Preparation method of denitrogenated bacteriochlorin

Abstract

The present application relates to the technical fields of organic chemical synthesis, and particularly relates to a preparation method of deazaflavins II, comprising the following steps: 6-chloro-3-methyluracil and 2-(ethylamino)benzaldehyde are used as raw materials, and deazaflavins II is obtained by reaction under the action of inorganic base, and the reaction can be carried out in a dynamic tubular reactor. According to the method, 2-(ethylamino)benzaldehyde and 6-chloro-3-methyluracil are reacted in a dynamic tubular reactor under the action of inorganic base to generate deazaflavins II, the process condition is simple, the reaction condition is accurately controlled, the reaction selectivity is good, the speed is fast, the yield is high, the product quality is good, the solvent consumption is low, high-toxicity materials are not used, and the safety is high.

Description

Technical Field

[0001] This invention relates to the field of organic chemical synthesis technology, specifically to a method for preparing second-generation denitrified flavin. Background Technology

[0002] NAD+, or nicotinamide adenine dinucleotide, is an important cofactor essential for human cells, tissues, and overall health. However, with age, cellular NAD+ levels gradually decline, and this decline is associated with various diseases, including sarcopenia, metabolic disorders, neurodegenerative diseases, and cancer. Desoxyflavin II is an NAD+ analog that promotes NAD+ production in the body, thereby activating mitochondria and the sirtuin gene. This can help delay aging and prevent the aforementioned neurodegenerative diseases. It can also enhance immunity, maintain eye health, and protect the skin and oral mucosa. Currently, the main methods for preparing desoxyflavin II are as follows:

[0003] (1) In the literature J. Am. Chem. Soc. 1976, 98, 3, 830–835 and JCS Comm., 1976, 203-204, N-ethylaniline was first reacted with 6-chloro-3-methyluracil at 170-180°C. After purification and drying, the substituted product was obtained. Subsequently, the substituted product was reacted with phosphorus oxychloride and DMF at 90°C. After the reaction was completed, water was added and neutralized to obtain denitroflavin II. However, this method requires a high temperature of 170-180°C for the substitution reaction, and the cyclization reaction at 90°C is exothermic and difficult to control, resulting in a high safety risk.

[0004] .

[0005] (2) In the literature J.CHEM.SOC.,CHEM.COMMUN.,1989,44-45, (2-(ethylamino)phenyl)methanol and 6-chloro-3-methyluracil were refluxed in DMF at 153℃ for 24h, and then purified by reduced evaporation and silica gel column to obtain denitroflavin II. However, the reaction conditions of this method are severe, the required DMF equipment for reduced evaporation is high, and the column purification efficiency is low and the solvent consumption is large. The product yield is only 26%, which is not suitable for industrial production.

[0006] .

[0007] (3) Patent application CN202510916052 uses anthranilaldehyde and 1-methylbarbituric acid to condense and obtain intermediate I. Intermediate I reacts with an ethylating agent under alkaline conditions to obtain denitroflavin II. Although this method is simple to operate, has good selectivity and high yield, the ethylating agents used, such as diethyl sulfate, iodoethane, and bromoethane, are all hazardous chemicals with high toxicity, which are harmful to the human body and pose a high safety risk.

[0008] .

[0009] The above-mentioned routes each have their own advantages, but they all employ a batch-process method, which is cumbersome, highly dangerous, and cannot be used for continuous production. Dynamic tubular reactors, on the other hand, can significantly improve the safety of batch reactions, improve the mixing of reactants and heat transfer, enhance the reproducibility of reaction results, avoid the separation of dangerous or toxic intermediates, and avoid the drawbacks of microchannel reactors, such as pipe blockage and incomplete reactions when solids are involved or generated. Furthermore, they can, to a certain extent, prevent chemical production accidents. Summary of the Invention

[0010] To address the shortcomings of the existing technology, this invention provides a method for preparing denitroflavin II. This method involves reacting 2-(ethylamino)benzaldehyde with 6-chloro-3-methyluracil in a dynamic tubular reactor under the action of an inorganic base to generate denitroflavin II. This process is simple, with precise control of reaction conditions, good reaction selectivity, fast reaction rate, high yield, good product quality, low solvent consumption, and avoidance of highly toxic materials, thus ensuring high safety.

[0011] The specific plan is as follows:

[0012] A method for preparing denitroflavin II includes the following steps:

[0013] Using 6-chloro-3-methyluracil and 2-(ethylamino)benzaldehyde as raw materials, denitroflavin second generation was obtained by reaction under the action of inorganic base.

[0014] The reaction route is shown below:

[0015] .

[0016] Furthermore, the reaction temperature is 50~80℃.

[0017] Furthermore, the inorganic base is selected from at least one of potassium carbonate, sodium carbonate, cesium carbonate, lithium carbonate, and potassium phosphate.

[0018] Furthermore, the molar ratio of 6-chloro-3-methyluracil to 2-(ethylamino)benzaldehyde is 1:(1.02~1.04); the molar ratio of 6-chloro-3-methyluracil to inorganic base is 1:(1.55~1.70).

[0019] Preferably, the reaction is carried out in a dynamic tubular reactor. Specifically, a mixed solution is prepared using 6-chloro-3-methyluracil, 2-(ethylamino)benzaldehyde, and a solvent; the mixed solution and a solid inorganic base are then introduced into the dynamic tubular reactor to react and obtain denitrifying flavin II.

[0020] The solvent is preferably at least one of DMF, DMAc, acetonitrile, acetone, methanol, ethanol, and isopropanol; the concentration of 6-chloro-3-methyluracil in the mixed solution is 0.05~0.5 g / mL; the flow rate of the mixed solution is 2~20 mL / min; and the feed rate of the solid inorganic alkali is 1~10 g / min.

[0021] Preferably, the reaction time is 0.5 to 8 minutes.

[0022] The beneficial effects are as follows:

[0023] The technical solution of this invention features short reaction steps, simple process, high efficiency, and low cost. It can achieve continuous preparation with fast reaction speed and short reaction time. The reaction process does not use highly toxic or hazardous materials, and there are no harsh process conditions such as high temperature, ensuring high safety. The process uses less solvent, making it more environmentally friendly. At the same time, the dynamic tubular reactor can effectively enhance mass and heat transfer, accurately control temperature, effectively avoid the generation of side reactions, and significantly improve product quality and yield. It avoids problems such as pipeline blockage and incomplete reaction caused by solid particles in raw materials and products, which is more conducive to industrial production. Attached Figure Description

[0024] Figure 1 The NMR spectrum of the denitrified flavin II prepared in Example 1 of this invention;

[0025] Figure 2 This is the liquid phase spectrum of the denitrified flavin II prepared in Example 1 of the present invention. Detailed Implementation

[0026] The embodiments of the present invention will be described in further detail below. The following examples are for illustrative purposes only and should not be construed as limiting the scope of the invention. Unless otherwise specified, the experimental methods used in the following examples are conventional methods. Unless otherwise specified, the materials and reagents used in the following examples are commercially available.

[0027] Example 1

[0028] Weigh 100g of 6-chloro-3-methyluracil and 94.7g of 2-(ethylamino)benzaldehyde, then dilute to 1000mL with DMF and stir until dissolved to obtain a mixed solution, which is then connected to a constant flow pump. Weigh 137.7g of potassium carbonate and add it to the solid feeder. Set the constant flow pump flow rate to 10mL / min and the solid feeder feed rate to 1.38g / min. Add the mixed solution and potassium carbonate to a dynamic tubular reactor. The residence time of the liquid is 2.5min, and the temperature is 55℃. The outlet of the pipeline yields a second-generation semi-solid liquid containing denitrifying flavin. Then add 3L of deionized water. After the addition is complete, cool to 20℃ and stir for 30min. Filter and dry to obtain 148.1g of product with an HPLC purity of 99.7% and a yield of 93.2%.

[0029] Figure 1 The NMR spectrum of the denitrified flavin II prepared in Example 1 of this invention; Figure 2 Table 1 shows the liquid phase spectrum of the denitroflavin II prepared in Example 1 of this invention, with the corresponding peak results in Table 1.

[0030] Table 1 Peak Results

[0031]

[0032] Example 2

[0033] Weigh 100g of 6-chloro-3-methyluracil and 95.7g of 2-(ethylamino)benzaldehyde, then dilute to 1500mL with acetone and stir until dissolved to obtain a mixed solution, which is then connected to a constant flow pump. Weigh 320.6g of cesium carbonate and add it to the solid feeder. Set the constant flow pump flow rate to 12mL / min and the solid feeder feed rate to 2.56g / min. Add the mixed solution and cesium carbonate to a dynamic tubular reactor. The residence time of the liquid is 2.1min, and the temperature is 60℃. The liquid containing desaturated flavin is obtained from the outlet of the pipeline. Then add 3.5L of deionized water. After the addition is complete, cool to 30℃ and stir for 30min. Filter and dry to obtain 145.4g of product with HPLC purity of 99.8% and yield of 91.5%.

[0034] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A method for preparing second-generation desoxyflavin, characterized in that, The process includes the following steps: using 6-chloro-3-methyluracil and 2-(ethylamino)benzaldehyde as raw materials, a reaction is carried out under the action of an inorganic base to obtain denitrifying flavin II.

2. The preparation method according to claim 1, characterized in that, The inorganic base is selected from at least one of potassium carbonate, sodium carbonate, cesium carbonate, lithium carbonate, and potassium phosphate.

3. The preparation method according to claim 1, characterized in that, The molar ratio of 6-chloro-3-methyluracil to 2-(ethylamino)benzaldehyde is 1:(1.02~1.04); the molar ratio of 6-chloro-3-methyluracil to inorganic base is 1:(1.55~1.70).

4. The preparation method according to claim 1, characterized in that, The reaction temperature is 50~80℃.

5. The preparation method according to claim 1, characterized in that, The reaction takes place in a dynamic tubular reactor.

6. The preparation method according to claim 5, characterized in that, A mixed solution was prepared using 6-chloro-3-methyluracil, 2-(ethylamino)benzaldehyde, and a solvent; the mixed solution and an inorganic base were then introduced into a dynamic tubular reactor to react and obtain denitrified flavin II.

7. The preparation method according to claim 6, characterized in that, The solvent is at least one of DMF, DMAc, acetonitrile, acetone, methanol, ethanol, and isopropanol.

8. The preparation method according to claim 6, characterized in that, In the mixed solution, the concentration of 6-chloro-3-methyluracil is 0.05~0.5 g / mL.

9. The preparation method according to claim 6, characterized in that, The flow rate of the mixed solution is 2~20 mL / min, and the feed rate of the inorganic alkali is 1~10 g / min.

10. The preparation method according to claim 6, characterized in that, The reaction time is 0.5 to 8 minutes.

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