromatographic column with equivalent efficiency), acetonitrile-water (10:90) is used as mobile phase, and flow rate is 1.0 mL/min; the column temperature was 35 ℃; the detection wavelength was 210nm and the injection volume was 10. mu.L.
The determination method comprises the following steps: and (3) respectively injecting the reference substance solution and the test solution into a liquid chromatograph, recording a chromatogram, and calculating according to the peak area by an external standard method to obtain the test solution.
The lactic acid was measured by high performance liquid chromatography (general rule 0512) as follows:
control solution: precisely weighing about 50mg of lactic acid, placing the lactic acid into a 50mL measuring flask, adding water to dissolve the lactic acid and diluting the lactic acid to a scale, and shaking up; precisely measuring 1mL, placing in a 100mL measuring flask, adding water to dilute to scale, shaking, and filtering to obtain a control solution.
Test solution: taking about 20mg of the product, accurately weighing, placing in a 10mL measuring flask, adding water to dissolve and dilute to scale, shaking up, and filtering to obtain a test solution.
Chromatographic conditions are as follows: octadecylsilane chemically bonded silica was used as a filler (such as a Welch Ultimate AQ-C184.6 mm × 250mm, 5 μm or other chromatographic column with equivalent performance), acetonitrile-0.12% phosphoric acid aqueous solution (2:98) was used as a mobile phase, and the flow rate was 1.0 mL/min; the column temperature was 35 ℃; the detection wavelength was 210nm and the injection volume was 20. mu.L.
The determination method comprises the following steps: and (3) respectively injecting the reference substance solution and the test solution into a liquid chromatograph, recording a chromatogram, and calculating according to the peak area by an external standard method to obtain the test solution.
Test method of tin: ICP-MS method.
The instrument comprises the following steps: ICP-MS Agilent 7900.
Element mixing standard mother liquor: respectively transferring 0.1ml of Li, Ti, V, Cr, Mn, Co, Ni, Cu, As, Sn, Nb, Mo, Pd, Cd, Sb, Ba, Pt, Tl and Pb element standard solution (1mg/ml) into a 100ml measuring flask, adding 5% dilute nitric acid for dilution, fixing the volume to the scale, shaking up for later use.
Working standard curve solution: respectively and precisely transferring a proper amount of element mixed standard mother liquor (1mg/L), placing the mother liquor into a 25ml measuring flask, fixing the volume by using 5% dilute nitric acid, and preparing standard solutions (0.1 mu g/L, 5 mu g/L, 10 mu g/L, 30 mu g/L and 50 mu g/L) with different concentrations of series of concentrations.
Test solution: taking about 0.5g of the product, adding 10ml of concentrated nitric acid, placing in a fume hood, heating on an electric heating plate at 160 ℃ for 30min, cooling to room temperature, transferring the solution to a 50ml volumetric flask, diluting with 5% dilute nitric acid, and fixing the volume to obtain the product. The results are given in table 1 below:
TABLE 1
As can be seen from table 1, comparative examples 1, 3, 5, 6, 7, and 12 show a significant decrease in yield and a significant loss.
Comparative example 2 the final product was in a better state, but the tin impurities, lactide and lactic acid were high, exceeding the pharmaceutical limits.
Comparative example 4 the product after primary crystallization was slightly viscous and had a large effect on the final yield.
Comparative example 7 the product was in a poor condition, had a high viscosity and was not a good solid, and lost significantly upon suction filtration.
The product of the comparative example 8 has high contents of tin impurity, lactide and lactic acid.
Comparative example 9 no water washing, the molecular weight distribution of the product is wide, and the PD value is high; the impurity content of tin element is too high, and the medicinal requirement is not met.
The product of the comparative example 10 has high state viscosity, certain fluidity and high pumping filtration loss.
Comparative example 11 the pretreatment of the reaction was not proper, resulting in low molecular weight and low yield of the product.
In comparative example 12, the polymerization reaction was incomplete, the molecular weight was low and the yield was low.
Under the conditions of comparative example 13, the product yield was low and the relative molecular weight was low.
Although the invention has been described in detail hereinabove with respect to a general description and specific embodiments thereof, it will be apparent to those skilled in the art that modifications or improvements may be made thereto based on the invention. Accordingly, such modifications and improvements are intended to be within the scope of the invention as claimed.
Claims (10)
1. The method for preparing the polyethylene glycol monomethyl ether-polylactic acid segmented copolymer is characterized by comprising a crude product post-treatment step after the reaction is finished, wherein the crude product post-treatment step comprises the following steps:
(1) crystallizing by using a first crystallization solvent, wherein the first crystallization solvent is a mixture of n-hexane and anhydrous ether;
(2) washing with water;
(3) and crystallizing by using a second crystallization solvent, wherein the second crystallization solvent is diethyl ether.
2. The method according to claim 1, wherein the first crystallization solvent has a volume ratio of n-hexane to dehydrated ether of (0.8-1.5): 1.
3. the method according to claim 2, wherein the crystallization in steps (1) and (3) is carried out at-20 ℃ to-12 ℃.
4. The method according to any one of claims 1 to 3,
during the crystallization in the step (1) and the step (3), firstly, dissolving a product to be crystallized by using dichloromethane, and then adding a dichloromethane solution of the product to be crystallized into a crystallization solvent under stirring, wherein the stirring speed is 200-600 rpm; when washing in the step (2), dissolving a product to be washed with water with dichloromethane, and then adding water for washing;
preferably, in the step (1), the first crystallization solvent is used in an amount of 20 times the volume of the dichloromethane used in the step (1);
and/or, when the water is washed, the using amount of the water is 0.8-1.1 times of the volume of the dichloromethane used in the step (2);
and/or the second crystallization solvent is used in an amount of 15 to 20 times the volume of the dichloromethane used in the step (3).
5. The method as claimed in any one of claims 1 to 4, wherein the polyethylene glycol monomethyl ether-polylactic acid block copolymer is prepared by simultaneously adding polyethylene glycol monomethyl ether, lactide and stannous octoate into a reactor, continuously evacuating at room temperature to maintain the system vacuum, then raising the temperature to 50-85 ℃, continuously evacuating while stirring, then raising the temperature to 110-120 ℃, stopping evacuating and maintaining the stirring, and finally raising the temperature to the temperature at which the polymerization reaction is carried out.
6. The method according to claim 5, wherein the polyethylene glycol monomethyl ether-polylactic acid block copolymer is prepared by evacuating at room temperature for 2-6h, evacuating under stirring for 20-60min, and stopping evacuation and maintaining agitation for 15-25 min.
7. The method as claimed in claim 6, wherein polyethylene glycol monomethyl ether, lactide and stannous octoate are added into the reactor simultaneously, the air pumping is continued for 2h at room temperature, then the temperature is raised to 85 ℃, the vacuum pumping is carried out for 20min under stirring, the temperature is raised to 120 ℃, the vacuum pumping is stopped, the stirring is maintained for 20min, and finally the temperature is raised to the temperature at which the polymerization reaction is carried out.
8. The method according to any one of claims 5 to 7, wherein the mass ratio of the polyethylene glycol monomethyl ether to the lactide is 1: (1.15-1.25), the temperature of the polymerization reaction is 130-145 ℃, and the time of the polymerization reaction is 24-40 h;
preferably, the feeding mass ratio of the polyethylene glycol monomethyl ether to the lactide is 1: 1.2, the temperature of the polymerization reaction is 135 ℃, and the time of the polymerization reaction is 40 h.
9. A methoxy polyethylene glycol-polylactic acid block copolymer, which is prepared by the method according to any one of claims 1 to 8.
10. Use of the methoxy polyethylene glycol-polylactic acid block copolymer according to claim 9 as a hydrophobic drug carrier.
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