Specification
Title of Invention: Purification method and production method of difluoromethyl-1,2,2,2-tetrafluoroethyl ether
Technical field
[0001]
　The present invention relates to a method for purifying and manufacturing difluoromethyl-1,2,2,2-tetrafluoroethyl ether known as an inhalation anesthetic.
Background technology
[0002]
　Difluoromethyl-1,2,2,2-tetrafluoroethyl ether (generic name desflurane, hereinafter sometimes referred to as desflurane) is known as a general inhalation anesthesia agent that provides an appropriate depth of anesthesia and provides good alertness.
[0003]
　As a method for producing desflurane, as shown below, methyl-1,2,2,2-tetrafluoroethyl ether represented by the formula (2) is reacted with chlorine to be chlorinated, and is represented by the formula (3). It is known that dichloromethyl-1,2,2,2-tetrafluoroethyl ether is obtained by further reacting with anhydrous hydrogen fluoride to fluorinate to obtain desflurane represented by the formula (1). ~ 3 are disclosed.
[Chemical 1]

Prior art documents
Patent literature
[0004]
Patent Document 1: West German Patent No. 2361058
Patent Document 2: Japanese Patent Laid-Open No. 2-104545
Patent Document 3: Japanese Patent Laid-Open No. 6-0877777
Summary of the invention
Problems to be Solved by the Invention
[0005]
　An object of the present invention is to provide a method for purifying desflurane and a method for producing desflurane capable of obtaining highly pure desflurane.
Means for solving the problems
[0006]
　The present inventors fluorinated dichloromethyl-1,2,2,2-tetrafluoroethyl ether represented by the formula (3) by a fluorination reaction using anhydrous hydrogen fluoride represented by the following formula, Desflurane represented by the formula (1) was synthesized. Then, in addition to desflurane, chlorofluoromethyl-1,2,2,2-tetrafluoroethyl ether represented by the formula (4), chloroform represented by the formula (A) and formula (B) in addition to desflurane. Dichlorofluoromethane represented by the following formula was produced (see [Preparation Example 1] in Examples).
[Chemical

　Formula 2] Chlorofluoromethyl-1,2,2,2-tetrafluoroethyl ether represented by the formula (4) is a dichloromethyl-1,2,2,2-toluene represented by the formula (3). It is a compound in which one chlorine atom of fluoroethyl ether is substituted with a fluorine atom. When another remaining chlorine atom is further substituted with a fluorine atom, desflurane represented by the formula (1) is obtained. Chloroform and dichlorofluoromethane are ethers of ether compounds represented by the formulas (1), (3) and (4), which have been subjected to a fluorination reaction under severe conditions using anhydrous hydrogen fluoride. It was speculated that the site (-O-) was generated by cleavage.
[0007]
　Therefore, the present inventors have desulfuran, chlorofluoromethyl-, in order to obtain only desflurane by removing the by-products chlorofluoromethyl-1,2,2,2-tetrafluoroethyl ether, chloroform and dichlorofluoromethane. The product containing 1,2,2,2-tetrafluoroethyl ether, chloroform and dichlorofluoromethane was fine distilled. As a result, chlorofluoromethyl-1,2,2,2-tetrafluoroethyl ether and dichlorofluoromethane were removed, but chloroform could not be removed.
[0008]
　The present inventors have confirmed that the reason why chloroform cannot be removed is that desflurane and chloroform form an azeotropic composition and cannot be separated (see Example [Desflurane and chloroform azeotropic composition formation]).
[0009]
　Therefore, the present inventors have conducted extensive studies to solve this problem, and chloroform is decomposed by bringing desflurane containing chloroform into contact with a base in the presence of water and a phase transfer catalyst, Surprisingly, it turns out that desflurane does not break down. It was also found that other trihalomethanes were similarly decomposed. The present invention has been completed based on these findings.
[0010]
　The present invention includes the following inventions 1 to 9.
[0011]
　[Invention 1]
　A mixture containing difluoromethyl-1,2,2,2-tetrafluoroethyl ether represented by the formula (1) and trihalomethane is brought into contact with a base in the presence of water and a phase transfer catalyst to give trihalomethane. A method for purifying difluoromethyl-1,2,2,2-tetrafluoroethyl ether, which comprises the step of decomposing
[Chemical 3]

[0012]
　[Invention 2] A
　method for purifying difluoromethyl-1,2,2,2-tetrafluoroethyl ether of Invention 1, wherein the trihalomethane is chloroform.
[0013]
　[Invention 3] The
　method for purifying difluoromethyl-1,2,2,2-tetrafluoroethyl ether according to Invention 1 or 2, wherein the phase transfer catalyst is an ammonium salt phase transfer catalyst.
[0014]
　[Invention 4]
　The amount of the phase transfer catalyst is 0.001% by mass or more and 30% by mass or less, expressed as a percentage based on the mass of difluoromethyl-1,2,2,2-tetrafluoroethyl ether. A method for purifying difluoromethyl-1,2,2,2-tetrafluoroethyl ether according to Inventions 1 to 3.
[0015]
　[Invention 5] A
　method for purifying difluoromethyl-1,2,2,2-tetrafluoroethyl ether according to Inventions 1 to 4, wherein the base is a hydroxide of an alkali metal.
[0016]
　[Invention 6] An
　alkali metal hydroxide is used in an amount of 0.001% by mass or more and 100% by mass or less, expressed as a percentage based on the mass of difluoromethyl-1,2,2,2-tetrafluoroethyl ether. A method for purifying difluoromethyl-1,2,2,2-tetrafluoroethyl ether according to Invention 5.
[0017]
　[Invention 7]
　Difluoromethyl-1,2,2,2-tetrafluoroethyl according to Inventions 1 to 6, wherein the temperature at which the mixture is brought into contact with a base in the presence of a phase transfer catalyst is from 5°C to 50°C. Purification method of ether.
[0018]
　[Invention 8]
　of difluoromethyl-1,2,2,2-tetrafluoroethyl ether, comprising the step of purifying difluoromethyl-1,2,2,2-tetrafluoroethyl ether by the purification method of Inventions 1 to 7 Production method.
[0019]
　[Invention 9]
　Further, chlorinating methyl-1,2,2,2-tetrafluoroethyl ether represented by the formula (2) with chlorine to give dichloromethyl-1,2 represented by the formula (3). A step of obtaining difluoromethyl-1,2,2,2-tetrafluoroethyl ether represented by the formula (1) by reacting with 2,2-tetrafluoroethyl ether and then fluorinating it with anhydrous hydrogen fluoride is included. A method for producing difluoromethyl-1,2,2,2-tetrafluoroethyl ether according to Invention 8.
[Chemical 4]

[Chemical 5]

[Chemical 6]

Effect of the invention
[0020]
　According to the method for purifying desflurane of the present invention, high-purity desflurane can be obtained by decomposing only trihalomethane, which is a by-product, from desflurane containing trihalomethane without degrading desflurane.
MODE FOR CARRYING OUT THE INVENTION
[0021]
　Hereinafter, the present invention will be described in detail. The present invention is not limited to the following embodiments, and appropriate modifications and improvements are made to the following embodiments based on ordinary knowledge of those skilled in the art within a range not impairing the gist of the present invention. Those are also within the scope of the present invention.
[0022]
　Here, as a method of decomposing chloroform, there is known a Reimer-Chiemann reaction in which chloroform is reacted with potassium hydroxide or sodium hydroxide to form dichlorocarbene (CCl 2 ).
[0023]
　However, even when desflurane containing 250 ppm of chloroform was brought into contact with a 30% aqueous sodium hydroxide solution, chloroform was reduced only to 100 ppm and could not be reduced to the detection limit (1 ppm) or less (Comparative Example 1). .. When desflurane containing 250 ppm of chloroform was brought into contact with sodium ethylate in ethanol, chloroform could be decomposed. However, the target product, desflurane, decomposed (Comparative Example 5).
[0024]
　Chloroform is suspected of inducing arrhythmia, adversely affecting the liver and kidneys, and carcinogenicity, and it is preferably removed as much as possible. Chloroform in desflurane is regulated to 60 ppm or less in the United States (described in USP39 USP39) and 20 ppm or less in Europe (described in European Pharmacopoeia EP9.0).
[0025]
　Other trihalomethanes are also suspected of having carcinogenic and adverse effects on health, and removal of chloroform and other trihalomethanes from desflurane is extremely important for using desflurane as an inhalation anesthetic.
[0026]
　1. Purification method of desflurane
　purification process of desflurane of the invention, the desflurane (difluoromethyl 1,2,2,2-tetrafluoroethyl ether of the formula (1)), a mixture comprising a trihalomethane, water and interphase Contacting with a base in the presence of a transfer catalyst to decompose trihalomethane.
[Chemical 7]

[0027]
　[Trihalomethane] In the
　method for purifying desflurane of the present invention, examples of trihalomethane to be decomposed include chloroform, dichlorofluoromethane, chlorodifluoromethane and trifluoromethane. However, except for trihalomethane which is azeotropic with Desflurane, it can be removed by distillation without contact with a base. The trihalomethane to be removed in the desflurane purification method of the present invention is preferably chloroform.
[0028]
　[Phase Transfer Catalyst]
　The phase transfer catalyst used in the desflurane purification method of the present invention is not particularly limited, but examples thereof include ammonium salt, phosphonium salt, and phase transfer catalysts belonging to ethers. By using the phase transfer catalyst, the reaction between the trihalomethane and the base can proceed smoothly.
[0029]
　Examples of the phase transfer catalyst include tetrabutylammonium bromide which is an ammonium salt, tetraethylammonium chloride, tributylbenzylammonium chloride, or tetrabutylammonium iodide, tetrabutylphosphonium bromide which is a phosphonium salt, triphenylethylphosphonium bromide, or tributylammonium bromide. Phenylmethylphosphonium bromide, 1,4,7,10,13,16-hexaoxacyclooctadecane (common name 18 crown-6), or polyethylene glycol (common name polyethylene glycol 200, polyethylene glycol 400, CAS number: 25322-68-3) ) Can be illustrated.
[0030]
　Among these phase transfer catalysts, ammonium salts having high solubility in water and capable of smoothly proceeding the reaction between trihalomethane and a base are preferable, and among them, tetrabutylammonium bromide is particularly preferable. These phase transfer catalysts may be used alone or in combination of two or more. These phase transfer catalysts are available from reagent manufacturers such as Wako Pure Chemical Industries, Ltd. and Tokyo Kasei Co., Ltd., or chemical manufacturers.
[0031]
　The amount of the phase transfer catalyst is 0.001% by mass or more and 30% by mass or less, expressed as a percentage based on the mass of desflurane. It is preferably 0.01% by mass or more and 20% by mass or less, and particularly preferably 0.01% by mass or more and 10% by mass or less. If it is less than 0.001% by mass, the trihalomethane may not be sufficiently removed. It is not necessary to use more than 30% by mass.
[0032]
　[Base]
　Examples of the base used in the desflurane purification method of the present invention include alkali metal hydrogen carbonate, carbonate, and hydroxide.
[0033]
　For example, lithium hydrogen carbonate which is an alkali metal hydrogen carbonate, sodium hydrogen carbonate or potassium hydrogen carbonate, lithium carbonate, sodium carbonate or potassium carbonate which is an alkali metal carbonate, lithium hydroxide which is an alkali metal hydroxide. , Sodium hydroxide or potassium hydroxide.
[0034]
　Among these bases, hydroxides having a high solubility in water and allowing a reaction with trihalomethane to proceed smoothly are preferable, and sodium hydroxide is particularly preferable. These bases may be used alone or in combination of two or more. These bases are available from reagent manufacturers such as Wako Pure Chemical Industries, Ltd. and Tokyo Kasei Co., Ltd.
[0035]
　Depending on the type of base, the amount used is 0.001% by mass or more and 100% by mass or less, preferably 0.1% by mass or more and 50% by mass, expressed as a percentage based on the mass of desflurane. It is the following. If it is less than 0.001% by mass, the trihalomethane may not be sufficiently removed. There is no particular limitation on the use in excess, however, in order to facilitate the separation operation of desflurane after removal of trihalomethane, specifically the two-layer separation, it is preferable that the amount of base is small, and the alkali metal hydroxide The amount used need not exceed 100% by mass.
[0036]
　The base concentration of the aqueous solution during the reaction is 1% by mass or more and 50% by mass or less, and preferably 10% by mass or more and 30% by mass or less. If it is less than 1% by mass, the trihalomethane may not be sufficiently removed. Although the concentration is not limited, there is a risk of alkali metal hydroxide being precipitated, and the concentration of the aqueous solution need not exceed 50% by mass.
[0037]
　[Temperature] In
　the desflurane purification method of the present invention, the temperature at which the mixture containing desflurane and trihalomethane is brought into contact with a base in the presence of a phase transfer catalyst is 5°C or higher and 50°C or lower. If the temperature is lower than 5°C, the trihalomethane may not be sufficiently removed, and the alkali metal hydroxide may be solidified. Higher temperatures will remove trihalomethane faster, but need not exceed 50°C.
[0038]
　[Pressure] In
　the desflurane purification method of the present invention, the pressure at which a mixture containing desflurane and trihalomethane is brought into contact with a base in the presence of a phase transfer catalyst is preferably 0.1 MPa or more and 3.0 MPa or less on an absolute pressure basis. It is more preferably 0.1 MPa or more and 1.0 MPa or less, and particularly preferably 0.1 MPa or more and 0.3 MPa or less.
[0039]
　[Organic solvent] In
　the desflurane purification method of the present invention, when a mixture containing desflurane and trihalomethane is brought into contact with a base in the presence of a phase transfer catalyst, only water may be present, or an organic solvent may be further added. .. By using an organic solvent, the operation of separating desflurane after decomposing trihalomethane may be simple. As the organic solvent, an organic solvent having low water solubility is preferable.
[0040]
　The organic solvent may be any water-insoluble solvent that dissolves desflurane and does not inhibit the decomposition of trihalomethane, and examples thereof include an aliphatic hydrocarbon, an aromatic hydrocarbon, a nitrile, an acid amide and a lower ether.
[0041]
　For example, n-pentane, n-hexane or n-heptane which is an aliphatic hydrocarbon, benzene, toluene or xylene which is an aromatic hydrocarbon, acetonitrile which is a nitrile, propionitrile, phenylacetonitrile, isobutyronitrile or benzo. Nitrile, acid amide dimethylformamide, dimethylacetamide, methylformamide, formamide, hexamethylphosphoric triamide or N-methylpyrrolidone, lower ether diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, Examples are 1,2-epoxyethane, 1,4-dioxane, dibutyl ether, t-butyl methyl ether or tetrahydrofuran having a substituent. These organic solvents may be used alone or in combination.
[0042]
　The water-soluble organic solvent is not preferable because it separates into layers and remains in the water layer, which complicates wastewater treatment.
[0043]
　For example, methanol and ethanol have high solubility of both desflurane and base and are effective for the decomposition of trihalomethane, but may accelerate the decomposition of desflurane, and when desflurane is recovered after removal of trihalomethane, It is not preferable because it cannot be separated.
[0044]
　The amount of the organic solvent used is preferably 0.03 liters (sometimes referred to as L) or more and 10 L or less, more preferably 0.05 L or more and 10 L or less, and particularly preferably 0. It is 07 or more and 7 L or less.
[0045]
　[Separation Step]
　The method for purifying desflurane of the present invention may further include a separation step of separating a decomposed product of desflurane and trihalomethane.
[0046]
　After contacting a mixture containing desflurane and trihalomethane with a base in the presence of a phase transfer catalyst, in a reaction product separated into two layers, desflurane is distributed to an organic layer and a decomposition product generated from trihalomethane to an aqueous layer. For example, since sodium formate generated when chloroform comes into contact with sodium hydroxide is distributed to the aqueous layer, desflurane containing no sodium formate can be obtained from the organic layer separated by two-layer separation.
[0047]
　Preferably, thereafter, highly pure desflurane can be obtained through distillation of the organic solvent from the organic layer by an evaporator, flash distillation, precision distillation, and the like.
[0048]
　2. Method for producing desflurane In the method for producing desflurane of the
　present invention, as described above, a mixture containing desflurane (difluoromethyl-1,2,2,2-tetrafluoroethyl ether represented by the formula (1)) and trihalomethane is used. , Contacting with a base in the presence of water and a phase transfer catalyst to decompose trihalomethane.
[Chemical 8]

[0049]
　Further, in the method for producing desflurane of the present invention, the mixture containing desflurane and trihalomethane is prepared by chlorinating methyl-1,2,2,2-tetrafluoroethyl ether represented by the formula (2) with chlorine to obtain the compound represented by the formula ( After the dichloromethyl-1,2,2,2-tetrafluoroethyl ether represented by 3) is formed, it is further reacted with anhydrous hydrogen fluoride to fluorinate, and desflurane (difluoromethyl-1 represented by the formula (1) is represented. , 2,2,2-Tetrafluoroethyl ether) can be obtained as a product of the step.
[Chemical 9]

[Chemical 10]

[Chemical 11]

[0050]
　The method for producing desflurane of the present invention may further include the step of separating desflurane described above.
Example
[0051]
　Hereinafter, the present invention will be described in detail with reference to Examples, but the present invention is not limited to these embodiments.
[0052]
　Here, "%" of the composition analysis value represents "area%" of the composition obtained by measuring the raw material or the product by gas chromatography. A hydrogen flame ionization type detector (commonly called FID (Flame Ionization Detector)) was used as a detector. A Karl Fischer measuring device was used to measure the water content.
[0053]
　[Production of Desflurane]
　5.00 kg of dichloromethyl-1,2,2,2-tetrafluoroethyl ether (purity: 95.6) was placed in a pressure-resistant reactor made of stainless steel having an internal volume of 30 L equipped with a stirrer and a pressure gauge. %) and 5.96 kg (10 equivalents) of anhydrous hydrogen fluoride were charged, and the inside of the reactor was gradually heated to 100° C. with stirring. While maintaining the pressure inside the reactor at 2.1 MPa, the produced hydrogen chloride was discharged to the outside of the system, reacted at 100° C. for 8 hours, returned to room temperature, and then degassed. Next, 10 kg of water for absorbing unreacted hydrogen fluoride was added into the reactor to separate the two layers.
　The composition of the organic layer was analyzed by gas chromatography to find that desflurane was 83.8%, the reaction intermediate, chlorofluoromethyl-1,2,2,2-tetrafluoroethyl ether, was 10.00%, and was a by-product. Some chloroform was 0.07%, dichlorofluoromethane was 0.47%, and other impurities were 6.70% in total.
　The obtained organic layer was subjected to precision distillation under atmospheric pressure using a distillation column having 25 theoretical plates. When the composition of the main fraction was analyzed by gas chromatography, desflurane was 99.89%, chloroform was 0.09%, and other impurities were 0.02% in total.
[0054]
　[Confirmation of azeotropic boiling of
　desflurane and chloroform ] The vapor-liquid equilibrium of desflurane and chloroform was measured. After adding 0.14 g of chloroform (boiling point 61.2°C) to 2.0 g of desflurane (boiling point 23°C) alone, the mixture was heated, and the composition of desflurane and chloroform in the gas phase and the liquid phase was measured by gas chromatography. As a result, the composition of both vapor phase and liquid phase was desflurane 99.3% to 99.4%, chloroform 0.06% to 0.07%, and the vapor temperature was 23.6°C to 23.7°C. Thus, desflurane and chloroform formed an azeotropic composition.
[0055]
　[Purification of desflurane]
　[Example 1]
　2.00 g of desflurane containing chloroform having a concentration of 250 ppm and 2 parts of an aqueous sodium hydroxide solution having a concentration of 48 mass% were placed in a pressure-resistant glass reactor having an inner volume of 100 mL equipped with a stirrer and a pressure gauge. Then, 0.000 g and 0.02 g of tetrabutylammonium bromide (hereinafter sometimes referred to as PTC-1) as a phase transfer catalyst were charged.
　Then, the inside of the reactor was heated to 40° C. with stirring, heated at 40° C. for 1.5 hours, then returned to room temperature and deaerated. When the content was transferred to a separating funnel, it was separated into two layers, an organic layer and an aqueous layer. When the chloroform content in the organic layer was measured by gas chromatography, it was below the detection limit (1 ppm or less), and the water content measured by a Karl Fischer meter was 160 ppm.
　Flash distillation of the organic layer was performed under normal pressure. The main fraction was 1.86 g. When the main fraction was measured by gas chromatography, desflurane with a purity of 99.95% or higher was obtained with a recovery rate of 93%.
[0056]
　[Example 2] In
　a pressure-resistant glass reactor having an internal volume of 100 mL equipped with a stirrer and a pressure gauge, 2.00 g of desflurane containing chloroform of 250 ppm in concentration, 2.00 g of 48 mass% concentration of sodium hydroxide aqueous solution, and interphase 0.02 g of PTC-1 was charged as a transfer catalyst.
　Then, while stirring the inside of the reactor at room temperature (about 25° C.), deaeration was performed after 4 hours had elapsed. When the contents were transferred to a separating funnel, two layers, an organic layer and an aqueous layer, were separated. When the chloroform content in the organic layer was measured by gas chromatography, it was below the detection limit (1 ppm or less), and the water content measured by a Karl Fischer meter was 150 ppm.
　Flash distillation of the organic layer was performed under normal pressure. The main fraction was 1.83 g. When the main fraction was measured by gas chromatography, desflurane with a purity of 99.95% or higher was obtained with a recovery rate of 92%.
[0057]
　[Example 3] In
　a pressure-resistant glass reactor having an internal volume of 100 mL equipped with a stirrer and a pressure gauge, 2.00 g of desflurane containing 250 ppm of chloroform, 2.00 g of 30% aqueous sodium hydroxide solution, and phase transfer. 0.02 g of PTC-1 was charged as a catalyst.
　Then, the inside of the reactor was heated to 40° C. with stirring, heated at 40° C. for 7 hours, then returned to room temperature and deaerated. When the content was transferred to a separating funnel, it was separated into two layers, an organic layer and an aqueous layer. When the chloroform content in the organic layer was measured by gas chromatography, it was below the detection limit (1 ppm or less), and the water content measured by a Karl Fischer meter was 170 ppm.
　Flash distillation of the organic layer was performed under normal pressure. The main fraction was 1.79 g, and when the main fraction was measured by gas chromatography, desflurane with a purity of 99.95% or higher was obtained with a recovery rate of 90%.
[0058]
　[Example 4] In
　a pressure-resistant glass reactor having an internal volume of 100 mL equipped with a stirrer and a pressure gauge, 2.00 g of desflurane containing chloroform at a concentration of 3200 ppm, 2.00 g of an aqueous sodium hydroxide solution at a concentration of 30% by mass, and an interphase 0.10 g of PTC-1 was charged as a transfer catalyst.
　Next, the inside of the reactor was heated to 40° C. with stirring, heated at 14° C. for 14 hours, then returned to room temperature and deaerated. When the content was transferred to a separating funnel, it was separated into two layers, an organic layer and an aqueous layer. When the chloroform content in the organic layer was measured by gas chromatography, it was below the detection limit (1 ppm or less), and the water content measured by a Karl Fischer meter was 170 ppm.
　Flash distillation of the organic layer was performed under normal pressure. The main fraction was 1.83 g. When the main fraction was measured by gas chromatography, desflurane with a purity of 99.95% or higher was obtained with a recovery rate of 92%.
[0059]
　[Example 5] In
　a pressure-resistant glass reactor having an internal volume of 100 mL equipped with a stirrer and a pressure gauge, 2.00 g of desflurane containing 250 ppm of concentration of chloroform, 2.00 g of 48 mass% concentration of potassium hydroxide aqueous solution, and interphase 0.02 g of PTC-1 was charged as a transfer catalyst.
　Then, the inside of the reactor was heated to 40° C. with stirring, heated at 40° C. for 1.5 hours, then returned to room temperature and deaerated. When the contents were transferred to a separating funnel, two layers of an organic layer and an aqueous layer were separated. When the chloroform content in the organic layer was measured by gas chromatography, it was below the detection limit (1 ppm or less), and the water content measured by a Karl Fischer meter was 160 ppm.
　Flash distillation of the organic layer was performed under normal pressure. The main fraction was 1.94 g, and when the main fraction was measured by gas chromatography, desflurane with a purity of 99.95% or higher was obtained with a recovery rate of 97%.
[0060]
　[Example 6] In
　a pressure-resistant glass reactor having an internal volume of 100 mL equipped with a stirrer and a pressure gauge, 2.00 g of desflurane containing chloroform of 250 ppm concentration, 2.00 g of sodium hydroxide aqueous solution of 30 mass% concentration, and interphase As a transfer catalyst, 0.02 g of tetraethylammonium chloride (hereinafter sometimes referred to as PTC-2) was charged.
　Then, the inside of the reactor was heated to 40° C. with stirring, heated at 40° C. for 7 hours, then returned to room temperature and deaerated. When the content was transferred to a separating funnel, it was separated into two layers, an organic layer and an aqueous layer. When the chloroform content in the organic layer was measured by gas chromatography, it was below the detection limit (1 ppm or less), and the water content measured by a Karl Fischer meter was 200 ppm.
　Flash distillation of the organic layer was performed under normal pressure. The main fraction was 1.88 g, and when the main fraction was measured by gas chromatography, desflurane with a purity of 99.95% or higher was obtained with a recovery rate of 94%.
[0061]
　[Example 7] In
　a pressure-resistant glass reactor having an internal volume of 100 mL equipped with a stirrer and a pressure gauge, 2.00 g of desflurane containing chloroform at a concentration of 250 ppm, 2.00 g of an aqueous sodium hydroxide solution at a concentration of 30 mass%, and an interphase As a transfer catalyst, 0.02 g of tributylbenzylammonium chloride (hereinafter sometimes referred to as PTC-3) was charged.
　Then, the inside of the reactor was heated to 40° C. with stirring, heated at 40° C. for 7 hours, then returned to room temperature and deaerated. When the content was transferred to a separating funnel, it was separated into two layers, an organic layer and an aqueous layer. When the chloroform content in the organic layer was measured by gas chromatography, it was 6 ppm, and the water content measured by a Karl Fischer meter was 180 ppm.
　Flash distillation of the organic layer was performed under normal pressure. The main fraction was 1.80 g, and when the main fraction was measured by gas chromatography, desflurane with a purity of 99.95% or higher was obtained with a recovery rate of 90%.
[0062]
　[Example 8] In
　a pressure-resistant glass reactor having an internal volume of 100 mL equipped with a stirrer and a pressure gauge, 2.00 g of desflurane containing chloroform of 250 ppm in concentration, 2.00 g of sodium hydroxide aqueous solution of concentration of 30% by mass, and interphase As a transfer catalyst, 0.02 g of tetrabutylammonium iodide (hereinafter sometimes referred to as PTC-4) was charged.
　Then, the inside of the reactor was heated to 40° C. with stirring, heated at 40° C. for 7 hours, then returned to room temperature and deaerated. When the content in the reactor was transferred to a separating funnel, it was separated into two layers, an organic layer and an aqueous layer. When the chloroform content in the organic layer was measured by gas chromatography, it was 18 ppm, and the water content measured by a Karl Fischer meter was 170 ppm.
　Flash distillation of the organic layer was performed under normal pressure. The main fraction was 1.82 g, and when the main fraction was measured by gas chromatography, desflurane with a purity of 99.95% or higher was obtained with a recovery rate of 91%.
[0063]
　[Example 9] In
　a pressure-resistant glass reactor having an internal volume of 100 mL equipped with a stirrer and a pressure gauge, 2.00 g of desflurane containing chloroform at a concentration of 250 ppm, 2.00 g of an aqueous sodium hydroxide solution at a concentration of 30 mass%, and an interphase As a transfer catalyst, 0.02 g of tetrabutylphosphonium bromide (hereinafter sometimes referred to as PTC-5) was charged.
　Then, the inside of the reactor was heated to 40° C. with stirring, heated at 40° C. for 7 hours, then returned to room temperature and deaerated. When the content was transferred to a separating funnel, it was separated into two layers, an organic layer and an aqueous layer. When the chloroform content in the organic layer was measured by gas chromatography, it was below the detection limit (1 ppm or less), and the water content measured by a Karl Fischer meter was 140 ppm.
　Flash distillation of the organic layer was performed under normal pressure. The main fraction was 1.86 g. When the main fraction was measured by gas chromatography, desflurane with a purity of 99.95% or higher was obtained with a recovery rate of 93%.
[0064]
　[Example 10] In
　a pressure-resistant glass reactor having an internal volume of 100 mL equipped with a stirrer and a pressure gauge, 2.00 g of desflurane containing chloroform of 250 ppm concentration, 2.00 g of sodium hydroxide aqueous solution of 30 mass% concentration, and interphase As a transfer catalyst, 0.2 g of polyethylene glycol 400 (hereinafter sometimes referred to as PEG400) was charged.
　Then, the inside of the reactor was heated to 50° C. with stirring, heated at 50° C. for 5 hours, then returned to room temperature and deaerated. When the content was transferred to a separating funnel, it was separated into two layers, an organic layer and an aqueous layer. When the chloroform content in the organic layer was measured by gas chromatography, it was below the detection limit (1 ppm or less), and the water content measured by a Karl Fischer meter was 190 ppm.
　Flash distillation of the organic layer was performed under normal pressure. The main fraction was 1.80 g, and when the main fraction was measured by gas chromatography, desflurane with a purity of 99.95% or higher was obtained with a recovery rate of 90%.
[0065]
　[Example 11] In
　a pressure-resistant glass reactor having an internal volume of 100 mL equipped with a stirrer and a pressure gauge, 2.00 g of desflurane containing chloroform of 250 ppm in concentration, 2.00 g of sodium hydroxide aqueous solution of 30 wt% in concentration, and interphase As a transfer catalyst, 0.20 g of polyethylene glycol 200 (hereinafter sometimes referred to as PEG200) was charged.
　Next, the inside of the reactor was heated to 40° C. with stirring, heated at 40° C. for 5 hours, then returned to room temperature and deaerated. When the content was transferred to a separating funnel, it was separated into two layers, an organic layer and an aqueous layer. When the chloroform content in the organic layer was measured by gas chromatography, it was below the detection limit (1 ppm or less), and the water content measured by a Karl Fischer meter was 200 ppm.
　Flash distillation of the organic layer was performed under normal pressure. The main fraction was 1.79 g, and when the main fraction was measured by gas chromatography, desflurane with a purity of 99.95% or higher was obtained with a recovery rate of 90%.
[0066]
　[Example 12] In
　a pressure-resistant glass reactor having an internal volume of 1 L equipped with a stirrer, a reflux condenser and a jacket, 500.0 g of desflurane containing chloroform of 250 ppm in concentration and 500.0 g of sodium hydroxide aqueous solution of 30 mass% in concentration, Further, 5.0 g of tetrabutylammonium bromide (hereinafter sometimes referred to as PTC-1) was charged as a phase transfer catalyst.
　Next, warm water of 40° C. was put in the jacket, and the contents were refluxed for 27 hours while stirring while keeping the contents at 40° C. Then, the chloroform content in the organic layer was measured by gas chromatography to find that it was below the detection limit ( It was 1 ppm or less).
　Then, the water in the jacket was heated to 50° C., and the organic layer was collected. The recovery rate was 94%, and the water content was 160 ppm.
　The obtained organic layer was subjected to precision distillation under atmospheric pressure using a distillation column having 10 theoretical plates. The main fraction after precision distillation was 465.0 g, and it was determined by gas chromatography that desflurane with a purity of 99.95% or higher was obtained with a recovery rate of 93%.
[0067]
　[Comparative Example 1]
　A pressure-resistant glass reactor having an internal volume of 100 mL equipped with a stirrer and a pressure gauge was charged with 2.00 g of desflurane containing chloroform having a concentration of 250 ppm and 2.00 g of a sodium hydroxide aqueous solution having a concentration of 30% by mass.
　Then, the inside of the reactor was heated to 40° C. with stirring, heated at 40° C. for 7 hours, then returned to room temperature and deaerated. When the content was transferred to a separating funnel, it was separated into two layers, an organic layer and an aqueous layer. When the chloroform content in the organic layer was measured by gas chromatography, it was 100 ppm.
[0068]
　[Comparative Example 2]
　2.00 g of desflurane containing chloroform having a concentration of 250 ppm and 0.40 g of sodium hydroxide pellets were charged into a pressure-resistant glass reactor having an internal volume of 100 mL equipped with a stirrer and a pressure gauge.
　Then, the inside of the reactor was heated to 40° C. with stirring, heated at 40° C. for 3 hours, then returned to room temperature and deaerated. When the chloroform content of the content was measured by gas chromatography, it was 250 ppm, and the chloroform was not decomposed.
[0069]
　[Comparative Example 3] In
　a pressure-resistant glass reactor having an internal volume of 100 mL equipped with a stirrer and a pressure gauge, 2.00 g of desflurane containing chloroform of 250 ppm in concentration, 2.0 g of sodium hydroxide aqueous solution of 30% by weight in concentration, and hexa 2.0 g of fluoroisopropanol (HFIP) was charged.
　Then, the inside of the reactor was heated to 40° C. with stirring, heated at 40° C. for 7 hours, then returned to room temperature and deaerated. When the content was transferred to a separating funnel, it was separated into two layers, an organic layer and an aqueous layer. When the chloroform content in the organic layer was measured by gas chromatography, it was 250 ppm, and the chloroform was not decomposed.
[0070]
　[Comparative Example 4] In
　a pressure-resistant glass reactor having an inner volume of 100 mL equipped with a stirrer and a pressure gauge, 2.00 g of desflurane containing chloroform of concentration 250 ppm, 2.00 g of sodium hydroxide aqueous solution of concentration 30 mass%, and isopropanol. 2.00 g of (IPA) was charged.
　Then, the inside of the reactor was heated to 40° C. with stirring, heated at 40° C. for 7 hours, then returned to room temperature and deaerated. When the content was transferred to a separating funnel, it was separated into two layers, an organic layer and an aqueous layer. When the chloroform content in the organic layer was measured by gas chromatography, it was 250 ppm, and the chloroform was not decomposed.
[0071]
　[Comparative Example 5] In
　a pressure-resistant glass reactor having an internal volume of 100 mL equipped with a stirrer and a pressure gauge, 2.00 g of desflurane containing chloroform at a concentration of 250 ppm and a sodium ethylate (NaOEt) ethanol solution at a concentration of 20% by mass were used. I prepared 00g. Then, the inside of the reactor was heated to 40° C. with stirring and heated at 40° C. for 7 hours, and then the content of chloroform in the content was measured by gas chromatography. )Met. However, it was confirmed by gas chromatography that Desflurane was decomposed.
[0072]
　[Comparative Example 6] In
　a pressure-resistant glass reactor having an inner volume of 100 mL equipped with a stirrer and a pressure gauge, 2.00 g of desflurane containing chloroform of 250 ppm in concentration, 2.00 g of sodium hydroxide aqueous solution of concentration of 30% by mass, and methanol. 2.00 g of (MeOH) was charged.
　Then, the inside of the reactor was heated to 40° C. with stirring, heated at 40° C. for 7 hours, then returned to room temperature and deaerated. When the chloroform content in the content was measured by gas chromatography, it was below the detection limit (1 ppm or less). However, it was confirmed by gas chromatography that Desflurane was decomposed.
[0073]
　Table 1 shows the results of decomposition of chloroform in desflurane in Examples 1 to 11.
[table 1]

[0074]
　The phase transfer catalysts in Table 1 are shown below.
[Chemical 12]

[0075]
　Table 2 shows the results of chloroform decomposition in desflurane in Comparative Examples 1 to 6.
[Table 2]

The scope of the claims
[Claim 1]
　A step of decomposing trihalomethane by bringing a mixture containing difluoromethyl-1,2,2,2-tetrafluoroethyl ether represented by the formula (1) and trihalomethane into contact with a base in the presence of water and a phase transfer catalyst. A method for purifying difluoromethyl-1,2,2,2-tetrafluoroethyl ether, comprising:
[Chemical 13]

[Claim 2]
　The method for purifying difluoromethyl-1,2,2,2-tetrafluoroethyl ether according to claim 1, wherein the trihalomethane is chloroform.
[Claim 3]
　The method for purifying difluoromethyl-1,2,2,2-tetrafluoroethyl ether according to claim 1 or 2, wherein the phase transfer catalyst is an ammonium salt phase transfer catalyst.
[Claim 4]
　The amount of the phase transfer catalyst is 0.001% by mass or more and 30% by mass or less, expressed as a percentage based on the mass of difluoromethyl-1,2,2,2-tetrafluoroethyl ether. The method for purifying difluoromethyl-1,2,2,2-tetrafluoroethyl ether according to claim 3.
[Claim 5]
　The method for purifying difluoromethyl-1,2,2,2-tetrafluoroethyl ether according to any one of claims 1 to 4, wherein the base is an alkali metal hydroxide.
[Claim 6]
　The alkali metal hydroxide is used in an amount of 0.001% by mass or more and 100% by mass or less, expressed as a percentage based on the mass of difluoromethyl-1,2,2,2-tetrafluoroethyl ether. A method for purifying difluoromethyl-1,2,2,2-tetrafluoroethyl ether as described.
[Claim 7]
　The difluoromethyl-1,2,2 according to any one of claims 1 to 6, wherein the temperature at which the mixture is brought into contact with the base in the presence of a phase transfer catalyst is 5°C or higher and 50°C or lower. , 2-Tetrafluoroethyl ether purification method.
[Claim 8]
　Difluoromethyl-1,2,2,2, comprising the step of purifying difluoromethyl-1,2,2,2-tetrafluoroethyl ether by the purification method according to any one of claims 1 to 7. -Method for producing tetrafluoroethyl ether.
[Claim 9]
　Further, methyl-1,2,2,2-tetrafluoroethyl ether represented by the formula (2) is chlorinated with chlorine to give dichloromethyl-1,2,2,2-represented by the formula (3). The method comprising the step of obtaining tetrafluoroethyl ether represented by the formula (1) by fluorinating tetrafluoroethyl ether and then reacting it with anhydrous hydrogen fluoride to obtain difluoromethyl-1,2,2,2-tetrafluoroethyl ether. The method for producing difluoromethyl-1,2,2,2-tetrafluoroethyl ether according to 1.
[Chemical 14]

[Chemical 15]

[Chemical 16]