CN113582884A - Preparation method of sodium azulene sulfonate monohydrate with high stability - Google Patents
Preparation method of sodium azulene sulfonate monohydrate with high stability Download PDFInfo
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- CN113582884A CN113582884A CN202110788824.XA CN202110788824A CN113582884A CN 113582884 A CN113582884 A CN 113582884A CN 202110788824 A CN202110788824 A CN 202110788824A CN 113582884 A CN113582884 A CN 113582884A
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- azulene sulfonate
- sodium azulene
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/32—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of salts of sulfonic acids
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/42—Separation; Purification; Stabilisation; Use of additives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/02—Ortho- or ortho- and peri-condensed systems
- C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
- C07C2603/30—Ortho- or ortho- and peri-condensed systems containing three rings containing seven-membered rings
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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Abstract
The invention provides a preparation method of sodium azulene sulfonate monohydrate with high stability, belonging to the technical field of synthesis methods. The invention provides a preparation method of sodium azulene sulfonate monohydrate with high stability, which comprises the following steps: (1) mixing sodium azulene sulfonate and water according to a mass ratio of 1: 10-50, and fully stirring; (2) adjusting the pH value to be alkaline, heating and stirring until sodium azulene sulfonate is completely dissolved, cooling and crystallizing to obtain high-stability sodium azulene sulfonate monohydrate, wherein the crystallizing temperature is controlled to be 0-25 ℃. The sodium azulene sulfonate monohydrate prepared by the method is very stable, the content of the sodium azulene sulfonate monohydrate after being placed for 10 days at 60 ℃ basically does not change, and the sodium azulene sulfonate monohydrate can well meet the relevant requirements of 2015 edition of 9001 raw material medicament and preparation stability test guiding principles published by the commission of national pharmacopoeia.
Description
Technical Field
The invention belongs to the technical field of chemical synthesis, and particularly relates to a preparation method of sodium azulene sulfonate monohydrate with high stability.
Background
The sodium azulene sulfonate is short for guaiazulene sulfonate, has the chemical name of 1, 4-dimethyl-7-isopropyl azulene-3-sodium sulfonate, has the functions of diminishing inflammation, resisting bacteria, resisting allergy, regenerating tissues and the like, is widely applied to various pharmaceutical preparations due to high safety, and has obvious effect of treating ophthalmic diseases, gastrointestinal diseases, skin diseases and oral diseases.
In Europe, America, Japan and the like, the sodium azulene sulfonate is popular in the fields of health care products, cosmetics and the like besides being used as a raw material of medicines.
The stability of the medicine is one of the important indexes for evaluating the quality of the medicine preparation, and the medicine is decomposed and deteriorated due to the influence of various factors in the processes of production, storage and use, so that the curative effect of the medicine is reduced or the side effect of the medicine is increased, and some of the medicine even generates toxic substances. Therefore, the stable crystal form or crystal hydrate is preferably selected as the raw material drug in the drug development.
The sodium azulene sulfonate is unstable in chemical property, can be decomposed under illumination, air oxidation and high-temperature environment, and is easy to remove sulfonic groups. According to reports that the crystal water of sodium azulene sulfonate has two types of semi-water and mono-water, and the molecular formulas are respectively C15H17NaO3S·1/2H2O and C15H17NaO3S·H2And O, long-term experimental data show that the sodium azulene sulfonate monohydrate is more stable than the sodium azulene sulfonate hemihydrate. The azulene sodium sulfonate hemihydrate can meet the requirement of impurity limit under the conditions of 10 days of illumination and 60 percent of relative humidity, and the azulene sodium sulfonate monohydrate can meet the requirement of impurity limit under the conditions. The standard of the medicine in the Japanese pharmacopoeia is sodium azulene sulfonate monohydrate.
As for the preparation method of the azulene sodium sulfonate monohydrate, European patent 88958A1 and Chinese patent CN 106748912A respectively show corresponding preparation methods, but according to the guidelines of 9001 raw material drug and preparation stability test issued by the Commission of the national pharmacopoeia 2015 edition, the raw material drug and preparation stability test needs to be placed at 60 ℃ for 10 days, samples are taken on the 5 th day and the 10 th day, and the detection is carried out according to the stability focus examination item. However, the monohydrate prepared in the above two patents is subjected to stability test at 40 ℃, and does not meet the relevant regulation. In addition, the monohydrate prepared by the Chinese patent CN 106748912A is completely converted into other impurities at the temperature of 40 ℃ on the 5 th day, almost no longer contains active ingredients, and far less meets the requirement of the stability of related raw material medicines. Therefore, the sodium azulene sulfonate monohydrate prepared by the above two methods is still not a stable monohydrate.
How to find a new preparation method to provide a high-stability sodium azulene sulfonate monohydrate compound is a technical problem to be solved urgently.
Disclosure of Invention
The invention aims to solve the technical problems and provide a preparation method of a sodium azulene sulfonate monohydrate compound with high stability. The sodium azulene sulfonate monohydrate prepared by the invention can well meet the requirement of raw material stability specified in 2015 edition 9001 raw material drug and preparation stability test guiding principle issued by the commission of national pharmacopoeia, and has extremely high stability after being placed at 60 ℃ for 10 days.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows:
the preparation method of the sodium azulene sulfonate monohydrate with high stability comprises the following steps:
(1) dissolving sodium azulene sulfonate in water, and fully stirring;
(2) adjusting the pH value of the solution to be alkaline, heating to 85-100 ℃, stirring until sodium azulene sulfonate is completely dissolved, cooling and crystallizing to obtain the sodium azulene sulfonate monohydrate with high stability.
In the preparation method, on one hand, the pH value of the solution is adjusted to be alkaline, on the other hand, the temperature is increased to more than 85 ℃ under the alkaline condition, then the temperature is reduced and crystallization is carried out to obtain a target product, and the sodium azulene sulfonate monohydrate with high stability can be obtained by controlling the two conditions.
Further, the mass ratio of the sodium azulene sulfonate to the water in the step (1) is 1: 10-50.
Further, in step (2), the pH value is more than 7.
Further, the base used for adjusting the pH value in the step (2) is sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium phosphate, potassium phosphate, sodium acetate or the like.
Further, the temperature of the crystallization in the step (2) is controlled to be 0 to 25 ℃.
Further, after crystals are precipitated in the step (2), the precipitated crystals are subjected to suction filtration and vacuum drying to constant weight.
Further, in the step (1), the sodium azulene sulfonate is crude sodium azulene sulfonate.
The invention has the following beneficial effects:
(1) the preparation method provided by the invention can obtain single and stable sodium azulene sulfonate monohydrate, and the preparation method is simple and rapid;
(2) the sodium azulene sulfonate monohydrate prepared by the method has high stability after being placed for 10 days at 60 ℃, and tests show that the sodium azulene sulfonate monohydrate has the advantages of 96.00 percent of HPLC content, -0.77 percent of azulene loss rate, 99.85 percent of HPLC main peak, 0.000 percent of guaiazulene content, 8 impurity peaks, 0.136 percent of total content of other unknown impurities, 0.136 percent of total impurity content, 1.27 percent of total peak loss rate and basically no change in content, so that the sodium azulene sulfonate monohydrate prepared by the method is very stable and meets the relevant requirements of 2015 edition 9001 raw material medicament and preparation stability test guiding principle issued by the Commission of the national pharmacopoeia;
(3) in the synthesis process of the method, the used reagent is only water, and other organic solvents are not needed, so that the pollution to the environment is greatly reduced.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more clearly understood, the present invention is described in detail below with reference to the following embodiments, and it should be noted that the following embodiments are only for explaining and illustrating the present invention and are not intended to limit the present invention. The invention is not limited to the embodiments described above, but rather, may be modified within the scope of the invention.
Example 1
The embodiment provides a preparation method of high-stability sodium azulene sulfonate monohydrate, which relates to the following reaction formula:
the preparation method comprises the following specific steps: adding 1.2g of sodium azulene sulfonate solid and 30mL of water into a 100mL single-mouth bottle, adjusting the pH value to 13.3 by using a sodium hydroxide solution under full stirring, then heating to 100 ℃, keeping the temperature and stirring for 1 hour, placing the system in an ice bath after 1 hour, continuously stirring, separating out crystals, performing suction filtration on the separated out crystals by using a Buchner funnel, and performing vacuum drying on a filter cake at 35 ℃ to constant weight to obtain 1g of sodium azulene sulfonate monohydrate. The moisture content was 5.95% by Karl Fischer moisture tester.
The product obtained by the method is subjected to a stability test at 60 ℃, the sample is placed at 60 ℃ for 10 days, and the test of a stability key investigation project is carried out according to the relevant requirements of 2015 version 9001 guiding principle of a raw material drug and preparation stability test, and the obtained results are shown in table 1:
TABLE 1
The data in table 1 above show that the sodium azulene sulfonate monohydrate prepared according to example 1 of the present invention has an HPLC purity of 95.27%, and after 6 days and 10 days of stability test at 60 ℃ the HPLC purity is 97.2% and 96%, respectively, and the total impurity content is as follows: 0.349% after 0 days and 0.118% and 0.136% after 6 days and 10 days, respectively, show that the sodium azulene sulfonate monohydrate prepared by the method of the present invention is very stable and has substantially no change in content. Meets the relevant requirements of the guidelines of the stability test of 9001 raw material medicaments and preparations published by the Commission of the national pharmacopoeia of 2015 edition.
Comparative example 1
Examination of acid-base conditions:
in a 100mL single-neck bottle, 1.2g of sodium azulene sulfonate solid and 15 mL of water are added, the temperature is raised to 100 ℃ by stirring, after 1 hour, the system is placed in an ice bath for continuous stirring, and crystals are separated out. And (3) carrying out suction filtration on the precipitated crystals by using a Buchner funnel, drying a filter cake at 35 ℃ in vacuum to constant weight, carrying out a stability experiment on the obtained product at 60 ℃, and obtaining results shown in table 2:
TABLE 2
Comparative example 2
Temperature rise examination:
in a 100mL single-neck bottle, 2.2 g of sodium azulene sulfonate solid and 20 mL of water are added, sodium hydroxide solution is added to adjust the pH value to 12, the temperature is raised to 80 ℃ by stirring, and after 1 hour, the system is placed in an ice bath to be continuously stirred, and crystals are separated out. And (4) carrying out suction filtration on the precipitated crystals by using a Buchner funnel, and carrying out vacuum drying on a filter cake at the temperature of 35 ℃ to constant weight. The product obtained was subjected to a stability test at 60 ℃ and the results are shown in table 3:
TABLE 3
Comparative example 3
Whether temperature rise is examined:
2g of sodium azulene sulfonate and 40 ml of a hydrochloric acid solution with a volume ratio of 1:4 are added into a 100ml single-mouth bottle and stirred and dissolved at room temperature. Slowly adding sodium hydroxide solution to adjust the pH value to about 9, stirring for 24 hours at room temperature, and precipitating crystals.
And (4) carrying out suction filtration on the precipitated crystals by using a Buchner funnel, and carrying out vacuum drying on a filter cake at the temperature of 35 ℃ to constant weight. The product obtained was subjected to a stability test at 60 ℃ and the results are shown in table 4:
TABLE 4
The combination of the above results shows that:
1. the preparation of stable sodium azulene sulfonate monohydrate requires an alkaline solution, comparative example 1 is a recrystallization in the aqueous phase, and the product obtained is essentially lost after two days of standing for a stability experiment at 60 ℃.
2. Heating conditions are required for preparing the stable sodium azulene sulfonate monohydrate, the products prepared in comparative example 2 and comparative example 3 are products prepared under the alkaline condition, but the temperature condition is not achieved, the heating conditions of the normal temperature and the temperature below 85 ℃ are insufficient for preparing the stable sodium azulene sulfonate monohydrate, and the data in the tables 3 and 4 show that the two prepared products can not achieve the stability experiment requirement result of 10 days at the temperature of 60 ℃.
Claims (8)
1. The preparation method of the sodium azulene sulfonate monohydrate with high stability is characterized by comprising the following steps:
(1) dissolving sodium azulene sulfonate in water, and fully stirring;
(2) adjusting the pH value of the solution to be alkaline, heating to 85-100 ℃, stirring to completely dissolve the sodium azulene sulfonate, cooling and crystallizing to obtain the sodium azulene sulfonate monohydrate with high stability.
2. The preparation method according to claim 1, wherein the mass ratio of the sodium azulene sulfonate to water in step (1) is 1: 10-50.
3. The method according to claim 1, wherein the pH in step (2) is > 7.
4. The method according to claim 1, wherein the base used for adjusting the pH in step (2) comprises at least one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium phosphate, potassium phosphate, or sodium acetate.
5. The production method according to claim 1, wherein the temperature of the crystallization in the step (2) is controlled to 0 to 25 ℃.
6. The production method according to claim 1, wherein after the crystals are precipitated in the step (2), the precipitated crystals are suction-filtered and vacuum-dried to a constant weight.
7. The method according to claim 5, wherein the temperature of the vacuum drying is 35 ℃.
8. The preparation method according to claim 1, wherein the sodium azulene sulfonate in the step (1) is crude sodium azulene sulfonate.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013000315A1 (en) * | 2011-06-27 | 2013-01-03 | 四川国康药业有限公司 | Guaiazulene derivative, preparation method and use thereof |
| CN106748912A (en) * | 2016-12-30 | 2017-05-31 | 南京济群医药科技股份有限公司 | A kind of synthesis technique of sodium azulenesulfonate monohydrate |
| CN108863859A (en) * | 2018-09-04 | 2018-11-23 | 江西依思特香料有限公司 | The preparation method of sodium azulenesulfonate |
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2021
- 2021-07-13 CN CN202110788824.XA patent/CN113582884A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013000315A1 (en) * | 2011-06-27 | 2013-01-03 | 四川国康药业有限公司 | Guaiazulene derivative, preparation method and use thereof |
| CN106748912A (en) * | 2016-12-30 | 2017-05-31 | 南京济群医药科技股份有限公司 | A kind of synthesis technique of sodium azulenesulfonate monohydrate |
| CN108863859A (en) * | 2018-09-04 | 2018-11-23 | 江西依思特香料有限公司 | The preparation method of sodium azulenesulfonate |
Non-Patent Citations (1)
| Title |
|---|
| SAKOTA, NAOKAZU等: "Sulfonation of guaiazulene with trialkyl phosphate-sulfur trioxide complexes", 《NIPPON KAGAKU ZASSHI 》 * |
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