CN114306363A - Method for industrially preparing citrus flavone bulk drug - Google Patents
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Abstract
The invention discloses a method for industrially preparing a citrus flavone bulk drug, which comprises the following steps: s1, taking hesperidin as a raw material, taking pyridine as a solvent, adding iodine and a catalyst for reaction to prepare a crude product; s2, dissolving the crude product with alkali, adjusting the pH value to acidity, filtering, washing with water, and drying to obtain the citrus flavone bulk drug, wherein the citrus flavone bulk drug comprises the following components in percentage by weight: diosmin: 85.0-95.0%; hesperidin: 2.5-5.0%; linarin and isorhamnocitrin: 0.9-2.8%; diosmetin: less than or equal to 1 percent. The invention solves the domestic vacancy in the industrial production field of the citrus flavonoid bulk drug, and can realize the industrial production of the citrus flavonoid bulk drug with the process characteristics of stabilization, high yield, low cost, easy control and the like.
Description
Technical Field
The invention belongs to the technical field of pharmacy, and particularly relates to a method for industrially preparing a citrus flavone bulk drug.
Background
Citrus flavonoid tablets (Ireland) are approved by the State drug administration for the treatment of symptoms associated with venous lymphatic insufficiency, such as heavy legs, pain, morning soreness, discomfort and acute haemorrhoids, and are recommended by the Chinese guidelines for the diagnosis and treatment of chronic venous diseases. The main component of the citrus flavone tablet is diosmin (90%), and simultaneously, the citrus flavone tablet also comprises 4 other effective components (10%), namely hesperidin, diosmetin, linarin and isorhamnocitrin, and in clinical application, the 5 components are synergistic, so that the curative effect is stronger.
In the synthesis process of diosmin (laboratory research and exploration, 8.2010, volume 29 at stage 8, pages 39-41), in Liyushan et al, hesperidin is taken as a raw material, dissolved in pyridine to perform iodination reaction with iodine, and the diosmin can be prepared through dehydrogenation reaction, wherein factors influencing the yield and the content of a product, such as the feed ratio, the reaction time, the reaction temperature, the hydrolysis condition and the like are considered, and the optimal reaction conditions are obtained as follows: the feeding ratio is 5: 1 (hesperidin vw), the reaction time is 10 h, the reaction temperature is 90-95 ℃, the hydrolysis pH is 11, the time is 1 h, and the temperature is 70 ℃. Obtaining products with 2 specifications, wherein the content of the product I is 95.82 percent, and the yield is 78.26 percent; the content of product II was 90.31%, yield l 6.43%. The process has the advantages of low production cost, stable process, high yield and content, and remarkably reduced material consumption and energy consumption.
The invention patent with the publication number CN106967138A discloses a production method of diosmin based on a dimethyl sulfoxide system. Dissolving hesperidin and potassium iodide in dimethyl sulfoxide, adding concentrated sulfuric acid for reaction, dripping methanol into the reaction solution, separating out solids, and performing suction filtration, washing and drying to obtain diosmin. In the method, hesperidin reacts in a potassium iodide/concentrated sulfuric acid/dimethyl sulfoxide system, and the problems of low purity and low yield of diosmin can be solved. The diosmin prepared by the method has the purity of 96%, the yield of 95%, the purity of 95% and the yield of 89.9%.
The invention patent with the publication number of CN113292618A discloses a low-cost preparation method of diosmin. Dissolving hesperidin and iodine in pyridine, heating, introducing ozone, adjusting pH to neutrality, filtering, washing, dissolving, filtering, acidifying, and recrystallizing to obtain diosmin. The method takes ozone as an oxidant, and utilizes the reaction of ozone and iodide ions to ensure that iodine catalyzes and oxidizes hesperidin without generating other side reactions, thereby achieving the aims of reducing the iodine dosage and reducing the cost.
At present, the prior art discloses a method for preparing diosmin from hesperidin, but no related preparation process of citrus flavonoid raw material medicines is reported.
Disclosure of Invention
The invention aims to solve the domestic vacancy in the industrial production field of the citrus flavonoid bulk drug, and provides the method for industrially preparing the citrus flavonoid bulk drug, which has the process characteristics of stabilization, high yield, low cost and easy control and is suitable for large-scale industrial production.
The invention is realized by the following technical scheme: a method for industrially preparing a citrus flavone bulk drug comprises the following steps:
s1, taking hesperidin as a raw material, taking pyridine as a solvent, adding iodine and a catalyst for reaction to prepare a crude product;
s2, dissolving the crude product with alkali, adjusting the pH value to acidity, filtering, washing with water, and drying to obtain the citrus flavonoid bulk drug,
the citrus flavone bulk drug comprises the following components in percentage by weight:
diosmin: 85.0-95.0%;
hesperidin: 2.5-5%;
linarin and isorhamnocitrin: 0.9-2.8%;
diosmetin: less than or equal to 1 percent.
In the step S1, hesperidin, iodine and a catalyst are added into a reaction container, pyridine is added, stirring and heating are carried out to 80-90 ℃ for reaction, HPLC monitoring is carried out on reaction liquid, and the reaction is stopped when the concentration of hesperidin in the reaction liquid is less than or equal to 5%.
In the step S1, after the reaction is finished, water is added to the reaction solution, and then a crude product is prepared after stirring, crystallization, cooling, filtering and washing.
The volume ratio of the reaction liquid to the added water is 1: 0.8-1.
In the step S1, the mass ratio of hesperidin, pyridine, iodine and catalyst is as follows: 1: 5-7: 0.38-0.4: 0.28-0.29.
In the step S2, the crude product is added into a dissolving tank containing an alkali solution, stirred until the crude product is completely dissolved, and the pH value of the dissolved solution is adjusted to be less than or equal to 3.
In step S2, the alkali is selected from sodium hydroxide or potassium hydroxide.
The concentration of the alkali is controlled to be 4-5%.
In the step S2, hydrochloric acid or glacial acetic acid is added to adjust the pH value to acidity.
The method further comprises the step of repeating the operation of the step S2 for 2-3 times on the citrus flavonoid bulk drug prepared in the step S2.
Compared with the prior art, the invention has the following advantages and beneficial effects:
(1) the invention provides an industrial production process for preparing a citrus flavonoid raw material medicament by using hesperidin as a raw material and reasonably controlling the proportion of the hesperidin raw material to pyridine, iodine and a catalyst, and a related method for stable production of citrus flavonoid is not existed at home temporarily.
(2) The method effectively and reasonably controls the feed ratio of reaction materials, reduces the consumption of iodine, can save the process production cost, has the reaction temperature (80-90 ℃) lower than the existing reaction temperature (about 110 ℃), further reduces the energy consumption of equipment, and simultaneously can further control the reaction easily due to the control of the variable, thereby further improving the conversion rate.
(3) Compared with the prior art, the method reduces the pyridine recovery link after the reaction is finished, simplifies the process flow, further saves the process production time, and improves the production efficiency and the equipment utilization rate.
In conclusion, the invention provides a preparation process suitable for the citrus flavonoid bulk drug, which has the process effects of simple preparation flow, high production efficiency, high equipment utilization rate, low process cost, easy control, high conversion rate, stable yield and the like, has industrial production prospect, and can make a contribution to the popularization and application of the existing citrus flavonoid bulk drug.
Drawings
FIG. 1 is a monitoring profile of HPLC in example 1.
FIG. 2 is a HPLC detection profile of the final product of example 1.
Detailed Description
The present invention will be described in further detail with reference to examples, but the embodiments of the present invention are not limited thereto.
Example 1:
weighing 100g of hesperidin, 38g of iodine and 29g of sodium carbonate, adding into a reaction bottle, weighing 680ml of pyridine, adding into the reaction bottle, stirring and heating to 85 +/-5 ℃ for reaction, taking reaction liquid, carrying out HPLC monitoring (the hesperidin is less than or equal to 5%), and referring to a terminal map shown in figure 1. After the reaction is finished, 600ml of water is added, the temperature is reduced, stirring is carried out, crystallization is carried out, the filtration is carried out when the temperature is room temperature, and a filter cake is washed by drinking water to obtain a crude product I.
Weighing 24g of sodium hydroxide, dissolving in 480ml of water, adding the crude product I after complete dissolution, and stirring for dissolution; after complete dissolution, hydrochloric acid is dripped to adjust the pH value to 3, and the filter cake is obtained after filtration and water washing. Repeating the operation for 3 times to obtain the final product with detection spectrum shown in FIG. 2.
Example 2:
weighing 100g of hesperidin, 40g of iodine and 28g of sodium carbonate, adding into a reaction bottle, weighing 500ml of pyridine, adding into the reaction bottle, stirring, heating to 85 +/-5 ℃ for reaction, and taking reaction liquid for HPLC monitoring (the hesperidin is less than or equal to 5%). After the reaction is finished, 500ml of water is added, the temperature is reduced, stirring is carried out, crystallization is carried out, the filtration is carried out when the temperature is room temperature, and a filter cake is washed by drinking water to obtain a crude product I.
Weighing 24g of sodium hydroxide, dissolving in 600ml of water, adding the crude product I after complete dissolution, and stirring for dissolution; after complete dissolution, hydrochloric acid is dripped to adjust the pH value to 3, and the filter cake is obtained after filtration and water washing. Repeating the operation for 2 times to obtain the final product.
Example 3:
weighing 100g of hesperidin, 39g of iodine and 28g of sodium carbonate, adding into a reaction bottle, weighing 700ml of pyridine, adding into the reaction bottle, stirring, heating to 85 +/-5 ℃ for reaction, and taking reaction liquid for HPLC monitoring (the hesperidin is less than or equal to 5%). And after the reaction is finished, adding 700ml of water, cooling, stirring, crystallizing, filtering after the temperature is room temperature, and washing a filter cake by using drinking water to obtain a crude product I.
Weighing 24g of sodium hydroxide, dissolving in 480ml of water, adding the crude product I after complete dissolution, and stirring for dissolution; after complete dissolution, hydrochloric acid is dripped to adjust the pH value to 3, and the filter cake is obtained after filtration and water washing. Repeating the operation for 3 times to obtain the final product.
Example 4:
weighing 100g of hesperidin, 38g of iodine and 29g of sodium carbonate, adding the hesperidin, weighing 580ml of pyridine, adding the pyridine into a reaction bottle, stirring and heating to 85 +/-5 ℃ for reaction, and taking reaction liquid for HPLC monitoring (the hesperidin is less than or equal to 5%). After the reaction is finished, 550ml of water is added, the temperature is reduced, stirring is carried out, crystallization is carried out, the filtration is carried out when the temperature is room temperature, and a filter cake is washed by drinking water to obtain a crude product I.
Weighing 25g of sodium hydroxide, dissolving in 500ml of water, adding the crude product I after complete dissolution, and stirring for dissolution; after complete dissolution, hydrochloric acid is dripped to adjust the pH value to 3, and the filter cake is obtained after filtration and water washing. Repeating the operation for 3 times to obtain the final product.
Example 5:
weighing 100g of hesperidin, 38g of iodine and 28g of sodium carbonate, adding into a reaction bottle, weighing 600ml of pyridine, adding into the reaction bottle, stirring and heating to 85 +/-5 ℃ for reaction, and taking reaction liquid for HPLC monitoring (the hesperidin is less than or equal to 5%). And after the reaction is finished, adding 580ml of water, cooling, stirring, crystallizing, filtering after the temperature is room temperature, and washing a filter cake by using drinking water to obtain a crude product I.
Weighing 30g of sodium hydroxide, dissolving in 750ml of water, adding the crude product I after complete dissolution, and stirring for dissolution; after complete dissolution, hydrochloric acid is dripped to adjust the pH value to 3, and the filter cake is obtained after filtration and water washing. Repeating the operation for 3 times to obtain the final product.
Example 6:
weighing 100g of hesperidin, 40g of iodine and 29g of sodium carbonate, adding the hesperidin, weighing 650ml of pyridine, adding the pyridine into a reaction bottle, stirring and heating to 85 +/-5 ℃ for reaction, and taking reaction liquid for HPLC monitoring (the hesperidin is less than or equal to 5%). After the reaction is finished, 600ml of water is added, the temperature is reduced, stirring is carried out, crystallization is carried out, the filtration is carried out when the temperature is room temperature, and a filter cake is washed by drinking water to obtain a crude product I.
Weighing 20g of sodium hydroxide, dissolving in 400ml of water, adding the crude product I after complete dissolution, and stirring for dissolution; after complete dissolution, hydrochloric acid is dripped to adjust the pH value to 3, and the filter cake is obtained after filtration and water washing. Repeating the operation for 2 times to obtain the final product.
Example 7:
weighing 100g of hesperidin, 40g of iodine and 29g of sodium carbonate, adding into a reaction bottle, weighing 700ml of pyridine, adding into the reaction bottle, stirring, heating to 85 +/-5 ℃ for reaction, and taking reaction liquid for HPLC monitoring (the hesperidin is less than or equal to 5%). After the reaction is finished, 680ml of water is added, the temperature is reduced, stirring and crystallization are carried out, filtration is carried out when the temperature is room temperature, and a filter cake is washed by drinking water to obtain a crude product I.
Weighing 28g of sodium hydroxide, dissolving in 700ml of water, adding the crude product I after complete dissolution, and stirring for dissolution; after complete dissolution, hydrochloric acid is dripped to adjust the pH value to 3, and the filter cake is obtained after filtration and water washing. Repeating the operation for 3 times to obtain the final product.
Example 8:
850L of pyridine, 47.5kg of iodine, 125kg of hesperidin and 36kg of sodium carbonate are added into a reaction kettle, stirred and heated, the temperature is controlled to be 85 +/-5 ℃, and HPLC (hesperidin is less than or equal to 5%) is monitored. And (3) adding 750L of drinking water into the reaction kettle after the reaction is finished, transferring the reactant into a buffer tank for crystallization, filtering at room temperature, washing the filter cake by using the drinking water until the filtrate is clear and transparent and has no peculiar smell, and collecting the filter cake to obtain a crude product I.
Dissolving 600 +/-50L of drinking water and 30Kg of sodium hydroxide in a purification dissolving tank, adding the crude product I, stirring until the crude product I is completely dissolved, dropwise adding hydrochloric acid to adjust the pH value to 3, filtering, washing a filter cake with drinking water until a washing liquid is clear, transparent and odorless, and collecting the filter cake, namely a crude product II. Repeating the operation for 2 times to obtain a crude product IV.
Dissolving 600 +/-50L of purified water and 30Kg of sodium hydroxide in a refining dissolving tank, adding the crude product IV, and stirring until the crude product IV is completely dissolved; filtering with pipeline, adding into a refining crystallization tank in a clean area, adding dropwise hydrochloric acid to adjust pH to 3, filtering, washing the filter cake with drinking water until the washing liquid is clear and transparent, and removing foreign odor to obtain the final product.
The finished products obtained in the above examples 1 to 8 were tested by HPLC method, and the contents of the components in the compositions are shown in table 1 below.
TABLE 1
The production was carried out according to the procedure of example 8, and the component contents and the yields of 10 batches of the finished product were counted as shown in Table 2 below.
TABLE 2
The above description is only a preferred embodiment of the present invention, and is not intended to limit the present invention in any way, and all simple modifications and equivalent variations of the above embodiments according to the technical spirit of the present invention are included in the scope of the present invention.
Claims (10)
1. A method for industrially preparing a citrus flavone bulk drug is characterized by comprising the following steps: the method comprises the following steps:
s1, taking hesperidin as a raw material, taking pyridine as a solvent, adding iodine and a catalyst for reaction to prepare a crude product;
s2, dissolving the crude product with alkali, adjusting the pH value to acidity, filtering, washing with water, and drying to obtain the citrus flavonoid bulk drug,
the citrus flavone bulk drug comprises the following components in percentage by weight:
diosmin: 85.0-95.0%;
hesperidin: 2.5-5.0%;
linarin and isorhamnocitrin: 0.9-2.8%;
diosmetin: less than or equal to 1 percent.
2. The method for industrially preparing the citrus flavone bulk drug according to claim 1, is characterized in that: in the step S1, hesperidin, iodine and a catalyst are added into a reaction container, pyridine is added, stirring and heating are carried out to 80-90 ℃ for reaction, HPLC monitoring is carried out on reaction liquid, and the reaction is stopped when the concentration of hesperidin in the reaction liquid is less than or equal to 5%.
3. The method for industrially preparing the citrus flavone bulk drug according to claim 1, is characterized in that: in the step S1, after the reaction is finished, water is added to the reaction solution, and then a crude product is prepared after stirring, crystallization, cooling, filtering and washing.
4. The method for industrially preparing the citrus flavone bulk drug according to claim 3, is characterized in that: the volume ratio of the reaction liquid to the added water is 1: 0.8-1.
5. The method for industrially preparing the citrus flavone bulk drug according to claim 1, is characterized in that: in the step S1, the mass ratio of hesperidin, pyridine, iodine and catalyst is as follows: 1: 5-7: 0.38-0.4: 0.28-0.29.
6. The method for industrially preparing the citrus flavone bulk drug according to claim 1, is characterized in that: in the step S2, the crude product is added into a dissolving tank containing an alkali solution, stirred until the crude product is completely dissolved, and the pH value of the dissolved solution is adjusted to be less than or equal to 3.
7. The method for industrially preparing the citrus flavone bulk drug according to claim 1, is characterized in that: in step S2, the alkali is selected from sodium hydroxide or potassium hydroxide.
8. The method for industrially preparing the citrus flavone bulk drug according to claim 1, is characterized in that: the concentration of the alkali is controlled to be 4-5%.
9. The method for industrially preparing the citrus flavone bulk drug according to claim 1, is characterized in that: in the step S2, hydrochloric acid or glacial acetic acid is added to adjust the pH value to acidity.
10. The method for industrially preparing the citrus flavone bulk drug according to claim 1, is characterized in that: the method further comprises the step of repeating the operation of the step S2 for 2-3 times on the citrus flavonoid bulk drug prepared in the step S2.
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| DE2740950A1 (en) * | 1977-09-10 | 1979-03-22 | Merck Patent Gmbh | METHOD OF MANUFACTURING FLAVONS |
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