JP2025513901A - Methods for producing polyethylene glycol-glycerin derivatives and their intermediates - Google Patents

Abstract

The present invention provides a method for preparing a polyethylene glycol-glycerin derivative and an intermediate thereof. The method includes esterifying a raw material including a polyethylene glycol having at least one terminal group of a hydroxyl group and a sulfonyl chloride resin to obtain a first product system including a polyethylene glycol-glycerin derivative intermediate, where the sulfonyl chloride resin is a polystyrene resin containing a sulfonyl chloride group. By utilizing the resin polymer solid phase characteristics of the sulfonyl chloride resin, a product system including a polyethylene glycol-glycerin derivative intermediate can be obtained using a solid phase synthesis method, and the polyethylene glycol-glycerin derivative intermediate can be separated and used in a subsequent reaction by simply performing a simple solid-liquid separation method on the obtained product system, greatly simplifying the separation and purification operations and making it easier to obtain a target product with a high yield and high purity. All of the reagents used in the production process can be recycled, greatly reducing costs.
[Selected Figure] Figure 1

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority from a Chinese application having CN application number 202210424440.4 and filed on April 22, 2022, the disclosure of which is hereby incorporated by reference in its entirety.

The present invention relates to the field of manufacturing technology for polyethylene glycol-glycerin derivatives, and more specifically, to manufacturing methods for polyethylene glycol-glycerin derivatives and their intermediates.

Polyethylene glycol (PEG) is a polymer with the structure H(OCH ₂ -CH ₂ ) _n OH. As an amphiphilic molecule, PEG is not only soluble in water, but also soluble in organic solvents. Therefore, even if a substance is poorly soluble in water, it can be transformed into a hydrophilic substance after being bound to PEG. In drug development research, the modified polyethylene glycol can be bound to proteins, polypeptides, small molecule organic drugs and liposomes by certain means to increase the in vivo half-life of protein or polypeptide drugs, reduce immunogenicity, and increase the water solubility and targeting of the drugs. PEG can also be bound to liposomes after modification to make the liposomes have a stronger passive targeting effect on tumors. Therefore, the development of an efficient and simple PEG modification process has important research significance in the fields of bioengineering and drug development.

The modification of PEG includes modification of active functional groups such as polyethylene glycol maleimide derivatives (PEG-Mal), polyethylene glycol succinimide derivatives (PEG-NHS), polyethylene glycol aldehyde derivatives (PEG-ALD), and the production of polyethylene glycol glycerin derivatives (PEG-Gly) used in PEG synthesis intermediates or liposomes. Conventional PEG modification processes are usually small molecule liquid phase synthesis, and the production processes of PEG-Mal and PEG-CM (polyethylene glycol carboxy derivatives) involve multiple and complicated separation and purification steps, making it difficult to achieve high purity of the target product, as in the US patents with patent application numbers US6828401 and US10752732.

The preparation of PEG-Gly used in PEG synthesis intermediates or liposomes also faces the above problems, and currently there are two processes for the preparation of PEG-Gly. One is to replace the terminal hydroxyl group of PEG with epichlorohydrin, and then carry out hydrolysis and ring-opening of the epoxide group to obtain the target product. One is to first esterify PEG with 4-methoxybenzenesulfonyl chloride, as in the Chinese patent application with the patent application disclosure number CN102665685A, and then replace it with activated acetone glycerol, and obtain the target product after acid hydrolysis of the resulting intermediate product. All of the above routes involve separation and extraction operations of the intermediate product, otherwise the subsequent target product will be further contaminated, so the multi-step separation process not only complicates the entire manufacturing process, but also increases the production cost of the process.

The main objective of the present invention is to provide a method for producing a polyethylene glycol-glycerin derivative and its intermediates, which solves the problems of the conventional technology, such as the complexity and high cost of the PEG-Gly production process.

In order to achieve the above object, according to one aspect of the present invention, a method for producing a polyethylene glycol-glycerin derivative intermediate is provided, the method comprising esterifying a raw material containing polyethylene glycol, at least one of whose terminal groups is a hydroxyl group, and a sulfonyl chloride resin to obtain a first product system containing a polyethylene glycol-glycerin derivative intermediate, wherein the sulfonyl chloride resin is a polystyrene resin containing a sulfonyl chloride group, and the structural formula of the sulfonyl chloride resin is:

Furthermore, 1 g of the above sulfonyl chloride resin contains 1.78 to 4.61 mmol of sulfonyl chloride groups, and preferably, the sulfonyl chloride resin is one or more selected from HC9001-1-1 sulfonyl chloride resin and a derivative sulfonyl chloride resin of commercially available strong acid resin 001*7.

Furthermore, the molecular weight of the polyethylene glycol is 194 to 5000, preferably the molar ratio of the polyethylene glycol to the sulfonyl chloride group of the sulfonyl chloride resin is 1:0.9 to 4, the other terminal group of the polyethylene glycol is a hydroxyl group or a protecting group functional group, preferably the protecting group functional group is any one selected from a methoxy group, a tert-butoxy group, and a benzyloxy group, preferably a methoxy group, and preferably the polyethylene glycol-glycerin derivative intermediate has a structure represented by formula I.

Formula I

Furthermore, the above raw material further contains an acid binder, and the molar ratio of the acid binder to polyethylene glycol is preferably 10 to 50:1, and the acid binder is preferably one or more selected from NaOH, KOH, triethylamine, and pyridine.

Furthermore, the above raw material further comprises a catalyst, preferably the molar ratio of the catalyst to polyethylene glycol is 0.05-2.2:1, preferably the catalyst is a basic substance, preferably the basic substance is 4-dimethylaminopyridine.
Furthermore, the temperature of the above esterification reaction is 0 to 90° C., and preferably the time of the esterification reaction is 4 to 72 hours.

Furthermore, the above-mentioned production method further includes performing a first solid-liquid separation on the first product system to obtain a polyethylene glycol-glycerin derivative intermediate, and preferably, the first solid-liquid separation is filtration.

According to another aspect of the present invention, there is provided a method for producing a polyethylene glycol-glycerin derivative, the polyethylene glycol-glycerin derivative having a structure represented by formula II,

The manufacturing method includes step S1 of obtaining a polyethylene glycol-glycerin derivative intermediate using the above manufacturing method, and step S2 of subjecting the polyethylene glycol-glycerin derivative intermediate to a substitution reaction with acetone glycerol to obtain compound 1 having a structure represented by formula III.

and Step S3 of subjecting Compound 1 to a hydrolysis reaction to obtain a polyethylene glycol-glycerin derivative.

Furthermore, the above step S2 includes reacting a strong basic reagent with acetone glycerol at 0-25°C to obtain a reaction intermediate system, and performing a substitution reaction of the reaction intermediate system with a polyethylene glycol-glycerin derivative intermediate at 0-65°C to obtain a second product system containing compound 1, performing a second solid-liquid separation on the second product system to obtain a solid phase and a liquid phase, and extracting and separating the liquid phase to obtain compound 1. Preferably, the strong basic reagent is any one or more selected from KOtBu, NaH, and butyl lithium. Preferably, the reaction time is 1-4 h. Preferably, the substitution reaction time is 15-24 h. Preferably, the production method further includes washing the solid phase to obtain a regenerated sulfonyl chloride resin. Preferably, the regenerated sulfonyl chloride resin is used in the esterification reaction of step S1. Preferably, the second solid-liquid separation is filtration. Preferably, the reaction is performed in an ice bath.

Furthermore, the H 2 ⁺ concentration in the above hydrolysis reaction is 0.1-4 mol/L, the temperature of the hydrolysis reaction is preferably 40-80° C., and the time of the hydrolysis reaction is preferably 2-24 h.

By applying the technical solution of the present invention, in this application, the resin polymer solid-phase characteristics of sulfonyl chloride resin can be utilized to produce a product system containing a polyethylene glycol-glycerin derivative intermediate by using a solid-phase synthesis method. Specifically, the sulfonyl chloride group in the sulfonyl chloride resin and the hydroxyl group in the polyethylene glycol are esterified to release small molecule hydrogen chloride, and the obtained first product system can be separated and used in the subsequent reaction by simply performing a simple solid-liquid separation method. Due to the polymer insolubility of the polyethylene glycol-glycerin derivative intermediate, in addition to the hydrolysis reaction, the subsequent reaction is still a solid-phase synthesis reaction, and the obtained product system can still be separated and purified by a simple solid-liquid separation method. Compared with the conventional synthesis route of PEG-Gly using liquid-phase small molecules, the complicated separation and purification operations in the liquid-phase synthesis can be avoided, the separation and purification operations can be greatly simplified, and the target product can be obtained with high yield and high purity more easily. In addition, all the reagents used in the manufacturing process can be recycled, greatly reducing the process cost.

The accompanying drawings of the specification forming a part of this application are intended to provide a further understanding of the present invention, and the schematic embodiments of the present invention and the description thereof are intended to interpret the present invention and are not intended to unduly limit the present invention.
FIG. 2 is a schematic diagram showing the detection results of mPEG2000-Gly provided in Example 1 of the present invention using a high-resolution liquid chromatograph mass spectrometer (TOF).

The examples and features of the examples in this application may be combined with each other as long as they are not inconsistent. The present invention will be described in detail below with reference to the drawings and examples.

As analyzed in the background art, the manufacturing process for PEG-Gly in the prior art has problems of complexity and high cost. To solve these problems, the present invention provides a method for manufacturing a polyethylene glycol-glycerin derivative and its intermediate.

In one exemplary embodiment of the present application, a method for producing a polyethylene glycol-glycerin derivative intermediate is provided, the method comprising esterifying a raw material including a polyethylene glycol having at least one terminal group being a hydroxyl group and a sulfonyl chloride resin to obtain a first product system including a polyethylene glycol-glycerin derivative intermediate, wherein the sulfonyl chloride resin is a polystyrene resin containing a sulfonyl chloride group, and the structural formula of the sulfonyl chloride resin is:

In the present application, the resin polymer solid-phase characteristics of sulfonyl chloride resin can be utilized to produce a product system containing a polyethylene glycol-glycerin derivative intermediate using a solid-phase synthesis method. Specifically, the sulfonyl chloride group in the sulfonyl chloride resin and the hydroxyl group in the polyethylene glycol are esterified to release small molecule hydrogen chloride, and the resulting first product system can be separated and used in the subsequent reaction by simply performing a simple solid-liquid separation method. Due to the polymer insolubility of the polyethylene glycol-glycerin derivative intermediate, the subsequent reaction other than the hydrolysis reaction is still a solid-phase synthesis reaction, and the resulting product system can still be separated and purified using a simple solid-liquid separation method. Compared with the conventional synthetic route for PEG-Gly using liquid-phase small molecules, the complicated separation and purification operations in multiple steps in liquid-phase synthesis can be avoided, the separation and purification operations can be greatly simplified, and the target product can be obtained with a high yield and high purity more easily. In addition, all of the reagents used in the manufacturing process can be recycled, greatly reducing the process cost.

In addition, one of the large resin molecules of the sulfonyl chloride resins described above contains at least one sulfonyl chloride group linked to the side chain position of the corresponding benzene ring. Preferably, 1 g of the sulfonyl chloride resin contains 1.78 to 4.61 mmol of sulfonyl chloride groups, and preferably, the sulfonyl chloride resin is one or more selected from HC9001-1-1 sulfonyl chloride resin and a derivative sulfonyl chloride resin of commercially available strong acid resin 001*7, which is advantageous in improving the efficiency of the esterification reaction between polyethylene glycol and the sulfonyl chloride resin.

The above-mentioned commercially available strong acid resin 001*7 derivative sulfonyl chloride resin can be produced by using the strong acid resin 001*7 as a reaction raw material and the production method disclosed in "Production of polystyrene sulfonyl chloride resin and its use in the synthesis of nitrogen-containing basic resins".

In one embodiment of the present application, the molecular weight of the polyethylene glycol is 194 to 5000, preferably the molar ratio of the polyethylene glycol to the sulfonyl chloride group of the sulfonyl chloride resin is 1:0.9 to 4, the other end group of the polyethylene glycol is a hydroxyl group or a protecting group functional group, preferably the protecting group functional group is any one selected from a methoxy group, a tert-butoxy group, and a benzyloxy group, preferably a methoxy group, and preferably the polyethylene glycol-glycerin derivative intermediate has a structure represented by formula I.

Formula I
In the above formula I, the value of n is the degree of polymerization of the polyethylene glycol, obtained by dividing its molecular weight by the molecular weight of the repeating unit, where n is about 4-113.

The above-mentioned molecular weight range of polyethylene glycol and the molar ratio range of polyethylene glycol to the sulfonyl chloride group of the sulfonyl chloride resin can provide a polyethylene glycol-glycerin derivative intermediate with a wider molecular weight range, and the molar ratio range of polyethylene glycol to the sulfonyl chloride group of the sulfonyl chloride resin is advantageous for improving the efficiency of the esterification reaction between polyethylene glycols of different molecular weights and the sulfonyl chloride resin. By grafting as much polyethylene glycol as possible onto the solid-phase sulfonyl chloride resin, a wide variety of polyethylene glycol-glycerin derivatives can be obtained, and the polyethylene glycol-glycerin derivatives that can be handled by the polyethylene glycol-glycerin derivative intermediate with the structure represented by the preferred formula I are more suitable for the current market needs.

In one embodiment of the present application, the raw material further includes an acid binder, preferably with a molar ratio of the acid binder to polyethylene glycol of 10 to 50:1, and preferably the acid binder is one or more selected from NaOH, KOH, triethylamine, and pyridine. This is advantageous in that hydrogen chloride molecules are released in the esterification reaction, preferably under the action of the acid binder, to remove as many hydrogen chloride molecules as possible, thereby promoting the progress of the esterification reaction.

Preferably, the above raw material further contains a catalyst, preferably the molar ratio of catalyst to polyethylene glycol is 0.05 to 2.2:1, and preferably the catalyst is a basic substance, preferably the basic substance is 4-dimethylaminopyridine, thereby promoting the progress of the esterification reaction.

To improve the efficiency of the esterification reaction, the temperature of the esterification reaction is preferably 0 to 90°C, and the time of the esterification reaction is preferably 4 to 72 hours.

In one embodiment of the present application, the above-mentioned preparation method further includes performing a first solid-liquid separation on the first product system to obtain a polyethylene glycol-glycerin derivative intermediate, and preferably, the first solid-liquid separation is filtration. The above-mentioned polyethylene glycol-glycerin derivative intermediate is insoluble in organic solvents (including low molecular weight polyethylene glycols), and high molecular weight polyethylene glycols are solid, so that the polyethylene glycol-glycerin derivative intermediate is insoluble in excess polyethylene glycol, and therefore the polyethylene glycol-glycerin derivative intermediate can be separated by simple filtration.
In another exemplary embodiment of the present application, there is provided a method for producing a polyethylene glycol-glycerin derivative having a structure represented by formula II,

The manufacturing method includes step S1 of obtaining a polyethylene glycol-glycerin derivative intermediate using the above manufacturing method, and step S2 of subjecting the polyethylene glycol-glycerin derivative intermediate to a substitution reaction with acetone glycerol to obtain compound 1 having a structure represented by formula III.

and Step S3 of subjecting Compound 1 to a hydrolysis reaction to obtain a polyethylene glycol-glycerin derivative.

In both steps S1 and S2 of the above-mentioned manufacturing method of the present application, solid-phase synthesis is used, and the target product can be separated from the obtained product system by simple solid-liquid separation. Finally, a polyethylene glycol-glycerin derivative can be obtained by hydrolysis reaction of compound 1 having a structure represented by formula III, and finally, a polyethylene glycol-glycerin derivative can be obtained with a high yield by simple extraction. As can be seen from this, compared with the conventional synthetic route of PEG-Gly using liquid-phase small molecules, the multi-step complicated separation and purification operations in liquid-phase synthesis are avoided, the separation and purification operations are greatly simplified, and the target product can be obtained with a high yield and high purity more easily. Furthermore, all of the reagents used in the manufacturing process can be recycled, significantly reducing the process cost.

In one embodiment of the present application, the above step S2 includes reacting a strong basic reagent with acetone glycerol at 0-25°C to obtain a reaction intermediate system, performing a substitution reaction of the reaction intermediate system with a polyethylene glycol-glycerin derivative intermediate at 0-65°C to obtain a second product system containing compound 1, performing a second solid-liquid separation on the second product system to obtain a solid phase and a liquid phase, and extracting and separating the liquid phase (for example, performing extraction and separation three times on the obtained liquid phase using dichloromethane) to obtain compound 1, preferably the strong basic reagent is any one or more selected from KOtBu, NaH, and butyl lithium, preferably the reaction time is 1-4h, preferably the substitution reaction time is 15-24h, preferably the second solid-liquid separation is filtration, and preferably the reaction is performed in an ice bath.

In the above reaction, the hydrogen of the hydroxyl group of acetone glycerol is removed by the action of strong alkali to obtain an oxygen anion intermediate, and the reaction is obviously exothermic and dangerous. Therefore, it is preferable to first carry out the reaction under the above conditions to generate a large amount of oxygen anion intermediate, and then the oxygen anion intermediate is subjected to a substitution reaction with a solid-phase polyethylene glycol-glycerin derivative intermediate, thereby obtaining a second product system containing the structure represented by formula III, and compound 1 is insoluble, and compound 1 can be separated by simple filtration, and compound 1 can be further hydrolyzed to obtain a polyethylene glycol-glycerin derivative.

Also, preferably, the preparation method further includes washing the solid phase to obtain a regenerated sulfonyl chloride resin, which is preferably used in the esterification reaction of step S1, thereby significantly reducing costs and being more environmentally friendly.

In order to improve the efficiency of the hydrolysis reaction, the H ⁺ concentration of the hydrolysis reaction is preferably 0.1-4 mol/L, the temperature of the hydrolysis reaction is preferably 40-80° C., and the time of the hydrolysis reaction is preferably 2-24 h.
The beneficial effects of the present invention will be described below with reference to specific examples and comparative examples.

In the following examples, the sulfonyl chloride resins used may be purchased directly or may be obtained by the preparation method disclosed in DOI:10.1007/s00289-005-0417-y or in "Preparation of Polystyrene Sulfonyl Chloride Resin and Its Use in the Synthesis of Nitrogen-Containing Basic Resins."
Example 1
First step

Mixture: At room temperature, 1 g of sulfonyl chloride resin (Nankai Hecheng Co., Ltd., model number: HC9001-1-1, sulfonyl chloride content: 1.78 mmol/g) and 25 mL of DCM were added to a 250 mL four-neck flask, stirred and expanded to obtain a mixture.

Solution: In an ice bath, 2.5 g of mPEG2000 and 50 mL of DCM were added to a 100 mL four-neck flask. After the substrate was completely dissolved, 30 mg of 4-dimethylaminopyridine (DMAP) and 4 mL of triethylamine were added and the mixture was stirred for 15 min.

The mixture was placed in an ice bath, and the prepared solution was slowly added dropwise to form a reaction system. The reaction system was then slowly warmed to room temperature to carry out the esterification reaction for 20 h to obtain the first product system. The first product system was filtered and washed with DCM, and the washing liquid was collected. The resin obtained was mPEG2000-sulfonyl chloride resin, and the weight of the resin after drying increased to 1.37 g (the increase in the resin weight is the grafted amount of mPEG2000), and the purity of the product at this step was 100%, and no further purification was required.
Second step

22 mg of KOtBu and 0.5 mL of dry THF were added in an ice bath, and the mixture was stirred for 30 min., followed by the addition of a THF solution (25 μL/200 μL) of acetone glycerol (the concentration of acetone glycerol itself is close to 100%), followed by 2 h of reaction in an ice bath to obtain a reaction intermediate system. Then, 1.37 g of the resin from the first step and 12 mL of dry THF were added to the reaction intermediate system, and the system was slowly heated to 65° C., and the substitution reaction was carried out for 20 h (including the time for heating up) to obtain a second product system, which was cooled to room temperature and filtered, and the resin was washed with ice water and THF in sequence, and then prepared for regeneration. The washings were collected, and the THF was rotary evaporated, and the aqueous phase was extracted with DCM three times, and the DCM phase was concentrated to obtain mPEG2000-acetone glycerol.
Third step: mPEG2000-acetone glycerol was added to 2 mol/L hydrochloric acid solution and hydrolyzed at 60° C. for 8 h to obtain the target product mPEG2000-Gly.

After the reaction was completed, the weight of the resin used was reduced to 1.02 g, i.e., 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 about 95%. Here, the results of detection of mPEG2000-Gly by high-resolution liquid chromatography mass spectrometry (TOF) are shown in FIG. 1.
Example 2
First step

Mixture: In an ice bath, 1 g of sulfonyl chloride resin (same as in Example 1), 2 g of NaOH, and 25 mL of THF were added to a 250 mL four-neck flask, stirred and expanded to obtain a mixture.
Solution: In an ice bath, 2.5 g of mPEG2000 and 50 mL of THF were added to a 100 mL 4-neck flask to completely dissolve the substrate.

The prepared solution was slowly added dropwise to the mixture to form a reaction system, and then the reaction system was slowly warmed to room temperature to carry out the esterification reaction for 20 h to obtain the first product system. The first product system was filtered and washed with THF, and the washing liquid was collected. The resin obtained was mPEG2000-sulfonyl chloride resin, and the weight of the resin after drying increased to 1.68 g (the increase in the resin weight is the grafted amount of mPEG2000), and the purity of the product at this step was 100%, and no further purification was required.
Second step

Add 41 mg of KOtBu and 1 mL of dry THF in an ice bath, stir for 30 min, then add 45 μL/400 μL of acetone glycerol THF solution, and continue to react in an ice bath for 2 h to obtain a reaction intermediate system. Then, add 1.68 g of the resin from the first step and 12 mL of dry THF to the reaction intermediate system, slowly warm the system to 65° C., and perform a substitution reaction for 20 h to obtain a second product system, which is cooled to room temperature and filtered, and the resin is washed with ice water and THF in sequence, and then prepared for regeneration. The washings are collected, and the THF is rotary evaporated, and the aqueous phase is extracted with DCM three times, and the DCM phase is concentrated to obtain mPEG2000-acetone glycerol.
Third step: mPEG2000-acetone glycerol was added to 2 mol/L hydrochloric acid solution and hydrolyzed at 60° C. for 8 h 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 about 95%.
Example 3

Regeneration of sulfonyl chloride resin: 10 g of the resin after producing mPEG200-Gly (see Example 2 or 3) was taken, 20 mL of thionyl chloride was added, and the mixture was refluxed for more than 8 hours, after which the excess thionyl chloride was distilled off. The remaining system was placed in an ice bath and rapidly washed with ice water and acetone in that order. Finally, the resin was dried under reduced pressure at 40°C to obtain the regenerated sulfonyl chloride resin.

Recovery of mPEG2000 mother liquor: The DCM phase in Example 1 was rotary evaporated and concentrated to obtain recovered mPEG2000; in Example 2, the THF/water mixture was rotary evaporated, and the remaining water phase was extracted with DCM three times, and the resulting DCM phase was rotary evaporated to obtain recovered mPEG2000.
First step

Mixture: In an ice bath, 1 g of regenerated sulfonyl chloride resin, 2 g of NaOH, and 25 mL of THF were added to a 250 mL four-neck flask, stirred, and allowed to expand to obtain a mixture.

Solution: In an ice bath, the recovered mPEG2000 was added to a 100 mL four-neck flask and 2 g of mPEG2000 was added, followed by 50 mL of THF to dissolve the substrate.

The prepared solution was slowly added dropwise to the mixture to form a reaction system, and then the reaction system was slowly warmed to room temperature to carry out the esterification reaction for 20 h to obtain the first product system. The first product system was filtered and washed with ice water and THF in sequence, and the washings were collected. The resulting resin was mPEG2000-sulfonyl chloride resin, and the weight of the resin after drying increased to 1.70 g (the increase in the resin weight is the grafted amount of mPEG2000), and the purity of the product in this step was 100%, and no further purification was required.
Second step

In an ice bath, 41 mg of KOtBu and 1 mL of dry THF were added, and after stirring for 30 min, a solution of acetone glycerol in THF (45 μL/400 μL) was added, followed by reaction in an ice bath for 2 h to obtain a reaction intermediate system. Then, 1.70 g of the resin from the first step and 12 mL of dry THF were added to the reaction intermediate system, and the system was slowly warmed to room temperature and then to 65° C., and the substitution reaction was carried out for 20 h to obtain a second product system, which was cooled to room temperature and filtered, and the resin was washed with ice water and THF in sequence, and then prepared for regeneration. The washings were collected, and the THF was rotary evaporated, and the aqueous phase was extracted with DCM three times, and the DCM phase was concentrated to obtain mPEG2000-acetone glycerol.
Third step: mPEG2000-acetone glycerol was added to 2 mol/L hydrochloric acid solution and hydrolyzed at 60° C. for 8 h 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 about 95%.
Example 4
The difference between Example 4 and Example 2 is that the mass of mPEG2000 used was 0.9 g, and the weight of the resin after treatment increased to 1.25 g.
Second step

In an ice bath, 20 mg of KOtBu and 0.5 mL of dry THF were added, and after stirring for 30 min, a THF solution of acetone glycerol (20 μL/200 μL) was added, followed by reaction in an ice bath for 2 h to obtain a reaction intermediate system. Then, 1.25 g of the resin from the first step and 12 mL of dry THF were added to the reaction intermediate system, and the system was slowly heated to 65° C. and reacted for 20 h to obtain a second product system, which was cooled to room temperature and filtered, and the resin was washed with ice water and THF in sequence, and then prepared for regeneration. The washings were collected, and the THF was rotary evaporated, and the aqueous phase was extracted with DCM three times, and the DCM phase was concentrated to obtain mPEG2000-acetone glycerol.
Third step: mPEG2000-acetone glycerol was added to 2 mol/L hydrochloric acid solution and hydrolyzed at 60° C. for 8 h 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 about 97%.
Example 5

The difference between Example 5 and Example 2 is that the mass of mPEG2000 used in the first step was 4 g, and the weight of the resin after the treatment increased to 1.65 g. After the second and third steps, mPEG2000-Gly was finally obtained with a yield of 70% and a product purity of 95%.
Example 6

The difference between Example 6 and Example 2 is that the mass of mPEG2000 used in the first step was 0.5 g, and the weight of the resin after the treatment increased to 1.12 g. After the second and third steps, mPEG2000-Gly was finally obtained with a yield of 58% and a product purity of 96%.
(Example 7)

The difference between Example 7 and Example 2 is that the mass of mPEG2000 used in the first step was 8 g, and the weight of the resin after the treatment increased to 1.68 g, that is, increasing the amount of mPEG2000 used had no benefit in terms of the grafting amount of PEG. After the second and third steps, mPEG2000-Gly was finally obtained with a yield of 71% and a product purity of 92%.
(Example 8)

The difference between Example 8 and Example 2 is that the sulfonyl chloride resin in the first step is a self-made resin obtained by derivatizing and modifying the commercial resin 001*7, the sulfonyl chloride content is 4.61 mmol/g, the modification method is the same as that in "Preparation of polystyrene sulfonyl chloride resin and its use in the synthesis of nitrogen-containing basic resin", and the weight of the resin after treatment increases to 1.86 g. After the second and third steps, mPEG2000-Gly is finally obtained, with a yield of 69% and a product purity of 91%.
(Example 9)

The difference between Example 9 and Example 2 is that the polyethylene glycol used in the first step was 0.3 g of mPEG ₄ , the mass of the sulfonyl chloride resin was 1 g, 1.19 g of PEG-grafted resin was obtained, and the reaction in the second step was completed using 1.5 eq of potassium tert-butoxide and 2 eq of acetone glycerol based on the loading amount of PEG grafted to the resin, and finally, the weight of mPEG _4- Gly obtained by hydrolysis was 0.17 g, the yield was 89%, and the purity was 89%.
(Example 10)

The difference between Example 10 and Example 2 is that in the first step, the polyethylene glycol was 0.6 g of mPEG ₈ , the mass of the sulfonyl chloride resin was 1 g, and the weight of the finally obtained mPEG ₈ -Gly was 0.31 g, the yield was 76%, and the purity was 92%.
Example 11

The difference between Example 11 and Example 2 is that in the first step, the molecular weight of the polyethylene glycol was 3500, the mass was 4.4 g, the mass of the sulfonyl chloride resin was 1 g, and the finally obtained mPEG3500-Gly was 0.75 g, the yield was 77%, and the purity was 97%.
Example 12

The difference between Example 12 and Example 2 is that in the first step, the molecular weight of the polyethylene glycol was 5000, the mass was 7.5 g, the mass of the sulfonyl chloride resin was 1 g, the weight of the resin obtained in the first step increased to 2.36 g, and the finally obtained mPEG5000-Gly was 1.1 g, the yield was 81%, and the purity was 98%.
Example 13

The difference between Example 13 and Example 2 is that in the first step, the molar ratio of sodium hydroxide to mPEG2000 was 10:1, and the weight of the resulting resin grafted with PEG increased to 1.43 g. After the second and third steps, mPEG2000-Gly was finally obtained with a yield of 75% and a purity of 95%.
(Example 14)

The difference between Example 14 and Example 2 is that in the first step, the molar ratio of sodium hydroxide to mPEG2000 was 50:1, and the weight of the resulting resin grafted with PEG increased to 1.68 g. After the second and third steps, mPEG2000-Gly was finally obtained with a yield of 72% and a purity of 95%.
(Example 15)

The difference between Example 15 and Example 2 is that in the first step, the molar ratio of sodium hydroxide to mPEG2000 was 8:1, and the weight of the resulting PEG-grafted resin increased to 1.29 g. The final yield of mPEG2000-Gly was 71%, and the purity of the product was 94%.
(Example 16)

The difference between Example 16 and Example 2 is that in the first step, pyridine was used as an acid binder, the weight of the resulting PEG-grafted resin increased to 1.21 g, the final yield of mPEG2000-Gly was 68%, and the purity of the product was 92%.
(Example 17)

The difference between Example 17 and Example 2 is that in the first step, DMAP was added as a catalyst, the molar ratio of DMAP to mPEG2000 was 0.05:1, the weight of the resulting PEG-grafted resin increased to 1.81 g, and 0.55 g of mPEG2000-Gly was finally obtained, with a yield of 71% and a purity of 96%.
(Example 18)

The difference between Example 18 and Example 2 is that in the first step, DMAP was added as a catalyst, the molar ratio of DMAP to mPEG2000 was 2.2:1, the weight of the resulting PEG-grafted resin increased to 1.89 g, and finally 0.59 g of mPEG2000-Gly was obtained, with a yield of 69% and a purity of 95%.
(Example 19)

The difference between Example 19 and Example 2 is that in the first step, DMAP was added as a catalyst, the molar ratio of DMAP to mPEG2000 was 0.03:1, the weight of the resulting PEG-grafted resin increased to 1.68 g, and 0.49 g of mPEG2000-Gly was finally obtained, the yield was 72%, and the purity of the product was about 95%.
(Example 20)

The difference between Example 20 and Example 2 is that in the first step, the esterification reaction temperature was 90° C., the esterification reaction time was 8 h, and the weight of the resin to which PEG was grafted increased from 1 g to 1.33 g, which was smaller than that in Example 2. The final mPEG2000-Gly was 0.22 g, the yield was 67%, and the purity of the product was about 97%.
(Example 21)

The difference between Example 21 and Example 2 is that in the second step, the strong basic reagent was NaH, the final amount of mPEG2000-Gly was 0.3 g, the yield was 44%, and the purity of the product was about 82%.
(Example 22)

The difference between Example 22 and Example 2 is that in the second step, potassium tert-butoxide and acetone glycerol were reacted at 25°C for 4 hours to obtain a reaction intermediate system, and the final yield of mPEG2000-Gly was 70%, and the purity of the product was 85%.
(Example 23)
The differences between Example 23 and Example 2 are as follows.

In the second step, the resin from the first step and 12 mL of dry THF were added to the reaction intermediate system, the system was slowly restored to room temperature, and reacted for 20 h to obtain the second product system, after the reaction was completed, the system was filtered, and the resin was washed with ice water and THF in sequence, and then prepared for regeneration. The washings were collected, and the THF was rotary evaporated, after which the aqueous phase was extracted with DCM three times, and the DCM phase was concentrated to obtain mPEG2000-acetone glycerol.
Third step: mPEG2000-acetone glycerol was added to 2 mol/L hydrochloric acid solution and hydrolyzed at 60° C. for 8 h 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 24)

The difference between Example 24 and Example 2 is that in the second step reaction, after the system was returned to room temperature, the reaction was continued for 48 h to obtain a second product system, and after the obtained intermediate was hydrolyzed, the weight of the final product mPEG-Gly was 0.42 g, the yield was 62%, and the purity of the product was about 92%.
(Example 25)

The difference between Example 25 and Example 2 is that in the third step, the concentration of the hydrochloric acid solution used in the hydrolysis reaction was 1 mol/L, and mPEG2000-Gly was finally obtained with a yield of 72% and a product purity of 88%.
(Example 26)

The difference between Example 26 and Example 2 is that in the third step, the hydrolysis temperature was 80° C., the hydrolysis time was 5 hours, the yield of the final mPEG2000-Gly was 74%, and the purity of the product was 91%.
The types, yields and purities of the polyethylene glycol-glycerin derivatives obtained in the above Examples 1 to 26 are shown in Table 1.

As can be seen from the data in Table 1 above, compared to Examples 2, 4, and 5, when the ratio of mPEG2000:sulfonyl chloride resin in Example 6 is 1:7.12, i.e. outside the range, the amount of mPEG grafted per gram of resin in the first step reaction is significantly reduced, and when the ratio of mPEG2000:sulfonyl chloride resin in Example 7 is 1:0.445, i.e. outside the range, the amount of mPEG grafted per gram of resin in the first step reaction does not significantly decrease, but there is a large waste of the mPEG2000 raw material.

Compared to Examples 2, 13, and 14, when the molar ratio of the acid binder to polyethylene glycol in Example 15 was outside the range, the amount of mPEG grafted per gram of resin in the first step reaction of Example 15 was clearly reduced.

Compared to Examples 2, 17, and 18, in Example 19, the effect of adding too little DMAP catalyst was almost the same as the effect of adding no DMAP catalyst.
As can be seen from the above description, the above embodiments of the present invention can achieve the following technical advantages:

In the present application, the resin polymer solid-phase characteristics of sulfonyl chloride resin can be utilized to produce a product system containing a polyethylene glycol-glycerin derivative intermediate using a solid-phase synthesis method. Specifically, the sulfonyl chloride group in the sulfonyl chloride resin and the hydroxyl group in the polyethylene glycol are esterified to release small molecule hydrogen chloride, and the resulting first product system can be separated and used in the subsequent reaction by simply performing a simple solid-liquid separation method. Due to the polymer insolubility of the polyethylene glycol-glycerin derivative intermediate, the subsequent reaction other than the hydrolysis reaction is still a solid-phase synthesis reaction, and the resulting product system can still be separated and purified using a simple solid-liquid separation method. Compared with the conventional synthetic route for PEG-Gly using liquid-phase small molecules, the complicated separation and purification operations in multiple steps in liquid-phase synthesis can be avoided, the separation and purification operations can be greatly simplified, and the target product can be obtained more easily with a high yield and high purity. In addition, all of the reagents used in the manufacturing process can be recycled, greatly reducing the process cost.

The above is merely a preferred embodiment of the present invention, and is not intended to limit the present invention. Those skilled in the art may make various modifications and changes to the present invention. Any modifications, equivalent replacements, improvements, etc. made within the scope of the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims (18)

The method includes esterifying a raw material including a polyethylene glycol having at least one hydroxyl end group and a sulfonyl chloride resin to obtain a first product system including a polyethylene glycol-glycerin derivative intermediate;
Here, the sulfonyl chloride resin is a polystyrene resin containing a sulfonyl chloride group, and the structural formula of the sulfonyl chloride resin is
The present invention relates to a method for producing a polyethylene glycol-glycerin derivative intermediate. 1 g of the sulfonyl chloride resin contains 1.78 to 4.61 mmol of sulfonyl chloride groups;
The method according to claim 1 . The sulfonyl chloride resin is any one or more selected from HC9001-1-1 sulfonyl chloride resin and a derivative sulfonyl chloride resin of commercially available strong acid resin 001*7;
The method according to claim 2 . The molecular weight of the polyethylene glycol is 194 to 5000.
The method according to any one of claims 1 to 3. the molar ratio of the polyethylene glycol to the sulfonyl chloride group of the sulfonyl chloride resin is 1:0.9-4, and another terminal group of the polyethylene glycol is a hydroxyl group or a protecting group functional group;
The method according to claim 4 . the protecting group functional group is any one selected from a methoxy group, a tert-butoxy group, and a benzyloxy group;
The method according to claim 5 . The polyethylene glycol-glycerin derivative intermediate has the structure represented by Formula I:
The method according to claim 6 .
Formula I The raw material further comprises an acid binder.
The method according to any one of claims 1 to 3. the molar ratio of the acid binder to the polyethylene glycol is 10 to 50:1, and the acid binder is one or more selected from NaOH, KOH, triethylamine, and pyridine;
The method according to claim 8 . The feedstock further comprises a catalyst.
The method according to any one of claims 1 to 3. the molar ratio of the catalyst to the polyethylene glycol is 0.05-2.2:1, and the catalyst is a basic substance;
The method according to claim 10 . The basic substance is 4-dimethylaminopyridine.
The method according to claim 11 . The temperature of the esterification reaction is 0 to 90° C., and the time of the esterification reaction is 4 to 72 h.
The method according to any one of claims 1 to 3. The method further includes subjecting the first product system to a first solid-liquid separation to obtain the polyethylene glycol-glycerin derivative intermediate.
The method according to claim 1 . A method for producing a polyethylene glycol-glycerin derivative, the polyethylene glycol-glycerin derivative having a structure represented by formula II:
The manufacturing method includes:
Step S1 of obtaining a polyethylene glycol-glycerin derivative intermediate by using the production method according to any one of claims 1 to 14;
Step S2 of carrying out a substitution reaction between the polyethylene glycol-glycerin derivative intermediate and acetone glycerol to obtain a compound 1 having a structure represented by formula III;
and step S3 of hydrolyzing the compound 1 to obtain the polyethylene glycol-glycerin derivative.
The present invention relates to a method for producing a polyethylene glycol-glycerin derivative. The step S2 is
Reacting a strongly basic reagent with acetone glycerol at 0-25° C. to obtain a reaction intermediate system;
subjecting the reaction intermediate system to the substitution reaction with the polyethylene glycol-glycerin derivative intermediate at 0-65° C. to obtain a second product system comprising the compound 1;
subjecting the second product system to a second solid-liquid separation to obtain a solid phase and a liquid phase;
and subjecting the liquid phase to extraction and separation to obtain compound 1.
The method according to claim 15 . The strong basic reagent is at least one selected from the group consisting of KOtBu, NaH, and butyllithium;
The reaction time is 1 to 4 hours, and the substitution reaction time is 15 to 24 hours;
The method further includes washing the solid phase to obtain a regenerated sulfonyl chloride resin, and using the regenerated sulfonyl chloride resin in the esterification reaction of step S1;
The reaction is carried out in an ice bath.
The method according to claim 16 . The H ⁺ concentration of the hydrolysis reaction is 0.1-4 mol/L, the temperature of the hydrolysis reaction is 40-80° C., and the time of the hydrolysis reaction is 2-24 h;
The method according to claim 16 .