CN112624919B - Low-cost preparation method of pharmaceutic adjuvant sodium stearyl fumarate - Google Patents
Low-cost preparation method of pharmaceutic adjuvant sodium stearyl fumarate Download PDFInfo
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- C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
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- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
- B01J31/06—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides containing polymers
- B01J31/08—Ion-exchange resins
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- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
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- B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
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- B01J2231/52—Isomerisation reactions
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Abstract
The invention belongs to the technical field of pharmaceutic adjuvant preparation, and discloses a low-cost preparation method of a pharmaceutic adjuvant sodium stearyl fumarate. Adding octadecanol and maleic anhydride into an organic solvent, heating to 90-130 ℃, stirring for reaction to obtain maleic acid mono-octadecanol ester, then adding a solid isomerization catalyst at 90-130 ℃, continuing to keep the temperature and stir for reaction to obtain fumaric acid mono-octadecanol ester, filtering and separating the solid isomerization catalyst in a system, then adding an alkali solution into the reaction system, stirring for reaction at 35-55 ℃, separating and purifying a product, and obtaining the sodium stearyl fumarate. The invention adopts solid isomerization catalyst and one-pot synthesis, and can be separated from the reaction system by simple filtration after the catalysis is finished, thereby simplifying the production process, reducing the production cost and having high product quality.
Description
Technical Field
The invention relates to the technical field of pharmaceutic adjuvants, in particular to a low-cost preparation method of a pharmaceutic adjuvant sodium stearyl fumarate.
Background
Stearyl fumarate sodium (C) 22 H 39 NaO 4 ) Is an important pharmaceutic adjuvant with wide application. During the metabolism process of the sodium stearyl fumarate in animal bodies, most of the sodium stearyl fumarate can be absorbed, and the sodium stearyl fumarate is hydrolyzed to generate stearyl alcohol and stearic acid, and a small part of the sodium stearyl fumarate can be directly and rapidly metabolized, so that the sodium stearyl fumarate is non-toxic and non-irritant. In the field of medicines, sodium stearyl fumarate is added into a medicinal preparation, can be used as a lubricant for tablets and capsules, can also form a protective film in effervescent tablets, can solve the problems of a stearate lubricant, such as influence and over lubrication of a main medicine, and can play a role in improving disintegration of the medicine and promoting dissolution of the medicine, thereby improving bioavailability.
The common synthesis method of sodium stearyl fumarate is to adopt stearyl alcohol to react with maleic anhydride, and then isomerize reaction products and form salt to obtain the sodium stearyl fumarate. If the following steps are adopted: s1, mixing maleic anhydride, octadecanol and a reaction solvent, and carrying out a ring-opening reaction at a temperature of 80 ℃ or above; s2, adding a conversion agent (such as thiourea/hydrochloric acid) into the reaction system to perform conversion reaction; s3, cooling to 40-50 ℃, dropwise adding a sodium-containing alkali solution into the reaction system, stirring, reacting, cooling, and crystallizing to obtain a crude sodium stearyl fumarate; and S4, refining the crude sodium stearyl fumarate to obtain a sodium stearyl fumarate product.
The invention patent CN 104177260A discloses a preparation method of common auxiliary materials, which comprises the steps of firstly, reacting octadecanol with maleic anhydride in the presence of an organic alkaline catalyst to prepare maleic acid monostearyl ester, then, isomerizing the maleic acid monostearyl ester under the action of hydrochloric acid to obtain fumaric acid monostearyl ester, and finally, reacting with alkali to obtain sodium salt to obtain sodium stearyl fumarate.
In the method, hydrochloric acid is used as an isomerization catalyst, and the consumption of the alkali solution is increased in the subsequent salifying process of the alkali solution; and an intermediate product needs to be separated in advance in each step, so that the preparation process is not simplified, and the preparation cost is high.
Disclosure of Invention
Aiming at the defects and shortcomings of the prior art, the invention aims to provide a preparation method of a pharmaceutic adjuvant sodium stearyl fumarate.
In order to achieve the purpose, the invention provides the following technical scheme:
a low-cost preparation method of a pharmaceutic adjuvant sodium stearyl fumarate comprises the following preparation steps:
(1) Adding octadecanol and maleic anhydride into an organic solvent, heating to 90-130 ℃, and stirring for reaction to obtain maleic acid monostearyl ester;
(2) Adding a solid isomerization catalyst into the reaction system in the step (1), and continuously keeping the temperature at 90-130 ℃ and stirring for reaction to obtain the monostearyl fumarate;
(3) And filtering the solid isomerization catalyst in the separation system, then adding an alkali solution into the reaction system, stirring and reacting at the temperature of 35-55 ℃, and separating and purifying the product to obtain the sodium stearyl fumarate.
The solid isomerization catalyst can be any solid catalyst which can catalyze the isomerization reaction of the maleic acid monostearyl ester to obtain the fumaric acid monostearyl ester and can be separated in an organic solvent by simple filtration.
In order to achieve a good isomerization effect, the solid isomerization catalyst used in the invention is aluminum trichloride loaded by sulfonated polystyrene microspheres, and the solid isomerization catalyst is prepared by the following method:
(a) Adding polystyrene microspheres into concentrated sulfuric acid, and performing sulfonation reaction at the temperature of 25-80 ℃ to obtain sulfonated polystyrene microspheres;
(b) And adding the sulfonated polystyrene microspheres into an aluminum chloride solution for ultrasonic treatment to carry out adsorption and fixation reaction, and washing and drying to obtain the sulfonated polystyrene microsphere-loaded aluminum trichloride.
Further, the particle size of the polystyrene microsphere in the step (a) is 0.5-100 μm.
Further, the aluminum chloride solution in the step (b) is an aluminum chloride ethanol solution with the mass concentration of 5-50%.
Furthermore, the charging molar ratio of the octadecanol to the maleic anhydride in the step (1) is 1 (1-1.2).
Further, the organic solvent in the step (1) is selected from toluene or cyclohexane.
Further, the adding amount of the solid isomerization catalyst in the step (2) is 5-50 g/L.
Further, the alkali solution in the step (3) refers to any one of sodium hydroxide, sodium carbonate and sodium bicarbonate solution.
Further, the stirring reaction time in the step (1) is 4-6 h, the stirring reaction time in the step (2) is 4-6 h, and the stirring reaction time in the step (3) is 1-3 h.
Further, the solid isomerization catalyst in the step (3) is recycled, or is repeatedly used after being subjected to activation treatment after being subjected to repeated use and activity reduction for many times; the activating treatment process comprises the steps of adding the recovered solid isomerization catalyst into an aluminum chloride solution again for ultrasonic adsorption and fixation reaction, washing and drying.
Further, the separation and purification step in the step (3) comprises the steps of cooling to below 30 ℃, filtering, washing and drying a solid product to obtain white solid sodium stearyl fumarate.
The principle of the invention is as follows: the method utilizes the characteristics of high specific surface area and easy adsorption of metal ions of the sulfonated polystyrene microspheres to compound the sulfonated polystyrene microspheres with an isomerization catalyst aluminum trichloride, utilizes the solid acid characteristics of the sulfonated polystyrene microspheres and the catalytic characteristics of the aluminum trichloride to obtain the solid isomerization catalyst which can be used for isomerizing the maleic acid monostearyl ester to generate the fumaric acid monostearyl ester, and can be removed by simple filtration after the catalysis is finished without influencing the subsequent salifying process of an alkali-added solution. The whole process adopts a one-pot method, does not need to separate out an intermediate product in advance, and has the advantages of simple operation and low production cost.
Compared with the prior art, the invention has the beneficial effects that:
(1) The invention adopts the solid isomerization catalyst to replace the existing hydrochloric acid isomerization catalyst, can be separated from a reaction system through a simple filtering mode after the catalysis is finished, and directly carries out the subsequent alkali-adding salt-forming process, thereby reducing the consumption of alkali liquor in the subsequent alkali-adding salt-forming process, simplifying the production process, reducing the production cost, having no residue in the product and high product quality.
(2) The method adopts the aluminum trichloride loaded by the sulfonated polystyrene microspheres as the isomerization catalyst of the maleic acid monostearyl ester, utilizes the solid acid characteristic of the sulfonated polystyrene microspheres and the catalytic characteristic of the aluminum trichloride, and has the advantages of high catalytic efficiency and high product purity.
(3) The method adopts toluene or cyclohexane as a reaction solvent, and the esterification reaction in the first step can directly react without adding a catalyst; the second step of isomerization reaction adopts a solid isomerization catalyst, can be removed by simple filtration after the reaction is finished, has less impurity introduction in the whole reaction process, adopts a one-pot method for synthesis, does not need to separate out an intermediate product in advance, has high product yield and does not influence the product quality.
(4) The sulfonated polystyrene microsphere loaded aluminum trichloride isomerization catalyst adopted by the invention can be recycled after being separated and recovered, or can be reused after being activated after being reduced in activity after being reused for many times, so that the production cost can be further reduced.
Drawings
FIG. 1 is a gas chromatogram of the maleic acid monostearyl ester obtained in step (2) of example 1;
FIG. 2 is a gas chromatogram of monostearyl fumarate obtained in step (3) of example 1;
FIG. 3 is a gas chromatogram of the final sodium stearyl fumarate product of example 1;
FIG. 4 is a graph showing the particle size distribution of the final sodium stearyl fumarate product of example 1;
FIG. 5 is a gas chromatogram of the maleic acid monostearyl ester obtained in step (2) of example 2;
FIG. 6 is a gas chromatogram of monostearyl fumarate obtained in step (3) of example 2;
FIG. 7 is a gas chromatogram of the final sodium stearyl fumarate product of example 2;
FIG. 8 is a graph showing the particle size distribution of the final sodium stearyl fumarate product of example 2;
FIG. 9 is a gas chromatogram of the maleic acid monostearyl ester obtained in step (2) of example 3;
FIG. 10 is a gas chromatogram of monostearyl fumarate obtained in step (3) of example 3;
FIG. 11 is a gas chromatogram of the final sodium stearyl fumarate product of example 3;
FIG. 12 is a graph showing the final particle size distribution of the sodium stearyl fumarate product of example 3;
FIG. 13 is a graph of the product yield results of example 4 in which the catalyst was reused 10 times and after activation, it was reused 10 times.
Detailed Description
The present invention will be described in further detail with reference to examples, but the embodiments of the present invention are not limited thereto.
Example 1
(1) Adding PS microspheres with the average particle size of 10 mu m into concentrated sulfuric acid, reacting for 12 hours at the temperature of 60 ℃ under the stirring condition, washing reaction products by water and absolute ethyl alcohol in sequence, and drying in vacuum at the temperature of 60 ℃ to obtain sulfonated polystyrene microspheres; and adding the obtained sulfonated polystyrene microspheres into an aluminum chloride ethanol solution with the mass concentration of 20% for ultrasonic treatment for 2 hours to carry out adsorption and fixation reaction, washing with ethanol, and carrying out vacuum drying at 60 ℃ to obtain the sulfonated polystyrene microsphere-loaded aluminum trichloride.
(2) Adding octadecanol and maleic anhydride into a toluene solvent according to a molar ratio of 1.02. The detection yield is 95%, the detection product is detected according to Chinese pharmacopoeia CP2020 edition, the maleic acid monostearyl alcohol peak time RT13.998, and the detection spectrum is shown in figure 1.
(3) Adding a solid isomerization catalyst, namely sulfonated polystyrene microsphere-loaded aluminum trichloride, into the reaction system in the step (2), wherein the addition amount of the solid isomerization catalyst is 20g/L, and continuously keeping the temperature at 120-130 ℃ and stirring for reaction for 6 hours to obtain the monostearyl fumarate; according to the detection product of the Chinese pharmacopoeia CP2020 edition, the peak-off time RT14.417 of the fumaric acid monostearyl ester is shown in the detection map of figure 2.
(4) And filtering the solid isomerization catalyst in the separation system, then adding 1mol/L NaOH solution into the reaction system, stirring and reacting for 2 hours at the temperature of 40 ℃, cooling to 20 ℃ after the reaction is finished, filtering, washing the solid product with acetone and water in sequence, and drying to obtain white solid sodium stearyl fumarate. The yield is 90%, and the product purity is 99.7% by using a CP2020 non-aqueous titration method; the detection spectrum of the peak time RT14.384 of sodium stearyl fumarate is shown in figure 3.
The particle size distribution diagram of the obtained sodium stearyl fumarate product is shown in figure 4.
Example 2
(1) Adding PS microspheres with the average particle size of 50 microns into concentrated sulfuric acid, reacting for 8 hours at the temperature of 80 ℃ under the stirring condition, washing reaction products by water and absolute ethyl alcohol in sequence, and drying in vacuum at the temperature of 80 ℃ to obtain sulfonated polystyrene microspheres; and adding the obtained sulfonated polystyrene microspheres into an aluminum chloride ethanol solution with the mass concentration of 10% for ultrasonic treatment for 4 hours to carry out adsorption and fixation reaction, washing with ethanol, and carrying out vacuum drying at 80 ℃ to obtain the sulfonated polystyrene microsphere-loaded aluminum trichloride.
(2) Adding octadecanol and maleic anhydride into a toluene solvent according to the molar ratio of 1.05, heating to 120-130 ℃, stirring, refluxing and reacting for 5 hours to obtain the maleic acid monostearyl ester. The detection yield is 97.5%, the detection product is the monostearyl maleate peak time RT14.016 according to Chinese pharmacopoeia CP2020 edition, and the detection spectrum is shown in figure 5.
(3) Adding a solid isomerization catalyst, namely sulfonated polystyrene microsphere-loaded aluminum trichloride, into the reaction system in the step (2), wherein the addition amount of the solid isomerization catalyst is 20g/L, and continuously keeping the temperature at 120-130 ℃ and stirring for reaction for 6 hours to obtain the monostearyl fumarate; according to the detection product of the Chinese pharmacopoeia CP2020 edition, the peak-off time RT14.355 of the fumaric acid monostearyl ester is shown in the detection map of figure 6.
(4) And filtering the solid isomerization catalyst in the separation system, then adding 1mol/L NaOH solution into the reaction system, stirring and reacting for 3 hours at the temperature of 50 ℃, cooling to 20 ℃ after the reaction is finished, filtering, washing the solid product with acetone and water in sequence, and drying to obtain white solid sodium stearyl fumarate. The yield is 92.6%, and the product purity is 100.2% by using a non-aqueous titration method of CP 2020; the peak time RT14.328 of sodium stearyl fumarate, the detection pattern is shown in FIG. 7.
The particle size distribution diagram of the obtained sodium stearyl fumarate product is shown in fig. 8.
Example 3
(1) Adding PS microspheres with the average particle size of 80 microns into concentrated sulfuric acid, reacting for 24 hours at the temperature of 40 ℃ under the stirring condition, washing reaction products by water and absolute ethyl alcohol in sequence, and drying in vacuum at the temperature of 80 ℃ to obtain sulfonated polystyrene microspheres; and adding the obtained sulfonated polystyrene microspheres into an aluminum chloride ethanol solution with the mass concentration of 20% for ultrasonic treatment for 4 hours to carry out adsorption and fixation reaction, washing with ethanol, and carrying out vacuum drying at 80 ℃ to obtain the sulfonated polystyrene microsphere-loaded aluminum trichloride.
(2) Adding octadecanol and maleic anhydride into a cyclohexane solvent according to the molar ratio of 1.1, heating to 90 ℃, stirring and refluxing for 5 hours to obtain the maleic acid monostearyl ester. The yield is 90.7%, the detection result is according to Chinese pharmacopoeia CP2020 edition, the peak time of maleic acid monostearyl alcohol ester RT14.079, and the detection map is shown in figure 9.
(3) Adding a solid isomerization catalyst, namely sulfonated polystyrene microsphere-loaded aluminum trichloride, into the reaction system in the step (2), wherein the addition amount of the solid isomerization catalyst is 20g/L, and continuously keeping the temperature and stirring at 90 ℃ for reacting for 6 hours to obtain the monostearyl fumarate; according to the detection product of Chinese pharmacopoeia CP2020 edition, the peak-off time RT14.310 of the fumaric acid monostearyl ester is shown in the detection map as figure 10.
(4) And filtering the solid isomerization catalyst in the separation system, then adding 1mol/L NaOH solution into the reaction system, stirring and reacting for 1h at the temperature of 55 ℃, cooling to 20 ℃ after the reaction is finished, filtering, washing the solid product with acetone and water in sequence, and drying to obtain white solid sodium stearyl fumarate. The yield is 91.6%, and the product purity adopts a non-aqueous titration method of CP2020, so that the result is 99.9%; the peak time RT14.658 of sodium stearyl fumarate, the detection pattern is shown in FIG. 11.
The particle size distribution diagram of the obtained sodium stearyl fumarate product is shown in fig. 12.
Example 4
The solid isomerization catalyst used in example 2 was recovered and reused, and the solid isomerization reaction was repeated for 10 times under the conditions of example 2, and then the recovered solid isomerization catalyst was added again to the aluminum chloride ethanol solution with the mass concentration of 10% and subjected to ultrasonic treatment for 4h to perform adsorption and fixation reaction, ethanol washing, and after vacuum drying at 80 ℃, the solid isomerization reaction was repeated for 10 times under the conditions of example 2, and the product yield results in the same time are shown in fig. 13. As can be seen from the results in fig. 13, the solid isomerization catalyst obtained in the present invention has good catalytic activity after being reused for 10 times, and can recover the initial catalytic activity after being activated.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such modifications are intended to be included in the scope of the present invention.
Claims (9)
1. A low-cost preparation method of a pharmaceutic adjuvant sodium stearyl fumarate is characterized by comprising the following preparation steps:
(1) Adding octadecanol and maleic anhydride into an organic solvent, heating to 90-130 ℃, and stirring for reaction to obtain maleic acid monostearyl ester;
(2) Adding a solid isomerization catalyst into the reaction system in the step (1), and continuously keeping the temperature for stirring and reacting at 90-130 ℃ to obtain the monostearyl fumarate;
(3) Filtering the solid isomerization catalyst in the separation system, then adding an alkali solution into the reaction system, stirring and reacting at the temperature of 35-55 ℃, and separating and purifying a product to obtain sodium stearyl fumarate;
the solid isomerization catalyst is sulfonated polystyrene microsphere loaded aluminum trichloride, and is prepared by the following method:
(a) Adding polystyrene microspheres into concentrated sulfuric acid, and carrying out sulfonation reaction at the temperature of 25-80 ℃ to obtain sulfonated polystyrene microspheres;
(b) And adding the sulfonated polystyrene microspheres into an aluminum chloride solution for ultrasonic treatment to carry out adsorption and fixation reaction, and washing and drying to obtain the sulfonated polystyrene microsphere-loaded aluminum trichloride.
2. The low-cost preparation method of sodium stearyl fumarate as a pharmaceutical adjuvant according to claim 1, which is characterized in that: the particle size of the polystyrene microsphere in the step (a) is 0.5 to 100 mu m; the aluminum chloride solution in the step (b) is an aluminum chloride ethanol solution with the mass concentration of 5-50%.
3. The low-cost preparation method of sodium stearyl fumarate as a pharmaceutical adjuvant according to claim 1, which is characterized in that: in the step (1), the charging molar ratio of the octadecanol to the maleic anhydride is 1 (1 to 1.2).
4. The low-cost preparation method of sodium stearyl fumarate as a pharmaceutical adjuvant according to claim 1, which is characterized in that: in the step (1), the organic solvent is selected from toluene or cyclohexane.
5. The low-cost preparation method of sodium stearyl fumarate as a pharmaceutical adjuvant according to claim 1, which is characterized in that: the addition amount of the solid isomerization catalyst in the step (2) is 5 to 50g/L.
6. The low-cost preparation method of sodium stearyl fumarate as a pharmaceutical adjuvant according to claim 1, which is characterized in that: the alkali solution in the step (3) is any one of sodium hydroxide, sodium carbonate and sodium bicarbonate solution.
7. The low-cost preparation method of sodium stearyl fumarate as a pharmaceutical adjuvant according to claim 1, which is characterized in that: the stirring reaction time in the step (1) is 4-6 h, the stirring reaction time in the step (2) is 4-6 h, and the stirring reaction time in the step (3) is 1-3 h.
8. The low-cost preparation method of sodium stearyl fumarate as a pharmaceutical adjuvant according to claim 1, which is characterized in that: the solid isomerization catalyst in the step (3) is recycled, or is repeatedly used after being repeatedly used for many times, the activity of the solid isomerization catalyst is reduced, and the solid isomerization catalyst is repeatedly used after being activated; the activating treatment process comprises the steps of adding the recovered solid isomerization catalyst into an aluminum chloride solution again for ultrasonic adsorption and fixation reaction, washing and drying.
9. The low-cost preparation method of sodium stearyl fumarate as a pharmaceutical adjuvant according to claim 1, which is characterized in that: and (3) cooling to below 30 ℃, filtering, washing and drying a solid product to obtain white solid sodium stearyl fumarate.
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| CN108586250A (en) * | 2018-06-29 | 2018-09-28 | 苏州东南药业股份有限公司 | A kind of sodium stearyl fumarate auxiliary material and preparation method thereof |
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