阅读说明：本技术 一种炎琥宁及其中间体的制备方法 (Preparation method of potassium sodium dehydroandroan drographolide succinate and intermediate thereof ) 是由 尹家平 郭文胜 刘大鹏 赵秀林 秦志平 于 2019-04-08 设计创作，主要内容包括：本发明公开了一种炎琥宁及其中间体的制备方法。炎琥宁的制备方法包括下列步骤：醇溶剂和水中,将脱水穿心莲内酯琥珀酸半酯与钾盐和钠盐在微通道反应器进行成盐反应,制得炎琥宁；钾盐为碳酸氢钾,钠盐为碳酸氢钠。本发明的制备方法反应时间短,反应条件温和,溶剂耗量小,节约成本,安全性高,通过简单后处理得到纯度较高的产物,更适用于工业化生产。(The invention discloses a preparation method of potassium sodium dehydroandroan drographolide succinate and an intermediate thereof. The preparation method of potassium sodium dehydroandroan drographolide succinate comprises the following steps: alcohol solvent and water, the dehydroandrographolide succinate and potassium salt and sodium salt are subjected to salt forming reaction in a microchannel reactor to prepare potassium sodium dehydroandroan drographolide succinate; the potassium salt is potassium bicarbonate and the sodium salt is sodium bicarbonate. The preparation method has the advantages of short reaction time, mild reaction conditions, low solvent consumption, cost saving, high safety, and high purity of the product obtained by simple post-treatment, and is more suitable for industrial production.)

1. The preparation method of potassium sodium dehydroandroan drographolide succinate is characterized by comprising the following steps: alcohol solvent and water, the dehydroandrographolide succinate and potassium salt and sodium salt are subjected to salt forming reaction in a microchannel reactor to prepare the potassium sodium dehydroandroan drographolide succinate;

the potassium salt is potassium bicarbonate, and the sodium salt is sodium bicarbonate.

2. The process for preparing potassium sodium dehydroandroan drographolide succinate as claimed in claim 1, wherein: which comprises the following steps:

mixing the dehydroandrographolide succinate with the alcohol solvent to obtain a mixed solution A;

mixing the potassium salt, the sodium salt and the water to obtain a mixed solution B;

and (3) mixing the mixed solution A and the mixed solution B to carry out the salt forming reaction.

3. The process for preparing potassium sodium dehydroandroan drographolide succinate as claimed in claim 2, wherein: which comprises the following steps: simultaneously feeding the mixed solution A and the mixed solution B into the microchannel reactor through a metering pump;

the flow rate of the mixed solution A is preferably 1.5-2.7 mL/min, more preferably 1.6-2.2 mL/min, and even more preferably 1.8 mL/min; the flow rate of the mixed solution B is preferably 1.1 to 2.7mL/min, and more preferably 1.2 to 2.2 mL/min.

4. A process for the preparation of potassium sodium dehydroandroan drographolide succinate as claimed in any one of claims 1 to 3, characterized in that: the alcohol solvent is ethanol water solution with the concentration of more than or equal to 95 vol%;

and/or the mass-volume ratio of the dehydroandrographolide succinate to the alcohol solvent is 0.5-1 kg/L;

and/or the mass volume ratio of the potassium salt to the water is 0.12-0.21 kg/L;

and/or the mass volume ratio of the sodium salt to the water is 0.11-0.14 kg/L;

and/or the molar ratio of the dehydroandrographolide succinate to the potassium salt is 1: 0.9-1.1;

and/or the molar ratio of the dehydroandrographolide succinate to the sodium salt is 1: 0.9-1.1;

and/or in the salt forming reaction, the reaction time is 50-100 s;

and/or in the salt forming reaction, the reaction temperature is 45-55 ℃.

5. The process for preparing potassium sodium dehydroandroan drographolide succinate as claimed in claim 4, wherein: the mass volume ratio of the potassium salt to the water is 0.13-0.17 kg/L, preferably 0.14 kg/L;

and/or the mass volume ratio of the sodium salt to the water is 0.12-0.13 kg/L;

and/or the molar ratio of the dehydroandrographolide succinate to the potassium salt is 1: 1;

and/or the molar ratio of the dehydroandrographolide succinate to the sodium salt is 1: 1;

and/or in the salt forming reaction, the reaction time is 70-85 s, preferably 80 s;

and/or in the salt forming reaction, the reaction temperature is 50 ℃.

6. The process for the preparation of potassium sodium dehydroandroan drographolide succinate as claimed in any one of claims 1 to 5, wherein: it further comprises the following steps: in a solvent, performing esterification reaction on andrographolide and succinic anhydride in a microchannel reactor to prepare the dehydroandrographolide succinate.

7. The method for preparing potassium sodium dehydroandroan drographolide succinate as claimed in claim 6, wherein: in the esterification reaction, the molar ratio of andrographolide to succinic anhydride is 1: 2-3.5, preferably 1: 2.5 to 3.1, and more preferably 1: 3;

and/or, in the esterification reaction, the solvent is pyridine;

and/or in the esterification reaction, the mass-volume ratio of the andrographolide to the solvent is 1-2 kg/L, preferably 1.1-1.5 kg/L, and more preferably 1.4 kg/L;

and/or in the esterification reaction, the reaction time is 150-270 s, preferably 180-220 s, and further preferably 195 s;

and/or in the esterification reaction, the reaction temperature is 50-80 ℃, and preferably 60-70 ℃;

and/or, in the esterification reaction, the esterification reaction is carried out under normal pressure;

and/or in the esterification reaction, the esterification reaction does not need to be carried out under the protection of inert gas, and does not need to be carried out under the condition of adding an antioxidant.

8. The method for preparing potassium sodium dehydroandroan drographolide succinate as claimed in claim 6 or 7, wherein: the preparation method of the dehydroandrographolide succinate comprises the following steps:

simultaneously feeding the mixed solution formed by the andrographolide and the solvent and the mixed solution formed by the succinic anhydride and the solvent into a micro-channel reactor through a metering pump;

the flow rate of the mixed solution of the andrographolide and the solvent is preferably 0.9-1.6 mL/min, more preferably 1.1-1.3 mL/min, and even more preferably 1.2 mL/min; the flow rate of the mixed solution of the succinic anhydride and the solvent is preferably 0.6 to 1.1mL/min, more preferably 0.7 to 0.9mL/min, and still more preferably 0.8 mL/min.

9. An potassium sodium dehydroandroan drographolide succinate prepared by the potassium sodium dehydroandroan drographolide succinate preparation method as claimed in any one of claims 1-8, wherein the HPLC purity of the potassium sodium dehydroandroan drographolide succinate is 99.1-99.7%, such as 99.2%, 99.3%, 99.6% or 99.7%; the mass percentage of potassium ions in the potassium sodium dehydroandroan drographolide succinate is 5.89-6.65%, such as 5.94%, 6.07%, 6.12%, 6.15%, 6.18%, 6.55%, 6.59% or 6.61%; the mass percentage of sodium ions in the potassium sodium dehydroandroan drographolide succinate is 3.48-3.85%, for example, 3.52%, 3.57%, 3.68%, 3.71%, 3.79%, 3.81% or 3.82%.

10. A preparation method of dehydroandrographolide succinate is characterized by comprising the following steps: which comprises the following steps: in a solvent, performing esterification reaction on andrographolide and succinic anhydride in a microchannel reactor to prepare dehydroandrographolide succinate; the molar ratio of the andrographolide to the succinic anhydride is 1: 2-3.5; the flow rate of a mixed solution formed by the andrographolide and the solvent is 0.9-1.6 mL/min; the flow rate of the mixed liquid formed by the succinic anhydride and the solvent is 0.6-1.1 mL/min;

the method for preparing dehydroandrographolide succinate comprises the same conditions as those for preparing dehydroandrographolide succinate according to any one of claims 6-8.

Technical Field

The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a preparation method of potassium sodium dehydroandroan drographolide succinate and an intermediate thereof.

Background

The chemical name of the potassium sodium dehydroandrographolide succinate is 14-dehydroxy-11, 12-didehydro andrographolide-3, 19-disuccinate monohydrate, and the structural formula of the potassium sodium dehydroandrographolide succinate is as follows:

modern pharmacological research shows that potassium sodium dehydroandroan drographolide succinate has the effects of clearing away heat and toxic materials, resisting inflammation, inhibiting the growth and reproduction of microorganisms such as bacteria and viruses, relieving inflammatory exudation and edema by inhibiting capillary permeability, improving the activity and content of serum lysozyme by promoting the phagocytic function of neutrophil-macrophage, protecting the barrier structure of respiratory mucosa, and promoting the recovery of immune function, thereby playing the roles of enhancing the non-specific immunity of respiratory tract and the like. Is widely applied to treating respiratory tract infection, gastrointestinal tract infection, hyperpyrexia, epidemic virus and other toxic diseases clinically.

Chinese patent CN1927854A discloses a method for preparing andrographolide, an andrographolide preparation and a preparation method thereof, wherein the method for preparing andrographolide uses pyridine as a solvent, andrographolide reacts with succinic anhydride under the protection of nitrogen to obtain dehydroandrographolide succinate, and the dehydroandrographolide succinate is mixed with KOH and KHCO₃Or K₂CO₃Reacting to generate potassium andrographolide succinate, and then using NaOH and NaHCO₃Or Na₂CO₃Treating to obtain potassium sodium dehydroandroan drographolide succinate. The method needs high-temperature reflux, large solvent consumption, long reaction time, product purity of only 96 percent, and can reach the standard only by using various solvents for multiple purification.

Chinese patent CN103113331A discloses a method for synthesizing andrographolide, which comprises the steps of reacting andrographolide, succinic anhydride, pyridine and anhydrous sodium sulfite under the vacuum condition of 0.08MPa to obtain dehydroandrographolide succinate, then respectively dripping potassium salt and sodium salt, and reacting to obtain andrographolide. Although the yield of the product is high, the reaction is carried out under the low pressure of 0.08MPa, the charging treatment time is long, the industrial production is not facilitated, the product is not easy to crystallize and evacuate due to overhigh reaction temperature, the reaction kettle is large in size, and a large factory building is required during the industrial production.

Therefore, there is a need in the art for a method that has a short reaction time, a simple and easily controllable process, high safety and efficiency, and can improve the purity and yield of the product, so as to solve the above technical problems.

Disclosure of Invention

The invention aims to overcome the defects that the reaction time of potassium sodium dehydroandroan drographolide succinate in the prior art is long, the potassium sodium dehydroandroan drographolide succinate needs to be carried out under the protection of nitrogen or under vacuum, the post-treatment process is complex, a large amount of solvent needs to be used, and the like. The invention provides a preparation method of potassium sodium dehydroandroan drographolide succinate and an intermediate thereof. The method has the advantages of short reaction time, mild reaction conditions, low solvent consumption, cost saving, high safety, and high purity of the product obtained by simple post-treatment, and is more suitable for industrial production.

The invention mainly solves the technical problems through the following technical scheme.

The invention provides a preparation method of potassium sodium dehydroandroan drographolide succinate, which comprises the following steps:

alcohol solvent and water, the dehydroandrographolide succinate and potassium salt and sodium salt are subjected to salt forming reaction in a microchannel reactor to prepare potassium sodium dehydroandroan drographolide succinate;

the potassium salt is potassium bicarbonate, and the sodium salt is sodium bicarbonate.

The preparation method of the potassium sodium dehydroandroan drographolide succinate preferably comprises the following steps:

mixing the dehydroandrographolide succinate with the alcohol solvent to obtain a mixed solution A;

mixing the potassium salt, the sodium salt and the water to obtain a mixed solution B;

and (3) mixing the mixed solution A and the mixed solution B to carry out the salt forming reaction.

The preparation method of the potassium sodium dehydroandroan drographolide succinate preferably comprises the following steps:

and simultaneously feeding the mixed liquor A and the mixed liquor B into a micro-channel reactor through a metering pump.

The flow rates of the mixed liquor A and the mixed liquor B are within the flow rate allowable range of the microchannel reactor, and can be the flow rates which are conventionally used for carrying out the reactions by adopting the microchannel reactor in the field.

The flow rate of the mixed solution A may be 1.5 to 2.7mL/min, preferably 1.6 to 2.2mL/min, and more preferably 1.8 mL/min. The flow rate of the mixed solution B can be 1.1-2.7 mL/min, preferably 1.2-2.2 mL/min.

The alcohol solvent and the water may be solvents conventional in the art for such reactions, so as not to interfere with the reaction. The alcohol solvent can be ethanol water solution with the concentration of more than or equal to 95 vol%.

The mass-volume ratio of the dehydroandrographolide succinate to the alcohol solvent can be 0.5-1 kg/L.

The mass volume ratio of the potassium salt to the water may be 0.12 to 0.21kg/L, preferably 0.13 to 0.17kg/L, and more preferably 0.14 kg/L. The mass volume ratio of the sodium salt to the water can be 0.11-0.14 kg/L, preferably 0.12-0.13 kg/L.

The molar ratio of the dehydroandrographolide succinate to the potassium salt can be 1: 0.9-1.1, and 1:1 is preferred.

The molar ratio of the dehydroandrographolide succinate to the sodium salt can be 1: 0.9-1.1, preferably 1: 1.

In the salt forming reaction, the reaction time can be 50-100 s, preferably 70-85 s, and further preferably 80 s.

In the salt forming reaction, the reaction temperature can be the conventional temperature for the reaction in the field, and the reaction temperature is preferably 45-55 ℃, and further preferably 50 ℃.

The method can further comprise a post-treatment process of salt-forming reaction after the salt-forming reaction is finished. The post-treatment process of the salt-forming reaction can adopt the conventional post-treatment operation of the reaction in the field, and the invention preferably comprises the following steps: and mixing the reaction liquid obtained after the salt forming reaction is finished with ethanol, crystallizing, filtering and drying to obtain the potassium sodium dehydroandroan drographolide succinate.

In the post-treatment process of the salifying reaction, the dosage of the ethanol is not specifically limited, and the volume-to-mass ratio of the ethanol to the dehydroandrographolide succinate can be 1L/kg. The ethanol is preferably anhydrous ethanol.

In the post-treatment process of the salt-forming reaction, the crystallization temperature is the conventional crystallization temperature in the field, preferably-10-0 ℃, further preferably-4-8 ℃, and more preferably-6 ℃.

In the post-treatment process of the salt-forming reaction, the crystallization time is not particularly limited, and preferably 4-5 hours, and further preferably 4.5 hours, based on no crystal precipitation.

The drying temperature in the salt forming reaction post-treatment process can be a conventional drying temperature in the field, preferably 40-50 ℃, further preferably 42-47 ℃, and more preferably 45 ℃.

The drying time in the post-treatment process of the salt forming reaction is not particularly limited, and is preferably 6-8 hours, and further preferably 7 hours.

The preparation method of potassium sodium dehydroandroan drographolide succinate can further comprise the following steps:

in a solvent, performing esterification reaction on andrographolide and succinic anhydride in a microchannel reactor to prepare the dehydroandrographolide succinate.

In the esterification reaction, the molar ratio of andrographolide to succinic anhydride can be 1: 2-3.5, preferably 1: 2.5 to 3.1, and more preferably 1: 3.

in the esterification reaction, the solvent may be pyridine.

In the esterification reaction, the mass-volume ratio of the andrographolide to the solvent can be 1-2 kg/L, preferably 1.1-1.5 kg/L, and more preferably 1.4 kg/L.

In the esterification reaction, the reaction time can be 150-270 s, preferably 180-220 s, and more preferably 195 s.

In the esterification reaction, the reaction temperature can be the temperature conventional in the field, and the temperature is preferably 50-80 ℃ and is further preferably 60-70 ℃.

In the esterification reaction, the esterification reaction is preferably carried out under normal pressure conditions.

In the esterification reaction, the esterification reaction is preferably carried out without protection of inert gas or addition of an antioxidant.

In the esterification reaction, the esterification reaction can further comprise an esterification reaction post-treatment process after the esterification reaction is finished. The esterification post-treatment process may employ conventional post-treatment operations of such reactions in the art, and the present invention preferably comprises the steps of: and mixing the reaction liquid obtained after the esterification reaction with water, crystallizing, filtering and drying to obtain the dehydroandrographolide succinate.

In the post-treatment process of the esterification reaction, the amount of the water is not particularly limited, and the volume mass ratio of the water to the andrographolide can be 20L/kg.

In the post-treatment process of the esterification reaction, the crystallization temperature can be a crystallization conventional temperature in the field, preferably 0-10 ℃, further preferably 3-8 ℃, and more preferably 5 ℃.

In the post-treatment process of the esterification reaction, the crystallization time is not particularly limited, and is preferably 2 to 3 hours, and more preferably 2.5 hours, based on no more crystal precipitation. In the post-treatment process of the esterification reaction, the drying temperature is the conventional drying temperature in the field, preferably 40-50 ℃, further preferably 42-47 ℃, and more preferably 45 ℃. In the esterification reaction post-treatment process, the drying time is not particularly limited, preferably 6-8 hours, and more preferably 7 hours.

In the esterification reaction, the following steps are preferably included:

and simultaneously feeding the mixed solution formed by the andrographolide and the solvent and the mixed solution formed by the succinic anhydride and the solvent into a micro-channel reactor through a metering pump.

The flow rates of the mixed liquid of the andrographolide and the solvent and the mixed liquid of the succinic anhydride and the solvent are within the allowable range of the flow rate of the microchannel reactor, and can be the flow rates which are conventionally used in the field for carrying out the reactions by adopting the microchannel reactor.

The flow rate of the mixed solution of andrographolide and the solvent can be 0.9-1.6 mL/min, preferably 1.1-1.3 mL/min, and more preferably 1.2 mL/min.

The flow rate of the mixed solution of the succinic anhydride and the solvent may be 0.6 to 1.1mL/min, preferably 0.7 to 0.9mL/min, and more preferably 0.8 mL/min.

The preparation method of the dehydroandrographolide succinate has the same conditions as the above.

The invention also provides potassium sodium dehydroandroan drographolide succinate prepared by the preparation method of potassium sodium dehydroandroan drographolide succinate.

The HPLC purity of the potassium sodium dehydroandroan drographolide succinate can be 99.1-99.7%, for example, 99.2%, 99.3%, 99.6% or 99.7%.

The mass percentage of potassium ions in the potassium sodium dehydroandroan drographolide succinate can be 5.89-6.65%, such as 5.94%, 6.07%, 6.12%, 6.15%, 6.18%, 6.55%, 6.59% or 6.61%.

The mass percentage of sodium ions in the potassium sodium dehydroandroan drographolide succinate can be 3.48-3.85%, for example, 3.52%, 3.57%, 3.68%, 3.71%, 3.79%, 3.81% or 3.82%.

The invention also provides a preparation method of the dehydroandrographolide succinate, which comprises the following steps: in a solvent, performing esterification reaction on andrographolide and succinic anhydride in a microchannel reactor to prepare dehydroandrographolide succinate; the molar ratio of the andrographolide to the succinic anhydride is 1: 2-3.5; the flow rate of a mixed solution formed by the andrographolide and the solvent is 0.9-1.6 mL/min; the flow rate of the mixed liquid formed by the succinic anhydride and the solvent is 0.6-1.1 mL/min.

In the present invention, the letter s in the description of time means seconds, and h in the description of time means hours.

The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.

The reagents and starting materials used in the present invention are commercially available.

The positive progress effects of the invention are as follows:

the invention adopts the microreactor to react under normal pressure, and the reaction condition is easy to control, thereby ensuring the stability of product quality and the safety of reaction. The esterification reaction does not need to be carried out under the protection of inert gas, and an antioxidant does not need to be added. The reaction time is shortened from traditional hours to tens of seconds to minutes, and a large amount of reaction time is saved. The product purity is improved by simple post-treatment. According to the invention, potassium bicarbonate and sodium bicarbonate are used, the ratio of potassium ion to sodium potassium dehydroandroan drographolide succinate is strictly controlled to be 0.9-1.1, the national standard of potassium dehydroandroan drographolide succinate is met, the quality of the product is improved, and the phenomenon of raw material or product precipitation does not occur in the preferable range of the invention.

Drawings

FIG. 1 is a schematic process flow diagram of a microchannel reactor used in the present invention.

Wherein 1 and 3 denote raw material tanks, 2 and 4 denote metering pumps, 5 and 6 denote microchannel reactors, and 6 denotes a product crystallization tank.

Detailed Description

The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.

In the following examples, the purity of potassium sodium dehydroandroan drographolide succinate refers to the HPLC purity, which is not specifically described.