WO2010022645A1 - 一种制备氟甲基-1,1,1,3,3,3-六氟异丙基醚的方法 - Google Patents

一种制备氟甲基-1,1,1,3,3,3-六氟异丙基醚的方法 Download PDF

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WO2010022645A1
WO2010022645A1 PCT/CN2009/073484 CN2009073484W WO2010022645A1 WO 2010022645 A1 WO2010022645 A1 WO 2010022645A1 CN 2009073484 W CN2009073484 W CN 2009073484W WO 2010022645 A1 WO2010022645 A1 WO 2010022645A1
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fluoromethyl
hexafluoroisopropanol
reaction
hexafluoroisopropyl ether
ether according
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PCT/CN2009/073484
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English (en)
French (fr)
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徐卫国
李华
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浙江蓝天环保高科技股份有限公司
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Priority to EP09809230.7A priority Critical patent/EP2343269B1/en
Priority to US13/123,190 priority patent/US8530704B2/en
Publication of WO2010022645A1 publication Critical patent/WO2010022645A1/zh

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    • 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
    • C07C41/16—Preparation of ethers by reaction of esters of mineral or organic acids with hydroxy or O-metal groups

Definitions

  • the present invention relates to a process for preparing fluoromethyl-1,1,1,3,3,3-hexafluoroisopropyl ether, in particular 1,1,1,3,3,3-hexafluoro
  • a method of preparing fluoromethyl-1,1,3,3,3-hexafluoroisopropyl ether from isopropanol and CH 2 FX as a raw material in the presence of an acid binding agent isopropanol and CH 2 FX as a raw material in the presence of an acid binding agent.
  • Fluoromethyl-1,1,1,3,3,3-hexafluoroisopropyl ether (also known as "sevoflurane”) is a safe inhalation anesthetic. It has the characteristics of low blood/gas distribution coefficient, no irritability, incombustibility and non-explosion, stable and rapid induction of anesthesia, stable maintenance, quick recovery, easy regulation of anesthesia depth, and unique value in the field of surgical anesthesia.
  • 1,1,1,3,3,3-hexafluoroisopropanol and CX 2 F 2 (X is a halogen) reaction
  • 1,1, 1,3, 3, 3-hexafluoroisopropanol reacts with formaldehyde (trimaldehyde) and anhydrous hydrogen fluoride under concentrated sulfuric acid as a dehydrating agent
  • 1,1,1 , 3,3,3-hexafluoroisopropanol reacts with CH 2 FOCH 2 F
  • (CF 3 ) 2 CH0CH 2 C1 reacts with a fluorinating reagent
  • bromine trifluoride and (CN) 2 CHOCH 3 Preparation (X is a halogen) reaction
  • 1,1, 1,3, 3, 3-hexafluoroisopropanol reacts with formaldehyde (trimaldehyde) and anhydrous hydrogen fluoride under concentrated sulfuric acid as a dehydrating agent
  • 1,1,1 , 3,3,3-hexafluoroisopropanol react
  • 1186303831 discloses the formation of halomethyl hexafluoroisopropyl ether with 1,1,1,3,3,3-hexafluoroisopropanol and CX 2 F 2 (X is a halogen) under basic conditions. Fluorinated reagent is used to prepare sevoflurane. After 18 hours of reaction, the conversion of the starting material 1, 1 , 1 , 3, 3, 3-hexafluoroisopropanol was 92%, and the yield of sevoflurane was 40%. The method has the disadvantages of long reaction time, reaction must be carried out in two steps, low conversion rate of raw materials (low selectivity of product), low product yield, high price of raw materials CBr 2 F 2 and CI 2 F 2 , and the like .
  • U.S. Patent No. 3,683,092, US Pat. A method of preparing sevoflurane by reaction. Take When potassium fluoride and sodium fluoride are fluorinating reagents, it is necessary to use a high boiling point solvent such as sulfolane to react at a high temperature (250-325 ° C) and a high pressure (60-80 atm), and the reaction time is long and the yield is low. When anhydrous hydrogen fluoride is used as the fluorinating reagent, the reaction temperature is 50-80 ° C, and the reaction is carried out under normal pressure, but the conversion of the raw material is low, and the product yield is 50-60%.
  • a high boiling point solvent such as sulfolane
  • ⁇ 097/25303 and 1182004/0073070 disclose the addition of bis(fluoromethyl)ether ([11 2 0 0 [11 2 ] ), 1,1,1,3,3,3-hexafluoroisopropanol and sulfuric acid to each other.
  • the mixture was combined to obtain fluoromethyl-1,1,1,3,3,3-hexafluoroisopropyl ether and unreacted bis(fluoromethyl)ether and acetal.
  • the raw material CH 2 FOCH 2 F is not easily obtained, and the reaction yield is low, less than 30% (based on 1, 1, 1, 3, 3, 3 -hexafluoroisopropanol).
  • the target product fluoromethyl-1,1,1,3,3,3-hexafluoroisopropyl ether is partially decomposed into fluoromethyl-1,1,3,3,3-pentafluoroisopropenyl ether due to
  • the two substances have very close boiling points and are difficult to separate.
  • a large amount of concentrated sulfuric acid is used as a dehydrating agent and a large amount of hydrogen fluoride is used as a fluorinating agent in the method.
  • Hydrogen fluoride is extremely corrosive, requires high material requirements for equipments, pipes, and the like, and generates a large amount of inorganic or organic substances after the reaction. Acidic wastewater, in industrial scale-up production, will bring a series of serious problems such as three-waste treatment.
  • US 3,897,502 discloses the preparation of fluoromethyl groups by fluorination of methyl-2,2,2-trifluoro-1-(trifluoromethyl)ethyl ether with argon-diluted fluorine gas (fluorine content of 20%).
  • the method has a low yield, and the fluorine gas used is highly toxic, expensive, and difficult to control in industrial applications. Therefore, it is necessary to develop a new preparation route of fluoromethyl-1,1,1,3,3,3-hexafluoroisopropyl ether to solve the technical problems existing in the above preparation process.
  • a method for producing fluoromethyl-1,1,1,3,3,3-hexafluoroisopropyl ether which is characterized by the following formula (1)
  • the compound represented by the reaction with 1,1,1,3,3,3-hexafluoroisopropanol in the presence of an acid binding agent is characterized by the following formula (1)
  • X is selected from Cl, Br or I. Since the reactivity of the three raw materials of CH 2 FC1, CH 2 FBr and CH 2 FI is sequentially increased, the effect of the reaction with 1,1,1,3,3,3-hexafluoroisopropanol under the same conditions is achieved. It is also sequentially increased, but CH 2 FI is expensive, so from the viewpoints of operability and economy, C3 ⁇ 4FI is preferable, and C3 ⁇ 4FBr is further preferable.
  • the acid binding agent of the present invention refers to an alkaline substance added to the reaction system for absorbing the acid generated during the reaction. The acid binding agent can form a salt with the acid to prevent the acid from affecting the reaction or the reaction balance.
  • the acid binding agent is selected from the group consisting of an inorganic base or a combination of organic bases.
  • the inorganic base is selected from a combination of one or more of a metal oxide, a metal hydroxide, a metal carbonate or a metal acid carbonate.
  • the metal oxide is selected from the group consisting of one or more of an alkali metal oxide or an alkaline earth metal oxide selected from the group consisting of one or more of an alkali metal hydroxide or an alkaline earth metal hydroxide, a metal
  • the carbonate is selected from the group consisting of one or more of an alkali metal carbonate or an alkaline earth metal carbonate
  • the metal acid carbonate is selected from the group consisting of an alkali metal acid carbonate or an alkaline earth metal acid carbonate. Combination of species or multiples.
  • the alkali metal hydroxide is preferably sodium hydroxide or potassium hydroxide from the viewpoints of easy availability and price factors.
  • the above inorganic base may be added to the reactor as an aqueous solution or may be directly added to the reactor as a solid.
  • the organic base is selected from the group consisting of one or more of pyridine or an amine.
  • the amine may be selected from the group consisting of triethylamine, diethylamine, monoethanolamine, diethanolamine, 1,2-propylenediamine, and tert-butylamine.
  • the present invention may be carried out either in the presence of a solvent or in the absence of a solvent. It is preferred to carry out the reaction in the presence of a solvent.
  • the solvent may be selected from the group consisting of water, linear ether, cyclic ether, nitrile compound, hydrazine, hydrazine-dimethylformamide, hydrazine, hydrazine-dimethylacetamide, hydrazine-methylpyrrolidone or dimethyl sulfoxide. a combination of one or more of them.
  • the linear ether is preferably diethyl ether and/or ethylene glycol dimethyl ether.
  • the cyclic ether is preferably dioxane and/or tetrahydrofuran.
  • the nitrile compound is preferably acetonitrile and/or propionitrile.
  • the reaction system may be added using a combination of one or more of the above solvents.
  • the amount of the solvent to be used in the present invention is not particularly limited, but the mass ratio of the solvent to 1,1,1,3,3,3-hexafluoroisopropanol is preferably considered in view of economy and ease of industrial amplification. 50:1 to 1:1, further preferably 7:1 to 1:1.
  • the present invention can also be carried out in the presence of a phase transfer catalyst.
  • the phase transfer catalyst may be selected from a combination of one or more of a quaternary ammonium salt, a scale salt, a cerium oxide salt, a pyridinium salt or a polyether compound.
  • the quaternary ammonium salt is tetrabutylammonium bromide, tetraethylammonium bromide or tetrabutylammonium hydrogen sulfate.
  • the scale salt is preferably triphenylphosphine.
  • the polyether compound is preferably polyethylene glycol.
  • the amount of the phase transfer catalyst used in the present invention is not particularly limited. However, the molar ratio of the phase transfer catalyst to 1,1,1,3,3,3-hexafluoroisopropanol is preferably 0.0001:1 to 1:1, more preferably 0.01, for economical and practical effects. :1 ⁇ 0.2:1.
  • the present invention does not have strict requirements on the reaction temperature.
  • the reaction temperature is preferably 0 to 300 ° C, and more preferably 0 to 100 ° C.
  • the invention can be carried out in a batch or continuous manner under pressurized or atmospheric conditions. A continuous feed mode is preferred.
  • the reaction does not impose strict requirements on the pressure, but from the viewpoint of increasing the reaction rate, the pressure is increased to facilitate the reaction, but the reaction pressure is too large, and the removal of hydrogen fluoride to form fluoromethyl-1, 1, 3, 3 is likely to occur. l-2.0MPa, Further preferably, the reaction is preferably 0.
  • the olefin is formed by a reaction.
  • l-0.3MPa 0. l-0.5MPa, particularly preferably 0. l-0.3MPa.
  • the amount of the acid binding agent to be used in the present invention is not particularly limited, but the molar ratio of 1,1,1,3,3,3-hexafluoroisopropanol to the acid binding agent is preferably selected in terms of increasing the reaction rate and lowering the raw material cost. It is 2:1 ⁇ 1:2.
  • the present invention can be accomplished by any ratio of C3 ⁇ 4FX to 1,1,1,3,3,3-hexafluoroisopropanol.
  • the ratio of CH 2 FX in the feed will help to increase the reaction rate and the conversion of 1,1,1,3,3,3-hexafluoroisopropanol when the ratio of CH 2 FX in the feed is too high, although CH 2 FX can be recycled through recycling, but it is still difficult to avoid partial loss of CH 2 FX, and it also increases the recycling process, resulting in increased production costs, so CH 2 FX and 1,1, 1,3,3,3- six
  • the molar ratio of fluoroisopropanol is preferably from 20:1 to 0.5:1, further preferably from 3:1 to 0.8:1.
  • the reactor of the present invention may be a glass-shaped flask or a stainless steel or a high-pressure reactor lined with a PTFE-lined drum.
  • the choice of the reactor may be selected according to the magnitude of the reaction pressure.
  • the invention provides another method for preparing fluoromethyl-1,1,1,3,3,3-hexafluoroisopropyl ether, which makes CH 2 FBr and 1,1,1,3,3,3-hexa Fluoroisopropanol is reacted in the presence of an acid binding agent, a solvent, and a phase transfer catalyst.
  • the acid binding agent may be a combination of one or more of the above inorganic bases or organic bases, preferably sodium hydroxide and/or potassium hydroxide.
  • the phase transfer catalyst may be a combination of one or more of the above quaternary ammonium salts, scale salts, cerium oxide salts, pyridinium salts or polyether compounds.
  • the quaternary ammonium salt is tetrabutylammonium bromide, tetraethylammonium bromide or tetrabutylammonium hydrogen sulfate.
  • the scale salt is preferably triphenylphosphine.
  • the polyether compound is preferably polyethylene glycol.
  • the solvent may be the above water, a linear ether, a cyclic ether, a nitrile compound, hydrazine, hydrazine-dimethylformamide, hydrazine, hydrazine-dimethylacetamide, hydrazine-methylpyrrolidone or dimethyl sulfoxide. a combination of one or more of them.
  • the linear ether is preferably diethyl ether and/or ethylene glycol dimethyl ether.
  • the cyclic ether is preferably dioxane and/or tetrahydrofuran.
  • the nitrile compound is preferably acetonitrile and/or propionitrile.
  • the mass ratio of the solvent to 1,1,1,3,3,3-hexafluoroisopropanol is preferably 50:1 to 1:1, and more preferably 7:1 to 1:1.
  • the molar ratio of 1,1,1,3,3,3-hexafluoroisopropanol to the acid binding agent is preferably 2:1 to 1:2, and more preferably 0.01:1 to 0.2:1.
  • the molar ratio of the phase transfer catalyst to 1,1,1,3,3,3-hexafluoroisopropanol is preferably 0.0001:1 to 1:1, more preferably 0.01:1 to 0.2:1, and the reaction temperature is preferably 0. 300 ° C, further preferably 0 to 100 ° C.
  • the reaction pressure is preferably 0.1 to 2.0 MPa, further preferably 0.1 to 0.5 MPa, particularly preferably 0.1 to 0.3 MPa.
  • the product of the present invention and the unreacted starting material can be separated by any suitable method in the art, such as a liquid separation method, a rectification method, a column chromatography separation method, or the like, and is preferably a liquid separation and a rectification.
  • the product is separated from the reaction system by rectification or liquid separation operation, and the product is separated and purified, and the operation is simple and convenient.
  • the product after the reaction was qualitatively analyzed by mass spectrometry and quantitatively analyzed by gas chromatography.
  • the present invention can be carried out under the condition that water is a solvent.
  • the acid binding agent, phase transfer catalyst and the like can also be used in the form of an aqueous solution.
  • water is used as the solvent, the reaction product sevoflurane is hardly dissolved in water, and the solution after the reaction is divided into two layers. After separating the lower organic layer, sevoflurane can be separated, and the post-treatment is extremely simple.
  • Raw material 1,1,1,3,3,3-hexafluoroiso The propanol is completely miscible with water, and the system is still weakly alkaline after the reaction is completed. 1,1,1,3,3,3-hexafluoroisopropanol can be separated from the organic phase better. .
  • a good experimental result can also be obtained by reacting under the condition of using water as a solvent and controlling the reaction rate by the use of a phase transfer catalyst.
  • the method for preparing fluoromethyl-1,1,1,3,3,3-hexafluoroisopropyl ether has the advantages of high raw material conversion rate, high product yield, easy separation and purification of the product, and rapid reaction. The operation steps are simple, the operating conditions are mild and easy to control, and it is an ideal preparation route for industrial application.
  • Example 1 In a three-necked flask having a volume of 250 ml, 90 g of 1,1,3,3,3-hexafluoroisopropanol, 71 g of fluoroiodomethane and 31 g of potassium hydroxide were added. The reaction was carried out for 10 hours under the conditions that the reaction temperature was not higher than 40 ° C and the stirring speed was 300 r / min. The solution after completion of the reaction was distilled to obtain 80 g of a colorless transparent liquid. The liquid obtained by distillation was analyzed by gas chromatography, the conversion of fluoroiodomethane was 95%, and the liquid of 80 g contained 85.05% of sevoflurane, and the yield of the reaction was 80.65 %. . Unreacted 1,1,1,3,3,3-hexafluoroisopropanol and fluoroiodomethane can be recycled.
  • Example 2 In a lining PTFE autoclave having a volume of 500 ml, 30 g of 1,1,3,3,3-hexafluoroisopropanol, 10 g of sodium hydroxide and 150 g of DMF were added in one portion. After replacing the air in the kettle with nitrogen, 36 g of chlorofluoromethane was injected at once. The autoclave was heated to 90 ° C and reacted for 6 hours under stirring at a speed of 300 r / min. The solution after completion of the reaction was distilled to obtain 20 g of a colorless transparent liquid.
  • the liquid obtained by distillation was analyzed by gas chromatography, the conversion of 1,1,1,3,3,3-hexafluoroisopropanol was 96%, and the 20 g of liquid contained 80% of sevoflurane to 1 1,1,3,3,3-hexafluoroisopropanol was used as a standard, and the reaction yield was 46.99%. Unreacted 1,1,1,3,3,3-hexafluoroiso Propanol and chlorofluoromethane can be recycled.
  • Example 3 The feed mode for changing chloroform methane was continuous feed, and the others were the same as in Example 2. After the end of the reaction, the product was evaporated to give 25 g of pale yellow transparent liquid. The resulting pale yellow liquid was analyzed by gas chromatography, the conversion of 1,1,1,3,3,3-hexafluoroisopropanol was 98%, and the 25 g of liquid contained 75% of sevoflurane. 1,1,1,3,3,3-hexafluoroisopropanol was used as a standard, and the reaction yield was 53.44%. Unreacted 1,1,1,3,3,3-hexafluoroisopropanol and chlorofluoromethane can be recycled.
  • Example 4 The reactor was changed to a 500 ml stainless steel reaction vessel, and the others were the same as in Example 2. The solution after the reaction was divided into two layers, and the lower layer of a pale yellow organic layer was separated and weighed to 32 g. The resulting pale yellow liquid was analyzed by gas chromatography to contain 70% of sevoflurane. The conversion ratio of 1,1,1,3,3,3-hexafluoroisopropanol is 95%, and the reaction yield is 1,1,1,3,3,3-hexafluoroisopropanol. 65.86 %. Unreacted 1,1,1,3,3,3-hexafluoroisopropanol and chlorofluoromethane can be recycled.
  • the manner of selecting the continuous feed helps to increase the conversion rate of the raw material and the yield of the target product, and the reaction vessel of the stainless steel material is more effective than the reactor for lining the tetrafluorocarbon.
  • Example 5 In a three-necked flask having a capacity of 250 ml, 30 g of 1,1,3,3,3-hexafluoroisopropanol, 100 g of N-methylpyrrolidone, 20 g of fluorobromomethane and 2 g of polyethylene glycol-600 were added in one portion. After dissolving 20 g of sodium carbonate in 40 g of water to prepare a sodium carbonate solution, it was slowly added dropwise to the reaction system to control the dropping rate to control the exothermic rate of the reaction so that the reaction temperature did not rise sharply. The reaction was carried out at room temperature for 8 hours under stirring at a stirring speed of 300 r/min.
  • the solution after completion of the reaction was distilled to obtain 32 g of a colorless transparent liquid.
  • the liquid obtained by distillation is analyzed by gas chromatography, the conversion of 1,1,1,3,3,3-hexafluoroisopropanol is 88%, and the liquid of 32 g contains 78.4% sevoflurane.
  • the reaction yield was 79.51% based on 1,1,1,3,3,3-hexafluoroisopropanol. Unreacted 1,1,1,3,3,3-hexafluoroisopropanol and fluorobromomethane can be recycled.
  • Example 6 In a stainless steel autoclave having a volume of 500 ml, 50 g of 1,1,3,3,3-hexafluoroisopropanol, 60 g of N-methylpyrrolidone and 21 g of chlorofluoromethane were charged. 45 g of sodium carbonate was dissolved in 150 g of water to prepare a sodium carbonate solution at a reaction temperature of not higher than 50 ° C, and then slowly added dropwise to the system. The reaction was carried out for 6 hours under the conditions of a stirring speed of 300 r/min and a reaction temperature of 50 °C. The solution after completion of the reaction was distilled to obtain 45 g of a pale yellow transparent liquid.
  • the liquid obtained by distillation was analyzed by gas chromatography, the conversion of chlorofluoromethane was 80%, and the liquid of 45 g contained 78.2% of sevoflurane, and the yield of the reaction was 71.57 %. . Unreacted 1,1,1,3,3,3-hexafluoroisopropanol and chlorofluoromethane can be recycled.
  • Example 7 In a three-necked flask having a capacity of 250 ml, 30 g, 1,1,3,3,3-hexafluoroisopropanol, 100 g of water, lg of polyethylene glycol-400, and fluoroiodomethane 30 g were added in one portion. . After dissolving 10 g of potassium hydroxide in 40 g of water to prepare a sodium hydroxide solution, it was slowly added dropwise to the reaction system to control the dropping rate to control the exothermic rate of the reaction so that the reaction temperature did not rise. The mixture was reacted at room temperature for 10 hours with stirring. The solution after the reaction was divided into two layers, and the lower layer of the colorless transparent organic layer was separated and weighed to 38 g.
  • the liquid obtained by layering was analyzed by gas chromatography, and 38 g of the liquid contained 80.11% of sevoflurane, and the conversion ratio of 1,1,3,3,3-hexafluoroisopropanol was about 100. %. Based on 1,1,1,3,3,3-hexafluoroisopropanol, the reaction yield was 85.03%, and unreacted fluoroiodomethane was recovered. Sevoflurane, g selectivity, % conversion, % yield, % Example 5 25.04 78.24 88 79.51 Example 6 35.11 78.02 80 71.57 Example 7 30.44 80.11 About 100 85.03 From the above examples, it is known that phase transfer is added. The catalyst helps to increase the conversion of the feedstock, the selectivity and yield of the target product. Similarly, increasing the reaction temperature also contributes to the progress of the reaction, which leads to an improvement in the conversion rate of the raw material.
  • Example 8 In a lining tetrafluorocarbon reactor having a volume of 500 ml, 50 g, 1, 1, 3, 3, 3 - hexafluoroisopropanol, 60 g of N-methylpyrrolidone, 4 g of tetrabutylammonium hydrogen sulfate, and 21 g of fluorine were added. Methyl chloride, 54 g potassium carbonate and 150 g water. The reaction was carried out at room temperature for 9 hours under stirring at a stirring speed of 300 r/min. The solution after completion of the reaction was distilled to obtain 48 g of a colorless transparent liquid. The liquid obtained by distillation was analyzed by gas chromatography.
  • Example 9 The reaction was carried out for 9 hours in the same manner as in Example 8 except that 35 g of fluorobromomethane was used instead of 21 g of chlorofluoromethane.
  • the solution obtained by the reaction was distilled to obtain 50 g of a colorless transparent liquid.
  • the liquid obtained by distillation was analyzed by gas chromatography.
  • the conversion of fluorobromomethane was 84%, and the liquid of 50 g contained 80.53 % of sevoflurane.
  • the reaction yield was 78.20% based on fluorobromomethane. Unreacted fluorobromomethane and 1,1,1,3,3,3-hexafluoroisopropanol can be recycled.
  • Example 10 The reaction was carried out for 9 hours in the same manner as in Example 8 except that 49 g of fluoroiodomethane was used instead of chlorofluoromethane. Will The solution obtained by the reaction was subjected to distillation to obtain 59 g of a colorless transparent liquid. The liquid obtained by distillation was analyzed by gas chromatography. The conversion of fluoroiodomethane was 100%, and the liquid of 59 g contained 91.23% of sevoflurane. The reaction yield was 87.81% based on fluoroiodomethane. Unreacted 1,1,1,3,3,3-hexafluoroisopropanol can be recycled.
  • Example 11 In a three-necked flask having a capacity of 250 ml, 30 g of 1,1,3,3,3-hexafluoroisopropanol, 100 g of hydrazine, hydrazine-dimethylformamide, 20 g of fluorobromomethane and 5 g were added in one portion. Tetrabutylammonium bromide. After dissolving 20 g of potassium hydroxide in 40 g of water to prepare a potassium hydroxide solution, it was slowly added dropwise to the reaction system. The reaction was carried out at room temperature for 6 hours under stirring at a rate of 300 r/min. The solution after completion of the reaction was distilled to obtain 30 g of a colorless transparent liquid.
  • the liquid obtained by distillation was analyzed by gas chromatography, and the conversion of fluorobromomethane was 80%, and that of 30 g of liquid contained 75.43% of sevoflurane, and the reaction yield was 79.90 % based on fluorobromomethane. Unreacted 1,1,1,3,3,3-hexafluoroisopropanol and fluorobromomethane can be recycled.
  • Example 12 instead of fluorobromomethane, 12 g of chlorofluoromethane was used. The reaction was carried out for 6 hours in the same manner as in Example 11. The solution obtained by the reaction was distilled to obtain 25 g of a colorless transparent liquid. The liquid obtained by distillation was analyzed by gas chromatography. The conversion of chlorofluoromethane was 73%, and the liquid of 25 g contained 72.15% of sevoflurane. The reaction yield was 69.80% based on chlorofluoromethane. Unreacted chlorofluoromethane and 1,1,1,3,3,3-hexafluoroisopropanol can be recycled.
  • Example 13 The reaction was carried out for 6 hours in the same manner as in Example 11 except that 28 g of fluoroiodomethane was used instead of fluorobromomethane.
  • the solution obtained by the reaction was distilled to obtain 34 g of a colorless transparent liquid.
  • the liquid obtained by distillation was analyzed by gas chromatography.
  • the conversion of fluoroiodomethane was 94%, and the liquid of 34 g contained 88.03% of sevoflurane.
  • the reaction yield was 89.91% based on fluoroiodomethane. Unreacted fluoroiodomethane and 1,1,1,3,3,3-hexafluoroisopropanol can be recycled.
  • Example 14 In a stainless steel autoclave having a volume of 500 ml, 30 g of 1,1,3,3,3-hexafluoroisopropanol, 15 g of triethylamine and 150 g of acetonitrile were added in one portion. After replacing the air in the kettle with nitrogen, 10 g of chlorofluoromethane was injected at a time. The autoclave was heated to 60 ° C and reacted for 8 hours at a stirring speed of 300 r / min. The solution after completion of the reaction was distilled to obtain 21 g of a pale yellow transparent liquid. The liquid obtained by distillation was analyzed by gas chromatography.
  • Example 15 The reaction was carried out in the same manner as in Example 14 for 8 hours except that 17 g of fluorobromomethane was used instead of fluorobromomethane.
  • the solution obtained by the reaction was distilled to obtain 28 g of a colorless transparent liquid.
  • the liquid obtained by distillation was analyzed by gas chromatography, and the conversion of fluorobromomethane was 89%, and 78.01% of sevoflurane was contained in 28 g of liquid, and the reaction yield was 81.80% based on fluorobromomethane. Unreacted fluorobromomethane and 1,1,1,3,3,3-hexafluoroisopropanol Used for recycling.
  • Example 16 The reaction was carried out in the same manner as in Example 14 for 8 hours except that 27 g of fluoroiodomethane was used instead of fluorobromomethane.
  • the solution obtained by the reaction was distilled to obtain 30 g of a colorless transparent liquid.
  • the liquid obtained by distillation was analyzed by gas chromatography, and the conversion of fluoroiodomethane was 99%.
  • 30 g of liquid contained 90.52% of sevoflurane.
  • the yield of the reaction was 91.43% based on fluoroiodomethane. Unreacted chlorofluoromethane and 1,1,1,3,3,3-hexafluoroisopropanol can be recycled.
  • Example 17 In a stainless steel autoclave having a capacity of 500 ml, 30 g of 1,1,3,3,3-hexafluoroisopropanol, 210 g of acetonitrile, 3.6 g of polyethylene glycol-400, and 37 g of chlorofluoromethane were added in one portion. , 15g sodium hydroxide and 60g water. The reaction was carried out at 50 ° C for 4 hours with stirring. After the reaction, the temperature was lowered to room temperature, and after the gas phase was taken into the air bag, the resulting solution was separated into two layers, and the upper layer of the colorless transparent organic layer was separated and weighed to 35 g. The liquid obtained by layering was analyzed by gas chromatography, and the conversion rate of 65.
  • Example 18 In a three-necked flask having a capacity of 250 ml, 30 g of 1,1,3,3,3-hexafluoroisopropanol, 30 g of hydrazine, hydrazine-dimethylformamide, and 12 g of tetrabutyl were added in one portion. Ammonium bromide, 16 g of fluorobromomethane.

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Description

说明书 一种制备氟甲基 -1，1，1，3，3，3-六氟异丙基醚的方法
技术领域 本发明涉及一种氟甲基 -1,1, 1,3,3,3-六氟异丙基醚的制备方法， 特别是以 1,1,1,3,3,3- 六氟异丙醇和 CH2FX为原料在缚酸剂存在下制备氟甲基 -1,1, 1,3,3,3-六氟异丙基醚的方 法。
背景技术 氟甲基 -1,1, 1,3,3,3-六氟异丙基醚 (又称 "七氟醚"）是一种使用安全的吸入麻醉剂。 具有血 /气分配系数低， 无剌激性， 不燃不爆， 麻醉诱导平稳迅速， 维持平稳， 苏醒快， 麻醉深度易调控等特点， 在手术麻醉领域具有独特的价值。 对于氟甲基 -1,1, 1,3,3,3-六氟异丙基醚的制备， 目前主要有 1,1, 1,3, 3, 3-六氟异丙 醇与 CX2F2 (X为卤素） 反应， 1,1, 1,3, 3, 3-六氟异丙醇与甲醛（三聚甲醛）和 无水氟化氢在浓硫酸为脱水剂下反应， 1,1,1,3,3,3-六氟异丙醇与 CH2FOCH2F 反应， （CF3)2CH0CH2C1 与氟化试剂反应， 和三氟化溴与 (CN)2CHOCH3反应等 6种制备方法。
1186303831公开了以 1,1,1,3,3,3-六氟异丙醇与 CX2F2 (X为卤素） 在碱性 条件下先生成卤甲基六氟异丙基醚， 再经与氟化试剂氟化制备七氟醚。 经 18 个小时反应后，原料 1 , 1 , 1 ,3,3,3-六氟异丙醇的转化率为 92%，七氟醚收率 40%。 该方法具有反应时间长、 反应必须分两步法进行、 原料转化率低（产品的选 择性低）、 产品收率低、 原料 CBr2F2和 CI2F2价格高等缺点。
US3683092 US3689571与 US3911024公开了氯甲基 -1,1, 1,3,3,3-六氟异丙基醚与氟 化钾、氟化钠、氟化氢或者三氟化溴等氟化试剂进行卤交换反应制备七氟醚的方法。 以 氟化钾和氟化钠为氟化试剂时， 需要使用环丁砜等高沸点溶剂， 在高温 (250-325 °C)、 高压 (60-80 大气压)下反应， 反应时间长， 收率低。 以无水氟化氢为氟化试剂时， 反应 温度为 50-80°C， 常压下反应， 但是原料的转化率低， 产物收率为 50-60 %。 以三氟化 溴为氟化试剂时， 反应条件温和， 但是原料三氟化溴价格过于昂贵。上述 3件专利还公 开了 1, 1, 1, 3, 3, 3-六氟异丙醇和硫酸二甲酯与氢氧化钠溶液的反应， 先得到甲基 -2, 2, 2-三氟- (三氟甲基）乙基醚，再用氯气氯化甲基 -2, 2, 2-三氟- (三氟甲基）乙基醚以 生产氯甲基 -1,1, 1,3,3,3-六氟异丙基醚的方法。 此方法反应过程复杂。
^¥097/25303与1182004/0073070公开了将双(氟甲基)醚（〔112?0〔112? )、1,1,1,3,3,3- 六氟异丙醇和硫酸相互混合，从而得到氟甲基 -1,1, 1,3,3,3-六氟异丙基醚以及未反应的双 (氟甲基)醚和乙缩醛。 该方法中原料 CH2FOCH2F 不易得， 反应收率低， 低于 30 % (以 1 , 1 , 1 ,3 , 3 , 3 -六氟异丙醇计）。
US4250334、US4469898与 US6469219公开了通过氟甲基化反应制备七氟醚的方法。 将浓硫酸和氟化氢加入多聚甲醛中，得到一种反应混合物，然后在加热状态下向该反应 混合物中滴加 1,1, 1,3,3,3-六氟异丙醇， 从而产生待收集的气体。但该方法不仅有甲缩醛 以及乙缩醛等副产物生成，还不可避免地生成氟甲基 -1,1, 1,3,3,3-六氟异丙基醚以外的氟 代醚类物质， 1,1,1,3,3,3-六氟异丙醇的转化率仅为 33-38 %。 同时目标产物氟甲基 -1,1, 1,3,3,3-六氟异丙基醚部分分解成氟甲基 -1,1,3,3,3-五氟异丙烯基醚， 由于该两种物 质沸点很接近， 难于分离。 此外该方法中还需要使用大量的浓硫酸作为脱水剂 和大量的氟化氢作为氟化剂， 氟化氢腐蚀性极强， 对设备、 管道等材料材 质要求很高， 而且反应后会产生大量的无机或有机酸性废水， 在工业化放 大生产中会带来三废处理等一系列很严重的问题。
US3897502公开了将甲基 -2,2,2-三氟 -1- (三氟甲基)乙基醚用氩气稀释的氟气 (氟气含 量为 20%)进行氟化反应制备氟甲基 -1,1,1,3,3,3-六氟异丙基醚的方法。该方法收率较低， 且使用的氟气有剧毒， 价格昂贵， 工业应用时不易控制。 所以需要开发一种新的氟甲基 -1,1, 1,3,3,3-六氟异丙基醚的制备路线， 以解决上述制 备过程中存在的技术问题。 发明内容 为解决上述制备方法反应时间长、 反应步骤复杂、 产品选择性差、 产品收率低、 后 处理困难、反应条件苛刻、原料价格高等问题，发明人开发了一种新的氟甲基 -1,1, 1,3,3,3- 六氟异丙基醚的制备方法， 只需单步法反应即可实施， 操作条件温和、 易控， 原料转化 率高、 产品收率高， 产物分离提纯容易。 为实现上述目的， 发明人采取了如下技术措施： 一种制备氟甲基 -1,1,1,3,3,3-六氟异丙基醚的方法， 其特征在于将下列通式 （1 ) 表 示的化合物与 1,1, 1,3,3,3-六氟异丙醇在缚酸剂存在下反应，
CH2FX ( 1 )
式中 X选自 Cl、 Br或 I。 由于 CH2FC1、 CH2FBr和 CH2FI这三种原料的反应活性依次增加， 从而在同等条件 下与 1,1, 1,3,3,3-六氟异丙醇反应时的实施效果也依次递增，但是 CH2FI价格昂贵， 因此 从可操作性和经济性两方面考虑， 优选 C¾FI， 进一步优选 C¾FBr。 本发明所述缚酸剂是指为吸收反应过程中产生的酸，而向反应体系中加入的碱性物 质。 缚酸剂可以与酸形成盐， 从而避免酸影响反应或者反应平衡。 缚酸剂选自无机碱或有机碱的一种或多种的组合。 无机碱选自金属氧化物、 金属氢 氧化物、金属碳酸盐或金属酸式碳酸盐的一种或多种的组合。金属氧化物选自碱金属氧 化物或碱土金属氧化物的一种或多种的组合，金属氢氧化物选自碱金属氢氧化物或碱土 金属氢氧化物的一种或多种的组合，金属碳酸盐选自碱金属碳酸盐或碱土金属碳酸盐的 一种或多种的组合，金属酸式碳酸盐选自碱金属酸式碳酸盐或碱土金属酸式碳酸盐的一 种或多种的组合。 从容易获得及价格因素等方面考虑， 碱金属氢氧化物优选氢氧化钠或氢氧化钾。 上 述无机碱既可以以水溶液形式加入反应器， 也可以直接以固体形式加入反应器。 有机碱选自吡啶或胺中的一种或多种的组合。 胺可以选用三乙胺、 二乙胺、 一乙醇 胺、 二乙醇胺、 1, 2-丙二胺、 叔丁胺。 本发明既可以在溶剂存在下进行， 也可以不在溶剂存在下进行。 优选在溶剂存在下 进行反应。 溶剂可以选自水、 直链状醚、 环状醚、 腈类化合物、 Ν,Ν-二甲基甲酰胺、 Ν,Ν-二甲基乙酰胺、 Ν-甲基吡咯烷酮或二甲基亚砜中的一种或多种的组合。 直链状醚 优选乙醚和 /或乙二醇二甲基醚。 环状醚优选二噁烷和 /或四氢呋喃。 腈类化合物优选乙 腈和 /或丙腈。 可以使用上述溶剂中的一种或多种的组合加入反应体系。本发明对溶剂的使用量没 有特别的限定， 但出于经济性和易于工业放大性方面的考虑， 溶剂与 1,1, 1,3,3,3-六氟异 丙醇的质量比优选为 50:1~1:1， 进一步优选为 7:1~1:1。 本发明也可以在相转移催化剂存下进行反应。相转移催化剂可以选自季铵盐、鱗盐、 氧化锍盐、吡啶盐或聚醚类化合物的一种或多种的组合。季铵盐为四丁基溴化铵、 四乙 基溴化铵或四丁基硫酸氢铵。 鱗盐优选三苯基膦。 聚醚类化合物优选聚乙二醇。 本发明对于相转移催化剂用量没有特别的限制。但出于经济性和实施效果方面的考 虑， 相转移催化剂与 1,1, 1,3,3,3-六氟异丙醇的摩尔比优选为 0.0001:1~1:1， 进一步优选 为 0.01:1~0.2:1。 本发明对反应温度没有严格的要求。 提高反应温度可以加快反应速度， 但是在过高 的温度下反应时， 会降低反应的选择性， 生成大量的烯烃以及烯烃聚合物。 反应温度优 选 0~300°C， 进一步优选 0~100°C。 本发明可以在加压或常压条件下以分批或连续的方式进行。 优选连续进料方式。 反 应对压力不作严格的要求，但从提高反应速度的角度来考虑，提高压力有利于反应地进 行， 但反应压力过大， 容易发生脱除氟化氢生成氟甲基 -1,1,3,3,3-五氟异丙烯基醚的副 反应，而且生成的烯烃容易发生聚合反应生成分子量很大的粘稠聚合物， 导致产物的选 择性降低，所以反应压力优选 0. l-2.0MPa，进一步优选 0. l-0.5MPa，特别优选 0. l-0.3MPa。 本发明对缚酸剂的用量没有特别限制，但出于提高反应速度和降低原料成本方面考 虑， 1,1,1,3,3,3-六氟异丙醇与缚酸剂的摩尔比优选为 2:1~1:2。 缚酸剂用量过高， 容易生 成副产物（CF3)2CHOCH2X并导致产物七氟醚分解成氟甲基 -1,1,3,3,3-五氟异丙烯基醚， 影响产物收率以及增加产物分离提纯步骤。 理论上 C¾FX与 1,1, 1,3,3,3-六氟异丙醇的任意投料比均可以完成本发明。 增加投 料中 CH2FX的比例， 将有利于提高反应速度和 1,1, 1,3,3,3-六氟异丙醇的转化率， 当投 料中 CH2FX 的比例过高时， 虽然 CH2FX 可以通过回收循环使用， 但还是难以避免 CH2FX的部分损失， 同时也增加了回收处理步骤， 导致生产成本增加， 所以 CH2FX与 1,1, 1,3,3,3-六氟异丙醇的摩尔比优选为 20:1~0.5:1， 进一步优选 3:1~0.8:1。 本发明的反应器可以为玻璃材质的烧瓶也可以为不锈钢或者是衬四氟衬桶的高压 反应釜， 反应器的选择可以根据反应压力的大小来进行选择。 本发明提供另一种制备氟甲基 -1,1,1,3,3,3-六氟异丙基醚的方法， 使 CH2FBr 与 1,1, 1,3,3,3-六氟异丙醇在缚酸剂、 溶剂和相转移催化剂存在下反应。 缚酸剂可以是上述无机碱或有机碱的一种或多种的组合，优选氢氧化钠和 /或氢氧化 钾。相转移催化剂可以是上述季铵盐、鱗盐、 氧化锍盐、 吡啶盐或聚醚类化合物的一种 或多种的组合的组合。季铵盐为四丁基溴化铵、 四乙基溴化铵或四丁基硫酸氢铵。鱗盐 优选三苯基膦。 聚醚类化合物优选聚乙二醇。 溶剂可以是上述水、 直链状醚、 环状醚、 腈类化合物、 Ν,Ν-二甲基甲酰胺、 Ν,Ν-二甲基乙酰胺、 Ν-甲基吡咯烷酮或二甲基亚砜 中的一种或多种的组合。 直链状醚优选乙醚和 /或乙二醇二甲基醚。 环状醚优选二噁烷 和 /或四氢呋喃。 腈类化合物优选乙腈和 /或丙腈。 溶剂与 1,1,1,3,3,3-六氟异丙醇的质量比优选为 50:1~1:1， 进一步优选为 7:1~1:1。 1,1, 1,3,3,3-六氟异丙醇与缚酸剂的摩尔比优选为 2:1~1:2， 进一步优选为 0.01:1~0.2:1。 相转移催化剂与 1,1, 1,3,3,3-六氟异丙醇的摩尔比优选为 0.0001:1~1:1， 进一步优选为 0.01:1-0.2:1 反应温度优选优选 0~300 °C， 进一步优选 0~100 °C。 反应压力优选 0.1-2.0MPa, 进一步优选 0.1-0.5MPa， 特别优选 0.1-0.3MPa。 本发明的产物和未反应的原料可以通过本领域任意适宜的方法分离， 如分液法、 精 馏法， 柱层析分离法等， 优选为分液和精馏。 在反应结束后， 通过精馏或分液操作把产 物从反应体系中分离出来， 进行产物的分离与提纯， 操作简单方便。 反应后的产物通过质谱进行定性分析， 用气相色谱进行定量分析。 本发明可以在水为溶剂的条件下进行。 缚酸剂、 相转移催化剂等也可以以水溶液的 形式使用。 当使用水为溶剂时， 反应产物七氟醚几乎不溶解于水， 反应后的溶液分为两 层， 分离下层有机层后就可以分离出七氟醚， 后处理极为简单。 原料 1,1, 1,3,3,3-六氟异 丙醇与水完全互溶， 且在反应完成后的体系仍处在弱碱性的条件下， 1,1, 1,3,3,3-六氟异 丙醇与有机相可以更好的进行分离。 根据本发明的方法， 在以水为溶剂的条件下反应， 通过相转移催化剂的使用控制反应速度， 也可以得到好的实验结果。 本发明制备氟甲基 -1,1, 1,3,3,3-六氟异丙基醚的方法， 不仅具有原料转化率高、产品 收率高， 产物分离提纯容易的优点， 而且反应迅速、 操作步骤简单、 操作条件温和、 易 控， 是一种可工业化应用的较为理想的制备路线。
具体实施方式 采用以下实施例来进一步说明本发明，这些实施例仅用于说明，绝非要限制本发明。
实施例 1 在容积为 250ml的三口烧瓶中， 加入 90gl, 1, 1, 3, 3, 3_六氟异丙醇、 71g氟碘甲烷 和 31g氢氧化钾。 在反应温度不高于 40°C， 搅拌转速为 300r/min的条件下反应 10小 时。将反应结束后的溶液进行蒸馏， 得到 80g的无色透明液体。通过气相色谱法对蒸馏 得到的液体进行分析，氟碘甲烷的转化率为 95 %， 80g的液体中含有 85. 05 %的七氟醚， 以氟碘甲烷为标准， 该反应收率为 80.65 %。 未反应的 1,1, 1,3,3,3-六氟异丙醇和氟碘甲 烷可以回收使用。
实施例 2 在容积为 500ml的衬四氟高压反应釜中， 一次性加入 30gl, 1,1,3,3,3-六氟异丙醇， 10g氢氧化钠， 150g的 DMF后合釜。 用氮气置换釜内的空气后一次性压入 36g氟氯甲 烷。 将高压釜升温至 90°C， 在搅拌转速为 300r/min的条件下反应 6小时。 将反应结束 后的溶液进行蒸馏，得到 20g的无色透明液体。通过气相色谱法对蒸馏得到的液体进行 分析， 1, 1, 1, 3, 3, 3-六氟异丙醇的转化率为 96 %， 20g的液体中含有 80 %的七氟醚， 以 1,1, 1,3,3,3-六氟异丙醇为标准， 该反应收率为 46.69 %。 未反应的 1,1, 1,3,3,3-六氟异 丙醇和氟氯甲烷可以回收使用。
实施例 3 改变氟氯甲烷的进料方式为连续进料， 其他与实施例 2相同。 反应结束后将产物蒸 出， 得到 25g 的淡黄色透明液体。 通过气相色谱法对所得的淡黄色液体进行分析， 1,1, 1,3,3,3-六氟异丙醇的转化率为 98 %，25g的液体中含有 75 %的七氟醚，以 1,1,1,3,3,3- 六氟异丙醇为标准， 该反应收率为 53.44 %。 未反应的 1,1, 1,3,3,3-六氟异丙醇和氟氯甲 烷可以回收使用。
实施例 4 改变反应器为 500ml的不锈钢反应釜， 其他与实施例 2相同。 反应后的溶液分为两 层， 分出下层的淡黄色的有机层， 称重为 32g。 通过气相色谱法对所得的淡黄色液体进 行分析，其中含有 70 %的七氟醚。 1,1,1,3,3,3-六氟异丙醇的转化率为 95 %，以 1,1,1,3,3,3- 六氟异丙醇为标准， 该反应收率为 65.86 %。 未反应的 1,1, 1,3,3,3-六氟异丙醇和氟氯甲 烷可以回收使用。
Figure imgf000008_0001
从上述实施例中可以看出选择连续性进料的方式有助于提高原料转化率和目标产物的 收率， 且不锈钢材质的反应釜比衬四氟反应釜的效果好。
实施例 5 在容量为 250ml的三口烧瓶中， 一次性加入 30gl, 1,1,3,3,3-六氟异丙醇， 100g的 N- 甲基吡咯烷酮， 氟溴甲烷 20g， 2g聚乙二醇 -600。 将 20g碳酸钠溶于 40g的水中配成碳 酸钠溶液后， 缓慢滴加到反应体系中， 控制滴加速度， 以控制反应放热速度， 使反应温 度不会出现骤升。 在搅拌转速为 300r/min的条件于室温反应 8小时。 将反应结束后的 溶液进行蒸馏，得到 32g的无色透明液体。通过气相色谱法对蒸馏得到的液体进行分析， 1, 1, 1, 3, 3, 3-六氟异丙醇的转化率为 88 %， 32g 的液体中含有 78. 24 %的七氟醚， 以 1,1, 1,3,3,3-六氟异丙醇为标准， 该反应收率为 79.51 %。未反应的 1,1, 1,3,3,3-六氟异丙醇 和氟溴甲烷可以回收使用。
实施例 6 在容积为 500ml的不锈钢反应釜中，加入 50gl, 1, 1, 3, 3, 3_六氟异丙醇、 60gN_甲基 吡咯烷酮和 21g氟氯甲烷。在反应温度不高于 50°C的条件下将 45g碳酸钠溶于 150g水 中配成碳酸钠溶液后缓慢滴加到体系中。 在搅拌转速为 300r/min， 反应温度为 50°C的 条件下反应 6小时。将反应结束后的溶液进行蒸馏， 得到 45g的淡黄色透明液体。通过 气相色谱法对蒸馏得到的液体进行分析，氟氯甲烷的转化率为 80 %， 45g的液体中含有 78. 02 %的七氟醚， 以氟氯甲烷为标准， 该反应收率为 71.57 %。 未反应的 1,1,1,3,3,3- 六氟异丙醇和氟氯甲烷可以回收使用。
实施例 7 在容量为 250ml的三口烧瓶中， 一次性加入 30gl, 1,1,3,3,3-六氟异丙醇， 100g的水， lg的聚乙二醇 -400， 氟碘甲烷 30g。将 10g氢氧化钾溶于 40g的水中配成氢氧化钠溶液 后， 缓慢滴加到反应体系中， 控制滴加速度， 以控制反应放热速度， 使反应温度不会出 现骤升。 在搅拌的状态下于室温反应 10小时。 反应后的溶液分为两层， 分出下层的无 色透明的有机层， 称重为 38g。 通过气相色谱法对分层得到的液体进行分析， 38g的液 体中含有 80. 11 %的七氟醚， 1, 1, 1, 3, 3, 3-六氟异丙醇的转化率约为 100 %。 以 1,1, 1,3,3,3-六氟异丙醇为标准， 该反应收率为 85.03 %， 未反应的氟碘甲烷可以回收使 用。 七氟醚， g 选择性， ％ 转化率， ％ 收率， ％ 实施例 5 25.04 78.24 88 79.51 实施例 6 35.11 78.02 80 71.57 实施例 7 30.44 80.11 约 100 85.03 从上述实施例可以得知，加入相转移催化剂有助于提高原料转化率、 目标产物的选 择性和收率。 同样提高反应温度也有助于反应的进行， 带来原料转化率提高等优点。
实施例 8 在容积为 500ml的衬四氟反应釜中，加入 50gl, 1, 1, 3, 3, 3_六氟异丙醇、 60gN_甲基 吡咯烷酮、 4g四丁基硫酸氢铵、 21g氟氯甲烷、 54g碳酸钾和 150g水。 在搅拌转速为 300r/min的条件于室温反应 9小时。 将反应结束后的溶液进行蒸馏， 得到 48g的无色 透明液体。 通过气相色谱法对蒸馏得到的液体进行分析， 氟氯甲烷的转化率为 86 %， 48g的液体中含有 77. 65 %的七氟醚， 以氟氯甲烷为标准， 该反应收率为 70.70 %。未反 应的 1,1, 1,3,3,3-六氟异丙醇和氟氯甲烷可以回收使用。
实施例 9 用 35g氟溴甲烷代替 21g氟氯甲烷， 其他与实施例 8同样的方式进行反应 9小时。 将反应得到的溶液进行蒸馏，得到 50g的无色透明液体。经气相色谱法对蒸馏得到的液 体进行分析， 氟溴甲烷的转化率为 84 %， 50g的液体中含有 80.53 %的七氟醚， 以氟溴 甲烷为标准， 该反应收率为 78.20 %。 未反应完的氟溴甲烷和 1,1, 1,3,3,3-六氟异丙醇可 以回收使用。
实施例 10 用 49g氟碘甲烷代替氟氯甲烷， 其他以与实施例 8同样的方式进行反应 9小时。 将 反应得到的溶液进行蒸馏，得到 59g的无色透明液体。经气相色谱法对蒸馏得到的液体 进行分析， 氟碘甲烷的转化率为 100 %， 59g的液体中含有 91.23 %的七氟醚， 以氟碘甲 烷为标准， 该反应收率为 87.81 %。 未反应完的 1,1, 1,3,3,3-六氟异丙醇可以回收使用。
Figure imgf000011_0001
实施例 11 在容量为 250ml的三口烧瓶中，一次性加入 30gl, 1,1,3,3,3-六氟异丙醇， 100g的 Ν,Ν- 二甲基甲酰胺， 20g氟溴甲烷和 5g四丁基溴化铵。 将 20g氢氧化钾溶于 40g的水中配 成氢氧化钾溶液后， 缓慢滴加到反应体系中。 在搅拌转速为 300r/min的条件于室温反 应 6小时。将反应结束后的溶液进行蒸馏， 得到 30g的无色透明液体。通过气相色谱法 对蒸馏得到的液体进行分析， 氟溴甲烷的转化率为 80 %， 30g的液体中含有 75. 43 %的 七氟醚， 以氟溴甲烷为标准， 该反应收率为 79.90 %。 未反应的 1,1, 1,3,3,3-六氟异丙醇 和氟溴甲烷可以回收使用。
实施例 12 用 12g氟氯甲烷代替氟溴甲烷。 其他以与实施例 11同样的方式进行反应 6小时。 将反应得到的溶液进行蒸馏，得到 25g的无色透明液体。经气相色谱法对蒸馏得到的液 体进行分析， 氟氯甲烷的转化率为 73 %， 25g的液体中含有 72.15 %的七氟醚， 以氟氯 甲烷为标准， 该反应收率为 69.80 %。 未反应完的氟氯甲烷和 1,1, 1,3,3,3-六氟异丙醇可 以回收使用。 实施例 13 用 28g的氟碘甲烷代替氟溴甲烷， 其他以与实施例 11同样的方式进行反应 6小时。 将反应得到的溶液进行蒸馏，得到 34g的无色透明液体。经气相色谱法对蒸馏得到的液 体进行分析， 氟碘甲烷的转化率为 94 %， 34g的液体中含有 88.03 %的七氟醚， 以氟碘 甲烷为标准， 该反应收率为 89.91 %。 未反应完的氟碘甲烷和 1,1, 1,3,3,3-六氟异丙醇可 以回收使用。
Figure imgf000012_0001
实施例 14 在容积为 500ml的不锈钢材质高压反应釜中， 一次性加入 30gl, 1,1,3,3,3-六氟异丙 醇， 15g三乙胺， 150g乙腈后合釜。用氮气置换釜内的空气后一次性压入 10g氟氯甲烷。 将高压釜升温至 60°C， 在搅拌转速为 300r/min的条件下反应 8小时。 将反应结束后的 溶液进行蒸馏，得到 21g的淡黄色透明液体。通过气相色谱法对蒸馏得到的液体进行分 析， 氟氯甲烷的转化率为 76 %， 21g的液体中含有 71. 73 %的七氟醚， 以氟氯甲烷为标 准， 该反应收率为 67.88 %。未反应的 1,1, 1,3,3,3-六氟异丙醇和氟氯甲烷可以回收使用。
实施例 15 以与实施例 14同样的方式进行反应 8小时， 只是用 17g的氟溴甲烷代替氟溴甲烷。 将反应得到的溶液进行蒸馏，得到 28g的无色透明液体。经气相色谱法对蒸馏得到的液 体进行分析， 氟溴甲烷的转化率为 89 %， 28g的液体中含有 78.01 %的七氟醚， 以氟溴 甲烷为标准， 该反应收率为 81.80 %。 未反应完的氟溴甲烷和 1,1, 1,3,3,3-六氟异丙醇可 以回收使用。 实施例 16 以与实施例 14同样的方式进行反应 8小时， 只是用 27g的氟碘甲烷代替氟溴甲烷。 将反应得到的溶液进行蒸馏，得到 30g的无色透明液体。经气相色谱法对蒸馏得到的液 体进行分析， 氟碘甲烷的转化率为 99 %。 30g的液体中含有 90.52 %的七氟醚。 以氟碘 甲烷为标准， 该反应的收率为 91.43 %。 未反应完的氟氯甲烷和 1,1, 1,3,3,3-六氟异丙醇 可以回收使用。
Figure imgf000013_0001
从实施结果可以看出， 以 CH2FI为原料与 1,1, 1,3,3,3-六氟异丙醇反应时， 实施效果 最好， 原料转化率、 目标产物的选择性和收率在同等条件下最高， CH2FBr次之。 同样 提高 CH2FX与 1,1, 1,3,3,3-六氟异丙醇的配比也有助于反应的进行， 带来原料转化率、 目标产物的选择性和收率提高的技术效果。
实施例 17 在容量为 500ml的不锈钢反应釜中， 一次性加入 30gl, 1,1,3,3,3-六氟异丙醇， 210g 乙腈， 3.6g聚乙二醇 -400， 37g氟氯甲烷， 15g氢氧化钠和 60g水。 在搅拌的状态下于 50°C反应 4小时。 反应后降至室温， 将气相收入气袋中后， 再将所得的溶液分为两层， 分出上层的无色透明的有机层， 称重为 35g。 通过气相色谱法对分层得到的液体进行分 析， 35g的液体中含有 65. 12 %的七氟醚， 1, 1, 1, 3, 3, 3_六氟异丙醇的转化率约为 98 %。 以 1,1, 1,3,3,3-六氟异丙醇为标准， 该反应收率为 65.15 %， 未反应的氟氯甲烷可以回收 使用。 实施例 18 在容量为 250ml的三口烧瓶中，一次性加入 30gl, 1,1,3,3,3-六氟异丙醇， 30g的 Ν,Ν- 二甲基甲酰胺， 12g的四丁基溴化铵， 氟溴甲烷 16g。 将 10g碳酸钠溶于 40g的水中配 成碳酸钠溶液后， 缓慢滴加到反应体系中， 在搅拌的状态下于 10CTC反应 5小时。 将反 应结束后的溶液进行蒸馏，得到 20g的淡黄色透明液体。通过气相色谱法对蒸馏得到的 液体进行分析， 20g的液体中含有 65. 86 %的七氟醚， 氟溴甲烷的转化率约为 71 %。 以 氟溴甲烷为标准， 该反应收率为 64.94 %， 未反应的氟碘甲烷可以回收使用。

Claims

权利要求书 、 一种制备氟甲基 -1,1,1,3,3,3-六氟异丙基醚的方法， 其特征在于将下列通式 （1 ) 表 示的化合物与 1,1, 1,3,3,3-六氟异丙醇在缚酸剂存在下反应，
CH2FX ( 1 )
式中 X选自 Cl、 Br或 I。
、 按照权利要求 1所述的制备氟甲基 -1,1, 1,3,3,3-六氟异丙基醚的方法， 其特征在于所 述缚酸剂选自无机碱或有机碱的一种或多种的组合。
、 按照权利要求 2所述的制备氟甲基 -1,1, 1,3,3,3-六氟异丙基醚的方法， 其特征在于所 述无机碱选自金属氧化物、 金属氢氧化物、 金属碳酸盐或金属酸式碳酸盐的一种或 多种的组合。
、 按照权利要求 3所述的制备氟甲基 -1,1, 1,3,3,3-六氟异丙基醚的方法， 其特征在于所 述金属氧化物选自碱金属氧化物或碱土金属氧化物的一种或多种的组合， 所述金属 氢氧化物选自碱金属氢氧化物或碱土金属氢氧化物的一种或多种的组合， 所述金属 碳酸盐选自碱金属碳酸盐或碱土金属碳酸盐的一种或多种的组合， 所述金属酸式碳 酸盐选自碱金属酸式碳酸盐或碱土金属酸式碳酸盐的一种或多种的组合。
、 按照权利要求 2所述的制备氟甲基 -1,1, 1,3,3,3-六氟异丙基醚的方法， 其特征在于所 述有机碱选自胺或吡啶的一种或多种的组合。
、 按照权利要求 5所述的制备氟甲基 -1,1, 1,3,3,3-六氟异丙基醚的方法， 其特征在于所 述胺选自三乙胺、 二乙胺、 一乙醇胺、 二乙醇胺、 1, 2-丙二胺或叔丁胺的一种或多 种的组合。
、 按照权利要求 1至 6之一所述的制备氟甲基 -1,1, 1,3,3,3-六氟异丙基醚的方法， 其特 征在于反应在溶剂存在下进行。
、 按照权利要求 7所述的制备氟甲基 -1,1, 1,3,3,3-六氟异丙基醚的方法， 其特征在于所 述溶剂选自水、 直链状醚、 环状醚、 腈类化合物、 Ν,Ν-二甲基甲酰胺、 Ν,Ν-二甲 基乙酰胺、 Ν-甲基吡咯烷酮或二甲基亚砜中的一种或多种的组合。
、 按照权利要求 8所述的制备氟甲基 -1,1, 1,3,3,3-六氟异丙基醚的方法， 其特征在于所 述直链状醚为乙醚和 /或乙二醇二甲基醚， 所述环状醚为二噁烷和 /或四氢呋喃， 所 述腈类化合物为乙腈和 /或丙腈。 、 按照权利要求 7所述的制备氟甲基 -1,1, 1,3,3,3-六氟异丙基醚的方法， 其特征在 于所述溶剂与 1,1,1,3,3,3-六氟异丙醇的质量比为 50: 1~1 : 1。
、 按照权利要求 10所述的制备氟甲基 -1,1, 1,3,3,3-六氟异丙基醚的方法， 其特征 在于所述溶剂与 1,1,1,3,3,3-六氟异丙醇的质量比为 7: 1~1 : 1。
、 按照权利要求 7所述的制备氟甲基 -1,1, 1,3,3,3-六氟异丙基醚的方法， 其特征在 于在相转移催化剂存在下反应。
、 按照权利要求 12所述的制备氟甲基 -1,1, 1,3,3,3-六氟异丙基醚的方法， 其特征 在于所述相转移催化剂选自季铵盐、 鱗盐、 氧化锍盐、 吡啶盐或聚醚类化合物的一 种或多种的组合。
、 按照权利要求 13 所述的制备氟甲基 -1,1, 1,3,3,3-六氟异丙基醚的方法， 其特征 在于所述季铵盐为四丁基溴化铵、 四乙基溴化铵或四丁基硫酸氢铵， 所述鱗盐为三 苯基膦， 所述聚醚类化合物为聚乙二醇。
、 按照权利要求 12所述的制备氟甲基 -1,1, 1,3,3,3-六氟异丙基醚的方法， 其特征 在于所述相转移催化剂与 1,1, 1,3,3,3-六氟异丙醇的摩尔比为 0.0001 : 1~1 : 1。
、 按照权利要求 15 所述的制备氟甲基 -1,1, 1,3,3,3-六氟异丙基醚的方法， 其特征 在于所述相转移催化剂与 U, 1,3,3,3-六氟异丙醇的摩尔比为 0.01 : 1~0.2: 1。
、 按照权利要求 12所述的制备氟甲基 -1,1, 1,3,3,3-六氟异丙基醚的方法， 其特征 在于反应温度为 0~300°C。
、 按照权利要求 17所述的制备氟甲基 -1,1, 1,3,3,3-六氟异丙基醚的方法， 其特征 在于所述反应温度为 0~100°C。
、 按照权利要求 12所述的制备氟甲基 -1,1, 1,3,3,3-六氟异丙基醚的方法， 其特征 在于 1,1,1,3,3,3-六氟异丙醇与缚酸剂的摩尔比为 2: 1~1 :2。
、 按照权利要求 1所述的制备氟甲基 -1,1, 1,3,3,3-六氟异丙基醚的方法， 其特征在 于所述 CH2FX与 1,1, 1,3,3,3-六氟异丙醇的摩尔比为 20: 1~0.5: 1。
、 按照权利要求 20所述的制备氟甲基 -1,1, 1,3,3,3-六氟异丙基醚的方法， 其特征 在于所述 CH2FX与 1,1,1,3,3,3-六氟异丙醇的摩尔比为 3: 1~0.8: 1。
、 按照权利要求 12所述的制备氟甲基 -1,1, 1,3,3,3-六氟异丙基醚的方法， 其特征 在于反应压力为 0.1-2.0MPa。
、 按照权利要求 22所述的制备氟甲基 -1,1, 1,3,3,3-六氟异丙基醚的方法， 其特征 在于反应压力为 0.1-0.5MPa。 、 按照权利要求 23 所述的制备氟甲基 -1,1, 1,3,3,3-六氟异丙基醚的方法， 其特征 在于反应压力为 0.1-0.3MPa。
、 一种制备氟甲基 -1,1,1,3,3,3-六氟异丙基醚的方法， 其特征在于 CH2FBr 与 1,1, 1,3,3,3-六氟异丙醇在缚酸剂、 溶剂和相转移催化剂存在下反应。
、 按照权利要求 25 所述的制备氟甲基 -1,1, 1,3,3,3-六氟异丙基醚的方法， 其特征 在于在 0~300°C温度和 0.1-2.0MPa反应压力下反应， 溶剂与 1,1, 1,3,3,3-六氟异丙醇 的质量比为 50:1~1:1， 相转移催化剂与 1,1, 1,3,3,3-六氟异丙醇的摩尔比为 0.0001:1-1:1, 1,1, 1,3,3,3-六氟异丙醇与缚酸剂的摩尔比为 2:1-1:2, CH2FBr 与 1,1, 1,3,3,3-六氟异丙醇的摩尔比为 20:1~0.5:1。
、 按照权利要求 26所述的制备氟甲基 -1,1, 1,3,3,3-六氟异丙基醚的方法， 其特征 在于在 0~100°C温度和 0.1-0.3MPa反应压力下反应， 溶剂与 1,1, 1,3,3,3-六氟异丙醇 的质量比为 7:1~1:1， 相转移催化剂与 1,1, 1,3,3,3-六氟异丙醇的摩尔比为 0.01:1-0.2:1, C¾FBr与 1,1, 1,3,3,3-六氟异丙醇的摩尔比为 3:1~0.8:1。
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