Preparation method of diosmin

Abstract

The invention belongs to the field of chemical synthesis, and particularly relates to a preparation method of diosmin. According to the method, potassium iodate and sodium iodide are slowly subjected to a neutralization reaction in an acid environment, and hesperidin is oxidized by using a newly prepared low-concentration iodine simple substance to prepare diosmin. The optimal diosmin preparation method is obtained through screening of a large number of experiments, and by means of the method, the purity and yield of diosmin are high, and the impurity content is low; meanwhile, the method is safe, environment-friendly, low in production cost and suitable for industrial production.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of chemical synthesis, and particularly relates to a preparation method of diosmin. BACKGROUND

[0002] Diosmin is an important flavonoid drug, which is widely used in the treatment of hemorrhoids and chronic venous insufficiency, and has multiple effects such as enhancing venous tension, improving microcirculation, promoting lymphatic return, anti-inflammatory and hemostasis. Although there are certain adverse reactions, its curative effect is significant, and it shows good safety and tolerance in clinical application. It is usually prepared by dehydrogenation reaction of plant extract hesperidin, and with the continuous optimization of the preparation process, the production cost and purity of dioxin are continuously improved, which provides better drug selection for clinical treatment.

[0003] The existing synthesis method generally adopts the following methods:

[0004] Scheme I: hesperidin is dissolved in anhydrous pyridine, iodine (I2) is added as an oxidant, and the reaction is carried out at room temperature or under slight heating, and then cooled to low temperature (such as 0-5℃), and ozone (O3) gas is introduced for ozone oxidation reaction, and dioxin is obtained after purification;

[0005] Scheme II: hesperidin is added to a proper amount of pyridine, sodium iodide (NaI) is added, and then hydrogen peroxide (H2O2) is slowly added dropwise, hydrogen peroxide reacts with sodium iodide to generate iodine (I2), and iodine further oxidizes the specific hydroxyl group in the structure of hesperidin to obtain dioxin;

[0006] Since pyridine is used as a solvent in scheme I and scheme II, it has toxicity and irritation, and at the same time, hydrogen peroxide and ozone are high-concentration oxidants, which have the risk of explosion.

[0007] Scheme III: hesperidin is added to N,N-dimethylformamide solvent, and sodium iodide, iodine and sodium carbonate are sequentially added to synthesize dioxin, and the yield is only 20-30%, the preparation method has low yield, high cost and high content of impurity 6-iodine dioxin.

[0008] For the problems of high cost, low safety and low yield of the current preparation method of dioxin, a low-cost, high-safety and high-yield preparation method of dioxin is needed. SUMMARY

[0009] In view of the problems in the prior art, the present application provides a preparation method of dioxin.

[0010] The present application provides a preparation method of dioxin, comprising the following steps:

[0011] Step 1: dissolve hesperidin, iodate, iodide in polar aprotic solvent, heat, adjust pH to acidic, react until hesperidin content is less than 5%; the molar mass ratio of hesperidin, iodate, iodide is 1:(0.8-1.2):(0.2-0.4);

[0012] Step 2: add carbonate, continue to react;

[0013] Step 3: after concentration, add water to crystallize, adjust to neutralize, get diosmin.

[0014] Preferably, in step 1, the iodate is selected from at least one of potassium iodate, sodium iodate, calcium iodate, ammonium iodate;

[0015] and / or, the iodide is selected from at least one of sodium iodide, potassium iodide, calcium iodide, ammonium iodide, hydrogen iodide;

[0016] and / or, the polar aprotic solvent is selected from at least one of N,N dimethylformamide, N,N-dimethylacetamide;

[0017] and / or, in step 2, the carbonate is selected from potassium carbonate.

[0018] Preferably, the molar ratio of hesperidin, iodate, iodide is 1:1:(0.2-0.3).

[0019] Preferably, in step 1, the heating temperature is 45-65℃.

[0020] Preferably, the heating temperature is 50-60℃.

[0021] Preferably, in step 1, the pH is 1-6.

[0022] Preferably, the pH is 3-5.

[0023] Preferably, the molar ratio of hesperidin to carbonate is 1:(0.4-0.7).

[0024] Preferably, the molar ratio of hesperidin to carbonate is 1:(0.5-0.6).

[0025] Preferably, in step 2, the reaction time is 6-10h.

[0026] The application obtains the optimal preparation method of diosmin through experiment screening. The purity of diosmin reaches more than 90% and the molar yield reaches more than 85% by using the method, and the impurity content is low. Meanwhile, the method of slowly releasing iodine monomer under the acid condition of potassium iodate and sodium iodide avoids the problems of local high concentration, violent reaction and iodine volatilization loss when solid iodine is directly used, is conducive to controlling the reaction rate, improving the utilization rate of iodine and the purity of the product, is more safe and environmentally friendly to operate, and can effectively reduce the cost because the price of potassium iodate and sodium iodide is relatively low. It can be seen that the preparation method has the advantages of low cost, high safety, high yield and the like, is suitable for industrial production, and has good application prospect.

[0027] Obviously, according to the above content of the application, according to the ordinary technical knowledge and common means in the art, other various forms of modifications, replacements or changes can be made without departing from the above technical idea of the application.

[0028] The above content of the application will be further described in detail through the specific embodiments in the form of examples. However, this should not be understood as the scope of the above subject matter of the application being limited to the following examples. Any technology realized based on the above content of the application belongs to the scope of the application. DETAILED DESCRIPTION

[0029] In the following examples and experimental examples, the reagents and raw materials not specifically described are commercially available.

[0030] In the embodiments of the application, hesperidin, potassium iodate and sodium iodide are dissolved in an N,N-dimethylformamide solution, and the system is adjusted to an acid environment. Under this system, potassium iodate and sodium iodide slowly prepare iodine monomer through a central reaction, iodine monomer rapidly reacts with hesperidin, potassium carbonate is added in the later stage to perform an elimination reaction, and iodine ions in impurity 6-iodine dioxadim are quickly removed to make them become dioxadim, so as to ensure the product quality and yield. Specifically, the chemical equation is as follows:

[0031]

[0032] The potassium iodate and sodium iodide occur a central reaction under the acid environment, the central reaction is slow and controllable, and not all iodine monomers are generated to react, but the iodine monomers are generated and reacted through a one-pot method.

[0033] Example 1: Preparation method of dioxadim

[0034] Step 1: Put N,N dimethylformamide 480 kg into a reaction kettle, put hesperidin 120 kg into, stir and dissolve, then put potassium iodate 42 kg into, then put 5.9 kg of sodium iodide into, heat, when the temperature reaches 55℃, add 6N hydrochloric acid dropwise, adjust the pH to 3, and continue to react for 12 h. The residual purity of hesperidin in the reaction solution is 3.5%.

[0035] Step 2: Put potassium carbonate 13.6 kg into, continue to react for 6 h, and the generation purity of diosmin in the reaction solution is 83%.

[0036] Step 3: Concentrate and recover N,N dimethylformamide, form a block in the kettle, add 1200 kg of deionized water into the kettle to crystallize and disperse, adjust the pH to neutral with 6N hydrochloric acid, punch into a plate frame, wash with pure water, obtain dioxin crystals, blow dry, unload, then wet products are dried in a blast drying oven at 70℃ for 10 h, crush, package, obtain dioxin 104.6 kg, the yield is 87.45%, and the purity is 94.92%. The yield refers to molar yield, and the calculation method is: dioxin molar yield = (product mass / 608.545) / (hesperidin feed amount / 610.561) * 100%; the product purity is detected by high performance liquid chromatograph.

[0037] Example 2: Preparation method of dioxin

[0038] Step 1: Put N,N dimethylformamide 480 kg into a reaction kettle, put hesperidin 120 kg into, stir and dissolve, then put potassium iodate 42 kg into, then put 5.9 kg of sodium iodide into, heat, when the temperature reaches 55℃, add 6N hydrochloric acid dropwise, adjust the pH to 3, and continue to react for 12 h. The residual purity of hesperidin in the reaction solution is 3.5%.

[0039] Step 2: Put potassium carbonate 13.6 kg into, continue to react for 6 h, and the generation purity of dioxin in the reaction solution is 83%.

[0040] Step 3: Concentrate and recover N,N dimethylformamide, form a block in the kettle, add 1200 kg of deionized water into the kettle to crystallize and disperse, adjust the pH to neutral with 6N hydrochloric acid, punch into a plate frame, wash with pure water, obtain dioxin crystals, blow dry, unload, then wet products are dried in a blast drying oven at 70℃ for 10 h, crush, package, obtain dioxin 104.6 kg, the yield is 87.45%, and the purity is 94.92%. The yield refers to molar yield, and the calculation method is: dioxin molar yield = (product mass / 608.545) / (hesperidin feed amount / 610.561) * 100%; the product purity is detected by high performance liquid chromatograph.

[0041] Example 3: Preparation method of dioxin

[0042] In a reaction kettle, 480 kg of dimethylformamide was put in, 120 kg of hesperidin was put in, stirred and dissolved, 42 kg of potassium iodate was then put in, 5.9 kg of sodium iodide was then put in, the temperature was raised to 55°C, 6N hydrochloric acid was added dropwise, and the pH was adjusted to 5. The subsequent steps were prepared according to Example 1, and diosmin was obtained, with a yield of 88.67% and a purity of 93.63%.

[0043] The following is the preparation method of the control sample.

[0044] Preparation method of dioximine in Comparative Example 1

[0045] Step 1: In a reaction kettle, 550 kg of dimethylformamide was put in, 120 kg of hesperidin was put in, stirred and dissolved, 33.6 kg of potassium iodate was then put in, 8.8 kg of sodium iodide was then put in, the temperature was raised to 55°C, 6N hydrochloric acid was added dropwise, and the pH was adjusted to 5. The reaction was continued for 12 h, and the residual purity of hesperidin in the reaction solution was detected to be 11.2%.

[0046] Step 2: 16.3 kg of potassium carbonate was put in, and the reaction was continued for 6 h. The purity of dioximine generated in the reaction solution was detected to be 77%.

[0047] Step 3: The dimethylformamide was concentrated and recovered, and the kettle formed a block. 1200 kg of deionized water was added to the kettle for crystallization and dispersion. The pH was adjusted to neutral with 6N hydrochloric acid. The product was punched into a frame and washed with pure water to obtain dioximine crystals. After blowing and unloading, the wet product was dried in a blast drying oven at 70°C for 10 h. After crushing and packaging, 95.2 kg of dioximine was obtained, with a yield of 62.60% and a purity of 83.32%.

[0048] Preparation method of dioximine in Comparative Example 2

[0049] Step 1: In a reaction kettle, 550 kg of dimethylformamide was put in, 120 kg of hesperidin was put in, stirred and dissolved, 42 kg of potassium iodate was then put in, 5.9 kg of sodium iodide was then put in, the temperature was raised to 55°C, 6N hydrochloric acid was added dropwise, and the pH was adjusted to 5. The reaction was continued for 12 h, and the residual purity of hesperidin in the reaction solution was detected to be 11.2%.

[0050] Step 2: 16.3 kg of potassium carbonate was put in, and the reaction was continued for 6 h. The purity of dioximine generated in the reaction solution was detected to be 77%.

[0051] Step 3: The dimethylformamide was concentrated and recovered, and the kettle formed a block. 1200 kg of deionized water was added to the kettle for crystallization and dispersion. The pH was adjusted to neutral with 6N hydrochloric acid. The product was punched into a frame and washed with pure water to obtain dioximine crystals. After blowing and unloading, the wet product was dried in a blast drying oven at 70°C for 10 h. After crushing and packaging, 95.2 kg of dioximine was obtained, with a yield of 62.60% and a purity of 83.32%.

[0052] The differences between the preparation methods of the diosmin of Example 1-2 and Comparative Example 1-2 are summarized as follows (Table 1).

[0053] Table 1

[0054]

[0055] As can be seen from Table 1, compared with Comparative Example 1, Example 2 reduces the amount of potassium iodate, resulting in the presence of hesperidin residue, and the product has a molar yield of only 62.60% and a purity of 83.32%; compared with Comparative Example 2, Example 2 increases the amount of potassium carbonate, which can promote the reaction of hesperidin, but the product yield and purity are reduced. Therefore, when the molar ratio of hesperidin, potassium iodate and sodium iodide is 1:1:0.2-0.3, and the molar ratio of hesperidin and potassium carbonate is 1:0.5-0.6, the prepared dioxym has a high molar yield (>89%) and a high purity (>93%).

[0056] The beneficial effects of the present application are further illustrated by the following experimental examples.

[0057] Experimental Example 1 Preparation Process Optimization of Diosmin

[0058] I. Experimental Methods

[0059] According to the preparation method of Example 1, the process parameters (the ratio of sodium iodide to potassium iodate, temperature, system pH value, and alkali amount) were changed accordingly to obtain experimental sequences 1-13, and the specific parameters of the optimization are shown in Table 2. The hesperidin content, dioxym purity, 6-iododioxym content, diosmin content, and dioxym molar yield were used as the evaluation items. Among them, the hesperidin content refers to the mass percentage of hesperidin in the final dioxym product; the 6-iododioxym content refers to the mass percentage of 6-iododioxym in the final dioxym product; and the diosmin content refers to the mass percentage of diosmin in the final dioxym product.

[0060] Table 2

[0061]

[0062] II. Experimental Results

[0063] As shown in Table 3, according to the data results of experimental sequences 1, 2, and 3, adjusting the molar ratio of potassium iodate affects the consumption of hesperidin and the generation of dioxym, and also affects the removal of 6-iododioxym. When the molar ratio of potassium iodate to sodium iodide is 1:0.2, the purity and yield of dioxym are the best.

[0064] According to the experimental sequence 2, 4, 5 data result analysis, the proportion of sodium iodide is adjusted, which influences the consumption of hesperidin and the generation of diosmin, and mainly influences the removal of 6-iodine diosmin, when the molar ratio of potassium iodate and sodium iodide is 1:0.2-0.3, the purity and yield of diosmin are better.

[0065] According to the experimental sequence 2, 6, 7 data result analysis, the reaction temperature is adjusted, the higher the reaction temperature (experimental sequence number 7), the lower the purity of diosmin, which leads to higher impurity eriodictyol; the lower the reaction temperature (experimental sequence number 6), which leads to high hesperidin residue, high 6-iodine diosmin and low yield, therefore the best reaction temperature is 55 DEG C.

[0066] According to the experimental sequence 2, 8, 9, 10 data result analysis, the pH value of the system is adjusted, which mainly influences the hesperidin residue, and the purity and yield of the product are reduced when the pH value is too high or too low, and the best pH range is 3-5.

[0067] According to the experimental sequence 2, 11, 12, 13 data result analysis, the amount of potassium carbonate is adjusted, which influences the purity of diosmin product, mainly the generation of 6-iodine diosmin and eriodictyol, when the ratio of hesperidin and potassium carbonate is 1:0.5-0.6, the purity and yield of diosmin are better.

[0068] According to the above data, the best process conditions for preparing diosmin are as follows: the molar ratio of hesperidin, potassium iodate and sodium iodide is 1:1:0.2-0.3; the system temperature is 55 DEG C±5 DEG C, the system pH value is 3-5; the molar ratio of hesperidin and potassium carbonate is 1:0.5-0.6, under the conditions, the purity of diosmin reaches more than 90%, and the molar yield reaches more than 85%.

[0069] Table 3

[0070]

[0071] In conclusion, the best preparation method of diosmin is obtained by experiment screening, the purity of diosmin reaches more than 90% and the molar yield reaches more than 85% by using the method, and the impurity content is low; meanwhile, by the method that potassium iodate and sodium iodide slowly release iodine element under acidic conditions, the problems of local high concentration, violent reaction, iodine volatilization loss and the like caused by directly using solid iodine are avoided, which is conducive to controlling the reaction rate, improving the utilization rate of iodine and the purity of the product, and the operation is safer and more environmentally friendly, and the price of potassium iodate and sodium iodide is relatively low, which can effectively reduce the cost. The method has the advantages of low cost, high safety, high yield and the like, is suitable for industrial production, and has good application prospect.

Claims

1. A method for preparing diosmin, characterized in that: The steps include: Step 1: dissolving hesperidin, iodate, and iodide in a polar aprotic solvent, heating, adjusting the pH to acidic, and reacting until the hesperidin content is less than 5%; the molar mass ratio of hesperidin, iodate, and iodide is 1:(0.8-1.2):(0.2-0.4); Step 2: Add carbonate and continue the reaction; Step 3: After concentration, add water for crystallization, adjust acid for neutralization, and obtain diosmin.

2. The preparation method according to claim 1, characterized in that: In step 1, the iodate is selected from at least one of potassium iodate, sodium iodate, calcium iodate, and ammonium iodate; And / or, the iodide is at least one selected from sodium iodide, potassium iodide, calcium iodide, ammonium iodide, and hydrogen iodide; and / or, the polar aprotic solvent is selected from at least one of N,N-dimethylformamide and N,N-dimethylacetamide; And / or, in step 2, the carbonate is selected from potassium carbonate.

3. The preparation method according to claim 1, characterized in that: The molar ratio of hesperidin, iodate and iodide is 1:1:(0.2-0.3).

4. The preparation method according to claim 1, characterized in that In step 1, the heating temperature is 45°C-65°C.

5. The preparation method according to claim 4, characterized in that: The heating temperature is 50°C-60°C.

6. The preparation method according to claim 1, characterized in that: In step 1, the pH is 1-6.

7. The preparation method according to claim 6, characterized in that: The pH is 3-5.

8. The preparation method according to claim 1, characterized in that: The molar ratio of hesperidin to carbonate is 1:(0.4-0.7).

9. The preparation method according to claim 8, characterized in that: The molar ratio of hesperidin to carbonate is 1:(0.5-0.6).

10. The preparation method according to claim 1, characterized in that: In step 2, the reaction time is 6 h to 10 h.

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