Mixture of experts models with sparsified weights

Abstract

A method is presented for operating a machine learning model including one or more mixture of experts layers. The method comprises receiving one or more input data shards at a routing gate network for a mixture of experts layer comprising a plurality of neural network experts. One or more neural network experts in the mixture of experts layer is designated layer to evaluate each input data shard. For each designated neural network expert, a weight matrix is retrieved having a predetermined sparsity to generate a sparsified designated neural network expert. Each input data shard is evaluated with a respective sparsified designated neural network expert.

Description

Technical FieldThe present disclosure relates to the technical field of preparing a polyethylene glycol-glycerol derivative, in particular to a preparation method for a polyethylene glycol-glycerol derivative and an intermediate thereof.Background Polyethylene glycol (PEG) is a polymer with a structure of H(OCH2-CH2)n. As an amphiphilic molecule, PEG is soluble not only in water but also in an organic solvent. Therefore, even a substance that is insoluble in water can be converted into a hydrophilic substance when coupled with PEG. In drug development research, coupling modified polyethylene glycol to a protein, a peptide, a small molecule organic drug, and a liposome through certain means can increase the half-life of a protein or peptide drug in vivo, reduce immunogenicity, and increase the water solubility and targeting of a drug. The binding of modified polyethylene glycol to a liposome can also enhance the passive targeting effect of a liposome on a tumor. Therefore, the development of efficient and simple PEG modification processes has important research significance in the fields of biological engineering and drug development. The modification of PEG includes the modification of active functional groups such as a polyethylene glycol maleimide derivative (PEG Mal), a polyethylene glycol succinimide derivative (PEG-NHS), a polyethylene glycol aldehyde derivative (PEG-ALD), etc., as well as the preparation of a polyethylene glycol glycerol derivative (PEG-Gly) for PEG synthesis of an intermediate or a liposome. The traditional PEG modification process is usually small molecule liquid-phase synthesis. For example, in the US Patent Application Nos. US6828401 and US10752732, the preparation process of PEG-Mal and PEG-CM (polyethylene glycol carboxyl derivatives) involves multiple cumbersome separation and purification operations, making it difficult to achieve high purity of the target product.The preparation of PEG-Gly for PEG synthesis of an intermediate or a liposome, also faces the above-mentioned problems. Currently, there are two processes for the preparation of PEG-Gly. One method is to use epichlorohydrin to replace hydroxyl at the PEG end, followed by hydrolysis and ring opening of the epoxy group to obtain the target product; secondly, in the Chinese Patent Application No. CN102665685A, PEG is first esterified with p-toluenesulfonyl chloride, and then replaced with activated solketal. The intermediate product obtained is acidified to obtain the target product. All of the above routes involve the separation and extraction of the intermediate product, otherwise it will further contaminate the subsequent target product. Therefore, the multi-step separation process not only makes the entire preparation process cumbersome, but also increases the production cost of the process.Summary The main object of the present disclosure is to provide a preparation method for a polyethylene glycol-glycerol derivative and an intermediate thereof to solve the problems of cumbersome preparation process and high cost of PEG-Gly in the prior art.In order to achieve the object above, according to an aspect of the present disclosure, a preparation method for a polyethylene glycol-glycerol derivative intermediate is provided, which includes: enabling a raw material comprising polyethylene glycol and sulfonyl chloride resin to perform an esterification reaction, to obtain a first product system comprising the polyethylene glycol-glycerol derivative intermediate, and at least one end group of the polyethylene glycol is a hydroxyl, wherein, the sulfonyl chloride resin is a polystyrene resin containing a sulfonyl chloride group, and the structural formula of the sulfonyl chloride resin is expressed as .Furthermore, 1 g of the above-mentioned sulfonyl chloride resin contains 1.78-4.61 mmol of the sulfonyl chloride groups, preferably the sulfonyl chloride resin is selected from arbitrary one or more of a HC9001-1-1 sulfonyl chloride resin, and a sulfonyl chloride resin derived from a commercialized strong acid resin 001*7. Furthermore, the molecular weight of the above-mentioned polyethylene glycol is 194-5000,preferably the molar ratio of the polyethylene glycol to the sulfonyl chloride group of the sulfonyl chloride resin is 1:0.9-4, the other end group of the polyethylene glycol is a hydroxyl group or a protective group functional group, preferably the protective group functional group is selected from arbitrary one of a methoxy, a tert-butoxy, and a benzyloxy, preferably the methoxy, and preferably the polyethylene glycol-glycerol derivative intermediate has a structure shown in Formula I:Formula I.Furthermore, the above-mentioned raw material further comprises an acid binding agent, preferably the molar ratio of the acid binding agent to the polyethylene glycol is 10-50:1, and preferably, the acid binding agent is selected from arbitrary one or more of NaOH, KOH, triethylamine, and pyridine. Furthermore, the above-mentioned raw material further comprises a catalyst, preferably the molar ratio of the catalyst to the polyethylene glycol is 0.05-2.2:1, preferably, the catalyst is an alkaline substance, and preferably the alkaline substance is 4-dimethylaminopyridine.Furthermore, the temperature of the above-mentioned esterification reaction is 0-90°C, and preferably the time of the esterification reaction is 4-72 hours. Furthermore, the above-mentioned preparation method further comprises: enabling the first product system to perform first solid-liquid separation, and obtain the polyethylene glycol-glycerol derivative intermediate, preferably the first solid-liquid separation is filtration.According to another aspect of the present disclosure, a preparation method for a polyethylene glycol-glycerol derivative is provided, wherein the polyethylene glycol-glycerol derivative has a structure shown in Formula II:The preparation method includes: Step S1, using the above-mentioned preparation method to obtain a polyethylene glycol-glycerol derivative intermediate; Step S2: enabling the polyethylene glycol-glycerol derivative intermediate to perform a substitution reaction with solketal, to obtain a compound 1, wherein the compound 1 has a structure shown in Formula III:Formula III. Step S3, enabling the compound 1 to perform a hydrolysis reaction, to obtain the polyethylene glycol-glycerol derivative.Furthermore, the above-mentioned step S2 includes: enabling a strong alkaline reagent to react with the solketal at 0-25°C, to obtain a reaction intermediate system; enabling the reaction intermediate system to perform the substitution reaction with the polyethylene glycol-glycerol derivative intermediate at 0-65°C, to obtain a second product system comprising the compound 1; enabling the second product system to perform second solid-liquid separation, to obtain a solid phase and a liquid phase; and enabling the liquid phase to extract and separate, to obtain the compound 1, preferably, the strong alkaline reagent is selected from arbitrary one or more of KOtBu, NaH, and butyl lithium, preferably the reaction time is 1-4 hours, and preferably the substitution reaction time is 15-24 hours, preferably the preparation method further comprises: enabling the solid phase to wash, to obtain a regenerated sulfonyl chloride resin, and preferably the regenerated sulfonyl chloride resin is used in the esterification reaction of the Step S1, preferably, the second solid-liquid separation is filtration, and preferably, the reaction is performed in an ice bath.Furthermore, the concentration of H+ of the above-mentioned hydrolysis reaction is 0.1-4 mol / L, preferably the temperature of the hydrolysis reaction is 40-80°C, and preferably the time of the hydrolysis reaction is 2-24 hours.By applying the technical solution of the present disclosure, the present application utilizes the solid-phase characteristics of the sulfonyl chloride resin as a resin macromolecule, the product system comprising the polyethylene glycol-glycerol derivative intermediate can be prepared by means of a solid-phase synthesis method. Specifically, the sulfonyl chloride group in the sulfonyl chloride resin undergoes esterification reaction with a hydroxyl in polyethylene glycol to remove small molecule hydrogen chloride. In the resultant first product system, the polyethyleneglycol-glycerol derivative intermediate can be separated by a simple solid-liquid separation method and used for subsequent reactions. Due to the high molecular weight insolubility of the polyethylene glycol-glycerol derivative intermediate, in addition to hydrolysis reactions, subsequent reactions are still solid-phase synthesis reactions. The product system obtained can still be separated and purified using a simple solid-liquid separation method. Compared with the traditional liquid-phase small molecule synthesis route of PEG-Gly, it avoids the multi-step cumbersome separation and purification operations in liquid-phase synthesis, greatly simplifies the separation and purification procedures and can acquire the target product with high yield and purity. Moreover, all of the reagents used in the preparation process can be recycled, which greatly reduces the process cost.Brief Description of the DrawingsThe drawings of the description constituting a portion of the present application serve to provide further understanding of the present disclosure. Exemplary examples of the present disclosure and description thereof are used to explain the present disclosure, and do not constitute improper limitation to the present disclosure. In the drawings:FIG. 1 shows a schematic diagram of the high-resolution liquid chromatography-mass spectrometry (TOF) detection results of mPEG2000-Gly provided in Example 1 of the present disclosure.Detailed Description of the EmbodimentsIt should be noted that the examples and the features of the examples in the present application can be combined with each other under the circumstances that there is no conflict. The present disclosure is described in detail with reference to the drawings and in combination with the examples hereinafter.As analyzed in the background technology, the preparation process of PEG-Gly in the prior art has the problems of complexity and high cost. To solve this problem, the present disclosure provides a preparation method for a polyethylene glycol-glycerol derivative and an intermediate thereof. In a typical embodiment of the present application, a preparation method for a polyethylene glycol-glycerol derivative intermediate is provided, which includes: enabling a raw material comprising polyethylene glycol and sulfonyl chloride resin to perform an esterification reaction, to obtain a first product system comprising the polyethylene glycol-glycerol derivative intermediate, and at least one end group of the polyethylene glycol is a hydroxyl, wherein, the above-mentionedformula of the sulfonyl chloride resin is expressed as . The present application utilizes the solid-phase characteristics of the sulfonyl chloride resin as a resin macromolecule; the product system comprising the polyethylene glycol-glycerol derivative intermediate can be prepared by means of a solid-phase synthesis method. Specifically, the sulfonyl chloride group in the sulfonyl chloride resin undergoes esterification reaction with a hydroxyl in polyethylene glycol to remove small molecule hydrogen chloride. In the resultant first product system, the polyethylene glycol-glycerol derivative intermediate can be separated by a simple solid-liquid separation method and used for subsequent reactions. Due to the high molecular weight insolubility of the polyethylene glycol-glycerol derivative intermediate, in addition to hydrolysis reactions, subsequent reactions are still solid-phase synthesis reactions. The product system obtained can still be separated and purified using a simple solid-liquid separation method. Compared with the traditional liquid-phase small molecule synthesis route of PEG-Gly, it avoids the multi-step cumbersome separation and purification operations in liquid-phase synthesis, greatly simplifies the separation and purification procedures and can acquire the target product with high yield and purity. Moreover, all of the reagents used in the preparation process can be recycled, which greatly reduces the process cost. It should be noted that one of the resin macromolecules in the above-mentioned sulfonyl chloride resin contains at least one sulfonyl chloride group, which is connected to the corresponding benzene ring side chain position. Preferably 1 g of the sulfonyl chloride resin contains 1.78-4.61 mmol of the sulfonyl chloride groups, preferably the sulfonyl chloride resin is selected from arbitrary one or more of a HC9001-1-1 sulfonyl chloride resin, and a sulfonyl chloride resin derived from a commercialized strong acid resin 001*7, which is beneficial for improving the esterification reaction efficiency between polyethylene glycol and sulfonyl chloride resin.The above-mentioned commercialized strong acid resin 001*7 derived sulfonyl chloride resin can be prepared using the strong acid resin 001*7 as the reaction raw material and the preparation method disclosed in "PREPARATION OF POLYSTYRENE SULFONYL CHLORIDE RESIN AND USE THEREOF IN SYNTHESIS OF NITROGEN-CONTAINING ALKALINE RESIN".In one embodiment of the present application, the molecular weight of the above-mentionedpolyethylene glycol is 194-5000, preferably the molar ratio of the polyethylene glycol to the sulfonyl chloride group of the sulfonyl chloride resin is 1:0.9-4, the other end group of the polyethylene glycol is a hydroxyl group or a protective group functional group, preferably the protective group functional group is selected from arbitrary one of a methoxy, a tert-butoxy, and a benzyloxy, preferably the methoxy, and preferably the polyethylene glycol-glycerol derivative intermediate has a structure shown in Formula I: Formula I.The value of n in the above-mentioned formula I is the degree of polymerization of polyethylene glycol, which can be obtained by dividing its molecular weight by the molecular weight of the repeating unit. The value of n is approximately 4-113. The above-mentioned molecular weight range of polyethylene glycol and the molar ratio range of polyethylene glycol to sulfonyl chloride resin's sulfonyl chloride group can provide a polyethylene glycol-glycerol derivative intermediate with a wider molecular weight range, and the molar ratio range of polyethylene glycol to sulfonyl chloride resin's sulfonyl chloride group is conducive to improving the esterification reaction efficiency of polyethylene glycol with different molecular weights and sulfonyl chloride resin. Polyethylene glycol can be grafted onto solid-phase sulfonyl chloride resin as much as possible to obtain rich polyethylene glycol-glycerol derivatives. Preferably the polyethylene glycol-glycerol derivative intermediate with a structure shown in Formula I can correspond to a polyethylene glycol-glycerol derivative that is more suitable for the current market demand. In one embodiment of the present application, the above-mentioned raw material further comprises an acid binding agent, preferably the molar ratio of the acid binding agent to the polyethylene glycol is 10-50:1, and preferably, the acid binding agent is selected from arbitrary one or more of NaOH, KOH, triethylamine, and pyridine. The above-mentioned esterification reaction requires the removal of hydrogen chloride molecules, preferably under the action of the acid binding agent above, which is beneficial for removing hydrogen chloride molecules as much as possible, soPreferably the above-mentioned raw material further comprises a catalyst, preferably the molarratio of the catalyst to the polyethylene glycol is 0.05-2.2:1, preferably, the catalyst is an alkalinesubstance, and preferably the alkaline substance is 4-dimethylaminopyridine, so as to promote theesterification reaction.To improve the efficiency of esterification reaction, preferably the temperature of theabove-mentioned esterification reaction is 0-90°C, and preferably the time of the esterificationreaction is 4-72 hours.In one embodiment of the present application, the above-mentioned preparation method furthercomprises: enabling the first product system to perform first solid-liquid separation, and obtain thepolyethylene glycol-glycerol derivative intermediate, preferably the first solid-liquid separation isfiltration. The above-mentioned polyethylene glycol-glycerol derivative intermediate is insoluble inorganic solvents (including low molecular weight polyethylene glycol), and high molecular weightpolyethylene glycol is a solid. Therefore, the polyethylene glycol-glycerol derivative intermediate willnot dissolve in excess polyethylene glycol, and can be separated by simple filtration.In another typical embodiment of the present application, a preparation method for apolyethylene glycol-glycerol derivative is provided, wherein the polyethylene glycol-glycerolderivative has a structure shown in Formula II:Formula II.The preparation method includes: Step S1, using the above-mentioned preparation method toobtain a polyethylene glycol-glycerol derivative intermediate; Step S2: enabling the polyethyleneglycol-glycerol derivative intermediate to perform a substitution reaction with solketal, to obtain acompound 1, wherein the compound 1 has a structure shown in Formula III:Formula III.Step S3, enabling the compound 1 to perform a hydrolysis reaction, to obtain the polyethyleneglycol-glycerol derivative. In the above-mentioned preparation method of the present application, Steps S1 and S2 both adopt solid-phase synthesis method, and in the resultant product system, the target product can be separated through simple solid-liquid separation. Finally, the compound 1 with the structure shown in Formula III can be hydrolyzed to obtain a polyethylene glycol-glycerol derivative, and a polyethylene glycol-glycerol derivative at high yield can be obtained through simple extraction. It can be seen that compared with the traditional liquid-phase small molecule synthesis route of PEG-Gly, it avoids the multi-step cumbersome separation and purification operations in liquid-phase synthesis, greatly simplifies the separation and purification procedures and can acquire the target product with high yield and purity. Moreover, all of the reagents used in the preparation process can be recycled, which greatly reduces the process cost. In one embodiment of the present application, the above-mentioned step S2 comprises: enabling a strong alkaline reagent to react with the solketal at 0-25°C, to obtain a reaction intermediate system; enabling the reaction intermediate system to perform the substitution reaction with the polyethylene glycol-glycerol derivative intermediate at 0-65°C, to obtain a second product system comprising the compound 1; enabling the second product system to perform second solid-liquid separation, to obtain a solid phase and a liquid phase; extracting and separating the liquid phase (e.g. using dichloromethane for three extractions and separations of the obtained liquid phase) to obtain the compound 1, preferably, the strong alkaline reagent is selected from arbitrary one or more of KOtBu, NaH, and butyl lithium, preferably the reaction time is 1-4 hours, and preferably the substitution reaction time is 15-24 hours, preferably, the second solid-liquid separation is filtration, and preferably, the reaction is performed in an ice bath.The above-mentioned reaction removes hydrogen on a hydroxyl of solketal through the action of a strong alkali to obtain an oxygen anion intermediate. This reaction is exothermic and dangerous, so it is preferred to react under the above-mentioned conditions to generate a large amount of oxygen anion intermediates. Then, the oxygen anion intermediate is performed a substitution reaction with a solid-phase polyethylene glycol-glycerol derivative intermediate to obtain a second product system including the structure shown in Formula III. By utilizing the insolubility of the compound 1, the compound 1 can be separated through simple filtration, and then can be hydrolyzed to obtain a polyethylene glycol-glycerol derivative.In addition, the preferred preparation method also comprises: washing the solid phase to obtain regenerated sulfonyl chloride resin, and preferably using the regenerated sulfonyl chloride resin for the esterification reaction in step S1, thereby greatly reducing costs and being moreenvironmentally friendly. To improve the efficiency of the above-mentioned hydrolysis reaction, preferably the concentration of H+ of the above-mentioned hydrolysis reaction is 0.1-4 mol / L, preferably the temperature of the hydrolysis reaction is 40-80°C, and preferably the time of the hydrolysis reaction is 2-24 hours.The following will explain the beneficial effects of the present application in conjunction with specific embodiments and comparative examples.In the following examples, the sulfonyl chloride resin used can be purchased directly or obtained using DOI:10.1007 / s00289-005-0417-y or the preparation method disclosed in "PREPARATION OF POLYSTYRENE SULFONYL CHLORIDE RESIN AND USE THEREOF IN SYNTHESIS OF NITROGEN-CONTAINING ALKALINE RESIN". Example 1Step 1,mixture: at room temperature, 1 g of sulfonyl chloride resin (Nankai Hecheng Co., Ltd., model: HC9001-1-1, sulfonyl chloride content: 1.78 mmol / g) and 25 mL of DCM were added to a 250 mL four-necked bottle, stirred and swelled to obtain the mixture. Solution: under an ice bath, 2.5 g of mPEG2000 and 50 mL of DCM were added to a 100 mL four-necked bottle. After the substrate was completely dissolved, 30 mg of 4-dimethylaminopyridine (DMAP) and 4 mL of triethylamine were added to continue stirring for 15 minutes.The above-mentioned mixture was placed in an ice bath and the above-mentioned prepared solution was slowly added dropwise to form a system to be reacted. Then the system to be reacted was slowly raised to room temperature for esterification reaction for 20 hours to obtain a first product system. The first product system was filtered and washed with DCM, and the washing solution was recovered. The resultant resin was mPEG2000-sulfonyl chloride resin, and after drying, the weight of the resin increased to 1.37 g (the weight gain of the resin was the grafting amount of mPEG2000). The purity of the product in this step was 100%, and no further purification was required.Step 2,22 mg of KOtBu and 0.5 mL of dry THF were added in an ice bath, stirred for 30 minutes, and then a THF solution of solketal (the concentration of solketal itself was close to 100%) (25 μL / 200μL) was added to continue the reaction in an ice bath for 2 hours to obtain an intermediate system of the reaction. Then 1.37 g of the resin from Step 1 and 12 mL of dry THF were added to the intermediate system of the reaction, the system was slowly heated to 65°C, and a substitution reaction was performed for 20 hours (including the heating time) to obtain a second product system. The second product system was lowered to room temperature and filtered. The resin was washed with ice water and THF in sequence and kept for future regeneration. The washing solution was collected, THF was evaporated by rotary evaporation, and the aqueous phase was extracted three times with DCM. The DCM phase was concentrated to obtain mPEG2000-solketal.Step 3,mPEG2000-solketal was placed in a 2 mol / L hydrochloric acid solution and hydrolyzed at 60°C for 8 hours to obtain the target product mPEG2000-Gly. After the reaction was completed, the weight of the resin used was reduced to 1.02 g, indicating that the grafted PEG was almost completely replaced. The weight of mPEG2000-Gly was 0.25 g, the yield was 68%, and the purity of the product was approximately 95%. Among them, the high-resolution liquid chromatography-mass spectrometry (TOF) detection results of mPEG2000-Gly are shown in FIG. 1. Example 2Step 1,mixture: under an ice bath, 1 g of sulfonyl chloride resin (as in Example 1), 2 g of NaOH, and 25 mL of THF were added to a 250 mL four-necked bottle, stirred and swelled to obtain the mixture.Solution: under an ice bath, 2.5 g of mPEG2000 and 50 mL of THF were added to a 100 mL four-necked bottle to wait for the substrate to be completely dissolved.The above-mentioned prepared solution was slowly added dropwise to the mixture to form a system to be reacted. Then the system to be reacted was slowly raised to room temperature for esterification reaction for 20 hours to obtain a first product system. The first product system was filtered and washed with THF, and the washing solution was recovered. The resultant resin was mPEG2000-sulfonyl chloride resin, and after drying, the weight of the resin increased to 1.68 g (the weight gain of the resin was the grafting amount of mPEG2000). The purity of the product in this step was 100%, and no further purification was required.Step 2,41 mg of KOtBu and 1 mL of dry THF were added in an ice bath, stirred for 30 minutes, and then 45 μL / 400 μL of THF solution of solketal was added to continue the reaction in an ice bath for 2 hours to obtain an intermediate system of the reaction. Then 1.68 g of the resin from Step 1 and 12 mL of dry THF were added to the intermediate system of the reaction, the system was slowly heated to 65°C, and a substitution reaction was performed for 20 hours to obtain a second product system. The second product system was lowered to room temperature and filtered. The resin was washed with ice water and THF in sequence and kept for future regeneration. The washing solution was collected, THF was evaporated by rotary evaporation, and the aqueous phase was extracted three times with DCM. The DCM phase was concentrated to obtain mPEG2000-solketal.Step 3,mPEG2000-solketal was placed in a 2 mol / L hydrochloric acid solution and hydrolyzed at 60°C for 8 hours to obtain the target product mPEG2000-Gly.After the reaction was completed, the weight of the resin used was reduced to 1.05 g. The weight of mPEG2000-Gly was 0.49 g, the yield was 72%, and the purity of the product was approximately 95%.Example 3 Sulfonyl chloride resin regeneration: 10 g of the resin prepared by mPEG200-Gly (see Example 2 or 3) was taken, 20 mL of thionyl chloride was added to reflux for more than 8 h, then excess thionyl chloride was evaporated. The remaining system was placed in an ice bath and quickly cleaned with ice water and acetone in sequence. Finally, the resin was dried under reduced pressure at 40°C to obtain the regenerated sulfonyl chloride resin. mPEG2000 mother liquor recovery: the recovered mPEG2000 was obtained by rotary evaporation and concentration of the DCM phase in Example 1; in Example 2, after rotary evaporation of the THF / water mixed solution, the remaining aqueous phase was extracted three times with DCM, and the recovered mPEG2000 was obtained by rotary evaporation of the resultant DCM phase. Step 1,mixture: under an ice bath, 1 g of the regenerated sulfonyl chloride resin, 2 g of NaOH, and 25 mL of THF were added to a 250 mL four-necked bottle, stirred and swelled to obtain the mixture.Solution: under an ice bath, the recovered mPEG2000 were added to a 100 mL four-necked bottle, and 2 g of mPEG2000 was added. Then 50 mL of THF was added to dissolve the substrate.The above-mentioned prepared solution was slowly added dropwise to the mixture to form a system to be reacted. Then the system to be reacted was slowly raised to room temperature for esterification reaction for 20 hours to obtain a first product system. The first product system was filtered and washed with ice water and THF sequentially, and the washing solution was recovered. The resultant resin was mPEG2000-sulfonyl chloride resin, and after drying, the weight of the resin increased to 1.70 g (the weight gain of the resin was the grafting amount of mPEG2000). The purity of the product in this step was 100%, and no further purification was required.Step 2,41 mg of KOtBu and 1 mL of dry THF were added in an ice bath, stirred for 30 minutes, and then THF solution of solketal (45 μL / 400 μL) was added to continue the reaction in an ice bath for 2 hours to obtain an intermediate system of the reaction. Then 1.70 g of the resin from Step 1 and 12 mL of dry THF were added to the intermediate system of the reaction, the system was slowly heated to room temperature and then heated to 65°C, and a substitution reaction was performed for 20 hours to obtain a second product system. The second product system was lowered to room temperature and filtered. The resin was washed with ice water and THF in sequence and kept for future regeneration. The washing solution was collected, THF was evaporated by rotary evaporation, and the aqueous phase was extracted three times with DCM. The DCM phase was concentrated to obtain mPEG2000-solketal.Step 3,mPEG2000-solketal was placed in a 2 mol / L hydrochloric acid solution and hydrolyzed at 60°C for 8 hours to obtain the target product mPEG2000-Gly. After the reaction was completed, the weight of the resin used was reduced to 1.03 g. The weight of mPEG2000-Gly was 0.48 g, the yield was 69%, and the purity of the product was approximately 95%.Example 4Example 4 is different from Example 2 in that the mass of mPEG2000 used was 0.9 g, and after post-treatment, the resin weight increased to 1.25 g.Step 2,20 mg of KOtBu and 0.5 mL of dry THF were added in an ice bath, stirred for 30 min, and then THF solution of solketal (20 μL / 200 μL) was added to continue the reaction in an ice bath for 2 hours to obtain an intermediate system of the reaction. Then 1.25 g of the resin from Step 1 and 12mL of dry THF were added to the intermediate system of the reaction, the system was slowly heated to 65°C to react for 20 hours to obtain a second product system. The second product system was lowered to room temperature and filtered. The resin was washed with ice water and THF in sequence and kept for future regeneration. The washing solution was collected, THF was evaporated by rotary evaporation, and the aqueous phase was extracted three times with DCM. The DCM phase was concentrated to obtain mPEG2000-solketal. Step 3,mPEG2000-solketal was placed in a 2 mol / L hydrochloric acid solution and hydrolyzed at 60°C for 8 hours to obtain the target product mPEG2000-Gly.After the reaction was completed, the weight of the resin used was reduced to 1.01 g. The weight of mPEG2000-Gly was 0.19 g, the yield was 76%, and the purity of the product was approximately 97%.Example 5Example 5 is different from Example 2 in that the mass of mPEG2000 used in Step 1 was 4 g, and after post-treatment, the resin weight increased to 1.65 g. After Step 2 and Step 3, mPEG2000-Gly was finally obtained with a yield of 70% and a product purity of 95%. Example 6Example 6 is different from Example 2 in that the mass of mPEG2000 used in Step 1 was 0.5 g, and after post-treatment, the resin weight increased to 1.12 g. After Step 2 and Step 3, mPEG2000-Gly was finally obtained with a yield of 58% and a product purity of 96%.Example 7 Example 7 is different from Example 2 in that the mass of mPEG2000 used in Step 1 was 8 g, and after post-treatment, the resin weight increased to 1.68 g, which means that increasing the amount of mPEG2000 did not benefit the grafting amount of PEG. After Step 2 and Step 3, mPEG2000-Gly was finally obtained with a yield of 71% and a product purity of 92%.Example 8 Example 8 is different from Example 2 in that the sulfonyl chloride resin in Step 1 was a self-made resin derived and modified from the commercial resin 001*7, with a sulfonyl chloride content of 4.61 mmol / g. The modification method was the same as "PREPARATION OF POLYSTYRENE SULFONYL CHLORIDE RESIN AND USE THEREOF IN SYNTHESIS OFNITROGEN-CONTAINING ALKALINE RESIN". After post-treatment, the resin weight increased to 1.86 g. After Step 2 and Step 3, mPEG2000-Gly was finally obtained with a yield of 69% and a product purity of 91%.Example 9Example 9 is different from Example 2 in that the polyethylene glycol used in Step 1 was 0.3 g of mPEG4, the mass of the sulfonyl chloride resin was 1 g, and 1.19 g of PEG grafted resin was obtained. Based on the loading amount of PEG grafted on the resin, 1.5 eq of potassium tert butoxide and 2 eq of solketal were used to complete Step 2 reaction. Finally, the weight of mPEG4-Gly obtained by hydrolysis was 0.17 g, with a yield of 89% and a purity of 89%.Example 10Example 10 is different from Example 2 in that in Step 1, the polyethylene glycol was 0.6 g of mPEG8, the mass of the sulfonyl chloride resin was 1 g, and mPEG8-Gly was finally obtained with a weight of 0.31 g, a yield of 76% and a purity of 92%.Example 11Example 11 is different from Example 2 in that in Step 1, the molecular weight of polyethylene glycol was 3500, with a mass of 4.4 g, the mass of sulfonyl chloride resin was 1 g, and mPEG3500-Gly was finally obtained to be 0.75 g, with a yield of 77% and a purity of 97%.Example 12Example 12 is different from Example 2 in that in Step 1, the molecular weight of polyethylene glycol was 5000, with a mass of 7.5 g, the mass of sulfonyl chloride resin was 1 g, the weight of the resin obtained in Step 1 increased to 2.36 g, and mPEG5000-Gly was finally obtained to be 1.1 g, with a yield of 81% and a purity of 98%.Example 13Example 13 is different from Example 2 in that in Step 1, the molar ratio of sodium hydroxide to mPEG2000 was 10:1, and the weight of the PEG grafted resin obtained increased to 1.43 g. After Step 2 and Step 3, mPEG2000-Gly was finally obtained with a yield of 75% and a purity of 95%. Example 14Example 14 is different from Example 2 in that in Step 1, the molar ratio of sodium hydroxide to mPEG2000 was 50:1, and the weight of the PEG grafted resin obtained increased to 1.68 g. AfterExample 15 Example 15 is different from Example 2 in that in Step 1, the molar ratio of sodium hydroxide to mPEG2000 was 8:1, and the weight of the PEG grafted resin obtained increased to 1.29 g. MPEG2000-Gly was finally obtained with a yield of 71% and a product purity of 94%.Example 16Example 16 is different from Example 2 in that pyridine was used as an acid-binding agent in Step 1, the weight of the PEG grafted resin obtained increased to 1.21 g, and mPEG2000-Gly was finally obtained with a yield of 68% and a product purity of 92%.Example 17Example 17 is different from Example 2 in that in Step 1, DMAP was added as a catalyst, and the molar ratio of DMAP to mPEG2000 was 0.05:1, the weight of the PEG grafted resin obtained increased to 1.81 g, and mPEG2000-Gly was finally obtained to be 0.55 g, with a yield of 71% and a purity of 96%.Example 18Example 18 is different from Example 2 in that in Step 1, DMAP was added as a catalyst, and the molar ratio of DMAP to mPEG2000 was 2.2:1, the weight of the PEG grafted resin obtained increased to 1.89 g, and mPEG2000-Gly was finally obtained to be 0.59 g, with a yield of 69% and a purity of 95%.Example 19Example 19 is different from Example 2 in that in Step 1, DMAP was added as a catalyst, and the molar ratio of DMAP to mPEG2000 was 0.03:1, the weight of the PEG grafted resin obtained increased to 1.68 g, and mPEG2000-Gly was finally obtained to be 0.49 g, with a yield of 72% and a product purity of approximately 95%.Example 20Example 20 is different from Example 2 in that in Step 1, the temperature of the esterification reaction was 90°C, the time of the esterification reaction was 8 hours, and the weight of the PEG grafted resin obtained increased from 1 g to 1.33 g, with a smaller weight gain compared to Example 2. MPEG2000-Gly was finally obtained to be 0.22 g, with a yield of 67% and a product purity of approximately 97%.Example 21 is different from Example 2 in that in Step 2, the strong alkaline reagent was NaH, and mPEG2000-Gly was finally obtained to be 0.3 g, with a yield of 44% and a product purity of approximately 82%.Example 22Example 22 is different from Example 2 in that in Step 2, the reaction between potassium tert butoxide and solketal was carried out at 25°C. After 4 hours of reaction, an intermediate system of the reaction was obtained, and mPEG2000-Gly was finally obtained with a yield of 70% and a product purity of 85%.Example 23Example 23 is different from Example 2 in that:in Step 2, the resin from Step 1 and 12 mL of dry THF were added to an intermediate system of the reaction, and the system was slowly restored to room temperature to react for 20 hours to obtain a second product system. After the reaction was complete, the system was filtered, and the resin was washed with ice water and THF in sequence and kept for future regeneration. The washing solution was collected, THF was evaporated by rotary evaporation, and the aqueous phase was extracted three times with DCM. The DCM phase was concentrated to obtain mPEG2000-solketal. Step 3,mPEG2000-solketal was placed in a 2 mol / L hydrochloric acid solution and hydrolyzed at 60°C for 8 hours to obtain the target product mPEG2000-Gly.After the reaction was completed, the weight of the resin used was reduced to 1.26 g. The weight of mPEG2000-Gly was 0.35 g, the yield was 51%, and the purity of the product was about 95%.Example 24Example 24 is different from Example 2 in that in Step 2 of the reaction, after the system was restored to room temperature, the reaction was continued for 48 h to obtain a second product system. The weight of the final product mPEG-Gly obtained by hydrolyzing the intermediate was 0.42 g, the yield was 62%, and the product purity was approximately 92%.Example 25Example 25 is different from Example 2 in that in Step 3, the concentration of hydrochloric acidyield of 72% and a product purity of 88%. Example 26Example 26 is different from Example 2 in that in Step 3, the temperature of the hydrolysis reaction was 80°C, the time of the hydrolysis reaction was 5 hours, and mPEG2000-Gly was finally obtained with a yield of 74% and a product purity of 91%.The categories, yields, and purities of polyethylene glycol-glycerol derivatives obtained in Examples 1 to 26 are listed in Table 1.Table 1From the data in Table 1 above, it can be seen that compared with Examples 2, 4, and 5, when the ratio of mPEG2000 to sulfonyl chloride resin in Example 6 is 1:7.12, which is outside the range, the grafting amount of mPEG per gram of the resin in Step 1 reaction will be significantly reduced. When the ratio of mPEG2000 to sulfonyl chloride resin in Example 7 is 1:0.445, which is outside the range, although the grafting amount of mPEG per gram of the resin in Step 1 reaction will not be significantly reduced, it will cause great waste of mPEG2000 raw materials. Compared with Examples 2, 13, and 14, when the molar ratio of the acid binding agent to polyethylene glycol in Example 15 is outside the range, the grafting amount of mPEG per gram of the resin in Step 1 reaction of Example 15 will be significantly reduced.Compared with Examples 2, 17, and 18, the effect of adding too little DMAP catalyst in Example 19 is similar to that of not adding DMAP catalyst. From the above description, it can be seen that the above-mentioned embodiments of the present disclosure achieve the following technical effects:The present application utilizes the solid-phase characteristics of the sulfonyl chloride resin as a resin macromolecule, the product system comprising the polyethylene glycol-glycerol derivativeintermediate can be prepared by means of a solid-phase synthesis method. Specifically, the sulfonyl chloride group in the sulfonyl chloride resin undergoes esterification reaction with a hydroxyl in polyethylene glycol to remove small molecule hydrogen chloride. In the resultant first product system, the polyethylene glycol-glycerol derivative intermediate can be separated by a simple solid-liquid separation method and used for subsequent reactions. Due to the high molecular weight insolubility of the polyethylene glycol-glycerol derivative intermediate, in addition to hydrolysis reactions, subsequent reactions are still solid-phase synthesis reactions. The product system obtained can still be separated and purified using a simple solid-liquid separation method. Compared with the traditional liquid-phase small molecule synthesis route of PEG-Gly, it avoids the multi-step cumbersome separation and purification operations in liquid-phase synthesis, greatly simplifies the separation and purification procedures and can acquire the target product with high yield and purity. Moreover, all of the reagents used in the preparation process can be recycled, which greatly reduces the process cost.The embodiments described above are just preferred embodiments of the present disclosure and are not used for limiting the present disclosure. For those skilled in the art, the present disclosure may have various modifications and variations. Any modification, equivalent replacement, improvement and the like made within the spirit and principle of the present disclosure shall be still included in the protection scope of the present disclosure.

Claims

1. A preparation method for a polyethylene glycol-glycerol derivative intermediate, wherein the preparation method comprises: enabling a raw material comprising polyethylene glycol and sulfonyl chloride resin to perform an esterification reaction, to obtain a first product system comprising the polyethylene glycol-glycerol derivative intermediate, and at least one end group of the polyethylene glycol is a hydroxyl, wherein, the sulfonyl chloride resin is a polystyrene resin containing a sulfonyl chloride group, and a structural formula of the sulfonyl chloride resin is expressed as .

2. The preparation method according to claim 1, wherein 1 g of the sulfonyl chloride resin contains 1.78-4.61 mmol of the sulfonyl chloride groups, preferably the sulfonyl chloride resin is selected from arbitrary one or more of a HC9001-1-1 sulfonyl chloride resin, and a sulfonyl chloride resin derived from a commercialized strong acid resin 001*7.

3. The preparation method according to claim 1 or 2, wherein the molecular weight of the polyethylene glycol is 194-5000, preferably the molar ratio of the polyethylene glycol to the sulfonyl chloride group of the sulfonyl chloride resin is 1:0.9-4, the other end group of the polyethylene glycol is a hydroxyl or a protective group functional group, preferably the protective group functional group is selected from arbitrary one of a methoxy, a tert-butoxy, and a benzyloxy, preferably the methoxy, and preferably the polyethylene glycol-glycerol derivative intermediate has a structure shown in Formula I: Formula I.

4. The preparation method according to any one of claims 1 to 3, wherein the raw material further comprises an acid binding agent, preferably the molar ratio of the acid binding agent to the polyethylene glycol is 10-50:1, and preferably, the acid binding agent is selected from arbitrary one or more of NaOH, KOH, triethylamine, and pyridine.

5. The preparation method according to any one of claims 1 to 4, wherein the raw material further comprises a catalyst, preferably the molar ratio of the catalyst to the polyethylene glycol is 0.05-2.2:1, preferably, the catalyst is an alkaline substance, and preferably the alkaline substance is 4-dimethylaminopyridine.

6. The preparation method according to any one of claims 1 to 5, wherein the temperature of the esterification reaction is 0-90°C, and preferably the time of the esterification reaction is 4-72 hours.

7. The preparation method according to claim 1, wherein the preparation method further comprises: enabling the first product system to perform first solid-liquid separation, and obtain the polyethylene glycol-glycerol derivative intermediate, preferably the first solid-liquid separation is filtration.

8. A preparation method for a polyethylene glycol-glycerol derivative, wherein the polyethylene glycol-glycerol derivative has a structure shown in Formula II: Formula II the preparation method comprises: Step S1, using the preparation method according to any one of claims 1 to 7 to obtain a polyethylene glycol-glycerol derivative intermediate; Step S2: enabling the polyethylene glycol-glycerol derivative intermediate to perform a substitution reaction with solketal, to obtain a compound 1, wherein the compound 1 has a structure shown in Formula III: Formula III Step S3, enabling the compound 1 to perform a hydrolysis reaction, to obtain the polyethylene glycol-glycerol derivative.

9. The preparation method according to claim 8, wherein the Step S2 comprises: enabling a strong alkaline reagent to react with the solketal at 0-25°C, to obtain a reaction intermediate system; enabling the reaction intermediate system to perform the substitution reaction with the polyethylene glycol-glycerol derivative intermediate at 0-65°C, to obtain a second product system comprising the compound 1; enabling the second product system to perform second solid-liquid separation, to obtain a solid phase and a liquid phase; and enabling the liquid phase to extract and separate, to obtain the compound 1, preferably, the strong alkaline reagent is selected from arbitrary one or more of KOtBu, NaH, and butyl lithium, preferably the reaction time is 1-4 h, and preferably the substitution reaction time is 15-24 h, preferably the preparation method further comprises: enabling the solid phase to wash, to obtain a regenerated sulfonyl chloride resin, and preferably the regenerated sulfonyl chloride resin is used in the esterification reaction of the Step S1, preferably, the second solid-liquid separation is filtration, and preferably, the reaction is performed in an ice bath.

10. The preparation method according to claim 8, wherein the concentration of H+ of the hydrolysis reaction is 0.1-4 mol / L, preferably the temperature of the hydrolysis reaction is 40-80°C, and preferably the time of the hydrolysis reaction is 2-24 h.