Method for removing impurities in azilsartan ethyl ester and recovering ethanol

Abstract

Hydroxylamine, dimethyl sulfoxide (DMSO) and a decomposition product dimethyl sulfide thereof exist in an ethanol recovery product obtained by simply and roughly steaming a centrifugal mother solution of an azilsartan ethyl ester adduct crude product, and the impurities enable the ethanol recovery product to have an unpleasant odor, harm human health and pollute the environment at the same time. In order to solve the problem, the invention provides a method for recovering impurities in ethanol by removing azilsartan ethyl ester, which comprises the following steps of: adding acid to acidify to remove hydroxylamine impurities, desalting and separating out, oxidizing by using sodium hypochlorite to remove thioether substances, and rectifying to remove high-boiling-point dimethyl sulfoxide (DMSO) to obtain clean ethanol with high purity and no peculiar smell. Optimized resource reutilization is achieved, the production cost is reduced, and the sustainable development road is met.

Description

Technical Field

[0001] This invention relates to the field of solvent recovery and impurity removal, and particularly to a method for removing impurities from recovered ethanol containing azisartan ethyl ester. Background Technology

[0002] Azilsartan ethyl ester is an intermediate product in the preparation of azilsartan medoxomil. In existing technologies, the purification process for azilsartan ethyl ester involves quenching the reaction with an aqueous solution of NaHSO3, extracting the reaction solution with ethyl acetate, washing the organic phase with saturated brine, evaporating the solvent under reduced pressure, refluxing with ethanol, filtering to obtain solid azilsartan ethyl ester, and then vacuum drying. For environmental protection and energy conservation, pharmaceutical manufacturers typically recycle the ethanol used in the purification process of azilsartan ethyl ester. The inventors have analyzed the ethanol solution recovered through conventional methods and found the presence of hydroxylamine, dimethyl sulfoxide (DMSO), and dimethyl sulfide. The hydroxylamine and sulfide compounds give the ethanol solution an unpleasant odor and pose health risks, while also polluting the environment.

[0003] Currently, there are no literature reports on methods for removing the aforementioned impurities from the ethanol recovery of azisartan ethyl ester. The common method for removing hydroxylamine and thioether impurities from wastewater is sodium hypochlorite oxidation. Although dimethyl sulfoxide (DMSO) is a colorless, odorless, and non-toxic liquid organic solvent with low toxicity, it is still necessary to remove DMSO from the ethanol recovery to obtain pure ethanol solvent. Currently, the main methods for removing DMSO include biological methods, water washing, and distillation. However, biological methods are difficult to use for treating wastewater containing DMSO. Aerobic biological methods cannot achieve a high degree of degradation, while anaerobic methods produce volatile and toxic products (dimethyl sulfide and hydrogen sulfide), making the process difficult to control. Furthermore, DMSO easily decomposes into dimethyl sulfides during the process. Water washing often leads to the precipitation of many products in the water, resulting in cumbersome steps and excessive time consumption. Multiple water washing processes can also affect the sample recovery rate. Distillation is only suitable for removing DMSO from waste liquids with high boiling points and is not suitable for low-boiling-point substances like ethanol.

[0004] Therefore, in order to solve the above problems, we propose a method for removing impurities from the recovered ethanol of azisartan ethyl ester. First, acidification is added to remove hydroxylamine impurities and desalting them out. Then, sodium hypochlorite is used to oxidize and remove sulfide substances. Finally, distillation is used to remove high-boiling-point dimethyl sulfoxide (DMSO) to obtain high-purity, clean and odorless ethanol, thereby optimizing resource reuse and reducing production costs. Summary of the Invention

[0005] The purpose of this invention is to provide a method for removing impurities from the recovered ethanol of azisartan ethyl ester. Studies have shown that the recovered ethanol of azisartan ethyl ester contains hydroxylamine, dimethyl sulfoxide (DMSO), and dimethyl sulfide. The method provided by this invention can effectively remove the above-mentioned impurities from the recovered ethanol, obtaining pure and odorless ethanol, realizing resource reuse, and reducing production costs.

[0006] The technical solution of this invention is as follows: A method for removing impurities from recovered ethanol containing azisartan ethyl ester, characterized by comprising the following steps: (1) Mix and neutralize an appropriate amount of dimethyl sulfoxide (DMSO), anhydrous ethanol, hydroxylamine hydrochloride and sodium bicarbonate to obtain a mixture. Then add a certain amount of candesartan cyclase to the mixture and carry out the addition reaction under controlled temperature. After cooling, crystallize, centrifuge and filter to obtain crude azilsartan ethyl ester adduct mother liquor. Then add the crude azilsartan ethyl ester adduct mother liquor to a single-effect evaporator and distill under normal pressure until the liquid level reaches 5% of the tank body. During the process, collect the distillate, which is the ethanol recovery product. (2) First, add an appropriate amount of concentrated sulfuric acid to the ethanol recovery product with an odor to cause hydroxylamine impurities to precipitate as salts; (3) After centrifugation and filtration to remove salt, add an appropriate amount of sodium hydroxide solution to the ethanol filtrate to adjust it to neutral; (4) Then add an appropriate amount of sodium hypochlorite solution; (5) Finally, the ethanol fraction is collected by distillation.

[0007] In step (1) above, the rough distillation is stopped when the liquid level in the single-effect evaporator drops to 5% of the tank or when there is no obvious liquid droplet flowing out at the distillation port. The remaining liquid in the tank is a solid-liquid mixture, which is disposed of as waste.

[0008] In step (3), the concentration of sodium hydroxide solution is 25-35%.

[0009] The chlorine content of the sodium hypochlorite solution in step (4) is 5-15%.

[0010] In step (5), the distillate collected is the distillate from the top of the distillation column at 78~79℃ with a reflux ratio of 1:1.5.

[0011] The reaction equation is as follows:

[0012]

[0013] The process and equipment flow chart is as follows:

[0014] The samples before and after the impurity removal treatment were then analyzed using a gas chromatograph, and the chromatograms were recorded.

[0015] The beneficial effects of this invention are as follows: After the impurity removal process of this invention, dimethyl sulfoxide (DMSO) and its decomposition product dimethyl sulfide are completely removed from the ethanol fraction, the hydroxylamine content is reduced to near zero, and the ethanol purity can be increased to a maximum of 99.81%. This invention can effectively remove impurities such as hydroxylamine, dimethyl sulfoxide (DMSO), and its decomposition product dimethyl sulfide from ethanol recovery products, which are harmful to human health and pollute the environment, to obtain pure and odorless ethanol, optimize resource reuse, and reduce production costs. Attached Figure Description

[0016] Figure 1 DMSO detection chromatogram of recovered ethanol before impurity removal treatment Figure 2 DMSO detection chromatogram of recovered ethanol after impurity removal treatment Figure 3 Chromatogram of recovered ethanol before impurity removal treatment Figure 4 Chromatogram of recovered ethanol after impurity removal treatment Figure 5 Chromatogram of hydroxylamine detection in recovered ethanol after impurity removal treatment Detailed Implementation Example 1

[0017] A method for removing impurities from ethanol recovered from azilsartan ethyl ester includes the following steps: The crude azilsartan ethyl ester adduct is centrifuged and the mother liquor is added to a single-effect evaporator. Distillation is carried out at atmospheric pressure until the liquid level reaches 5% of the tank volume. During this process, the distillate is collected; this distillate is the recovered ethanol. The recovered ethanol flows into a mother liquor storage tank. Then, 2000L of the recovered ethanol from the centrifuged section of the crude azilsartan ethyl ester adduct in the mother liquor storage tank is pumped into an acid-adjusting reaction tank via a booster pump. Next, 25 kg of concentrated sulfuric acid is added dropwise to the acid-adjusting tank while stirring. The material is then transferred to a centrifuge for filtration. The filter residue is treated as a solid salt, and the filtrate is transferred to… The solution was transferred to an alkali-adjusting tank, and then 20 L of a 30% sodium hydroxide solution was added dropwise while stirring. After the addition was complete, the solution was transferred to an oxidation reaction tank, and 100 kg of a 10% sodium hypochlorite solution was slowly added dropwise while stirring, with the addition time controlled at 1 hour. After the addition was complete, the reaction was stirred for another 3 hours. Subsequently, the solution was pumped into the reboiler of a distillation column for fractional distillation. The distillate collected at a top temperature of 78-79°C and a reflux ratio of 1:1.5 was stored in an ethanol storage tank. Before impurity removal treatment, the recovered ethanol was analyzed for DMSO and ethanol, and the chromatograms obtained were as follows: Figure 1 , Figure 3As shown, the chromatograms obtained by further detecting DMSO, ethanol, and hydroxylamine in the sample after impurity removal treatment are shown in the figures below. Figure 2 , Figure 4 , Figure 5 As shown, Table 1, a comparison table of purity data before and after impurity removal treatment, was finally obtained according to the formula (1): Example 2

[0018] A method for removing impurities from ethanol recovered from azilsartan ethyl ester includes the following steps: The crude azilsartan ethyl ester adduct is centrifuged and the mother liquor is added to a single-effect evaporator. Distillation is carried out at atmospheric pressure until the liquid level reaches 5% of the tank volume. During this process, the distillate is collected; this distillate is the recovered ethanol. The recovered ethanol flows into a mother liquor storage tank. Then, 2000L of the recovered ethanol from the centrifuged section of the crude azilsartan ethyl ester adduct in the mother liquor storage tank is pumped into an acid-adjusting reaction tank via a booster pump. 25 kg of concentrated sulfuric acid is then added dropwise to the acid-adjusting tank while stirring. The material is then transferred to a centrifuge for filtration. The filter residue is treated as a solid salt. The filtrate is transferred to an alkali-adjusting tank, where 20 L of a 30% sodium hydroxide solution is added dropwise while stirring. After the addition was completed, the solution was transferred to an oxidation reaction vessel. While stirring, 100 kg of sodium hypochlorite solution with a chlorine content of 5% was slowly added dropwise, with the addition time controlled at 1 hour. After the addition was completed, the reaction was stirred for another 3 hours. Subsequently, the solution was pumped into the reboiler of the distillation column to perform distillation and separation of components. The distillate collected at a top temperature of 78~79℃ with a reflux ratio of 1:1.5 was collected and stored in an ethanol storage tank. Before the ethanol was treated for impurity removal, DMSO and ethanol were detected to obtain chromatograms. After the impurity removal treatment, DMSO, ethanol, and hydroxylamine were detected to obtain chromatograms. Finally, the purity data before and after impurity removal treatment were calculated according to the formula. Table 2 shows the comparison of purity data before and after impurity removal treatment (2). Example 3

[0019] A method for removing impurities from ethanol recovered from azilsartan ethyl ester includes the following steps: The crude azilsartan ethyl ester adduct is centrifuged and the mother liquor is added to a single-effect evaporator. Distillation is carried out at atmospheric pressure until the liquid level reaches 5% of the tank volume. During this process, the distillate is collected; this distillate is the recovered ethanol. The recovered ethanol flows into a mother liquor storage tank. Then, 2000L of the recovered ethanol from the centrifuged section of the crude azilsartan ethyl ester adduct in the mother liquor storage tank is pumped into an acid-adjusting reaction tank via a booster pump. 25 kg of concentrated sulfuric acid is then added dropwise to the acid-adjusting tank while stirring. The material is then transferred to a centrifuge for filtration. The filter residue is treated as a solid salt. The filtrate is transferred to an alkali-adjusting tank, where 20 L of a 30% sodium hydroxide solution is added dropwise while stirring. After the addition was completed, the solution was transferred to an oxidation reaction vessel. While stirring, 100 kg of sodium hypochlorite solution with a chlorine content of 15% was slowly added dropwise, with the addition time controlled at 1 hour. After the addition was completed, the reaction was stirred for another 3 hours. Subsequently, the solution was pumped into the reboiler of the distillation column to perform distillation and separation of components. The distillate collected at a top temperature of 78~79℃ with a reflux ratio of 1:1.5 was collected and stored in an ethanol storage tank. Before the ethanol was treated for impurity removal, DMSO and ethanol were detected to obtain chromatograms. After the impurity removal treatment, DMSO, ethanol, and hydroxylamine were detected to obtain chromatograms. Finally, the purity data before and after impurity removal treatment were calculated according to the formula. Table 3 shows the comparison of purity data before and after impurity removal treatment (3).

[0020] As can be seen from the above embodiments, after the recovered ethanol is treated with impurity removal according to the conditions of the present invention, dimethyl sulfoxide (DMSO) and its decomposition product dimethyl sulfide can be completely removed from the ethanol fraction, the hydroxylamine content is reduced to near zero, and the ethanol purity can be increased to a maximum of 99.81%. The present invention can effectively remove impurities such as hydroxylamine, dimethyl sulfoxide (DMSO) and its decomposition product dimethyl sulfide, which are harmful to human health and pollute the environment, from the recovered ethanol, obtaining pure and odorless ethanol, optimizing resource reuse, and reducing production costs.

[0021] Matters not covered in this invention are common knowledge.

[0022] The above embodiments are only for illustrating the technical concept and features of the present invention, and are intended to enable those skilled in the art to understand the content of the present invention and implement it accordingly. They should not be construed as limiting the scope of protection of the present invention. All equivalent changes or modifications made in accordance with the spirit and essence of the present invention should be covered within the scope of protection of the present invention.

Claims

1. A method for removing impurities in recycled ethanol of azilsartan prodrug, characterized by: The method comprises the following steps: (1) mixing dimethyl sulfoxide (DMSO), anhydrous ethanol, hydroxylamine hydrochloride and sodium bicarbonate to obtain a mixed solution, adding a certain amount of candesartan cyclic compound into the mixed solution, controlling temperature to perform addition reaction, lowering temperature to perform crystallization, centrifugal filtration, obtaining crude azilsartan ethyl ester addition product centrifugal mother liquor, adding the crude azilsartan ethyl ester addition product centrifugal mother liquor into a single-effect evaporation tank, performing normal pressure distillation until the liquid level reaches 5% of the tank body, collecting the distillate during the distillation, and the distillate is ethanol recovery product; (2) adding a certain amount of concentrated sulfuric acid into the ethanol recovery product with peculiar smell to make hydroxylamine impurities into salt and precipitate; (3) performing centrifugal filtration to remove salt, and then adding a certain amount of sodium hydroxide solution into the ethanol filtrate to adjust the solution to neutral; (4) subsequently adding a certain amount of sodium hypochlorite solution; (5) finally, collecting ethanol distillate through rectification.

2. The method of claim 1, wherein: In step (1), the rough distillation is stopped when the liquid level of the single-effect evaporation tank decreases to 5% of the tank body or no obvious liquid drops flow out from the distillation opening, and the remaining solid-liquid mixture in the tank body is treated as waste.

3. The method of claim 1, wherein: In step (3), the concentration of the sodium hydroxide solution is 25%-35%.

4. The method of claim 1, wherein: In step (4), the chlorine content of the sodium hypochlorite solution is 5%-15%.

5. The method of claim 1, wherein: In step (5), the collected distillate is obtained through rectification at the top of a rectification column at 78-79 ℃, and the reflux ratio is controlled to be 1:1.5.

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