CN115073375B

CN115073375B - Method for preparing sinomenine hydrochloride

Info

Publication number: CN115073375B
Application number: CN202210889638.XA
Authority: CN
Inventors: 龚行楚; 瞿海斌; 程翼宇; 任丹丹
Original assignee: Jinhua Research Institute Of Zhejiang University; Zhejiang University ZJU
Current assignee: Jinhua Research Institute Of Zhejiang University; Zhejiang University ZJU
Priority date: 2022-07-27
Filing date: 2022-07-27
Publication date: 2023-12-01
Anticipated expiration: 2042-07-27
Also published as: CN115073375A

Abstract

The application discloses a method for preparing sinomenine hydrochloride, which is characterized by comprising the following steps: (1) taking caulis sinomenii, crushing, alkalizing and stacking; (2) Adding a solvent into the alkalized medicinal materials for extraction, and collecting an extracting solution; (3) Washing the extracting solution with water, separating the liquid phase and discarding the water phase; (4) Adding hydrochloric acid into the water-washed extracting solution until the system is acidic, and obtaining sinomenine hydrochloride crystals. The application has the outstanding advantages of few process steps, and the sinomenine hydrochloride crystal can be prepared by only three steps after alkalizing medicinal materials, thereby being beneficial to reducing the loss of sinomenine hydrochloride in the pharmaceutical process, shortening the production period and improving the production efficiency.

Description

Method for preparing sinomenine hydrochloride

Technical Field

The application belongs to the field of medicines, and relates to a method for preparing sinomenine hydrochloride.

Background

The caulis Sinomenii is a dry rattan of Sinomenii and Sinomenii of Menispermaceae, such as Sinomenii caulis, herba Aristolochiae Mollissimae, etc. As a traditional medicinal plant, the Chinese medicinal composition has remarkable effects of resisting inflammation, promoting urination, dispelling wind-dampness and the like. Caulis Sinomenii contains abundant alkaloids such as sinomenine, bisinomenine, tetrahydropalmatine, spiniferin, kadsura longepedunculata, magnolone, etc., wherein sinomenine is the main alkaloid monomer in caulis Sinomenii, and has been used as index component of caulis Sinomenii in Chinese pharmacopoeia of 2020 edition. Sinomenine has various pharmacological activities, and can be used for treating arrhythmia, rheumatic or rheumatoid arthritis, neuralgia, etc. by using its hydrochloric acid preparation such as ZHENGQINGFENGTONGNING tablet, ZHENGQINGFENGTONGNING injection, and sinomenine hydrochloride enteric coated tablet.

The extraction and preparation process of sinomenine hydrochloride in the current industry is mainly divided into two modes of solvent reflux extraction and preparation process and acid water extraction and preparation process. Wherein, the solvent reflux extraction preparation process is divided into a direct reflux process and an alkalization reflux process. The sinomenine hydrochloride can be obtained by directly refluxing with ethanol as solvent and performing microfiltration, concentration, multiple times of pH adjustment, solvent extraction, reduced pressure concentration, drying and the like for more than 10 steps. The alkalizing reflux often comprises the following steps: alkalizing the medicinal materials, extracting under reflux with solvent, concentrating to obtain crude product, re-dissolving with water, adjusting pH, adsorbing with activated carbon, and crystallizing. The acid water extraction preparation process comprises the steps of acid water impregnation, multiple pH adjustment, alkali precipitation, solvent extraction, back extraction, crystallization and the like. The comprehensive view is that the prior process adopted in industry has complicated steps and long flow and needs to be improved. In addition, the extraction preparation process has low selectivity to sinomenine by using solvents or extracting agents such as hydrochloric acid aqueous solution and the like in the extraction step, the obtained extracting solution has more impurities, and due to the limitation that the extracting agents can be mutually dissolved with water, the extracting agents can not be directly used for removing impurities in a water washing way, and further purification is required by taking other solvents as extracting agents, so that the problems of a plurality of subsequent purification and refining steps, high cost and the like are caused. Therefore, a new process for extracting sinomenine hydrochloride with simple subsequent purification mode, short flow and low cost still needs to be developed.

Disclosure of Invention

The application aims to provide a method for preparing sinomenine hydrochloride, aiming at the problems of complex purification process, long flow and the like in the existing sinomenine hydrochloride extraction and preparation process.

The application aims at realizing the following technical scheme:

a method for preparing sinomenine hydrochloride, comprising the steps of:

(1) Pulverizing caulis Sinomenii, alkalizing and stacking;

(2) Adding a solvent into the alkalized medicinal materials for extraction, and collecting an extracting solution;

(3) Washing the extracting solution with water, separating the liquid phase and discarding the water phase;

(4) Adding hydrochloric acid into the water-washed extracting solution until the system is acidic, and obtaining sinomenine hydrochloride crystals.

Further, the solvent comprises chloroform, or anisole, or methyl isobutyl ketone and anisole.

Further, when the solvent is a mixed solvent, the methyl isobutyl ketone accounts for less than 50% of the volume fraction of the mixed solvent.

Preferably, when the solvent is added, the ratio of the volume (mL) of the solvent to the mass (g) of the medicinal material is 5/1-10/1.

The extraction time is 0.5-2h.

Preferably, the number of extraction times is 2-3.

Further preferably, when the sinomenine extracting solution is washed by the water, the volume ratio of the water phase to the extracting solution is 1:2-1:4.

Further, the mass ratio of the medicinal materials to the calcium hydroxide is 10-30:1-6; the concentration of the hydrochloric acid is 0.5-10 mol/L.

Preferably, the mass ratio of the medicinal materials to the calcium hydroxide is 15-25:2-4; the concentration of the hydrochloric acid is 1-8 mol/L.

Furthermore, the method for preparing sinomenine hydrochloride further comprises a purification step, wherein the solid obtained after the reaction is washed by adding ethanol and dried to obtain the sinomenine hydrochloride.

The application has the advantages that the anisole, chloroform and the mixed solvent of anisole and methyl isobutyl ketone have the advantages of strong extraction capacity and high selectivity. The solvent is not only an extractant of sinomenine, but also can utilize the characteristic of non-mutual solubility of sinomenine and water, and a water washing impurity removing mode can be directly adopted in the follow-up process, so that the purification difficulty is obviously reduced, the process flow is shortened, the impurity content of the obtained extract is low, and the purity of sinomenine is high. The application has the outstanding advantages of few process steps, and the sinomenine hydrochloride crystal can be prepared by only three steps after alkalizing medicinal materials, thereby being beneficial to reducing the loss of sinomenine hydrochloride in the pharmaceutical process, shortening the production period and improving the production efficiency. The organic solvent adopted by the application can be reused after being regenerated in a distillation mode and the like, thereby being beneficial to controlling the cost. The sinomenine hydrochloride crystal obtained by the application is a crude product, and high-purity sinomenine hydrochloride refined products can be obtained by recrystallization. In general, the application can obviously shorten the production process flow of sinomenine hydrochloride, improve the overall production efficiency, reduce the cost and have good industrial prospect.

The extraction method and the extraction solvent are technical innovations, not only can use extremely toxic solvents such as benzene and the like be avoided, but also high-purity sinomenine hydrochloride can be prepared.

Detailed Description

The following experimental examples and examples serve to further illustrate but not limit the application.

Experimental example 1: research on the effect of single solvent extraction of sinomenine in sinomenine

15g of the powdered sinomenine medicinal material powder is weighed, 6g of calcium hydroxide and 22.5mL of purified water are added into the medicinal material, and the mixture is stirred uniformly, so that the medicinal material is wetted, alkalized and stacked for 3 hours. Measuring 120mL of solvent, adding into the alkalified medicinal materials, extracting at corresponding temperature for 1 hr (solvent with boiling point higher than 85deg.C is uniformly heated at 85deg.C for extraction, solvent with boiling point lower than 85deg.C is uniformly heated at room temperature 25 deg.C), and filtering to obtain residue. The purity and extraction amount of sinomenine in the extract were measured, and the specific results are shown in table 1.

TABLE 1 Single solvent extraction Effect

As can be seen from Table 1, sinomenine was not extracted from both cyclohexane and n-heptane. From the purity point of view, the purity of chloroform and anisole is highest, the purity of ethyl acetate and methyl isobutyl ketone is next highest, and the purity of acetic acid is lowest. The extraction amount of chloroform and anisole is the highest, and the extraction amount of benzyl alcohol and other solvents are less. Therefore, sinomenine extracted by chloroform and anisole has high purity and large extraction quantity.

Experimental example 2: research on the effect of extracting sinomenine from sinomenine by mixed solvent

Taking 20g of the powdered sinomenine, adding 3g of calcium hydroxide powder and 20mL of purified water into the drug, alkalizing and stacking for 3h. Adding 160mL of mixed organic solvent into the alkalized medicinal materials, stirring and extracting at 75 ℃ for 45min, filtering the residues, and preserving the filtrate; 140mL of mixed organic solvent is added into the filter residue, the mixture is stirred and extracted for 45min at 75 ℃, then the mixture is filtered, the two extracts are combined, and the purity and the extraction amount of the extracts are detected, and the results are shown in Table 2.

TABLE 2 Mixed solvent extraction Effect

In the comprehensive view, the three groups of mixed solvents have better extraction effect, water is added into the three groups of extracting solutions according to the volume ratio of 1:3 for water washing, then 6mL of concentrated hydrochloric acid with the concentration of 2mol/L is added, the system is acidic, the mixing and stirring are carried out, the solid is filtered, a small amount of ethanol is added for washing, and the sinomenine hydrochloride crystals with the purities of 48.5%, 14.3% and 73.25% in terms of mass fraction are obtained after drying. The sinomenine hydrochloride crystal obtained by the mixed solvent composed of n-heptane, n-octane and anisole has low purity, and the methyl isobutyl ketone used as the solvent mixed with anisole can reduce the emulsification degree, and the purity of the proposed sinomenine hydrochloride crystal is higher.

Experimental example 3: contrast of alkalization effects of medicinal materials

The effect of the medicinal material alkalization step related by the application is studied, and experiments are carried out under the conditions of medicinal material alkalization and non-alkalization respectively:

alkalization: weighing 30g of medicinal materials, adding 4.0435g of calcium hydroxide powder, adding 30mL of water, stirring uniformly to moisten the medicinal materials, alkalizing and stacking for 4 hours, directly adding 150mL of anisole (the volume ratio of the solvent to the mass of the medicinal materials is 5/1), stirring and extracting for 1 hour at 90 ℃, and filtering while the medicinal materials are hot to obtain anisole extract. The extraction amount of sinomenine in the extracting solution is measured to be 16.07mg/g of medicinal material.

Not alkalized: weighing 40g of caulis sinomenii, adding 200mL of solvent (the volume ratio of the solvent to the mass ratio of the drug is 5/1), stirring and heating at 90 ℃ for extraction for 1h, and filtering while the mixture is hot to obtain anisole extract. The extraction amount of sinomenine in the extracting solution is measured to be 11.28mg/g of medicinal material.

Experimental results show that the extraction amount of the medicinal materials is obviously improved after the medicinal materials are alkalized, so that the step of alkalizing the medicinal materials is necessary to be reserved.

Experimental example 4: comparison of the extraction and preparation process of sinomenine hydrochloride

The present application was compared laterally with the three processes currently most widely used in industry in terms of solvent toxicity, number of process steps, as shown in table 3. Residual solvents are classified into three categories in the ICH Q3 guidelines: the class 1 solvent is a solvent to be avoided, namely known human carcinogens, strong suspected human carcinogens and environmental hazards; class 2 solvents are solvents that should be limited to use in formulations, i.e., non-genotoxic animal carcinogens, or may cause other irreversible toxicity (e.g., neurotoxicity or teratogenicity), or may have other serious but reversible toxicity; class 3 solvents are solvents with low potential toxicity, i.e., solvents with a low risk of human health hazard. In the process development stage, 3 types of solvents should be selected preferentially, 2 types of solvents are controlled, and 1 type of solvents are avoided to the greatest extent. The solvents involved in the application are in class 2 and class 3. In addition, the application has the outstanding characteristics of short process flow, and the sinomenine hydrochloride crystal can be obtained by only 4 steps, and compared with other industrial processes, the process flow is shortened by more than 50%, the product loss is reduced, the production efficiency is improved, and the production cost is reduced.

In conclusion, compared with the existing process, the application has obvious improvement and improvement on solvent toxicity and process flow, accords with the green chemical concept, and has good industrial application prospect.

Table 3 comparison of sinomenine hydrochloride extraction and preparation process

Comparative example 1: extracting by using n-heptane-anisole as a mixed solvent:

pulverizing caulis Sinomenii, and weighing 40g of pulverized caulis Sinomenii. 6.0053g of calcium hydroxide and 40mL of purified water are added into the medicinal materials, and the mixture is stirred uniformly, so that the medicinal materials are wetted, alkalized and stacked for 3 hours. 224mL anisole and 56mL heptane were measured and mixed solvent for the first extraction was prepared. Adding mixed solvent into the alkalized medicinal materials, stirring and extracting at 75deg.C for 45min, and filtering the residues. 192mL anisole and 48mL heptane were measured and mixed solvent for the second extraction was prepared. Adding the mixed solvent for the second extraction into the extracted medicinal materials, stirring at 75deg.C for 45min, and filtering to obtain residue. Combining the two extracting solutions to finally obtain 450mL sinomenine extracting solution. 150mL of purified water is taken to wash the extract, shaking is carried out fully, standing is carried out for phase separation, and the water phase is discarded. Adding 8mL of concentrated hydrochloric acid with the concentration of 3mol/L into the water-washed extracting solution, mixing and stirring, filtering the solid, adding a small amount of ethanol for washing, and drying to obtain sinomenine hydrochloride crystals with the purity of 56.25 percent in mass fraction.

Comparative example 2: extracting with n-octane-anisole as a mixed solvent:

pulverizing caulis Sinomenii, and weighing 20g of pulverized caulis Sinomenii. 3.0013g of calcium hydroxide and 30mL of purified water are added into the medicinal materials, and the mixture is stirred uniformly, so that the medicinal materials are wetted, alkalized and stacked for 3 hours. 98mL anisole and 42mL heptane were measured and mixed solvent for the first extraction was prepared. Adding mixed solvent into the alkalized medicinal materials, stirring and extracting at 75deg.C for 45min, and filtering the residues. 84mL anisole and 36mL heptane were measured and mixed solvent for the second extraction was prepared. Adding the mixed solvent for the second extraction into the extracted medicinal materials, stirring at 75deg.C for 45min, and filtering to obtain residue. Combining the two extracting solutions to finally obtain 258mL sinomenine extracting solution. 86mL of purified water is measured to wash the extract, shaking is carried out fully, standing is carried out for phase separation, and the water phase is discarded. Adding 6mL of concentrated hydrochloric acid with the concentration of 2mol/L into the water-washed extracting solution, mixing and stirring, filtering the solid, adding a small amount of ethanol for washing, and drying to obtain sinomenine hydrochloride crystals with the purity of 13.20 percent in mass fraction.

Example 1

Pulverizing caulis Sinomenii, and weighing 35g of pulverized caulis Sinomenii. 5.2511g of calcium hydroxide and 35mL of purified water are added into the medicinal materials, and the mixture is stirred uniformly, so that the medicinal materials are wetted, alkalized and stacked for 4 hours. 200mL of chloroform was measured and added to the alkalized medicinal material, and the mixture was stirred and extracted at room temperature for 45 minutes, and the residue was filtered. Repeating the above operation, extracting twice, and finally combining the three extractive solutions to obtain 556mL of extractive solution. 278mL of purified water is measured to wash the extract, shaking is carried out fully, standing is carried out for phase separation, and the water phase is discarded. Adding 10mL of concentrated hydrochloric acid with the concentration of 2.4mol/L into the water-washed extracting solution, mixing and stirring, filtering the solid, adding a small amount of ethanol for washing, and drying to obtain sinomenine hydrochloride crystals with the purity of 90.1 percent in terms of mass fraction.

Example 2

Pulverizing caulis Sinomenii, and weighing 30g of pulverized caulis Sinomenii. 6.0412g of calcium hydroxide and 30mL of purified water are added into the medicinal materials, and the mixture is stirred uniformly, so that the medicinal materials are wetted, alkalized and stacked for 2 hours. 300mL of anisole is measured and added into the alkalized medicinal materials, the mixture is stirred and extracted for 45 minutes at 90 ℃, and the residues are filtered. Repeating the above operation, extracting twice, and finally combining the three extractive solutions to obtain 550mL of extractive solution. The extract was washed with 137.5mL of purified water, shaken well and then allowed to stand for phase separation, and the aqueous phase was discarded. Adding 9mL of concentrated hydrochloric acid with the concentration of 2mol/L into the water-washed extracting solution, mixing and stirring, filtering the solid, adding a small amount of ethanol for washing, and drying to obtain sinomenine hydrochloride crystals with the purity of 88.52 percent in mass fraction.

Example 3

Pulverizing caulis Sinomenii, and weighing 40g of pulverized caulis Sinomenii. 6.0180g of calcium hydroxide and 30mL of purified water are added into the medicinal materials, and the mixture is stirred uniformly, so that the medicinal materials are wetted, alkalized and stacked for 3 hours. 140mL anisole and 140mL methyl isobutyl ketone (1:1) are measured to prepare a mixed solvent for the first extraction. Adding mixed solvent into the alkalized medicinal materials, stirring and extracting at 75deg.C for 45min, and filtering the residues. 120mL anisole and 120mL methyl isobutyl ketone (1:1) are measured to prepare a mixed solvent for the second extraction. Adding the mixed solvent for the second extraction into the extracted medicinal materials, stirring at 75deg.C for 45min, and filtering to obtain residue. The two extracts were combined to finally obtain 480mL of extract. 160mL of purified water is measured to wash the extract, shaking is carried out fully, standing is carried out for phase separation, and the water phase is discarded. Adding 8mL of concentrated hydrochloric acid with the concentration of 3mol/L into the water-washed extracting solution, mixing and stirring, filtering the solid, adding a small amount of ethanol for washing, and drying to obtain sinomenine hydrochloride crystals with the purity of 88.75 percent in mass fraction.

Example 4

A method for preparing sinomenine hydrochloride, comprising the steps of:

(1) Pulverizing caulis Sinomenii, alkalizing and stacking;

(4) Adding hydrochloric acid into the water-washed extracting solution until the system is acidic to obtain sinomenine hydrochloride crystals;

the solvent is chloroform.

Example 5

A method for preparing sinomenine hydrochloride, comprising the steps of:

(1) Pulverizing caulis Sinomenii, alkalizing and stacking;

(4) Adding hydrochloric acid into the water-washed extracting solution until the system is acidic to obtain sinomenine hydrochloride crystals; the solvent is anisole;

when the solvent is added, the ratio of the volume (mL) of the solvent to the mass (g) of the medicinal material is 6/1; when the sinomenine extracting solution is washed by the water, the volume ratio of the water phase to the extracting solution is 1:3;

the method for preparing sinomenine hydrochloride further comprises a purification step, wherein the solid obtained after the reaction is washed by adding ethanol and dried to obtain the sinomenine hydrochloride.

Example 6

A method for preparing sinomenine hydrochloride, comprising the steps of:

(1) Pulverizing caulis Sinomenii, alkalizing and stacking;

The solvent is methyl isobutyl ketone and anisole; methyl isobutyl ketone accounts for 20 percent of the volume fraction of the mixed solvent;

when the solvent is added, the ratio of the volume (mL) of the solvent to the mass (g) of the medicinal material is 7/1;

the extraction time is 1h.

Preferably, the extraction times are 2 times;

when the sinomenine extracting solution is washed by the water, the volume ratio of the water phase to the extracting solution is 1:2.

Example 7

A method for preparing sinomenine hydrochloride, comprising the steps of:

(1) Pulverizing caulis Sinomenii, alkalizing and stacking;

The mass ratio of the medicinal materials to the calcium hydroxide is 20:2;

the method also comprises a purification step, wherein the solid obtained after the reaction is washed by adding ethanol and dried to obtain the catalyst; the solvent is methyl isobutyl ketone and anisole; the methyl isobutyl ketone accounts for 10 percent of the volume fraction of the mixed solvent.

Example 8

A method for preparing sinomenine hydrochloride, comprising the steps of:

(1) Pulverizing caulis Sinomenii, alkalizing and stacking;

chloroform as the solvent;

when the solvent is added, the ratio of the volume (mL) of the solvent to the mass (g) of the medicinal material is 5.5/1;

the extraction time is 0.8h.

Preferably, the number of extraction times is 3.

When the sinomenine extracting solution is washed by the water, the volume ratio of the water phase to the extracting solution is 1:2.5;

the mass ratio of the medicinal materials to the calcium hydroxide is 25:2; the concentration of the hydrochloric acid is 3mol/L.

Example 9 a process for preparing sinomenine hydrochloride comprising the steps of:

(1) Pulverizing caulis Sinomenii, alkalizing and stacking;

The solvent is methyl isobutyl ketone and anisole; methyl isobutyl ketone accounts for 45% of the volume fraction of the mixed solvent; when the solvent is added, the ratio of the volume (mL) of the solvent to the mass (g) of the medicinal material is 9/1; the extraction time is 2 hours; when the sinomenine extracting solution is washed by the water, the volume ratio of the water phase to the extracting solution is 1:3.5; the mass ratio of the medicinal materials to the calcium hydroxide is that the method also comprises a purification step, and the solid obtained after the reaction is added with ethanol for washing, and the ratio of the ethanol to the calcium hydroxide is 22:2; the concentration of the hydrochloric acid is 3mol/L; the sinomenine hydrochloride is prepared after drying.

Other embodiments of the application will be apparent to those skilled in the art from consideration of the specification and practice of the application disclosed herein. This application is intended to cover any variations, uses, or adaptations of the application following, in general, the principles of the application and including such departures from the present disclosure as come within known or customary practice within the art to which the application pertains. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the application being indicated by the following claims. It will be understood that the application is not limited to what has been described above and that various modifications and changes may be made without departing from the scope thereof. The scope of the application is limited only by the appended claims.

Claims

1. A method for preparing sinomenine hydrochloride, comprising the steps of:

(1) Pulverizing caulis Sinomenii, alkalizing and stacking;

(4) Adding hydrochloric acid into the water-washed extracting solution until the system is acidic to obtain sinomenine hydrochloride crystals; the solvent is selected from anisole, or a mixed solvent of methyl isobutyl ketone and anisole; when the solvent is added, the ratio of the volume mL of the solvent to the mass g of the medicinal material is 5/1-10/1; when the solvent is a mixed solvent, the methyl isobutyl ketone accounts for less than 50 percent of the volume fraction of the mixed solvent.

2. The method for preparing sinomenine hydrochloride according to claim 1, wherein the extraction time is 0.5 to 2 hours.

3. The method for preparing sinomenine hydrochloride according to claim 1, wherein the number of extraction is 2 to 3.

4. The method for preparing sinomenine hydrochloride according to claim 1, wherein the volume ratio of the aqueous phase to the extract is 1:2-1:4 when the sinomenine extract is washed with water.

5. The method for preparing sinomenine hydrochloride according to claim 1, wherein the base used for the alkalization is calcium hydroxide.

6. The method for preparing sinomenine hydrochloride according to claim 5, wherein the mass ratio of the medicinal material to the calcium hydroxide is 10-30:1-6; the concentration of the hydrochloric acid is 0.5-10 mol/L _。

7. The method for preparing sinomenine hydrochloride according to claim 6, wherein the mass ratio of the medicinal material to the calcium hydroxide is 15-25:2-4; the concentration of the hydrochloric acid is 1-8 mol/L.

8. The method for preparing sinomenine hydrochloride according to claim 1, further comprising a purification step, wherein the solid obtained after the reaction is washed with ethanol and dried.