A method for synthesizing 4-hydroxy-5,6-dimethylpyridin-2(1H)-one

Abstract

The application discloses a synthesis method of 4-hydroxy-5,6-dimethylpyridine-2(1H)-ketone, which comprises the following steps: taking 3-methyl-2,4-pentanedione as raw material, reacting with NaHMDS and dimethyl carbonate, and then regulating the obtained mixed solution to a specific pH value, so as to synthesize the compound 4-hydroxy-5,6-dimethylpyridine-2(1H)-ketone by one-pot method. The synthesis method adopts the cheap 3-methyl-2,4-pentanedione as raw material, realizes one-pot synthesis of the target product, and finally obtains the compound 4-hydroxy-5,6-dimethylpyridine-2(1H)-ketone at low cost, short steps, relatively mild reaction conditions, simple post-treatment and ideal yield.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis, specifically relating to a method for synthesizing 4-hydroxy-5,6-dimethylpyridine-2(1H)-one. Background Technology

[0002] 4-Hydroxy-2-pyridone compounds are a class of novel natural alkaloids extracted and isolated from the fermentation broths of endophytic bacteria, including plants and animals. Examples include Tenellin (A), Funiculosin (B), and Ilicicolin (H, C). They are also important drugs and their synthetic intermediates; for instance, the antitumor drug Gimeracil (D) contains a 4-hydroxy-2-pyridone structural core. Bioactivity studies have shown that 4-hydroxy-2-pyridone compounds possess a variety of biological activities, including antifungal, antibacterial, antiviral, and antitumor effects, making their research a hot topic in natural product chemistry and organic synthetic chemistry.

[0003]

[0004] In this class of compounds, 4-hydroxy-5,6-dimethylpyridin-2(1H)-one serves as an important molecular building block. For example, it was used in the synthesis of the antiviral immunomodulator 1H-imidazo[4,5-c]pyridine-4-amine derivative in patent US2003 / 232852A1, and in the synthesis of an immunomodulator for Toll-like receptors (TLRs) in patent US2007197478A1. These inhibitors can be used to treat a variety of diseases, including infectious diseases such as hepatitis (e.g., HCV, HBV), genetically related viral infections, and cancer. Therefore, research on the synthesis method of 4-hydroxy-5,6-dimethylpyridin-2(1H)-one is of great significance.

[0005] In the existing technology, there are three main routes for the synthesis of 4-hydroxy-5,6-dimethylpyridine-2(1H)-one. The first route uses ethyl 2-methylacetoacetate as a starting material and obtains the target product through three steps (as shown in Formula 1). This route uses inexpensive starting materials but requires multiple steps and is relatively cumbersome. The second route uses ethyl (E)-3-((3-methoxy-3-oxopropionyl)imino)-2-methylbutyrate as a starting material and obtains the target product through multiple steps (as shown in Formula 2). This route also requires multiple steps. The third route uses 5,6-dimethyl-4-hydroxy-2-carbonylpyran as a starting material and converts it into the target product in one step (as shown in Formula 3). Although this route only requires one step, the starting materials are expensive.

[0006]

[0007] Therefore, based on the current state of the technology, it is necessary to develop a method for preparing 4-hydroxy-5,6-dimethylpyridine-2(1H)-one that uses inexpensive raw materials, involves simple steps, has relatively mild reaction conditions, and yields a high product. Summary of the Invention

[0008] In view of the shortcomings of the existing methods for synthesizing 4-hydroxy-5,6-dimethylpyridin-2(1H)-one, the present invention aims to provide a method for synthesizing 4-hydroxy-5,6-dimethylpyridin-2(1H)-one that is low in cost, has a short procedure, relatively mild reaction conditions, and ideal yield.

[0009] To achieve the above objectives, the present invention provides the following technical solution:

[0010] A method for synthesizing 4-hydroxy-5,6-dimethylpyridin-2(1H)-one, wherein the method uses 3-methyl-2,4-pentanedione as a raw material, reacts it with NaHMDS and dimethyl carbonate, and then strictly controls the resulting mixture to a specific pH to obtain the compound 4-hydroxy-5,6-dimethylpyridin-2(1H)-one in a one-pot process.

[0011] Preferably, the synthetic route for the 4-hydroxy-5,6-dimethylpyridin-2(1H)-one is as follows:

[0012]

[0013] Specifically, the synthesis method includes the following steps:

[0014] (1) Add raw material 1 to organic solvent I, add NaHMDS solution under inert gas protection and low temperature conditions, stir for 2-6 hours after the addition is complete, add dimethyl carbonate at low temperature, stir for 5-30 hours after the addition is complete; after the raw material is completely consumed, add acidic aqueous solution to adjust to a specific pH, stir for 2-30 hours to obtain reaction solution.

[0015] (2) The reaction solution obtained in step (1) was post-treated to obtain the compound 4-hydroxy-5,6-dimethylpyridine-2(1H)-one.

[0016] Further, the detailed operation process of step (2) is as follows: filter the reaction solution obtained in step (1), collect the filter cake, and obtain a part of the product; extract the filtrate with organic solvent II, combine the organic phases, wash the organic phases, concentrate under reduced pressure, filter again, collect the filter cake, and obtain another part of the product; combine the two parts of the product to obtain the compound 4-hydroxy-5,6-dimethylpyridine-2(1H)-one.

[0017] Preferably, in step (1), the organic solvent I is selected from one or more of tetrahydrofuran, diethyl ether, methyl tert-butyl ether, and toluene.

[0018] More preferably, the organic solvent I is tetrahydrofuran, and the specific acidity / alkalinity is pH = 2-3.

[0019] Preferably, in step (1), the mass-to-volume ratio of raw material 1 to organic solvent I is 1:5-40 (g / mL).

[0020] Preferably, in step (1), the molar ratio of raw material 1 to NaHMDS is 1.0:1.0-5.0.

[0021] More preferably, in step (1), the molar ratio of raw material 1 to NaHMDS is 1.0:3.0.

[0022] Preferably, in step (1), the molar ratio of raw material 1 to dimethyl carbonate is 1.00:1.00-5.00.

[0023] More preferably, in step (1), the molar ratio of raw material 1 to dimethyl carbonate is 1.00:1.01.

[0024] Preferably, in step (1), the acidic aqueous solution is selected from one or more of hydrochloric acid solution, sulfuric acid solution, nitric acid solution, and acetic acid solution.

[0025] Preferably, in step (1), the inert gas is selected from nitrogen and / or argon.

[0026] Preferably, in step (2), the organic solvent II is selected from one or more of ethyl acetate, butyl acetate, chloroform, toluene, dichloromethane, and dichloroethane.

[0027] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0028] This invention proposes a method for preparing 4-hydroxy-5,6-dimethylpyridin-2(1H)-one. Using inexpensive and readily available 3-methyl-2,4-pentanedione as a starting material, it reacts with NaHMDS and dimethyl carbonate. The resulting mixture is then precisely controlled to a specific pH level to synthesize 4-hydroxy-5,6-dimethylpyridin-2(1H)-one in a one-pot process. This synthetic method uses inexpensive 3-methyl-2,4-pentanedione as a starting material and achieves the one-pot synthesis of the target product. It has advantages such as a short procedure, low cost, relatively mild reaction conditions, simple post-processing, and high product yield. It not only provides a potential route for the process synthesis of 4-hydroxy-5,6-dimethylpyridin-2(1H)-one but also contributes to the development and utilization of 4-hydroxy-2-pyridinone compounds. Attached Figure Description

[0029] Figure 1 The image shows the 1H NMR spectrum of the target product 4-hydroxy-5,6-dimethylpyridine-2(1H)-one in Example 1. Detailed Implementation

[0030] To make the technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some, not all, of the embodiments of the present invention. All other embodiments obtained by those skilled in the art based on the described embodiments of the present invention without creative effort are within the scope of protection of the present invention.

[0031] The following examples provide a method for synthesizing 4-hydroxy-5,6-dimethylpyridin-2(1H)-one. Using 3-methyl-2,4-pentanedione as a starting material, it is reacted with NaHMDS and dimethyl carbonate. The resulting mixture is then precisely controlled to a specific pH level to synthesize 4-hydroxy-5,6-dimethylpyridin-2(1H)-one in a one-pot process. The synthetic route is as follows:

[0032]

[0033] The present invention will be further described below through specific embodiments.

[0034] Example 1

[0035] In this embodiment, the compound 4-hydroxy-5,6-dimethylpyridin-2(1H)-one was synthesized using the following steps:

[0036] (1) At room temperature, 150.00 g (1.31 mol, 1.0 eq) of 3-methyl-2,4-pentanedione was dissolved in 1500 mL of anhydrous THF. Under argon protection and cooling to -78 °C, 1.97 L (2.0 M, 3.94 mol, 3.0 eq) of NaHMDS tetrahydrofuran solution was added dropwise. During the addition, the system turned into a white turbid liquid, and the temperature rose significantly. After the addition was complete, the mixture was stirred at room temperature for 4 hours, and the system turned into a clear orange liquid. The temperature was then lowered to -78 °C, and dimethyl carbonate (119.56 g, 1.33 mol, 1.01 eq) was slowly added dropwise. After the addition was complete, the mixture was stirred at room temperature for 12 hours. After the raw material was completely consumed, 2 M hydrochloric acid aqueous solution was added to adjust the pH to 2, and the mixture was stirred for 3 hours.

[0037] (2) The obtained reaction solution was filtered, and the filter cake was collected to obtain 98g of product; the filtrate was extracted twice with ethyl acetate (200mL×3), the organic phases were combined, the organic phase was washed once with saturated brine (500mL), concentrated under reduced pressure, and when at least a small amount of solvent remained, it was filtered and the filter cake was collected to obtain 73g of product; the two parts of the product were combined to obtain a total of 171.00g of white solid compound 4-hydroxy-5,6-dimethylpyridin-2(1H)-one with a purity of 97% and a yield of 91%.

[0038] The 1H NMR spectrum of the obtained compound 4-hydroxy-5,6-dimethylpyridin-2(1H)-one is as follows: Figure 1 As shown, the obtained characterization data are as follows:

[0039] 1 H NMR (400MHz, dmso) δ10.78(s,1H),10.51(s,1H),5.48(s,1H),2.08(s,3H),1.78(s,3H).

[0040] Example 2-3

[0041] Examples 2-3 are the same as Example 1, except that the organic solvent I and specific acidity / alkalinity (pH) in the reaction are adjusted, as shown in Table 1.

[0042] Comparative Examples 1-2

[0043] Comparative Examples 1-2 are the same as Example 1, except that specific acidity / alkalinity (pH) and other parameters in the reaction are adjusted, as shown in Table 1.

[0044] The effects of various reaction conditions on the reaction yield in the synthesis of 4-hydroxy-5,6-dimethylpyridin-2(1H)-one were tested using Examples 1-3 and Comparative Examples 1-2. The results are shown in Table 1.

[0045] Table 1

[0046] Example 1 THF 2 91 Example 2 THF 3 88 Example 3 Diethyl ether 2 86 Comparative Example 1 THF 4 ＜10 Comparative Example 2 THF 5 0

[0047] Combination Figure 1 As shown in Table 1:

[0048] Comparative Examples 1 and 2 and Comparative Examples 1 and 2, when the pH was adjusted to 4 or 5, the reaction could not proceed. When the pH was adjusted to 2 or 3, the reaction could proceed smoothly. Adjusting the pH to 2 resulted in better performance.

[0049] Comparing Examples 1 and 3, the reaction can proceed smoothly in both tetrahydrofuran and diethyl ether solvents, with tetrahydrofuran showing better performance as a solvent.

[0050] The above description represents a preferred embodiment of the present invention, but the present invention should not be limited to the content disclosed in this embodiment. Therefore, any equivalent or modified versions made without departing from the spirit of the present invention fall within the scope of protection of the present invention.

Claims

1. A method for synthesizing 4-hydroxy-5,6-dimethylpyridin-2(1H)-one, characterized in that, The synthesis route is as follows: ； The method for synthesizing the 4-hydroxy-5,6-dimethylpyridin-2(1H)-one includes the following steps: (1) Add raw material 1 to organic solvent I, add NaHMDS solution under inert gas protection and low temperature conditions, stir for 2-6 hours after the addition is complete, add dimethyl carbonate at low temperature, stir for 5-30 hours after the addition is complete; after the raw material is completely consumed, add acidic aqueous solution to adjust to a specific pH, stir for 2-30 hours to obtain reaction solution; the molar ratio of raw material 1 to NaHMDS is 1.0:3.0; (2) The reaction solution obtained in step (1) was post-treated to obtain compound 4-hydroxy-5,6-dimethylpyridine-2(1H)-one; In step (1), the low temperature is -78°C; The specific acidity or alkalinity is pH=2-3.

2. The method for synthesizing 4-hydroxy-5,6-dimethylpyridin-2(1H)-one according to claim 1, characterized in that, In step (1), the organic solvent I is selected from one or more of tetrahydrofuran, diethyl ether, methyl tert-butyl ether, and toluene; And / or the acidic aqueous solution is selected from one or more of hydrochloric acid solution, sulfuric acid solution, nitric acid solution, and acetic acid solution; And / or the inert gas is selected from nitrogen and / or argon.

3. The method for synthesizing 4-hydroxy-5,6-dimethylpyridin-2(1H)-one according to claim 1, characterized in that, In step (1), the mass-volume ratio of raw material 1 to organic solvent I is 1:5-40 (g / mL).

4. The method for synthesizing 4-hydroxy-5,6-dimethylpyridin-2(1H)-one according to claim 1, characterized in that, In step (1), the molar ratio of raw material 1 to dimethyl carbonate is 1.00:1.00-5.

00.

5. The method for synthesizing 4-hydroxy-5,6-dimethylpyridin-2(1H)-one according to claim 1, characterized in that, In step (1), the organic solvent I is tetrahydrofuran.

6. The synthesis method according to claim 1, characterized in that, The post-processing method is as follows: filter the reaction solution obtained in step (1), collect the filter cake, and obtain a portion of the product; The filtrate was extracted with organic solvent II, the organic phases were combined, the organic phases were washed, concentrated under reduced pressure, filtered again, and the filter cake was collected to obtain another part of the product; the two parts of the product were combined to obtain the compound 4-hydroxy-5,6-dimethylpyridine-2(1H)-one.

7. The method for synthesizing 4-hydroxy-5,6-dimethylpyridin-2(1H)-one according to claim 6, characterized in that, In step (2), the organic solvent II is selected from one or more of ethyl acetate, butyl acetate, chloroform, toluene, dichloromethane, and dichloroethane.

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