Preparation method of polyethylene glycol

Abstract

The invention relates to the technical field of organic synthesis, and particularly provides a preparation method of polyethylene glycol, which comprises the following steps: S1, reacting triethylene glycol with triphenylchloromethane to generate a first intermediate; s2, reacting the first intermediate with paratoluensulfonyl chloride to generate a second intermediate; s3, reacting the second intermediate with a diol compound to generate a third intermediate; and S4, removing a protecting group at the tail end of the third intermediate to obtain the polyethylene glycol. According to the preparation method provided by the embodiment of the invention, the purification method of the intermediate product is simple, the operation condition is mild and simple, the production cost is reduced, the operation is convenient, and the method is more suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of compound preparation, and more specifically, relates to a method for preparing polyglycol. Background Art

[0002] When polyethylene glycol (PEG) is incorporated into peptides, proteins and biopolymers, the physical properties and biological activities of these compounds are usually changed. Therefore, some precise length polyethylene glycols are widely used in the design and synthesis of biomolecules. PEG is commercially available in various molecular weights, but only a limited number of precise length polyethylene glycols are high-purity. With the increasing interest in the use of polyethylene glycol in polymer solid phase synthesis, cyclic ethers and new materials, the synthesis of some high-purity precise length polyethylene glycols has been reported. At present, the disclosed process routes for nonaethylene glycol all use triethylene glycol as the starting material. The specific methods are mainly the following: Route 1 (as shown in the following formula (4)): Using triethylene glycol as the starting material, first monobenzyl protection is performed to obtain intermediate-1, then p-toluenesulfonyl chloride is used to protect intermediate-2, and then the intermediate-3 is synthesized with a dibenzyl protection, and finally deprotection is performed to obtain nonaethylene glycol ( J. Org. Chem. 2006, 71（26） , 9884-9886; Tetrahedron Letters 2001, 42 ,3819-3822.).

[0003] (4) However, although the intermediate-1 in the first step of the method is a high-boiling oil that can be purified by vacuum distillation, the intermediate-2 and intermediate-3 in the second and third steps are also oily and require column chromatography purification. If the intermediate-2 is not purified, the column chromatography separation of the intermediate-3 is very difficult, the operation is cumbersome, and the cost is high, and even the purity of the nonaglycone is unqualified. In addition, the use of sodium hydride in the first and third steps and the operation of palladium carbon hydrogenation in the fourth step make the process costly and difficult to scale up, making it difficult to apply to industrial production. Summary of the invention

[0004] In view of this, the object of the present invention is to provide a method for preparing polyethylene glycol which is simple to operate and convenient to purify, and which can be used not only for synthesizing nonaethylene glycol, but also for synthesizing heptaethylene glycol, octaethylene glycol and decaethylene glycol.

[0005] In order to solve the above technical problems, the present invention adopts the following technical solutions.

[0006] According to the method for preparing polyglycol in an embodiment of the present invention, the structural formula of the polyglycol is as shown in formula (1): (1) The preparation method comprises the following steps: Step S1, triethylene glycol reacts with triphenylmethane to generate a first intermediate, wherein the first intermediate is 2-[(1,1,1-triphenyl-2,5-dioxahept-7-yl)oxy]ethan-1-ol; Step S2, the first intermediate reacts with p-toluenesulfonyl chloride to generate a second intermediate, wherein the second intermediate is 4-methylbenzenesulfonic acid-1,1,1-triphenyl-2,5,8-trioxadecan-10-yl ester; Step S3, the second intermediate reacts with a diol compound to generate a third intermediate, wherein the diol compound has a structural formula as shown in formula (2): (2) The structural formula of the third intermediate is shown in formula (3): (3); Step S4, removing the terminal protecting group of the third intermediate to obtain the polyglycol.

[0007] In some embodiments of the present invention, the reaction of step S1 is carried out in a dichloromethane solvent in the presence of a first base, wherein the first base is selected from one or more of triethylamine, diisopropyldiethylamine, and bicyclic amidine. In step S1, the molar ratio of triethylene glycol: first base: triphenylmethane is (3-20): (2.0-3.0): 1, the reaction temperature is 0-30°C, and the reaction time is 5-24 hours.

[0008] In some embodiments of the present invention, after the reaction of step S1 is completed, the reaction solution is directly washed with water, dried, filtered, and concentrated to obtain a crude product, which is directly used in step S2 to synthesize the second intermediate.

[0009] In some embodiments of the present invention, the reaction of step S2 is carried out in a dichloromethane solvent in the presence of a second base, the second base is selected from one or more of sodium hydroxide, potassium hydroxide, triethylamine, diisopropyldiethylamine, and bicyclic amidine, the molar ratio of the first intermediate: the second base: p-toluenesulfonyl chloride is 1.0: (2.0-4.0): (1.0-1.2), the reaction temperature is 0-30 ° C, and the reaction time is 2-24 hours.

[0010] In some embodiments of the present invention, after the reaction of step S2 is completed, the reaction solution is directly washed with water, dried, filtered, and concentrated to obtain a crude oily product, which is recrystallized with ethyl acetate and petroleum ether to obtain the second intermediate, which is an off-white solid with a purity of ≥97%.

[0011] In some embodiments of the present invention, step S3 is performed in a first solvent in the presence of a third base, the first solvent is selected from any one or more of dichloromethane, dichloroethane, tetrahydrofuran or 2-methylfuran, and the third base is selected from one or more of potassium tert-butoxide, sodium tert-butoxide, and sodium hydride.

[0012] In some embodiments of the present invention, the third base is potassium tert-butoxide, and in step S3, the molar ratio of the second intermediate: potassium tert-butoxide: diol compound is 2.0: (2.0-8.0): 1.0, the reaction temperature is 0-70°C, and the reaction time is 5-48 hours.

[0013] In some embodiments of the present invention, in step S3, after the reaction is completed, the reaction solution is quenched and concentrated, and then directly extracted and separated, dried, filtered, and concentrated to obtain a crude product, and the crude product is washed through a short column to obtain a third intermediate with a purity of ≥97%.

[0014] In some embodiments of the present invention, in step S4, the third intermediate is deprotected in the presence of an acid to obtain the polyglycol, wherein the acid is selected from one or more of hydrochloric acid, acetic acid and sulfuric acid, the mass of the acid is 5-10 times that of the third intermediate, the reaction temperature is 0-40°C, and the reaction time is 2-24 hours.

[0015] In some embodiments of the present invention, after the reaction of step S4 is completed, the reaction solution is directly filtered, washed with water, the mother liquor is decolorized with activated carbon, filtered, and concentrated to obtain a crude product as an oily substance, and dichloromethane is added to the crude product to stir, filter, and concentrate to obtain the polyglycol as a colorless oily substance with a purity of ≥99%.

[0016] The above technical solution of the present invention has at least one of the following beneficial effects: According to the preparation method of the polyglycol of the embodiment of the present invention, compared with the existing preparation method in which each intermediate is an oily substance with a high boiling point, the first intermediate obtained in the first step does not need to be purified, but is purified by recrystallization in the second step which is simpler and easier to purify to obtain a solid second intermediate, thereby avoiding high-temperature distillation and column chromatography, being easy to operate, and being able to obtain a second intermediate with high purity, which helps to improve the purity of the final product polyglycol; Furthermore, the synthesis of the third intermediate not only improves the safety of production but also further reduces the production cost by replacing sodium hydride with potassium tert-butoxide; By reacting substrate diol compounds with different chain lengths with the second intermediate, a third intermediate with different carbon chain lengths can be obtained, and polyglycols with different carbon chain lengths can be obtained by hydrolysis; According to the preparation method of the present application, the purification method of the intermediate product in each step is simple, and the operating conditions are mild and simple, which reduces the production cost, facilitates the operation, and is more suitable for industrial production. DETAILED DESCRIPTION

[0017] In order to make the purpose, technical solution and advantages of the embodiments of the present invention clearer, the technical solution of the present invention will be clearly and completely described in combination with the embodiments of the present invention. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the described embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field belong to the scope of protection of the present invention.

[0018] The following first describes in detail the method for preparing polyglycol according to an embodiment of the present invention.

[0019] The preparation method of the present invention can be applied to the preparation of polyglycol having a structural formula as shown in formula (1).

[0020] (1) That is to say, the preparation method of the present invention can be used to prepare polyglycols such as heptaethylene glycol (corresponding to n=0), octaethylene glycol (corresponding to n=1), nonaethylene glycol (corresponding to n=2), and decaethylene glycol (corresponding to n=3).

[0021] The preparation method according to the present invention comprises the following steps: Step S1, triethylene glycol reacts with triphenylmethane to generate a first intermediate, wherein the first intermediate is 2-[(1,1,1-triphenyl-2,5-dioxahept-7-yl)oxy]ethan-1-ol; Step S2, the first intermediate reacts with p-toluenesulfonyl chloride to generate a second intermediate, wherein the second intermediate is 4-methylbenzenesulfonic acid-1,1,1-triphenyl-2,5,8-trioxadecan-10-yl ester; Step S3, the second intermediate reacts with a diol compound to generate a third intermediate, wherein the diol compound has a structural formula as shown in formula (2): (2) The structural formula of the third intermediate is shown in formula (3): (3); Step S4, removing the terminal protecting group of the third intermediate to obtain the polyglycol.

[0022] Specifically, the synthesis route of polyglycol according to the present invention is shown in the following formula (5): (5) That is to say, in the second step of the present invention, by preparing a second intermediate that is easy to purify, the treatment of the first intermediate in the first step (no purification is required, the crude product is directly used in the next step) and the purification of the second intermediate in the second step are simplified, which can not only reduce the production cost, but also help to improve the purity of the target product.

[0023] Below, each step is described in detail.

[0024] Step S1, triethylene glycol reacts with triphenylmethane to generate a first intermediate, wherein the first intermediate is 2-[(1,1,1-triphenyl-2,5-dioxahept-7-yl)oxy]ethan-1-ol.

[0025] That is, according to the preparation method of the present invention, compared with the prior art, the single protecting group benzyl is replaced by trityl. On the one hand, the steric hindrance is large and can play a good protective effect. On the other hand, the deprotection of trityl is simpler and easier to operate than the deprotection of benzyl, and there is no need to use high-priced palladium-carbon catalysts for deprotection, which is more suitable for industrial large-scale production.

[0026] In some embodiments of the present invention, the reaction of step S1 is carried out in a dichloromethane solvent in the presence of a first base, wherein the first base is selected from one or more of triethylamine, diisopropyldiethylamine, and bicyclic amidine. The presence of the base is beneficial to the dehydrogenation of the terminal hydroxyl group of triethylene glycol and can promote the protection of the trityl protecting group.

[0027] Among them, the first base is preferably triethylamine, and the ratio of mono- and di-products obtained by triethylamine is the highest relative to other bases.

[0028] In step S1, the molar ratio of triethylene glycol: first base: triphenylmethane is (3-20): (2.0-3.0): 1. In consideration of reducing the by-products of double protection, the efficiency and cost of the reactor must also be taken into account, so the amount of triethylene glycol cannot be infinitely increased. In addition, the amount of the first base must consider the reaction rate and conversion rate. Setting it within the above range can take into account the above issues.

[0029] In addition, in this step, the reaction temperature is, for example, 0-30° C., and the reaction time is, for example, 5-24 hours.

[0030] In some embodiments of the present invention, after the reaction of step S1 is completed, the reaction solution is directly washed with water, dried, filtered, and concentrated to obtain a crude product, which is directly used in step S2 to synthesize the second intermediate. In other words, this step does not require purification treatment, and only requires simple filtration and concentration to extract the crude product. There are few wastes, low costs, and it is suitable for large-scale production.

[0031] Step S2, the first intermediate reacts with p-toluenesulfonyl chloride to generate a second intermediate, wherein the second intermediate is 4-methylbenzenesulfonic acid 1,1,1-triphenyl-2,5,8-trioxadecan-10-yl ester.

[0032] That is to say, after obtaining the above-mentioned first intermediate, it is reacted with "p-toluenesulfonyl chloride" to obtain a second intermediate in a solid state that is easy to purify, thereby eliminating the need to spend a large amount of money to purify the first intermediate to ensure the purity of the target product, thereby effectively reducing production costs.

[0033] In some embodiments of the present invention, the reaction of step S2 is carried out in a dichloromethane solvent in the presence of a second base.

[0034] The second base is selected from one or more of sodium hydroxide, potassium hydroxide, triethylamine, diisopropyldiethylamine, and dicyclic amidine (DBU). The presence of the base is conducive to the dehydrogenation of the hydroxyl group at the other end of the first intermediate and promotes its reaction with "p-toluenesulfonyl chloride". Among them, triethylamine is preferred.

[0035] In some embodiments of the present invention, the molar ratio of the first intermediate: the second base: p-toluenesulfonyl chloride is 1.0: (2.0-4.0): (1.0-1.2).

[0036] In this step, the reaction temperature is 0-30°C and the reaction time is 2-24 hours.

[0037] In some embodiments of the present invention, after the reaction of step S2 is completed, the reaction solution is directly washed with water, dried, filtered, and concentrated to obtain a crude oily product, which is recrystallized from ethyl acetate and petroleum ether to obtain a second intermediate of an off-white solid with a purity of ≥97%. The purification of the second intermediate does not require column treatment, and the crude product only needs to be recrystallized from ethyl acetate and petroleum ether to obtain a second intermediate with a purity of ≥97%. This greatly reduces costs and three wastes.

[0038] Step S3, the second intermediate reacts with a diol compound to generate a third intermediate, wherein the diol compound has a structural formula as shown in formula (2): (2) The structural formula of the third intermediate is shown in formula (3): (3)

[0039] That is, after obtaining the second intermediate, further reacting it with a diol compound can obtain a polyglycol with trityl groups protected at both ends.

[0040] For example, the second intermediate is reacted with ethylene glycol (n=0) to obtain heptaethylene glycol with both ends protected by trityl groups; the second intermediate is reacted with diethylene glycol (n=1) to obtain octaethylene glycol with both ends protected by trityl groups; the second intermediate is reacted with triethylene glycol (n=2) to obtain nonaethylene glycol with both ends protected by trityl groups; the second intermediate is reacted with tetraethylene glycol (n=3) to obtain decaethylene glycol with both ends protected by trityl groups. Subsequent deprotection can obtain heptaethylene glycol, octaethylene glycol, nonaethylene glycol, and decaethylene glycol, respectively.

[0041] In some embodiments of the present invention, step S3 is performed in the presence of a third base in a first solvent, wherein the first solvent is selected from any one or more of dichloromethane, dichloroethane, tetrahydrofuran or 2-methylfuran. Among them, dichloromethane is conventionally available and inexpensive, so it is preferred.

[0042] In some embodiments of the present invention, the third base is selected from one or more of potassium tert-butoxide, sodium tert-butoxide, and sodium hydride. The third base is preferably potassium tert-butoxide. The present application uses potassium tert-butoxide instead of potassium hydride, a compound with poor safety, to greatly improve the reaction safety while ensuring the reaction efficiency.

[0043] In some embodiments of the present invention, in step S3, the molar ratio of the second intermediate: potassium tert-butoxide: diol compound is 2.0: (2.0-8.0): 1.0. Setting it within the above range can minimize the intermediate impurities while taking into account the reaction efficiency and yield.

[0044] In this step, the reaction temperature is 0-70°C and the reaction time is 5-48 hours.

[0045] In some embodiments of the present invention, in step S3, after the reaction is completed, the reaction solution is quenched and concentrated, and then directly extracted and separated, dried, filtered, and concentrated to obtain a crude product, and the crude product is washed through a short column to obtain a third intermediate with a purity of ≥97%.

[0046] Step S4, removing the terminal protecting group of the third intermediate to obtain the polyglycol.

[0047] That is to say, after obtaining the third intermediate, it can be subjected to a hydrolysis reaction to remove the trityl protecting groups at both ends to obtain the target product polyglycol.

[0048] In some embodiments of the present invention, in step S4, the third intermediate is deprotected in the presence of an acid to obtain the polyglycol. Wherein, the acid is selected from one or more of hydrochloric acid, acetic acid and sulfuric acid, preferably acetic acid. That is to say, according to the preparation method of the present application, there is no need to use an expensive catalyst such as palladium carbon during the deprotection process, and it can be achieved under acidic conditions. The cost is greatly reduced and it is more suitable for large-scale production. Considering that the third intermediate has more ether bonds, the acidity of the acid treatment should not be too strong, so acetic acid is preferably used.

[0049] In some embodiments of the present application, the mass of the acid is 5-10 times that of the third intermediate. The acid here is both a solvent and a reaction reagent, so its amount is significantly higher than the reaction equivalent. In addition, similarly, considering that the third intermediate has more ether bonds, the acidity of the acid treatment should not be too strong, so it is preferably set within the above range.

[0050] In this step, the reaction temperature is 0-40°C and the reaction time is 2-24 hours. The reaction conditions are controllable and easy to operate.

[0051] In some embodiments of the present invention, after the reaction of step S4 is completed, the reaction solution is directly filtered, washed with water, the mother liquor is decolorized with activated carbon, filtered, and concentrated to obtain a crude product as an oily substance, and dichloromethane is added to the crude product to stir, filter, and concentrate to obtain the polyglycol as a colorless oily substance with a purity of ≥99%.

[0052] Next, nonaethylene glycol is used to further illustrate the preparation method of the polyethylene glycol of the present invention through specific examples.

[0053] It should be noted that the preparation of other polyglycols, such as heptaethylene glycol, octaethylene glycol, and decaethylene glycol, can be achieved by using different substrate diol compounds, and the inventors have also verified it through laboratory experiments. For the sake of simplicity, only the example of nonaethylene glycol is shown here, and detailed descriptions of the others are omitted.

[0054] Example 1 (1) Synthesis of the first intermediate 2-[(1,1,1-triphenyl-2,5-dioxahept-7-yl)oxy]ethan-1-ol Add triethylene glycol (118.54 g), dichloromethane and triethylamine (25.4 g) to a 5 L reaction flask, cool to 0 °C in an ice bath, add a DCM solution (0.1 mol / L) of triphenylmethane (35 g) dropwise, return to room temperature naturally after the addition, and react for 8 hours. TLC monitors the end of the reaction. After post-treatment, the reaction solution was washed once with a saturated sodium bicarbonate solution, washed three times with water, and washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 50 g of a yellow viscous liquid (theoretical value 49.3 g), which was directly used in the next step without purification.

[0055] The NMR results of the intermediate product are as follows: 1 H NMR (400 MHz, CDCl3): = 3.23-3.24 (m, 4H, 2CH2), 3.61-3.67 (m, 9H,OH & 4CH2), 7.20-7.24 (m, 3H, ArH), 7.27-7.31 (m, 6H, ArH), 7.44-7.47 (m, 6H,ArH). The detection results are consistent with the structure of the theoretical product first intermediate, 2-[(1,1,1-triphenyl-2,5-dioxahept-7-yl)oxy]ethan-1-ol (the structural formula is shown in the structure of the product corresponding to step S1 in formula (5)).

[0056] (2) Synthesis of the Second Intermediate 4-Methylbenzenesulfonic Acid-1,1,1-Triphenyl-2,5,8-Trioxadecan-10-yl Ester Add the above crude product (50 g), dichloromethane and triethylamine (45.1 g) to a 1 L three-necked flask, cool to below 0 °C in an ice-salt bath, add a DCM solution (0.27 mol / L) of p-toluenesulfonyl chloride (25.5 g) dropwise, return to room temperature naturally after the addition is complete, and react for 6 h. The reaction is monitored by TLC. After post-treatment, the reaction solution is washed twice with a saturated sodium bicarbonate solution, once with 1N hydrochloric acid, twice with water, and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 67 g of a yellow viscous solid (theoretical value 69.64 g). Add n-heptane to slurry, solids precipitate overnight, filter, and dry at 45 °C to obtain 59.4 g of a light yellow solid. Recrystallize from ethyl acetate and n-heptane to obtain 52 g of a white solid with a liquid phase purity of 97.68%.

[0057] The NMR results of the intermediate product are as follows: 1H NMR (400 MHz, CDCl3): = 2.35 (s, 3H, CH3), 3.75-4.13 (m, 10H,5CH2), 3.56-3.60 (m, 2H, CH2), 7.20-7.24 (m, 3H, ArH), 7.27-7.31 (m, 6H, ArH),7.33-7.35 (d, 2H, ArH), 7.44-7.47 (m, 6H, ArH), 7.78-7.80 (d, 2H, ArH). The detection results are consistent with the structure of the target product, the second intermediate, 4-methylbenzenesulfonic acid-1,1,1-triphenyl-2,5,8-trioxadecan-10-yl ester (the structural formula is shown in the structure of the product corresponding to step S2 in formula (5)).

[0058] (3) Synthesis of the third intermediate Triethylene glycol (6.9 g) and tetrahydrofuran were added to a 2 L three-necked flask, and potassium tert-butoxide (30.8 g) was added in batches under ice bath cooling to 0 °C, and stirred for half an hour. At this temperature, a tetrahydrofuran solution of intermediate 2 (50 g) was added dropwise, and stirred for 1 hour and then heated to reflux for 24 hours. The reaction was monitored by TLC. After treatment, methanol was added dropwise under ice bath to quench the reaction, concentrated, added dichloromethane, washed twice with 5% hydrochloric acid and once with brine, dried, filtered, and concentrated to obtain 42 g of oil (theoretical value 41.1 g). The obtained crude product was purified by flash column (after washing away impurities with PE:EA=2:1, and then washing out the product with DCM:MeOH=10:1), and 32 g of the third intermediate was obtained. The liquid HPLC purity calculated by the integrated peak area method was 97%, and the yield was 78%.

[0059] 1 H NMR (400 MHz, CDCl3): = 3.23-3.24 (m, 4H, 2CH2), 3.61-3.67 (m, 32H,16CH2), 7.21-7.23 (m, 6H, ArH), 7.28-7.30 (m, 12H, ArH), 7.45-7.47 (m, 12H,ArH). The detection results are consistent with the structure of the target product third intermediate (1,1,1,30,30,30-hexaphenyl-2,5,8,11,14,17,20,23,26,29-decaoxatriacontane, the structural formula is shown in formula (5) corresponding to the structure of the product of step S3 with n=2).

[0060] (4) Synthesis of nonaethylene glycol Add the above third intermediate (16.3 g) and 80% acetic acid (146.5 g) to a 500 mL three-necked flask, heat to 40°C and react for 2 hours. The reaction gradually generates white granular solids. TLC detects the post-reaction treatment of the raw materials. Add purified water to the reaction solution, cool to 10°C and filter, concentrate the acetic acid water, add water after concentration, extract with toluene three times, spot the TLC plate until there is no ultraviolet point, decolorize the aqueous phase with activated carbon and filter, concentrate the aqueous phase, add DCM to dilute, filter, concentrate and dry to obtain 7.2 g of nonaglycone (theoretical value 7.5 g), and the liquid HPLC purity calculated by the integral peak area method is 99.6%.

[0061] 1 H NMR (400 MHz, CDCl3): = 3.40-3.43 (m, 4H, 2CH2), 3.47-3.50 (m, 4H,CH2), 3.51-3.53 (m, 30H, 2OH & 14CH2). The test results are consistent with the structure of nonaethylene glycol.

[0062] In summary, the preparation method of the polyglycol of the present invention has the advantages of simple purification method, mild and simple operating conditions, low production cost, high yield, easy operation, and more suitable for industrial production.

[0063] The above is a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principles of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A method for preparing polyglycol, characterized in that: The structural formula of the polyglycol is shown in formula (1): （1） The preparation method comprises the following steps: Step S1, triethylene glycol reacts with triphenylmethane to generate a first intermediate, wherein the first intermediate is 2-[(1,1,1-triphenyl-2,5-dioxahept-7-yl)oxy]ethan-1-ol; Step S2, the first intermediate reacts with p-toluenesulfonyl chloride to generate a second intermediate, wherein the second intermediate is 4-methylbenzenesulfonic acid 1,1,1-triphenyl-2,5,8-trioxadecan-10-yl ester; Step S3, the second intermediate reacts with a diol compound to generate a third intermediate, wherein the diol compound has a structural formula as shown in formula (2): （2） The structural formula of the third intermediate is shown in formula (3): （3）； Step S4, removing the terminal protecting group of the third intermediate to obtain the polyglycol.

2. The preparation method according to claim 1, characterized in that The reaction of step S1 is carried out in a dichloromethane solvent in the presence of a first base, wherein the first base is selected from one or more of triethylamine, diisopropyldiethylamine, and bicyclic amidine. In step S1, the molar ratio of triethylene glycol: first base: triphenylmethane is (3-20): (2.0-3.0): 1, the reaction temperature is 0-30°C, and the reaction time is 5-24 hours.

3. The preparation method according to claim 2, characterized in that: After the reaction in step S1 is completed, the reaction solution is directly washed with water, dried, filtered, and concentrated to obtain a crude product, which is directly used in step S2 to synthesize the second intermediate.

4. The preparation method according to claim 1, characterized in that The reaction of step S2 is carried out in a dichloromethane solvent in the presence of a second base, wherein the second base is selected from one or more of sodium hydroxide, potassium hydroxide, triethylamine, diisopropyldiethylamine, and bicyclic amidine, and the molar ratio of the first intermediate: the second base: p-toluenesulfonyl chloride is 1.0: (2.0-4.0): (1.0-1.2), the reaction temperature is 0-30°C, and the reaction time is 2-24 hours.

5. The preparation method according to claim 4, characterized in that: After the reaction in step S2 is completed, the reaction solution is directly washed with water, dried, filtered, and concentrated to obtain a crude oily product, which is recrystallized with ethyl acetate and petroleum ether to obtain the second intermediate, which is an off-white solid with a purity of ≥97%.

6. The preparation method according to claim 1, characterized in that: The step S3 is performed in a first solvent in the presence of a third base, wherein the first solvent is selected from any one or more of dichloromethane, dichloroethane, tetrahydrofuran or 2-methylfuran, and the third base is selected from one or more of potassium tert-butoxide, sodium tert-butoxide, and sodium hydride.

7. The preparation method according to claim 6, characterized in that The third base is potassium tert-butoxide. In step S3, the molar ratio of the second intermediate: potassium tert-butoxide: diol compound is 2.0: (2.0-8.0): 1.0, the reaction temperature is 0-70° C., and the reaction time is 5-48 hours.

8. The preparation method according to claim 6, characterized in that: In the step S3, after the reaction is completed, the reaction solution is quenched and concentrated, and then the liquid is directly extracted and separated, dried, filtered, and concentrated to obtain a crude product, and the crude product is washed with a short column to obtain a third intermediate with a purity of ≥97%.

9. The preparation method according to claim 1, characterized in that In the step S4, the third intermediate is deprotected in the presence of an acid to obtain the polyglycol, wherein the acid is selected from one or more of hydrochloric acid, acetic acid and sulfuric acid, the mass of the acid is 5-10 times that of the third intermediate, the reaction temperature is 0-40°C, and the reaction time is 2-24 hours.

10. The preparation method according to claim 9, characterized in that: After the reaction of step S4 is completed, the reaction solution is directly filtered, washed with water, the mother liquor is decolorized with activated carbon, filtered, and concentrated to obtain a crude product as an oily substance. Dichloromethane is added to the crude product to stir, filter, and concentrate to obtain the polyglycol as a colorless oily substance with a purity of ≥99%.

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