CN114671742A - Preparation method of sevoflurane - Google Patents
Preparation method of sevoflurane Download PDFInfo
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- CN114671742A CN114671742A CN202011552147.3A CN202011552147A CN114671742A CN 114671742 A CN114671742 A CN 114671742A CN 202011552147 A CN202011552147 A CN 202011552147A CN 114671742 A CN114671742 A CN 114671742A
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- sevoflurane
- trifluoro
- trifluoromethyl
- ethyl ether
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- DFEYYRMXOJXZRJ-UHFFFAOYSA-N sevoflurane Chemical compound FCOC(C(F)(F)F)C(F)(F)F DFEYYRMXOJXZRJ-UHFFFAOYSA-N 0.000 title claims abstract description 52
- 229960002078 sevoflurane Drugs 0.000 title claims abstract description 51
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 238000006243 chemical reaction Methods 0.000 claims abstract description 33
- HHYFUCXZHKDNPT-UHFFFAOYSA-N 2-(chloromethoxy)-1,1,1,3,3,3-hexafluoropropane Chemical compound FC(F)(F)C(C(F)(F)F)OCCl HHYFUCXZHKDNPT-UHFFFAOYSA-N 0.000 claims abstract description 25
- JPOXNPPZZKNXOV-UHFFFAOYSA-N bromochloromethane Chemical group ClCBr JPOXNPPZZKNXOV-UHFFFAOYSA-N 0.000 claims abstract description 25
- 238000000034 method Methods 0.000 claims abstract description 18
- BYEAHWXPCBROCE-UHFFFAOYSA-N 1,1,1,3,3,3-hexafluoropropan-2-ol Chemical compound FC(F)(F)C(O)C(F)(F)F BYEAHWXPCBROCE-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000012025 fluorinating agent Substances 0.000 claims abstract description 9
- 238000003756 stirring Methods 0.000 claims description 25
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 18
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 claims description 18
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 12
- ZIBGPFATKBEMQZ-UHFFFAOYSA-N triethylene glycol Chemical compound OCCOCCOCCO ZIBGPFATKBEMQZ-UHFFFAOYSA-N 0.000 claims description 12
- 239000011698 potassium fluoride Substances 0.000 claims description 9
- 235000003270 potassium fluoride Nutrition 0.000 claims description 9
- 238000005406 washing Methods 0.000 claims description 9
- PUZPDOWCWNUUKD-UHFFFAOYSA-M sodium fluoride Chemical compound [F-].[Na+] PUZPDOWCWNUUKD-UHFFFAOYSA-M 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 5
- 239000011775 sodium fluoride Substances 0.000 claims description 4
- 235000013024 sodium fluoride Nutrition 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- 239000002585 base Substances 0.000 claims description 2
- WUKWITHWXAAZEY-UHFFFAOYSA-L calcium difluoride Chemical compound [F-].[F-].[Ca+2] WUKWITHWXAAZEY-UHFFFAOYSA-L 0.000 claims description 2
- 229910001634 calcium fluoride Inorganic materials 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 239000002253 acid Substances 0.000 abstract description 9
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 abstract description 8
- 229910000040 hydrogen fluoride Inorganic materials 0.000 abstract description 8
- 239000002994 raw material Substances 0.000 abstract description 7
- 239000012535 impurity Substances 0.000 abstract description 5
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- 230000009286 beneficial effect Effects 0.000 abstract description 4
- 230000007547 defect Effects 0.000 abstract description 3
- 125000005843 halogen group Chemical group 0.000 abstract description 3
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 3
- 239000000463 material Substances 0.000 abstract description 3
- 238000007086 side reaction Methods 0.000 abstract description 3
- 239000002699 waste material Substances 0.000 abstract description 3
- 239000012043 crude product Substances 0.000 description 9
- 239000000047 product Substances 0.000 description 8
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 6
- 238000004821 distillation Methods 0.000 description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 238000005260 corrosion Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000003682 fluorination reaction Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- 208000003443 Unconsciousness Diseases 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 230000003444 anaesthetic effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000007797 corrosion Effects 0.000 description 1
- NKDDWNXOKDWJAK-UHFFFAOYSA-N dimethoxymethane Chemical compound COCOC NKDDWNXOKDWJAK-UHFFFAOYSA-N 0.000 description 1
- 238000004880 explosion Methods 0.000 description 1
- 150000004673 fluoride salts Chemical class 0.000 description 1
- 239000003193 general anesthetic agent Substances 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000003999 initiator Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910001512 metal fluoride Inorganic materials 0.000 description 1
- -1 methoxymethylene hexafluoroisopropyl ether Chemical compound 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000013386 optimize process Methods 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- UOULCEYHQNCFFH-UHFFFAOYSA-M sodium;hydroxymethanesulfonate Chemical compound [Na+].OCS([O-])(=O)=O UOULCEYHQNCFFH-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- HIFJUMGIHIZEPX-UHFFFAOYSA-N sulfuric acid;sulfur trioxide Chemical compound O=S(=O)=O.OS(O)(=O)=O HIFJUMGIHIZEPX-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
- C07C41/22—Preparation of ethers by reactions not forming ether-oxygen bonds by introduction of halogens; by substitution of halogen atoms by other halogen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides an improved preparation method of sevoflurane, which comprises the steps of reacting hexafluoroisopropanol with bromochloromethanes substituted by different halogen atoms under an alkaline condition to obtain an intermediate chloromethyl-2, 2, 2-trifluoro-1- (trifluoromethyl) ethyl ether, and then fluorinating by using a fluorinating agent to obtain the sevoflurane. The method not only solves the technical defect that hydrogen fluoride or strong acid is needed in the sevoflurane production process in the prior art and is not beneficial to large-scale production; meanwhile, the production of side reaction impurities can be avoided, the high-yield and high-purity sevoflurane is obtained, the waste of materials is avoided, and the utilization rate of raw materials is improved. The method has the advantages of easily available raw materials, low cost, mild reaction conditions, convenient operation and high safety, and is suitable for industrial application.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to an improved preparation method of sevoflurane.
Background
Sevoflurane (fluoromethyl-2, 2, 2-trifluoro-1- (trifluoromethyl) ethyl ether) is used as an inhalation general anesthetic, is colorless and transparent liquid, has the characteristics of quick unconsciousness and quick recovery, and is a clinical common anesthetic.
At present, the preparation methods of sevoflurane are reported, but the mature preparation methods all involve the use of strong-corrosion virulent gas hydrogen fluoride or strong acid with strong corrosion, have certain potential safety hazards to equipment and operators, and are not beneficial to large-scale industrial production. For example, U.S. patent No. 4469824, which produces sevoflurane by heating a mixture of concentrated sulfuric acid, hydrogen fluoride, paraformaldehyde and hexafluoroisopropanol; chinese patent CN1074759C, by heating concentrated sulfuric acid, hydrogen fluoride and (CF)3)2CHOCH2OCH3To prepare sevoflurane. The above patents all use hydrogen fluoride gas directly.
Chinese patent CN101337863A reports an optimized process for the preparation of sevoflurane by reacting hexafluoroisopropanol with dimethoxymethane in the presence of a catalyst and reacting the resulting intermediate methoxymethylene hexafluoroisopropyl ether with metal fluorides or other fluoride salts normally present in solid form in the presence of strong acid, which avoids the direct use of highly corrosive and virulent hydrogen fluoride gas, compared to the above process. However, the strong acid used in the reaction still has strong corrosiveness, for example, fuming sulfuric acid has the characteristics of being easy to cause explosion when meeting water, organic matters and oxidizing agents, and the like, and the reaction route is as follows:
in addition, chinese patent CN101314560A reports another sevoflurane preparation method, which does not use strong corrosive acid in the fluorination step of intermediate halomethyl-2, 2, 2-trifluoro-1- (trifluoromethyl) ethyl ether, but still uses strong acid such as sulfuric acid, hydrochloric acid, etc. in the preparation of the intermediate.
Although, chinese patent CN1431987A reports a method for preparing sevoflurane without strong acid, in which halogenated alcohol and dihalomethane are refluxed under alkaline condition to obtain intermediate, and then fluorinated under fluorinating agent condition to obtain sevoflurane, the dihalomethane used in the method has the same halogen atom, which is easy to form bis (1,1,1,3,3, 3-hexafluoroisopropoxy) methane, and the intermediate is difficult to be fluorinated to obtain sevoflurane, thus resulting in low yield and crude sevoflurane with high impurity content.
Although there are patents reporting sevoflurane obtained by directly using chloromethyl-2, 2, 2-trifluoro-1- (trifluoromethyl) ethyl ether as a raw material and performing fluorination reaction; although the reaction conditions are relatively mild and have relatively ideal reaction effects when a polyhydroxy compound such as diethylene glycol, triethylene glycol or ethylene glycol is used as a reaction activator and is reacted with a salt such as potassium fluoride or sodium fluoride in a solvent or non-solvent state, the amount of diethylene glycol and triethylene glycol used is large, and such a solvent containing a hydroxyl group is easily reacted with chloromethyl-2, 2, 2-trifluoro-1- (trifluoromethyl) ethyl ether, so that a large amount of impurity byproducts are generated, thereby affecting the yield and the quality of the product.
Disclosure of Invention
Aiming at the problems in the prior art, the invention provides an improved preparation method of sevoflurane, which comprises the steps of reacting hexafluoroisopropanol with bromochloromethane substituted by different halogen atoms under an alkaline condition to obtain an intermediate chloromethyl-2, 2, 2-trifluoro-1- (trifluoromethyl) ethyl ether, and then fluorinating the intermediate chloromethyl-2, 2, 2-trifluoro-1- (trifluoromethyl) ethyl ether by using a fluorinating agent to obtain the sevoflurane. The method not only solves the technical defect that hydrogen fluoride or strong acid is needed in the sevoflurane production process in the prior art and is not beneficial to large-scale production; meanwhile, the production of side reaction impurities can be avoided, the high-yield and high-purity sevoflurane is obtained, the waste of materials is avoided, and the utilization rate of raw materials is improved. The method has the advantages of easily available raw materials, low cost, mild reaction conditions, convenient operation and high safety, and is suitable for industrial application.
The synthetic route of the invention is as follows:
step 1: adding bromochloromethane, alkali and an organic solvent into a reaction vessel, stirring at room temperature, adding hexafluoroisopropanol, stirring at controlled temperature for reaction, distilling at normal pressure to obtain a fraction, and washing the fraction for three times to obtain chloromethyl-2, 2, 2-trifluoro-1- (trifluoromethyl) ethyl ether;
step 2: adding chloromethyl-2, 2, 2-trifluoro-1- (trifluoromethyl) ethyl ether, triethylene glycol, a fluorinating agent and sevoflurane into a reaction vessel, stirring and reacting at controlled temperature, distilling at normal pressure to obtain a fraction after the reaction is finished, washing the fraction with water, and then rectifying and purifying to obtain a sevoflurane pure product.
Preferably, the organic solvent in step 1 is selected from one or more of N, N-dimethylformamide, dimethyl sulfoxide and acetonitrile; wherein the mass volume ratio of the chlorobromomethane to the organic solvent is 1: 15-25, wherein the mass is g, and the volume is ml; preferably 1: 20.
preferably, the base in step 1 is selected from potassium carbonate, sodium carbonate, triethylamine; wherein the molar ratio of the chlorobromomethane to the alkali is 1: 1.5 to 3; preferably 1: 2 to 2.2.
Preferably, the mass ratio of bromochloromethane to hexafluoroisopropanol in the step 1 is 0.8-1.1: 1; preferably 0.9 to 1.0: 1.
preferably, the temperature control in the step 1 is 80-90 ℃.
Preferably, the stirring time in the step 1 is 12-16 hours.
Preferably, the fluorinating agent in the step 2 is potassium fluoride, sodium fluoride, calcium fluoride; anhydrous potassium fluoride is preferred. Wherein the molar ratio of chloromethyl-2, 2, 2-trifluoro-1- (trifluoromethyl) ethyl ether to fluorinating agent is 1: 1 to 2.5; preferably 1: 1.3 to 1.5.
Preferably, the mass ratio of chloromethyl-2, 2, 2-trifluoro-1- (trifluoromethyl) ethyl ether to triethylene glycol described in step 2 is 1: 0.05 to 0.1.
Preferably, the mass volume ratio of chloromethyl-2, 2, 2-trifluoro-1- (trifluoromethyl) ethyl ether to sevoflurane in step 2 is 1: 0.5-2, wherein the mass is g, and the volume is ml; preferably 1: 0.5 to 0.8.
Preferably, the temperature control in the step 2 is 80-90 ℃.
Preferably, the stirring reaction time in the step 2 is 6-9 hours.
Compared with the prior art, the invention has the following technical effects:
1. the method provided by the invention overcomes the technical defect that hydrogen fluoride or strong acid is needed in the sevoflurane production process in the prior art, which is not beneficial to large-scale production.
2. By improving the process conditions, particularly adding sevoflurane, the invention can avoid the generation of side reaction impurities, obtain sevoflurane with high yield and higher purity, reduce the use of triethylene glycol, avoid the waste of materials and improve the utilization efficiency of raw materials.
3. The process method takes hexafluoroisopropanol as an initiator, has the advantages of easily obtained raw materials, low cost, mild reaction conditions, convenient operation and high safety, and is suitable for continuous industrial production of sevoflurane.
Detailed Description
The invention is further illustrated by the following examples, which should be properly understood: the examples of the present invention are intended to be illustrative only and not to be limiting, and therefore, the present invention is intended to be simply modified within the scope of the present invention as claimed.
Example 1
154g of bromochloromethane, 328g of potassium carbonate and 3.0L of N, N-dimethylformamide are added into a reactor, 154g of hexafluoroisopropanol is added after stirring for three hours at room temperature, the temperature is controlled to be 80-90 ℃, stirring reaction is carried out for 12 hours, the reaction is finished, distillation is carried out at the temperature of 85-110 ℃ under normal pressure to obtain fraction, and the fraction is washed with water for three times to obtain 178.2g of chloromethyl-2, 2, 2-trifluoro-1- (trifluoromethyl) ethyl ether with the GC purity of 97.66%.
Adding 178.2g of chloromethyl-2, 2, 2-trifluoro-1- (trifluoromethyl) ethyl ether, 12.4g of triethylene glycol, 71.3g of anhydrous potassium fluoride and 73.5g of sevoflurane into a reactor, controlling the temperature to be 80-90 ℃, stirring for reacting for 6 hours, obtaining fraction after the reaction is finished, distilling at the normal pressure of 90-120 ℃, washing the fraction once to obtain a sevoflurane crude product, rectifying the crude product to collect the fraction at the temperature of 58-59 ℃, obtaining 225.5g of sevoflurane pure product with the real yield of 92.2 percent (without the added sevoflurane) and the GC purity of 99.91 percent.
Example 2
154g of bromochloromethane, 360.8g of potassium carbonate and 2.3L of N, N-dimethylformamide are added into a reactor, stirring is carried out for three hours at room temperature, 171g of hexafluoroisopropanol is added, the temperature is controlled to be 80-90 ℃, stirring is carried out for 12 hours, the reaction is finished, distillation is carried out at the temperature of 85-110 ℃ under normal pressure to obtain a fraction, and the fraction is washed with water for three times to obtain 193.4g of chloromethyl-2, 2, 2-trifluoro-1- (trifluoromethyl) ethyl ether with the GC purity of 97.63%.
Adding 193.4g of chloromethyl-2, 2, 2-trifluoro-1- (trifluoromethyl) ethyl ether, 19g of triethylene glycol, 66.8g of anhydrous potassium fluoride and 110.1g of sevoflurane into a reactor, controlling the temperature to be 80-90 ℃, stirring for reaction for 6 hours, obtaining a fraction after the reaction is finished, distilling at the temperature of 90-120 ℃ under normal pressure, washing the fraction once to obtain a sevoflurane crude product, rectifying the crude product to collect the fraction at the temperature of 58-59 ℃, obtaining 274.4g of sevoflurane pure product, achieving the real yield of 91.9% (without adding sevoflurane), and obtaining the GC purity of 99.92%.
Example 3
185g of bromochloromethane, 300g of sodium carbonate and 3.5L of dimethyl sulfoxide are added into a reactor, stirring is carried out for three hours at room temperature, 168g of hexafluoroisopropanol is added, the temperature is controlled to be 80-90 ℃, stirring is carried out for reaction for 12 hours, after the reaction is finished, distillation is carried out at 85-110 ℃ under normal pressure to obtain a fraction, and the fraction is washed with water for three times to obtain 192g of chloromethyl-2, 2, 2-trifluoro-1- (trifluoromethyl) ethyl ether with the GC purity of 97.65%.
Adding 192g of chloromethyl-2, 2, 2-trifluoro-1- (trifluoromethyl) ethyl ether, 10g of triethylene glycol, 56g of anhydrous sodium fluoride and 60.3g of sevoflurane into a reactor, controlling the temperature to be 80-90 ℃, stirring for reacting for 6 hours, finishing the reaction, distilling at 90-120 ℃ under normal pressure to obtain a fraction, washing the fraction once to obtain a sevoflurane crude product, rectifying the crude product to collect a fraction at 58-59 ℃ to obtain 217g of sevoflurane pure product, and really collecting 88.3% (without the added sevoflurane) with the GC purity of 99.91%.
Example 4
Adding 218g of bromochloromethane, 273g of potassium carbonate and 3.0L of N, N-dimethylformamide into a reactor, stirring at room temperature for three hours, adding 168g of hexafluoroisopropanol, controlling the temperature to be 70 ℃, stirring for reacting for 16 hours, after the reaction is finished, distilling at 85-110 ℃ under normal pressure to obtain a fraction, and washing the fraction with water for three times to obtain 177g of chloromethyl-2, 2, 2-trifluoro-1- (trifluoromethyl) ethyl ether with the GC purity of 97.56%.
Adding 177g of chloromethyl-2, 2, 2-trifluoro-1- (trifluoromethyl) ethyl ether, 25g of triethylene glycol, 138g of anhydrous potassium fluoride and 100ml of sevoflurane into a reactor, controlling the temperature to be 80-90 ℃, stirring for 10 hours of reaction, obtaining a fraction after the reaction is finished, distilling at 90-120 ℃ under normal pressure, washing the fraction once to obtain a sevoflurane crude product, rectifying the crude product to collect a fraction at 58-59 ℃ to obtain 208g of sevoflurane pure product, wherein the real yield is 83.4% (no added sevoflurane), and the GC purity is 99.90%.
Example 5
154g of bromochloromethane, 328g of potassium carbonate and 3.0L of N, N-dimethylformamide are added into a reactor, 154g of hexafluoroisopropanol is added after stirring for three hours at room temperature, the temperature is controlled to be 80-90 ℃, stirring reaction is carried out for 12 hours, the reaction is finished, distillation is carried out at the temperature of 85-110 ℃ under normal pressure to obtain a fraction, and the fraction is washed with water for three times to obtain 173.9g of chloromethyl-2, 2, 2-trifluoro-1- (trifluoromethyl) ethyl ether with the GC purity of 97.21%.
173.9g of chloromethyl-2, 2, 2-trifluoro-1- (trifluoromethyl) ethyl ether, 100g of triethylene glycol and 69.2g of anhydrous potassium fluoride are added into a reactor, the temperature is controlled to be 80-90 ℃, the stirring reaction is carried out for 6 hours, the reaction is finished, the distillation is carried out at the temperature of 90-120 ℃ under normal pressure to obtain the fraction, the fraction is washed once to obtain the crude sevoflurane product, the crude product is rectified to collect the 58-59 ℃ fraction, 105g of pure sevoflurane product is obtained, the true yield is 65.6 percent, and the GC purity is 99.87 percent.
Claims (10)
1. The preparation method of sevoflurane is characterized by comprising the following reaction steps:
2. the preparation method according to claim 1, wherein the preparation method comprises the following specific steps:
step 1: adding bromochloromethane, alkali and an organic solvent into a reaction vessel, stirring at room temperature, adding hexafluoroisopropanol, stirring at controlled temperature for reaction, distilling at normal pressure to obtain a fraction, and washing the fraction for three times to obtain chloromethyl-2, 2, 2-trifluoro-1- (trifluoromethyl) ethyl ether;
step 2: adding chloromethyl-2, 2, 2-trifluoro-1- (trifluoromethyl) ethyl ether, triethylene glycol, a fluorinating agent and sevoflurane into a reaction vessel, stirring and reacting at controlled temperature, distilling at normal pressure to obtain a fraction after the reaction is finished, washing the fraction with water, and then rectifying and purifying to obtain a sevoflurane pure product.
3. The method according to claim 2, wherein the organic solvent used in step 1 is one or more selected from the group consisting of N, N-dimethylformamide, dimethylsulfoxide and acetonitrile.
4. The method of claim 2, wherein the base in step 1 is selected from the group consisting of potassium carbonate, sodium carbonate, and triethylamine.
5. The method according to claim 2, wherein the mass ratio of bromochloromethane to hexafluoroisopropanol in step 1 is 0.8 to 1.1: 1.
6. the preparation method according to claim 2, wherein the temperature control in step 1 is 80-90 ℃; the stirring time in the step 1 is 12-16 hours.
7. The method according to claim 2, wherein the fluorinating agent in the step 2 is potassium fluoride, sodium fluoride, calcium fluoride; anhydrous potassium fluoride is preferred. Wherein the molar ratio of chloromethyl-2, 2, 2-trifluoro-1- (trifluoromethyl) ethyl ether to fluorinating agent is 1: 1 to 2.5.
8. The method according to claim 2, wherein the mass ratio of chloromethyl-2, 2, 2-trifluoro-1- (trifluoromethyl) ethyl ether to triethylene glycol in step 2 is 1: 0.05 to 0.1.
9. The method according to claim 2, wherein the mass-to-volume ratio of chloromethyl-2, 2, 2-trifluoro-1- (trifluoromethyl) ethyl ether to sevoflurane in step 2 is 1: 0.5-2, mass in g and volume in ml.
10. The method according to claim 2, wherein the temperature controlled in step 2 is 80-90 ℃; the stirring reaction time is 6-9 hours.
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