CN113045571A - Preparation method of matrine quaternary ammonium salt - Google Patents
Preparation method of matrine quaternary ammonium salt Download PDFInfo
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- CN113045571A CN113045571A CN201911361311.XA CN201911361311A CN113045571A CN 113045571 A CN113045571 A CN 113045571A CN 201911361311 A CN201911361311 A CN 201911361311A CN 113045571 A CN113045571 A CN 113045571A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed systems contains four or more hetero rings
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Abstract
The invention discloses a preparation method of matrine quaternary ammonium salt, which comprises the steps of crushing cleaned and dried sophora alopecuroides into coarse powder, adding 60% ethanol, heating and refluxing for 5 hours, filtering, extracting filter residue again, and repeating the steps for three times. Concentrating the obtained filtrate to paste, dissolving in water, adding dilute hydrochloric acid to adjust acidic pH to 3-4, filtering insoluble substance, adding sodium hydroxide solution to the filtrate to adjust pH to 10-11, filtering insoluble substance, concentrating the filtrate to paste, and lyophilizing to obtain total matrine. Dissolving in water, heating, adding appropriate amount of sulfite, dissolving in water to obtain saturated solution, dropwise adding into the total matrine solution while stirring, and heating and stirring. Cooling to room temperature after reaction is stopped, extracting with chloroform of the same volume, concentrating the filtrate to paste, adding absolute ethyl alcohol for dissolving, recrystallizing, filtering and drying to obtain the sophocarpidine total sulfonate. Thereby providing a more efficient way for preparing the matrine quaternary ammonium salt.
Description
Technical Field
The invention relates to a preparation method of matrine quaternary ammonium salt, belonging to the field of pharmaceutical chemicals.
Background
Matrine alkaloids are alkaloids with similar chemical structure and represented by matrine. Is widely present in plants of Sophora of Leguminosae, such as radix Sophorae Flavescentis and herba Sophorae Alopecuroidis, and is the main effective component of this Hechuan Chinese herbal medicine. The matrine-based alkaloids include oxymatrine (oxymatrine), sophocarpine (sophocarpine), oxysophocarpine (N-oxysophocarpine), Sophoramine (Sophoramine), sophoridine (sophoridine), sophoranol (sophoranan 01), and leishmanine (1ehmannine) in addition to matrine, which is a typical compound.
Matrine alkaloid is widely used in clinic due to its good pharmacological activity, and has analgesic, tranquilizing, cooling, antitumor, antiarrhythmic, and antiviral effects. Although the matrine compound has wide pharmacological action but low activity and has certain toxic and side effects on the central nervous system, as is well known, the physicochemical property of the medicament is determined by the structure of the medicament, and the pharmacokinetic process of the medicament in vivo is determined by the physicochemical property of the medicament, so that the pharmacological action of the medicament is determined. The structure, physicochemical properties, pharmacological action and in vivo metabolism of the medicine are closely related to the toxic and side effects of the medicine. The compound with higher activity and lower toxicity can be obtained by carrying out structural modification on the compound. The matrine alkaloid derivatives include quaternary ammonium salt, double salt, 13-position and 14-position addition derivatives synthesized by taking sophocarpine as a raw material, derivatives obtained by breaking amide bonds and compounds obtained by substituting carbonyl groups.
The Chinese patent with the application number of 2017101825664 discloses a matrine water emulsion compounded by quaternary ammonium salt grafted phosphate and a preparation method thereof. The preparation method adopts ultrasonic extraction and microwave extraction combined technology and chloroform extraction to extract and separate matrine; then, preparing quaternary ammonium salt by dodecyl dimethyl tertiary amine and epoxy chloropropane under the catalysis of acid, and grafting the quaternary ammonium salt on the phosphate to obtain quaternary ammonium salt grafted phosphate; and finally, preparing the matrine water emulsion compounded by the quaternary ammonium salt grafted phosphate by adopting an oil-in-water mode. The matrine water emulsion compounded by the quaternary ammonium salt grafted phosphate is a pure plant source, is safe and environment-friendly, and has a good mosquito killing effect.
The existing preparation method of the main matrine quaternary ammonium salt has the disadvantages of complex preparation process, time consumption, high cost, high toxicity of the added reagent and high environmental pollution, and cannot meet the requirements of the added reagent as a medicinal raw material.
Disclosure of Invention
The invention aims to solve the problems in the prior art and provides a novel preparation method of matrine quaternary ammonium salt.
In order to achieve the above object, the present invention adopts the following technical solution, including the steps of:
s1: pulverizing cleaned and dried herba Sophorae Alopecuroidis into coarse powder, adding 60% ethanol, heating and refluxing for 5 hr, filtering, extracting the residue again, and repeating for three times.
S2: mixing the filtrates obtained in step S1, concentrating into paste, dissolving in water, adding dilute hydrochloric acid to adjust pH to 3-4, filtering insoluble substance, adding sodium hydroxide solution to adjust pH to 10-11, filtering insoluble substance, concentrating the filtrate into paste, and lyophilizing to obtain total matrine.
S3: dissolving the total matrine obtained in step S2 in water, heating, adding appropriate amount of sulfite, adding water to dissolve, dropwise adding into the total matrine solution while stirring, heating and stirring, and monitoring reaction progress with thin layer chromatography.
S4: cooling to room temperature after reaction is stopped, extracting with chloroform of the same volume, concentrating the filtrate to paste, adding absolute ethyl alcohol for dissolving, recrystallizing, filtering and drying to obtain the one of the matrine quaternary ammonium salts.
Preferably, the multiple of 60% ethanol in the step S1 is 6-15 times of the weight of the sophora alopecuroides coarse powder, and the heating reflux temperature is 50-75 ℃.
More preferably, the amount of water in the step S2 is 10-15 times of the weight of the extract.
More preferably, in the step S3, the heating temperature is 70-90 ℃, and the molar ratio of the total matrine to the sulfite is 1: 1.1-1.5, wherein the molecular weight of the total matrine is calculated by the molecular weight of oxymatrine, and the total reaction time is 11-14 h.
Further preferably, the filtrate is concentrated in step S4 until the water content of the paste is less than 25%, the amount of anhydrous ethanol for recrystallization is 10-20 times of the amount of the paste, the temperature for recrystallization is 5-15 ℃, and the time for recrystallization is 24-36 h.
Still more preferably, the amount of the 60% ethanol added in the step S1 is 8-12 times of the weight of the sophora alopecuroides coarse powder, and the heating reflux temperature is 60-70 ℃.
Still more preferably, in the step S3, the heating temperature is 75 to 85 ℃, and the sulfite is potassium salt, sodium salt or ammonium salt.
And in the step S4, the anhydrous ethanol for recrystallization is 13-17 times of the weight of the extract, and the recrystallization time is 24-30 h.
The invention has the advantages that:
(1) according to the preparation method of the matrine quaternary ammonium salt, the matrine quaternary ammonium salt is prepared from the sophora alopecuroides by using the method, and the method has the advantages of clear flow, simple method, low cost, good color of the purified product, high yield and high purity, and the raw materials are practically nontoxic and harmless and are environment-friendly;
(2) the preparation method of the matrine quaternary ammonium salt mainly comprises the preparation method of the matrine quaternary ammonium salt, and can improve the pH value of the aqueous solution of the matrine quaternary ammonium salt, so that the matrine quaternary ammonium salt and some auxiliary materials have no incompatibility, have good thermal stability, are favorable for long-term storage of medicines, and open up wide fields for the preparation development and clinical application of matrine alkaloids.
Detailed Description
The present invention is further illustrated by the following examples, which are not intended to limit the scope of the invention.
Example 1:
pulverizing cleaned and dried herba Sophorae Alopecuroidis into coarse powder 1.0kg, adding 60% ethanol 8.0kg, heating and refluxing at 60 deg.C for 5 hr, filtering, extracting the residue again, repeating for three times, mixing filtrates, concentrating to obtain paste, 745g, dissolving in 8.5L of water, adding diluted hydrochloric acid to adjust acidity to pH value of 3-4, filtering insoluble substance, adding sodium hydroxide solution to the filtrate to adjust pH value to 10-11, filtering insoluble substance, concentrating the filtrate to paste, and lyophilizing to obtain 600g of total matrine.
Taking 600g of total matrines, adding water for dissolving, heating to 75 ℃, taking 210g of sodium sulfite, adding water for preparing saturated solution, dropwise adding the solution into the total matrines solution while stirring, continuing heating and stirring after the addition is finished, monitoring the reaction progress by using thin-layer chromatography (a developing agent is methanol: ethyl acetate = 1: 4), and reacting for 12 hours in total. Stopping reaction, cooling to room temperature, extracting with chloroform of the same volume, concentrating the filtrate to paste (water content is 20%), adding anhydrous ethanol 13 times of the extract amount to dissolve, recrystallizing at 7 deg.C for 24h, filtering, and drying to obtain 480g of white matrine sulfonate.
Example 2:
pulverizing cleaned and dried herba Sophorae Alopecuroidis into coarse powder 1.0kg, adding 60% ethanol 10.0kg, heating and refluxing at 65 deg.C for 5 hr, filtering, extracting the residue again, repeating for three times, mixing filtrates, concentrating into paste, dissolving 789g in water for 8L, adding diluted hydrochloric acid to adjust acidity to pH value of 3-4, filtering insoluble substance, adding sodium hydroxide solution to the filtrate to adjust pH to 10-11, filtering insoluble substance, concentrating the filtrate into paste, and lyophilizing to obtain total matrine 650 g.
Dissolving 650g of total matrines in water, heating to 80 ℃, taking 264g of sodium sulfite, adding water to prepare saturated solution, dropwise adding the solution into the total matrines solution while stirring, continuing heating and stirring after the addition, monitoring the reaction progress by using thin-layer chromatography (a developing agent is methanol: ethyl acetate = 1: 4), and reacting for 14 hours in total. Cooling to room temperature after reaction is stopped, extracting with chloroform of the same volume, concentrating the filtrate to paste (the water content is 17%), adding absolute ethyl alcohol of 15 times of the extract amount to dissolve, recrystallizing at 10 ℃ for 27h, filtering, and drying to obtain 510g of white sophocarpidine sulfonate.
Example 3:
pulverizing cleaned and dried herba Sophorae Alopecuroidis into coarse powder 1.0kg, adding 60% ethanol 12.0kg, heating and refluxing at 65 deg.C for 5 hr, filtering, extracting the residue again, repeating for three times, mixing filtrates, concentrating to paste, dissolving 800g in water 10.5L, adding dilute hydrochloric acid to adjust pH to 3-4, filtering insoluble substance, adding sodium hydroxide solution to the filtrate to adjust pH to 10-11, filtering insoluble substance, concentrating the filtrate to paste, and lyophilizing to obtain total matrine 680 g.
680g of total matrine is taken, water is added for dissolution, the mixture is heated to 80 ℃, 300g of sodium sulfite is taken, water is added for saturated dissolution, the mixture is dropwise added into the total matrine solution while stirring, heating and stirring are continued after the addition, the reaction progress is monitored by thin-layer chromatography (a developing agent is methanol: ethyl acetate = 1: 4), and the total reaction time is 14 hours. Cooling to room temperature after reaction is stopped, extracting with chloroform of the same volume, concentrating the filtrate to paste (the water content is 15%), adding absolute ethyl alcohol of 17 times of the extract amount to dissolve, recrystallizing at 10 ℃ for 30h, filtering, and drying to obtain 505g of white sophocarpidine total sulfonate.
The detection shows that the matrine quaternary ammonium salt obtained by the extraction method meets the extraction requirement of the invention, and the extraction result is shown in the above examples.
In summary, the sophora alopecuroides after cleaning and drying is crushed into coarse powder, the sophora alopecuroides is heated, refluxed, filtered, extracted, combined, concentrated, hydrolyzed, filtered, concentrated and freeze-dried to obtain the total matrine, then the total matrine is melted and heated, prepared, heated, cooled, extracted, concentrated and dissolved, and then the dissolved solution is recrystallized, filtered and dried to obtain the total matrine sulfonate, thereby providing a more efficient way for preparing the quaternary ammonium salt of the matrine.
In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above do not necessarily refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples.
The foregoing illustrates and describes the principles, general features, and advantages of the present invention. It should be understood by those skilled in the art that the above embodiments do not limit the present invention in any way, and all technical solutions obtained by using equivalent alternatives or equivalent variations fall within the scope of the present invention.
Claims (8)
1. A preparation method of matrine quaternary ammonium salt is characterized by comprising the following steps:
s1: pulverizing cleaned and dried herba Sophorae Alopecuroidis into coarse powder, adding 60% ethanol, heating and refluxing for 5 hr, filtering, extracting the residue again, and repeating for three times;
s2: mixing the filtrates obtained in step S1, concentrating into paste, dissolving in water, adding dilute hydrochloric acid to adjust pH to 3-4, filtering insoluble substance, adding sodium hydroxide solution to adjust pH to 10-11, filtering insoluble substance, concentrating the filtrate into paste, and lyophilizing to obtain total matrine;
s3: dissolving the total matrine obtained in the step S2 in water, heating, adding an appropriate amount of sulfite into water to prepare saturated solution, dropwise adding the solution into the total matrine solution while stirring, continuing heating and stirring after adding, and monitoring the reaction progress by using a thin-layer chromatography;
s4: cooling to room temperature after reaction is stopped, extracting with chloroform of the same volume, concentrating the filtrate to paste, adding absolute ethanol for dissolving, recrystallizing, filtering, and drying to obtain the sophocarpidine sulfonate which is one of sophocarpidine quaternary ammonium salts.
2. The method of claim 1, wherein the amount of 60% ethanol in step S1 is 6-15 times the weight of the coarse powder of herba Sophorae Alopecuroidis, and the heating reflux temperature is 50-75 deg.C.
3. The method for preparing matrine quaternary ammonium salt according to claim 1, wherein the amount of water in step S2 is 10-15 times the weight of the extract.
4. The method for preparing the matrine quaternary ammonium salt according to claim 1, wherein the heating temperature in the step S3 is 70-90 ℃, and the molar ratio of the matrine to the sulfite is 1: 1.1-1.5, wherein the molecular weight of the total matrine is calculated by the molecular weight of oxymatrine, and the total reaction time is 11-14 h.
5. The method of claim 1, wherein the filtrate of step S4 is concentrated to a paste with a water content of less than 25%, the weight of the paste is 10-20 times of the anhydrous ethanol for recrystallization, the temperature of recrystallization is 5-15 ℃, and the time of recrystallization is 24-36 h.
6. The method of claim 1, wherein the amount of 60% ethanol added in step S1 is 8-12 times the weight of the coarse powder of Sophora alopecuroides L.and the heating reflux temperature is 60-70 ℃.
7. The method for preparing matrine quaternary ammonium salt according to claim 1, wherein the heating temperature in step S3 is 75-85 ℃, and the sulfite is potassium salt, sodium salt or ammonium salt.
8. The method for preparing matrine quaternary ammonium salt according to claim 1, wherein the weight of anhydrous ethanol used for recrystallization in step S4 is 13-17 times of the weight of the extract, and the recrystallization time is 24-30 h.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101129455A (en) * | 2007-09-18 | 2008-02-27 | 新疆维吾尔自治区药物研究所 | Sophora extractive and method of preparing the same and application of the same |
| CN101585838A (en) * | 2009-06-15 | 2009-11-25 | 西南大学 | Matrine sodium sulfonate and preparation method |
| CN102633798A (en) * | 2012-04-26 | 2012-08-15 | 宁夏紫荆花制药有限公司 | Method for preparing high-purity matrine from sophora alopecuroides |
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- 2019-12-26 CN CN201911361311.XA patent/CN113045571A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101129455A (en) * | 2007-09-18 | 2008-02-27 | 新疆维吾尔自治区药物研究所 | Sophora extractive and method of preparing the same and application of the same |
| CN101585838A (en) * | 2009-06-15 | 2009-11-25 | 西南大学 | Matrine sodium sulfonate and preparation method |
| CN102633798A (en) * | 2012-04-26 | 2012-08-15 | 宁夏紫荆花制药有限公司 | Method for preparing high-purity matrine from sophora alopecuroides |
Non-Patent Citations (2)
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| 么厉等: "《中药材规范化种植（养殖）技术指南》", 31 May 2006, 中国农业出版社 * |
| 陈明岭等: "《皮肤病常用中药药理及临床》", 31 October 2017, 中国科学技术出版社 * |
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