WO2023201805A1 - Method for preparing polyethylene glycol-glycerol derivative and intermediate thereof - Google Patents

Abstract

The present invention provides a method for preparing a polyethylene glycol-glycerol derivative and an intermediate thereof. The method comprises: performing an esterification reaction on a starting material comprising polyethylene glycol and a sulfonyl chloride resin to give a first product system comprising the intermediate of the polyethylene glycol-glycerol derivative. At least one end group of the polyethylene glycol is hydroxyl, and the sulfonyl chloride resin is a polystyrene resin containing a sulfonyl chloride group. By utilizing the solid-phase characteristics of the sulfonyl chloride resin as a resin macromolecule, the product system comprising the intermediate of the polyethylene glycol-glycerol derivative can be prepared by means of a solid-phase synthesis method. In the resultant product system, the intermediate of the polyethylene glycol-glycerol derivative can be easily separated by a solid-liquid separation method and used for subsequent reactions, which greatly simplifies the separation and purification procedures and can acquire the target product with high yield and purity. All of the reagents used in the preparation process can be recycled, which greatly improves the cost-efficiency.

Description

Preparation methods of polyethylene glycol-glycerin derivatives and intermediates thereof

This application is based on the Chinese application with CN application number 202210424440.4 and the filing date is April 22, 2022, and claims its priority. The disclosure content of the CN application is once again introduced into this application as a whole.

Technical field

The present invention relates to the technical field of preparation of polyethylene glycol-glycerin derivatives, and specifically, to a method for preparing each polyethylene glycol-glycerin derivative and its intermediate.

Background technique

Polyethylene glycol (PEG) is a polymer with the structure H(OCH ₂ -CH ₂ ) _n OH. As an amphiphilic molecule, PEG is not only soluble in water, but also soluble in organic solvents. Therefore, even substances that are poorly soluble in water can be converted into hydrophilic substances when coupled with PEG. In drug development research, modified polyethylene glycol is coupled to proteins, peptides, small molecule organic drugs and liposomes by certain means, which can increase the half-life of protein or peptide drugs in the body, reduce immunogenicity, and increase Water solubility and targeting of drugs. The combination of modified PEG and liposomes can also make liposomes have a stronger passive targeting effect on tumors. Therefore, the development of efficient and simple PEG modification processes is of great research significance in the fields of bioengineering and drug development.

Modifications to PEG include modification of active functional groups such as polyethylene glycol maleimide derivatives (PEG-Mal), polyethylene glycol succinimide derivatives (PEG-NHS), polyethylene glycol aldehyde groups Derivatives (PEG-ALD), etc., also include the preparation of polyethylene glycol glycerol derivatives (PEG-Gly) used for PEG synthesis intermediates or liposomes. The traditional PEG modification process is usually liquid phase synthesis of small molecules. For example, in the US patents with patent application numbers US6828401 and US10752732, the preparation process of PEG-Mal and PEG-CM (polyethylene glycol carboxyl derivatives) involves multiple tedious steps. It is difficult to achieve higher target product purity during separation and purification operations.

The preparation of PEG-Gly used for PEG synthesis intermediates or liposomes also faces the above problems. Currently, there are two processes for the preparation of PEG-Gly. The first is to use epichlorohydrin to replace the PEG terminal hydroxyl group, and then hydrolyze the epoxy group to obtain the target product; the second is to first combine PEG with paramethylmethacrylate in the Chinese patent application No. CN102665685A. Benzene sulfonyl chloride undergoes an ester-forming reaction, and is subsequently substituted with activated acetone glycidyl chloride. The obtained intermediate product is acidolyzed to obtain the target product. No matter which route is mentioned above, it involves the separation and extraction operation of the intermediate product, otherwise it will further contaminate the subsequent target product. Therefore, the multi-step separation process not only makes the entire preparation process cumbersome, but also increases the production cost of the process.

Contents of the invention

The main purpose of the present invention is to provide a method for preparing polyethylene glycol-glycerol derivatives and intermediates thereof, so as to solve the problems of cumbersome 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, a method for preparing a polyethylene glycol-glycerol derivative intermediate is provided, which method includes: esterifying raw materials including polyethylene glycol and sulfonyl chloride resin. Reaction to obtain a first product system including a polyethylene glycol-glycerin derivative intermediate, and at least one terminal group of the 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 to 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 commercial strong acid resin 001*7. one or more.

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

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

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

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

Furthermore, the above preparation method also includes subjecting the first product system to a first solid-liquid separation 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 method for preparing a polyethylene glycol-glycerol derivative is provided. The polyethylene glycol-glycerol derivative has a structure represented by 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 between the polyethylene glycol-glycerol derivative intermediate and acetone glycidol to obtain compound 1; compound 1 has the structure shown in formula III:

Step S3: Compound 1 is subjected to a hydrolysis reaction to obtain a polyethylene glycol-glycerol derivative.

Further, the above step S2 includes: reacting a strong alkaline reagent with acetone glycidyl at 0-25°C to obtain a reaction intermediate system; reacting the reaction intermediate system with a 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. 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, which is preferably strongly alkaline. The reagent is selected from any one or more of KOtBu, NaH, and butyllithium. The preferred reaction time is 1 to 4 hours, and the preferred substitution reaction time is 15 to 24 hours. The preferred preparation method also includes: washing the solid phase, A regenerated sulfonyl chloride resin is obtained. The regenerated sulfonyl chloride resin is preferably used in the esterification reaction of step S1. It is preferred that the second solid-liquid separation is filtration, and the reaction is preferably carried out in an ice bath.

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

Applying the technical solution of the present invention, this application utilizes the resin polymer solid phase properties of sulfonyl chloride resin and adopts a solid phase synthesis method to prepare a product system containing polyethylene glycol-glycerin derivative intermediates. Specifically, sulfonyl chloride The sulfonyl chloride group in the resin undergoes an esterification reaction with the hydroxyl group in polyethylene glycol to remove small molecular hydrogen chloride. The resulting first product system only needs to be derived from polyethylene glycol-glycerin through a simple solid-liquid separation method. The intermediates are isolated and used in subsequent reactions. Due to the polymer insolubility of the polyethylene glycol-glycerol derivative intermediate, in addition to the hydrolysis reaction, the subsequent reaction is still a solid-phase synthesis reaction, and the resulting product system can still be separated and purified using a simple solid-liquid separation method, and Comparison of traditional liquid-phase small molecule synthesis routes for PEG-Gly, which avoids the multi-step tedious separation and purification operations in liquid-phase synthesis, greatly simplifies the separation and purification operations, and makes it easier to obtain high-yield, high-purity target products. Moreover, the reagents used in the preparation process can be recycled, which greatly reduces the process cost.

Description of the drawings

The description and drawings that constitute a part of this application are used to provide a further understanding of the present invention. The illustrative 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 picture:

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

Detailed ways

It should be noted that, as long as there is no conflict, the embodiments and features in the embodiments of this application can be combined with each other. The present invention will be described in detail below with reference to the accompanying drawings and embodiments.

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

In a typical embodiment of the present application, a method for preparing a polyethylene glycol-glycerol derivative intermediate is provided. The preparation method includes: esterifying raw materials including polyethylene glycol and sulfonyl chloride resin. Reaction to obtain a first product system including a polyethylene glycol-glycerin derivative intermediate, and at least one terminal group of the 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

This application utilizes the solid phase properties of the resin polymer of the sulfonyl chloride resin and uses a solid phase synthesis method to prepare a product system containing polyethylene glycol-glycerin derivative intermediates. Specifically, the sulfonyl chloride group in the sulfonyl chloride resin Perform an esterification reaction with the hydroxyl group in polyethylene glycol to remove small molecule hydrogen chloride. The first product system obtained only needs a simple solid-liquid separation method to separate the polyethylene glycol-glycerol derivative intermediate and use it. Subsequent reactions. Due to the polymer insolubility of the polyethylene glycol-glycerol derivative intermediate, in addition to the hydrolysis reaction, the subsequent reaction is still a solid-phase synthesis reaction, and the resulting product system can still be separated and purified using a simple solid-liquid separation method, and Comparison of traditional liquid-phase small molecule synthesis routes for PEG-Gly, which avoids the multi-step tedious separation and purification operations in liquid-phase synthesis, greatly simplifies the separation and purification operations, and makes it easier to obtain high-yield, high-purity target products. Moreover, the reagents used in the preparation process can be recycled, which greatly reduces the process cost.

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

The derivative sulfonyl chloride resin of the above-mentioned commercial strong acid resin 001*7 can use strong acid resin 001*7 as the reaction raw material and adopt the method disclosed in "Preparation of polystyrene sulfonyl chloride resin and its application in the synthesis of nitrogen-containing alkaline resin" The corresponding sulfonyl chloride resin is prepared by the preparation method.

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

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

The polyethylene glycol in the above molecular weight range and the molar ratio range of the sulfonyl chloride group of polyethylene glycol and the sulfonyl chloride resin can provide polyethylene glycol-glycerin derivative intermediates with a wider molecular weight range, and polyethylene glycol and sulfonyl chloride resin The molar ratio range of the sulfonyl chloride group of the acid chloride resin is conducive to improving the esterification reaction efficiency of polyethylene glycol with different molecular weights and the sulfonyl chloride resin, and grafting polyethylene glycol to the solid phase sulfonyl chloride resin as much as possible to obtain There are abundant polyethylene glycol-glycerol derivatives, and the polyethylene glycol-glycerol derivative intermediate with the structure shown in the preferred formula I can correspond to the polyethylene glycol-glycerol derivatives that are more suitable for the current market demand.

In one 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 to polyethylene glycol is 10 to 50:1. Preferably, the acid-binding agent is selected from NaOH, KOH, and triethylamine. , any one or more of pyridine. The above-mentioned esterification reaction requires removal of hydrogen chloride molecules, preferably under the action of the above-mentioned acid binding agent, which is beneficial to removing hydrogen chloride molecules as much as possible, thereby promoting the progress of the esterification reaction.

Preferably, the above-mentioned raw materials also include a catalyst. Preferably, the molar ratio of the catalyst to polyethylene glycol is 0.05 to 2.2:1. Preferably, the catalyst is an alkaline substance. Preferably, the alkaline substance is 4-dimethylaminopyridine, thereby promoting the esterification reaction. .

In order to improve the efficiency of the esterification reaction, the temperature of the above-mentioned esterification reaction is preferably 0 to 90°C, and the time of the esterification reaction is preferably 4 to 72 hours.

In one embodiment of the present application, the above preparation method further includes subjecting the first product system to a first solid-liquid separation to obtain a polyethylene glycol-glycerol derivative intermediate. Preferably, the first solid-liquid separation is filtration. The above polyethylene glycol-glycerin derivative intermediate is insoluble in organic solvents (including low molecular weight polyethylene glycol), and high molecular weight polyethylene glycol is solid, so the polyethylene glycol-glycerin derivative intermediate 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 method for preparing a polyethylene glycol-glycerol derivative is provided. The polyethylene glycol-glycerol derivative has a structure shown in 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 between the polyethylene glycol-glycerol derivative intermediate and acetone glycerol to obtain compound 1; Compound 1 has the structure shown in formula III:

Step S3: Compound 1 is subjected to a hydrolysis reaction to obtain a polyethylene glycol-glycerol derivative.

Steps S1 and S2 in the above-mentioned preparation method of the present application adopt a solid-phase synthesis method. The obtained product system can be separated from the target product through simple solid-liquid separation. Finally, compound 1 with the structure shown in formula III is hydrolyzed The polyethylene glycol-glycerin derivative can be obtained through the reaction, and finally the polyethylene glycol-glycerin derivative can be obtained in high yield through simple extraction. It can be seen that compared with the traditional liquid phase small molecule synthesis route of PEG-Gly, it avoids the multi-step tedious separation and purification operations in liquid phase synthesis, greatly simplifies the separation and purification operations, and makes it easier to obtain high yield and high purity targets. product. And the reagents used in the preparation process can be recycled, which greatly reduces the process cost.

In one embodiment of the present application, the above-mentioned step S2 includes: reacting a strong alkaline reagent with acetone glycidol at 0-25°C to obtain a reaction intermediate system; and reacting the reaction intermediate system with poly(glycidol) at 0-65°C. The ethylene glycol-glycerol derivative intermediate undergoes a substitution reaction to obtain a second product system including compound 1. 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 subjected to extraction separation (for example, , use dichloromethane to extract and separate the obtained liquid phase three times) to obtain compound 1. Preferably, the strong alkaline reagent is selected from any one or more of KOtBu, NaH, and butyllithium. The preferred reaction time is 1 to 4h, preferably the substitution reaction time is 15 to 24h, preferably the second solid-liquid separation is filtration, and preferably the reaction is carried out in an ice bath.

The above reaction uses the action of a strong base to remove the hydrogen from the hydroxyl group of acetone glycidyl to obtain an oxygen anion intermediate. This reaction is obviously exothermic and dangerous, so it is preferred to react under the above conditions first to generate a large amount of oxygen anion intermediates, and then The oxygen anion intermediate is subjected to a substitution reaction with the solid-phase polyethylene glycol-glycerol derivative intermediate to obtain a second product system including the structure shown in formula III. By utilizing the insolubility of compound 1, it can be obtained by simple filtration. Compound 1 is isolated, and compound 1 undergoes hydrolysis reaction to obtain polyethylene glycol-glycerol derivatives.

In addition, the preferred preparation method also includes: washing the solid phase to obtain a regenerated sulfonyl chloride resin. The regenerated sulfonyl chloride resin is preferably used in the esterification reaction of step S1, thereby greatly reducing the cost and being more environmentally friendly.

In order to improve the efficiency of the above-mentioned hydrolysis reaction, it is preferred that the H ⁺ concentration of the above-mentioned 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 hours.

The beneficial 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 can be purchased directly or can be purchased from DOI: 10.1007/s00289-005-0417-y or "Preparation of polystyrene sulfonyl chloride resin and its application in the synthesis of nitrogen-containing alkaline resin" Obtained from the disclosed preparation method.

Example 1

first step,

Mixture: At room temperature, add 1g of sulfonyl chloride resin (Nankai Hecheng Co., Ltd., model: HC9001-1-1, sulfonyl chloride content: 1.78mmol/g) and 25mL of DCM into a 250mL four-neck bottle, stir and swell. A mixture is obtained.

Solution: Under ice bath, add 2.5g of mPEG2000 and 50mL of DCM into a 100mL four-neck bottle. After the substrate is completely dissolved, add 30mg of 4-dimethylaminopyridine (DMAP) and 4mL of triethylamine, and continue stirring for 15 minutes.

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 to perform an esterification reaction for 20 hours to obtain the first product system. The first product system was filtered and washed with DCM, and the washing liquid was recovered. The obtained resin is mPEG2000-sulfonyl chloride resin. After drying, the weight of the resin increases to 1.37g (the weight gain of the resin is the grafting amount of mPEG2000). The purity of the product 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 minutes, then add a THF solution of glycidyl acetone (the concentration of glycidyl acetone itself is close to 100%) (25 μL/200 μL), and continue the reaction under an ice bath for 2 hours to obtain Reaction intermediate system. Then add 1.37g of the resin in the first step and 12 mL of dry THF to the reaction intermediate system, slowly heat the system to 65°C, and perform a substitution reaction for 20 hours (including the heating time) to obtain the second product system. The product system was lowered to room temperature and filtered. The resin was washed with ice water and THF in sequence and set aside for regeneration. Collect the washing liquid, spin off the THF and extract the water phase three times with DCM. Concentrate the DCM phase to obtain mPEG2000-acetone glycidyl.

third step,

mPEG2000-glycidyl acetate was placed in 2 mol/L hydrochloric acid solution and hydrolyzed at 60°C for 8 hours to obtain the target product mPEG2000-Gly.

After the reaction was completed, the weight of the resin used was reduced to 1.02g, that is, the grafted PEG was almost completely replaced. The weight of mPEG2000-Gly is 0.25g, the yield is 68%, and the product purity is about 95%. Among them, the high-resolution liquid mass spectrometry (TOF) detection results of mPEG2000-Gly are shown in Figure 1.

Example 2

first step,

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

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

The above prepared solution was slowly added dropwise into the mixture to form a system to be reacted, and then the system to be reacted was slowly raised to room temperature to perform an esterification reaction for 20 hours to obtain the first product system. The first product system was filtered and washed with THF, and the washing liquid was recovered. The obtained resin is mPEG2000-sulfonyl chloride resin. After drying, the weight of the resin increases to 1.68g (the weight gain of the resin is the grafting amount of mPEG2000). The purity of the product in this step is 100%, and no further purification is required.

The second step,

Add 41 mg of KOtBu and 1 mL of dry THF under an ice bath, stir for 30 minutes, add 45 μL/400 μL of acetone glycidyl THF solution, and continue the reaction under an ice bath for 2 hours to obtain an intermediate reaction system. Then, 1.68g 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. The substitution reaction was carried out for 20 hours to obtain the second product system. The second product system was lowered to room temperature and filtered. The resin was Wash with ice water and THF in sequence and set aside for regeneration. Collect the washing liquid, spin-evaporate the THF, extract the aqueous phase three times with DCM, and concentrate the DCM phase to obtain mPEG2000-glycidyl acetone.

third step,

mPEG2000-glycidyl acetate was placed in 2 mol/L hydrochloric acid solution and hydrolyzed at 60°C for 8 hours to obtain the target product mPEG2000-Gly.

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

Example 3

Regeneration of sulfonyl chloride resin: Take 10 g of the resin prepared by mPEG200-Gly (see Example 2 or 3), add 20 mL of thionyl chloride and reflux for more than 8 hours, and then evaporate excess thionyl chloride. The remaining system was placed in an ice bath and quickly washed with ice water and acetone in sequence. Finally, the resin was dried under reduced pressure at 40°C to obtain the regenerated sulfonyl chloride resin.

Recovery of mPEG2000 mother liquor: The DCM phase in Example 1 is rotary evaporated and concentrated to obtain recovered mPEG2000; in Example 2, after the THF/water mixed solution is rotary evaporated, the remaining aqueous phase is extracted three times with DCM, and the resulting DCM phase is rotary evaporated. That is, the recovered mPEG2000 is obtained.

first step,

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

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

The above prepared solution was slowly added dropwise into the mixture to form a system to be reacted, and then the system to be reacted was slowly raised to room temperature to perform an esterification reaction for 20 hours 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. After drying, the weight of the resin increases to 1.70g (the weight gain of the resin is the grafting amount of mPEG2000). The purity of the product in this step is 100%, and no further purification is required.

The second step,

Add 41 mg of KOtBu and 1 mL of dry THF under an ice bath, stir for 30 minutes, add acetone glycidyl THF solution (45 μL/400 μL), and continue the reaction under an ice bath for 2 hours to obtain an intermediate reaction system. Then, 1.70g of the resin in the first step and 12mL of dry THF were added to the reaction intermediate system, and the system was slowly raised to room temperature and then to 65°C. The substitution reaction was carried out for 20 hours to obtain the second product system. The second product system was lowered to room temperature and Filter, wash the resin with ice water and THF in sequence and set it aside for regeneration. Collect the washing liquid, spin-evaporate the THF, extract the aqueous phase three times with DCM, and concentrate the DCM phase to obtain mPEG2000-glycidyl acetone.

third step,

mPEG2000-glycidyl acetate was placed in 2 mol/L hydrochloric acid solution and hydrolyzed at 60°C for 8 hours to obtain the target product mPEG2000-Gly.

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

Example 4

The difference between Example 4 and Example 2 is that the mass of mPEG2000 used is 0.9g, and the weight of the resin increases to 1.25g after post-processing.

The second step,

Add 20 mg of KOtBu and 0.5 mL of dry THF under an ice bath, stir for 30 min, add acetone glycidyl THF solution (20 μL/200 μL), and continue the reaction under an ice bath for 2 h to obtain an intermediate reaction system. Then 1.25g of the resin in the first step and 12mL of dry THF were added to the reaction intermediate system, and the system was slowly heated to 65°C. The reaction was carried out for 20 hours to obtain the second product system. The second product system was lowered to room temperature and filtered. The resin was treated with ice water. and THF are washed in sequence and reserved for standby regeneration. Collect the washing liquid, spin-evaporate the THF, extract the aqueous phase three times with DCM, and concentrate the DCM phase to obtain mPEG2000-glycidyl acetone.

third step,

mPEG2000-glycidyl acetate was placed in 2 mol/L hydrochloric acid solution and hydrolyzed at 60°C for 8 hours to obtain the target product mPEG2000-Gly.

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

Example 5

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

Example 6

The difference between Example 6 and Example 2 is that the mass of mPEG2000 used in the first step is 0.5g. After post-processing, the weight of the resin increases to 1.12g. 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 8g. After post-treatment, the weight of the resin increases to 1.68g. That is, increasing the amount of mPEG2000 is not beneficial to the PEG grafting amount. After the second and third steps, the weight of the resin increases to 1.68g. After this step, 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 derived and modified from commercial resin 001*7. The sulfonyl chloride content: 4.61mmol/g, the modification method is the same as "Polystyrene Sulfonate" Preparation of acid chloride resin and its application in the synthesis of nitrogen-containing alkaline resin", the weight of the resin increased to 1.86g 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 0.3g of mPEG ₄ , the mass of the sulfonyl chloride resin is 1g, and 1.19g of resin grafted with PEG is obtained. Based on the PEG loading amount on the substrate, 1.5eq of potassium tert-butoxide and 2eq of glycidyl acetone were used to complete the second step of the reaction. The final weight of mPEG ₄ -Gly obtained after hydrolysis was 0.17g, the yield was 89%, and the purity was 89%.

Example 10

The difference between Example 10 and Example 2 is that in the first step, the polyethylene glycol is 0.6g of mPEG ₈ and the mass of the sulfonyl chloride resin is 1g. The final weight of mPEG ₈ -Gly is 0.31g, and the yield is 76 %, purity is 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 and the mass is 4.4g. The mass of the sulfonyl chloride resin is 1g. The final mPEG3500-Gly is 0.75g and the yield is 77 %, purity is 97%.

Example 12

The difference between Example 12 and Example 2 is that the molecular weight of polyethylene glycol in the first step is 5000 and the mass is 7.5g. The mass of the sulfonyl chloride resin is 1g. The weight of the resin obtained in the first step increases to 2.36g. The final mPEG5000-Gly obtained was 1.1g, with a yield of 81% and a purity of 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 is 10:1, and the weight of the obtained PEG graft resin increases to 1.43g. 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 is 50:1, and the weight of the obtained PEG graft resin increases to 1.68g. 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 is 8:1, and the weight of the obtained PEG graft resin increases to 1.29g. 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 is used as the acid binding agent, the weight of the obtained PEG graft resin increases to 1.21g, the final mPEG2000-Gly yield is 68%, and the product purity is 92 %.

Example 17

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

Example 18

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

Example 19

The difference between Example 19 and Example 2 is that DMAP is added as a catalyst in the first step. The molar ratio of DMAP to mPEG2000 is 0.03:1. The weight of the obtained PEG graft resin increases to 1.68g, and finally mPEG2000-Gly 0.49g is 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 is 90°C, the time of the esterification reaction is 8 hours, and the weight of the obtained grafted PEG resin increases from 1g to 1.33g. Smaller than Example 2. Finally, 0.22g of mPEG2000-Gly was obtained, with a yield of 67% and a product purity of approximately 97%.

Example 21

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

Example 22

The difference between Example 22 and Example 2 is that in the second step, the reaction of potassium tert-butoxide and glycidyl acetone is carried out at 25°C. After 4 hours of reaction, an intermediate reaction system is obtained, and finally mPEG2000-Gly is obtained with a yield of 70%. , the product purity is 85%.

Example 23

The difference between Example 23 and Example 2 is that,

In the second step, add the resin from the first step and 12 mL of dry THF to the reaction intermediate system, and slowly return the system to room temperature. React for 20 hours to obtain the second product system. After the reaction is completed, the system is filtered, and the resin is washed with ice water and THF in sequence. Reserved for later regeneration. Collect the washing liquid, spin-evaporate the THF, extract the aqueous phase three times with DCM, and concentrate the DCM phase to obtain mPEG2000-glycidyl acetone.

third step,

mPEG2000-glycidyl acetate was placed in 2 mol/L hydrochloric acid solution and hydrolyzed at 60°C for 8 hours to obtain the target product mPEG2000-Gly.

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

Example 24

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

Example 25

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

Example 26

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

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

Table 1

It can be seen from the data in Table 1 above that compared with Examples 2, 4, and 5, when the ratio of mPEG2000:sulfonyl chloride resin in Example 6 is 1:7.12, that is, when it is outside the range, every The mPEG grafting amount 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 mPEG grafting amount per gram of resin in the first step reaction will not. Significantly reduced, but it 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 to polyethylene glycol in Example 15 is outside the range, the grafting amount of mPEG 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:

This application utilizes the solid phase properties of the resin polymer of the sulfonyl chloride resin and uses a solid phase synthesis method to prepare a product system containing polyethylene glycol-glycerin derivative intermediates. Specifically, the sulfonyl chloride group in the sulfonyl chloride resin Perform an esterification reaction with the hydroxyl group in polyethylene glycol to remove small molecule hydrogen chloride. The first product system obtained only needs a simple solid-liquid separation method to separate the polyethylene glycol-glycerol derivative intermediate and use it. Subsequent reactions. Due to the polymer insolubility of the polyethylene glycol-glycerol derivative intermediate, in addition to the hydrolysis reaction, the subsequent reaction is still a solid-phase synthesis reaction, and the resulting product system can still be separated and purified using a simple solid-liquid separation method, and Comparison of traditional liquid-phase small molecule synthesis routes for PEG-Gly, which avoids the multi-step tedious separation and purification operations in liquid-phase synthesis, greatly simplifies the separation and purification operations, and makes it easier to obtain high-yield, high-purity target products. Moreover, 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 modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention shall be included in the protection scope of the present invention.

Claims (18)

1. A method for preparing a polyethylene glycol-glycerin derivative intermediate, characterized in that the preparation method includes:

   The raw materials including polyethylene glycol and sulfonyl chloride resin are subjected to an esterification reaction to obtain a first product system including a polyethylene glycol-glycerol derivative intermediate, and at least one end group of the polyethylene glycol is a hydroxyl group,

   Wherein, the sulfonyl chloride resin is a polystyrene resin containing a sulfonyl chloride group, and the structural formula of the sulfonyl chloride resin is expressed as

   
2. The preparation method according to claim 1, wherein 1 g of the sulfonyl chloride resin contains 1.78 to 4.61 mmol of sulfonyl chloride groups.
3. The preparation method according to claim 2, characterized in that the sulfonyl chloride resin is selected from any one or more of HC9001-1-1 sulfonyl chloride resin and commercial strong acid resin 001*7 derived sulfonyl chloride resin. .
4. The preparation method according to any one of claims 1 to 3, characterized in that the molecular weight of the polyethylene glycol is 194-5000.
5. The preparation method according to claim 4, characterized in that the molar ratio of the sulfonyl chloride group of the polyethylene glycol to the sulfonyl chloride resin is 1:0.9-4, and the other end of the polyethylene glycol The group is a hydroxyl or protecting group functional group.
6. The preparation method according to claim 5, characterized in that the protecting group functional group is selected from any one of methoxy, tert-butoxy and benzyloxy.
7. The preparation method according to claim 6, characterized in that the polyethylene glycol-glycerol derivative intermediate has the structure shown in formula I:

   
8. The preparation method according to any one of claims 1 to 3, characterized in that the raw materials further include an acid binding agent.
9. The preparation method according to claim 8, characterized in that the molar ratio of the acid binding agent to the polyethylene glycol is 10 to 50:1, and the acid binding agent is selected from the group consisting of NaOH, KOH, triethylamine, Any one or more of pyridines.
10. The preparation method according to any one of claims 1 to 3, characterized in that the raw material further includes a catalyst.
11. The preparation method according to claim 10, characterized in that the molar ratio of the catalyst to the polyethylene glycol is 0.05-2.2:1, and the catalyst is an alkaline substance.
12. The preparation method according to claim 11, characterized in that the alkaline substance is 4-dimethylaminopyridine.
13. The preparation method according to any one of claims 1 to 3, characterized in that the temperature of the esterification reaction is 0-90°C, and the time of the esterification reaction is 4-72 hours.
14. The preparation method according to claim 1, characterized in that the preparation method further includes subjecting the first product system to a first solid-liquid separation to obtain the polyethylene glycol-glycerin derivative intermediate.
15. A method for preparing polyethylene glycol-glycerol derivatives, characterized in that the polyethylene glycol-glycerol derivative has a structure represented by formula II:

    

    The preparation method includes:

    Step S1, using the preparation method described in any one of claims 1 to 14 to obtain a polyethylene glycol-glycerol derivative intermediate;

    Step S2, perform a substitution reaction between the polyethylene glycol-glycerin derivative intermediate and acetone glycidyl to obtain compound 1; the compound 1 has the structure shown in formula III:

    

    In step S3, the compound 1 is subjected to a hydrolysis reaction to obtain the polyethylene glycol-glycerol derivative.
16. The preparation method according to claim 15, characterized in that step S2 includes:

    Make a strong alkaline reagent react with acetone glycidyl at 0 to 25°C to obtain a reaction intermediate system;

    The reaction intermediate system is subjected to the substitution reaction with the polyethylene glycol-glycerol derivative intermediate at 0 to 65°C to obtain a second product system including the compound 1,

    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 subjected to extraction and separation to obtain the compound 1.
17. The preparation method according to claim 16, characterized in that:

    The strong alkaline reagent is selected from any one or more of KOtBu, NaH, and butyllithium,

    The reaction time is 1 to 4 hours, and the substitution reaction time is 15 to 24 hours.

    The preparation method also includes: washing the solid phase to obtain a regenerated sulfonyl chloride resin, and using the regenerated sulfonyl chloride resin for the esterification reaction of step S1,

    The reaction was carried out in an ice bath.
18. The preparation method according to claim 16, characterized in that the H ⁺ concentration of the hydrolysis reaction is 0.1~4mol/L, the temperature of the hydrolysis reaction is 40~80°C, and the time of the hydrolysis reaction is 2~ 24h.

Images