A method for preparing methylhesperidin using a microchannel reactor

Abstract

This invention discloses a method for preparing methyl hesperidin using a microchannel reactor, relating to the field of methyl hesperidin synthesis technology. The method includes: dissolving hesperidin and sodium hydroxide in a solvent, adding dimethyl sulfate, and then passing the solution into a microchannel reactor for reaction; wherein the molar ratio of hesperidin to dimethyl sulfate is 1:(2~2.5). The method is safe, efficient, and suitable for continuous industrial production.

Description

Technical Field

[0001] This invention relates to the field of methyl hesperidin synthesis technology, specifically to a method for preparing methyl hesperidin using a microchannel reactor. Background Technology

[0002] Methyl hesperidin, also known as methyl hesperidin or 3-methyl hesperidin, has the chemical name 3'-methyl-7-(rhamnosyl-L-glucose)hesperidin, molecular formula C29H38O15, and molecular weight 624.59. It is a yellow or pale yellow crystalline powder with a characteristic odor, a slightly bitter taste, and strong hygroscopic properties. It is soluble in water, very slightly soluble in ethanol and acetone, and insoluble in ether.

[0003] Methyl hesperidin is a water-soluble mixture of various dihydroflavonoid-type methyl hesperidins. It possesses vitamin P-like efficacy, enhances the effects of vitamin C, and has strong antiviral and antibacterial properties; high doses can inhibit the replication of influenza viruses. It can inhibit the action of tyrosinase, which causes skin darkening, and can be used to treat skin diseases such as dark spots and freckles. It maintains normal vascular permeability, improves capillary resistance, enhances capillary elasticity and resilience, and prevents and treats capillary bleeding, gingival bleeding, etc. It has the same pharmacological effects as hesperidin, strengthening capillary resistance, normalizing capillary permeability, and preventing vascular disorders caused by arteriosclerosis; its efficacy is enhanced when used in combination with vitamin C. It can be used for nosebleeds, retinal hemorrhage, gingival bleeding, alveolar bleeding, gastrointestinal bleeding, hemorrhoidal bleeding, and for the prevention and treatment of bleeding before or after surgery.

[0004] Methylhesperidin is present in very low amounts in natural plants, which cannot meet the large-scale demands of modern medicine. Currently, commercially available methylhesperidin is obtained from hesperidin through semi-synthetic methods. However, in the production process of hesperidin via methylation, solvents commonly used include methanol, ethanol, N,N-dimethylformamide, and water, while methylating agents are mainly dimethyl sulfate, iodomethane, methyl trifluoromethanesulfonate, and tetramethylammonium bromide. Traditional production processes pose significant hazards to the environment and operators. Furthermore, the reaction time of traditional processes is as long as 2-5 hours, consuming considerable time and energy. Therefore, researching a safe, efficient, and rapid new production process for preparing methylhesperidin is of great significance. Summary of the Invention

[0005] In view of the shortcomings of the prior art described above, the purpose of this invention is to provide a method for preparing methyl hesperidin using a microchannel reactor, so as to solve the problems of high environmental pollution and low efficiency in the synthesis of methyl hesperidin.

[0006] This invention first provides a method for preparing methyl hesperidin using a microchannel reactor. The method includes the following steps: dissolving hesperidin and sodium hydroxide in a solvent, adding dimethyl sulfate, and then passing the solution into a microchannel reactor for reaction; wherein the molar ratio of hesperidin to dimethyl sulfate is 1:(2~2.5).

[0007] In one embodiment, the molar ratio of hesperidin to dimethyl sulfate is 1:2.

[0008] In one embodiment, the method includes: dissolving hesperidin and sodium hydroxide in a solvent, adding dimethyl sulfate, stirring until homogeneous, and then passing the solution into a microchannel reactor for reaction; or dissolving hesperidin and sodium hydroxide in a solvent, and then passing the sodium hydroxide solution of hesperidin and dimethyl sulfate into a microchannel reactor for reaction.

[0009] In one embodiment, the mixing is performed under normal pressure.

[0010] In one embodiment, the mixing is performed by stirring and mixing at room temperature and normal pressure for 10 minutes.

[0011] In one embodiment, the flow rate when the material is introduced into the microchannel reactor is 0.1 mL / min to 2.5 mL / min.

[0012] In one embodiment, the flow rate introduced into the microchannel reactor is 0.5 mL / min to 2.0 mL / min.

[0013] In one embodiment, the flow rate introduced into the microreactor is 1.0 mL / min.

[0014] In one embodiment, the solvent is any one or more combinations of methanol, ethanol, N,N-dimethylformamide, and water.

[0015] In one embodiment, the solvent is water.

[0016] In one embodiment, the reaction temperature is 20°C to 40°C, and the reaction time is 0.3 min to 10 min.

[0017] In one embodiment, the reaction temperature is 30°C and the reaction time is 8 min.

[0018] In one embodiment, the reaction is a reaction under normal pressure or a reaction under pressure.

[0019] In one embodiment, the pressure during the pressurized reaction is 0.8–1.2 MPa.

[0020] In one embodiment, the reaction is carried out under normal pressure.

[0021] This invention provides a method for preparing methyl hesperidin using a microchannel reactor, which has the following advantages:

[0022] This invention uses a microchannel reactor to prepare methyl hesperidin. Under the microchannel reactor reaction process of this invention, not only is the product conversion rate and yield comparable to those of traditional processes achieved, but the reaction time is also shortened from 2-5 hours in traditional processes to 8.35 minutes. The reaction process is safer, more efficient, and faster, thereby achieving inherent safety in the industrial production of methyl hesperidin and further enhancing market competitiveness. Detailed Implementation

[0023] The raw materials and equipment used in the specific embodiments of the present invention are all known products, obtained by purchasing commercially available products.

[0024] This invention employs high-performance liquid chromatography (HPLC) for determination. The analytical conditions are as follows: octadecylsilane gel and silica gel (Agilent Zorbax Eclipse XDB-C18, 4.6 mm * 150 mm, 5 μm or equivalent column); mobile phase: methanol-glacial acetic acid aqueous solution (4.5: 56.5, v / v) = 39: 61; flow rate: 1.0 ml / min; detection wavelength: 283 nm; column temperature: 35 °C.

[0025] The synthesis of methyl hesperidin in this invention involves using hesperidin as a raw material and preparing it through a methylation reaction with dimethyl sulfate under alkaline conditions. The synthetic route is as follows:

[0026]

[0027] Microchannel reaction procedure: First, hesperidin and sodium hydroxide are dissolved separately in solutions. Then, the hesperidin-sodium hydroxide solution and dimethyl sulfate are separately pumped into the microchannel reaction system for mixing and reaction using a set flow pump. Alternatively, a mixed solution of hesperidin and sodium hydroxide can be prepared, dimethyl sulfate is added and stirred, and then the raw material solution is pumped into the microreaction system using a set flow pump. The solution flows smoothly through the reaction module to carry out the reaction. This reaction can be carried out under normal pressure or under pressure.

[0028] After the system has stabilized, sampling begins. The pH of the reaction solution is adjusted to 4-6 with 1 mol of hydrochloric acid, diluted to a final volume with DMSO, and then analyzed by HPLC.

[0029] The microchannel reactor is model JY-STR-01 from Sichuan Jiuyuan Chemical Technology Co., Ltd.

[0030] Example 1: Preparation of methylhesperidin using a microchannel reactor under ambient pressure according to the present invention.

[0031] The specific method for preparing methyl hesperidin in a microchannel reactor under normal pressure is as follows: a microchannel continuous flow reactor (operating temperature -25~195℃, single module liquid holding volume 6ml, pressure range 0~20bar, reaction throughput 0.1-100mL / min) is used as the reaction equipment.

[0032] Hesperidin was prepared into a hesperidin solution with a concentration of 27 mg / ml using sodium hydroxide aqueous solution. The hesperidin solution and dimethyl sulfate were mixed evenly at a molar ratio of 1:2. After 10 minutes, the mixture was injected into the reactor at a certain flow rate and then reacted to obtain the reaction solution.

[0033] The pH of the reaction solution was adjusted to 4-6 with 1 mol / L hydrochloric acid, and after being diluted to a final volume with DMSO, it was analyzed by HPLC to determine the yield of methyl hesperidin and the conversion rate of hesperidin.

[0034] The solvent is water, and the molar ratio of hesperidin to dimethyl sulfate is 1:2.

[0035] The selection of reaction temperature, reaction time (reaction residence time), and injection flow rate of hesperidin solution and dimethyl sulfate are shown in Table 1. The yield and conversion rate of methyl hesperidin obtained under different reaction conditions are also shown in Table 1.

[0036] Table 1. Yields and conversion rates of methylhesperidin obtained under different reaction conditions.

[0037] serial number solvent molar ratio of hesperidin to dimethyl sulfate Reaction temperature (°C) Reaction time (min) Flow rate (ml / min) Yield (%) Hesperidin conversion rate (%) 1 water 1:2 20 5.13 2.0 66.19% 82.38% 2 water 1:2 20 9.38 1.0 73.77% 88.68% 3 water 1:2 25 4.88 2.0 74.38% 89.78% 4 water 1:2 25 8.65 1.0 81.57% 94.62% 5 water 1:2 30 4.18 2.0 75.78% 92.32% 6 water 1:2 30 8.02 1.0 83.72% 97.88% 7 water 1:2 35 3.87 2.0 75.33% 91.51% 8 water 1:2 35 7.57 1.0 67.03% 87.57% 9 water 1:2 40 3.66 2.0 61.65% 81.44% 10 water 1:2 40 7.22 1.0 56.75% 79.38%

[0038] The above experimental results indicate that, under normal pressure, different reaction temperatures, reaction times, and injection flow rates significantly affect the yield and conversion of methyl hesperidin in a microchannel reactor. The optimal process conditions are: water as solvent, sodium hydroxide as alkali, a 1:2 molar ratio of hesperidin to sodium hydroxide, a 1:2 molar ratio of hesperidin to dimethyl sulfate, an injection flow rate of 1.0 ml / min, a temperature of 30℃, and a reaction time of 8.02 min. Under these conditions, the yield of methyl hesperidin is 83.72%, and the conversion rate of hesperidin is 97.88%.

[0039] Example 2: Preparation of methylhesperidin using a microchannel reactor under pressure according to the present invention.

[0040] The specific method for preparing methyl hesperidin under pressure in a microchannel reactor is as follows: a microchannel continuous flow reactor (operating temperature -25~195℃, single module liquid holding volume 6ml, pressure range 0~20bar, reaction throughput 0.1-100mL / min) is used as the reaction equipment, and a back pressure valve is added to the reactor to increase the system pressure, with a back pressure of 10Bar.

[0041] A hesperidin alkaline solution with a concentration of 27 mg / ml was prepared using sodium hydroxide aqueous solution. The hesperidin solution and dimethyl sulfate were mixed thoroughly at a molar ratio of 1:2. After 10 min, the mixture was injected into a reactor at a controlled flow rate, and the reaction proceeded to obtain the reaction solution. The pH of the reaction solution was adjusted to 4-6 with 1 mol / L hydrochloric acid, and after dilution with DMSO, the solution was analyzed by HPLC to determine the yield of methyl hesperidin and the conversion rate of hesperidin.

[0042] The solvent is water, and the molar ratio of hesperidin to dimethyl sulfate is 1:2.

[0043] The selection of reaction temperature, reaction time (reaction residence time), and injection flow rate of hesperidin solution and dimethyl sulfate are shown in Table 2. The yield and conversion rate of methyl hesperidin obtained under different reaction conditions are also shown in Table 2.

[0044] Table 2. Yields and conversion rates of methylhesperidin obtained under different reaction conditions.

[0045] serial number solvent molar ratio of hesperidin to dimethyl sulfate Reaction temperature (°C) Reaction time (min) Flow rate (ml / min) Yield (%) Hesperidin conversion rate (%) 1 water 1:2 20 4.98 2.0 63.19% 76.19% 2 water 1:2 20 8.79 1.0 70.77% 82.63% 3 water 1:2 25 4.77 2.0 72.78% 86.22% 4 water 1:2 25 8.35 1.0 78.55% 91.76% 5 water 1:2 30 3.86 2.0 71.38% 83.74% 6 water 1:2 30 7.75 1.0 75.57% 88.67% 7 water 1:2 35 3.47 2.0 72.33% 85.51% 8 water 1:2 35 6.57 1.0 64.03% 81.75% 9 water 1:2 40 3.16 2.0 58.65% 75.58% 10 water 1:2 40 6.22 1.0 53.75% 73.83%

[0046] The above experimental results indicate that the preparation of methyl hesperidin in a microchannel reactor under pressure is significantly affected by different reaction temperatures, reaction times, and injection flow rates, both in terms of yield and conversion rate. The optimal process conditions are: water as solvent, sodium hydroxide as alkali, a hesperidin to sodium hydroxide molar ratio of 1:2, a hesperidin to dimethyl sulfate molar ratio of 1:2, an injection flow rate of 1.0 ml / min, a temperature of 25℃, and a reaction time of 8.35 min. Under these conditions, the yield of methyl hesperidin is 78.55%, and the conversion rate is 91.76%.

[0047] Comparative Example 1: Preparation of methylhesperidin in the laboratory using glass reaction flasks

[0048] The effects of the molar ratio of solvent, alkali, hesperidin and dimethyl sulfate, reaction temperature and reaction time (reaction residence time) on the yield and conversion of methyl hesperidin were investigated under glass reaction flask conditions.

[0049] When water is used as the solvent and sodium hydroxide is selected as the alkali, the specific preparation method is as follows: Under normal pressure, weigh out 8g of sodium hydroxide (200mmol) and dissolve it in water, along with hesperidin (61g, 100.0mmol). Stir until the hesperidin is completely dissolved, and slowly add dimethyl sulfate (25.2g, 200mmol) dropwise. The molar ratio of hesperidin to dimethyl sulfate is 1:2. After the addition is complete, raise the temperature to 20~40℃ and keep it at that temperature for 2~5 hours (the reaction endpoint is determined by HPLC monitoring until the hesperidin is completely converted).

[0050] Table 3. Yields and conversion rates of methylhesperidin obtained under different reaction conditions.

[0051] serial number solvent molar ratio of hesperidin to dimethyl sulfate Reaction temperature (°C) Reaction time (h) Yield (%) Hesperidin conversion rate (%) 1 water 1:2 20 2 51.02% 68.23% 2 water 1:2 20 3 58.77% 71.43% 3 water 1:2 25 3 66.78% 82.11% 4 water 1:2 25 4 68.89% 87.67% 5 water 1:2 30 3 74.88% 91.47% 6 water 1:2 30 4 76.26% 93.76% 7 water 1:2 35 5 75.33% 90.15% 8 water 1:2 35 5 72.03% 87.27% 9 water 1:2 40 4 64.56% 78.85% 10 water 1:2 40 4 58.82% 68.11%

[0052] The above experimental results indicate that the yield and conversion of methyl hesperidin are significantly affected by different reaction temperatures, reaction times, and injection flow rates when preparing methyl hesperidin using a glass reaction flask. The optimal process conditions are water as the solvent, sodium hydroxide as the alkali, a 1:2 molar ratio of hesperidin to sodium hydroxide, a 1:2 molar ratio of hesperidin to dimethyl sulfate, a temperature of 30℃, and a reaction time of 4 hours. Under these conditions, the yield of methyl hesperidin is 76.29%, and the conversion rate of hesperidin is 93.76%.

[0053] The above embodiments are merely illustrative of the principles and effects of the present invention and are not intended to limit the invention. When numerical ranges are given in the embodiments, it should be understood that, unless otherwise stated in the present invention, both endpoints of each numerical range and any value between the two endpoints may be selected. Unless otherwise defined, all technical and scientific terms used in the present invention have the same meaning as commonly understood by those skilled in the art. In addition to the specific methods, devices, and materials used in the embodiments, based on the knowledge of those skilled in the art and the description of the present invention, any prior art methods, devices, and materials similar to or equivalent to those described, used, and materials in the embodiments of the present invention can be used to implement the present invention. Any person skilled in the art can modify or change the above embodiments without departing from the spirit and scope of the present invention. Therefore, all equivalent modifications or changes made by those skilled in the art without departing from the spirit and technical concept disclosed in the present invention should still be covered by the claims of the present invention.

Claims

1. A method for preparing methylhesperidin using a microchannel reactor, the method comprising the following steps: After dissolving hesperidin and sodium hydroxide in a solvent, dimethyl sulfate is added and the mixture is passed into a microchannel reactor for reaction; wherein the molar ratio of hesperidin to dimethyl sulfate is 1:(2~2.5).

2. The method according to claim 1, characterized in that: The molar ratio of hesperidin to dimethyl sulfate is 1:

2.

3. The method according to claim 1, characterized in that: The method includes: dissolving hesperidin and sodium hydroxide in a solvent, adding dimethyl sulfate, stirring evenly, and then passing the solution into a microchannel reactor for reaction; or dissolving hesperidin and sodium hydroxide in a solvent, and then passing the sodium hydroxide solution of hesperidin and dimethyl sulfate into a microchannel reactor for reaction.

4. The method according to claim 3, characterized in that: The term "mixed evenly" refers to mixing evenly under normal pressure.

5. The method according to claim 1, characterized in that: The flow rate when introducing the material into the microchannel reactor is 0.1 mL / min to 2.5 mL / min.

6. The method according to claim 5, characterized in that: The flow rate when introducing the material into the microchannel reactor is 0.5 mL / min to 2.0 mL / min.

7. The method according to claim 1, characterized in that: The solvent is any one or more of methanol, ethanol, N,N-dimethylformamide, and water.

8. The method according to claim 1, characterized in that: The reaction temperature is 20℃~40℃, and the reaction time is 0.3min~10min.

9. The method according to claim 8, characterized in that: The reaction temperature is 30°C, and the reaction time is 8 minutes.

10. The method according to claim 1, characterized in that: The reaction is carried out under normal pressure or under pressure, wherein the pressure of the reaction under pressure is 0.8 to 1.2 MPa.

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