A clean production process of sevoflurane

Abstract

The present invention relates to the technical field of chemical synthesis, and specifically discloses a clean production process of sevoflurane. After the etherification reaction is completed, water is used instead of hydrochloric acid for acidolysis, and the addition mode of the feed liquid is controlled. On the premise of ensuring the hydrolysis effect, not only the use of a large amount of hydrochloric acid and the generation of a large amount of acid-containing wastewater are avoided, but also the materials in the hydrolysis process maintain a good flowable state, effectively ensuring the stirring and heat transfer effects, avoiding local overheating, and reducing potential safety hazards; after the fluorination reaction is completed, the method of pressure filtration for salt removal is adopted, and the filtrate is allowed to stand and phase-separate at a specific temperature, so that the reaction solvent and the sevoflurane product are effectively phase-separated, thereby effectively reducing the contents of the reaction solvent and inorganic salts in the sevoflurane, not only improving the product quality, but also avoiding the use of a large amount of water in the traditional water washing process, and at the same time, avoiding the emulsification problem that is prone to occur in the traditional water washing process, effectively shortening the post-treatment time.

Description

Technical Field

[0001] The present invention relates to the technical field of chemical synthesis, and particularly to a clean production process of sevoflurane. Background Art

[0002] Sevoflurane, chemically named 1,1,1,3,3,3-hexafluoro-2-(fluoromethoxy)propane, is an important inhalation anesthetic, which has the advantages of rapid induction, fast recovery, easy adjustment of anesthesia depth, and little irritation to the respiratory tract. It is widely used in the process of modern medical surgical anesthesia, can effectively ensure the smooth progress of the operation, and relieve the discomfort of patients after surgery. It is one of the indispensable drugs in the current clinical anesthesia field.

[0003] The existing industrial production process of sevoflurane is as follows: under the action of strong acid, hexafluoroisopropanol, paraformaldehyde and aluminum trichloride are subjected to an etherification reaction, and then sevoflurane is obtained through a fluorination reaction. This route has a simple process, mild reaction and controllable quality, but has the following disadvantages: (1) After the etherification reaction is completed, a large amount of hydrochloric acid needs to be added for acidolysis, the raw material cost is relatively high, and a large amount of acidic wastewater will be generated, increasing the wastewater treatment cost; at the same time, during the acidolysis process, the state of the liquid material changes from a flowable liquid to a viscous and non-flowable material, and finally changes back to a flowable liquid. This change in the state of the material will lead to a decrease in the stirring effect, and then a decrease in the heat transfer effect, local overheating, so there are certain safety hazards, and it will also cause a sharp increase in the stirring resistance of the reaction equipment, an increase in the equipment load, and a significant reduction in the service life of the equipment; (2) After the fluorination reaction is completed, a large amount of water is required to wash the product, generating a large amount of wastewater containing high concentrations of reaction solvents and inorganic salts, with a relatively high treatment cost. At the same time, the crude sevoflurane prepared contains about 24% of a mixture composed of water, reaction solvents and inorganic salts, and the content of sevoflurane is reduced (only about 76%), and emulsification is extremely likely to occur during the water washing process, making it difficult to phase-separate, resulting in low production efficiency. Therefore, in order to improve the atom economy and environmental protection of the reaction, it is necessary to provide a clean production process of sevoflurane. Summary of the Invention

[0004] Aiming at the problems in the existing synthesis method of sevoflurane, such as the large consumption of hydrochloric acid and water, the generation of a large amount of difficult-to-treat wastewater, poor process safety and environmental protection, and low production efficiency, the present invention provides a clean production process of sevoflurane.

[0005] To solve the above technical problems, the technical solution provided by the present invention is:

[0006] A clean production process of sevoflurane, comprising the following steps:

[0007] S1. Using hexafluoroisopropanol, anhydrous aluminum trichloride, and paraformaldehyde as raw materials, an etherification reaction is carried out to obtain an etherification reaction solution. The etherification reaction solution is slowly added to water for a hydrolysis reaction. After the hydrolysis is completed, it is allowed to stand for phase separation. The obtained oil phase is washed and dried to obtain 1,1,1,3,3,3 - hexafluoro - 2 - (chloromethoxy) - propane.

[0008] S2. The 1,1,1,3,3,3 - hexafluoro - 2 - (chloromethoxy) - propane and anhydrous potassium fluoride are added to a reaction solvent, mixed evenly, and a fluorination reaction is carried out to obtain a fluorination reaction solution. The fluorination reaction solution is cooled to 40°C - 50°C, filtered under pressure. The obtained filtrate is cooled to 0°C - 5°C and allowed to stand for phase separation to obtain sevoflurane.

[0009] Compared with the prior art, in the clean production process of sevoflurane provided by the present invention, after the etherification reaction is completed, water is used instead of hydrochloric acid for acidolysis, and the feeding mode of the feed liquid is controlled. On the premise of ensuring the hydrolysis effect, not only the use of a large amount of hydrochloric acid and the generation of a large amount of acid - containing wastewater are avoided, but also the materials in the hydrolysis process maintain a good flowable state, effectively ensuring the stirring and heat transfer effects, avoiding local overheating, reducing potential safety hazards. In addition, the equipment load is reduced and the service life of the equipment is extended. After the fluorination reaction is completed, a specific temperature is directly used for pressure filtration to remove salts, effectively removing inorganic salts (such as potassium fluoride, potassium chloride, etc.) in the reaction solution. At the same time, the filtrate is allowed to stand for phase separation at a specific temperature, enabling effective phase separation of the reaction solvent and the sevoflurane product. Thus, the content of the reaction solvent and inorganic salts in sevoflurane is effectively reduced, not only improving the product quality, but also avoiding the use of a large amount of water in the traditional water - washing process, and at the same time, avoiding the emulsification problem that easily occurs in the traditional water - washing process, effectively shortening the post - treatment time.

[0010] The production process of sevoflurane provided by the present invention not only avoids the generation of a large amount of acid - containing wastewater and salt - containing wastewater, effectively reducing the wastewater treatment cost, but also significantly reduces the usage amount of washing water, improves the safety and environmental protection of the process, realizes the clean production of sevoflurane, more meets the requirements of the green production process, is conducive to realizing large - scale industrial production, and has very important significance for the development of sevoflurane.

[0011] Further, in S1, the temperature of the etherification reaction is 28°C - 32°C, and the reaction time is 10h - 20h.

[0012] Further, in S1, the molar ratio of hexafluoroisopropanol, anhydrous aluminum trichloride, and paraformaldehyde is 1:(1.0 - 1.2):(1.0 - 1.25).

[0013] Further, in S1, in the hydrolysis reaction, the addition amount of water is 1.5 - 2.0 times the mass of hexafluoroisopropanol.

[0014] Further, in S1, the etherification reaction liquid is added in a dropping manner, the dropping time is 2 h to 4 h, and the system temperature is controlled not to exceed 60°C during the dropping process.

[0015] The present invention uses hydrolysis to replace the acidolysis of the traditional process, and controls the temperature and time of hydrolysis. On the premise of ensuring the hydrolysis effect, the use of a large amount of hydrochloric acid is avoided, thereby effectively reducing the material cost and the wastewater treatment cost, and being more energy-saving and environmentally friendly.

[0016] Further, in S1, the washing specifically includes the following steps: adding water to the oil phase, performing the first stirring and washing, standing for phase separation to obtain the first oil phase; adding a sodium hydroxide solution to the first oil phase, performing the second stirring and washing, standing for phase separation to obtain the second oil phase; adding water to the second oil phase again, performing the third stirring and washing, standing for phase separation, and drying to obtain 1,1,1,3,3,3-hexafluoro-2-(chloromethoxy)propane.

[0017] Further, during the washing process, in the first and third stirring and washing processes, the mass ratio of the water used to hexafluoroisopropanol is (1.5 - 2.0):1.

[0018] Further, during the second stirring and washing process, the molar ratio of NaOH to hexafluoroisopropanol in the sodium hydroxide solution is (0.02 - 0.04):1, and the mass ratio of water to hexafluoroisopropanol in the sodium hydroxide solution is (1.5 - 2.0):1.

[0019] Specifically, the stirring and washing time for the first to third times is 30 min to 40 min, and the standing phase separation time is 30 min to 40 min.

[0020] Specifically, in S1, after washing, the obtained oil phase is dried with anhydrous potassium carbonate. Exemplarily, anhydrous potassium carbonate is loaded into a bag filter, and then the oil phase is pressed into the filter for drying.

[0021] Further, in S2, the reaction solvent is polyethylene glycol 400.

[0022] Further, in S2, the mass ratio of 1,1,1,3,3,3-hexafluoro-2-(chloromethoxy)propane to the reaction solvent is 1:(1.5 - 2.0).

[0023] Further, in S2, the molar ratio of 1,1,1,3,3,3-hexafluoro-2-(chloromethoxy)propane to anhydrous potassium fluoride is 1:(1.5 - 2.0).

[0024] Further, in S2, the temperature of the fluorination reaction is 70°C to 80°C, and the reaction time is 3h to 5h.

[0025] Further, in S2, the fluorination reaction solution is cooled to 42°C to 46°C.

[0026] Filter pressing the fluorination reaction solution at a certain temperature can improve the separation degree of sevoflurane and inorganic salts and ensure the yield of sevoflurane.

[0027] Further, in S2, the time for static phase separation is 1h to 1.5h.

[0028] In the traditional process, after the fluorination reaction is completed, polyethylene glycol 400 in sevoflurane is removed by means of water washing, which will waste a large amount of precious water resources. The inventor tried to adopt a method of separating sevoflurane and polyethylene glycol 400 without consuming water. However, it was found that the solubility of sevoflurane in polyethylene glycol 400 is relatively high and it is difficult to separate. The inventor unexpectedly found that by standing for 1h to 1.5h at a specific temperature of 0°C to 5°C, the effective separation of polyethylene glycol 400 and sevoflurane can be achieved, obtaining a two-phase system with polyethylene glycol 400 in the upper layer and sevoflurane in the lower layer. Subsequently, through simple liquid separation, a crude sevoflurane product with a content of 95% can be obtained, which not only effectively improves the post-treatment efficiency, but also saves water resources and avoids the generation of a large amount of wastewater containing polyethylene glycol and inorganic salts, which is of great significance for realizing the sustainable development of the sevoflurane production process.

[0029] As an implementation mode of the present invention, the present invention provides a preparation process of sevoflurane, including the following steps:

[0030] S1, adding hexafluoroisopropanol to a reaction tank, turning on the stirrer, slowly adding anhydrous aluminum trichloride to the reaction tank, and then slowly adding paraformaldehyde to the reaction tank, and carrying out an etherification reaction at 28°C to 32°C for heat preservation to obtain an etherification reaction solution; dropping the etherification reaction solution into water for hydrolysis, controlling the temperature of the feed liquid not to exceed 60°C during the dropping process, and after adding, washing and drying the hydrolysis reaction solution to obtain 1,1,1,3,3,3-hexafluoro-2-(chloromethoxy)propane;

[0031] S2, adding the 1,1,1,3,3,3-hexafluoro-2-(chloromethoxy)propane into a reaction tank, adding polyethylene glycol 400 and anhydrous potassium fluoride, starting the stirrer after the feeding is completed, heating to 70°C to 80°C for a fluorination reaction, sampling and monitoring until the reaction is completed, cooling the feed liquid to 40°C to 50°C, then carrying out filter pressing, after the filter pressing is completed, turning on the cold brine in the jacket of the reaction tank for cooling, when the feed liquid drops to 0°C to 5°C, stopping the stirrer and standing for phase separation to obtain a crude sevoflurane product.

[0032] Specifically, in S2, a plate-and-frame filter press is used for pressure filtration, and the feed liquid is pressed into the plate-and-frame filter press in multiple batches.

[0033] It should be noted that the water used for hydrolysis and washing in the present invention is all drinking water.

[0034] The preparation process of sevoflurane provided by the present invention uses water instead of hydrochloric acid for hydrolysis reaction, greatly reducing the discharge of acid-containing waste, effectively reducing the pressure on the environment, and reducing the cost of wastewater treatment. At the same time, after the fluorination reaction, instead of using water washing to separate polyethylene glycol and inorganic salts, pressure filtration combined with low-temperature phase separation technology is used to separate inorganic salts and polyethylene glycol, effectively improving the purity and production efficiency of the prepared sevoflurane. The process provided by the present invention not only significantly reduces the reaction cost and energy consumption, but also is green and environmentally friendly, suitable for large-scale industrial production, and has broad application prospects. Specific Embodiments

[0035] In order to make the objectives, technical solutions and advantages of the present invention clearer, the present invention will be further described in detail below with reference to embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0036] To better illustrate the present invention, further examples are given below through embodiments.

[0037] Example 1

[0038] A preparation process of sevoflurane:

[0039] 1. Etherification process

[0040] Add 631.5 kg of hexafluoroisopropanol to the reaction tank, turn on the stirrer, slowly add 600 kg of anhydrous aluminum trichloride to the reaction tank, and then slowly add 139.2 kg of paraformaldehyde to the reaction tank. Control the temperature at 30 °C and keep the reaction for 15 h. Slowly drop the reaction material liquid into 1144.5 kg of drinking water for hydrolysis. The dropping time is 3 h, and the temperature of the system is controlled not to exceed 60 °C during the dropping process. After adding, let it stand for 30 min and separate the phases. Add 1050 L of drinking water to the obtained oily phase, stir for 30 min, let it stand for 30 min and separate the phases. Add a mixed solution of 1050 L of drinking water and 4.5 kg of industrial sodium hydroxide to the obtained oily phase, stir for 30 min, let it stand for 30 min and separate the phases. Add 1050 L of drinking water to the obtained oily phase again, stir for 30 min, let it stand for 30 min and separate the phases. Use 12 kg of industrial anhydrous potassium carbonate for drying to obtain 1,1,1,3,3,3-hexafluoro-2-(chloromethoxy)propane, with a molar yield of 95% and a purity of 99%;

[0041] 2. Fluorination process

[0042] Add 645 kg of 1,1,1,3,3,3 - hexafluoro - 2 - (chloromethoxy) - propane obtained in the previous step into the reaction tank, add 1103 kg of polyethylene glycol 400 and 259.2 kg of industrial anhydrous potassium fluoride. After the feeding is completed, start stirring, turn on the heating, and react at 75 °C for 4 h. After the reaction is completed, cool the liquid material to 45 °C, and press it into the plate - frame filter in batches. After all the liquid material is completely filtered, turn on the cold brine in the jacket of the reaction tank for cooling. When the liquid material cools to 3 °C, stop stirring, let it stand for 1.5 h, separate the phases to obtain the crude sevoflurane. The mass yield is 85%, the sevoflurane content in the crude sevoflurane can reach more than 96%, and the total content of polyethylene glycol 400, potassium fluoride, and potassium chloride does not exceed 4%.

[0043] Example 2

[0044] A preparation process of sevoflurane:

[0045] 1. Etherification process

[0046] Add 631.5 kg of hexafluoroisopropanol into the reaction tank, turn on the stirring, slowly add 502 kg of anhydrous aluminum trichloride into the reaction tank, and then slowly add 112.8 kg of paraformaldehyde into the reaction tank. Control the temperature at 28 °C and keep the reaction for 20 h. Slowly drop the reaction liquid material into 948 kg of drinking water for hydrolysis. The dropping time is 2 h, and control the system temperature not to exceed 60 °C during the dropping process. After adding, let it stand for 30 min, separate the phases. Add 948 L of drinking water to the obtained oily phase, stir for 30 min, let it stand for 30 min, separate the phases. Add a mixed solution of 948 L of drinking water and 3.2 kg of industrial sodium hydroxide to the obtained oily phase, stir for 30 min, let it stand for 30 min, separate the phases. Add 948 L of drinking water to the obtained oily phase again, stir for 30 min, let it stand for 30 min, separate the phases. Use 12 kg of industrial anhydrous potassium carbonate for drying to obtain 1,1,1,3,3,3 - hexafluoro - 2 - (chloromethoxy) - propane. The molar yield is 80% and the purity is 97.5%.

[0047] 2. Fluorination process

[0048] Add 645 kg of 1,1,1,3,3,3 - hexafluoro - 2 - (chloromethoxy) - propane obtained in the previous step into the reaction tank, add 968 kg of polyethylene glycol 400 and 294 kg of industrial anhydrous potassium fluoride. After the feeding is completed, start stirring, turn on the heating, and react at 70 °C for 5 h. After the reaction is completed, cool the liquid material to 50 °C, and press it into the plate - frame filter in batches. After all the liquid material is completely filtered, turn on the cold brine in the jacket of the reaction tank for cooling. When the liquid material cools to 5 °C, stop stirring, let it stand for 1.5 h, separate the phases to obtain the crude sevoflurane. The mass yield is 75%, the sevoflurane content in the crude sevoflurane can reach 95%, and the total content of polyethylene glycol 400, potassium fluoride, and potassium chloride does not exceed 5%.

[0049] Example 3

[0050] A preparation process of sevoflurane:

[0051] 1. Etherification process

[0052] Add 631.5 kg of hexafluoroisopropanol into the reaction tank, turn on the stirrer, slowly add 552 kg of anhydrous aluminum trichloride into the reaction tank, then slowly add 135.3 kg of paraformaldehyde into the reaction tank, control the temperature at 32 °C, keep the reaction for 10 h, slowly drop the reaction liquid into 1263 kg of drinking water for hydrolysis, the dropping time is 4 h, control the system temperature not to exceed 60 °C during the dropping process. After adding, let it stand for 30 min, separate the phases, add 1263 L of drinking water to the obtained oil phase, stir for 30 min, let it stand for 30 min, separate the phases, add a mixed solution of 1263 L of drinking water and 6 kg of industrial sodium hydroxide to the obtained oil phase, stir for 30 min, let it stand for 30 min, separate the phases, add 1263 L of drinking water to the obtained oil phase again, stir for 30 min, let it stand for 30 min, separate the phases, and dry it with 12 kg of industrial anhydrous potassium carbonate to obtain 1,1,1,3,3,3 - hexafluoro - 2 - (chloromethoxy) - propane, with a molar yield of 85% and a purity of 98%;

[0053] 2. Fluorination process

[0054] Add 645 kg of 1,1,1,3,3,3 - hexafluoro - 2 - (chloromethoxy) - propane prepared in the previous step into the reaction tank, add 1290 kg of polyethylene glycol 400 and 346 kg of industrial anhydrous potassium fluoride. After feeding, start the stirrer, turn on the heating, react at 80 °C for 3 h. After the reaction is completed, cool the liquid to 40 °C, press it into the plate - frame filter in batches. After all the liquid is pressed and filtered, turn on the cold brine in the jacket of the reaction tank for cooling. When the liquid cools to 0 °C, stop stirring, let it stand for 1 h, separate the phases to obtain the crude sevoflurane, with a mass yield of 80%. The content of sevoflurane in the crude sevoflurane can reach 95%, and the total content of polyethylene glycol 400, potassium fluoride, and potassium chloride does not exceed 5%.

[0055] Comparative Example 1

[0056] This comparative example provides a preparation process of sevoflurane:

[0057] 1. Etherification process

[0058] Add 631.5 kg of hexafluoroisopropanol to the reaction tank. Turn on the stirrer and slowly add 600 kg of anhydrous aluminum trichloride to the reaction tank. Then slowly add 139.2 kg of paraformaldehyde to the reaction tank. Control the temperature at 30 °C and keep the reaction for 15 h. Slowly add 1144.5 kg of dilute hydrochloric acid (a mixture of 525 L of drinking water and 619.5 kg of concentrated hydrochloric acid) dropwise to the reaction solution over 3 h. After the addition, let it stand for 30 min and separate the phases. Add 1050 L of drinking water to the obtained oily phase, stir for 30 min, let it stand for 30 min, and separate the phases. Add a mixed solution of 1050 L of drinking water and 4.5 kg of industrial sodium hydroxide to the obtained oily phase, stir for 30 min, let it stand for 30 min, and separate the phases. Add 1050 L of drinking water to the obtained oily phase again, stir for 30 min, let it stand for 30 min, and separate the phases. Dry it with 12 kg of industrial anhydrous potassium carbonate to obtain 1,1,1,3,3,3-hexafluoro-2-(chloromethoxy)propane with a molar yield of 95% and a purity of 99%.

[0059] 2. Fluorination process

[0060] Add 645 kg of 1,1,1,3,3,3-hexafluoro-2-(chloromethoxy)propane prepared in the previous step to the reaction tank. Add 1103 kg of polyethylene glycol 400 and 259.2 kg of industrial anhydrous potassium fluoride. After feeding, start the stirrer, turn on the heating, and react at 75 °C for 4 h. After the reaction is completed, cool the liquid to 45 °C. Stir with 1290 L, 968 L, and 968 L of drinking water for 30 min in sequence, let it stand for 30 min and separate the phases to obtain the crude product of sevoflurane with a mass yield of 95%. The content of sevoflurane in the crude product of sevoflurane is 76%, and the total content of polyethylene glycol 400, potassium fluoride, and potassium chloride reaches 24%.

[0061] In summary, the synthesis process of sevoflurane provided by the present invention not only avoids the use of a large amount of hydrochloric acid solution, significantly reduces the water consumption, effectively improves the purity of the obtained crude product of sevoflurane, and also has a certain improvement in the total yield, realizes cost reduction and efficiency improvement, and greatly improves the environmental protection of the process and significantly reduces the wastewater treatment cost, having high practical value.

[0062] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent replacements, or improvements made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims

1. A production process of sevoflurane, characterized in that It includes the following steps: S1. Using hexafluoroisopropanol, anhydrous aluminum trichloride, and paraformaldehyde as raw materials, carry out an etherification reaction to obtain an etherification reaction solution; slowly drop the etherification reaction solution into water for a hydrolysis reaction. After the hydrolysis ends, let it stand for phase separation. Add water to the obtained oil phase, carry out the first stirring and washing, let it stand for phase separation, and obtain the first oil phase; add a sodium hydroxide solution to the first oil phase, carry out the second stirring and washing, let it stand for phase separation, and obtain the second oil phase; add water to the second oil phase again, carry out the third stirring and washing, let it stand for phase separation, and dry to obtain 1,1,1,3,3,3-hexafluoro-2-(chloromethoxy)propane; The dropping time of the etherification reaction solution is 2 h to 4 h, and the temperature of the system is controlled not to exceed 60 °C during the dropping process S2. Add the 1,1,1,3,3,3-hexafluoro-2-(chloromethoxy)propane and anhydrous potassium fluoride to a reaction solvent, mix evenly, and carry out a fluorination reaction to obtain a fluorination reaction solution; cool the fluorination reaction solution to 40 °C to 50 °C, filter it under pressure, cool the obtained filtrate to 0 °C to 5 °C, let it stand for phase separation, and obtain sevoflurane.

2. The production process of sevoflurane according to claim 1, characterized in that, In S1, the temperature of the etherification reaction is 28 °C to 32 °C, and the reaction time is 10 h to 20 h.

3. The production process of sevoflurane according to claim 1, characterized in that, In S1, the molar ratio of hexafluoroisopropanol, anhydrous aluminum trichloride, and paraformaldehyde is 1:(1.0 - 1.2):(1.0 - 1.25); and / or In S1, in the hydrolysis reaction, the addition amount of water is 1.5 to 2.0 times the mass of hexafluoroisopropanol.

4. The production process of sevoflurane according to claim 1, wherein, During the washing process, in the first and third stirring and washing processes, the mass ratio of the water used to hexafluoroisopropanol is both (1.5 - 2.0):1; and / or In the second stirring and washing process, the molar ratio of NaOH to hexafluoroisopropanol in the sodium hydroxide solution is (0.02 - 0.04):1, and the mass ratio of water to hexafluoroisopropanol in the sodium hydroxide solution is (1.5 - 2.0):

1.

5. The production process of sevoflurane according to claim 1, characterized in that, In S2, the reaction solvent is polyethylene glycol 400.

6. The production process of sevoflurane according to claim 1 or 5, characterized in that, In S2, the mass ratio of 1,1,1,3,3,3-hexafluoro-2-(chloromethoxy)propane to the reaction solvent is 1:(1.5 - 2.0).

7. The production process of sevoflurane according to claim 1, characterized in that, In S2, the molar ratio of 1,1,1,3,3,3-hexafluoro-2-(chloromethoxy)propane to anhydrous potassium fluoride is 1:(1.5 - 2.0).

8. The production process of sevoflurane according to claim 1, characterized in that, In S2, the temperature of the fluorination reaction is 70 °C to 80 °C, and the reaction time is 3 h to 5 h; and / or In S2, the time for standing and phase separation is 1 h to 1.5 h.