KR20250003949A - Method for producing polyethylene glycol-glycerol derivatives and intermediates thereof - Google Patents

Abstract

The present invention provides a method for producing a polyethylene glycol-glycerol derivative and an intermediate thereof. The method comprises a step of performing an esterification reaction on a raw material including polyethylene glycol and a sulfonyl chloride resin to obtain a first product system including a polyethylene glycol-glycerol derivative intermediate, wherein at least one terminal group of the polyethylene glycol is a hydroxyl group, and the sulfonyl chloride resin is a polystyrene resin containing a sulfonyl chloride group. By utilizing the solid-phase properties of the resin polymer of the sulfonyl chloride resin, a product system including a polyethylene glycol-glycerol derivative intermediate can be obtained by a solid-phase synthesis method, and the obtained product system can be used for a subsequent reaction by separating the polyethylene glycol-glycerol derivative intermediate only by a simple solid-liquid separation method, thereby greatly simplifying the separation and purification work, and making it easier to obtain a target product having a high yield and high purity. In addition, all reagents used in the manufacturing process can be recycled, thereby greatly reducing the cost.

Description

Method for producing polyethylene glycol-glycerol derivatives and intermediates thereof

This application claims priority to Chinese application having CN application number 202210424440.4 and filing date April 22, 2022, the entire disclosure of which is incorporated herein by reference.

The present invention relates to the field of technology for producing polyethylene glycol-glycerol derivatives, and more specifically, to a method for producing polyethylene glycol-glycerol derivatives and intermediates thereof.

Polyethylene glycol (PEG) is a polymer with the H(OCH ₂ -CH ₂ ) _n OH structure, and PEG, an amphiphilic molecule, can be dissolved in not only water but also organic solvents. Therefore, even a substance that is poorly soluble in water can be converted into a hydrophilic substance when coupled with PEG. In drug development research, coupling modified polyethylene glycol to proteins, peptides, small molecule organic drugs, and liposomes by certain means can increase the half-life of protein or peptide drugs in the body, reduce immunogenicity, and increase the water solubility and targetability of the drugs. The combination of modified PEG and liposomes can also enable liposomes to have a stronger passive targeting effect on tumors. Therefore, the development of a highly efficient and simple PEG modification process has important research implications in the fields of biotechnology and drug development.

Modifications of PEG include modification of active functional groups such as polyethylene glycol-maleimide derivatives (PEG-Mal), polyethylene glycol-succinimide derivatives (PEG-NHS), and polyethylene glycol-aldehyde derivatives (PEG-ALD), and also preparation of polyethylene glycol-glycerol derivatives (PEG-Gly) for PEG synthetic intermediates or liposomes. Existing PEG modification processes are generally liquid-phase syntheses of small molecules, for example, the preparation processes of PEG-Mal and PEG-CM (polyethylene glycol carboxyl derivatives) in the U.S. patents of Patent Application Nos. US6828401 and US10752732 involve multi-step cumbersome separation and purification operations, making it difficult to achieve high purity of the target product.

The preparation of PEG-Gly for PEG synthetic intermediates or liposomes also faces the above problems, and there are currently two processes for the preparation of PEG-Gly. One is to substitute the terminal hydroxyl group of PEG with epichlorohydrin, and then perform hydrolysis and ring opening of the epoxy group to obtain the target product; another is to firstly perform an esterification reaction of PEG with p-toluenesulfonyl chloride, and then perform substitution with activated Solketal, and then perform acidolysis of the obtained intermediate to obtain the target product, for example, in the Chinese patent application publication number CN102665685A, the process is as follows. Regardless of the above-mentioned route, the separation and extraction work of the intermediate product is necessary, otherwise it may further contaminate the subsequent target product, so the multi-step separation process not only makes the entire preparation process cumbersome, but also increases the process production cost.

The main purpose of the present invention is to provide a method for producing a polyethylene glycol-glycerol derivative and an intermediate thereof to solve the problems of the prior art in that the production process of PEG-Gly is cumbersome and expensive.

In order to achieve the above object, according to one aspect of the present invention, a method for producing a polyethylene glycol-glycerol derivative intermediate is provided, the method comprising the step of performing an esterification reaction on a raw material including polyethylene glycol and a sulfonyl chloride resin to obtain a first product system including a polyethylene glycol-glycerol derivative intermediate, wherein at least one terminal group of the polyethylene glycol is a hydroxyl group, the sulfonyl chloride resin is a polystyrene resin containing a sulfonyl chloride group, and the structural formula of the sulfonyl chloride resin is It is displayed as .

Further, 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, sulfonyl chloride resin derived from commercial strong acid resin 001*7.

Further, 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 functional group, preferably, the protecting functional group is any one selected from methoxy, tert-butoxy, and benzyloxy, preferably methoxy, and preferably, the polyethylene glycol-glycerol derivative intermediate has a structure represented by Formula I.

Food I

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

Further, the raw material further comprises a catalyst, preferably, the molar ratio of the catalyst to polyethylene glycol is 0.05 to 2.2:1, preferably, the catalyst is an alkaline substance, preferably, the alkaline substance is 4-dimethylaminopyridine.

Further, the esterification reaction temperature is 0 to 90°C, and preferably, the esterification reaction time is 4 to 72 hours.

Further, the above manufacturing method further comprises a step of subjecting the first product system to primary solid-liquid separation to obtain a polyethylene glycol-glycerol derivative intermediate, and preferably, the primary solid-liquid separation is filtration.

According to another aspect of the present invention, a method for producing a polyethylene glycol-glycerol derivative is provided, wherein the polyethylene glycol-glycerol derivative has a structure represented by formula II.

Food II

The manufacturing method comprises: step S1 of obtaining a polyethylene glycol-glycerol derivative intermediate using the above manufacturing method; step S2 of subjecting the polyethylene glycol-glycerol derivative intermediate to a substitution reaction with Solketal to obtain compound 1, wherein compound 1 has a structure represented by formula III; and

Food III

It includes step S3 of obtaining a polyethylene glycol-glycerol derivative by hydrolyzing compound 1.

Further, the step S2 includes a step of reacting a strong alkaline reagent with a solketal at 0 to 25°C to obtain a reaction intermediate system; a step of subjecting the reaction intermediate system to a substitution reaction with a polyethylene glycol-glycerol derivative intermediate at 0 to 65°C to obtain a second product system including compound 1, and a step of performing a secondary solid-liquid separation of the second product system to obtain a solid phase and a liquid phase; and a step of extracting and separating the liquid phase to obtain compound 1. Preferably, the strong alkaline reagent is one or more selected from KOtBu, NaH, and butyllithium, preferably, the reaction time is 1 to 4 hours, preferably, the substitution reaction time is 15 to 24 hours, and preferably, the production method further includes a step of washing the solid phase to obtain a regenerated sulfonyl chloride resin, and preferably, using the regenerated sulfonyl chloride resin in the esterification reaction of step S1, preferably, the secondary solid-liquid separation is filtration, and preferably, the reaction is performed in an ice bath.

Further, the H ⁺ concentration of the hydrolysis reaction is 0.1 to 4 mol/L, preferably, the hydrolysis reaction temperature is 40 to 80°C, and preferably, the hydrolysis reaction time is 2 to 24 hours.

According to the technical solution of the present invention, the present application can manufacture a product system including a polyethylene glycol-glycerol derivative intermediate by a solid-phase synthesis method by utilizing the resin polymer solid-phase characteristics of a sulfonyl chloride resin, and specifically, the first product system obtained by removing small molecule hydrogen chloride through an esterification reaction of a sulfonyl chloride group in a sulfonyl chloride resin and a hydroxyl group in polyethylene glycol can be used for a subsequent reaction by separating the polyethylene glycol-glycerol derivative intermediate only by a simple solid-liquid separation method. Due to the polymer insolubility of the polyethylene glycol-glycerol 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, so that compared with the existing liquid-phase small molecule synthesis route of PEG-Gly, the cumbersome multi-step separation and purification work performed in the liquid-phase synthesis is not necessary, and the separation and purification work is greatly simplified, and the target product with high yield and high purity is more easily obtained. In addition, all reagents used in the manufacturing process can be recycled, which greatly reduces the process cost.

The specification and drawings, which form a part of this application, are intended to provide a further understanding of the present invention, and the exemplary embodiments of the present invention and the description thereof are intended only to explain the present invention and do not inappropriately limit the present invention. The drawings are as follows:
FIG. 1 is a schematic diagram illustrating the results of high-resolution liquid mass spectrometry (TOF) detection of mPEG2000-Gly provided according to Example 1 of the present invention.

It should be noted that the embodiments and features of the embodiments of the present application may be combined with each other, unless they are contradictory. Hereinafter, the present invention will be described in detail with reference to the attached drawings and embodiments.

As analyzed in the background art, the conventional PEG-Gly manufacturing process has the problems of being cumbersome and expensive. To solve these problems, the present invention provides a method for manufacturing a polyethylene glycol-glycerol derivative and an intermediate thereof.

In a typical embodiment of the present application, a method for producing a polyethylene glycol-glycerol derivative intermediate is provided, the method comprising the step of performing an esterification reaction on a raw material comprising polyethylene glycol and a sulfonyl chloride resin to obtain a first product system comprising a polyethylene glycol-glycerol derivative intermediate, wherein at least one terminal group of the polyethylene glycol is a hydroxyl group, the sulfonyl chloride resin is a polystyrene resin containing a sulfonyl chloride group, and the structural formula of the sulfonyl chloride resin is It is displayed as .

The present application utilizes the solid-state properties of a sulfonyl chloride resin to produce a product system including a polyethylene glycol-glycerol derivative intermediate by a solid-state synthesis method, and specifically, the first product system obtained by removing small molecule hydrogen chloride through an esterification reaction of a sulfonyl chloride group in a sulfonyl chloride resin and a hydroxyl group in polyethylene glycol can separate the polyethylene glycol-glycerol derivative intermediate by a simple solid-liquid separation method and use it in a subsequent reaction. Due to the polymer insolubility of the polyethylene glycol-glycerol derivative intermediate, in addition to the hydrolysis reaction, the subsequent reaction is still a solid-state synthesis reaction, and the obtained product system can still be separated and purified by a simple solid-liquid separation method, so that compared with the existing liquid-phase small molecule synthesis route of PEG-Gly, the cumbersome multi-step separation and purification work performed in the liquid-phase synthesis is not necessary, and the separation and purification work is greatly simplified, and the target product with high yield and high purity is more easily obtained. In addition, all reagents used in the manufacturing process can be recycled, which greatly reduces the process cost.

It should be noted that one of the above sulfonyl chloride resins contains at least one sulfonyl chloride group linked to a corresponding benzene ring side chain position. 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 a plurality selected from HC9001-1-1 sulfonyl chloride resin, sulfonyl chloride resin derived from commercial 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 commercially available sulfonyl chloride resin derived from strong acid resin 001*7 uses strong acid resin 001*7 as a reaction raw material, and “ A corresponding sulfonyl chloride resin is prepared by the preparation method disclosed in “(Preparation of polystyrene sulfonyl chloride resin and its application in the synthesis of nitrogen-containing alkaline resin)”.

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 terminal group of the polyethylene glycol is a hydroxyl group or a protecting functional group, preferably, the protecting functional group is any one selected from methoxy, tert-butoxy, and benzyloxy, preferably methoxy, and preferably, the polyethylene glycol-glycerol derivative intermediate has a structure represented by Formula I.

Food I

In the above formula I, the n value is the degree of polymerization of polyethylene glycol, which can be obtained by dividing the molecular weight by the molecular weight of the repeating unit, and n is approximately 4 to 113.

The molar ratio range of polyethylene glycol and the sulfonyl chloride group of the polyethylene glycol to the sulfonyl chloride resin in the above molecular weight range can provide a polyethylene glycol-glycerol derivative intermediate having a wider molecular weight range, and the molar ratio range of the sulfonyl chloride group of the polyethylene glycol to the sulfonyl chloride resin is advantageous in improving the efficiency of the esterification reaction between polyethylene glycol and sulfonyl chloride resin having different molecular weights, so that an abundant polyethylene glycol-glycerol derivative is obtained by grafting polyethylene glycol onto the solid-state sulfonyl chloride resin as much as possible, and preferably, a polyethylene glycol-glycerol derivative intermediate having a structure represented by Formula I can correspond to a polyethylene glycol-glycerol derivative which is more suitable for the current market demand.

In one embodiment of the present application, the raw material further comprises an acid binder, and preferably, the molar ratio of the acid binder to polyethylene glycol is 10 to 50:1, and preferably, the acid binder is one or more selected from NaOH, KOH, triethylamine, and pyridine. The esterification reaction requires removal of hydrogen chloride molecules, and preferably, it is advantageous to promote the performance of the esterification reaction by removing hydrogen chloride molecules as much as possible under the action of the acid binder.

Preferably, the raw material further comprises a catalyst, preferably, the molar ratio of the catalyst to polyethylene glycol is 0.05 to 2.2:1, preferably, the catalyst is an alkaline substance, preferably, the alkaline substance is 4-dimethylaminopyridine, thereby promoting the performance of the esterification reaction.

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

In one embodiment of the present application, the manufacturing method further comprises a step of performing a first solid-liquid separation on the first product system to obtain a polyethylene glycol-glycerol derivative intermediate, and preferably, the first solid-liquid separation is filtration. Since the polyethylene glycol-glycerol derivative intermediate is insoluble in an organic solvent (including a low molecular weight polyethylene glycol) and a high molecular weight polyethylene glycol is a solid, the polyethylene glycol-glycerol derivative intermediate does not dissolve in an excess amount of polyethylene glycol, and thus the polyethylene glycol-glycerol derivative intermediate can be separated by simple filtration alone.

In another typical embodiment of the present application, a method for preparing a polyethylene glycol-glycerol derivative is provided, wherein the polyethylene glycol-glycerol derivative has a structure represented by formula II,

Food II

The above manufacturing method comprises: step S1 of obtaining a polyethylene glycol-glycerol derivative intermediate using the above manufacturing method; step S2 of subjecting the polyethylene glycol-glycerol derivative intermediate to a substitution reaction with solketal to obtain compound 1, wherein compound 1 has a structure represented by formula III; and

Food III

It includes step S3 of obtaining a polyethylene glycol-glycerol derivative by hydrolyzing compound 1.

In steps S1 and S2 of the manufacturing method of the present application, since both a solid-phase synthesis method is used, the obtained product system can separate the target product through simple solid-liquid separation, and finally, compound 1 having a structure represented by formula III can obtain a polyethylene glycol-glycerol derivative through a hydrolysis reaction, and finally, the polyethylene glycol-glycerol derivative can be obtained in high yield through simple extraction. From this, it can be seen that, compared with the existing liquid-phase small molecule synthesis route of PEG-Gly, multi-step cumbersome separation and purification work performed in liquid-phase synthesis is not necessary, so the separation and purification work is greatly simplified, and the target product with high yield and high purity is obtained more easily. In addition, all reagents used in the manufacturing process can be recycled, which greatly reduces the process cost.

In one embodiment of the present application, the step S2 includes: a step of reacting a strong alkaline reagent with a solketal at 0 to 25°C to obtain a reaction intermediate system; a step of subjecting the reaction intermediate system to a substitution reaction with a polyethylene glycol-glycerol derivative intermediate at 0 to 65°C to obtain a second product system including compound 1, a step of performing a secondary solid-liquid separation of the second product system to obtain a solid phase and a liquid phase; and a step of extracting and separating the liquid phase (for example, extracting and separating the obtained liquid phase three times with dichloromethane) to obtain compound 1. Preferably, the strong alkaline reagent is one or more selected from KOtBu, NaH, and butyllithium, preferably, the reaction time is 1 to 4 hours, preferably, the substitution reaction time is 15 to 24 hours, preferably, the secondary solid-liquid separation is filtration, and preferably, the reaction is performed in an ice bath.

The above reaction removes hydrogen from the solketal hydroxyl group through strong alkaline action to obtain an oxygen anion intermediate. Since this reaction is clearly exothermic and therefore dangerous, it is preferable to first react under the above conditions to generate a large amount of oxygen anion intermediate, and then perform a substitution reaction with the oxygen anion intermediate and a solid polyethylene glycol-glycerol derivative intermediate to obtain a second product system including a structure represented by Formula III, and then utilize the insolubility of compound 1 to isolate compound 1 through simple filtration, and then perform a hydrolysis reaction of compound 1 to obtain a polyethylene glycol-glycerol derivative.

Also preferably, the manufacturing method further comprises a step of washing the solid phase to obtain a regenerated sulfonyl chloride resin, and preferably using the regenerated sulfonyl chloride resin in the esterification reaction of step S1, thereby significantly reducing the cost and making it more environmentally friendly.

In order to improve the efficiency of the above hydrolysis reaction, preferably, the H ⁺ concentration of the hydrolysis reaction is 0.1 to 4 mol/L, preferably, the hydrolysis reaction temperature is 40 to 80°C, and preferably, the hydrolysis reaction time is 2 to 24 hours.

Hereinafter, the beneficial effects of the present application will be described with reference to specific examples and comparative examples.

The sulfonyl chloride resin used in the examples below can be purchased directly or from DOI:10.1007/s00289-005-0417-y or “ (Production of polystyrene sulfonyl chloride resin and its application in the synthesis of nitrogen-containing alkaline resin)” can be obtained using the production method disclosed in “Production of polystyrene sulfonyl chloride resin and its application in the synthesis of nitrogen-containing alkaline resin”.

Example 1

Step 1:

Mixture: 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 flask at room temperature, and stirred and swelled 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 4-necked flask, and after the substrate was completely dissolved, 30 mg of 4-dimethylaminopyridine (DMAP), 4 mL of triethylamine were added and stirring was continued for 15 minutes.

The above mixture was placed in an ice bath, and the solution prepared above was slowly added dropwise to form a reaction target system, and then the reaction target system was slowly warmed to room temperature and esterification reaction was performed 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 obtained resin is mPEG2000-sulfonyl chloride resin, and after drying, the weight of the resin increases to 1.37 g (the weight increase of the resin is the grafting amount of mPEG2000), and the purity of the product at this stage is 100%, and no additional purification is required.

Step 2:

In an ice bath, 22 mg of KOtBu and 0.5 mL of dry THF were added, stirred for 30 minutes, then a THF solution (25 μL/200 μL) of solketal (the concentration of solketal itself is close to 100%) was added, and the reaction was continued for 2 hours in an ice bath to obtain a reaction intermediate system. Then, 1.37 g of the resin of the first step and 12 mL of dry THF were added to the reaction intermediate system, 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 cooled to room temperature and filtered, and the resin was washed sequentially with ice water and THF to prepare for regeneration. The washings were collected, THF was rotary evaporated, the aqueous phase was extracted three times with DCM, and the DCM phase was concentrated to obtain mPEG2000-solketal.

Step 3:

mPEG2000-solketal was added to 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 used resin was reduced to 1.02 g, i.e., the grafted PEG was almost completely substituted. The weight of mPEG2000-Gly was 0.25 g, the yield was 68%, and the product purity was about 95%. Here, the high-resolution liquid mass spectrometry (TOF) detection result of mPEG2000-Gly is shown in Fig. 1.

Example 2

Step 1:

Mixture: In an ice bath, a 250 mL four-necked flask was added 1 g of sulfonyl chloride resin (same as in Example 1), 2 g of NaOH and 25 mL of THF, stirred and swelled to obtain a mixture.

Solution: In an ice bath, add 2.5 g of mPEG2000 and 50 mL of THF to a 100 mL 4-necked flask and wait until the substrate is completely dissolved.

The solution prepared above was slowly added dropwise to the mixture to form a reaction target system, and then the reaction target system was slowly heated to room temperature and esterification reaction was performed 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 obtained resin is mPEG2000-sulfonyl chloride resin, and after drying, the weight of the resin increases to 1.68 g (the weight increase of the resin is the grafting amount of mPEG2000), and the purity of the product at this stage is 100%, and no additional purification is required.

Step 2:

In an ice bath, 41 mg of KOtBu and 1 mL of dry THF were added, stirred for 30 minutes, 45 μL/400 μL of a THF solution of solketal was added, and the reaction was continued for 2 hours in an ice bath to obtain a reaction intermediate system. Then, 1.68 g of the resin of the first step and 12 mL of dry THF were added to the reaction intermediate system, 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 cooled to room temperature and filtered, and the resin was washed sequentially with ice water and THF to prepare for regeneration. The washings were collected, THF was rotary evaporated, the aqueous phase was extracted three times with DCM, and the DCM phase was concentrated to obtain mPEG2000-solketal.

Step 3:

mPEG2000-solketal was added to 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 used resin was reduced to 1.05 g, the weight of mPEG2000-Gly was 0.49 g, the yield was 72%, and the product purity was about 95%.

Example 3

Regeneration of sulfonyl chloride resin: 10 g of the resin prepared with mPEG2000-Gly (see Example 2 or Example 3) was added to 20 mL of thionyl chloride, and refluxed for more than 8 hours, and the excess thionyl chloride was evaporated. The remaining system was placed in an ice bath, and rapidly washed sequentially with ice water and acetone. 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 of Example 1 was rotary evaporated and concentrated to obtain the recovered mPEG2000; in Example 2, the THF/water mixture solution was rotary evaporated, the remaining aqueous phase was extracted three times with DCM, and the obtained DCM phase was rotary evaporated to obtain the recovered mPEG2000.

Step 1:

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-necked flask, stirred and allowed to swell to obtain a mixture.

Solution: In an ice bath, the recovered mPEG2000 was added to a 100 mL 4-necked flask, 2 g of mPEG2000 was added, and 50 mL of THF was added to dissolve the substrate.

The solution prepared above was slowly added dropwise to the mixture to form a reaction target system, and then the reaction target system was slowly heated to room temperature and esterification reaction was performed for 20 hours to obtain a first product system. The first product system was filtered and washed sequentially with ice water and THF, and the washing solution was recovered. The obtained resin is mPEG2000-sulfonyl chloride resin, and after drying, the weight of the resin increases to 1.70 g (the weight increase of the resin is the grafting amount of mPEG2000), and the purity of the product at this stage is 100%, and no additional purification is required.

Step 2:

In an ice bath, 41 mg of KOtBu and 1 mL of dry THF were added, stirred for 30 minutes, then a THF solution of solketal (45 μL/400 μL) was added, and the reaction was continued for 2 hours in an ice bath to obtain a reaction intermediate system. Then, 1.70 g of the resin of the first step and 12 mL of dry THF were added to the reaction intermediate system, the system was slowly warmed to room temperature, then warmed to 65 °C, and a substitution reaction was performed for 20 hours to obtain a second product system, the second product system was cooled to room temperature and filtered, and the resin was washed sequentially with ice water and THF to prepare for regeneration. The washings were collected, THF was rotary evaporated, the aqueous phase was extracted three times with DCM, and the DCM phase was concentrated to obtain mPEG2000-solketal.

Step 3:

mPEG2000-solketal was added to 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 used resin was reduced to 1.03 g, the weight of mPEG2000-Gly was 0.48 g, the yield was 69%, and the product purity 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 post-treatment increased to 1.25 g.

Step 2:

In an ice bath, 20 mg of KOtBu and 0.5 mL of dry THF were added, stirred for 30 minutes, then a THF solution of solketal (20 μL/200 μL) was added, and the reaction was continued for 2 hours in an ice bath to obtain a reaction intermediate system. Then, 1.25 g of the resin of the first step and 12 mL of dry THF were added to the reaction intermediate system, the system was slowly heated to 65 °C, and reacted for 20 hours to obtain a second product system, the second product system was cooled to room temperature and filtered, and the resin was washed sequentially with ice water and THF to prepare for regeneration. The washings were collected, THF was rotary evaporated, the aqueous phase was extracted three times with DCM, and the DCM phase was concentrated to obtain mPEG2000-solketal.

Step 3:

mPEG2000-solketal was added to 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 used resin was reduced to 1.01 g, the weight of mPEG2000-Gly was 0.19 g, the yield was 76%, and the product purity was about 97%.

Example 5

The difference between Example 5 and Example 2 is that the mass of mPEG2000 used in the first step is 4 g, the weight of the resin increases to 1.65 g after post-treatment, and mPEG2000-Gly is finally obtained through the second and third steps, 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 is 0.5 g, the weight of the resin after post-treatment increases to 1.12 g, and through the second and third steps, mPEG2000-Gly is 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 post-treatment increased to 1.68 g, that is, increasing the amount of mPEG2000 used does not help the grafting amount of PEG, and mPEG2000-Gly was finally obtained through the second and third steps, 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, derived and modified from commercial resin 001*7, the sulfonyl chloride content is 4.61 mmol/g, and the modification method is “ (Production of polystyrenesulfonyl chloride resin and its application in the synthesis of nitrogen-containing alkaline resin)”, and the weight of the resin after post-treatment increases to 1.86 g, and through 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 is 0.3 g of mPEG ₄ , the mass of the sulfonyl chloride resin is 1 g, 1.19 g of the PEG-grafted resin is obtained, and based on the PEG loading amount grafted onto the resin, 1.5 eq of potassium tert-butoxide and 2 eq of solketal were used to complete the second step reaction, and the weight of mPEG ₄ -Gly finally obtained through hydrolysis is 0.17 g, the yield is 89%, and the purity is 89%.

Example 10

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

Example 11

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

Example 12

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

Example 13

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

Example 14

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

Example 15

The difference between Example 15 and Example 2 is that the molar ratio of sodium hydroxide to mPEG2000 in the first step is 8:1, the weight of the obtained PEG grafted resin increases to 1.29 g, the yield of the finally obtained mPEG2000-Gly is 71%, and the product purity is 94%.

Example 16

The difference between Example 16 and Example 2 is that pyridine is used as an acid coupling agent in the first step, the weight of the obtained PEG grafted resin increases to 1.21 g, the yield of the finally obtained mPEG2000-Gly is 68%, and the product purity is 92%.

Example 17

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

Example 18

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

Example 19

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

Example 20

The difference between Example 20 and Example 2 is that the esterification reaction temperature in the first step is 90°C, the esterification reaction time is 8 hours, the weight of the obtained grafted PEG resin increases from 1 g to 1.33 g, and the weight increase is smaller than that of Example 2, and the weight of the finally obtained mPEG2000-Gly is 0.22 g, the yield is 67%, and the product purity is about 97%.

Example 21

The difference between Example 21 and Example 2 is that the strong alkaline reagent in the second step is NaH, the weight of the finally obtained mPEG2000-Gly is 0.3 g, the yield is 44%, and the product purity is about 82%.

Example 22

The difference between Example 22 and Example 2 is that in the second step, the reaction of potassium tert-butoxide and solketal was performed at 25°C for 4 hours to obtain a reaction intermediate system, and the yield of the finally obtained mPEG2000-Gly was 70% and the product purity was 85%.

Example 23

The differences between Example 23 and Example 2 are as follows.

In the second step, the resin of the first step and 12 mL of dry THF were added to the reaction intermediate system, the system was slowly returned to room temperature, and reacted for 20 hours to obtain the second product system, and after the reaction was completed, the system was filtered, and the resin was washed sequentially with ice water and THF to prepare for regeneration. The washing solution was collected, THF was rotary evaporated, the aqueous phase was extracted three times with DCM, and the DCM phase was concentrated to obtain mPEG2000-solketal.

Step 3:

mPEG2000-solketal was added to 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 used resin was reduced to 1.26 g, the weight of mPEG2000-Gly was 0.35 g, the yield was 51%, and the product purity was about 95%.

Example 24

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

Example 25

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

Example 26

The difference between Example 26 and Example 2 is that the hydrolysis reaction temperature in the third step is 80°C, the hydrolysis reaction time is 5 hours, the yield of the finally obtained mPEG2000-Gly is 74%, and the product purity is 91%.

The types, yields, and purities of the polyethylene glycol-glycerol derivatives obtained in Examples 1 to 26 are listed in Table 1.

As can be seen from the data in Table 1 above, compared with Examples 2, 4 and 5, the ratio of mPEG2000:sulfonyl chloride resin in Example 6 is 1:7.12, i.e., when it is out of the range, the grafting amount of mPEG per gram of resin in the first step reaction is obviously reduced, and the ratio of mPEG2000:sulfonyl chloride resin in Example 7 is 1:0.445, i.e., when it is out of the range, the grafting amount of mPEG per gram of resin in the first step reaction is not obviously reduced, but the waste of mPEG2000 raw material is very large.

Compared with Examples 2, 13 and 14, when the molar ratio of the acid binder to polyethylene glycol in Example 15 is out of the range, the amount of mPEG grafted per 1 g of resin in the first step reaction of Example 15 is obviously reduced.

Compared to Examples 2, 17, and 18, in Example 19, when too little DMAP catalyst was added, the effect was similar to that of not adding DMAP catalyst.

From the above explanation, it can be seen that the embodiment according to the present invention achieves the following technical effects.

The present application utilizes the solid-state properties of a sulfonyl chloride resin to produce a product system including a polyethylene glycol-glycerol derivative intermediate by a solid-state synthesis method, and specifically, the first product system obtained by removing small molecule hydrogen chloride through an esterification reaction of a sulfonyl chloride group in a sulfonyl chloride resin and a hydroxyl group in polyethylene glycol can separate the polyethylene glycol-glycerol derivative intermediate by a simple solid-liquid separation method and use it in a subsequent reaction. Due to the polymer insolubility of the polyethylene glycol-glycerol derivative intermediate, in addition to the hydrolysis reaction, the subsequent reaction is still a solid-state synthesis reaction, and the obtained product system can still be separated and purified by a simple solid-liquid separation method. Therefore, compared with the existing liquid-phase small molecule synthesis route of PEG-Gly, the cumbersome multi-step separation and purification work performed in the liquid-phase synthesis is not necessary, so the separation and purification work is greatly simplified, and the target product with high yield and high purity is more easily obtained. In addition, all reagents used in the manufacturing process can be recycled, which greatly reduces the process cost.

The above description is only a preferred embodiment of the present invention, and is not intended to limit the present invention. Those skilled in the art can make various changes and modifications to the present invention. All modifications, equivalent replacements, improvements, etc. made within the spirit and principle of the present invention should all be included within the protection scope of the present invention.

Claims (18)

A method for producing a polyethylene glycol-glycerol derivative intermediate,
A method comprising: performing an esterification reaction on a raw material including polyethylene glycol and a sulfonyl chloride resin to obtain a first product system including a polyethylene glycol-glycerol derivative intermediate;
At least one terminal group of the polyethylene glycol is a hydroxyl group, the sulfonyl chloride resin is a polystyrene resin containing a sulfonyl chloride group, and the structural formula of the sulfonyl chloride resin is A manufacturing method characterized by being indicated by .
In the first paragraph,
A manufacturing method characterized in that 1 g of the above sulfonyl chloride resin contains 1.78 to 4.61 mmol of sulfonyl chloride groups.
In the second paragraph,
A manufacturing method characterized in that the above sulfonyl chloride resin is one or more selected from HC9001-1-1 sulfonyl chloride resin and sulfonyl chloride resin derived from commercial strong acid resin 001*7.
In any one of claims 1 to 3,
A manufacturing method characterized in that the molecular weight of the above polyethylene glycol is 194 to 5000.
In paragraph 4,
A manufacturing method characterized in that the molar ratio of the sulfonyl chloride group of the polyethylene glycol to the sulfonyl chloride resin is 1:0.9 to 4, and the other terminal group of the polyethylene glycol is a hydroxyl group or a protecting functional group.
In paragraph 5,
A manufacturing method characterized in that the above protecting functional group is any one selected from methoxy, tert-butoxy, and benzyloxy.
In Article 6,
A manufacturing method characterized in that the above polyethylene glycol-glycerol derivative intermediate has a structure represented by Formula I.

Food I
In any one of claims 1 to 3,
A manufacturing method characterized in that the above raw material further contains an acid binder.
In Article 8,
A manufacturing method characterized in that 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.
In any one of claims 1 to 3,
A manufacturing method characterized in that the above raw material further contains a catalyst.
In Article 10,
A manufacturing method characterized in that the molar ratio of the catalyst to the polyethylene glycol is 0.05 to 2.2:1, and the catalyst is an alkaline substance.
In Article 11,
A manufacturing method characterized in that the alkaline substance is 4-dimethylaminopyridine.
In any one of claims 1 to 3,
A manufacturing method characterized in that the esterification reaction temperature is 0 to 90°C and the esterification reaction time is 4 to 72 hours.
In the first paragraph,
A manufacturing method characterized by further comprising a step of performing primary solid-liquid separation of the first product system to obtain the polyethylene glycol-glycerol derivative intermediate.
A method for producing a polyethylene glycol-glycerol derivative having a structure represented by Formula II,

Food II
Step S1 of obtaining a polyethylene glycol-glycerol derivative intermediate using a manufacturing method according to any one of claims 1 to 14;
Step S2 of obtaining compound 1 by substitution reaction of the above polyethylene glycol-glycerol derivative intermediate with Solketal, wherein the compound 1 has a structure represented by Formula III; and

Food III
A manufacturing method characterized by including step S3 of obtaining the polyethylene glycol-glycerol derivative by hydrolyzing the compound 1.
In Article 15,
The above step S2 is,
A step of obtaining a reaction intermediate system by reacting a strong alkaline reagent and solketal at 0 to 25°C;
A step of obtaining a second product system including the compound 1 by subjecting the above reaction intermediate system to the substitution reaction with the polyethylene glycol-glycerol derivative intermediate at 0 to 65°C;
A step of obtaining a solid phase and a liquid phase by performing a second solid-liquid separation of the above second product system; and
A manufacturing method characterized by comprising a step of extracting and separating the liquid phase to obtain the compound 1.
In Article 16,
The above strong alkaline reagent is one or more selected from KOtBu, NaH, and butyllithium,
The above reaction time is 1 to 4 hours, and the above substitution reaction time is 15 to 24 hours.
The above manufacturing method further includes a step of 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.
A manufacturing method characterized in that the above reaction is performed in an ice bath.
In Article 16,
A manufacturing method characterized in that the H ⁺ concentration of the hydrolysis reaction is 0.1 to 4 mol/L, the hydrolysis reaction temperature is 40 to 80°C, and the hydrolysis reaction time is 2 to 24 hours.