CN114736144B - Industrial preparation method of docusate calcium - Google Patents
Industrial preparation method of docusate calcium Download PDFInfo
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- CN114736144B CN114736144B CN202210455718.4A CN202210455718A CN114736144B CN 114736144 B CN114736144 B CN 114736144B CN 202210455718 A CN202210455718 A CN 202210455718A CN 114736144 B CN114736144 B CN 114736144B
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- 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
- C07C303/44—Separation; Purification
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
Abstract
The invention belongs to the technical field of pharmaceutical chemicals, and particularly relates to an industrial preparation method of docusate calcium. In the preparation method, maleic anhydride and 2-ethylhexanol are used as starting materials, p-toluenesulfonic acid is used for catalyzing and forming ester, then the ester and sodium bisulphite are sulfonated in an alcohol water solution, then calcium salt is prepared by one-pot boiling, a crude product of docusate calcium is obtained, and finally pure water is used for refining, so that a finished product of docusate calcium is obtained. Solves the residual problems of 2-ethylhexanol and sodium bisulphite, ensures that the refining yield of the docusate calcium reaches 95 percent, has short whole process route, high yield, reliable quality and low cost, is suitable for industrial production and has extremely high application value.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemicals, and particularly relates to an industrial preparation method of docusate calcium.
Background
Docusate calcium (Docusate calcium), chemical name 1, 4-di (2-ethylhexyl) succinate sulfonate calcium salt, i.e. 1,4-Bis (2-ethylhexyl) sulfosuccinate, calcium salt, CAS:128-49-4, molecular formula: C40H74CaO14S2, molecular weight: 883.22. it is used for treating constipation, and is used as laxative or stool softener. The drug effect of the docusate calcium is consistent with that of the docusate sodium, but the docusate sodium is a viscous product, is inconvenient to dry, store and transport, and is difficult to realize industrial production. The docusate calcium is a powdery solid, the product quality is easy to control, the transportation and the storage are convenient, and the docusate calcium can be prepared into various other dosage forms, thereby having wider prospect.
The prior art is mainly a preparation method of docusate sodium, and the preparation process of docusate calcium has not been reported yet. Under the action of inorganic acid or organic acid, maleic anhydride and 2-ethylhexanol are esterified, and the obtained di (2-ethyl) hexyl maleate and sodium bisulphite are sulfonated to obtain sodium docusate. The esterification reaction usually uses excessive 2-ethylhexanol, and the 2-ethylhexanol has high boiling point and poor water solubility, so that the 2-ethylhexanol is extremely difficult to remove cleanly. Even if the yield of di (2-ethyl) hexyl maleate is sacrificed and the amount of 2-ethylhexanol is reduced, the residue is inevitably caused by the esterification equilibrium reaction. In addition, docusate sodium has excellent water solubility and fat solubility, and purification is difficult, and especially when excessive sodium bisulphite is used, the removal of inorganic salt is a process difficulty.
In order to overcome the problems of the docusate sodium, the invention reports an industrial preparation method of high-purity docusate calcium, the docusate calcium is powdery solid, is convenient for post-treatment refining, drying, storage and transportation, is beneficial to product quality control, has extremely high market value and practical significance, and can replace the docusate sodium to realize industrialization.
Disclosure of Invention
The invention aims to overcome the defects in the preparation process of docusate sodium in the prior art and make up the blank of the domestic production process of docusate calcium.
For this purpose, the invention provides an industrial preparation method of docusate calcium, comprising the following steps:
(1) Esterification reaction: the maleic anhydride and excessive 2-ethylhexanol are condensed into maleic acid di (2-ethyl) hexyl ester under the catalysis of p-toluenesulfonic acid, after the reaction is finished, the maleic anhydride is supplemented, and the maleic acid di (2-ethyl) hexyl ester is obtained by reacting with residual 2-ethylhexanol, and the maleic acid mono (2-ethyl) hexyl ester impurity is removed by washing;
(2) Sulfonation reaction: sulfonation reaction is carried out on the maleic acid di (2-ethyl) hexyl ester obtained in the step (1) and sodium bisulphite, so as to obtain docusate sodium;
(3) Preparing calcium salt: directly reacting sodium docusate with calcium chloride to generate calcium docusate, concentrating after the reaction is finished, adding an organic solvent, filtering to remove salt, adding pure water, evaporating the organic solvent, crystallizing, and filtering to obtain a crude product of the calcium docusate;
(4) Refining and purifying: adding the crude docusate calcium into pure water for refining, and filtering to obtain pure docusate calcium.
Specifically, the esterification reaction in the step (1) is specifically: the molar ratio used is 1: (1.9-2.2) condensing maleic anhydride and 2-ethylhexanol into di (2-ethyl) hexyl maleate under the catalysis of p-toluenesulfonic acid, taking toluene as a solvent, adding 0.01-0.25 equivalent of maleic anhydride after the reaction is finished, reacting with residual 2-ethylhexanol to obtain mono (2-ethyl) hexyl maleate, and removing impurities of the mono (2-ethyl) hexyl maleate by using a washing solvent.
Specifically, the molar mass of the p-toluenesulfonic acid in the step (1) is 0.5-5% of maleic anhydride; the volume mass ratio of toluene to maleic anhydride is (0.5-2): 1.
specifically, the washing solvent in the step (1) includes at least one of water and an alkaline solution.
Specifically, the sulfonation reaction in the step (2) is specifically: the molar ratio was set to 1: (1.05-1.3) reflux reaction of di (2-ethyl) hexyl maleate and sodium bisulphite in alcohol-water mixed solvent, and ensuring complete sulfonation of the di (2-ethyl) hexyl maleate by central control to obtain sodium docusate.
Specifically, in the step (2), the volume ratio of alcohol to water in the alcohol-water mixed solvent is 1: (1-3); the alcohol in the alcohol-water mixed solvent comprises at least one of methanol, ethanol and isopropanol.
Specifically, the preparation of the calcium salt in the step (3) is specifically: reacting sodium docusate with calcium chloride at room temperature to generate calcium docusate, wherein the molar ratio of the calcium chloride to the sodium bisulphite in the step (2) is (0.5-1): 1, concentrating until the water content is 0-50% after the reaction is finished, adding an organic solvent for crystallization, filtering to remove salt, adding pure water into the filtrate, distilling to remove the organic solvent, crystallizing, and filtering to obtain a crude docusate calcium product.
Specifically, the organic solvent in the step (3) includes at least one of methanol, ethanol, isopropanol, acetone, acetonitrile and tetrahydrofuran.
Specifically, the volume-to-mass ratio of the organic solvent to the theoretical yield of docusate calcium in the step (3) is (1-10): 1, a step of; the volume ratio of the pure water to the organic solvent is (2-20): 1.
specifically, the refining and purifying in the step (4) specifically comprises the following steps: adding the crude docusate calcium into pure water for refining, wherein the mass volume ratio of the crude docusate calcium to the pure water is 1: (3-20), refluxing and pulping at 10-100 ℃ to disperse the product, and cooling and filtering to obtain the pure docusate calcium.
Compared with the prior art, the invention has the following advantages and beneficial effects:
(1) The industrial preparation method of the docusate calcium provided by the invention takes maleic anhydride and excessive 2-ethylhexanol as starting materials, under the catalysis of p-toluenesulfonic acid, maleic anhydride and 2-ethylhexanol can firstly generate maleic acid mono (2-ethyl) hexyl ester at room temperature, the reaction is easy to carry out, and monoester and 2-ethylhexanol are dehydrated at high temperature to generate maleic acid di (2-ethyl) hexyl ester. At this point the reaction reaches an equilibrium and there is no maleic anhydride in the system but there is still residual 2-ethylhexanol. In order to control the problem of 2-ethylhexanol residue, maleic anhydride is added at the reaction end point, so that the residual 2-ethylhexanol is changed into monoester in a mode of breaking the reaction balance, the reaction process is rapid and full, the generated maleic acid monoester (2-ethyl) hexyl ester is acidic, the water solubility is good, the maleic acid monoester is easily dissolved in an alkaline aqueous solution, the maleic acid anhydride can be removed by washing, and the problem of 2-ethylhexanol residue is successfully solved.
(2) The industrial preparation method of the docusate calcium provided by the invention reduces the feeding amount of sodium bisulphite as much as possible in the sulfonation reaction stage, adjusts the proportion of alcohol and water, and reduces the cost of raw materials and auxiliary materials. The preparation process of the sodium docusate and the calcium salt is carried out in a one-pot manner, and the sodium docusate directly reacts with the calcium chloride without post-treatment after the sodium docusate is completely reacted, so that the calcium salt is obtained. The calcium salt is easily dissolved in organic solvent, is difficult to dissolve in water, can remove most of water after concentration, and can separate out inorganic salt impurities after adding alcohol solution. And then refining and purifying in water to remove residual inorganic salt, thus obtaining the high-purity docusate calcium, wherein the product is powdery solid, and is easy to dry and post-treat.
(3) The industrial preparation method of the docusate calcium provided by the invention uses maleic anhydride and 2-ethylhexanol as starting materials, and obtains the high-purity docusate calcium through esterification, sulfonation, calcium salt preparation, refining and purification, and the whole process route is short, the yield is high, the quality is reliable, the cost is low, and the method is suitable for industrial production and has extremely high application value.
Detailed Description
The technical solutions of the present invention will be clearly and completely described in the following examples, and it is obvious that the described examples are only some examples of the present invention, but not all examples. Although representative embodiments of the present invention have been described in detail, those skilled in the art to which the invention pertains will appreciate that various modifications and changes can be made without departing from the scope of the invention. Accordingly, the scope of the invention should not be limited to the embodiments, but should be defined by the appended claims and equivalents thereof.
The invention provides an industrial preparation method of docusate calcium, which comprises the following steps:
(1) Esterification reaction: the molar ratio used is 1: (1.9-2.2), preferably 1:2.0, maleic anhydride and 2-ethylhexanol are condensed into di (2-ethyl) hexyl maleate under the catalysis of p-toluenesulfonic acid, the solvent is toluene, and the molar mass of the p-toluenesulfonic acid is 0.5-5 percent of maleic anhydride, preferably 1 percent; the volume mass ratio of toluene to maleic anhydride is (0.5-2): 1, preferably 1:1. stirring and dissolving the materials after feeding, heating, refluxing and separating water, and stopping heating after the internal temperature rises to 145 ℃ and no water is separated. After the reaction is finished, adding 0.01 to 0.25 equivalent of maleic anhydride, preferably 0.05 equivalent, continuously stirring and reacting for 0.5 to 1 hour, reacting with residual 2-ethylhexanol to obtain maleic acid mono (2-ethyl) hexyl ester, cooling to room temperature, washing with pure water, saturated sodium bicarbonate and pure water in sequence, and concentrating under reduced pressure to remove maleic acid mono (2-ethyl) hexyl ester impurities, thereby obtaining maleic acid di (2-ethyl) hexyl ester. The yield can reach 97 percent based on the initial maleic anhydride feeding amount.
(2) Sulfonation reaction: mixing the di (2-ethyl) hexyl maleate obtained in the step (1) with sodium bisulphite according to the weight ratio of 1: (1.05-1.3) in an alcohol-water mixed solvent, wherein the molar ratio is preferably 1:1.1. the volume ratio of alcohol to water in the alcohol-water mixed solvent is 1: (1-3), preferably 1:1.5, the alcohol in the alcohol-water mixed solvent comprises at least one of methanol, ethanol and isopropanol, preferably ethanol. And (3) carrying out reflux reaction until layering phenomenon does not exist, analyzing and controlling the residue of di (2-ethyl) hexyl maleate to meet the standard, and ensuring that the di (2-ethyl) hexyl maleate is sulfonated to obtain docusate sodium.
(3) Preparing calcium salt: reacting sodium docusate with calcium chloride at room temperature to form calcium docusate, preferably by reflux reaction, wherein the molar ratio of calcium chloride to sodium bisulphite in step (2) is (0.5-1): 1, preferably 0.6:1, the reaction time is more than 1 hour, preferably 2-3 hours. Concentrating until water content is 0-50%, adding organic solvent, stirring at room temperature for crystallization, filtering for desalting, adding pure water into filtrate, distilling for removing organic solvent, crystallizing, filtering and oven drying to obtain crude docusate calcium product with total yield of 92%. The organic solvent comprises at least one of methanol, ethanol, isopropanol, acetone, acetonitrile and tetrahydrofuran, preferably anhydrous ethanol and isopropanol, especially anhydrous ethanol. The volume mass ratio of the organic solvent to the theoretical yield of the docusate calcium is 1: (1-10), preferably 1: (1.5-3); the volume ratio of the pure water to the organic solvent is (2-20): 1, preferably (3-6): 1.
(4) Refining and purifying: adding the crude docusate calcium into the mixture with the mass-volume ratio of 1: refining in pure water of (3-20), and beating at 10-100deg.C for more than 0.5 hr, preferably at 40-50deg.C for 2-3 hr. Cooling, filtering, and drying the filter cake under reduced pressure to obtain the pure docusate calcium with the refining yield of about 95 percent.
The specific synthetic route is as follows:
the effect of the industrial production method of calcium docusate of the present invention is examined by the following specific examples.
Example 1:
the embodiment provides an industrial preparation method of docusate calcium, which comprises the following steps:
(1) Esterification reaction: in a 1000L reactor equipped with a water separator, mechanical stirring, reflux condenser and thermometer, 271kg (2.085 kmol) of 2-ethylhexanol, 102kg (1.041 kmol) of maleic anhydride, 100L of toluene, 2kg (0.012 kmol) of p-toluenesulfonic acid were added in this order with stirring, and heated to reflux. The internal temperature is gradually increased from 120 ℃ to 145 ℃, the water yield is collected and separated to a theoretical value, no water is distilled out, the water is continuously returned and separated for 0.5h, and the water separation is stopped. 5kg (0.051 kmol) of maleic anhydride was added and stirred for 0.5h. The reaction solution was cooled to room temperature, and was colorless or pale yellow. Washing with 400kg of pure water, 200kg of saturated sodium bicarbonate solution (2 times) and 400kg of pure water in sequence, and concentrating the organic phase under reduced pressure in a water bath at 70-80 ℃ to obtain 343.8kg (1.011 kmol) of pale yellow oily esterified material di (2-ethyl) hexyl maleate, wherein the GC purity is 98.6%, the 2-ethylhexanol content is 0.08%, and the yield is 97.1% based on the initial maleic anhydride feeding amount.
(2) Sulfonation reaction: into a 2000L reactor equipped with a reflux condenser and a thermometer, 343.8kg (1.011 kmol) of di (2-ethyl) hexyl maleate prepared in the step (1), 180kg of ethanol, 115.6kg (1.112 kmol) of sodium bisulphite and 340kg of pure water were sequentially added, heated to reflux, and reacted for 18 hours. The reaction solution turns yellow from white suspension to clear, and is sampled and analyzed, and the residue of di (2-ethyl) hexyl maleate is controlled to meet the standard, so that the sulfonation of the di (2-ethyl) hexyl maleate is ensured to obtain sodium docusate.
(3) Preparing calcium salt: 73.9kg (0.666 kmol) of calcium chloride was added to the sodium docusate prepared in step (2) at room temperature, and the mixture was refluxed for 3 hours to precipitate a large amount of white solid. Concentrating under reduced pressure, and controlling water content to be less than 50% to obtain viscous substance. 700L of absolute ethyl alcohol is added at room temperature, stirred for 0.5h to dissolve, inorganic salt is separated out, and the salt is removed by filtration. The filtrate was transferred to a kettle, and 700L of pure water was added to precipitate a white thick solid. Concentrating under reduced pressure, removing ethanol, supplementing 1000L pure water, stirring at room temperature, crystallizing for 3 hr, and filtering to obtain wet crude product. Vacuum drying at 50-60deg.C until water content is qualified to obtain 421.8kg (0.478 kmol) crude docusate calcium product with effective content of 98.6% and yield of 94.6%.
(4) Refining and purifying: 421.8kg (0.478 kmol) of docusate calcium as crude product was added to 1500L of purified water, heated to 40-50℃and stirred for 2h. Filtering at room temperature, vacuum drying the filter cake at 50-60deg.C until water content is qualified to obtain 401.5kg (0.455 kmol) of pure docusate calcium with effective content up to 99.3%, clarity detection and ignition residue both meet the standard, and refining yield is 95.2%.
The foregoing examples are merely illustrative of the present invention and are not intended to limit the scope of the present invention, and all designs that are the same or similar to the present invention are within the scope of the present invention.
Claims (10)
1. An industrial preparation method of docusate calcium is characterized by comprising the following steps:
(1) Esterification reaction: the molar ratio used is 1: the maleic anhydride of the (2.085/1.041) -2.2) is condensed with 2-ethylhexanol under the catalysis of p-toluenesulfonic acid to form di (2-ethyl) hexyl maleate, after the reaction is finished, the maleic anhydride is supplemented, and the maleic anhydride reacts with the residual 2-ethylhexanol to obtain mono (2-ethyl) hexyl maleate, and the mono (2-ethyl) hexyl maleate impurity is removed by washing;
(2) Sulfonation reaction: sulfonation reaction is carried out on the maleic acid di (2-ethyl) hexyl ester obtained in the step (1) and sodium bisulphite, so as to obtain docusate sodium;
(3) Preparing calcium salt: directly reacting sodium docusate with calcium chloride to generate calcium docusate, concentrating after the reaction is finished, adding an organic solvent, filtering to remove salt, adding pure water, evaporating the organic solvent, crystallizing, and filtering to obtain a crude product of the calcium docusate;
(4) Refining and purifying: adding the crude docusate calcium into pure water for refining, and filtering to obtain pure docusate calcium.
2. The industrial process for the preparation of docusate calcium according to claim 1, wherein the esterification reaction of step (1) is specifically: the molar ratio used is 1: the maleic anhydride and 2-ethylhexanol of (2.085/1.041) -2.2) are condensed into di (2-ethyl) hexyl maleate under the catalysis of p-toluenesulfonic acid, the solvent is toluene, 0.01-0.25 equivalent of maleic anhydride is added after the reaction is finished, the maleic anhydride reacts with residual 2-ethylhexanol to obtain mono (2-ethyl) hexyl maleate, and a washing solvent is used for removing impurities of the mono (2-ethyl) hexyl maleate.
3. The industrial process for the preparation of docusate calcium according to claim 2, wherein: the molar mass of the p-toluenesulfonic acid in the step (1) is 0.5-5% of maleic anhydride; the volume mass ratio of toluene to maleic anhydride is (0.5-2): 1.
4. the industrial process for the preparation of docusate calcium according to claim 2, wherein: the washing solvent in the step (1) comprises at least one of water and alkaline solution.
5. The industrial process for the preparation of docusate calcium according to claim 1, wherein the sulphonation reaction of step (2) is specifically: the molar ratio was set to 1: (1.05-1.3) reflux reaction of di (2-ethyl) hexyl maleate and sodium bisulphite in alcohol-water mixed solvent, and ensuring complete sulfonation of the di (2-ethyl) hexyl maleate by central control to obtain sodium docusate.
6. The industrial process for the preparation of docusate calcium according to claim 5, wherein: in the step (2), the volume ratio of alcohol to water in the alcohol-water mixed solvent is 1: (1-3); the alcohol in the alcohol-water mixed solvent comprises at least one of methanol, ethanol and isopropanol.
7. The industrial process for the preparation of docusate calcium according to claim 1, wherein the preparation of calcium salt in step (3) is specifically: reacting sodium docusate with calcium chloride at room temperature to generate calcium docusate, wherein the molar ratio of the calcium chloride to the sodium bisulphite in the step (2) is (0.5-1): 1, concentrating until the water content is 0-50% after the reaction is finished, adding an organic solvent for crystallization, filtering to remove salt, adding pure water into the filtrate, distilling to remove the organic solvent, crystallizing, and filtering to obtain a crude docusate calcium product.
8. The industrial process for the preparation of docusate calcium according to claim 7, wherein: the organic solvent in the step (3) comprises at least one of methanol, ethanol, isopropanol, acetone, acetonitrile and tetrahydrofuran.
9. The industrial process for the preparation of docusate calcium according to claim 7, wherein: the volume-mass ratio of the organic solvent to the docusate calcium in the step (3) is (1-10): 1, a step of; the volume ratio of the pure water to the organic solvent is (2-20): 1.
10. the industrial production method of docusate calcium according to claim 1, wherein the refining and purifying in the step (4) is specifically: adding the crude docusate calcium into pure water for refining, wherein the mass volume ratio of the crude docusate calcium to the pure water is 1: (3-20), refluxing and pulping at 10-100 ℃ to disperse the product, and cooling and filtering to obtain the pure docusate calcium.
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