JP2019064948A - Method for producing 1,2,2,2-tetrafluoroethyl difluoromethyl ether (desflurane) - Google Patents

Abstract

To provide a method for efficiently producing a high-purity 1,2,2,2-tetrafluoroethyl difluoromethyl ether (desflurane) using a fluorinating agent excellent in handlability.SOLUTION: The production of 1,2,2,2-tetrafluoroethyl difluoromethyl ether (desflurane) can be achieved efficiently while suppressing a side reaction by subjecting 1,2,2,2-tetrafluoroethyl dichloromethyl ether to a two-stage fluorination reaction in a liquid phase.SELECTED DRAWING: None

Description

  The present invention relates to a process for producing 1,2,2,2-tetrafluoroethyl difluoromethyl ether (desflurane, hereinafter sometimes simply referred to as desflurane) by a multistep fluorination reaction.

1,2,2,2-tetrafluoroethyl difluoromethyl ether is an important inhalational anesthetic known as "desflurane". The inhalation anesthetic has an extremely low in vivo metabolic rate, and is widely used as a drug that is gentle on the body and highly safe. The preparation method for desflurane uses fluorine as a starting material, using 1-chloro-2,2,2-trifluoroethyl difluoromethyl ether (isoflurane) and 1,2,2,2-tetrafluoroethyl dichloromethyl ether, respectively. An example of manufacturing is known. As the fluorination reaction to isoflurane, methods using hydrogen fluoride (Patent Document 1, Patent Document 2, Patent Document 3 and Patent Document 4) are mainly known. In addition, as a fluorination reaction for 1,2,2,2-tetrafluoroethyl dichloromethyl ether, a method using hydrogen fluoride (Patent Document 5, Patent Document 6, Patent Document 7) has been reported.
In addition, the manufacturing method of the desflurane by the multistep fluorination reaction with respect to 1,2,2,2- tetrafluoroethyl dichloro methyl ether disclosed by this invention is not known.

JP-A-2-279646 U.S. Pat. No. 6,800,786 WO 2006-076324 JP-A-2010-533211 West German Patent No. 2361058 JP-A-2-104545 JP-A-6-087777

  Regarding the production method of desflurane, due to the physical properties of the compound having an ether moiety ("-O-"), when the fluorination reaction is carried out under severe conditions, there is a problem that byproducts of decomposition products accompanied by the cleavage of the ether moiety It will be. Further, the impurities contained in the raw material are often analogues having an ether moiety, and in the process of manufacturing desflurane, these impurities may also be a generation factor of decomposition products. It can be said that it is necessary to use a high purity raw material for the process of producing desflurane in order to minimize byproducts of decomposition products.

  In the methods described in Patent Documents 1 to 4 using isoflurane as a raw material, fluorination with hydrogen fluoride is performed to obtain the desired desflurane in an intermediate yield. However, because hydrogen fluoride itself is an acidic substance and a catalyst with high reaction activity is generally used, it was derived from cleavage of the ether site of isoflurane, which is the raw material, and desflurane, which is the target substance. Many by-products of impurities were generated (In addition, isoflurane itself, which is a raw material, is one of the inhalation anesthetics already marketed. A very high purity compound is available, and the convenience is excellent. A compound).

  The methods described in Patent Documents 5, 6 and 7 have low yields and are difficult to adopt as a production method as an inhalation anesthetic, and any method still has problems. Further, the method described in Patent Document 7 is high in selectivity of the method for producing the ether (chlorination) in 1,2,2,2-tetrafluoroethyl dichloromethyl ether, which is a starting material of the document, because the selectivity is high. In order to obtain the ether of purity, complicated purification operations were required.

  Then, this invention makes it a subject to provide the method of manufacturing a high purity desflurane efficiently using the fluorinating agent excellent in handling with respect to the relatively easy starting material of preparation.

  The present inventors examined the production of desflurane by a fluorination reaction using 1,2,2,2-tetrafluoroethyl dichloromethyl ether as a starting material, with reference to the method described in the above-mentioned patent documents. Chloroform and fluorodichloromethane were found to be by-produced together with the compound desflurane. This appears notably by performing the fluorination reaction in a high temperature range and a high pressure range (see Reference Example 1 described later).

  It is speculated that this by-product is generated by causing decomposition reaction accompanied by cleavage of the ether site by subjecting 1,2,2,2-tetrafluoroethyl dichloromethyl ether to severe fluorination conditions Be done.

  Furthermore, since this by-product is extremely difficult to separate from desflurane even if it is subjected to a purification operation such as distillation, in consideration of the fact that desflurane, which is an inhalation anesthetic, is required to have extremely high purity, The production of organisms is one of the problems to be avoided in producing high purity desflurane.

  Therefore, the present inventors diligently studied in view of the above problems. As a result, equation [1]:

When fluorination is carried out to 1,2,2,2- tetrafluoroethyl dichloro methyl ether (Hereinafter, it may only be mentioned as "dichloro methyl ether body" in the present specification.) Represented by By employing the fluorination conditions, it was found that high purity desflurane can be produced with high selectivity.
That is, the reaction proceeds at a high conversion rate by fluorination reaction of dichloromethyl ether in a liquid phase under mild conditions, and the formula [2]:

And 1,2,2,2-tetrafluoroethyl fluorochloromethyl ether (hereinafter sometimes simply referred to as "fluoro chloromethyl ether" in the present specification), while suppressing the side reaction , High selectivity can be obtained.

  The fluorochloromethyl ether compound of the formula [2] itself is a stable compound without causing side reactions resulting from cleavage of the ether site and is easy to isolate, so the unreacted formula [1 It has been found that it is easy to separate and remove dichloromethyl ether or other compounds from the fluorochloromethyl ether of the formula [2].

  Subsequently, the fluorochloromethyl ether compound of the formula [2] is subjected to a fluorination reaction in a liquid phase under more severe conditions than the above fluorination reaction to allow the reaction to proceed at a high conversion rate, [3]:

It has been found that 1,2,2,2-tetrafluoroethyl difluoromethyl ether (desflurane) represented by is obtained with high selectivity while suppressing decomposition of the reaction substrate.
The present inventors once separate and remove the ether and other compounds (by-products etc.) by deriving the starting material dichloromethyl ether into the fluorochloromethyl ether of the formula [2]. We found that the properties are easy by repeating experiments, and by using the properties, it became possible to produce desflurane with high purity with high selectivity although it was stepwise.

  Thermal stability is improved due to the specific property of 1,2,2,2-tetrafluoroethyl fluorochloromethyl ether represented by the formula [2] itself, and the thermal history during the subsequent second-stage fluorination reaction It is presumed that it is possible to obtain desflurane with a high conversion rate and a high selectivity by minimizing by-production of impurities due to the cleavage of the ether site. This result can be said to be one of the extremely preferable fluorination conditions, considering that high purity is essential for use as an inhalation anesthetic.

  Further, although details will be described later, it has also been found that the yield is improved as compared to known methods by subjecting the fluorination reaction to specific conditions such as a preferable temperature range and preferable pressure conditions.

  The present invention is not limited to the fluorination reaction using 1-chloro-2,2,2-trifluoroethyl difluoromethyl ether (isoflurane) as a starting material, but the compound represented by the formula [1] It is advantageous to use 2,2-tetrafluoroethyl dichloromethyl ether in combination with the substrate specificity of the starting material and the conditions of the fluorination reaction of the present invention in producing desflurane (described later) Considering also Comparative Example 1), the present invention can be said to be a production method having a great advantage.

That is, the present invention provides a method for producing 1,2,2,2-tetrafluoroethyl difluoromethyl ether (desflurane) described in the following [Invention 1] to [Invention 9].
[Invention 1]
By fluorination reaction of 1,2,2,2-tetrafluoroethyl dichloromethyl ether represented by the formula [1], 1,2,2,2-tetrafluoroethyl difluoro represented by the formula [3] In the method of producing methyl ether (desflurane),
It is represented by the formula [2] by reacting 1,2,2,2-tetrafluoroethyl dichloromethyl ether with hydrogen fluoride or “a salt or complex consisting of an organic base and hydrogen fluoride” in a liquid phase. Obtaining a mixture containing 1,2,2,2-tetrafluoroethyl fluorochloromethyl ether and unreacted 1,2,2,2-tetrafluoroethyl dichloromethyl ether (first step);
By purifying the mixture obtained in the first step, 1,2,2,2-tetrafluoroethyl dichloromethyl ether contained in the mixture is separated and removed from the mixture, and the purity is enhanced 1,2, A step of obtaining 2,2-tetrafluoroethyl fluorochloromethyl ether (second step);
With respect to 1,2,2,2-tetrafluoroethyl fluorochloromethyl ether contained in the mixture obtained in the second step, hydrogen fluoride or “a salt or complex composed of an organic base and hydrogen fluoride” in the liquid phase A step of producing 1,2,2,2-tetrafluoroethyl difluoromethyl ether by reacting (third step);
Said manufacturing method including.
[Invention 2]
In the first step, the organic base in “a salt or complex consisting of an organic base and hydrogen fluoride” is triethylamine, diisopropylethylamine, tri n-propylamine, tri n-butylamine, pyridine, 2,6-lutidine, 2,4 Inventions which are 6,6-collidine, 4-dimethylaminopyridine, 1,5-diazabicyclo [4.3.0] non-5-ene or 1,8-diazabicyclo [5.4.0] undec-7-ene The manufacturing method of 1.
[Invention 3]
The manufacturing method according to the invention 1 or 2, wherein the reaction in the first step is carried out in the range of 0 to 50 ° C as the reaction temperature and in the range of 0.1 MPa to 2 MPa as the reaction pressure.
[Invention 4]
The method according to any one of Inventions 1 to 3, wherein the purification in the second step is carried out by distillation operation.
[Invention 5]
In the third step, the organic base in “a salt or complex consisting of an organic base and hydrogen fluoride” is triethylamine, diisopropylethylamine, tri n-propylamine, tri n-butylamine, pyridine, 2,6-lutidine, 2,4 Inventions which are 6,6-collidine, 4-dimethylaminopyridine, 1,5-diazabicyclo [4.3.0] non-5-ene or 1,8-diazabicyclo [5.4.0] undec-7-ene The manufacturing method according to any one of 1 to 4.
[Invention 6]
The process according to any one of Inventions 1 to 5, wherein the reaction in the third step is carried out by reacting hydrogen fluoride in the presence of a catalyst.
[Invention 7]
The catalyst is at least one selected from the group consisting of tin tetrachloride, tin dichloride, tin tetrafluoride, tin difluoride, titanium tetrachloride, antimony trichloride, antimony pentachloride, and antimony pentafluoride. The manufacturing method according to the sixth aspect.
[Invention 8]
The production method according to any one of the inventions 1 to 7, wherein the reaction in the third step is carried out at a reaction temperature of 80 to 180 ° C and a reaction pressure of 0.1 MPa to 4 MPa.
[Invention 9]
In the liquid phase, hydrogen fluoride or “a salt or complex composed of an organic base and hydrogen fluoride” is reacted with 1,2,2,2-tetrafluoroethyl fluorochloromethyl ether represented by the formula [2] A method of producing 1,2,2,2-tetrafluoroethyl difluoromethyl ether (desflurane) represented by the formula [3].

  ADVANTAGE OF THE INVENTION According to this invention, it is effective in the ability to manufacture efficiently highly purified 1,2,2,2- tetrafluoroethyl difluoro methyl ether (desflurane).

  Hereinafter, the present invention will be described in detail. The present invention is not limited to the following embodiments, and can be implemented as appropriate based on the ordinary knowledge of those skilled in the art within the scope of the present invention.

  The present invention is a manufacturing method including a two-stage fluorination step (first step, third step) and one purification step (second step), and the relationship between each step is shown below.

[First step (first step fluorination)]
First, the first step will be described. The first step is to react 1,2,2,2-tetrafluoroethyl dichloromethyl ether with hydrogen fluoride or “a salt or complex composed of an organic base and hydrogen fluoride” in the liquid phase to obtain the formula [ 2] is a step of obtaining a mixture containing 1,2,2,2-tetrafluoroethyl fluorochloromethyl ether represented by the formula 2] and unreacted 1,2,2,2-tetrafluoroethyl dichloromethyl ether.

The 1,2,2,2-tetrafluoroethyl dichloromethyl ether represented by the formula [1] of the starting material is, for example, the method described in Patent Document 7 (for example, 1,2,2,2-tetrafluoroethyl) The reaction using chlorine (Cl ₂ ) to methyl ether can be synthesized as a reference (Synthesis example described later). It can be said that this method is a useful technique that can produce dichloromethyl ether.

  In addition, when the dichloro methyl ether body of Formula [1] is manufactured referring to the method of patent document 7 other than a dichloro methyl ether body, Formula [5]:

A 1,2,2,2- tetrafluoroethyl trichloromethyl ether represented by (which may be simply referred to herein as "perchlorinated compound" or "trichloromethyl ether") is produced. The perchlorinated compound is a by-product which is difficult to completely separate from the dichloromethyl ether even after purification operation such as distillation (the synthesis example described later). In addition, the perchlorination compound proceeds through the first to third steps, so that the fluorination reaction for the perchlorination compound proceeds, and along with the desflurane which is the object of the present invention, the perchlorination compound is a fluorinated body for the perchlorination compound There is also obtained 1,2,2,2-tetrafluoroethylchlorodifluoromethyl ether, which is a compound that is very difficult to separate from desflurane during purification because the ether is similar in structure to desflurane. (See Reference Example 2 below).

  Therefore, in consideration of a series of production steps of desflurane, it is preferable to reduce perchlorinated compounds contained in the dichloromethyl ether of the formula [1] as much as possible before performing this step.

  In this step, the fluorination reaction sufficiently proceeds even in the case of a dichloromethyl ether of the formula [1] containing a perchlorinated compound, and the perchlorinated compound is efficiently separated and removed by the subsequent purification operation in the second step. Yes (see Examples below).

  In the present step, when carrying out the fluorination reaction, hydrogen fluoride or "a salt or complex composed of an organic base and hydrogen fluoride" is preferably used.

  The organic base in the salt or complex consisting of an organic base and hydrogen fluoride is triethylamine, diisopropylethylamine, tri-n-propylamine, tri-n-butylamine, pyridine, 2,6-lutidine, 2,4,6-collidine, 4 -Dimethylaminopyridine, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,8-diazabicyclo [5.4.0] undec-7-ene and the like. However, it is not limited to these, and an organic base generally used in organic synthesis can also be adopted. Among them, triethylamine, diisopropylethylamine, tri n-propylamine, tri n-butylamine, pyridine, 2,6-lutidine, 1,5-diazabicyclo [4.3.0] non-5-ene and 1,8-diazabicyclo [1. 5.4.0] Undec-7-ene is preferred, triethylamine, diisopropylethylamine, tri-n-butylamine, pyridine, 2,6-lutidine and 1,8-diazabicyclo [5.4.0] undec-7-ene Particularly preferred. These organic bases can be used alone or in combination.

  The molar ratio of organic base to hydrogen fluoride in “salt or complex consisting of organic base and hydrogen fluoride” may be in the range of 100: 1 to 1: 100, but 50: 1 to 1:50 Preferably, 25: 1 to 1:25 are particularly preferred. Using a “complex consisting of 1 mole of triethylamine and 3 moles of hydrogen fluoride” or a “complex consisting of 30% of pyridine and 70% of hydrogen fluoride” which is commercially available from Aldrich (Aldrich, 2012-2014 catalog) Is simple.

  The amount of hydrogen fluoride contained in hydrogen fluoride or “a salt or complex composed of an organic base and hydrogen fluoride” is 1,2,2,2-tetrafluoroethyl dichloromethyl represented by the formula [1] The amount is 0.1 to 200 mol, preferably 0.5 to 10 mol, and more preferably 1.0 to 50 mol, per 1.0 mol of ether. If the amount of hydrogen fluoride is less than 0.1 mol, the conversion in the reaction is bad. Further, the use of an amount of hydrogen fluoride exceeding 200 moles is not preferable from the economical point of view.

  In this step, when the fluorination reaction is carried out in the liquid phase, a catalyst can be used. The use of a catalyst may accelerate the reaction. Specific examples of the catalyst include at least one selected from the group consisting of tin tetrachloride, tin dichloride, tin tetrafluoride, tin difluoride, titanium tetrachloride, antimony trichloride, antimony pentachloride, and antimony pentafluoride. A kind of catalyst is available. Among them, use of tin tetrachloride, tin dichloride, tin tetrafluoride, and tin difluoride is preferable, and tin tetrachloride is particularly preferably used. These catalysts can be used alone or in combination.

  The amount used when using the above catalyst is 0.01 parts by mass to 50 parts by mass with respect to 100 parts by mass of 1,2,2,2-tetrafluoroethyl dichloromethyl ether represented by the formula [1]. Preferably, it is 0.1 mass part-20 mass parts, More preferably, it is 0.5 mass part-10 mass parts. When the amount of the catalyst is more than 50 parts by mass, the amount of tar formed of high boiling point compounds may be increased.

  In addition, although this process mentions later, by adopting a specific reaction temperature range and a specific pressure range, the reaction is performed in the absence of a catalyst to obtain the above-mentioned by-product (dichloromethyl ether of the formula [1] It is possible to obtain the fluorochloromethyl ether of the formula [2] with high selectivity while suppressing the formation of body-derived decomposition products) and the like).

  The reaction temperature in the fluorination reaction of this step may be in the range of -20 ° C to 150 ° C, usually -10 ° C to 100 ° C is preferable, and particularly preferably 0 ° C to 80 ° C.

  The pressure condition in the fluorination reaction of this step may be in the range of 0.1 MPa (absolute pressure standard, hereinafter the same in the present specification) to 4 MPa, and usually 0.1 MPa to 3 MPa is preferable, and particularly preferably 0. 1 MPa to 2 MPa is more preferable.

  Particularly preferable temperature and pressure conditions in this step are a temperature range of 0 ° C. to 50 ° C. and a pressure range of 0.1 MPa to 2 MPa. Furthermore, in addition to the above conditions, carrying out the reaction in the absence of a catalyst gives 1,2,2,2-tetrafluoroethyl fluorochloromethyl ether represented by the formula [2] with high selectivity. It is one of the particularly preferred embodiments.

  With regard to the reaction container used in this step, a pressure-resistant reaction container made of a material such as stainless steel (SUS) or a tetrafluoroethylene-perfluoroalkyl vinyl ether copolymer (PFA) or a polytetrat having corrosion resistance against hydrogen fluoride The reaction is preferably carried out using a pressure resistant reaction vessel whose inside is lined with a resin such as fluoroethylene (PTFE).

  The reaction time is usually within 24 hours, but depending on the reaction conditions caused by the amount of hydrogen fluoride used, analytical means such as gas chromatography, thin layer chromatography, liquid chromatography, nuclear magnetic resonance, etc. It is preferable to follow the progress of the reaction and to set the time when the starting substrate has almost disappeared as the end point of the reaction.

  In this step, it is considered at first glance that advancing the fluorination reaction to the dichloromethyl ether of the formula [1] as much as possible, that is, carrying out the reaction until the ether almost disappears. However, when this is actually tried, the reaction time is prolonged, and the dichloromethyl ether of the formula [1] itself is cleaved at the ether site under the conditions of the fluorination reaction (the decomposition reaction occurs), and desflurane In many cases, chloroform and fluorodichloromethane, which are difficult to separate, are by-produced. Therefore, in this step, in carrying out the fluorination, for example, the fluorination reaction is carried out while tracking the progress of the reaction by an analysis means such as gas chromatography in the above-mentioned specific temperature range and specific pressure range. It is preferable to proceed so as not to cause a decomposition reaction of unreacted dichloromethyl ether of the formula [1] while confirming the formation of the fluorochloromethyl ether of the formula [2].

  The conversion rate (%) of the dichloromethyl ether compound of the formula [1] is preferably about 95%, which is the end point of the reaction of this step. In addition, it is possible to continue the reaction so as to exceed 95%, but when the decomposition reaction of the dichloromethyl ether of the formula [1] becomes more than the formation of the fluorochloromethyl ether of the formula [2] There is.

  Thus, in this step, for example, by taking the above-mentioned preferred embodiment, the unreacted dichloromethyl ether of the formula [1] remains in the reaction system. It can be avoided and can be recovered in the subsequent purification operation of the second step and can be used again as the starting material of the first step.

  In addition to the fluorochloromethyl ether of the formula [2], the product in this step is an unreacted dichloromethyl ether of the formula [1], but depending on the conditions, desflurane, which is the object of the third step, Traces may be produced (trace amounts of desflurane produced here can be eventually isolated as a final product. In addition, it is necessary to remove desflurane in this step and the second step because it does not affect other reactions. Not necessarily). Furthermore, depending on the method for producing the ether of the dichloromethyl ether of the formula [1], a by-product derived from the ether (perchlorinated compound of the above formula [5]) may be included. With respect to compounds other than desflurane, the compounds can be separated and removed through the subsequent second step. This operation makes it possible to suppress side reactions in the third step (fluorination reaction).

[Second step (purification step)]
Next, the second step will be described. In the second step, 1,2,2,2-tetrafluoroethyl fluorochloromethyl ether represented by the formula [2] produced in the first step, and unreacted 1,2,2,2-tetrafluoro By purifying a mixture containing ethyl dichloromethyl ether, 1,2,2,2-tetrafluoroethyl dichloromethyl ether contained in the mixture is separated and removed from the mixture, and the purity is increased to 1,1,2. In this step, 2,2,2-tetrafluoroethyl fluorochloromethyl ether is obtained.

  In this step, together with obtaining high purity 1,2,2,2-tetrafluoroethyl fluorochloromethyl ether, the unreacted formula [1] contained in the fluorochloromethyl ether of the formula [2] In the present step, as mentioned above, the dichloromethyl ether of the formula [1] is by-produced when it is produced by a specific production method. The compound (perchlorinated compound of the above-mentioned formula [5]) can also be separated in this step.

  As described above, the dichloromethyl ether of the formula [1], which is the starting material of the first step, undergoes a decomposition reaction accompanied by the cleavage of the ether site under the conditions of the fluorination reaction, and the target compound desflurane Chloroform and fluorodichloromethane, which are difficult to separate, are often by-produced. Therefore, separating and removing the dichloromethyl ether compound of the formula [1] as much as possible in this step before performing the fluorination reaction of the third step is a preferable embodiment in order to obtain highly pure desflurane. (Before this, in the first step, the decomposition reaction of the dichloromethyl ether of the formula [1] can be performed by an analysis means such as gas chromatography or the like so that the dichloromethyl ether of the formula [1] can be reduced as much as possible. It is more preferable to proceed with fluorination so as not to occur because this can reduce the burden of purification in this step). The purification operation in this step includes distillation, activated carbon treatment, recrystallization, column chromatography, etc. With any method, it is possible to purify with high chemical purity, but among these, the distillation operation is the most simple. And since it is efficient, it is used preferably.

  When performing the distillation operation, it is possible to use the reaction liquid in the first step of the fluorination step as it is for distillation and purification, but if necessary, post treatment such as water washing is carried out to carry out the fluorination used in the reaction After removing the agent, the resulting crude reaction product may be used as it is for distillation. In addition, with regard to the distillation operation, “fractional distillation” (the fractional distillation) with the number of theoretical plates and the reflux ratio to be described later (note that “distillation” or “precision distillation” will be used for describing the “fractional distillation” referred to here). It is preferable to carry out. Distillation makes it possible to separate and remove the dichloromethyl ether of the formula [1], but if it is attempted to remove the dichloromethyl ether so completely, the distillation load will be excessive. For example, it is preferable to reduce it to such an extent that it does not affect the production and purification of desflurane described later. The effect of the present invention can be sufficiently obtained if it can be reduced to less than 1000 ppm.

  The number of stages of the distillation column varies depending on the degree of reduction of impurities and the like, but may be, for example, 2 or more and 50 or less. Among them, 3 or more and 40 or less are preferable, and 5 or more and 30 or less are more preferable. The reflux ratio is 0.5 to 8.0, preferably 0.5 to 7.0, more preferably 0.5 to 6.0.

  As a packing for packing the distillation column, either a regular packing or an irregular packing can be used. The regular filler may be one commonly used and includes, for example, Sulzer packing, Mela pack, Techno pack, Flexi pack and the like. The irregular packing may be one commonly used, and examples thereof include helipack, Raschig ring, Dixon packing, and the like.

  With regard to the material of the container that can be used in this process, stainless steel (SUS) having corrosion resistance to hydrogen fluoride or the like, or tetrafluoroethylene / perfluoroalkylvinylether copolymer (PFA) or polytetrafluoroethylene (PTFE) It is preferable to use a distillation vessel whose inside is lined with a resin such as However, when distilling the reaction crude body from which the acid is removed by the post-treatment operation, a normal borosilicate glass distillation vessel may be used.

[Third step (second step fluorination)]
Next, the third step will be described. In this step, hydrogen fluoride in the liquid phase, or 1,2,2,2-tetrafluoroethyl fluorochloromethyl ether represented by the formula [2] contained in the mixture obtained in the second step is used. In this step, 1,2,2,2-tetrafluoroethyl difluoromethyl ether represented by the formula [3] is produced by reacting “a salt or complex composed of an organic base and hydrogen fluoride”.

As the fluorinating agent in the fluorination reaction of this step, hydrogen fluoride or "a salt or complex composed of an organic base and hydrogen fluoride" is used,
-Kind of organic base in fluorinating agent-Molar ratio of organic base to hydrogen fluoride in "salt or complex consisting of organic base and hydrogen fluoride"-Hydrogen fluoride or "from organic base and hydrogen fluoride" The amount of hydrogen fluoride contained in the following “salt or complex” is used with respect to 1.0 mol of the raw material (in this step, fluorochloromethyl ether of formula [2]) under the conditions described in the first step described above and It can be carried out under exactly the same conditions. Furthermore, in this step, when the fluorination reaction is carried out in the liquid phase, the reaction can be carried out in the absence of a catalyst, but the specific type of the catalyst when using the catalyst, the amount of use of the catalyst and the use form Since the method described above can also be performed under the same conditions as those described in the first step described above, the form described above in this step omits repeated descriptions in order to avoid repeated description.

  The reaction temperature in this step may be in the range of −20 ° C. to 250 ° C., usually 20 ° C. to 200 ° C. is preferable, and particularly 80 ° C. to 180 ° C. is particularly preferable.

  The pressure condition in this step may be in the range of 0.1 MPa to 6 MPa, usually 0.1 MPa to 5 MPa is preferable, and particularly 0.1 MPa to 4 MPa is more preferable.

  In this step, since the preferable reaction temperature and the preferable reaction pressure are different as compared with the fluorination reaction in the first step, the conditions are described below.

  As a particularly preferable condition in this step, by adopting a temperature range of 80 ° C. to 180 ° C. and a pressure range of 0.1 MPa to 4 MPa, 1, 1 represented by the formula [3] with high selectivity It is possible to obtain 2,2,2-tetrafluoroethyl difluoromethyl ether. Furthermore, in this step, the fluorination reaction is carried out in the presence of a catalyst in the above-mentioned specific temperature range and specific pressure range, that is, the reaction temperature is 80 ° C. to 150 ° C., and the pressure condition is 0. By performing a fluorination reaction using tin tetrachloride as a catalyst under the conditions of 1 MPa to 3 MPa, it is possible to produce the desired product desflurane with high selectivity. This can be said to be one of the particularly preferred embodiments in this step.

  With regard to the reaction container in this step, a pressure-resistant reaction container made of a material such as stainless steel (SUS) or a tetrafluoroethylene-perfluoroalkyl vinyl ether copolymer (PFA) or polytetrafluoroethylene having corrosion resistance against hydrogen fluoride The reaction is preferably carried out using a pressure-resistant reaction vessel whose inside is lined with a resin such as ethylene (PTFE).

  The reaction time is usually within 24 hours, but depending on the reaction conditions caused by the amount of hydrogen fluoride used, analytical means such as gas chromatography, thin layer chromatography, liquid chromatography, nuclear magnetic resonance, etc. It is preferable to follow the progress of the reaction and to set the time when the starting substrate has almost disappeared as the end point of the reaction.

Further, the reaction solution after completion of the reaction is subjected to post-treatment such as water washing and the like, and high-purity desflurane can be obtained by using purification operation such as distillation. In addition, it is possible to apply the conditions of the distillation operation used at the 2nd process to this process as it is, and is a preferable aspect.
[Example]
Hereinafter, the present invention will be described in detail by way of examples, but the present invention is not limited to these embodiments. Here, "%" of the composition analysis value represents "area%" of the composition obtained by measuring the raw material or the product by gas chromatography (in the absence of a particular description, the detector is FID).
[Synthesis Example: Production of dichloromethyl ether of Formula [1]]

  A stirrer of polytetrafluoroethylene (PTFE) is placed in a reaction vessel of borosilicate glass equipped with a condenser and a thermometer, and 500 g (3.79 mol of 1,2,2,2-tetrafluoroethyl methyl ether) is added. 00 equivalents) were weighed out. Further, at the outlet of the condenser, a water trap for absorbing hydrochloric acid by-produced in the reaction was connected. While cooling, 537 g (7.58 mol, 2.00 equivalents) of chlorine is introduced over 12 hours while paying attention to heat generation while irradiating ultraviolet light from the outside of the reactor with a 400 W high-pressure mercury lamp (manufactured by Ushio Co., Ltd.) did. After the introduction of chlorine, the unreacted chlorine was purged with nitrogen to obtain 675 g of a reaction crude. When the obtained crude reaction product is subjected to analysis by gas chromatography, the raw material 1,2,2,2-tetrafluoroethyl methyl ether is not detected, and lower order chlorinated 1,2,2,2-tetrafluoro Ethyl chloromethyl ether is 3.0%, target 1,2,2,2-tetrafluoroethyl dichloromethyl ether represented by the formula [1] is 72.8%, perchlorinated 1,2,2 The amount of 2-tetrafluoroethyl trichloromethyl ether was 18.8%, and the others were 5.4%. The obtained reaction crude product was subjected to atmospheric distillation using a distillation column having 35 theoretical plates, and was recovered as a main fraction (82 ° C.) at 411 g and a reaction yield of 54%. The recovered main fraction is subjected to analysis by gas chromatography to find that the lower order chlorinated 1,2,2,2-tetrafluoroethyl chloromethyl ether is 0.1%, the target compound represented by the formula [1] 95.9% of 1,2,2,2-tetrafluoroethyl dichloromethyl ether, 2.8% of 1,2,2,2-tetrafluoroethyl trichloromethyl ether of perchlorate, others 1.2 %Met.

[Physical data]
1,2,2,2-tetrafluoroethyl methyl ether:
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 3.72 (3 H, s), 5. 28 (1 H, dq, J = 60.0, 3.2 Hz)
¹⁹ F-NMR (400 MHz, CDCl ₃ , CFCl ₃ ) δ (ppm): -84.33 (3F, s), -146.04 (1F, d, J = 60.7 Hz)
1,2,2,2-tetrafluoroethyl chloromethyl ether:
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 5.57 (2 H, dd, J = 9.5, 9.9 Hz), 5.73 (1 H, dq, J = 59.4, 3. 2 Hz)
¹⁹ F-NMR (400 MHz, CDCl ₃ , CFCl ₃ ) δ (ppm): -83.91 (3F, s), -152.60 (1F, d, J = 57.7 Hz)
Formula [1]: 1,2,2,2-tetrafluoroethyl dichloromethyl ether:
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 6.05 (1 H, dq, J = 54.2, 3.2 Hz), 7.27 (1 H, s)
¹⁹ F-NMR (400 MHz, CDCl ₃ , CFCl ₃ ) δ (ppm): -83.68 (3F, s), -148.66 (1F, d, J = 54.8 Hz)
Formula [5]: 1,2,2,2-tetrafluoroethyl trichloromethyl ether:
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 6.10 (1 H, dq, J = 52.7, 3.2 Hz)
¹⁹ F-NMR (400 MHz, CDCl ₃ , CFCl ₃ ) δ (ppm): -83.38 (3F, s), -148.06 (1F, d, J = 52.2 Hz)
[Example of preparation of complex consisting of organic base and hydrogen fluoride]
In a 1000 mL stainless steel (SUS) autoclave reactor equipped with a stirrer and a pressure gauge, 158 g (2 mol, 1 equivalent) of pyridine was weighed and cooled with dry ice. Thereafter, 200 g (10 mol, 5 equivalents) of hydrogen fluoride was slowly added dropwise at an internal temperature of 20 ° C. or less while paying attention to heat generation. After completion of the dropwise addition, the mixture was stirred at room temperature for 1 hour to prepare a pyridine / hydrogen fluoride complex (molar ratio, pyridine: hydrogen fluoride = 1: 5).

  In a 500 mL stainless steel (SUS) autoclave reactor equipped with a stirrer, pressure gauge, and condenser, 201 g of 1,2,2,2-tetrafluoroethyl dichloromethyl ether of the formula [1] prepared in the above synthesis example ( 1 mol, 1 equivalent) was weighed out and cooled with dry ice. Under cooling, 100 g (5 mol, 5 equivalents) of hydrogen fluoride was introduced with care for heat generation, and then the reaction was started by raising the temperature to 50 ° C. After the temperature rise, in order to control the reaction pressure at 1.0 MPa, the reaction was carried out for 15 hours while removing by-produced hydrochloric acid out of the system through a condenser. After the reaction, as a result of gas chromatography composition analysis on the reaction liquid, the desired product 1,2,2,2-tetrafluoroethyl fluorochloromethyl ether of the formula [2] is 85.1%, which is an unreacted material The 1,2,2,2-tetrafluoroethyl dichloromethyl ether of the formula [1] is 4.8%, the desflurane of the formula [3] which is the final object is 4.1%, and the formula is an impurity contained in the raw material 1, 2, 2, 2- tetrafluoroethyl trichloromethyl ether of [5] was 2.4%.

  The reaction liquid was washed with 500 g of ion exchanged water and then with 250 g of 5% aqueous sodium bicarbonate under cooling to remove excess hydrogen fluoride, whereby a crude reaction product of 187 g was obtained. The crude reaction product was subjected to atmospheric distillation using a distillation column with 25 theoretical plates, to give 149 g of a main fraction (50 ° C.) and a reaction yield of 81%. 2,2,2-tetrafluoroethyl fluorochloromethyl ether was obtained. The composition of the main fraction is 94.6% of the desired product 1,2,2,2-tetrafluoroethyl fluorochloromethyl ether of the formula [2], and the final desired product of the desflurane of the formula [3] .9%. 1,2,2,2-tetrafluoroethyl dichloromethyl ether of the formula [1] which is an unreacted raw material during main distillation, and 1,2,2,2 of the formula [5] which is an impurity contained in the raw material -Tetrafluoroethyl trichloromethyl ether was not detected.

[Physical data]
Formula [2]: 1,2,2,2-tetrafluoroethyl fluorochloromethyl ether:
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 6.06 (1 H, dq, J = 54.8, 2.9 Hz), 7.06 (1 H, dd, J = 56.6, 0. 6). 9 Hz)
¹⁹ F-NMR (400 MHz, CDCl ₃ , CFCl ₃ ) δ (ppm): −79.28 (1F, dd, J = 57.8, 11.6 Hz), −84.07 (3F, s), −147 .78 (1F, dq, J = 54.9, 5.8 Hz)

  In a 500 mL stainless steel (SUS) autoclave reactor equipped with a stirrer, a pressure gauge, and a condenser, 100 g of 1,2,2,2-tetrafluoroethyl fluorochloromethyl ether of the formula [2] obtained in Example 1 ( 542 mmol (1 equivalent) was weighed and cooled with dry ice. Under cooling, 54 g (2.71 mol, 5 equivalents) of hydrogen fluoride was introduced with caution for heat generation, and then the reaction was initiated by raising the temperature to 100 ° C. After the temperature rise, in order to control the reaction pressure at 1.5 MPa, the reaction was carried out for 24 hours while removing by-produced hydrochloric acid out of the system through a condenser. As a result of gas chromatography composition analysis of the reaction solution after the reaction, the desired product, desflurane of the formula [3] is 98.6%, and the unreacted raw material of the formula [2] is 1,2,2,2- The tetrafluoroethyl fluorochloromethyl ether was 1.0%, and the decomposition product derived from the cleavage of the ether site of the reaction substrate (Formula [2]) was not detected. The reaction solution was washed with 250 g of ion exchanged water and then 125 g of 5% aqueous sodium bicarbonate under cooling to remove excess hydrogen fluoride, thereby obtaining 84 g of a reaction crude. The crude reaction product was subjected to atmospheric distillation using a distillation column with 25 theoretical plates, and as a main fraction (23 ° C.), 72 g as a main product (79% reaction yield). I got desflurane. The composition of the main fraction was 99.9% of the target product, desflurane of the formula [3]. Decomposed products derived from cleavage of the ether moiety of the reaction substrate (formula [2]) or the reaction substrate (formula [2]), which is an unreacted raw material of 1,2,2,2-tetrafluoroethyl fluorochloromethyl ether of formula [2], which is unreacted during main distillation Was undetected.

[Physical data]
Formula [3]: 1,2,2,2-tetrafluoroethyl difluoromethyl ether (desflurane):
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 5.91 (1 H, dq, J = 2.8 Hz, 54.2 Hz), 6.43 (1 H, t, J = 70.5 Hz)
¹⁹ F-NMR (400 MHz, CDCl ₃ , CFCl ₃ ) δ (ppm): -146.5 (1 F, d, J = 54.8 Hz), -86.8 (1 F, dd, J = 69.3 Hz, J = 161.7 Hz), -85.5 (1 F, dd, J = 69.3 Hz, J = 161.7 Hz), -84.6 (3 F, s)

  Into a 500 mL stainless steel (SUS) autoclave reactor equipped with a stirrer, a pressure gauge, and a condenser 1,2,2,2-tetrafluoroethyl fluorochloromethyl ether represented by the formula [2] obtained in Example 1 40 g (217 mmol, 1 equivalent) was weighed and cooled with dry ice. While cooling, introduce carefully prepared 78 g (434 mmol, 2 equivalents) of a pyridine / hydrogen fluoride complex (molar ratio, pyridine: hydrogen fluoride = 1: 5) prepared separately, and raise the temperature to 120 ° C. Started the reaction. After the temperature rise, in order to control the reaction pressure at 1.5 MPa, the reaction was carried out for 15 hours while removing by-produced hydrochloric acid out of the system through a condenser. As a result of gas chromatography composition analysis after the reaction, the desired product, desflurane of the formula [3] is 96.2%, and the unreacted raw material of the formula [2] is 1,2,2,2-tetrafluoroethylfluoro of formula [2]. The amount of chloromethyl ether was 2.6%, and the decomposition product derived from the cleavage of the ether site of the reaction substrate (formula [2]) was not detected.

  A stirrer of polytetrafluoroethylene (PTFE) is put into a 100 mL stainless steel (SUS) autoclave reactor equipped with a pressure gauge and a condenser, and the 1, 2, 2 represented by the formula [1] prepared in the synthesis example 10 g (49.8 mmol, 1 equivalent) of 2, 2- tetrafluoroethyl dichloromethyl ether was weighed out and cooled with dry ice. Under cooling, 10 g (500 mmol, 10 equivalents) of hydrogen fluoride was introduced with care for heat generation, and then the reaction was initiated by raising the temperature to room temperature. After the temperature rise, in order to control the reaction pressure at 0.5 MPa, the reaction was carried out for 24 hours while removing by-produced hydrochloric acid out of the system through a condenser. As a result of gas chromatography composition analysis after the reaction, the desired product 1,2,2,2-tetrafluoroethyl fluorochloromethyl ether of the formula [2] is 78.1%, the unreacted raw material of the formula [1 ], 1,2,2,2-tetrafluoroethyl dichloromethyl ether is 5.4%, desflurane of the formula [3] which is the final object is 13.5%, and the impurities contained in the raw material are the formula [5] Of 1,2,2,2-tetrafluoroethyl trichloromethyl ether was 2.3%. In addition, 1,2,2,2-tetrafluoroethyl trichloromethyl ether of the formula [5] which is difficult to separate from the final object, ie, the desflurane of the formula [3] is partially fluorinated 1,2,2,2 The decomposition products derived from the cleavage of 2-tetrafluoroethyl difluorochloromethyl ether and the ether site of the reaction substrate (formula [1]) were not detected.

  In a 100 mL stainless steel (SUS) autoclave reactor equipped with a pressure gauge and a condenser, a polytetrafluoroethylene (PTFE) stirrer is placed, and the separately prepared gas chromatography composition 99.0% of the formula [2] Measure 10 g (54.2 mmol, 1 equivalent) of 1,2,2,2-tetrafluoroethyl fluorochloromethyl ether to be expressed, 0.71 g (2.71 mmol, 5 mol%) of tin tetrachloride, and dry ice It cooled. Under cooling, 10 g (500 mmol, 10 equivalents) of hydrogen fluoride was introduced with caution for heat generation, and then the reaction was initiated by raising the temperature to 100 ° C. After the temperature rise, in order to control the reaction pressure at 1.2 MPa, the reaction was carried out for 24 hours while removing by-produced hydrochloric acid out of the system through a condenser. As a result of gas chromatography composition analysis after the reaction, the desired product, desflurane of the formula [3] is 98.6%, and the unreacted raw material of 1,2,2,2-tetrafluoroethylfluoro of the formula [2] The amount of chloromethyl ether was 0.3%, and the decomposition product derived from the cleavage of the ether site of the reaction substrate (formula [2]) was not detected.

Comparative Example 1

Under dry ice cooling, a polytetrafluoroethylene (PTFE) stirrer is placed in a 100 mL stainless steel (SUS) autoclave reactor equipped with a pressure gauge and a condenser, and a separately prepared complex of pyridine and hydrogen fluoride (molar ratio 7.2 g (40.2 mmol) of 1 to 5) and 3.7 g (20.1 mmol) of isoflurane were weighed, respectively, and the mixture was naturally heated and stirred at room temperature to 130 ° C. for 12 hours. After the reaction, the reaction pressure of 1.2 MPa was released, and after washing the reaction solution with water, the organic substance obtained by separation of the two layers was measured by gas chromatography. Hardly progressed and ended up in the recovery of raw materials.
From these results, it is found that the reaction substrate (1,2,2,2-tetrafluoroethyl dichloromethyl ether represented by the formula [1]) used in the present invention is more reactive and is excellent in handling. There is.

[Reference Example 1]

  1,2,2,2-Tetrafluoroethyl dichloromethyl ether represented by the formula [1] prepared in the above synthesis example into a 500 mL stainless steel (SUS) autoclave reactor equipped with a stirrer, pressure gauge and condenser 140 g (697 mmol, 1 equivalent) were weighed and cooled with dry ice. Under cooling, 139 g (6.97 mol, 10 equivalents) of hydrogen fluoride was introduced with caution for heat generation, and then the reaction was started by immediately raising the temperature to 120 ° C. After the temperature rise, in order to control the reaction pressure at 1.5 MPa, the reaction was carried out for 24 hours while removing by-produced hydrochloric acid out of the system through a condenser. As a result of gas chromatography composition analysis after reaction, the final target product, desflurane of the formula [3] is 94.0%, and the unreacted raw material of 1,2,2,2-tetrafluoro, which is the formula [1] Ethyl dichloromethyl ether is 0.4%, 1,2,2,2-tetrafluoroethyl fluorochloromethyl ether of the formula [2] is 0.9%, and the impurities contained in the raw material are 1,1 of the formula [5] The amount of 2,2,2-tetrafluoroethyl trichloromethyl ether was 0.1%. Furthermore, 1.7% of 1,2,2,2-tetrafluoroethyl difluorochloromethyl ether in which 1,2,2,2-tetrafluoroethyl trichloromethyl ether of the formula [5] is partially fluorinated is a reaction substrate The decomposition product (chloroform or fluorodichloromethane) derived from the cleavage of the ether site of (the dichloromethyl ether of the formula [1]) was detected at 0.9%.

The reaction solution was washed with 500 g of ion exchanged water and then 250 g of 5% aqueous sodium bicarbonate under cooling to remove excess hydrogen fluoride, whereby 115 g of a reaction crude product was obtained. The reaction crude body was subjected to atmospheric distillation using a distillation column having 25 theoretical plates, whereby 53 g of a main fraction (22-23 ° C.) and a reaction yield of 45% were used as the final target products [ I obtained desflurane shown in 3]. The composition of the main fraction is 98.7% of the desired product, the desflurane of formula [3], and the partially fluorinated 1,2,2,2-tetrafluoroethyl trichloromethyl ether of formula [5] as an impurity 0.7% of the purified 1,2,2,2-tetrafluoroethyl difluorochloromethyl ether, a decomposition product (chloroform or fluoro) derived from cleavage of the ether moiety of the reaction substrate (dichloromethyl ether of formula [1]) Dichloromethane etc. contained 0.6%.
Thus, it was difficult to completely separate the objective product, the desflurane of the formula [3], and the impurities by-produced in the reaction.

[Reference Example 2; Example of Perchlorination Reaction under Fluorination Condition]

  Under dry ice cooling, a polytetrafluoroethylene (PTFE) stirrer is placed in a 100 mL stainless steel (SUS) autoclave reactor equipped with a pressure gauge and a condenser, and the reaction mixture is expressed by the formula [5] 5.0 g (21.2 mmol) of 2-tetrafluoroethyl trichloromethyl ether, 8.5 g (425 mmol) of hydrogen fluoride, and 329 mg (1.1 mmol) of antimony pentachloride were weighed, respectively, and the temperature was raised to 120 ° C. After the temperature rise, in order to control the reaction pressure at 1.2 MPa, the reaction was carried out for 12 hours while removing by-produced hydrochloric acid out of the system through a condenser. After the reaction, the reaction pressure of 1.2 MPa was released, and after washing the reaction solution with water, the organic substance obtained by separation of the two layers was measured by gas chromatography, and it was found that 1,2,2,2-tetrafluoroethylchlorodifluoromethyl Ether was obtained at 92.0%.

[Physical data]
1,2,2,2-tetrafluoroethyl difluorochloromethyl ether:
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 5.96 (1 H, dq, J = 53.4, 2.8 Hz)
¹⁹ F-NMR (400 MHz, CDCl ₃ , CFCl ₃ ) δ (ppm): −28.93 (1F, d, J = 86.8 Hz), −29.95 (1F, d, J = 92.8 Hz), -83.41 (3F, s), -146.75 (1F, d, J = 54.8 Hz)

  1,2,2,2-tetrafluoroethyl difluoromethyl ether (desflurane) targeted by the present invention can be used as an inhalation anesthetic.

Claims (9)

Formula [1]:

The fluorinated reaction of 1,2,2,2-tetrafluoroethyl dichloromethyl ether represented by the formula [3]:

In a method for producing 1,2,2,2-tetrafluoroethyl difluoromethyl ether (desflurane) represented by
By reacting 1,2,2,2-tetrafluoroethyl dichloromethyl ether with hydrogen fluoride or "a salt or complex consisting of an organic base and hydrogen fluoride" in the liquid phase, the formula [2]:

A step of obtaining a mixture containing 1,2,2,2-tetrafluoroethyl fluorochloromethyl ether represented by and unreacted 1,2,2,2-tetrafluoroethyl dichloromethyl ether (first step) When,
By purifying the mixture obtained in the first step, the 1,2,2,2-tetrafluoroethyl dichloromethyl ether contained in the mixture is separated and removed from the mixture, and the purity is enhanced 1,2, A step of obtaining 2,2-tetrafluoroethyl fluorochloromethyl ether (second step);
With respect to 1,2,2,2-tetrafluoroethyl fluorochloromethyl ether contained in the mixture obtained in the second step, hydrogen fluoride or “a salt or complex composed of an organic base and hydrogen fluoride” in the liquid phase A step of producing 1,2,2,2-tetrafluoroethyl difluoromethyl ether by reacting (third step);
Said manufacturing method including. In the first step, the organic base in “a salt or complex consisting of an organic base and hydrogen fluoride” is triethylamine, diisopropylethylamine, tri n-propylamine, tri n-butylamine, pyridine, 2,6-lutidine, 2,4 , 6-collidine, 4-dimethylaminopyridine, 1,5-diazabicyclo [4.3.0] non-5-ene or 1,8-diazabicyclo [5.4.0] undec-7-ene The manufacturing method according to Item 1. The method according to claim 1 or 2, wherein the reaction in the first step is carried out in the range of 0 to 50 ° C as the reaction temperature and in the range of 0.1 MPa to 2 MPa as the reaction pressure. The method according to any one of claims 1 to 3, wherein the purification in the second step is carried out by distillation operation. In the third step, the organic base in “a salt or complex consisting of an organic base and hydrogen fluoride” is triethylamine, diisopropylethylamine, tri n-propylamine, tri n-butylamine, pyridine, 2,6-lutidine, 2,4 , 6-collidine, 4-dimethylaminopyridine, 1,5-diazabicyclo [4.3.0] non-5-ene or 1,8-diazabicyclo [5.4.0] undec-7-ene Item 5. The method according to any one of Items 1 to 4. The method according to any one of claims 1 to 5, wherein the reaction in the third step is carried out by reacting hydrogen fluoride in the presence of a catalyst. The catalyst is at least one selected from the group consisting of tin tetrachloride, tin dichloride, tin tetrafluoride, tin difluoride, titanium tetrachloride, antimony trichloride, antimony pentachloride, and antimony pentafluoride. The manufacturing method of Claim 6. The method according to any one of claims 1 to 7, wherein the reaction in the third step is carried out at a reaction temperature of 80 to 180 ° C and a reaction pressure of 0.1 MPa to 4 MPa. Formula [2]:

By reacting hydrogen fluoride or “a salt or complex comprising an organic base and hydrogen fluoride” in a liquid phase with 1,2,2,2-tetrafluoroethyl fluorochloromethyl ether represented by [3]:

A method for producing 1,2,2,2-tetrafluoroethyl difluoromethyl ether (desflurane) represented by