阅读说明：本技术 一种穿琥宁雾化剂的纯化工艺 (Purification process of potassium dehydroandrographolide succinate atomizing agent ) 是由 蒋达博 范伟川 张庆坤 李永东 胡平 吴照军 梁星 岳苗闯 张安玲 陈熙英 于 2020-12-25 设计创作，主要内容包括：本发明公开了一种穿琥宁雾化剂的纯化工艺,解决了现有的穿琥宁由于原料和制备工艺的原因,导致产品纯度不够的技术问题。本发明包括脱水穿心莲内酯二琥珀酸半酯的粗制,所述脱水穿心莲内酯二琥珀酸半酯的粗制步骤中,以穿心莲内酯和琥珀酸酐为原料,以乙酸丙酯和乙酸丁酯的混合溶剂作为溶剂,加入催化剂三乙胺或二乙胺,通入氮气或氩气保护,抽真空并加热至100℃-120℃以上,经回流反应,再减压蒸馏得到脱水穿心莲内酯二琥珀酸半酯粗品。本发明具有穿琥宁的纯度高和产率高等优点。(The invention discloses a purification process of a potassium dehydroandrographolide succinate atomizing agent, which solves the technical problem that the product purity is insufficient due to raw materials and a preparation process of the conventional potassium dehydroandrographolide succinate. The method comprises the step of roughly preparing dehydroandrographolide disuccinic acid half ester, wherein in the step of roughly preparing the dehydroandrographolide disuccinic acid half ester, andrographolide and succinic anhydride are used as raw materials, a mixed solvent of propyl acetate and butyl acetate is used as a solvent, a catalyst of triethylamine or diethylamine is added, nitrogen or argon is introduced for protection, the raw materials are vacuumized and heated to be more than 100-120 ℃, reflux reaction is carried out, and then reduced pressure distillation is carried out to obtain a crude dehydroandrographolide disuccinic acid half ester. The invention has the advantages of high purity and high yield of the potassium dehydroandrographolide succinate.)

1. A purification process of a andrographolide succinate atomizing agent is characterized by comprising the step of roughly preparing dehydroandrographolide succinate, wherein in the step of roughly preparing the dehydroandrographolide succinate, andrographolide and succinic anhydride are used as raw materials, a mixed solvent of propyl acetate and butyl acetate is used as a solvent, a catalyst triethylamine or diethylamine is added, nitrogen or argon is introduced for protection, the mixture is vacuumized and heated to be more than 100-120 ℃, and a crude dehydroandrographolide succinate is obtained through reflux reaction and reduced pressure distillation.

2. The process for purifying a potassium dehydroandrographolide succinate aerosol as claimed in claim 1, further comprising the following steps: and purifying the crude dehydroandrographolide succinate to obtain a pure dehydroandrographolide succinate product, and preparing the potassium dehydroandrographolide succinate from the pure dehydroandrographolide succinate product.

3. The process for purifying a potassium dehydroandrographolide succinate aerosol as claimed in claim 1 or 2, wherein the specific operation steps in the crude dehydroandrographolide succinate are as follows: mixing andrographolide and succinic anhydride, adding into a three-neck flask equipped with a stirrer, a reflux condenser tube and a thermometer, adding into butyl acetate in the three-neck flask, stirring and heating to a reflux state under the protection of nitrogen or argon, introducing boiling propyl acetate in the reflux process, controlling the temperature to react, and cooling after the reaction is finished to obtain a reaction solution; and distilling the reaction liquid under reduced pressure to obtain crude dehydroandrographolide disuccinate oil.

4. The purification process of potassium dehydroandrographolide succinate atomizing agent according to claim 1 or 2, wherein the mass ratio of the propyl acetate to the butyl acetate is 2:1-1: 2.

5. The process for purifying the potassium dehydroandrographolide succinate aerosol as claimed in claim 2, wherein the vacuum degree of vacuumizing is-0.09 MPa, and the reflux reaction time is 3-5 h.

6. The purification process of a dehydroandrographolide succinate nebulizer as claimed in claim 2, wherein the crude dehydroandrographolide succinate is purified by performing multiple extraction with dichloromethane, performing column chromatography and thin layer chromatography detection, collecting the chromatography liquid, concentrating the chromatography liquid, and vacuum drying to obtain the purified dehydroandrographolide succinate.

7. The process for purifying potassium dehydroandrographolide succinate aerosol as claimed in claim 2, wherein the potassium dehydroandrographolide succinate is prepared by the following steps: dissolving a purified dehydroandrographolide succinate into a solution by using an organic solvent; dripping potassium alkaline compound solution into the dehydroandrographolide disuccinate solution for reaction to generate the potassium dehydroandrographolide succinate.

8. A process for purifying potassium dehydroandrographolide succinate aerosol as claimed in claim 1 or 2, wherein boiling propyl acetate is introduced from the bottom of the flask during refluxing.

Technical Field

The invention relates to the technical field of potassium dehydroandrographolide succinate purification, and discloses a purification process of a potassium dehydroandrographolide succinate atomizing agent.

Background

Potassium dehydroandrographolide succinate is 14-dehydroxy-11, 12-didehydro andrographolide-3, 19-succinate monopotassium salt; the antibiotic is widely used for treating acute upper respiratory tract infection, acute bronchitis and infantile bronchopneumonia caused by viral pneumonia and influenza virus, is particularly effective on viral and bacterial upper respiratory tract infection and dysentery, has excellent effect on infant pneumonia, and is an ideal important antibiotic at present.

The potassium dehydroandrographolide succinate can be injected in the using process, can be used for treating respiratory tract infection through aerosol inhalation of the respiratory tract, and is easy to cause respiratory tract infection along with serious environmental pollution, so the potassium dehydroandrographolide succinate is used as an aerosol increasingly, but if the purity is not enough, adverse reactions are easy to cause.

Andrographolide is prepared by reacting andrographolide with potassium succinate anhydride, and andrographolide is extracted from herba Andrographitis, but the purity of andrographolide is not high due to impure raw materials and poor control of preparation process.

In addition, most solvents adopted in the preparation process of the potassium dehydroandrographolide succinate are pyridine, the pyridine is toxic and has malodor, and meanwhile, the pyridine is difficult to remove, so that the pyridine solvent residue in the product is higher, and in addition, a large amount of acid water is used in the removal of the pyridine, a large amount of pyridine waste water or acid water is generated, and great pressure is caused to environmental protection.

Therefore, how to improve the yield and purity of the potassium dehydroandrographolide succinate by improving raw materials, equipment and a preparation method is a technical problem to be solved in the field.

Disclosure of Invention

The technical problem to be solved by the invention is as follows: the prior potassium dehydroandrographolide succinate has insufficient product purity due to raw materials and preparation process.

The invention can be realized by the following technical scheme:

a process for purifying the atomized agent of andrographolide includes such steps as preparing the semi-ester of dehydroandrographolide succinate, using andrographolide and succinic anhydride as raw materials, using the mixed solvent of propyl acetate and butyl acetate as solvent, adding triethylamine or diethylamine as catalyst, introducing nitrogen or argon gas for protection, vacuumizing, heating to 100-120 deg.C, reflux reaction, and vacuum distillation.

According to the invention, pyridine is changed into a mixed solvent of propyl acetate and butyl acetate, so that pyridine residue is avoided, and the final purity of potassium dehydroandrographolide succinate, the safety of the production process and the sample stability are improved.

The invention preferably discloses a purification process of a potassium dehydroandrographolide succinate atomizing agent, which further comprises the following steps: and purifying the crude dehydroandrographolide succinate to obtain a pure dehydroandrographolide succinate product, and preparing the potassium dehydroandrographolide succinate from the pure dehydroandrographolide succinate product.

The invention preferably discloses a purification process of a potassium dehydroandrographolide succinate nebulant, wherein in the crude dehydroandrographolide disuccinate, the specific operation steps are as follows: mixing andrographolide and succinic anhydride, adding into a three-neck flask equipped with a stirrer, a reflux condenser tube and a thermometer, adding into butyl acetate in the three-neck flask, stirring and heating to a reflux state under the protection of nitrogen or argon, introducing boiling propyl acetate in the reflux process, controlling the temperature to react, and cooling after the reaction is finished to obtain a reaction solution; and distilling the reaction liquid under reduced pressure to obtain crude dehydroandrographolide disuccinate oil.

This application is through improving the mode of addition of solvent, and the backward flow back lets in propyl acetate in to the system, can accelerate the mixing and the material exchange in the system to play the effect of accelerating the reaction.

The invention preferably discloses a purification process of a potassium dehydroandrographolide succinate atomizing agent, wherein the mass ratio of propyl acetate to butyl acetate is 2:1-1: 2.

Further, the mass ratio of the propyl acetate to the butyl acetate is 1: 2.

The invention preferably selects a purification process of the potassium dehydroandrographolide succinate atomizing agent, the vacuum degree of the vacuumizing is-0.09 MPa, and the reflux reaction time is 3-5 h.

The invention preferably selects a purification process of a potassium dehydroandrographolide succinate nebulizer, wherein dichloromethane is adopted for purification of a crude dehydroandrographolide succinate product for multiple extraction, column chromatography and thin-layer chromatography detection, a chromatography liquid of the dehydroandrographolide succinate is collected, and the chromatography liquid is concentrated and dried in vacuum to obtain a pure dehydroandrographolide succinate product.

The invention preferably discloses a purification process of a potassium dehydroandrographolide succinate atomizing agent, which comprises the following preparation steps of: dissolving a purified dehydroandrographolide succinate into a solution by using an organic solvent; dripping potassium alkaline compound solution into the dehydroandrographolide disuccinate solution for reaction to generate the potassium dehydroandrographolide succinate.

The invention preferably relates to a purification process of potassium dehydroandrographolide succinate atomizing agent, wherein boiling propyl acetate is introduced from the bottom of a flask in the reflux process.

Compared with the prior art, the invention has the following advantages and beneficial effects:

1. in the process of preparing the dehydroandrographolide succinate crude product, pyridine is replaced by a mixed solvent of propyl acetate and butyl acetate, so that the residue of pyridine is avoided, and the safety of the production process and the stability of a sample are improved.

2. In the process of preparing the dehydroandrographolide succinate crude product, propyl acetate is added firstly, heated to boil and then refluxed, and then boiled butyl acetate is added from the bottom, wherein the butyl acetate can further play a role in stirring, so that the reaction is more complete.

3. In the mixed solvent of propyl acetate and butyl acetate, the crude dehydroandrographolide disuccinate can be better generated when the mass ratio of the propyl acetate to the butyl acetate is 1: 2.

4. In the purification process of dehydroandrographolide succinate, the dehydroandrographolide succinate is extracted for many times, and the chromatographic purification effect is good;

5. the reaction temperature is higher, the reaction is complete, and the finally prepared potassium dehydroandrographolide succinate has high yield.

Detailed Description

In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail below with reference to examples, and the exemplary embodiments and descriptions thereof are only used for explaining the present invention and are not used as limitations of the present invention.

Example 1

Raw materials: 100g of andrographolide, 220g of succinic anhydride, 240g of propyl acetate, 480g of butyl acetate and 120g of triethylamine;

(1) the method comprises the following steps of preparing a crude dehydroandrographolide succinate product: taking andrographolide and succinic anhydride as raw materials, taking a mixed solution of butyl acetate and propyl acetate as a solvent, adding triethylamine as a catalyst, introducing nitrogen or argon for protection, vacuumizing to 0.09MPa, heating to 120 ℃, performing reflux reaction for 5 hours, and performing reduced pressure distillation to obtain a crude dehydroandrographolide disuccinate.

The adding mode of the solvent is as follows: mixing andrographolide and succinic anhydride, adding into a three-neck flask provided with a stirrer, a reflux condenser tube and a thermometer, adding into butyl acetate in the three-neck flask, stirring and heating to a reflux state under the protection of nitrogen, introducing boiling propyl acetate at the bottom of the three-neck flask in the reflux process, controlling the temperature to react, and cooling after the reaction is finished to obtain a reaction solution; and distilling the reaction liquid under reduced pressure to obtain crude dehydroandrographolide disuccinate oil.

In order to reduce heat loss, a layer of heat insulation material is coated outside the three-neck flask.

(2) Purification of dehydroandrographolide succinate: dissolving the crude dehydroandrographolide succinate in dichloromethane, extracting for three times, passing through silica gel column, and detecting by thin layer chromatography, wherein the mesh number of the silica gel is 200 meshes, and the mobile phase is dichloromethane: methanol: collecting chromatography liquid of dehydroandrographolide disuccinate, concentrating the chromatography liquid, and vacuum drying to obtain pure dehydroandrographolide disuccinate product;

(3) the preparation method of the potassium dehydroandrographolide succinate comprises the following steps: dissolving 104g of the pure dehydroandrographolide disuccinate product with 394.5g of ethanol to obtain a solution; at the temperature of 35 ℃, potassium bicarbonate solution (10g of potassium bicarbonate is dissolved in 50mL of water) is dripped into dehydroandrographolide disuccinate solution for reaction for 4 hours, and then the dehydroethanol is filtered, washed and dried to obtain the potassium dehydroandrographolide succinate. The yield is 89.5 percent, and the purity is 99.35 percent.

Example 2

This example differs from example 1 in that the solvent used in the preparation of the crude dehydroandrographolide disuccinate was a mixed solution of butyl acetate and propyl acetate, but the ratio of propyl acetate to butyl acetate was 1: 1.

Example 3

This example differs from example 1 in that the solvent used in the preparation of the crude dehydroandrographolide disuccinate was a mixed solution of butyl acetate and propyl acetate, but the ratio of propyl acetate to butyl acetate was 2: 1.

Example 4

This example differs from example 1 in that the solvent used in the preparation of the crude dehydroandrographolide succinate is butyl acetate.

Example 5

This example differs from example 1 in that the solvent used in the preparation of the crude dehydroandrographolide succinate is propyl acetate.

Example 6

This example is different from example 1 in that the mixed solution of butyl acetate and propyl acetate is added at once, not separately, just at the beginning.

By examining the yield and purity of the examples, the results are shown in table 1 below:

TABLE 1 yield and purity of different examples

As can be seen from table 1 above, when a mixed solvent of butyl acetate and propyl acetate is used as a solvent, and propyl acetate is added after refluxing, the yield of the finally obtained potassium dehydroandrographolide succinate is the highest.

The above-mentioned embodiments are intended to illustrate the objects, technical solutions and advantages of the present invention in further detail, and it should be understood that the above-mentioned embodiments are merely exemplary embodiments of the present invention, and are not intended to limit the scope of the present invention, and any modifications, equivalent substitutions, improvements and the like made within the spirit and principle of the present invention should be included in the scope of the present invention.