A method for preparing sodium houttuynin

Abstract

This invention discloses a method for preparing sodium houttuynia cordata, comprising the following steps: adding sodium methoxide and toluene to a reaction vessel, heating, then slowly adding nonanone and ethyl formate, and after the addition is complete, reacting with a gradient cooling process, and post-processing to obtain an aqueous phase containing intermediate I; adding the aqueous phase containing intermediate I and toluene to the reaction vessel, stirring, cooling, and rapidly introducing liquid sulfur dioxide, continuously stirring and reacting at 0-10°C for 5-15 minutes, cooling, and filtering to obtain crude sodium houttuynia cordata. The preparation method of this invention directly introduces liquid sulfur dioxide during the sulfonation reaction, greatly shortening the process time, while achieving high product yield and purity, and requiring less sulfur dioxide. Furthermore, in the post-processing of sodium houttuynia cordata, adding toluene to the reaction solution beforehand can effectively transfer the generated impurities to the toluene; recrystallization using a 50 v / v% ethanol aqueous solution removes water-soluble and oil-soluble impurities while further reducing the risk of fire and explosion during centrifuge operation.

Description

Technical Field

[0001] This invention relates to the field of houttuynin sodium preparation technology, and more particularly to a method for preparing houttuynin sodium. Background Technology

[0002] Sodium houttuynin is a chemically synthesized aldehyde component from the volatile oil of the whole herb of *Houttuynia cordata* (Saururaceae family). It exhibits significant inhibitory effects against *Streptococcus pneumoniae*, *Salmonella typhi*, *Staphylococcus aureus*, *Escherichia coli*, and *Sporothrix sp.* It can enhance the body's immunity, strengthen the phagocytic function of leukocytes, increase serum propertin levels, and improve the body's non-specific immunity.

[0003] Existing processes for preparing sodium houttuynia cordata suffer from problems such as long reaction times, difficult product post-processing, and low reaction yields. Therefore, there is an urgent need for a new method for preparing sodium houttuynia cordata that features short reaction times, simple product post-processing, and high reaction yields. Summary of the Invention

[0004] The purpose of this invention is to address the shortcomings of existing technologies by providing a method for preparing sodium houttuynin.

[0005] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0006] A method for preparing sodium houttuynin is provided, comprising the following steps:

[0007] Step 1: Add solid sodium methoxide and toluene to the reaction vessel, heat up, and then slowly add nonanone and ethyl formate, controlling the temperature at 50-60℃. After the addition is complete, gradually lower the temperature to react. After the reaction is complete, add cold water and stir to hydrolyze. After standing, separate the liquid and take the aqueous phase containing intermediate I.

[0008] Step 2: Add the aqueous phase containing intermediate I obtained in Step 1 and toluene to the reaction vessel, stir, cool to below 10°C, quickly introduce liquid sulfur dioxide, and continuously stir and react at 0-10°C for 5-15 minutes. After cooling and filtration, crude sodium houttuynia cordata is obtained.

[0009]

[0010] Furthermore, in step one, the gradient cooling reaction specifically involves cooling to 20–30°C and holding for 4–8 hours, then cooling to below 5°C.

[0011] Furthermore, in step one, the temperature of the cold water added after the reaction is complete is ≤5℃.

[0012] Furthermore, in step one, the stirring and hydrolysis time is 15-30 minutes; the settling time is 30-60 minutes.

[0013] Furthermore, step two also includes: re-agglomerating the crude houttuynia cordata product with a 50 v / v% ethanol aqueous solution, drying the crystals, and obtaining the houttuynia cordata product.

[0014] Furthermore, in step two, the reaction time is 5 to 10 minutes.

[0015] Furthermore, in step two, the molar ratio of intermediate I to sulfur dioxide is 1:(2-5).

[0016] Furthermore, in step two, the volume ratio of toluene to the starting material nonyl ketone is (0.8–2):1.

[0017] The present invention adopts the above technical solution and has the following technical effects compared with the prior art:

[0018] The present invention provides a method for preparing sodium houttuynin. During the sulfonation reaction, liquid sulfur dioxide is directly introduced, significantly shortening the process time. Simultaneously, the product yield is high, the purity is high, and the amount of sulfur dioxide used is small. Furthermore, in the post-treatment of sodium houttuynin, toluene is added to the reaction solution beforehand, which effectively transfers the generated impurities to the toluene. Compared with the existing technique of rinsing with petroleum ether, this reduces the risk and removes impurities more thoroughly. Recrystallization using a 50% v / v ethanol aqueous solution removes both water-soluble and oil-soluble impurities, further reducing the risk of fire and explosion during centrifuge operation. Detailed Implementation

[0019] The present invention will be further described below with reference to specific embodiments, but these are not intended to limit the invention. It should be noted that, unless otherwise specified, the embodiments and features described in the embodiments of the present invention can be combined with each other.

[0020] Example 1

[0021] This embodiment provides a method for preparing sodium houttuynin, including the following steps:

[0022] Step 1: Synthesize intermediate I

[0023] 28.5 g of solid sodium methoxide (0.528 mol) and 320 g of toluene were added to a reaction vessel and heated. When the temperature reached 50 °C, 50 g of nonanone (0.294 mol) and 26 g of ethyl formate (0.351 mol) were slowly added. The temperature was controlled at 50–60 °C. After the addition was complete, the temperature was lowered to 20 °C and kept at that temperature for 4 hours. Then the temperature was lowered to below 5 °C. After the reaction was completed, 350 g of cold water with a temperature ≤5 °C was added and the mixture was stirred and hydrolyzed for 15 min. After standing for 30 min, the liquid was separated, and the aqueous phase containing intermediate I was collected.

[0024] Step 2, sulfonation: The aqueous phase containing intermediate I obtained in Step 1, and toluene (50 ml) were added to a four-necked flask, stirred, and cooled to below 10°C. Liquid sulfur dioxide (45 g, 0.70 mol) was rapidly introduced, and the reaction was continuously stirred at 0–10°C for 10 min. The mother liquor was cooled, and after the crystals were fully separated, it was filtered through a Buchner funnel to obtain a white crude product of houttuynia cordata sodium. The product was then recrystallized with a 50 v / v% ethanol aqueous solution, and finally the crystals were dried to obtain 71.1 g of houttuynia cordata sodium with a titration purity of 99.5% and a yield of 80% (calculated based on methyl nonanone).

[0025] Comparative Example 1

[0026] Step 1: Synthesize intermediate I

[0027] 12.1 g of metallic sodium (0.528 mol) and 320 g of toluene were added to a reaction vessel and heated. When the temperature reached 50 °C, 50 g of nonanone (0.294 mol) and 26 g of ethyl formate (0.351 mol) were slowly added. The temperature was controlled at 50–60 °C. After the addition was complete, the temperature was lowered to 20 °C and kept at that temperature for 4 hours. Then the temperature was lowered to below 5 °C. After the reaction was completed, 350 g of cold water with a temperature ≤5 °C was added and the mixture was stirred and hydrolyzed for 15 min. After standing for 30 min, the mixture was separated and the aqueous phase containing intermediate I was collected.

[0028] Step 2, sulfonation: Sulfur dioxide gas (0.900 mol) is introduced into the aqueous phase containing intermediate I obtained in Step 1, and the reaction is continuously stirred at 0-10°C for 60 min. The mother liquor is cooled, and after the crystals have fully separated, it is filtered through a Buchner funnel to obtain yellow crystals. The yellow oily substance is washed away with diethyl ether to obtain crude houttuynia cordata sodium. The product is then recrystallized with ethanol, and finally the crystals are dried to obtain 40.0 g of houttuynia cordata sodium with a titration purity of 96% and a yield of 45% (calculated based on methyl nonanone).

[0029] The comparison and summary of Example 1 and Comparative Example 1 are shown in Table 1 below:

[0030] Table 1

[0031]

[0032] As can be seen, the preparation method of sodium houttuynin of this invention directly introduces liquid sulfur dioxide during the sulfonation reaction, greatly shortening the process time. From feeding to the end of the reaction, it only takes 10 minutes, while achieving high product yield and purity, and requiring less sulfur dioxide. Furthermore, in the post-treatment of sodium houttuynin, toluene is added to the reaction solution beforehand, which effectively transfers the generated impurities to the toluene. Compared with the existing technology of rinsing with petroleum ether, this reduces the risk and removes impurities more thoroughly. The crystallization process uses a 50% ethanol aqueous solution for recrystallization, which removes both water-soluble and oil-soluble impurities while further reducing the risk of fire and explosion during centrifuge operation.

[0033] The above description is merely a preferred embodiment of the present invention and does not limit the implementation and protection scope of the present invention. Those skilled in the art should realize that any equivalent substitutions and obvious changes made based on the content of the present invention specification should be included within the protection scope of the present invention.

Claims

1. A method for preparing sodium houttuynin, characterized in that, Includes the following steps: Step 1: Add solid sodium methoxide and toluene to a reaction vessel, heat the vessel, and then slowly add nonanone and ethyl formate, controlling the temperature at 50-60°C. After the addition is complete, allow the temperature to drop gradually. After the reaction is complete, add cold water and stir to hydrolyze the mixture. After standing, separate the liquids and take the aqueous phase containing intermediate I. In Step 1, the gradient cooling reaction specifically involves: cooling to 20-30°C and holding for 4-8 hours, then cooling to below 5°C. Step 2: Add the aqueous phase containing intermediate I obtained in Step 1 and toluene to the reactor, stir, cool to below 10°C, quickly introduce liquid sulfur dioxide, and continuously stir and react at 0~10°C for 5~15 minutes. Cool and filter to obtain crude sodium houttuynia cordata. The molar ratio of nonanone to sulfur dioxide is 1:(2~3). The volume ratio of toluene to the starting material nonanone in Step 2 is (0.8~2):

1.

2. The method for preparing sodium houttuynin according to claim 1, characterized in that, In step one, the temperature of the cold water added after the reaction is complete is ≤5℃.

3. The method for preparing sodium houttuynin according to claim 1, characterized in that, In step one, the stirring and hydrolysis time is 15-30 minutes; the settling time is 30-60 minutes.

4. The method for preparing sodium houttuynin according to claim 1, characterized in that, Step two further includes: recrystallizing the crude houttuynin sodium using a 50v / v% ethanol aqueous solution, drying the crystals, and obtaining the houttuynin sodium product.

Images