Synthesis method of tripolyethylene glycol-acetic acid

Abstract

The invention discloses a synthesis method of tripolyethylene glycol-acetic acid, which comprises the following steps: firstly converting a raw material 1-methyl-5-hydroxypyrazole into benzyl-PEG4-tert-butyl acetate, then converting into tert-butyl acetate-tripolyethylene glycol, reacting the tert-butyl acetate-tripolyethylene glycol under the action of cation exchange resin IR 120, and carrying out reduced pressure distillation to obtain the tripolyethylene glycol-acetic acid. The target compound tripolyethylene glycol-acetic acid is obtained. According to the synthesis route, an intermediate compound tert-butyl acetate-tripolyethylene glycol is converted into target tripolyethylene glycol-acetic acid by a simple method and ideal yield, and finally, the tripolyethylene glycol-acetic acid synthesis route which has the advantages of high yield, low cost, suitability for process amplification and the like is obtained.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and particularly relates to a method for synthesizing trimerethylene glycol-acetic acid. Background Art

[0002] Polyethylene glycol (PEG) compounds are a class of high molecular weight compounds with excellent water solubility, biocompatibility and chemical stability, and are widely used in the cosmetics industry, pharmaceuticals, industry, plant engineering and other fields. In the field of medicine, PEG compounds have a variety of applications. They can be used as drug carriers to increase the solubility and stability of drugs and improve bioavailability; they can be used as sustained-release agents to control the release rate of drugs and achieve continuous treatment; they can also be used as targeted carriers to deliver drugs to the lesion site in a targeted manner, improving the treatment effect and reducing side effects.

[0003] Triethylene glycol-acetic acid is an important PEG compound and also an important molecular building block. As a key intermediate and building block of drug molecules, for example, in patent document CN114044775A, it is used to synthesize a compound that targets ubiquitination-induced BCR-ABL protein degradation. The compound not only has excellent BCR-ABL protein degradation and anti-tumor activity, but also has little toxicity and side effects on the human body, and can be used to prepare anti-tumor drugs; in patent document CN116854754A, it is used to synthesize a GalNAc compound containing a ribose ring or its derivative structure and its oligonucleotide conjugate, which can achieve efficient liver-targeted delivery and improve drug efficacy.

[0004] In the prior art, the conventional synthesis route of triethylene glycol-acetic acid is to convert triethylene glycol raw material into triethylene glycol-acetic acid, but the conventional method has the disadvantages of easily generating by-products and low yield of target product. Therefore, it is of great significance to develop a new synthesis method of triethylene glycol-acetic acid. Summary of the invention

[0005] In view of the shortcomings of the synthesis method of triethylene glycol-acetic acid in the prior art, the purpose of the present invention is to provide a synthesis method of triethylene glycol-acetic acid, which has the advantages of low cost, ideal yield and great process scale-up potential.

[0006] To achieve the above object, the present invention adopts the following technical solution:

[0007] The present invention provides a method for synthesizing triethylene glycol-acetic acid, comprising: first converting compound 1 (1-methyl-5-hydroxypyrazole) into compound 2 (benzyl-PEG4-tert-butyl acetate), then converting compound 2 into compound 3 (tert-butyl acetate-triethylene glycol), and reacting compound 3 under the action of cation exchange resin IR 120 to obtain target compound 4 (triethylene glycol-acetic acid). The synthesis route is as follows:

[0008]

[0009] Further, the synthesis method of trimerized ethylene glycol-acetic acid comprises the following steps:

[0010] (1) Adding raw material 1 to organic solvent I, preparing a base into an aqueous solution and adding it to the reaction system, adding tert-butyl bromoacetate, and then slowly adding tetrabutylammonium bromide. After the addition is completed, the mixed solution is stirred at 20 to 60° C. for 10 to 40 hours. After the reaction is completed, the obtained reaction solution is post-treated to obtain compound 2;

[0011] (2) Compound 2 is added to methanol, palladium is slowly added, and the mixture is stirred at 20-60° C. for 10-30 hours under a hydrogen atmosphere. After the reaction is completed, the resulting reaction solution is post-treated to obtain Compound 3;

[0012] (3) Compound 3 is added to organic solvent II, and cation exchange resin IR 120 is slowly added. The mixed solution is stirred at 20-60° C. for 10-40 hours. After the reaction is completed, the obtained reaction solution is post-treated to obtain compound 4.

[0013] Furthermore, in step (1), the organic solvent I is selected from one or more of dichloromethane, dichloroethane and chloroform.

[0014] Furthermore, in step (1), the base is selected from one or more of potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium acetate, sodium tert-butoxide or potassium tert-butoxide.

[0015] Furthermore, in step (1), the molar ratio of the compound 1 to the base is 1.0:20.0-30.0.

[0016] Furthermore, in step (1), the molar ratio of compound 1 to tert-butyl bromoacetate is 1:1.0-3.0.

[0017] Furthermore, in step (1), the molar ratio of the compound 1 to tetrabutylammonium bromide is 1:1.0-1.5.

[0018] Furthermore, in step (1), the mass volume ratio of the compound 1 to the organic solvent I is 1:5 to 40 g / mL.

[0019] Furthermore, in step (1), the post-treatment process includes: after the reaction is completed, the reaction solution is separated to obtain an organic phase and an aqueous phase, the aqueous phase is extracted with an organic solvent III, all the organic phases are collected, dried, and spin-dried to obtain compound 2.

[0020] Furthermore, in step (1), the organic solvent III is selected from one or more of dichloromethane, dichloroethane, dichloropropane and chloroform.

[0021] Furthermore, in step (2), the mass volume ratio of the compound 2 to methanol is 1:5 to 40 g / mL.

[0022] Furthermore, in step (2), the molar ratio of the compound 2 to palladium is 1:0.02-0.10.

[0023] Furthermore, in step (2), the post-treatment process includes: after the reaction is completed, filtering the reaction solution, washing the filter cake with methanol, collecting the organic phase, and spinning to dryness to obtain compound 3.

[0024] Furthermore, in step (3), the organic solvent II is selected from one or more of acetonitrile, dichloromethane and acetone.

[0025] Furthermore, in step (3), the mass volume ratio of the compound 3 to the organic solvent II is 1:5 to 40 g / mL.

[0026] Furthermore, in step (3), the mass ratio of the compound 3 to the cation exchange resin IR 120 is 1:5.0-20.0.

[0027] Furthermore, in step (3), the post-treatment process includes: after the reaction is completed, filtering the reaction solution, washing the filter cake with an organic solvent IV, collecting the organic phase, and concentrating under reduced pressure to obtain compound 4.

[0028] Furthermore, in step (3), the organic solvent IV is selected from one or more of ethyl acetate, butyl acetate, chloroform, toluene, dichloromethane or dichloroethane.

[0029] Compared with the prior art, the present invention has the following beneficial effects:

[0030] The present invention provides a method for synthesizing triethylene glycol-acetic acid. The raw material 1-methyl-5-hydroxypyrazole is first converted into benzyl-PEG4-tert-butyl acetate, and then converted into tert-butyl acetate-triethylene glycol. The tert-butyl acetate-triethylene glycol is then reacted under the action of a cation exchange resin IR 120 to obtain a target compound triethylene glycol-acetic acid. The synthetic route converts the intermediate compound tert-butyl acetate-triethylene glycol into the target triethylene glycol-acetic acid in a simple method and with an ideal yield, and finally obtains a synthetic route of triethylene glycol-acetic acid with the advantages of high yield, low cost, and suitability for process amplification. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1 This is the H NMR spectrum of compound 2 (benzyl-PEG4-tert-butyl acetate) in Example 1.

[0032] Figure 2 It is the H NMR spectrum of compound 3 (tert-butyl acetate-triethylene glycol) in Example 1.

[0033] Figure 3 It is the H NMR spectrum of compound 4 (triethylene glycol-acetic acid) in Example 1. DETAILED DESCRIPTION

[0034] The present invention is described in detail below in conjunction with specific embodiments. The following embodiments will help those skilled in the art to further understand the present invention, but are not intended to limit the present invention in any form. It should be noted that, for those of ordinary skill in the art, several changes and improvements can also be made without departing from the concept of the present invention. These all belong to the protection scope of the present invention.

[0035] Unless otherwise specified in the following examples, all reagents and materials used were commercially available.

[0036] In the following example, triethylene glycol-acetic acid is synthesized. The raw material compound 1 (1-methyl-5-hydroxypyrazole) is first converted into compound 2 (benzyl-PEG4-tert-butyl acetate), and compound 2 is then converted into compound 3 (tert-butyl acetate-triethylene glycol). Compound 3 reacts under the action of cation exchange resin IR 120 to obtain the target compound 4 (triethylene glycol-acetic acid). The synthesis route is as follows:

[0037]

[0038] The technical solution of the present invention is further explained below by way of embodiments.

[0039] Example 1

[0040] This embodiment synthesizes triethylene glycol-acetic acid, and the steps are as follows:

[0041] (1) Add the raw material 1 triethylene glycol monobenzyl ether (200.00 g, 832.30 mmol, 1.00 eq) into dichloromethane (2.0 L), prepare a 3M sodium hydroxide solution with sodium hydroxide (808.93 g, 20.22 mol, 24.30 eq) and add it into the reaction system, add tert-butyl bromoacetate (405.86 g, 2.08 mol, 2.50 eq), and then slowly add tetrabutylammonium bromide (273.68 g, 848.94 mmol, 1.02 eq). After the addition is complete, the mixture is stirred at 25° C. for 12 hours. After the reaction is complete, the reaction solution is separated to obtain an organic phase and an aqueous phase. The aqueous phase is extracted three times with dichloromethane (500 mL×3). All organic phases are collected and dried over anhydrous sodium sulfate and spin-dried to obtain compound 2, namely benzyl-PEG4-acetic acid tert-butyl ester (weight 289.20 g, purity 98%, yield 96%).

[0042] The H NMR spectrum of the obtained compound 2 (benzyl-PEG4-tert-butyl acetate) is as follows: Figure 1 The characterization data are as follows: 1HNMR (400MHz, cdcl3) δ7.57-7.15 (m, 5H), 4.54 (s, 2H), 4.00 (s, 2H), 3.71-3.56 (m, 12H), 1.45 (s, 9H).

[0043] (2) Compound 2 (250.00 g, 705.33 mmol, 1.00 eq) was added to methanol (2.5 L), and palladium (10% on carbon (wet), 37.53 g, 35.27 mmol, 0.05 eq) was slowly added, and the gas was replaced by hydrogen three times. The mixed solution was stirred at 25° C. for 12 hours. After the reaction was complete, the reaction solution was filtered, the filter cake was washed with methanol, and the organic phase was collected. The obtained organic phase was spin-dried to obtain compound 3, i.e., tert-butyl acetate-triethylene glycol (weight 179.30 g, purity 97%, yield 93%).

[0044] The H NMR spectrum of the obtained compound 3 (tert-butyl acetate-triethylene glycol) is as follows Figure 2 As shown, the characterization data are as follows: 1HNMR (400MHz, cdcl3) δ3.96 (s, 2H), 3.69-3.61 (m, 10H), 3.57-3.53 (m, 2H), 1.42 (s, 9H).

[0045] (3) Compound 3 (150.00 g, 567.50 mmol, 1.00 eq) was added to acetonitrile (1.0 L), and cation exchange resin IR 120 (1500.00 g) was slowly added, and the mixture was stirred at 25° C. for 12 hours. After the reaction was completed, the reaction solution was filtered, the filter cake was washed with ethyl acetate, and the organic phase was collected. The organic phase was concentrated under reduced pressure to obtain compound 4, namely triethylene glycol-acetic acid (weight 145.30 g, purity 98%, yield 95%).

[0046] The H NMR spectrum of the obtained compound 4 (triethylene glycol-acetic acid) is as follows Figure 3 As shown, the characterization data are as follows: 1H NMR (400MHz, cdcl3) δ4.29 (s, 2H), 3.89 (s, 2H), 3.79-3.38 (m, 12H).

[0047] Embodiments 2 to 8

[0048] Examples 2 to 8 are the same as Example 1, except that the cation exchange resin IR 120, organic solvent II, reaction time and reaction temperature used in step (3) are adjusted, as shown in Table 1.

[0049] The effects of various reaction conditions on the reaction yield in the synthesis of target compound 4 (triethylene glycol-acetic acid) were verified through Examples 1 to 8. The results are shown in Table 1.

[0050] Table 1: Synthesis conditions and results of the examples

[0051]

[0052]

[0053] Combined with Table 1, we can see that:

[0054] Comparing Examples 1 to 3, when the mass ratio of compound 3 to cation exchange resin IR 120 is 1:10, the reaction effect is already better.

[0055] Comparing Examples 1, 4-5, acetonitrile, dichloromethane and acetone were used as reaction solvents, and the reaction could be carried out, among which acetonitrile was more effective as solvent.

[0056] Comparing Examples 1 and 6, when the reaction temperature is 25°C, the reaction effect is already better.

[0057] Comparing Examples 1, 7-8, when the reaction time is 12 h, the reaction effect is already better.

[0058] The above 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 variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A method for synthesizing trimerized ethylene glycol-acetic acid, characterized in that: include: Compound 1, i.e. 1-methyl-5-hydroxypyrazole, is first converted into compound 2, i.e. benzyl-PEG4-tert-butyl acetate, and compound 2 is then converted into compound 3, i.e. tert-butyl acetate-triethylene glycol. Compound 3 reacts under the action of cation exchange resin IR 120 to obtain target compound 4, i.e. triethylene glycol-acetic acid. The synthesis route is as follows:

2. The method for synthesizing triethylene glycol-acetic acid according to claim 1, characterized in that: The synthesis method comprises the following steps: (1) Adding raw material 1 to organic solvent I, preparing a base into an aqueous solution and adding it to the reaction system, adding tert-butyl bromoacetate, and then slowly adding tetrabutylammonium bromide. After the addition is completed, the mixed solution is stirred at 20 to 60° C. for 10 to 40 hours. After the reaction is completed, the obtained reaction solution is post-treated to obtain compound 2; (2) Compound 2 is added to methanol, palladium is slowly added, and the mixture is stirred at 20-60° C. for 10-30 hours under a hydrogen atmosphere. After the reaction is completed, the resulting reaction solution is post-treated to obtain Compound 3; (3) Compound 3 is added to organic solvent II, and cation exchange resin IR 120 is slowly added. The mixed solution is stirred at 20-60° C. for 10-40 hours. After the reaction is completed, the obtained reaction solution is post-treated to obtain compound 4.

3. The method for synthesizing triethylene glycol-acetic acid according to claim 2, characterized in that: In step (1), the post-treatment process includes: after the reaction is completed, the reaction solution is separated to obtain an organic phase and an aqueous phase, the aqueous phase is extracted with an organic solvent III, all the organic phases are collected, dried, and spin-dried to obtain compound 2.

4. The method for synthesizing triethylene glycol-acetic acid according to claim 3, characterized in that: The organic solvent III is selected from one or more of dichloromethane, dichloroethane, dichloropropane and chloroform.

5. The method for synthesizing triethylene glycol-acetic acid according to claim 2, characterized in that: In step (1), the organic solvent I is selected from one or more of dichloromethane, dichloroethane, and chloroform; and / or the base is selected from one or more of potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium acetate, sodium tert-butoxide or potassium tert-butoxide; and / or the molar ratio of the compound 1 to the base is 1.0:20.0-30.0; and / or the molar ratio of the compound 1 to tert-butyl bromoacetate is 1:1.0-3.0; and / or the molar ratio of the compound 1 to tetrabutylammonium bromide is 1:1.0-1.5; And / or the mass volume ratio of the compound 1 to the organic solvent I is 1:5-40 g / mL.

6. The method for synthesizing triethylene glycol-acetic acid according to claim 2, characterized in that: In step (2), the post-treatment process includes: after the reaction is completed, filtering the reaction solution, washing the filter cake with methanol, collecting the organic phase, and spinning to dryness to obtain compound 3.

7. The method for synthesizing triethylene glycol-acetic acid according to claim 2, characterized in that: In step (2), the mass volume ratio of the compound 2 to methanol is 1:5 to 40 g / mL; And / or the molar ratio of the compound 2 to palladium is 1:0.02-0.

10.

8. The method for synthesizing triethylene glycol-acetic acid according to claim 2, characterized in that: In step (3), the post-treatment process includes: after the reaction is completed, filtering the reaction solution, washing the filter cake with an organic solvent IV, collecting the organic phase, and concentrating under reduced pressure to obtain compound 4.

9. The method for synthesizing triethylene glycol-acetic acid according to claim 8, characterized in that: The organic solvent IV is selected from one or more of ethyl acetate, butyl acetate, chloroform, toluene, dichloromethane or dichloroethane.

10. The method for synthesizing triethylene glycol-acetic acid according to claim 2, characterized in that: In step (3), the organic solvent II is selected from one or more of acetonitrile, dichloromethane, and acetone; and / or the mass volume ratio of the compound 3 to the organic solvent II is 1:5-40 g / mL; And / or the mass ratio of the compound 3 to the cation exchange resin IR 120 is 1:5.0-20.0.

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