Preparation method of polyethylene glycol modified tetrahydrocurcumin

Abstract

The invention relates to a preparation method of polyethylene glycol modified tetrahydrocurcumin, and belongs to the technical field of polymer synthesis. According to the method, tetrahydrocurcumin is taken as an initial raw material and is subjected to etherification reaction with monomethoxy polyethylene glycol p-toluenesulfonate, and a polyethylene glycol modified tetrahydrocurcumin target product is obtained. The innovation point of the technical scheme provided by the invention is that a polyethylene glycol side chain is introduced into insoluble curcumin, so that the water solubility of a target object is improved, and tetrahydrocurcumin is more conveniently applied to corresponding industries.

Description

Technical Field

[0001] The invention relates to the technical field of polymer synthesis, and in particular to a method for preparing polyethylene glycol-modified tetrahydrocurcumin. Background Art

[0002] Turmeric is the dried rhizome of the plant Curcuma of the Zingiberaceae family. The 2020 edition of the Chinese Pharmacopoeia records that it has the effects of breaking blood and promoting qi, relieving menstruation and relieving pain. Tetrahydrocurcumin is a hydrogenated metabolite in turmeric and has similar pharmacological effects to curcumin. Studies have reported that tetrahydrocurcumin has pharmacological effects such as lowering blood sugar, lowering blood lipids, anti-metastasis, anti-cancer, anti-depression, and neuroprotection. At the same time, it was found that its pharmacological activity in anti-oxidation, lowering blood sugar and lowering blood lipids is better than curcumin. Although tetrahydrocurcumin has better biological activity than curcumin in all aspects, it is equally insoluble in water.

[0003] At present, tetrahydrocurcumin is mostly administered in the form of solid dispersion, which can effectively solve the shortcomings of poor water solubility and low bioavailability of tetrahydrocurcumin. However, the sustained release effect of solid dispersion administration is poor. Even if it is prepared into liposomes, there is still agglomeration and precipitation, which is not conducive to commercial application.

[0004] Polyethylene glycol (PEG) has good amphiphilicity and biocompatibility, low toxicity, and is one of the few synthetic polymers approved by the US FDA for use in drugs. It has been widely used in the synthesis and modification of compounds to improve the physical and chemical properties and biological activity of compounds. Polyethylene glycol (PEG) modification technology is a new drug delivery technology that has developed rapidly in recent years.

[0005] Therefore, there is still a need to study the preparation method of tetrahydrocurcumin to solve the problems of poor water solubility and low bioavailability of tetrahydrocurcumin. Summary of the invention

[0006] Aiming at the technical problems of poor water solubility and low bioavailability of tetrahydrocurcumin in the prior art, the present invention provides a method for preparing polyethylene glycol-modified tetrahydrocurcumin. The method comprises taking tetrahydrocurcumin as a starting material and carrying out an etherification reaction with monomethoxy polyethylene glycol p-toluenesulfonate to obtain the polyethylene glycol-modified tetrahydrocurcumin target product.

[0007] In order to solve the above technical problems, the present invention adopts the following technical solutions: The present invention provides a method for preparing polyethylene glycol-modified tetrahydrocurcumin, comprising: carrying out an etherification reaction of tetrahydrocurcumin with monomethoxy polyethylene glycol p-toluenesulfonate in a reaction solvent in the presence of a base at a certain reaction temperature to obtain the polyethylene glycol-modified tetrahydrocurcumin target product; the reaction process is as follows: ; Where n is a positive integer ranging from 8 to 455.

[0008] In some embodiments, n is a positive integer from 8 to 100; preferably 22.

[0009] In some embodiments, n is a positive integer ranging from 101 to 200.

[0010] In some embodiments, n is a positive integer ranging from 201 to 300.

[0011] In some embodiments, n is a positive integer ranging from 301 to 400.

[0012] In some embodiments, n is a positive integer between 401 and 455.

[0013] The reaction solvent is selected from at least one of tetrahydrofuran, acetone, N,N-dimethylformamide, N-methylpyrrolidone, methanol, ethanol, isopropanol, 1,4-dioxane, dichloromethane, chloroform and 1,2-dichloroethane.

[0014] The molecular weight of the monomethoxy polyethylene glycol is selected from at least one of 400, 600, 800, 1000, 2000, 4000, 6000, 8000, 10000, and 20000.

[0015] The molar ratio of the monomethoxy polyethylene glycol p-toluenesulfonate to tetrahydrocurcumin is 0.8:1 to 1.3:1.

[0016] The base is selected from at least one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, triethylamine, diisopropylethylamine, sodium methoxide, sodium ethoxide, sodium tert-butoxide and potassium tert-butoxide.

[0017] The reaction temperature is 10°C-120°C.

[0018] The molar ratio of the base to tetrahydrocurcumin is 1:1 to 5:1.

[0019] In some embodiments, a method for preparing polyethylene glycol-modified tetrahydrocurcumin comprises: stirring and dissolving tetrahydrocurcumin in a reaction solvent acetone, adding monomethoxy polyethylene glycol p-toluenesulfonate, adding potassium carbonate, heating to reflux reaction for 3-6 hours, sampling and testing whether the raw material tetrahydrocurcumin has reacted completely, and performing post-treatment to obtain polyethylene glycol-modified tetrahydrocurcumin; wherein the post-treatment comprises: filtering, concentrating the filtrate under reduced pressure, extracting and separating the liquids, collecting the organic phase, drying, concentrating under reduced pressure, adding ethanol for crystallization, and obtaining the target product polyethylene glycol-modified tetrahydrocurcumin.

[0020] Compared with the prior art, the present invention has the following beneficial technical effects: The innovative point of the technical solution of the present invention is to introduce polyethylene glycol side chains into the poorly soluble curcumin, thereby increasing the water solubility of the target substance, thereby making tetrahydrocurcumin more convenient to be applied to corresponding industries.

[0021] In the description of this specification, the description with reference to the terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" etc. means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described may be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art may combine and combine the different embodiments or examples described in this specification and the features of the different embodiments or examples, without contradiction.

[0022] In the present invention, expressions such as "Compound 1", "Compound represented by Formula 1" and "Formula 1" refer to the same compound. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 The polyethylene glycol-modified tetrahydrocurcumin prepared in Example 1 1 HNMR spectrum; Figure 2 The polyethylene glycol-modified tetrahydrocurcumin prepared in Example 1 13 CNMR spectrum. DETAILED DESCRIPTION

[0024] In order to enable those skilled in the art to better understand the technical solution of the present invention, some non-limiting embodiments are further disclosed below to further describe the present invention in detail.

[0025] The reagents used in the present invention can be purchased from the market or prepared by the method described in the present invention.

[0026] In the present invention, min means minute; h means hour; g means gram; and ml means milliliter.

[0027] In the present invention, HPLC means high performance liquid chromatography.

[0028] In the present invention, the completion of the reaction means that less than 5% of the reaction raw materials remain. Example 1

[0029] Tetrahydrocurcumin (37.2 g, 100 mmol, 1 eq) was added to a reaction flask, and then acetone (1000 ml) was added, stirred to dissolve, and then monomethoxy polyethylene glycol 1000 p-toluenesulfonate (128.4 g, 110 mmol, 1.1 eq) was added, and then potassium carbonate (30.3 g, 220 mmol, 2.2 eq) was added, and the reaction was heated to reflux for 5 hours. The raw material tetrahydrocurcumin was sampled and tested for complete reaction, filtered, rinsed with a small amount of acetone, and the filtrate was concentrated under reduced pressure. Water and ethyl acetate were added to extract the liquid, and the organic phase was collected, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and ethanol was added for crystallization to obtain a tetrahydrocurcumin compound (154.4 g, yield 65.1%) with a side chain modified with monomethoxy polyethylene glycol 400. Example 2

[0030] Optimization of reaction conditions:

[0031] According to the preparation method in Example 1, the other conditions were kept unchanged and the molecular weight of methoxy polyethylene glycol was optimized. The results are shown in the following table:

[0032] According to the preparation method in Example 1, other conditions were kept unchanged and the reaction solvent was optimized. The results are shown in the following table:

[0033] According to the preparation method in Example 1, other conditions were kept unchanged and the base was optimized. The results are shown in the following table: Example 3

[0034] Solubility test:

[0035] According to the 2020 edition of the Chinese Pharmacopoeia, the solubility of the examples was investigated: accurately weigh appropriate amounts of the sample (the product of the example) and tetrahydrocurcumin, add a certain amount of purified water, shake vigorously for 30 seconds every 5 minutes, and observe. If there are no solute particles visible to the naked eye for 30 minutes, it is considered to be completely dissolved. The results are shown in the following table:

[0036] It can be seen from the above experimental results that the polyethylene glycol-modified tetrahydrocurcumin of the present invention is easily soluble in water, and its water solubility is significantly improved compared with tetrahydrocurcumin.

[0037] The method of the present invention has been described through preferred embodiments, and relevant personnel can obviously modify or appropriately change and combine the methods and applications described herein within the content, spirit and scope of the present invention to implement and apply the technology of the present invention. Those skilled in the art can refer to the content of this article and appropriately improve the process parameters. It is particularly important to point out that all similar replacements and modifications are obvious to those skilled in the art, and they are all considered to be included in the present invention.

Claims

1. A method for preparing polyethylene glycol-modified tetrahydrocurcumin, characterized in that: Tetrahydrocurcumin is subjected to etherification reaction with monomethoxypolyethylene glycol p-toluenesulfonate in a reaction solvent in the presence of a base at a certain reaction temperature to obtain the target product of polyethylene glycol-modified tetrahydrocurcumin; the reaction process is as follows: ； Wherein, n is a positive integer ranging from 8 to 455.

2. The preparation method according to claim 1, characterized in that: The reaction solvent is selected from at least one of tetrahydrofuran, acetone, N,N-dimethylformamide, N-methylpyrrolidone, methanol, ethanol, isopropanol, 1,4-dioxane, dichloromethane, chloroform and 1,2-dichloroethane.

3. The preparation method according to claim 1, characterized in that: The molecular weight of the monomethoxy polyethylene glycol is selected from at least one of 400, 600, 800, 1000, 2000, 4000, 6000, 8000, 10000, and 20000.

4. The preparation method according to claim 1, characterized in that: The molar ratio of the monomethoxy polyethylene glycol p-toluenesulfonate to tetrahydrocurcumin is 0.8:1 to 1.3:

1.

5. The preparation method according to claim 1, characterized in that: The base is selected from at least one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, triethylamine, diisopropylethylamine, sodium methoxide, sodium ethoxide, sodium tert-butoxide and potassium tert-butoxide.

6. The preparation method according to claim 1, characterized in that: The reaction temperature is 10°C-120°C.

7. The preparation method according to claim 1, characterized in that: The molar ratio of the base to tetrahydrocurcumin is 1:1 to 5:1.

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