Clean production process of sevoflurane

Abstract

The invention relates to the technical field of chemical synthesis, and particularly discloses a clean production process of sevoflurane. After the etherification reaction is finished, water is adopted to replace hydrochloric acid for acidolysis, and the adding mode of the feed liquid is controlled, so that on the premise of ensuring the hydrolysis effect, the use of a large amount of hydrochloric acid and the generation of a large amount of acid-containing wastewater are avoided, and meanwhile, the materials in the hydrolysis process are kept in a good flowable state; the stirring and heat transfer effects are effectively guaranteed, local overheating is avoided, and potential safety hazards are reduced; after the fluorination reaction is finished, a filter pressing desalting mode is adopted, and filtrate is subjected to standing phase separation at a specific temperature, so that a reaction solvent and a sevoflurane product are effectively subjected to phase separation, the content of the reaction solvent and inorganic salt in sevoflurane is effectively reduced, the product quality is improved, the use of a large amount of water in the traditional water washing process is avoided, and the production cost is reduced. And meanwhile, the problem of emulsification easily occurring in a traditional washing process is also avoided, and the post-treatment time is effectively shortened.

Description

Technical Field

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

[0002] Sevoflurane, whose chemical name is 1,1,1,3,3,3-hexafluoro-2-(fluoromethoxy)propane, is an important inhalation anesthetic with the advantages of rapid induction, fast awakening, easy adjustment of anesthesia depth, and little irritation to the respiratory tract. It is widely used in modern medical surgical anesthesia. It can effectively ensure the smooth progress of the operation and reduce the patient's postoperative discomfort. It is one of the indispensable drugs in the current clinical anesthesia field.

[0003] The existing industrial production process of sevoflurane is: under the action of strong acid, hexafluoroisopropanol, paraformaldehyde and aluminum chloride undergo etherification reaction, and then undergo fluorination reaction to obtain sevoflurane. 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 acid hydrolysis, which has a high raw material cost and produces a large amount of acidic wastewater, increasing the cost of wastewater treatment; at the same time, during the acid hydrolysis process, the state of the material liquid changes from a flowable liquid to a viscous material that is not easy to flow, and finally changes back to a flowable liquid. This material change state will lead to a decrease in the stirring effect, which in turn leads to a decrease in the heat transfer effect and local overheating, thus posing certain safety hazards, and will also lead to 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 needs to be used to wash the product, generating a large amount of high-concentration wastewater containing reaction solvents and inorganic salts, which has a high treatment cost. At the same time, the prepared crude sevoflurane contains about 24% of a mixture composed of water, reaction solvents and inorganic salts, and the sevoflurane content is reduced (only about 76%), and emulsification is very likely to occur during the water washing process, which is not easy to separate into phases, resulting in low production efficiency. Therefore, in order to improve the atomic economy and environmental protection of the reaction, it is necessary to provide a clean production process for sevoflurane. Summary of the invention

[0004] In view of the problems in the prior art of the synthesis method of sevoflurane, such as large amount of hydrochloric acid and water used, large amount of waste water difficult to treat, poor process safety and environmental protection, and low production efficiency, the present invention provides a clean production process of sevoflurane.

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

[0006] A clean production process for sevoflurane comprises the following steps:

[0007] S1, using hexafluoroisopropanol, anhydrous aluminum chloride and paraformaldehyde as raw materials, performing an etherification reaction to obtain an etherification reaction liquid; slowly adding the etherification reaction liquid into water for a hydrolysis reaction, and after the hydrolysis is completed, standing for phase separation, washing the obtained oil phase, and drying to obtain 1,1,1,3,3,3-hexafluoro-2-(chloromethoxy)-propane;

[0008] S2, adding the 1,1,1,3,3,3-hexafluoro-2-(chloromethoxy)-propane and anhydrous potassium fluoride to a reaction solvent, mixing them evenly, and performing a fluorination reaction to obtain a fluorination reaction liquid; cooling the fluorination reaction liquid to 40°C to 50°C, filtering by pressure, cooling the obtained filtrate to 0°C to 5°C, standing for phase separation, and obtaining sevoflurane.

[0009] Compared with the prior art, the clean production process of sevoflurane provided by the present invention uses water instead of hydrochloric acid for acid hydrolysis after the etherification reaction is completed, and controls the addition method of the feed liquid. Under the premise of ensuring the hydrolysis effect, it not only avoids the use of a large amount of hydrochloric acid and the generation of a large amount of acid-containing wastewater, but also keeps the material in the hydrolysis process in a good flowable state, effectively ensures the stirring and heat transfer effects, avoids local overheating, reduces safety hazards, and in addition, reduces the equipment load and prolongs the service life of the equipment; after the fluorination reaction is completed, a specific temperature is directly used for pressure filtration and desalination, effectively removes inorganic salts (potassium fluoride, potassium chloride, etc.) in the reaction liquid, and at the same time, the filtrate is allowed to stand for phase separation at a specific temperature, so that the reaction solvent and the sevoflurane product are effectively phase separated, thereby effectively reducing the content of the reaction solvent and the inorganic salt 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 easy to occur in the traditional water washing process, and effectively shortening the post-processing 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 reduces the cost of wastewater treatment, but also significantly reduces the use of washing water, improves the safety and environmental protection of the process, realizes the clean production of sevoflurane, better meets the requirements of green production process, is conducive to the realization of large-scale industrial production, and is of great significance to the development of sevoflurane.

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

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

[0013] Furthermore, in S1, in the hydrolysis reaction, the amount of water added is 1.5 to 2.0 times the mass of hexafluoroisopropanol.

[0014] Furthermore, in S1, the etherification reaction liquid is added dropwise for 2 h to 4 h, and the temperature of the system is controlled not to exceed 60°C during the dropping process.

[0015] The present invention adopts hydrolysis to replace the acid hydrolysis of the traditional process, and controls the temperature and time of the hydrolysis, thereby avoiding the use of a large amount of hydrochloric acid while ensuring the hydrolysis effect, thereby effectively reducing the material cost and 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 a first stirring and washing, standing for phase separation, and obtaining a first oil phase; adding sodium hydroxide solution to the first oil phase, performing a second stirring and washing, standing for phase separation, and obtaining a second oil phase; adding water to the second oil phase again, performing a third stirring and washing, standing for phase separation, and drying to obtain 1,1,1,3,3,3-hexafluoro-2-(chloromethoxy)-propane.

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

[0018] Furthermore, 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 time for the first to third stirring washing is 30 minutes to 40 minutes, and the time for standing for phase separation is 30 minutes to 40 minutes.

[0020] Specifically, in S1, after washing, the obtained oil phase is dried using 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] Furthermore, in S2, the reaction solvent is polyethylene glycol 400.

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

[0023] Furthermore, 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] Furthermore, in S2, the temperature of the fluorination reaction is 70°C to 80°C, and the reaction time is 3h to 5h.

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

[0026] Controlling the fluorination reaction liquid at a certain temperature for filter pressing can improve the separation degree of sevoflurane and inorganic salts and ensure the yield of sevoflurane.

[0027] Furthermore, in S2, the standing phase separation time is 1 h to 1.5 h.

[0028] In the traditional process, after the fluorination reaction is completed, polyethylene glycol 400 in sevoflurane is removed by washing with water, which will waste a lot of precious water resources. The inventor tried to separate sevoflurane and polyethylene glycol 400 without consuming water, but found that the solubility of sevoflurane in polyethylene glycol 400 is high and it is difficult to separate. The inventor unexpectedly found that by standing at a specific temperature of 0℃ to 5℃ for 1h to 1.5h, polyethylene glycol 400 and sevoflurane can be effectively separated, and a two-phase system with polyethylene glycol 400 in the upper layer and sevoflurane in the lower layer can be obtained. Subsequently, a crude sevoflurane with a content of 95% can be obtained by simple liquid separation, which not only effectively improves the post-processing 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 achieving the sustainable development of the sevoflurane production process.

[0029] As an embodiment of the present invention, the present invention provides a process for preparing sevoflurane, comprising the following steps:

[0030] S1, add hexafluoroisopropanol to a reaction tank, start stirring, slowly add anhydrous aluminum chloride to the reaction tank, and then slowly add paraformaldehyde to the reaction tank, and react at 28°C to 32°C to obtain an etherification reaction liquid; dropwise add the etherification reaction liquid into water for hydrolysis, and control the temperature of the feed liquid not to exceed 60°C during the dropwise addition process. After the addition is completed, wash the hydrolysis reaction liquid and dry it 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, after the feeding is completed, starting stirring, heating to 70°C-80°C for fluorination reaction, taking samples for monitoring until the reaction is completed, cooling the feed liquid to 40°C-50°C, and then performing filter press, after the filter press is completed, opening the jacket of the reaction tank for cooling with cold brine, when the feed liquid drops to 0°C-5°C, stopping stirring, standing for phase separation, and obtaining crude sevoflurane.

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

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

[0034] The preparation process of sevoflurane provided by the present invention uses water instead of hydrochloric acid for hydrolysis reaction, which greatly reduces the emission of acid-containing waste, effectively reduces the pressure on the environment, and reduces the cost of wastewater treatment; at the same time, after the fluorination reaction is completed, water washing is no longer used to separate polyethylene glycol and inorganic salts, but filter pressing combined with low-temperature phase separation technology is used to separate inorganic salts and polyethylene glycol, which effectively improves 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. DETAILED DESCRIPTION

[0035] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the 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] In order to better illustrate the present invention, further examples are given below.

[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 stirring, slowly add 600 kg of anhydrous aluminum chloride to the reaction tank, and then slowly add 139.2 kg of paraformaldehyde to the reaction tank, control the temperature to 30 ° C, keep the reaction for 15 hours, slowly add the reaction liquid to 1144.5 kg of drinking water for hydrolysis, the addition time is 3 hours, and the temperature of the system is controlled not to exceed 60 ° C during the addition process. After the addition is completed, let it stand for 30 minutes, separate the phases, add 1050 L of drinking water to the obtained oily liquid, stir Stir for 30 minutes, let stand for 30 minutes, separate the phases, add a mixed solution of 1050L drinking water and 4.5kg industrial sodium hydroxide to the obtained oil phase, stir for 30 minutes, let stand for 30 minutes, separate the phases, add 1050L drinking water to the obtained oil phase again, stir for 30 minutes, let stand for 30 minutes, separate the phases, and use 12kg 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 prepared in the previous step into a reaction tank, add 1103 kg of polyethylene glycol 400 and 259.2 kg of industrial anhydrous potassium fluoride, start stirring, turn on heating, react at 75°C for 4 hours, and after the reaction is completed, cool the feed liquid to 45°C and press it into a plate and frame filter in batches. After all the feed liquid is completely filtered, open the jacket of the reaction tank to cool it with cold brine. When the feed liquid is cooled to 3°C, stop stirring, let it stand for 1.5 hours, separate the phases, and obtain a crude sevoflurane product with a mass yield of 85%. The sevoflurane content in the crude sevoflurane product 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 to the reaction tank, turn on the stirring, slowly add 502 kg of anhydrous aluminum chloride to the reaction tank, and then slowly add 112.8 kg of paraformaldehyde to the reaction tank, control the temperature to 28 ° C, keep the reaction for 20 hours, slowly add the reaction liquid to 948 kg of drinking water for hydrolysis, the addition time is 2 hours, and the temperature of the system is controlled not to exceed 60 ° C during the addition process. After the addition is completed, let it stand for 30 minutes, separate the phases, add 948 L of drinking water to the obtained oily liquid, stir for 3 hours, and then add 1000 kg of drinking water to the reaction tank. 0min, let stand for 30min, separate the phases, add a mixed solution of 948L drinking water and 3.2kg industrial sodium hydroxide to the obtained oil phase, stir for 30min, let stand for 30min, separate the phases, add 948L drinking water to the obtained oil phase again, stir for 30min, let stand for 30min, separate the phases, use 12kg industrial anhydrous potassium carbonate for drying, and obtain 1,1,1,3,3,3-hexafluoro-2-(chloromethoxy)-propane with a molar yield of 80% and a purity of 97.5%;

[0047] 2. Fluorination process

[0048] 645 kg of 1,1,1,3,3,3-hexafluoro-2-(chloromethoxy)-propane prepared in the previous step was added to a reaction tank, and 968 kg of polyethylene glycol 400 and 294 kg of industrial anhydrous potassium fluoride were added. After the feeding was completed, stirring was started, heating was turned on, and the reaction was carried out at 70° C. for 5 hours. After the reaction was completed, the feed liquid was cooled to 50° C. and pressed into a plate and frame filter in batches. After all the feed liquid was completely filtered, the jacket of the reaction tank was opened to cool the cold brine. When the feed liquid was cooled to 5° C., stirring was stopped, and it was allowed to stand for 1.5 hours. Phase separation was performed to obtain a crude sevoflurane product with a mass yield of 75%. The sevoflurane content in the crude sevoflurane product could reach 95%, and the total content of polyethylene glycol 400, potassium fluoride and potassium chloride did not exceed 5%.

[0049] Example 3

[0050] A preparation process of sevoflurane:

[0051] 1. Etherification process

[0052] Add 631.5 kg of hexafluoroisopropanol to the reaction tank, turn on stirring, slowly add 552 kg of anhydrous aluminum chloride to the reaction tank, and then slowly add 135.3 kg of paraformaldehyde to the reaction tank, control the temperature to 32 ° C, keep the reaction for 10 hours, slowly drop the reaction liquid into 1263 kg of drinking water for hydrolysis, the drop time is 4 hours, and the temperature of the system is controlled not to exceed 60 ° C during the drop process. After the addition is completed, let it stand for 30 minutes, separate the phases, add 1263 L of drinking water to the obtained oily liquid, stir Stir for 30 minutes, let stand for 30 minutes, separate the phases, add a mixed solution of 1263L drinking water and 6kg industrial sodium hydroxide to the obtained oil phase, stir for 30 minutes, let stand for 30 minutes, separate the phases, add 1263L drinking water to the obtained oil phase again, stir for 30 minutes, let stand for 30 minutes, separate the phases, and use 12kg industrial anhydrous potassium carbonate for drying 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] 645 kg of 1,1,1,3,3,3-hexafluoro-2-(chloromethoxy)-propane prepared in the previous step was added to a reaction tank, and 1290 kg of polyethylene glycol 400 and 346 kg of industrial anhydrous potassium fluoride were added. After the feeding was completed, stirring was started, heating was turned on, and the reaction was carried out at 80° C. for 3 hours. After the reaction was completed, the feed liquid was cooled to 40° C. and pressed into a plate and frame filter in batches. After all the feed liquid was completely filtered, the jacket of the reaction tank was opened to cool the cold brine. When the feed liquid was cooled to 0° C., stirring was stopped, and it was allowed to stand for 1 hour. Phase separation was performed to obtain a crude sevoflurane product with a mass yield of 80%. The sevoflurane content in the crude sevoflurane product could reach 95%, and the total content of polyethylene glycol 400, potassium fluoride and potassium chloride did 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 stirring, slowly add 600 kg of anhydrous aluminum chloride to the reaction tank, and then slowly add 139.2 kg of paraformaldehyde to the reaction tank, control the temperature to 30 ° C, keep the reaction for 15 hours, slowly add 1144.5 kg of dilute hydrochloric acid (525 L of drinking water and 619.5 kg of concentrated hydrochloric acid) to the reaction solution, the addition time is 3 hours, after the addition is completed, let it stand for 30 minutes, separate the phases, add 1050 L of drinking water to the obtained oily solution, stir Stir for 30 minutes, let stand for 30 minutes, separate the phases, add a mixed solution of 1050L drinking water and 4.5kg industrial sodium hydroxide to the obtained oil phase, stir for 30 minutes, let stand for 30 minutes, separate the phases, add 1050L drinking water to the obtained oil phase again, stir for 30 minutes, let stand for 30 minutes, separate the phases, and use 12kg 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%;

[0059] 2. Fluorination process

[0060] 645 kg of 1,1,1,3,3,3-hexafluoro-2-(chloromethoxy)-propane prepared in the previous step was added to a reaction tank, and 1103 kg of polyethylene glycol 400 and 259.2 kg of industrial anhydrous potassium fluoride were added. After the feeding was completed, stirring was started, heating was turned on, and the reaction was carried out at 75° C. for 4 hours. After the reaction was completed, the feed liquid was cooled to 45° C., and 1290 L, 968 L, and 968 L of drinking water were used in sequence to stir for 30 minutes, and the phases were allowed to stand for 30 minutes to obtain a crude sevoflurane product with a mass yield of 95%. The sevoflurane content in the crude sevoflurane product was 76%, and the total content of polyethylene glycol 400, potassium fluoride, and potassium chloride reached 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 amount of water used, but also effectively improves the purity of the prepared crude sevoflurane, and the total yield is also improved to a certain extent, achieving cost reduction and efficiency improvement, and the environmental protection of the process is greatly improved, the wastewater treatment cost is significantly reduced, and it has high practical value.

[0062] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modification, equivalent substitution or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A clean production process for sevoflurane, characterized in that: The steps include: S1, using hexafluoroisopropanol, anhydrous aluminum chloride and paraformaldehyde as raw materials, performing an etherification reaction to obtain an etherification reaction liquid; slowly adding the etherification reaction liquid into water for a hydrolysis reaction, and after the hydrolysis is completed, standing for phase separation, washing the obtained oil phase, and drying to obtain 1,1,1,3,3,3-hexafluoro-2-(chloromethoxy)-propane; S2, adding the 1,1,1,3,3,3-hexafluoro-2-(chloromethoxy)-propane and anhydrous potassium fluoride to a reaction solvent, mixing them evenly, and performing a fluorination reaction to obtain a fluorination reaction liquid; cooling the fluorination reaction liquid to 40°C to 50°C, filtering by pressure, cooling the obtained filtrate to 0°C to 5°C, standing for phase separation, and obtaining sevoflurane.

2. The clean 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 10h to 20h.

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

4. The clean production process of sevoflurane according to claim 1, characterized in that: In S1, the etherification reaction liquid is added dropwise for 2 h to 4 h, and the temperature of the system is controlled not to exceed 60°C during the dropping process.

5. The clean production process of sevoflurane according to claim 1, characterized in that: In S1, the washing specifically includes the following steps: adding water to the oil phase, performing a first stirring washing, standing for phase separation, and obtaining a first oil phase; adding sodium hydroxide solution to the first oil phase, performing a second stirring washing, standing for phase separation, and obtaining a second oil phase; adding water to the second oil phase again, performing a third stirring washing, standing for phase separation, and drying to obtain 1,1,1,3,3,3-hexafluoro-2-(chloromethoxy)-propane.

6. The clean production process of sevoflurane according to claim 5, characterized in that: During the washing process, the mass ratio of water to hexafluoroisopropanol used in the first and third stirring washing processes is (1.5-2.0):1; and / or 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.

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

8. The clean production process of sevoflurane according to claim 1 or 7, characterized in that: In S2, the mass ratio of the 1,1,1,3,3,3-hexafluoro-2-(chloromethoxy)-propane to the reaction solvent is 1:(1.5-2.0).

9. The clean 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).

10. The clean 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 3h to 5h; and / or In S2, the standing time for phase separation is 1 h to 1.5 h.