CN114524943B - Process for preparing polyethylene glycol-glycerol derivatives and intermediates thereof - Google Patents

Abstract

The invention provides respective preparation methods of a polyethylene glycol-glycerol derivative and an intermediate thereof. The preparation method comprises the following steps: raw materials comprising polyethylene glycol and sulfonyl chloride resin are subjected to esterification reaction to obtain a first product system comprising a polyethylene glycol-glycerol derivative intermediate, at least one end group of the polyethylene glycol is a hydroxyl group, and the sulfonyl chloride resin is polystyrene resin containing sulfonyl chloride groups. By utilizing the resin macromolecule solid phase characteristic of sulfonyl chloride resin, a product system containing the polyethylene glycol-glycerol derivative intermediate can be obtained by adopting a solid phase synthesis method, the obtained product system can be used for separating the polyethylene glycol-glycerol derivative intermediate only by a simple solid-liquid separation method and is used for subsequent reaction, the separation and purification operation is greatly simplified, and the target product with high yield and high purity is easier to obtain. And reagents used in the preparation process can be recycled, so that the cost is greatly reduced.

Description

The respective preparation methods of polyethylene glycol-glycerol derivatives and intermediates thereof

technical field

The present invention relates to the technical field of preparation of polyethylene glycol-glycerol derivatives, in particular to a preparation method of polyethylene glycol-glycerol derivatives and intermediates thereof.

Background technique

Polyethylene glycol (PEG) is a polymer with a structure of 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 substances that are poorly soluble in water can be converted into hydrophilic substances when coupled with PEG. In drug development research, the modified polyethylene glycol is coupled to proteins, polypeptides, small molecular organic drugs and liposomes by certain means, which can increase the half-life of protein or polypeptide drugs in vivo, reduce immunogenicity, and increase the Water solubility and targeting properties of drugs. The combination of PEG and liposomes after modification can also make liposomes have stronger passive targeting effect on tumors. Therefore, the development of efficient and simple PEG modification process has important research significance in the fields of bioengineering and drug development.

The modification of PEG includes the modification of active functional groups such as polyethylene glycol maleimide derivative (PEG-Mal), polyethylene glycol succinimide derivative (PEG-NHS), polyethylene glycol aldehyde group Derivatives (PEG-ALD), etc., also include the preparation of polyethylene glycol glycerol derivatives (PEG-Gly) for PEG synthesis intermediates or liposomes. The traditional PEG modification process is usually small molecule liquid phase synthesis. For example, in the U.S. patents with patent application numbers US6828401 and US10752732, the preparation process of PEG-Mal and PEG-CM (polyethylene glycol carboxyl derivatives) involves multiple steps and cumbersome steps. Separation and purification operations are difficult to achieve a higher purity of the target product.

The preparation of PEG-Gly used for PEG synthesis intermediates or liposomes also faces the above-mentioned problems. At present, there are two processes for the preparation of PEG-Gly. One is to use epichlorohydrin to replace the PEG terminal hydroxyl group, and then carry out the hydrolysis and ring-opening of the epoxy group to obtain the target product; The benzenesulfonyl chloride is subjected to ester-forming reaction, and then the activated acetone acetal is used for substitution, and the obtained intermediate product is subjected to acid hydrolysis to obtain the target product. No matter which route mentioned above is involved in the separation and extraction operation of the intermediate product, it will further pollute the subsequent target product. Therefore, the multi-step separation process not only causes the whole preparation process to be cumbersome, but also increases the process production cost.

SUMMARY OF THE INVENTION

The main purpose of the present invention is to provide a respective preparation method of a polyethylene glycol-glycerol derivative and its intermediate, so as to solve the problems of complicated and high cost in the preparation process of PEG-Gly in the prior art.

。In order to achieve the above object, according to one aspect of the present invention, a method for preparing a polyethylene glycol-glycerin derivative intermediate is provided, the preparation method comprising: esterifying raw materials comprising polyethylene glycol and sulfonyl chloride resin reaction to obtain a first product system comprising a polyethylene glycol-glycerol derivative intermediate, and at least one end group of polyethylene glycol is a hydroxyl group, wherein the sulfonyl chloride resin is a polystyrene resin containing a sulfonyl chloride group, The structural formula of sulfonyl chloride resin is expressed as

.

Further, 1 g of the above-mentioned sulfonyl chloride resin contains 1.78-4.61 mmol of sulfonyl chloride groups, preferably the sulfonyl chloride resin is selected from any of the derivative sulfonyl chloride resins of HC9001-1-1 sulfonyl chloride resin and commercialized strong acid resin 001*7 one or more.

Further, the molecular weight of the above-mentioned polyethylene glycol is 194～5000, the molar ratio of the sulfonyl chloride group of the preferred polyethylene glycol and the sulfonyl chloride resin is 1:0.9～4, and the other end group of the polyethylene glycol is a hydroxyl or The protective group functional group, preferably the protective group functional group is selected from any one of methoxy, tert-butoxy and benzyloxy, preferably methoxy, preferably the polyethylene glycol-glycerol derivative intermediate has the formula I Show structure:

Formula I.

Further, the above-mentioned raw materials also include an acid binding agent, preferably the mol ratio of the acid binding agent and polyethylene glycol is 10 to 50:1, and the preferred acid binding agent is selected from any one of NaOH, KOH, triethylamine, pyridine or variety.

Further, the above-mentioned raw materials also include a catalyst, and the molar ratio of the catalyst to polyethylene glycol is preferably 0.05 to 2.2:1, and the catalyst is preferably an alkaline substance, and the preferred alkaline substance is 4-dimethylaminopyridine.

Further, the temperature of the above-mentioned esterification reaction is 0-90 °C, and the time of the esterification reaction is preferably 4-72 h.

Further, the above preparation method further includes performing a first solid-liquid separation on the first product system to obtain a polyethylene glycol-glycerol derivative intermediate, preferably the first solid-liquid separation is filtration.

According to another aspect of the present invention, a preparation method of a polyethylene glycol-glycerin derivative is provided, and the polyethylene glycol-glycerin derivative has a structure shown in formula II:

Formula II

The preparation method includes: step S1, adopting the above preparation method to obtain a polyethylene glycol-glycerin derivative intermediate; step S2, subjecting the polyethylene glycol-glycerol derivative intermediate to a substitution reaction with acetone acetal to obtain compound 1; compound 1 has the structure shown in formula III:

Formula III

In step S3, compound 1 is subjected to a hydrolysis reaction to obtain a polyethylene glycol-glycerol derivative.

Further, the above-mentioned step S2 includes: reacting the strong alkaline reagent with acetone acetal at 0-25 °C to obtain a reaction intermediate system; reacting the reaction intermediate system with polyethylene glycol-glycerol derivative at 0-65 °C The intermediate is subjected to a substitution reaction to obtain a second product system including compound 1, and the second product system is subjected to a second solid-liquid separation to obtain a solid phase and a liquid phase; the liquid phase is extracted and separated to obtain compound 1, preferably strongly basic The reagent is selected from any one or more of KOtBu, NaH, and butyllithium, the preferred reaction time is 1~4h, the preferred substitution reaction time is 15~24h, and the preferred preparation method also 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, and preferably the reaction is carried out in an ice bath.

Further, the H ⁺ concentration of the above hydrolysis reaction is 0.1~4 mol/L, the preferred temperature of the hydrolysis reaction is 40~80°C, and the preferred time of the hydrolysis reaction is 2~24 h.

Applying the technical solution of the present invention, the present application utilizes the resin polymer solid-phase properties of the sulfonyl chloride resin, and a solid-phase synthesis method can be used to prepare a product system comprising a polyethylene glycol-glycerin derivative intermediate. Specifically, the sulfonyl chloride The sulfonyl chloride group in the resin is esterified with the hydroxyl group in the polyethylene glycol to remove the small molecule hydrogen chloride, and the obtained first product system only needs a simple solid-liquid separation method to derivatize the polyethylene glycol-glycerol The intermediates were isolated and used in subsequent reactions. Due to the macromolecule 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. Compared with the traditional liquid-phase small molecule synthesis route of PEG-Gly, the multi-step cumbersome separation and purification operation in liquid-phase synthesis is avoided, which greatly simplifies the separation and purification operation, and makes it easier to obtain high-yield and high-purity target products. In addition, all the reagents used in the preparation process can be recycled, which greatly reduces the process cost.

Description of drawings

The accompanying drawings forming a part of the present application are used to provide further understanding of the present invention, and the exemplary embodiments of the present invention and their descriptions are used to explain the present invention and do not constitute an improper limitation of the present invention. In the attached image:

FIG. 1 shows a schematic diagram of the high-resolution LC/MS (TOF) detection result of mPEG2000-Gly provided according to Example 1 of the present invention.

Detailed ways

It should be noted that the embodiments in the present application and the features of the embodiments may be combined with each other in the case of no conflict. The present invention will be described in detail below with reference to the accompanying drawings and in conjunction with the embodiments.

As analyzed in the background art, the preparation process of PEG-Gly in the prior art has the problems of tediousness and high cost. In order to solve the problem, the present invention provides a polyethylene glycol-glycerol derivative and its intermediates. Preparation.

。In a typical embodiment of the present application, a method for preparing a polyethylene glycol-glycerin derivative intermediate is provided, the preparation method comprising: esterifying raw materials including polyethylene glycol and sulfonyl chloride resin reaction to obtain a first product system comprising a polyethylene glycol-glycerol derivative intermediate, and at least one end group of polyethylene glycol is a hydroxyl group, wherein the above-mentioned sulfonyl chloride resin is a polystyrene resin containing a sulfonyl chloride group , the structural formula of sulfonyl chloride resin is expressed as

.

The present application utilizes the resin polymer solid-phase properties of the sulfonyl chloride resin, and a solid-phase synthesis method can be used to prepare a product system comprising a polyethylene glycol-glycerin derivative intermediate. Specifically, the sulfonyl chloride group in the sulfonyl chloride resin Esterification is carried out with the hydroxyl group in polyethylene glycol to remove the small molecule hydrogen chloride, and the obtained first product system only needs to separate the polyethylene glycol-glycerol derivative intermediate by a simple solid-liquid separation method and use it for subsequent reactions. Due to the macromolecule 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. Compared with the traditional liquid-phase small molecule synthesis route of PEG-Gly, the multi-step cumbersome separation and purification operation in liquid-phase synthesis is avoided, which greatly simplifies the separation and purification operation, and makes it easier to obtain high-yield and high-purity target products. In addition, all the reagents used in the preparation process can be recycled, which greatly reduces the process cost.

It should be noted that, in the above-mentioned sulfonyl chloride resin, one resin macromolecule contains at least one sulfonyl chloride group, which is connected to the corresponding benzene ring side chain position. Preferably, 1 g of the sulfonyl chloride resin contains 1.78-4.61 mmol of sulfonyl chloride groups, and preferably the sulfonyl chloride resin is selected from any one of HC9001-1-1 sulfonyl chloride resin, the derivative sulfonyl chloride resin of commercial strong acid resin 001*7 or There are many kinds, which are beneficial to improve the esterification reaction efficiency of polyethylene glycol and sulfonyl chloride resin.

The derivative sulfonyl chloride resin of the above-mentioned commercialized strong acid resin 001*7 can use strong acid resin 001*7 as a reaction raw material, and is disclosed in "Preparation of Polystyrene Sulfonyl Chloride Resin and Its Application in the Synthesis of Nitrogen-Containing Basic Resin" The corresponding sulfonyl chloride resin was prepared by the preparation method.

In an embodiment of the present application, the molecular weight of the above polyethylene glycol is 194~5000, preferably the molar ratio of polyethylene glycol to the sulfonyl chloride group of the sulfonyl chloride resin is 1:0.9~4, The other end group is a hydroxyl group or a protective group functional group, preferably the protective group functional group is selected from any one of methoxy, tert-butoxy and benzyloxy, preferably methoxy, preferably derived from polyethylene glycol-glycerol The compound intermediate has the structure shown in formula I:

Formula I.

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

The polyethylene glycol in the above molecular weight range and the molar ratio range of polyethylene glycol to the sulfonyl chloride group of the sulfonyl chloride resin can provide a polyethylene glycol-glycerol derivative intermediate with a wider molecular weight range, and polyethylene glycol and sulfonyl chloride can be provided. The molar ratio range of the sulfonyl chloride group of the acyl chloride resin is beneficial to improve the esterification reaction efficiency of polyethylene glycol with different molecular weights and the sulfonyl chloride resin, and the polyethylene glycol is grafted on the solid-phase sulfonyl chloride resin as much as possible, thereby obtaining Abundant polyethylene glycol-glycerol derivatives, preferably the polyethylene glycol-glycerol derivative intermediate of the structure shown in formula I can correspond to the polyethylene glycol-glycerol derivative more suitable for the needs of the current market.

In an embodiment of the present application, the above-mentioned raw materials also include an acid binding agent, preferably the molar ratio of the acid binding agent and polyethylene glycol is 10-50:1, and the acid binding agent is preferably selected from NaOH, KOH, triethylamine , any one or more of pyridine. The above-mentioned esterification reaction needs to remove the hydrogen chloride molecule, preferably under the action of the above-mentioned acid binding agent, it is beneficial to remove the hydrogen chloride molecule as much as possible, thereby promoting the progress of the esterification reaction.

Preferably, the above-mentioned raw materials also include a catalyst, and the molar ratio of the catalyst to polyethylene glycol is preferably 0.05 to 2.2:1. The catalyst is preferably an alkaline substance, and the alkaline substance is preferably 4-dimethylaminopyridine, so as to promote the esterification reaction .

In order 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 h.

In an embodiment of the present application, the above preparation method further includes performing a first solid-liquid separation on the first product system to obtain a polyethylene glycol-glycerol derivative intermediate, preferably the first solid-liquid separation is filtration. The above-mentioned polyethylene glycol-glycerin derivative intermediates are insoluble in organic solvents (including low-molecular-weight polyethylene glycols), and high-molecular-weight polyethylene glycols are solids, so the polyethylene glycol-glycerol derivative intermediates will not. Dissolved in excess polyethylene glycol, the polyethylene glycol-glycerol derivative intermediate can be isolated by simple filtration.

In another typical embodiment of the present application, a preparation method of a polyethylene glycol-glycerin derivative is provided, and the polyethylene glycol-glycerin derivative has a structure shown in formula II:

Formula II

The preparation method includes: step S1, using the above preparation method to obtain a polyethylene glycol-glycerin derivative intermediate; step S2, performing a substitution reaction on the polyethylene glycol-glycerol derivative intermediate with acetone acetal to obtain compound 1; Compound 1 has the structure shown in formula III:

Formula III

In step S3, compound 1 is subjected to a hydrolysis reaction to obtain a polyethylene glycol-glycerol derivative.

Step S1 and step S2 in the above preparation method of the present application both adopt solid-phase synthesis method, the obtained product system can be separated from the target product through simple solid-liquid separation, and finally the compound 1 of the structure shown in formula III is hydrolyzed The polyethylene glycol-glycerol derivative can be obtained by the reaction, and finally the polyethylene glycol-glycerol derivative with high yield can be obtained by simple extraction. It can be seen that, compared with the traditional liquid-phase small molecule synthesis route of PEG-Gly, the multi-step cumbersome separation and purification operation in liquid-phase synthesis is avoided, the separation and purification operation is greatly simplified, and it is easier to obtain high-yield and high-purity targets. product. In addition, all the reagents used in the preparation process can be recycled, which greatly reduces the process cost.

In an embodiment of the present application, the above step S2 includes: reacting a strong basic reagent with acetone acetal at 0-25 °C to obtain a reaction intermediate system; The ethylene glycol-glycerol derivative intermediate is subjected to a substitution reaction to obtain a second product system including compound 1, and the second product system is subjected to a second solid-liquid separation to obtain a solid phase and a liquid phase; the liquid phase is extracted and separated (for example, , using dichloromethane to carry out three extractions and separations to the obtained liquid phase) to obtain compound 1, preferably strong alkaline reagent is selected from any one or more in KOtBu, NaH, butyllithium, and the time of the preferred reaction is 1 ~ 4h, preferably the substitution reaction time is 15-24h, the second solid-liquid separation is preferably filtration, and the reaction is preferably carried out in an ice bath.

The above-mentioned reaction pulls out the hydrogen on the hydroxyl group of the acetone acetal by the effect of strong base to obtain an anion oxide intermediate. The reaction exotherm is obvious and relatively dangerous. Therefore, it is preferable to react first under the above-mentioned conditions to generate a large amount of anion oxide intermediate, and then again. The oxyanion intermediate is subjected to a substitution reaction with the solid-phase polyethylene glycol-glycerol derivative intermediate to obtain a second product system comprising the structure shown in formula III. Using the insolubility of compound 1, simple filtration can be used to convert Compound 1 is isolated, and compound 1 undergoes a hydrolysis reaction to obtain a polyethylene glycol-glycerol derivative.

In addition, the preferred preparation method further includes: washing the solid phase to obtain a regenerated sulfonyl chloride resin, preferably using the regenerated sulfonyl chloride resin for the esterification reaction in step S1, thereby greatly reducing costs and being more environmentally friendly.

In order to improve the efficiency of the above hydrolysis reaction ^, preferably the H concentration of the above hydrolysis reaction is 0.1~4mol/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 application will be described below with reference to specific embodiments and comparative examples.

In the following examples, the sulfonyl chloride resin used can also be directly purchased by DOI: 10.1007/s00289-005-0417-y or in "Preparation of Polystyrene Sulfonyl Chloride Resin and Its Application in Synthesis of Nitrogen-Containing Basic Resin" The published preparation method is obtained.

Example 1

first step,

Mixture: at room temperature, add 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 into a 250 mL four-necked flask, Stir to swell to obtain a mixture.

Solution: Under ice bath, add 2.5 g of mPEG2000 and 50 mL of DCM to a 100 mL four-neck flask, and after the substrate is completely dissolved, add 30 mg of 4-dimethylaminopyridine (DMAP) and 4 mL of triethylamine. Continue stirring for 15 min.

The above mixture was placed in an ice bath, and the above prepared solution was slowly added dropwise to form a system to be reacted, and then the system to be reacted was slowly raised to room temperature for esterification reaction for 20 h to obtain a first product system. The first product system was filtered and washed with DCM and the washings recovered. The obtained resin is mPEG2000-sulfonyl chloride resin, and the resin weight increases to 1.37 g after drying (resin weight gain is the grafting amount of mPEG2000), the product purity in this step is 100%, and no further purification is required.

The second step,

Add 22 mg of KOtBu and 0.5 mL of dry THF under an ice bath, stir for 30 min, add a THF solution (25 μL/200 μL of acetal acetal) (the concentration of acetal acetal itself is close to 100%), and continue in an ice bath. The reaction was carried out for 2 h to obtain a reaction intermediate system. Then, 1.37 g of the resin in 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 heating time) to obtain the first step. Two product systems, the second product system is lowered to room temperature and filtered, and the resin is left for standby regeneration after cleaning with ice water and THF successively.The washing solution is collected, and the water phase is extracted three times with DCM after the THF is evaporated, and the DCM phase is concentrated to be Obtain mPEG2000-acetone acetal.

third step,

The mPEG2000-acetone acetal was placed in a 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 resin used was reduced in weight to 1.02 g, that is, the grafted PEG was almost completely replaced. The weight of mPEG2000-Gly was 0.25 g, the yield was 68%, and the product purity was about 95%. Among them, the high-resolution LC/MS (TOF) detection results of mPEG2000-Gly are shown in Figure 1.

Example 2

first step,

Mixture: under ice bath, add 1 g of sulfonyl chloride resin (same as Example 1), 2 g of NaOH and 25 mL of THF to a 250 mL four-neck flask, stir and swell to obtain a mixture.

Solution: Under ice bath, add 2.5 g of mPEG2000 and 50 mL of THF to a 100 mL four-neck flask, and wait until the substrate is completely dissolved.

The above prepared solution was slowly added dropwise into the mixture to form the to-be-reacted system, and then the to-be-reacted system was slowly raised 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 washings were recovered. The obtained resin is mPEG2000-sulfonyl chloride resin, and the resin weight increases to 1.68 g after drying (resin weight gain is the grafting amount of mPEG2000). The product in this step has a purity of 100% and no further purification is required.

The second step,

41 mg of KOtBu and 1 mL of dry THF were added under an ice bath, and after stirring for 30 min, 45 μL/400 μL of THF solution of acetal acetal was added, and the reaction was continued for 2 h under an ice bath to obtain a reaction intermediate system. Subsequently, 1.68 g of the resin of 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 to obtain the second product system. The second product system was cooled to room temperature and filtered. The resin was washed with ice water and THF in turn and reserved for standby regeneration. The washing liquid was collected, the THF was evaporated by rotary evaporation, and the aqueous phase was extracted three times with DCM, and the DCM phase was concentrated to obtain mPEG2000-acetone acetal.

third step,

The mPEG2000-acetone acetal was placed in a 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 resin used was reduced in weight 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

Sulfonyl chloride resin regeneration: take 10 g of the resin prepared by mPEG200-Gly (see Example 2 or 3), add 20 mL of thionyl chloride to reflux for more than 8 h, and then evaporate the excess thionyl chloride. The remaining system was placed in an ice bath and quickly washed with ice water and acetone in turn. 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 concentrated by rotary evaporation to obtain the recovered mPEG2000; in Example 2, after the THF/water mixed solution was rotary evaporated, the remaining aqueous phase was extracted three times with DCM, and the obtained DCM phase was rotary evaporated That is, the recovered mPEG2000 is obtained.

first step,

Mixture: under ice bath, add 1 g of regenerated sulfonyl chloride resin, 2 g of NaOH and 25 mL of THF to a 250 mL four-neck flask, stir and swell to obtain a mixture.

Solution: Under ice bath, add recovered mPEG2000 to a 100 mL four-neck flask and add 2 g of mPEG2000, and then add 50 mL of THF to dissolve the substrate.

The above prepared solution was slowly added dropwise into the mixture to form the to-be-reacted system, and then the to-be-reacted system was slowly raised 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 washing liquid was recovered. The obtained resin is mPEG2000-sulfonyl chloride resin, and the resin weight increases to 1.70 g after drying (resin weight gain is the grafting amount of mPEG2000), the product purity in this step is 100%, and no further purification is required.

The second step,

41 mg of KOtBu and 1 mL of dry THF were added under an ice bath, stirred for 30 min, and then added with a THF solution of acetal acetal (45 μL/400 μL), and the reaction was continued for 2 h under an ice bath to obtain an intermediate reaction system. Subsequently, 1.70 g of the resin in the first step and 12 mL of dry THF were added to the reaction intermediate system, and the system was slowly raised to room temperature and then heated to 65 °C, and the substitution reaction was carried out for 20 h to obtain a second product system, which was reduced to At room temperature and filtered, the resin was washed with ice water and THF in turn and reserved for standby regeneration. The washing liquid was collected, the THF was evaporated by rotary evaporation, and the aqueous phase was extracted three times with DCM, and the DCM phase was concentrated to obtain mPEG2000-acetone acetal.

third step,

The mPEG2000-acetone acetal was placed in a 2 mol/L hydrochloric acid solution and hydrolyzed at 60 °C for 8 h to obtain the target product mPEG2000-Gly.

After the completion of the reaction, the resin used was reduced in weight 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 is 0.9 g, and the resin weight is increased to 1.25 g after post-treatment.

The second step,

20 mg of KOtBu and 0.5 mL of dry THF were added under an ice bath, stirred for 30 min, and then added with a THF solution of acetal acetal (20 μL/200 μL), and the reaction was continued for 2 h under an ice bath to obtain an intermediate reaction system. Subsequently, 1.25 g of the resin of 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 reaction was carried out for 20 h to obtain a second product system. The second product system was cooled to room temperature and filtered. The ice water and THF are washed in sequence and reserved for standby regeneration. The washing liquid was collected, the THF was evaporated by rotary evaporation, and the aqueous phase was extracted three times with DCM, and the DCM phase was concentrated to obtain mPEG2000-acetone acetal.

third step,

The mPEG2000-acetone acetal was placed in a 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 resin used was reduced in weight 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, and the resin is increased in weight to 1.65 g after post-treatment. After the second and third steps, mPEG2000-Gly is finally obtained. The yield was 70%, and the product purity was 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, and the resin is increased in weight to 1.12 g after post-treatment. After the second and third steps, mPEG2000-Gly is finally obtained. The yield was 58%, and the product purity was 96%.

Example 7

The difference between Example 7 and Example 2 is that the mass of mPEG2000 used in the first step is 8 g, and the resin weight is increased to 1.68 g after post-treatment, that is, increasing the amount of mPEG2000 is not beneficial to the PEG grafting amount. After three 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, which is obtained by derivation and modification of commercial resin 001*7. Preparation of Acyl Chloride Resin and Its Application in Synthesis of Nitrogen-Containing Basic Resin", the resin weight was increased to 1.86 g after post-treatment. After the second and third steps, mPEG2000-Gly was 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, and 1.19 g of the PEG-grafted resin is obtained to be grafted on The PEG loading amount on the resin is a benchmark, and the second step reaction is completed by using 1.5 eq potassium tert-butoxide and 2 eq acetal acetal, and the final weight of the mPEG ₄ -Gly obtained by hydrolysis is 0.17 g, and the yield is 89%, The purity is 89%.

Example 10

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

Example 11

The difference between Example 11 and Example 2 is that in the first step, the molecular weight of polyethylene glycol is 3500, the mass is 4.4 g, the mass of the sulfonyl chloride resin is 1 g, and the final mPEG3500-Gly obtained is 0.75 g, and the yield is 0.75 g. 77% with a purity of 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, and the weight of the resin obtained in the first step is increased to 2.36 g , the final mPEG5000-Gly obtained 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 obtained PEG grafted resin increased in weight 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 obtained PEG grafted resin increased in weight 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 obtained PEG grafted resin increased in weight to 1.29 g. The final yield of mPEG2000-Gly was 71%, and the product purity was 94%.

Example 16

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

Example 17

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

Example 18

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

Example 19

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

Example 20

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

Example 21

The difference between Example 21 and Example 2 is that in the second step, the strong basic reagent is NaH, and the final mPEG2000-Gly obtained 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 acetal acetal was carried out at 25° C. After the reaction for 4 h, a reaction intermediate system was obtained, and the yield of mPEG2000-Gly was finally 70%. , the product purity was 85%.

Example 23

The difference between Example 23 and Example 2 is that,

In the second step, the resin of the first step and 12 mL of dry THF were added to the reaction intermediate system, and the system was slowly returned to room temperature, and the reaction was performed for 20 h to obtain the second product system. After cleaning in sequence, it is reserved for standby regeneration. The washing liquid was collected, the THF was evaporated by rotary evaporation, and the aqueous phase was extracted three times with DCM, and the DCM phase was concentrated to obtain mPEG2000-acetone acetal.

third step,

The mPEG2000-acetone acetal was placed in a 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 resin used was reduced in weight 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 48h to obtain a second product system, and the weight of the final product mPEG-Gly after the obtained intermediate is hydrolyzed is 0.42 g, The yield was 62% and the product purity 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 finally mPEG2000-Gly was 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 temperature of the hydrolysis reaction was 80° C., and the time of the hydrolysis reaction was 5h, and the final yield of mPEG2000-Gly was 74%, and the product purity was 91%.

The classes of polyethylene glycol-glycerol derivatives obtained in Examples 1 to 26 above and their yields and purities are listed in Table 1.

Table 1

As can be seen from the data in Table 1 above, compared with Examples 2, 4, and 5, when the ratio of mPEG2000:sulfonyl chloride resin in Example 6 is 1:7.12, that is, outside the range, each time in the first step reaction The grafting amount of mPEG per gram of resin will be significantly reduced. When the ratio of mPEG2000:sulfonyl chloride resin in Example 7 is 1:0.445, that is, outside the range, the grafting amount of mPEG per gram of resin in the first step reaction will not Significantly lower, but will cause a great waste of mPEG2000 raw materials.

Compared with Examples 2, 13 and 14, when the molar ratio of the acid binding agent and polyethylene glycol of Example 15 is outside the range, the mPEG grafting amount per gram of resin in the first step reaction of Example 15 will be obvious. reduce.

Compared with Examples 2, 17 and 18, the effect of adding too little DMAP catalyst in Example 19 is similar to that of adding no DMAP catalyst.

From the above description, it can be seen that the above-mentioned embodiments of the present invention achieve the following technical effects:

The present application utilizes the resin polymer solid-phase properties of the sulfonyl chloride resin, and a solid-phase synthesis method can be used to prepare a product system comprising a polyethylene glycol-glycerol derivative intermediate. Specifically, the sulfonyl chloride group in the sulfonyl chloride resin Carry out an esterification reaction with the hydroxyl group in polyethylene glycol to remove the small molecule hydrogen chloride, and the obtained first product system only needs to separate the polyethylene glycol-glycerol derivative intermediate by a simple solid-liquid separation method and use it for subsequent reactions. Due to the macromolecule insolubility of the polyethylene glycol-glycerol derivative intermediate, except for 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 traditional liquid-phase small molecule synthesis route of PEG-Gly, the multi-step cumbersome separation and purification operation in liquid-phase synthesis is avoided, which greatly simplifies the separation and purification operation, and makes it easier to obtain high-yield and high-purity target products. In addition, all the reagents used in the preparation process can be recycled, which greatly reduces the process cost.

The above descriptions are only preferred embodiments of the present invention, and are not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and changes. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims (17)

1. A preparation method of a polyethylene glycol-glycerol derivative intermediate is characterized by comprising the following steps:

carrying out esterification reaction on raw materials comprising polyethylene glycol and sulfonyl chloride resin to obtain a first product system comprising a polyethylene glycol-glycerol derivative intermediate, wherein at least one end group of the polyethylene glycol is hydroxyl,

wherein the sulfonyl chloride resin is polystyrene resin containing sulfonyl chloride groups, and the structural formula of the sulfonyl chloride resin is shown as

;

The preparation method further comprises the step of carrying out first solid-liquid separation on the first product system to obtain the polyethylene glycol-glycerol derivative intermediate, wherein the polyethylene glycol-glycerol derivative intermediate is a solid phase, and the first solid-liquid separation is filtration.

2. The method according to claim 1, wherein 1g of the sulfonyl chloride resin contains 1.78 to 4.61mmol of sulfonyl chloride groups.

3. The method according to claim 2, wherein the sulfonyl chloride resin is selected from any one or more of HC9001-1-1 sulfonyl chloride resin, derivative sulfonyl chloride resin of commercial strong acid resin 001 x 7.

4. The method according to any one of claims 1 to 3, wherein the polyethylene glycol has a molecular weight of 194 to 5000.

5. The production method according to claim 4, wherein the molar ratio of the polyethylene glycol to the sulfonyl chloride group of the sulfonyl chloride resin is 1: 0.9-4, and the other end group of the polyethylene glycol is a hydroxyl group or a protecting group functional group.

6. The method according to claim 5, wherein the protecting group functional group is selected from the group consisting of a methoxy group, a tert-butoxy group and a benzyloxy group.

7. The method of claim 6, wherein the PEG-glycerol derivative intermediate has a structure represented by formula I:

formula I.

8. The method of any one of claims 1 to 3, wherein the feedstock further comprises an acid scavenger.

9. The preparation method according to claim 8, wherein the molar ratio of the acid-binding agent to the polyethylene glycol is 10-50: 1, the acid-binding agent is selected from one or more of NaOH, KOH, triethylamine and pyridine.

10. The production method according to any one of claims 1 to 3, characterized in that the raw material further comprises a catalyst.

11. The preparation method according to claim 10, wherein the molar ratio of the catalyst to the polyethylene glycol is 0.05-2.2: 1, the catalyst is a basic substance.

12. The method according to claim 11, wherein the basic substance is 4-dimethylaminopyridine.

13. The method according to any one of claims 1 to 3, wherein the temperature of the esterification reaction is 0 to 90 ℃ and the time of the esterification reaction is 4 to 72 hours.

14. A preparation method of a polyethylene glycol-glycerol derivative is characterized in that the polyethylene glycol-glycerol derivative has a structure shown in a formula II:

formula II

The preparation method comprises the following steps:

a step S1 of obtaining a polyethylene glycol-glycerin derivative intermediate by the production method according to any one of claims 1 to 13;

step S2, carrying out substitution reaction on the polyethylene glycol-glycerol derivative intermediate and acetone glycerol to obtain a compound 1; the compound 1 has the structure shown in formula III:

formula III

And step S3, carrying out hydrolysis reaction on the compound 1 to obtain the polyethylene glycol-glycerol derivative.

15. The method for preparing a composite material according to claim 14, wherein the step S2 includes:

reacting a strong alkaline reagent with acetonide at 0-25 ℃ to obtain a reaction intermediate system;

carrying out the substitution reaction on the reaction intermediate system and the polyethylene glycol-glycerol derivative intermediate at the temperature of 0-65 ℃ to obtain a second product system comprising the compound 1,

carrying out second solid-liquid separation on the second product system to obtain a solid phase and a liquid phase;

and (3) carrying out extraction separation on the liquid phase to obtain the compound 1.

16. The method of claim 15,

the strong alkaline reagent is selected from any one or more of KOtBu, NaH and butyl lithium,

the reaction time is 1-4 h, the substitution time is 15-24 h,

the preparation method further comprises the following steps: washing the solid phase to obtain regenerated sulfonyl chloride resin, using the regenerated sulfonyl chloride resin in the esterification reaction of the step S1,

the reaction was carried out in an ice bath.

17. The method of claim 15, wherein the H of the hydrolysis reaction is ⁺ The concentration is 0.1-4 mol/L, the temperature of the hydrolysis reaction is 40-80 ℃, and the time of the hydrolysis reaction is 2-24 h.

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