Docusate sodium bulk drug synthesis process

Abstract

The invention is applicable to the technical field of drug synthesis, and relates to a docusate sodium bulk drug synthesis process, which comprises the following steps: (1) monoester reaction; and (2) carrying out diester reaction. The process disclosed by the invention has the beneficial effects that the production rate of the diisooctyl maleate is improved, and the content of the docusate sodium product is improved; the operation process is simplified, and the production cost is saved; in addition, low alcohols are not adopted, so that genotoxic impurities are avoided, the safety of the docusate sodium product is ensured, and the quality of the product is improved.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical synthesis, and more specifically, it relates to a synthesis process of sodium dioctyl sulfosuccinate bulk drug. Background Art

[0002] Sodium dioctyl sulfosuccinate, also known as sodium bis(2-ethylhexyl) sulfosuccinate, is a digestive drug and an anionic surfactant. After oral administration, it promotes the entry of water and fat-like substances into feces in the intestine, and lubricates the intestine physically to achieve the effect of laxation. Its action is mild and it is suitable for patients with weak defecation ability such as those with anal and rectal diseases or postoperative patients. It has been widely used in the fields of textile, printing and dyeing, coating, papermaking, medicine, pesticide, daily chemical industry, etc.

[0003] The synthesis of sodium dioctyl sulfosuccinate usually adopts a two-step method. The first step is to carry out an esterification reaction between maleic anhydride and isooctanol under the action of an acid; the second step is to carry out a sulfonation reaction between the obtained ester and sodium bisulfite in an aqueous solution to obtain sodium dioctyl sulfosuccinate. Among them, the patent with the application number CN201510278926.1 discloses a method for preparing high-purity sodium dioctyl sulfosuccinate; it discloses an esterification step including maleic anhydride and isooctanol, and a sulfonation step of the obtained diester and sodium bisulfite in an aqueous solution; both the esterification and sulfonation steps are completed under nitrogen protection, and the esterification step is carried out in two stages: pre-esterification at 80-95°C and vacuum reaction at 115-125°C; this method not only obtains high-purity sodium dioctyl sulfosuccinate, but also has a simple process, few toxic solvents, no pollution, and high yield. However, the above method has the following problems: 1. In order to reduce the impurity removal cost, the addition amount of isooctanol is reduced during the esterification process in the above method, but this will lead to a low content of bis(2-ethylhexyl) maleate obtained by the esterification reaction and a small content of octyl maleate, thereby reducing the production amount of the subsequent sodium dioctyl sulfosuccinate product; 2. After the vacuum reaction is completed in the above method, it is washed with saturated sodium carbonate, and then dried with anhydrous magnesium sulfate subsequently; the use of saturated sodium carbonate for washing in the above method will cause emulsification, resulting in difficult separation of water and the organic phase, poor washing effect, and thus residual sodium salts in the organic phase, which has an obstructive effect on the reaction for generating sodium dioctyl sulfosuccinate, resulting in a low content of the sodium dioctyl sulfosuccinate product; when using anhydrous magnesium sulfate for drying, a large amount of it is required, increasing the cost, and it cannot be reused. At the same time, it will cake after absorbing water, making it difficult to handle, and there will be residual materials on its surface, causing material waste; 3. After the sulfonation reaction in the above method, a lower alcohol is added, and the lower alcohol includes methanol and ethanol, and it is stirred and dissolved. The above lower alcohol and sulfonic acid group (p-toluenesulfonic acid) are likely to generate genotoxic impurities, which have a serious impact on the human body; and a n-hexane solvent is introduced in the subsequent purification reaction in the above method, increasing the variety and quantity of solvents used, resulting in residues in the sodium dioctyl sulfosuccinate product and affecting the quality of the product. Summary of the Invention

[0004] Aiming at the deficiencies of the existing technology, the purpose of the present invention is to provide a sodium dioctyl sulfosuccinate synthesis process that simplifies the operation process, improves the productivity of diisooctyl maleate, and improves the product quality.

[0005] To achieve the above object, the present invention provides the following technical solution: A synthesis process of sodium dioctyl sulfosuccinate raw material medicine, which includes an esterification process and a sulfonation process. Both the esterification process and the sulfonation process are completed under nitrogen protection. The esterification process includes the following steps: (1) Monoester reaction: Add isooctanol to the reaction kettle, stir and heat up to 25 °C, then add maleic anhydride, and stir and react for 20 - 40 min under normal pressure, where the molar ratio of maleic anhydride to isooctanol is 1:2.0 - 2.5; (2) Diester reaction: Then add p-toluenesulfonic acid to step (1), stir and heat up to 80 - 90 °C, stir and react for 20 - 40 min under normal pressure, then start vacuum distillation, heat to reflux until the liquid level in the reaction kettle does not change; At 3 h, 3.5 h, and 4.5 h of vacuum distillation, add isooctanol to the reaction kettle respectively until the liquid level does not change, and then terminate the reaction; The molar ratio of maleic anhydride to the total isooctanol after 3 additions is 1:2.5 - 3.5.

[0006] Further, the molar ratio of maleic anhydride to p-toluenesulfonic acid is 1:0.01 - 0.02.

[0007] Further, the conditions of vacuum distillation in step (2): the temperature is 100 - 110 °C, and the pressure is -0.6~-0.8 MPa.

[0008] Further, the addition amount of isooctanol added each time in step (2) is 1 / 10 of the total added amount of isooctanol.

[0009] Further, it also includes the following steps: (3) Washing treatment: Cool the reaction solution completed in step (2) to 0 - 5 °C, then dropwise add sodium hydroxide solution, stir and adjust the pH value to 7.5 ± 0.5; Then add purified water to the reaction kettle for cleaning, let it stand for stratification, and separate the lower aqueous phase to obtain the organic phase; (4) Removal of isooctanol: Add deionized water to the organic phase in step (3), and the mass ratio of the organic phase to deionized water is 1:0.8 - 1.0; Then heat to 88 - 93 °C for distillation until the liquid level in the reaction kettle does not change, and obtain diisooctyl maleate.

[0010] Further, the purification water washing in step (3) is repeated 2 - 3 times.

[0011] Further, repeat step (4) 3 - 4 times.

[0012] Further, the sulfonation process includes the following steps: (a) Sulfonation reaction: Preheat the reaction kettle to 50 - 60°C, then add the diisooctyl maleate, sodium docusate, and sodium bisulfite obtained in step (4) into the reaction kettle, stir and heat up to 92 - 105°C until the solution in the reaction kettle is completely solidified to obtain a solidified product; (b) Cleaning and filtration: Cool the solidified product in step (a) to 25 - 30°C, then add ethyl acetate solvent thereto until the solidified product is completely dissolved to form a solution; then add deionized water to the solution, stir for 30 min and then let it stand for stratification to remove the lower aqueous phase; then add activated carbon to the remaining organic phase for decolorization, stir for 2 - 3 h, and finally obtain a sodium docusate solution product through filtration.

[0013] Further, the mass ratio of the diisooctyl maleate, the sodium docusate, and the sodium bisulfite in step (a) is 1:0.08 - 0.12:0.28 - 0.35.

[0014] Further, it further includes the following steps: (c) Refining: Wash with an aqueous sodium bicarbonate solution with a mass concentration of 2%, then let it stand for stratification to remove the aqueous phase, concentrate the remaining organic phase at a temperature of 55 - 60°C for 2 - 3 h, then dry at a temperature of 50 - 75°C until the water content is 2%, and finally obtain a sodium docusate product through pulverization.

[0015] The advantages of the present invention are: 1. In the process disclosed by the present invention, isooctanol is added during the esterification process to improve the yield and purity of diisooctyl maleate.

[0016] 2. In the process disclosed by the present invention, the pH value is adjusted to 7.5 ± 0.5 by adding sodium hydroxide during the washing process and directly washed with purified water without using saturated sodium carbonate for washing, avoiding the situation that sodium salts remain in the organic phase, thus ensuring the smooth progress of the subsequent reaction of sodium docusate and improving the content of the sodium docusate product; at the same time, the use of anhydrous magnesium sulfate for drying is also avoided, reducing the use of anhydrous magnesium sulfate material, as well as the subsequent drying time and filtration process, simplifying the operation process and saving production costs.

[0017] 3. In the process disclosed by the present invention, during the removal of isooctanol, it is fully mixed with deionized water and then heated and distilled to remove the excess isooctanol. The removal process is simple and the removal effect is good.

[0018] 4. In the process disclosed by the present invention, only ethyl acetate solvent is added for dissolution after the sulfonation process is completed. Therefore, the types of solvent residues in the produced sodium docusate product are single, that is, the content of solvent residues is reduced; and lower alcohols are not used in the present invention, thereby avoiding the generation of genotoxic impurities, that is, avoiding the esterification reaction between lower alcohols and sulfonic acid substances such as p-toluenesulfonic acid to generate sulfonic acid esters, and ethyl acetate itself does not have genotoxicity, ensuring the safety of the sodium docusate product, and thereby improving the quality of the product.

[0019] 5. In the process disclosed by the present invention, in the refining step during the sulfonation process, drying is carried out in a vacuum drying oven at a temperature of 50-75 °C, which greatly shortens the drying time compared with using hot air circulation drying. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 It is a process flow chart of the present invention. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0021] It should be noted that, without conflict, the embodiments in the present application and the features in the embodiments can be combined with each other. The present invention will be described in detail below with reference to the drawings and in conjunction with the embodiments.

[0022] It should be pointed out that, unless otherwise specified, all technical and scientific terms used in the present application have the same meaning as commonly understood by those of ordinary skill in the technical field to which the present application belongs.

[0023] In the present invention, unless otherwise stated, the orientations such as "upper and lower" are usually in the directions shown in the drawings, or in the vertical, perpendicular or gravitational directions; similarly, for ease of understanding and description, "left and right" are usually left and right as shown in the drawings; "inside and outside" refer to inside and outside the contours of the respective components, but the above orientation terms do not limit the present invention.

[0024] Example 1: As Figure 1 shown, a synthesis process of sodium docusate raw material medicine includes an esterification process and a sulfonation process, and both the esterification process and the sulfonation process are completed under nitrogen protection, wherein the esterification process includes the following steps: (1) Monoester reaction: Add 42 Kg of isooctanol to the reaction kettle, stir and heat up to 25 °C, then add 15 Kg of maleic anhydride, and stir and react at normal pressure for 20-40 min.

[0025] (2) Diester reaction: Then, 0.28 kg of p-toluenesulfonic acid was added to step (1), and the mixture was stirred and heated to 80 - 90 °C. Under atmospheric pressure, the mixture was stirred and reacted for 20 - 40 min. Then, vacuum distillation was started, with the temperature being 100 - 110 °C and the pressure being -0.6 to -0.8 MPa. It was heated to reflux until there was no change in the liquid level in the reaction kettle; at 3 h, 3.5 h, and 4.5 h of vacuum distillation, 4 Kg of isooctanol was added to the reaction kettle respectively; after there was no change in the liquid level, the reaction was terminated.

[0026] (3) Washing treatment: The reaction solution completed in step (2) was cooled to 0 - 5 °C, and then sodium hydroxide solution was added dropwise while stirring to adjust the pH value to 7.5 ± 0.5; then, purified water was added to the reaction kettle for washing, and after standing and separating layers, the lower aqueous phase was separated to obtain the organic phase; the purified water washing was repeated 2 - 3 times.

[0027] (4) Removal of isooctanol: 45 Kg of deionized water was added to the organic phase in step (3); then, it was heated to 88 - 93 °C for distillation until there was no change in the liquid level in the reaction kettle, and the above steps were repeated 3 - 4 times to obtain 50 Kg of diisooctyl maleate, with a yield of 95.5% and a purity of 99.2%.

[0028] The sulfonation process includes the following steps: (a) Sulfonation reaction: The reaction kettle was preheated to 50 - 60 °C, and then 49 Kg of diisooctyl maleate, 5 Kg of sodium dioctyl sulfosuccinate, and 17.4 Kg of sodium bisulfite obtained in step (4) were added to the reaction kettle. The mixture was stirred and heated to 92 - 105 °C until the solution in the reaction kettle was completely solidified to obtain a solidified product.

[0029] (b) Washing and filtration: The solidified product in step (a) was cooled to 25 - 30 °C, and then ethyl acetate solvent was added until the solidified product was completely dissolved to form a solution; then, deionized water was added to the solution, and after stirring for 30 min, it was allowed to stand and separate layers, and the lower aqueous phase was removed; then, activated carbon was added to the remaining organic phase for decolorization, and it was stirred for 2 - 3 h. Finally, a sodium dioctyl sulfosuccinate solution product was obtained through filtration.

[0030] (c) Refining: A 2% aqueous sodium bicarbonate solution was added for washing, and after standing and separating layers, the aqueous phase was removed. The remaining organic phase was concentrated at 55 - 60 °C for 2 - 3 h, and then dried in a vacuum drying oven at 50 - 75 °C until the water content was 2%, and the drying time was 36 - 48 h. Finally, 63 Kg of sodium dioctyl sulfosuccinate product was obtained through pulverization, with a yield of 91.1% and a purity of 99.8%.

[0031] Example 2: As Figure 1As shown in the figure, a synthetic process for sodium dioctyl sulfosuccinate API, which includes an esterification process and a sulfonation process. Both the esterification process and the sulfonation process are completed under nitrogen protection. The esterification process includes the following steps: (1) Monoester reaction: Add 44 Kg of isooctanol to the reaction kettle, stir and heat up to 25 °C, then add 15 Kg of maleic anhydride, and stir and react for 20 - 40 min under normal pressure.

[0032] (2) Diester reaction: Then add 0.3 Kg of p-toluenesulfonic acid to step (1), stir and heat up to 80 - 90 °C, stir and react for 20 - 40 min under normal pressure, and then start vacuum distillation, where the temperature is 100 - 110 °C and the pressure is -0.6 ~ -0.8 MPa, heat to reflux until the liquid level in the reaction kettle remains unchanged; At 3 h, 3.5 h, and 4.5 h of vacuum distillation, add 4 Kg of isooctanol to the reaction kettle respectively; After the liquid level remains unchanged, terminate the reaction.

[0033] (3) Washing treatment: Cool the reaction solution completed in step (2) to 0 - 5 °C, then dropwise add sodium hydroxide solution, stir and adjust the pH value to 7.5 ± 0.5; Then add purified water to the reaction kettle for cleaning, let it stand and separate layers, and separate the lower aqueous phase to obtain the organic phase; The purified water cleaning is repeated 2 - 3 times.

[0034] (4) Removal of isooctanol: Add 45 Kg of deionized water to the organic phase in step (3); Then heat to 88 - 93 °C for distillation until the liquid level in the reaction kettle remains unchanged, repeat the above steps 3 - 4 times to obtain 51 Kg of diisooctyl maleate, with a yield of 98.8% and a purity of 99.5%.

[0035] The sulfonation process includes the following steps: (a) Sulfonation reaction: Preheat the reaction kettle to 50 - 60 °C, then add 50 Kg of diisooctyl maleate, 5 Kg of sodium dioctyl sulfosuccinate, and 17.7 Kg of sodium bisulfite obtained in step (4) to the reaction kettle, stir and heat up to 92 - 105 °C until the solution in the reaction kettle is completely solidified to obtain a solidified product.

[0036] (b) Cleaning and filtration: Cool the solidified product in step (a) to 25 - 30 °C, then add ethyl acetate solvent to it until the solidified product is completely dissolved to form a solution; Then add deionized water to the solution, stir for 30 min and then let it stand and separate layers, remove the lower aqueous phase; Then add activated carbon to the remaining organic phase for decolorization, stir for 2 - 3 h, and finally obtain a sodium dioctyl sulfosuccinate solution product through filtration.

[0037] (c) Refining: Wash with an aqueous sodium bicarbonate solution with a mass concentration of 2%, then let it stand for layer separation to remove the aqueous phase. The remaining organic phase is concentrated at a temperature of 55 - 60°C for 2 - 3 h, and then dried in a vacuum drying oven at a temperature of 50 - 75°C until the water content is 2%, and the drying time is 36 - 48 h. Finally, it is pulverized to obtain 65 Kg of sodium docusate product, with a yield of 94.1% and a purity of 99.7%.

[0038] Example 3: As Figure 1 shown, a synthetic process for sodium docusate raw material medicine, which includes an esterification process and a sulfonation process. Both the esterification process and the sulfonation process are completed under nitrogen protection. The esterification process includes the following steps: (1) Monoester reaction: Add 46 Kg of isooctanol to the reaction kettle, stir and heat up to 25°C, then add 15 Kg of maleic anhydride, and stir and react at normal pressure for 20 - 40 min.

[0039] (2) Diester reaction: Then add 0.31 kg of p-toluenesulfonic acid to step (1), stir and heat up to 80 - 90°C, stir and react at normal pressure for 20 - 40 min, and then start vacuum distillation, where the temperature is 100 - 110°C and the pressure is -0.6 to -0.8 MPa, heat to reflux until the liquid level in the reaction kettle does not change; at 3 h, 3.5 h, and 4.5 h of vacuum distillation, add 5 Kg of isooctanol to the reaction kettle respectively; after the liquid level does not change, terminate the reaction.

[0040] (3) Washing treatment: Cool the reaction solution completed in step (2) to 0 - 5°C, then dropwise add sodium hydroxide solution, stir and adjust the pH value to 7.5 ± 0.5; then add purified water to the reaction kettle for cleaning, let it stand for layer separation, and separate the lower aqueous phase to obtain the organic phase; the purified water cleaning is repeated 2 - 3 times.

[0041] (4) Removal of isooctanol: Add 45 Kg of deionized water to the organic phase in step (3); then heat to 88 - 93°C for distillation until the liquid level in the reaction kettle does not change, and repeat the above steps 3 - 4 times to obtain 52 Kg of diisooctyl maleate, with a yield of 98.3% and a purity of 99.0%.

[0042] The sulfonation process includes the following steps: (a) Sulfonation reaction: Preheat the reaction kettle to 50 - 60°C, then add 50 Kg of diisooctyl maleate, 5 Kg of sodium docusate, and 17.8 Kg of sodium bisulfite obtained in step (4) to the reaction kettle, stir and heat up to 92 - 105°C until the solution in the reaction kettle is completely solidified to obtain a solidified product.

[0043] (b)Washing and filtration: Cool the solidified product in step (a) to 25 - 30 °C, then add ethyl acetate solvent thereto until the solidified product is completely dissolved to form a solution; then add deionized water to the solution, stir for 30 min and then let it stand for layering, and remove the lower aqueous phase; then add activated carbon to the remaining organic phase for decolorization, stir for 2 - 3 h, and finally obtain the sodium dioctyl sulfosuccinate solution product through filtration.

[0044] (c)Refining: Wash with an aqueous sodium bicarbonate solution with a mass concentration of 2%, then let it stand for layering to remove the aqueous phase, concentrate the remaining organic phase at a temperature of 55 - 60 °C for 2 - 3 h, then dry it in a vacuum drying oven at a temperature of 50 - 75 °C until the water content is 2%, and the drying time is 36 - 48 h. Finally, obtain 64 - 67 Kg of sodium dioctyl sulfosuccinate product through pulverization, with a yield of 92.6% - 97.4% and a purity of 99.8%.

[0045] Example 4: As Figure 1 shown, a synthesis process of sodium dioctyl sulfosuccinate raw material drug, which includes an esterification process and a sulfonation process, and both the esterification process and the sulfonation process are completed under nitrogen protection. The esterification process includes the following steps: (1)Monoester reaction: Add 48 Kg of isooctanol to the reaction kettle, stir and heat up to 25 °C, then add 15 Kg of maleic anhydride, and stir and react at normal pressure for 20 - 40 min.

[0046] (2)Diester reaction: Then add 0.35 kg of p-toluenesulfonic acid to step (1), stir and heat up to 80 - 90 °C, stir and react at normal pressure for 20 - 40 min, then start vacuum distillation, where the temperature is 100 - 110 °C and the pressure is -0.6 to -0.8 MPa, heat to reflux until the liquid level in the reaction kettle remains unchanged; at 3 h, 3.5 h and 4.5 h of vacuum distillation, add 5 Kg of isooctanol to the reaction kettle respectively; after the liquid level remains unchanged, terminate the reaction.

[0047] (3)Washing treatment: Cool the reaction solution completed in step (2) to 0 - 5 °C, then dropwise add sodium hydroxide solution, stir and adjust the pH value to 7.5 ± 0.5; then add purified water to the reaction kettle for cleaning, let it stand for layering, and separate out the lower aqueous phase to obtain the organic phase; the purified water cleaning is repeated 2 - 3 times.

[0048] (4)Removing isooctanol: Add 45 Kg of deionized water to the organic phase in step (3); then heat to 88 - 93 °C for distillation until the liquid level in the reaction kettle remains unchanged, repeat the above steps 3 - 4 times to obtain 51 Kg of diisooctyl maleate, with a yield of 96.3% and a purity of 98.9%.

[0049] The sulfonation process includes the following steps: (a) Sulfonation reaction: Preheat the reaction kettle to 50 - 60°C, then add 50 Kg of diisooctyl maleate, 5 Kg of sodium docusate, and 17.8 Kg of sodium bisulfite obtained in step (4) into the reaction kettle, stir and heat up to 92 - 105°C until the solution in the reaction kettle is completely solidified to obtain a solidified product.

[0050] (b) Cleaning and filtration: Cool the solidified product in step (a) to 25 - 30°C, then add ethyl acetate solvent thereto until the solidified product is completely dissolved to form a solution; then add deionized water to the solution, stir for 30 min and then let it stand for phase separation to remove the lower aqueous phase; then add activated carbon to the remaining organic phase for decolorization, stir for 2 - 3 h, and finally obtain a sodium docusate solution product through filtration.

[0051] (c) Refining: Wash with an aqueous sodium bicarbonate solution with a mass concentration of 2%, then let it stand for phase separation to remove the aqueous phase, concentrate the remaining organic phase at a temperature of 55 - 60°C for 2 - 3 h, then dry it in a vacuum drying oven at a temperature of 50 - 75°C until the water content is 2%, the drying time is 36 - 48 h, and finally obtain 64 Kg of sodium docusate product through pulverization, with a yield of 99.7% and a purity of 99.9%.

[0052] Comparative example 1: The overall method is the same as that of Example 1, the difference is that in the double - ester reaction of step (2), isooctanol is not supplemented; finally, 42 Kg of diisooctyl maleate is obtained, with a yield of 68.1% and a purity of 85%.

[0053] Comparative example 2: The overall method is the same as that of Example 1, the difference is that in the double - ester reaction of step (2), only 4 Kg of isooctanol is supplemented when vacuum distillation is carried out for 3 h; finally, 44 Kg of diisooctyl maleate is obtained, with a yield of 73.9% and a purity of 88%.

[0054] Comparative example 3: The overall method is the same as that of Example 1, the difference is that in the double - ester reaction of step (2), only 4 Kg of isooctanol is supplemented when vacuum distillation is carried out for 3.5 h; finally, 45 Kg of diisooctyl maleate is obtained, with a yield of 74.7% and a purity of 87%.

[0055] Comparative example 4: The overall method is the same as that of Example 1, the difference is that in the double - ester reaction of step (2), only 4 Kg of isooctanol is supplemented when vacuum distillation is carried out for 4 h; finally, 45 Kg of diisooctyl maleate is obtained, with a yield of 76.1% and a purity of 88%.

[0056] Comparative Example 5: The overall method is the same as that of Example 1, except that in the diester reaction of step (2), 4 Kg of isooctanol is added during the vacuum distillation for 3 h; 4 Kg of isooctanol is added during the vacuum distillation for 3.5 h; finally, 47 Kg of diisooctyl maleate is obtained, with a yield of 82.5% and a purity of 92%.

[0057] Comparative Example 6: The overall method is the same as that of Example 1, except that in the diester reaction of step (2), 4 Kg of isooctanol is added during the vacuum distillation for 3 h; 4 Kg of isooctanol is added during the vacuum distillation for 4 h; finally, 48 Kg of diisooctyl maleate is obtained, with a yield of 83.4% and a purity of 91%.

[0058] Comparative Example 7: The overall method is the same as that of Example 1, except that in the diester reaction of step (2), 4 Kg of isooctanol is added during the vacuum distillation for 3.5 h; 4 Kg of isooctanol is added during the vacuum distillation for 4 h; finally, 46 Kg of diisooctyl maleate is obtained, with a yield of 79.0% and a purity of 90%.

[0059] Comparative Example 8: The overall method is the same as that of Example 1, except that in the diester reaction of step (2), 8 Kg of isooctanol is added during the vacuum distillation for 3 h; 4 Kg of isooctanol is added during the vacuum distillation for 3.5 h; finally, 49 Kg of diisooctyl maleate is obtained, with a yield of 86.1% and a purity of 92%.

[0060] Comparative Example 9: The overall method is the same as that of Example 1, except that in the diester reaction of step (2), 8 Kg of isooctanol is added during the vacuum distillation for 3.5 h; 4 Kg of isooctanol is added during the vacuum distillation for 4 h; finally, 48 Kg of diisooctyl maleate is obtained, with a yield of 84.2% and a purity of 91.8%.

[0061] It can be seen from the above Example 1 and Comparative Examples 1-4 that by adding isooctanol to the reaction kettle during the vacuum distillation for 3 h, 3.5 h and 4.5 h respectively, the yield and purity of diisooctyl maleate can be effectively improved. And it can be seen from Comparative Examples 5-7 that adding twice is more effective in improving the yield and purity of diisooctyl maleate than adding once in Comparative Examples 1-4. At the same time, in Comparative Examples 8-9, adding isooctanol twice, with one time adding more isooctanol, does not improve the yield and purity of diisooctyl maleate obtained compared with adding three times in Example 1. In summary, in the process disclosed in the present invention, adding isooctanol three times during the esterification process effectively improves the yield and purity of diisooctyl maleate.

[0062] Comparative Example 10: The overall method is the same as that of Example 1, except that in the refining step (c), hot air circulation drying is used, the temperature of the hot air is 50-75 °C until the moisture content is 2%, and the drying time is 8-12 days. The drying time is much longer than that in the vacuum drying oven in Example 1. Therefore, in the process disclosed in the present invention, by using drying at a temperature of 50-75 °C in a vacuum drying oven in the refining step during the sulfonation process, compared with using hot air circulation drying, the drying time is greatly shortened.

[0063] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. For those skilled in the art, the present invention can have various changes and modifications. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

[0064] The above is only the preferred embodiment of the present invention, and the protection scope of the present invention is not limited to the above embodiments. All technical solutions within the idea of the present invention belong to the protection scope of the present invention. It should be pointed out that for those of ordinary skill in the art, several improvements and refinements made without departing from the principle of the present invention should also be regarded as the protection scope of the present invention.

Claims

1. A synthesis process of docusate sodium bulk drug, comprising an esterification process and a sulfonation process, wherein the esterification process and the sulfonation process are both completed under nitrogen protection, characterized in that: The esterification process includes the following steps: (1) Monoester reaction: add isooctyl alcohol to the reaction kettle, stir and heat to 25°C, then add maleic anhydride, stir and react for 20-40 minutes under normal pressure, wherein the molar ratio of maleic anhydride to isooctyl alcohol is 1:2.0-2.5; (2) Diester reaction: p-toluenesulfonic acid is then added to the reaction mixture in step (1), and the mixture is heated to 80-90°C with stirring. The mixture is reacted for 20-40 minutes under normal pressure with stirring, and then vacuum distillation is started and the mixture is heated to reflux until the liquid level in the reactor does not change. After vacuum distillation for 3 hours, 3.5 hours and 4.5 hours, isooctyl alcohol is added to the reactor respectively until the liquid level does not change, and the reaction is terminated. The molar ratio of maleic anhydride to the total isooctyl alcohol after three additions is 1:2.5-3.

5.

2. A synthesis process of docusate sodium bulk drug according to claim 1, characterized in that: The molar ratio of the maleic anhydride to the p-toluenesulfonic acid is 1:0.01-0.

02.

3. A synthesis process of docusate sodium bulk drug according to claim 1, characterized in that: The conditions for the reduced pressure distillation in step (2) are: temperature of 100-110° C. and pressure of -0.6 to -0.8 MPa.

4. A synthesis process of docusate sodium bulk drug according to claim 1, characterized in that: The amount of isooctyl alcohol added each time in step (2) is 1 / 10 of the total amount of isooctyl alcohol added.

5. A synthesis process of docusate sodium bulk drug according to claim 1, characterized in that: It also includes the following steps: (3) Washing treatment: the reaction solution after the reaction in step (2) is cooled to 0-5°C, and then a sodium hydroxide solution is added dropwise, and the pH value is adjusted to 7.5±0.5 by stirring; then purified water is added to the reaction kettle for washing, and the reaction mixture is allowed to stand for stratification, and the lower aqueous phase is separated to obtain an organic phase; (4) Removing isooctyl alcohol: adding deionized water to the organic phase in step (3), wherein the mass ratio of the organic phase to the deionized water is 1:0.8-1.0; then heating to 88-93° C. for distillation until the liquid level in the reactor does not change, thereby obtaining diisooctyl maleate.

6. A synthesis process of docusate sodium bulk drug according to claim 5, characterized in that: The purified water washing in step (3) is repeated 2-3 times.

7. A synthesis process of docusate sodium bulk drug according to claim 5, characterized in that: Repeat step (4) 3-4 times.

8. A synthesis process of docusate sodium bulk drug according to any one of claims 5-7, characterized in that: The sulfonation process comprises the following steps: (a) Sulfonation reaction: preheat the reactor to 50-60°C, then add the diisooctyl maleate, docusate sodium and sodium bisulfite obtained in step (4) into the reactor, stir and heat to 92-105°C until the solution in the reactor is completely solidified to obtain a solidified product; (b) Cleaning and filtration: The solidified material in step (a) is cooled to 25-30° C., and then ethyl acetate solvent is added thereto until the solidified material is completely dissolved to form a solution; deionized water is then added to the solution, and the solution is allowed to stand for 30 minutes after stirring, and the lower aqueous phase is removed; activated carbon is then added to the remaining organic phase for decolorization, and the mixture is stirred for 2-3 hours, and finally filtered to obtain a sodium docusate solution product.

9. A synthesis process of docusate sodium bulk drug according to claim 8, characterized in that: The mass ratio of the diisooctyl maleate, the docusate sodium and the sodium bisulfite in step (a) is 1:0.08-0.12:0.28-0.

35.

10. A synthesis process of docusate sodium bulk drug according to claim 8, characterized in that: It also includes the following steps: (c) Purification: Add a 2% sodium bicarbonate aqueous solution for washing, then let stand to separate and remove the aqueous phase, concentrate the remaining organic phase at 55-60°C for 2-3h, then dry in a vacuum drying oven at 50-75°C until the moisture content is 2%, and finally grind to obtain the docusate sodium product.

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