CN114524943B

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

Info

Publication number: CN114524943B
Application number: CN202210424440.4A
Authority: CN
Inventors: 洪浩; 詹姆斯·盖吉; 肖毅; 潘龙; 马利腾; 侯炳阳
Original assignee: Tianjin Asymchem Pharmaceutical Co Ltd
Current assignee: Tianjin Asymchem Pharmaceutical Co Ltd
Priority date: 2022-04-22
Filing date: 2022-04-22
Publication date: 2022-09-16
Anticipated expiration: 2042-04-22
Also published as: WO2023201805A1; CN114524943A

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

Process for preparing polyethylene glycol-glycerol derivatives and intermediates thereof

Technical Field

The invention relates to the technical field of preparation of polyethylene glycol-glycerol derivatives, and particularly relates to respective preparation methods of a polyethylene glycol-glycerol derivative and an intermediate thereof.

Background

Polyethylene glycol (PEG) is a compound with the structure of H (OCH) ₂ -CH ₂ ) _n The polymer of OH, an amphiphilic molecule, PEG is soluble not only in water but also in organic solvents. Therefore, even a substance that is poorly soluble in water can be converted into a hydrophilic substance when coupled with PEG. In the research of drug development, the modified polyethylene glycol is coupled to protein, polypeptide, small molecular organic drug and liposome by a certain means, so that the half-life of the protein or polypeptide drug in vivo can be increased, the immunogenicity can be reduced, and the water solubility and the targeting property of the drug can be increased. The PEG is also combined with liposome after being modifiedCan make the liposome have stronger passive targeting effect on the tumor. Therefore, the development of efficient and simple PEG modification process has important research significance in the fields of biological engineering and drug development.

The modification of PEG includes modification of active functional groups such as polyethylene glycol maleimide derivative (PEG-Mal), polyethylene glycol succinimide derivative (PEG-NHS), polyethylene glycol aldehyde derivative (PEG-ALD), etc., and also includes preparation of polyethylene glycol glycerol derivative (PEG-Gly) for PEG synthesis intermediate or liposome. The traditional PEG modification process is usually small molecule liquid phase synthesis, for example, in U.S. patent application nos. US6828401 and US10752732, the PEG-Mal and PEG-CM (polyethylene glycol carboxyl derivatives) preparation process involves complicated separation and purification operations, and it is difficult to achieve high target product purity.

The preparation of PEG-Gly for PEG synthesis intermediates or liposomes also faces the above problems, and there are two processes for preparing PEG-Gly at present. Firstly, replacing PEG terminal hydroxyl by epoxy chloropropane, and then carrying out hydrolytic ring opening of an epoxy group to obtain a target product; secondly, as in the Chinese patent application with the patent application number of CN102665685A, the PEG and the p-methyl benzene sulfonyl chloride are firstly subjected to ester forming reaction, then the activated acetone glycerin acetal is used for substitution, and the obtained intermediate product is subjected to acidolysis to obtain the target product. No matter which route involves the separation and extraction operation of the intermediate product, the subsequent target product can be further polluted, and therefore, the multi-step separation process not only causes the complexity of the whole preparation process, but also increases the process production cost.

Disclosure of Invention

The invention mainly aims to provide respective preparation methods of a polyethylene glycol-glycerol derivative and an intermediate thereof, so as to solve the problems of complicated preparation process and high cost of PEG-Gly in the prior art.

In order to achieve the above object, according to one aspect of the present invention, there is provided a method for preparing a polyethylene glycol-glycerol derivative intermediate, the method comprising: carrying out esterification reaction on raw materials comprising polyethylene glycol and sulfonyl chloride resin to obtainComprises a first product system of polyethylene glycol-glycerol derivative intermediate, at least one terminal 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

。

Further, 1g of the sulfonyl chloride resin contains 1.78 to 4.61mmol of sulfonyl chloride groups, and preferably the sulfonyl chloride resin is selected from any one or more of HC9001-1-1 sulfonyl chloride resin and derived sulfonyl chloride resin of commercial strong acid resin 001 × 7.

Further, the molecular weight of the polyethylene glycol is 194-5000, and the preferable molar ratio of the polyethylene glycol to the sulfonyl chloride group of the sulfonyl chloride resin is 1: 0.9-4, the other end group of the polyethylene glycol is a hydroxyl group or a protecting group functional group, preferably the protecting group functional group is any one of methoxy, tert-butoxy and benzyloxy, preferably methoxy, and preferably the polyethylene glycol-glycerol derivative intermediate has a structure shown in formula I:

formula I.

Further, the raw materials also comprise an acid-binding agent, and the molar ratio of the acid-binding agent to the polyethylene glycol is preferably 10-50: 1, preferably, the acid-binding agent is selected from any one or more of NaOH, KOH, triethylamine and pyridine.

Further, the raw materials also comprise a catalyst, and the molar ratio of the catalyst to the polyethylene glycol is preferably 0.05-2.2: 1, preferably the catalyst is a basic material, preferably the basic material is 4-dimethylaminopyridine.

Further, the temperature of the esterification reaction is 0-90 ℃, and the time of the esterification reaction is preferably 4-72 hours.

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

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

formula II

The preparation method comprises the following steps: step S1, obtaining a polyethylene glycol-glycerol derivative intermediate by adopting the preparation method; step S2, carrying out substitution reaction on the polyethylene glycol-glycerol derivative intermediate and acetone glycerol to obtain a compound 1; compound 1 has the structure shown in formula III:

formula III

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

Further, the step S2 includes: reacting a strong alkaline reagent with acetonide at 0-25 ℃ to obtain a reaction intermediate system; carrying out substitution reaction on the reaction intermediate system and a polyethylene glycol-glycerol derivative intermediate at 0-65 ℃ to obtain a second product system comprising the compound 1, and carrying out second solid-liquid separation on the second product system to obtain a solid phase and a liquid phase; extracting and separating the liquid phase to obtain a compound 1, preferably selecting a strong alkaline reagent from one or more of KOtBu, NaH and butyl lithium, preferably reacting for 1-4 h, preferably substituting for 15-24 h, and preferably further comprising: washing the solid phase to obtain regenerated sulfonyl chloride resin, preferably using the regenerated sulfonyl chloride resin for the esterification reaction in step S1, preferably performing the second solid-liquid separation as filtration, preferably performing the reaction in an ice bath.

Further, H of the above hydrolysis reaction ⁺ The concentration is 0.1-4 mol/L, the temperature of the hydrolysis reaction is preferably 40-80 ℃, and the time of the hydrolysis reaction is preferably 2-24 h.

By applying the technical scheme of the invention, a product system containing the polyethylene glycol-glycerol derivative intermediate can be prepared by utilizing the resin polymer solid-phase characteristic of sulfonyl chloride resin and adopting a solid-phase synthesis method, specifically, a sulfonyl chloride group in the sulfonyl chloride resin and a hydroxyl group in the polyethylene glycol are subjected to esterification reaction, micromolecule hydrogen chloride is removed, and the polyethylene glycol-glycerol derivative intermediate can be separated and used for subsequent reaction only by a simple solid-liquid separation method of the obtained first product system. Due to the insolubility of the macromolecule of the polyethylene glycol-glycerol derivative intermediate, the subsequent reaction is still a solid-phase synthesis reaction except for hydrolysis reaction, the obtained product system can still be separated and purified by adopting a simple solid-liquid separation method, compared with the traditional route for synthesizing PEG-Gly by using liquid-phase micromolecules, the method avoids the complicated separation and purification operations of multiple steps in the liquid-phase synthesis, greatly simplifies the separation and purification operations, and is easier to obtain the target product with high yield and high purity. In addition, reagents used in the preparation process can be recycled, so that the process cost is greatly reduced.

Drawings

The accompanying drawings, which are incorporated in and constitute a part of this application, are included to provide a further understanding of the invention, and are incorporated in and constitute a part of this specification, illustrate embodiment(s) of the invention and together with the description serve to explain the invention and not to limit the invention. In the drawings:

fig. 1 shows a schematic diagram of the results of high resolution liquid mass spectrometry (TOF) detection of mPEG2000-Gly provided according to example 1 of the present invention.

Detailed Description

It should be noted that the embodiments and features of the embodiments in the present application may be combined with each other without conflict. The present invention will be described in detail below with reference to the embodiments with reference to the attached drawings.

As analyzed by the background art, the preparation process of PEG-Gly in the prior art has the problems of complexity and high cost, and in order to solve the problems, the invention provides respective preparation methods of a polyethylene glycol-glycerol derivative and an intermediate thereof.

In a typical manner of the present applicationIn an embodiment, there is provided a method for preparing a polyethylene glycol-glycerin derivative intermediate, the method comprising: performing 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 a hydroxyl group, the sulfonyl chloride resin is polystyrene resin containing sulfonyl chloride groups, and the structural formula of the sulfonyl chloride resin is represented as

。

According to the method, a product system containing a polyethylene glycol-glycerol derivative intermediate can be prepared by utilizing the resin polymer solid-phase characteristic of sulfonyl chloride resin and adopting a solid-phase synthesis method, specifically, a sulfonyl chloride group in the sulfonyl chloride resin and a hydroxyl group in the polyethylene glycol are subjected to esterification reaction, micromolecule hydrogen chloride is removed, and the polyethylene glycol-glycerol derivative intermediate can be separated and used for subsequent reaction only by a simple solid-liquid separation method of the obtained first product system. Due to the insolubility of the macromolecule of the polyethylene glycol-glycerol derivative intermediate, the subsequent reaction is still a solid-phase synthesis reaction except for hydrolysis reaction, the obtained product system can still be separated and purified by adopting a simple solid-liquid separation method, compared with the traditional route for synthesizing PEG-Gly by using liquid-phase micromolecules, the method avoids the complicated separation and purification operations of multiple steps in the liquid-phase synthesis, greatly simplifies the separation and purification operations, and is easier to obtain the target product with high yield and high purity. In addition, reagents used in the preparation process can be recycled, so that the process cost is greatly reduced.

It should be noted that, in the above sulfonyl chloride resin, one resin macromolecule contains at least one sulfonyl chloride group, which is attached to the side chain position of the corresponding benzene ring. Preferably, 1g of sulfonyl chloride resin contains 1.78-4.61 mmol of sulfonyl chloride groups, and preferably, the sulfonyl chloride resin is selected from any one or more of HC9001-1-1 sulfonyl chloride resin and derivative sulfonyl chloride resin of commercial strong acid resin 001 × 7, so that the esterification reaction efficiency of polyethylene glycol and sulfonyl chloride resin is improved.

The derivative sulfonyl chloride resin of the commercial strong acid resin 001 × 7 can be prepared by using the strong acid resin 001 × 7 as a reaction raw material and adopting a preparation method disclosed in "preparation of polystyrene sulfonyl chloride resin and application thereof in synthesis of nitrogen-containing basic resin".

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

formula I.

The value of n in the formula I is the polymerization degree of the polyethylene glycol, the molecular weight of the polyethylene glycol is divided by the molecular weight of the repeating unit, and n is about 4-113.

The polyethylene glycol with the molecular weight range and the molar ratio range of the 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, the molar ratio range of the polyethylene glycol to the sulfonyl chloride group of the sulfonyl chloride resin is favorable for improving the esterification reaction efficiency of the polyethylene glycol with different molecular weights and the sulfonyl chloride resin, and the polyethylene glycol is grafted to the solid-phase sulfonyl chloride resin as far as possible, so that abundant polyethylene glycol-glycerol derivatives are obtained, and the preferable polyethylene glycol-glycerol derivative intermediate with the structure shown in the formula I can correspond to the polyethylene glycol-glycerol derivative and is more suitable for the requirements of the current market.

In an embodiment of the present application, the raw materials further include an acid-binding agent, preferably, the molar ratio of the acid-binding agent to the polyethylene glycol is 10 to 50: 1, preferably, the acid-binding agent is selected from any one or more of NaOH, KOH, triethylamine and pyridine. The esterification reaction is to remove hydrogen chloride molecules, preferably under the action of the acid-binding agent, so that the hydrogen chloride molecules are removed as much as possible to promote the esterification reaction.

Preferably, the raw materials also comprise a catalyst, and the molar ratio of the catalyst to the polyethylene glycol is preferably 0.05-2.2: 1, preferably the catalyst is a basic substance, preferably the basic substance is 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 0-90 ℃, and the time of the esterification reaction is preferably 4-72 hours.

In an embodiment of the present application, the above preparation method further comprises subjecting the first product system to a first solid-liquid separation to obtain the intermediate of the polyethylene glycol-glycerol derivative, preferably the first solid-liquid separation is filtration. The polyethylene glycol-glycerol derivative intermediate is insoluble in organic solvents (including polyethylene glycol with low molecular weight), and polyethylene glycol with high molecular weight is solid, so that the polyethylene glycol-glycerol derivative intermediate can not be dissolved in excessive polyethylene glycol, and the polyethylene glycol-glycerol derivative intermediate can be separated by simple filtration.

In another exemplary embodiment of the present application, there is provided a method for preparing a polyethylene glycol-glycerol derivative having a structure represented by formula II:

formula II

formula III

In the above preparation method of the present application, both step S1 and step S2 adopt a solid-phase synthesis method, the obtained product system can be separated from the target product by simple solid-liquid separation, and finally the compound 1 having the structure shown in formula III can be subjected to hydrolysis reaction to obtain the polyethylene glycol-glycerol derivative, and finally the polyethylene glycol-glycerol derivative with high yield can be obtained by simple extraction. Therefore, compared with the traditional route for synthesizing PEG-Gly by using liquid-phase micromolecules, the method avoids the complicated multi-step separation and purification operation in the liquid-phase synthesis, greatly simplifies the separation and purification operation, and is easier to obtain the target product with high yield and high purity. And reagents used in the preparation process can be recycled, so that the process cost is greatly reduced.

In an embodiment of the application, the step S2 includes: reacting a strong alkaline reagent with acetonide at 0-25 ℃ to obtain a reaction intermediate system; carrying out substitution reaction on the reaction intermediate system and a polyethylene glycol-glycerol derivative intermediate at 0-65 ℃ to obtain a second product system comprising the compound 1, and carrying out second solid-liquid separation on the second product system to obtain a solid phase and a liquid phase; and (3) performing extraction separation on the liquid phase (for example, performing extraction separation on the obtained liquid phase three times by using dichloromethane) to obtain the compound 1, preferably selecting one or more of a strong alkaline reagent from KOtBu, NaH and butyl lithium, preferably performing the reaction for 1-4 h, preferably performing the substitution reaction for 15-24 h, preferably performing the second solid-liquid separation for filtration, and preferably performing the reaction in an ice bath.

The reaction is carried out by pulling out hydrogen on the hydroxyl group of the acetonide glycerol through the action of strong base to obtain an oxyanion intermediate, the reaction is obvious in heat release and dangerous, so that the oxyanion intermediate is preferably reacted under the conditions to generate a large amount of oxyanion intermediate, then the oxyanion intermediate is subjected to substitution reaction with a solid-phase polyethylene glycol-glycerol derivative intermediate to obtain a second product system with the structure shown in formula III, the insolubility of the compound 1 is utilized, the compound 1 can be separated through simple filtration, and the compound 1 is subjected to hydrolysis reaction to obtain the polyethylene glycol-glycerol derivative.

In addition, the preparation method preferably further comprises: the solid phase is washed to obtain regenerated sulfonyl chloride resin, and the regenerated sulfonyl chloride resin is preferably used for the esterification reaction in the step S1, so that the cost is greatly reduced and the method is more environment-friendly.

In order to increase the efficiency of the hydrolysis reaction, H in the hydrolysis reaction is preferably used ⁺ The concentration is 0.1-4 mol/L, the temperature of the hydrolysis reaction is preferably 40-80 ℃, and the time of the hydrolysis reaction is preferably 2-24 h.

The advantageous effects of the present application will be described below with reference to specific examples and comparative examples.

In the following examples, the sulfonyl chloride resin used was purchased directly and can also be obtained by the preparation method disclosed in DOI 10.1007/s00289-005-0417-y or "preparation of polystyrene sulfonyl chloride resin and its use in the synthesis of nitrogen-containing basic resins".

Example 1

In the first step, the first step is that,

the mixture is as follows: 1g of a sulfonyl chloride resin (Nankai Kangji Co., Ltd., type: HC9001-1-1, sulfonyl chloride content: 1.78 mmol/g) and 25 mL of DCM were charged into a 250 mL four-necked flask at room temperature, and the mixture was swollen with stirring to obtain a mixture.

Solution: in a 100 mL four-necked flask, 2.5 g of mPEG2000 and 50 mL of DCM were added under ice-bath, and after the substrate was completely dissolved, 30 mg of 4-Dimethylaminopyridine (DMAP) and 4 mL of triethylamine were added, followed by stirring for 15 min.

And (3) placing the mixture in an ice bath, slowly dropwise adding the prepared solution into the ice bath to form a system to be reacted, and then slowly heating the system to be reacted to room temperature to perform esterification reaction for 20 hours to obtain a first product system. The first product system was filtered and washed with DCM and the washings recovered. The obtained resin is mPEG 2000-sulfonyl chloride resin, the weight of the dried resin is increased to 1.37 g (the weight increase of the resin is the grafting amount of mPEG 2000), the purity of the product in the step is 100%, and further purification is not needed.

In the second step, the first step is that,

adding 22 mg of KOtBu and 0.5 mL of dry THF under ice bath, stirring for 30 min, adding a THF solution (25 muL/200 muL) of acetone glycidol (the concentration of the acetone glycidol is close to 100%), continuing to react for 2 h under ice bath to obtain a reaction intermediate system, then adding 1.37 g of the resin and 12 mL of dry THF in the first step into the reaction intermediate system, slowly heating the system to 65 ℃, carrying out substitution reaction for 20 h (including heating time) to obtain a second product system, cooling the second product system to room temperature, filtering, sequentially cleaning the resin with ice water and THF for later regeneration, collecting a washing solution, removing THF by rotary evaporation, extracting a water phase with DCM for three times, and concentrating the DCM phase to obtain mPEG 2000-acetone glycidol.

In the third step, the first step is to use,

the mPEG 2000-acetonide condensed glycerol is put into a hydrochloric acid solution with the concentration of 2 mol/L and hydrolyzed for 8 hours at the temperature of 60 ℃ to obtain a target product mPEG 2000-Gly.

After the reaction was complete, the weight of the resin used was reduced to 1.02 g, i.e.the grafted PEG was almost completely replaced. The weight of mPEG2000-Gly is 0.25 g, the yield is 68%, and the purity of the product is about 95%. Wherein, the result of high resolution liquid chromatography-mass spectrometry (TOF) detection of mPEG2000-Gly is shown in figure 1.

Example 2

In the first step, the first step is that,

the mixture is as follows: in a 250 mL four-necked flask, 1g of sulfonyl chloride resin (same as in example 1), 2 g of NaOH and 25 mL of THF were placed under ice-bath, and the mixture was swollen with stirring.

Solution: in a 100 mL four-necked flask, 2.5 g of mPEG2000 and 50 mL of THF were added under ice-bath to dissolve the substrate completely.

And slowly adding the prepared solution into the mixture in a dropwise manner to form a system to be reacted, and then slowly heating the system to be reacted to room temperature to perform esterification reaction for 20 hours to obtain a first product system. The first product system was filtered and washed with THF and the washings recovered. The obtained resin is mPEG 2000-sulfonyl chloride resin, the weight of the dried resin is increased to 1.68 g (the weight increase of the resin is the grafting amount of mPEG 2000), the purity of the product in the step is 100%, and further purification is not needed.

In the second step, the first step is that,

41 mg of KOtBu and 1 mL of dry THF were added in ice bath, and after stirring for 30 min, a solution of acetone ketal in THF (45. mu.L/400. mu.L) was added, and the reaction was continued for 2 hours in ice bath to obtain an intermediate reaction system. And then adding 1.68 g of the resin in the first step and 12 mL of dry THF into the reaction intermediate system, slowly heating the system to 65 ℃, carrying out substitution reaction for 20 hours to obtain a second product system, cooling the second product system to room temperature, filtering, and sequentially cleaning the resin with ice water and THF for later use and regeneration. Collecting the washing liquid, removing THF by rotary evaporation, extracting the water phase with DCM for three times, and concentrating the DCM phase to obtain mPEG 2000-acetonide.

In the third step, the first step is to use,

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

Example 3

Regeneration of sulfonyl chloride resin: 10 g of the resin prepared from mPEG200-Gly (see example 2 or 3) is taken, 20 mL of thionyl chloride is added for refluxing for more than 8 h, and then the excessive thionyl chloride is distilled off. The remaining system was placed in an ice bath and washed rapidly with ice water, acetone in sequence. And finally, drying the resin at 40 ℃ under reduced pressure to obtain regenerated sulfonyl chloride resin.

mPEG2000 mother liquor recovery: carrying out rotary evaporation and concentration on the DCM in the example 1 to obtain recovered mPEG 2000; in example 2, after rotary evaporation of the THF/water mixed solution, the remaining aqueous phase was extracted three times with DCM, and the DCM phase obtained was rotary evaporated to give the recovered mPEG 2000.

In the first step, the first step is that,

the mixture is as follows: in a 250 mL four-necked flask, 1g of regenerated sulfonyl chloride resin, 2 g of NaOH and 25 mL of THF were placed under ice-bath, and the mixture was swollen with stirring.

Solution: recovered mPEG2000 was added to a 100 mL four-necked flask and supplemented with 2 g mPEG2000, followed by 50 mL THF to dissolve the substrate under ice-bath.

And slowly adding the prepared solution into the mixture in a dropwise manner to form a system to be reacted, and then slowly heating the system to be reacted to room temperature to perform esterification reaction for 20 hours to obtain a first product system. The first product system was filtered and washed with ice water, THF in order and the washings recovered. The obtained resin is mPEG 2000-sulfonyl chloride resin, the weight of the dried resin is increased to 1.70 g (the weight increase of the resin is the grafting amount of mPEG 2000), the purity of the product in the step is 100%, and further purification is not needed.

In the second step, the first step is that,

41 mg of KOtBu and 1 mL of dry THF were added under ice-bath, and after stirring for 30 min, a THF solution of glycerol acetonide (45. mu.L/400. mu.L) was added, and the reaction was continued for 2 hours under ice-bath to obtain a reaction intermediate system. And then adding 1.70 g of the resin and 12 mL of dry THF in the first step into the reaction intermediate system, slowly heating the system to room temperature, then heating to 65 ℃, carrying out substitution reaction for 20 hours to obtain a second product system, cooling the second product system to room temperature, filtering, and sequentially cleaning the resin with ice water and THF for later use and regeneration. Collecting the washing liquid, removing THF by rotary evaporation, extracting the water phase with DCM for three times, and concentrating the DCM phase to obtain mPEG 2000-acetonide.

In the third step, the first step is,

After the reaction was completed, the weight of the resin used was reduced to 1.03 g, the weight of mPEG2000-Gly was 0.48 g, the yield was 69%, and the purity of the product was about 95%.

Example 4

Example 4 differs from example 2 in that the mPEG2000 used had a mass of 0.9 g and the resin had increased to 1.25 g after the post-treatment.

In the second step, the first step is that,

20 mg of KOtBu and 0.5 mL of dry THF were added under ice-bath, and after stirring for 30 min, a THF solution of acetonide (20. mu.L/200. mu.L) was added, followed by continued reaction for 2 hours under ice-bath to obtain a reaction intermediate system. And then adding 1.25 g of the resin in the first step and 12 mL of dry THF into the reaction intermediate system, slowly heating the system to 65 ℃, reacting for 20 hours to obtain a second product system, cooling the second product system to room temperature, filtering, and sequentially cleaning the resin with ice water and THF for later use and regeneration. Collecting the washing liquid, removing THF by rotary evaporation, extracting the water phase with DCM for three times, and concentrating the DCM phase to obtain mPEG 2000-acetonide.

In the third step, the first step is,

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

Example 5

Example 5 differs from example 2 in that the mPEG2000 used in the first step had a mass of 4 g, the resin had been increased to 1.65 g after the post-treatment, and mPEG2000-Gly was finally obtained after the second and third steps, with a yield of 70% and a product purity of 95%.

Example 6

Example 6 differs from example 2 in that the mPEG2000 used in the first step had a mass of 0.5 g, the resin had increased to 1.12 g after the post-treatment, and after the second and third steps, mPEG2000-Gly was finally obtained in 58% yield and 96% purity.

Example 7

Example 7 differs from example 2 in that the mass of mPEG2000 used in the first step is 8 g, the resin after post-treatment is increased to 1.68 g, i.e. increasing the amount of mPEG2000 is not beneficial to the grafting amount of PEG, and after the second and third steps, mPEG2000-Gly is finally obtained with the yield of 71% and the purity of 92%.

Example 8

Example 8 differs from example 2 in that the sulfonyl chloride resin in the first step is a self-made resin, modified from a commercial resin 001 x 7, with a sulfonyl chloride content: 4.61mmol/g, the modification method is the same as the preparation of polystyrene sulfonyl chloride resin and the application thereof in the synthesis of nitrogen-containing alkaline resin, and the weight of the resin is increased to 1.86 g after the post-treatment. After the second step and the third step, mPEG2000-Gly is finally obtained, the yield is 69%, and the product purity is 91%.

Example 9

Example 9 differs from example 2 in that the polyethylene glycol used in the first step is 0.3 g of mPEG ₄ The mass of sulfonyl chloride resin is 1g, 1.19 g of resin grafted with PEG is obtained, 1.5 eq of potassium tert-butoxide and 2 eq of glycerol acetonide are used to complete the second step of reaction based on the loading of PEG grafted on the resin, and finally the mPEG obtained by hydrolysis ₄ The weight of-Gly was 0.17 g, the yield was 89%, and the purity was 89%.

Example 10

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

Example 11

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

Example 12

Example 12 differs from example 2 in that the molecular weight of polyethylene glycol in the first step was 5000, the mass was 7.5 g, the mass of sulfonyl chloride resin was 1g, the weight of the resin obtained in the first step was increased to 2.36 g, and the final mPEG5000-Gly content was 1.1 g, the yield was 81%, and the purity was 98%.

Example 13

Example 13 differs from example 2 in that the molar ratio of sodium hydroxide to mPEG2000 in the first step is 10: 1, the weight of the resulting PEG grafted resin was increased to 1.43 g. mPEG2000-Gly is finally obtained after the second step and the third step, the yield is 75 percent, and the purity is 95 percent.

Example 14

Example 14 differs from example 2 in that the molar ratio of sodium hydroxide to mPEG2000 in the first step is 50: 1, the weight of the resulting PEG grafted resin was increased to 1.68 g. mPEG2000-Gly is finally obtained after the second step and the third step, the yield is 72 percent, and the purity is 95 percent.

Example 15

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

Example 16

Example 16 differs from example 2 in that the weight of the resulting PEG-grafted resin was increased to 1.21 g in the first step using pyridine as an acid scavenger, resulting in a final mPEG2000-Gly yield of 68% and a product purity of 92%.

Example 17

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

Example 18

Example 18 differs from example 2 in that DMAP is added as catalyst in the first step, the molar ratio of DMAP to mPEG2000 is 2.2: 1, increasing the weight of the obtained PEG grafted resin to 1.89 g, and finally obtaining 0.59 g of mPEG2000-Gly with the yield of 69% and the purity of 95%.

Example 19

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

Example 20

Example 20 differs from example 2 in that in the first step, the temperature of the esterification reaction is 90 ℃ and the time of the esterification reaction is 8 h, the weight of the obtained resin grafted with PEG is increased from 1g to 1.33 g, and the weight increase is smaller than that of example 2. 0.22 g of mPEG2000-Gly was obtained in 67% yield and the product purity was about 97%.

Example 21

Example 21 differs from example 2 in that in the second step, the strong basic reagent was NaH, resulting in 0.3 g of mPEG2000-Gly in 44% yield and a product purity of about 82%.

Example 22

Example 22 differs from example 2 in that in the second step, potassium tert-butoxide is reacted with acetonide at 25 ℃ for 4h to give an intermediate system, mPEG2000-Gly in 70% yield and 85% purity.

Example 23

Example 23 differs from example 2 in that,

and in the second step, adding the resin and 12 mL of dry THF in the first step into the reaction intermediate system, slowly returning the system to room temperature, reacting for 20 h to obtain a second product system, filtering the system after the reaction is finished, and sequentially cleaning the resin with ice water and THF for later use and regeneration. Collecting the washing liquid, removing THF by rotary evaporation, extracting the water phase with DCM for three times, and concentrating the DCM phase to obtain mPEG 2000-acetonide.

In the third step, the first step is to use,

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

Example 24

Example 24 differs from example 2 in that in the second reaction step, the reaction was continued for 48 hours after the system was returned to room temperature to obtain a second product system, and the final product mPEG-Gly obtained by hydrolyzing the intermediate had a weight of 0.42 g, a yield of 62% and a product purity of about 92%.

Example 25

Example 25 differs from example 2 in that the concentration of the hydrochloric acid solution used in the hydrolysis reaction in the third step is 1 mol/L, resulting in mPEG2000-Gly with a yield of 72% and a product purity of 88%.

Example 26

Example 26 differs from example 2 in that in the third step, the hydrolysis temperature is 80 ℃ and the hydrolysis time is 5h, finally obtaining mPEG2000-Gly with 74% yield and 91% purity.

The classes of the polyethylene glycol-glycerol derivatives obtained in examples 1 to 26 above, as well as the yields and purities thereof, are listed in table 1.

TABLE 1

As can be seen from the data in table 1 above, when mPEG2000 in example 6 is compared to examples 2, 4, 5: the proportion of sulfonyl chloride resin is 1: 7.12, i.e., outside the range, the amount of mPEG grafted per gram of resin in the first step reaction is significantly reduced, when mPEG 2000: the proportion of sulfonyl chloride resin is 1: 0.445, i.e., outside the range, the amount of mPEG grafted per gram of resin in the first step is not significantly reduced, but results in significant waste of mPEG2000 raw material.

When the molar ratio of the acid-binding agent to the polyethylene glycol in example 15 is outside the range, the grafting amount of mPEG per gram of resin in the first reaction step in example 15 is significantly reduced, compared with examples 2, 13 and 14.

Example 19 had too little DMAP catalyst added and no DMAP catalyst added to be nearly as effective as examples 2, 17, and 18.

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

The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

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.