A method for the preparation of heptafluoroethane

Abstract

The application provides a preparation method of improved heptafluoroethane, which comprises the following steps: reacting hexafluoroisopropanol with bromochloromethane substituted with different halogen atoms under alkaline conditions 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 heptafluoroethane. The method not only solves the technical defect that hydrogen fluoride or strong acid needs to be used in the heptafluoroethane production process in the prior art, which is not conducive to large-scale production, but also can avoid the generation of by-reaction impurities, obtain heptafluoroethane with high yield and high purity, avoid material waste, and improve the raw material utilization rate. The method has the advantages of easy raw material acquisition, low cost, mild reaction condition, convenient operation, high safety, and suitability for industrial application.

Description

Technical Field

[0001] This invention belongs to the technical field of medicinal chemistry, specifically relating to an improved method for preparing sevoflurane. Background Technology

[0002] Sevoflurane (fluoromethyl-2,2,2-trifluoro-1-(trifluoromethyl)ethyl ether), as an inhaled general anesthetic, is a colorless and transparent liquid with the characteristics of rapid loss of consciousness and rapid recovery. Therefore, it is a commonly used anesthetic in clinical practice.

[0003] Currently, there are numerous reports on methods for preparing heptafluoroane. However, the more mature methods all involve the use of highly corrosive and toxic hydrogen fluoride gas or highly corrosive strong acids, posing certain safety hazards to equipment and operators, and hindering large-scale industrial production. For example, US Patent 4469898 prepares heptafluoroane by heating a mixture of concentrated sulfuric acid, hydrogen fluoride, paraformaldehyde, and hexafluoroisopropanol; Chinese Patent CN1074759C prepares heptafluoroane by heating a mixture of concentrated sulfuric acid, hydrogen fluoride, and (CF3)2CHOCH2OCH3. Both of these patents directly use hydrogen fluoride gas.

[0004] Chinese patent CN101337863A reports an optimized method for preparing heptafluoroane. This method involves reacting hexafluoroisopropanol with dimethoxymethane in the presence of a catalyst. The resulting intermediate, methoxymethylene hexafluoroisopropyl ether, is then reacted with a metal fluoride or other fluoride salts that exist in solid form under normal conditions in the presence of a strong acid to prepare heptafluoroane. Compared to the methods described above, this method avoids the direct use of highly corrosive and toxic hydrogen fluoride gas. However, the strong acids used in the reaction are still highly corrosive. For example, fuming sulfuric acid, which is involved, is prone to explosion upon contact with water, organic matter, and oxidants. The reaction route is shown below:

[0005]

[0006] In addition, Chinese patent CN101314560A reports another method for preparing heptafluoroane. In this method, strong acids such as sulfuric acid and hydrochloric acid are still used in the fluorination step of the intermediate halomethyl-2,2,2-trifluoro-1-(trifluoromethyl)ethyl ether, which does not use highly corrosive strong acids.

[0007]

[0008] Although Chinese patent CN1431987A reports a method for preparing heptafluoroane that does not involve strong acids, in which a haloalcohol is refluxed with a dihalomethane under alkaline conditions to obtain an intermediate, and then fluorinated under fluorinating conditions to obtain heptafluoroane, the dihalomethane used in this method has the same halogen atom in it, which easily forms di(1,1,1,3,3,3-hexafluoroisopropoxy)methane. This intermediate is difficult to fluorinate to obtain heptafluoroane, resulting in low yield and crude heptafluoroane with high impurity content.

[0009] Although there are patent reports of obtaining heptafluoroane directly from chloromethyl-2,2,2-trifluoro-1-(trifluoromethyl)ethyl ether via fluorination, and the use of polyhydroxy compounds such as diethylene glycol, triethylene glycol, or ethylene glycol as reaction activators to react with salts such as potassium fluoride and sodium fluoride in solvent or non-solvent states, although the reaction conditions are relatively mild and the reaction effect is relatively ideal, the amount of diethylene glycol and triethylene glycol used is relatively large, and these solvents containing hydroxyl groups easily react with chloromethyl-2,2,2-trifluoro-1-(trifluoromethyl)ethyl ether, producing a large number of impurity byproducts, thereby affecting the product yield and product quality. Summary of the Invention

[0010] To address the problems existing in the prior art, this invention provides an improved method for preparing heptafluoroane. Under alkaline conditions, hexafluoroisopropanol is reacted with bromochloromethane with different halogen atom substitutions to obtain the intermediate chloromethyl-2,2,2-trifluoro-1-(trifluoromethyl)ethyl ether, which is then fluorinated with a fluorinating agent to obtain heptafluoroane. This method not only solves the technical drawback of existing heptafluoroane production processes requiring hydrogen fluoride or strong acids, which is detrimental to large-scale production, but also avoids the generation of side reaction impurities, yielding heptafluoroane with high yield and high purity, avoiding material waste, and improving raw material utilization. This method uses readily available raw materials, has low cost, mild reaction conditions, is easy to operate, and has high safety, making it suitable for industrial applications.

[0011] The synthetic route of this invention is shown below:

[0012]

[0013] Step 1: Add chlorobromomethane, alkali and organic solvent to the reaction vessel, stir at room temperature and then add hexafluoroisopropanol. Stir the reaction under controlled temperature. After the reaction is completed, distill at atmospheric pressure to obtain the fraction. Wash the fraction with water three times to obtain chloromethyl-2,2,2-trifluoro-1-(trifluoromethyl)ethyl ether.

[0014] Step 2: Add chloromethyl-2,2,2-trifluoro-1-(trifluoromethyl)ethyl ether, triethylene glycol, fluorinating agent and heptafluoroane to the reaction vessel, stir the reaction under controlled temperature, and after the reaction is completed, distill at atmospheric pressure to obtain the fraction, wash the fraction with water, and then purify it by distillation to obtain pure heptafluoroane.

[0015] Preferably, the organic solvent in step 1 is selected from one or more of N,N-dimethylformamide, dimethyl sulfoxide, and acetonitrile; wherein the mass-to-volume ratio of chlorobromomethane to the organic solvent is 1:15-25, with mass in g and volume in ml; preferably 1:20.

[0016] Preferably, the alkali mentioned in step 1 is selected from potassium carbonate, sodium carbonate, and triethylamine; wherein the molar ratio of chlorobromomethane to alkali is 1:1.5 to 3; preferably 1:2 to 2.2.

[0017] Preferably, the mass ratio of bromochloromethane to hexafluoroisopropanol in step 1 is 0.8 to 1.1:1; more preferably, it is 0.9 to 1.0:1.

[0018] Preferably, the temperature controlled in step 1 is 80–90°C.

[0019] Preferably, the stirring time in step 1 is 12 to 16 hours.

[0020] Preferably, the fluorinating agent in step 2 is potassium fluoride, sodium fluoride, or calcium fluoride; more preferably, it is anhydrous potassium fluoride. The molar ratio of chloromethyl-2,2,2-trifluoro-1-(trifluoromethyl)ethyl ether to the fluorinating agent is 1:1 to 2.5; preferably, it is 1:1.3 to 1.5.

[0021] Preferably, 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.

[0022] Preferably, the mass-to-volume ratio of chloromethyl-2,2,2-trifluoro-1-(trifluoromethyl)ethyl ether to heptafluoroane in step 2 is 1:0.5 to 2, with mass in g and volume in ml; more preferably, it is 1:0.5 to 0.8.

[0023] Preferably, the temperature for temperature control in step 2 is 80–90°C.

[0024] Preferably, the stirring reaction time in step 2 is 6 to 9 hours.

[0025] Compared with the prior art, the technical effects achieved by the present invention are as follows:

[0026] 1. The method provided by this invention solves the technical defect in the existing technology of heptafluoroane production process that requires the use of hydrogen fluoride or strong acid, which is not conducive to large-scale production.

[0027] 2. By improving the process conditions, especially by adding heptafluoroane, this invention can avoid the generation of side reaction impurities and obtain heptafluoroane with high yield and high purity. This can reduce the use of triethylene glycol, avoid material waste, and improve the utilization efficiency of raw materials.

[0028] 3. The process of this invention uses hexafluoroisopropanol as a starting material, which is readily available, low in cost, has mild reaction conditions, is easy to operate, and is highly safe, making it suitable for continuous industrial production of heptafluoroane. Detailed Implementation

[0029] The present invention will be further illustrated by the following embodiments. It should be understood that the embodiments of the present invention are merely for illustrating the present invention and are not intended to limit the present invention. Therefore, any simple improvements to the present invention under the premise of the method of the present invention are within the scope of protection claimed by the present invention.

[0030] Example 1

[0031] 154 g of chlorobromomethane, 328 g of potassium carbonate, and 3.0 L of N,N-dimethylformamide were added to a reactor. After stirring at room temperature for three hours, 154 g of hexafluoroisopropanol was added. The temperature was controlled at 80–90 °C, and the reaction was stirred for 12 hours. After the reaction was completed, the fraction was distilled at atmospheric pressure at 85–110 °C. The fraction was washed three times with water to obtain 178.2 g of chloromethyl-2,2,2-trifluoro-1-(trifluoromethyl)ethyl ether with a GC purity of 97.66%.

[0032] 178.2 g of chloromethyl-2,2,2-trifluoro-1-(trifluoromethyl)ethyl ether, 12.4 g of triethylene glycol, 71.3 g of anhydrous potassium fluoride, and 73.5 g of heptafluoroane were added to a reactor. The temperature was controlled at 80–90 °C, and the mixture was stirred for 6 hours. After the reaction was completed, the mixture was distilled at 90–120 °C under normal pressure to obtain a fraction. The fraction was washed once with water to obtain crude heptafluoroane. The crude product was then fractionally distilled to collect the fraction at 58–59 °C, yielding 225.5 g of pure heptafluoroane. The actual yield was 92.2% (excluding the added heptafluoroane), and the GC purity was 99.91%.

[0033] Example 2

[0034] 154 g of chlorobromomethane, 360.8 g of potassium carbonate, and 2.3 L of N,N-dimethylformamide were added to a reactor. After stirring at room temperature for three hours, 171 g of hexafluoroisopropanol was added. The temperature was controlled at 80–90 °C, and the reaction was stirred for 12 hours. After the reaction was completed, the fraction was distilled at atmospheric pressure at 85–110 °C. The fraction was washed three times with water to obtain 193.4 g of chloromethyl-2,2,2-trifluoro-1-(trifluoromethyl)ethyl ether with a GC purity of 97.63%.

[0035] 193.4 g of chloromethyl-2,2,2-trifluoro-1-(trifluoromethyl)ethyl ether, 19 g of triethylene glycol, 66.8 g of anhydrous potassium fluoride, and 110.1 g of heptafluoroane were added to a reactor. The temperature was controlled at 80–90 °C, and the mixture was stirred for 6 hours. After the reaction was completed, the mixture was distilled at atmospheric pressure at 90–120 °C to obtain a fraction. The fraction was washed once with water to obtain crude heptafluoroane. The crude product was then fractionally distilled to collect the fraction at 58–59 °C, yielding 274.4 g of pure heptafluoroane. The actual yield was 91.9% (excluding the added heptafluoroane), and the GC purity was 99.92%.

[0036] Example 3

[0037] 185g of chlorobromomethane, 300g of sodium carbonate, and 3.5L of dimethyl sulfoxide were added to the reactor. After stirring at room temperature for three hours, 168g of hexafluoroisopropanol was added. The temperature was controlled at 80-90℃, and the reaction was stirred for 12 hours. After the reaction was completed, the fraction was distilled at atmospheric pressure at 85-110℃. The fraction was washed with water three times to obtain 192g of chloromethyl-2,2,2-trifluoro-1-(trifluoromethyl)ethyl ether with a GC purity of 97.65%.

[0038] 192 g of chloromethyl-2,2,2-trifluoro-1-(trifluoromethyl)ethyl ether, 10 g of triethylene glycol, 56 g of anhydrous sodium fluoride, and 60.3 g of heptafluoroane were added to a reactor. The temperature was controlled at 80–90 °C, and the mixture was stirred for 6 hours. After the reaction was completed, the mixture was distilled at atmospheric pressure at 90–120 °C to obtain a fraction. The fraction was washed once with water to obtain crude heptafluoroane. The crude product was then fractionally distilled to collect the fraction at 58–59 °C, yielding 217 g of pure heptafluoroane. The actual yield was 88.3% (excluding added heptafluoroane), and the GC purity was 99.91%.

[0039] Example 4

[0040] 218 g of chlorobromomethane, 273 g of potassium carbonate, and 3.0 L of N,N-dimethylformamide were added to the reactor. After stirring at room temperature for three hours, 168 g of hexafluoroisopropanol was added. The temperature was controlled at 70 °C, and the reaction was stirred for 16 hours. After the reaction was completed, the fraction was distilled at atmospheric pressure at 85–110 °C. The fraction was washed with water three times to obtain 177 g of chloromethyl-2,2,2-trifluoro-1-(trifluoromethyl)ethyl ether with a GC purity of 97.56%.

[0041] 177g of chloromethyl-2,2,2-trifluoro-1-(trifluoromethyl)ethyl ether, 25g of triethylene glycol, 138g of anhydrous potassium fluoride, and 100ml of heptafluoroane were added to a reactor. The temperature was controlled at 80-90℃, and the mixture was stirred for 10 hours. After the reaction was completed, the fraction was distilled at atmospheric pressure at 90-120℃. The fraction was washed once with water to obtain crude heptafluoroane. The crude product was further distilled to collect the fraction at 58-59℃, yielding 208g of pure heptafluoroane. The actual yield was 83.4% (excluding added heptafluoroane), and the GC purity was 99.90%.

[0042] Example 5

[0043] 154 g of chlorobromomethane, 328 g of potassium carbonate, and 3.0 L of N,N-dimethylformamide were added to a reactor. After stirring at room temperature for three hours, 154 g of hexafluoroisopropanol was added. The temperature was controlled at 80–90 °C, and the reaction was stirred for 12 hours. After the reaction was completed, the fraction was distilled at atmospheric pressure at 85–110 °C. The fraction was washed three times with water to obtain 173.9 g of chloromethyl-2,2,2-trifluoro-1-(trifluoromethyl)ethyl ether with a GC purity of 97.21%.

[0044] 173.9 g of chloromethyl-2,2,2-trifluoro-1-(trifluoromethyl)ethyl ether, 100 g of triethylene glycol, and 69.2 g of anhydrous potassium fluoride were added to a reactor. The temperature was controlled at 80–90 °C, and the mixture was stirred for 6 hours. After the reaction was completed, the mixture was distilled at 90–120 °C under normal pressure to obtain a fraction. The fraction was washed once with water to obtain crude heptafluoroane. The crude product was then fractionally distilled to collect the fraction at 58–59 °C to obtain 105 g of pure heptafluoroane, with an actual yield of 65.6% and a GC purity of 99.87%.

Claims

1. A method for preparing heptafluoroane, characterized in that, The reaction steps are as follows: ， The specific steps of the preparation method include: Step 1: Add chlorobromomethane, alkali and organic solvent to the reaction vessel, stir at room temperature and then add hexafluoroisopropanol. Stir the reaction under controlled temperature. After the reaction is completed, distill at atmospheric pressure to obtain the fraction. Wash the fraction with water three times to obtain chloromethyl-2,2,2-trifluoro-1-(trifluoromethyl)ethyl ether. Step 2: Add chloromethyl-2,2,2-trifluoro-1-(trifluoromethyl)ethyl ether, triethylene glycol, fluorinating agent and heptafluoroane to the reaction vessel, stir the reaction under controlled temperature, and after the reaction is completed, distill at atmospheric pressure to obtain the fraction, wash the fraction with water, and then purify it by distillation to obtain pure heptafluoroane. The alkali mentioned in step 1 is selected from potassium carbonate, sodium carbonate, and triethylamine; the mass ratio of bromochloromethane to hexafluoroisopropanol mentioned in step 1 is 0.8 to 1.1:1; the mass ratio of chloromethyl-2,2,2-trifluoro-1-(trifluoromethyl)ethyl ether to triethylene glycol mentioned in step 2 is 1:0.05 to 0.

1. The organic solvent mentioned in step 1 is selected from one or more of N,N-dimethylformamide, dimethyl sulfoxide, and acetonitrile, and the fluorinating agent mentioned in step 2 is potassium fluoride, sodium fluoride, or calcium fluoride.

2. The preparation method according to claim 1, characterized in that, The temperature controlled in step 1 is 80-90℃; the stirring time in step 1 is 12-16 hours.

3. The preparation method according to claim 1, characterized in that, In step 2, the molar ratio of chloromethyl-2,2,2-trifluoro-1-(trifluoromethyl)ethyl ether to the fluorinating agent is 1:1 to 2.

5.

4. The preparation method according to claim 1, characterized in that, The fluorinating agent mentioned in step 2 is anhydrous potassium fluoride.

5. The preparation method according to claim 1, characterized in that, The mass-to-volume ratio of chloromethyl-2,2,2-trifluoro-1-(trifluoromethyl)ethyl ether to heptafluoroane in step 2 is 1:0.5-2, with mass expressed in g and volume in ml.

6. The preparation method according to claim 1, characterized in that, The temperature controlled in step 2 is 80-90°C; the stirring reaction time is 6-9 hours.

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