WO2018155069A1 - Method for producing 1,2,2,2-tetrafluoroethyl difluoromethyl ether (desflurane) - Google Patents

Method for producing 1,2,2,2-tetrafluoroethyl difluoromethyl ether (desflurane) Download PDF

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WO2018155069A1
WO2018155069A1 PCT/JP2018/002377 JP2018002377W WO2018155069A1 WO 2018155069 A1 WO2018155069 A1 WO 2018155069A1 JP 2018002377 W JP2018002377 W JP 2018002377W WO 2018155069 A1 WO2018155069 A1 WO 2018155069A1
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reaction
desflurane
antimony
ether
formula
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健史 細井
峰男 渡辺
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セントラル硝子株式会社
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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J27/00—Catalysts comprising the elements or compounds of halogens, sulfur, selenium, tellurium, phosphorus or nitrogen; Catalysts comprising carbon compounds
    • B01J27/06—Halogens; Compounds thereof
    • B01J27/08—Halides
    • B01J27/10—Chlorides
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J27/00—Catalysts comprising the elements or compounds of halogens, sulfur, selenium, tellurium, phosphorus or nitrogen; Catalysts comprising carbon compounds
    • B01J27/06—Halogens; Compounds thereof
    • B01J27/08—Halides
    • B01J27/12—Fluorides
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J27/00—Catalysts comprising the elements or compounds of halogens, sulfur, selenium, tellurium, phosphorus or nitrogen; Catalysts comprising carbon compounds
    • B01J27/06—Halogens; Compounds thereof
    • B01J27/135—Halogens; Compounds thereof with titanium, zirconium, hafnium, germanium, tin or lead
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/01—Preparation of ethers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/01—Preparation of ethers
    • C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
    • C07C41/22—Preparation of ethers by reactions not forming ether-oxygen bonds by introduction of halogens; by substitution of halogen atoms by other halogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/03—Ethers having all ether-oxygen atoms bound to acyclic carbon atoms
    • C07C43/04—Saturated ethers
    • C07C43/12—Saturated ethers containing halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B61/00—Other general methods

Definitions

  • 1,2,2,2-tetrafluoroethyl difluoromethyl ether is an important inhalation anesthetic known as desflurane.
  • the inhalation anesthetic has a very low in vivo metabolic rate and is widely used as a safe and gentle drug for the living body.
  • the present inventors have obtained very useful knowledge that, by adopting specific reaction conditions (reaction substrate, reaction reagent, catalyst), desflurane can be synthesized in an extremely small number of steps as compared with conventional production methods. Obtained.
  • the present inventors used fluoral (2,2,2-trifluoroacetaldehyde) or an equivalent thereof as a starting material when synthesizing desflurane, and by reacting chloroform and hydrogen fluoride in the presence of a catalyst, When examination which manufactures desflurane was performed, desflurane was not produced
  • chloral is reacted with chloroform and hydrogen fluoride in the presence of a Lewis acid catalyst to induce 2,2,2-trichloro-1-fluoroethyldifluoromethyl ether, followed by fluorination to produce desflurane.
  • a Lewis acid catalyst to induce 2,2,2-trichloro-1-fluoroethyldifluoromethyl ether, followed by fluorination to produce desflurane.
  • Second step Antimony, tantalum, niobium, molybdenum in the gas phase with respect to 1-fluoro-2,2,2-trichloroethyldifluoromethyl ether represented by the formula [2] obtained in the first step Represented by the formula [3] by reacting hydrogen fluoride in the presence of a metal halide-supported catalyst in which a metal halide containing at least one metal selected from the group consisting of tin, titanium and titanium is supported on activated carbon.
  • a metal halide-supported catalyst in which a metal halide containing at least one metal selected from the group consisting of tin, titanium and titanium is supported on activated carbon.
  • the Lewis acid catalyst used in the first step is boron (III), tin (II), tin (IV), titanium (IV), zinc (II), aluminum (III), antimony (III), and antimony (V).
  • the manufacturing method of the invention 1 which is a metal halide containing at least one metal selected from the group consisting of:
  • Invention 3 Invention 1 or the Lewis acid catalyst used in the first step is at least one metal halide selected from the group consisting of boron trifluoride (III), tin tetrachloride (IV), and antimony pentachloride (V) 2. The production method according to 2.
  • 1,2,2,2-tetrafluoroethyldifluoromethyl is obtained by using the easily described chloral as a starting material and passing through the steps described above using various reagents that are safe to handle.
  • the effect is that ether (desflurane) can be produced efficiently.
  • the method for producing 1,2,2,2-tetrafluoroethyldifluoromethyl ether (desflurane) of the present invention includes the following steps (from the first step to the second step).
  • Second step Antimony, tantalum, niobium, molybdenum in the gas phase with respect to 1-fluoro-2,2,2-trichloroethyldifluoromethyl ether represented by the formula [2] obtained in the first step Represented by the formula [3] by reacting hydrogen fluoride in the presence of a metal halide-supported catalyst in which a metal halide containing at least one metal selected from the group consisting of tin, titanium and titanium is supported on activated carbon.
  • a metal halide-supported catalyst in which a metal halide containing at least one metal selected from the group consisting of tin, titanium and titanium is supported on activated carbon.
  • the first step is a reaction represented by the formula [2] by reacting 2,2,2-trichloroacetaldehyde represented by the formula [1] with chloroform and hydrogen fluoride in the presence of a Lewis acid catalyst. This is a step of obtaining fluoro-2,2,2-trichloroethyl difluoromethyl ether.
  • the amount of chloroform used in this step is usually 1.0 equivalent or more with respect to chloral, and in order to allow the reaction to proceed smoothly, it is preferable to use 1.0 equivalent to 20.0 equivalent. In view of the treatment operation after the reaction, 1.0 equivalent to 3.0 equivalent is particularly preferable.
  • the Lewis acid catalyst used in this step is a metal halide containing at least one metal selected from the group consisting of boron, tin, titanium, zinc, aluminum, and antimony.
  • the metal halide to be used is preferably a high valence metal halide, that is, a metal halide having the highest possible valence.
  • a thermally or chemically stable solvent can be suitably used as the reaction solvent.
  • fluorous solvents such as perfluorobutane, perfluoropentane, perfluorohexane, and perfluoroheptane can be used. These reaction solvents can be used alone or in combination.
  • this step by using an excessive amount of chloroform as a reaction substrate, it can be used as a reaction reagent, and at the same time, it can be expected to function as a reaction solvent that facilitates the reaction.
  • side reaction such as temporary fluorination may occur in the reaction system of chloroform which is also a reaction substrate.
  • chlorofluoromethane (HCFC-21) or chlorodifluoromethane (HCFC-22) which are fluorinated products of chloroform, may be produced temporarily, the reaction with chloral proceeds and the purpose of this process is finally reached. Since it is thought that it converges to 2,2,2-trichloro-1-fluoroethyldifluoromethyl ether, which is a product, the side reaction of chloroform in this step is not particularly a problem.
  • this step it is possible to carry out the reaction without using a reaction solvent.
  • the temperature condition in this step may be performed in the range of +25 to + 200 ° C., usually +50 to + 180 ° C., and particularly preferably +100 to + 150 ° C.
  • the pressure condition in this step may be in the range of 0.1 MPa (absolute pressure, hereinafter the same in the present specification) to 10.0 MPa, usually 1.0 MPa to 7.0 MPa, particularly 1.0 MPa. 5.0 MPa is more preferable. Therefore, a pressure resistant reaction vessel made of a material such as stainless steel (SUS), a tetrafluoroethylene / perfluoroalkyl vinyl ether copolymer (PFA) or a polytetrafluoroethylene (PTFE) having anticorrosion performance against hydrogen fluoride, etc. A pressure-resistant reaction vessel lined with resin can be used.
  • SUS stainless steel
  • PFA tetrafluoroethylene / perfluoroalkyl vinyl ether copolymer
  • PTFE polytetrafluoroethylene
  • the reaction time in this step is usually within 48 hours, but depending on the reaction conditions due to the amount of chloral and hydrogen fluoride used, gas chromatography, thin layer chromatography, liquid chromatography, nuclear magnetics It is preferable that the progress of the reaction is traced by an analytical means such as resonance, and the point of time when the starting substrate has almost disappeared is the end point of the reaction.
  • the target 2,2,2-trichloro-1-fluoroethyldifluoromethyl ether of the formula [2] can be easily obtained by carrying out a normal purification operation on the reaction end solution. Obtainable.
  • the target product can be purified to a higher chemical purity product by activated carbon treatment, distillation, recrystallization, column chromatography and the like, if necessary.
  • This step is performed by using a reactor made of a material substantially inert to hydrogen fluoride and introducing chloral into the reaction zone filled with the catalyst under temperature control.
  • the reaction vessel used in this step is usually tubular and made of metal such as stainless steel, Hastelloy TM , platinum, tetrafluoroethylene resin, chloro-trifluoroethylene resin, vinylidene fluoride resin It is preferable to use a reaction vessel that is lined with a PFA resin or the like and can sufficiently react even under normal pressure or under pressure.
  • the metal halide used for catalyst preparation is preferably a high-valence metal halide, that is, a halide having the highest valence that can be usually obtained. Therefore, as the high valent metal in the halide, antimony (V: an oxidation number; the same applies hereinafter)), tin (IV), titanium (IV), niobium (V), tantalum (V), molybdenum (V ) Is preferred. Of these metals, antimony and tantalum are preferable, and antimony is particularly preferable.
  • Preparation method is not particularly limited as long as the metal halide adheres to the activated carbon.
  • a compound that is liquid near room temperature for example, antimony pentachloride, tin tetrachloride, or titanium tetrachloride
  • a treatment with a basic aqueous solution, acid or hot water described below, or a pretreatment for dehydration treatment was performed as necessary. It can be directly attached to the activated carbon by a method such as dropping, spraying or dipping.
  • the activated carbon is immersed in a solution in which the compound is dissolved in a solvent, or impregnated, or attached to the activated carbon by a method such as spraying.
  • the activated carbon attached with the metal compound thus obtained is dried by heating or / and reducing the pressure, and then the activated carbon attached with the metal halide is heated under hydrogen fluoride, chlorine, hydrogen chloride, fluoride chloride.
  • a catalyst is prepared by contacting with a hydrocarbon or the like. In particular, when antimony pentachloride is supported, treatment with 1 equivalent or more of chlorine at 100 ° C. or higher is desirable for activating the catalyst.
  • the solvent used in this step may be any solvent that can dissolve the metal halide and does not decompose the metal halide.
  • lower alcohols referred to as alcohols having a linear or branched alkyl group having 1 to 6 carbon atoms or alcohols having a cyclic alkyl group having 3 to 6 carbon atoms
  • Ethers referred to as alcohols having a linear or branched alkyl group having 1 to 6 carbon atoms or alcohols having a cyclic alkyl group having 3 to 6 carbon atoms
  • Ethers referred to as alcohols having a linear or branched alkyl group having 1 to 6 carbon atoms or alcohols having a cyclic alkyl group having 3 to 6 carbon atoms
  • ketones referred to as ketones, aromatic compounds, esters, chlorinated solvents, fluorinated solvents, and the like.
  • the amount of the metal halide used in the preparation of the catalyst used in this step on the activated carbon is 0.1 to 500 parts by mass, preferably 1 to 250 parts by mass with respect to 100 parts by mass of the activated carbon. .
  • catalyst activity can also be adjusted combining 2 or more types of metals.
  • antimony halide especially antimony pentachloride
  • other niobium compounds especially niobium pentachloride
  • tantalum compounds especially tantalum pentachloride
  • tin, titanium, niobium, tantalum, molybdenum halides It is good to combine.
  • the atomic ratio of the minor component metal / major component metal may not include the minor component metal, but may be 50/50 to 0/100, and preferably 30/70 to 0/100.
  • Activated carbon used as a carrier is plant based on wood, charcoal, coconut shell charcoal, palm kernel charcoal, bare ash, etc., coal based on peat, lignite, lignite, bituminous coal, anthracite, etc., petroleum residue, oil car
  • petroleum-based or synthetic resin-based such as carbonized polyvinylidene chloride using Bonn as a raw material.
  • activated carbon manufactured from bituminous coal BPL granular activated carbon manufactured by Toyo Calgon
  • coconut shell charcoal granular white birch GX, SX, CX, XRC manufactured by Takeda Pharmaceutical Co., Ltd., Toyo Calgon
  • PCB PCB
  • the shape and size are usually used in a granular form, but may be adapted to a reactor such as a sphere, fiber, powder or honeycomb.
  • the catalyst used in this step is in contact with hydrogen fluoride and / or chlorine.
  • supplying chlorine, fluorinated chlorinated or chlorinated hydrocarbon into the reactor during the reaction is effective for extending the catalyst life, improving the reaction rate, and the reaction yield.
  • introduction of chlorine is preferable for improving and maintaining the catalytic activity, and it is desirable to bring about 0.1 to 10 mol with respect to 100 mol of 2,2,2-trichloro-1-fluoroethyldifluoromethyl ether as a raw material.
  • the fluorination reaction proceeds by circulating hydrogen fluoride in the gas phase.
  • the catalyst retention method can be any type such as fixed bed, fluidized bed, moving bed, etc. Although it does not matter, it is convenient and preferable to carry out on a fixed bed.
  • the molar ratio of 1-fluoro-2,2,2-trichloroethyldifluoromethyl ether: hydrogen fluoride supplied to the reaction zone can vary depending on the reaction temperature, but is from 1:50 to 1: 2. : 30 to 1: 4 is preferable, and 1:20 to 1: 5 is more preferable.
  • the hydrogen fluoride is in an excessive amount, the reduction of the organic matter throughput and the separation of the mixture of the unreacted hydrogen fluoride discharged from the reaction system and the product are hindered.
  • reaction conversion rate falls and the yield of a target object falls.
  • reaction pressure was purged to 0.1 MPa, and 200 g of ion exchanged water was added to the reaction solution while paying attention to heat generation to stop the reaction. Subsequently, after washing with water, separation of two layers was performed to obtain 99 g of a crude reaction product.
  • bis-1,4-trifluorobenzene was used as an internal standard, and the quantitative value of the target product by 19 F-NMR was calculated. As a result, 25.8 g of 1-fluoro-2,2 , 2-trichloroethyl difluoromethyl ether was confirmed to be contained. In this case, the quantitative yield of the target product was 35%.
  • Example 2 In a 50 ml stainless steel (SUS) autoclave reactor equipped with a pressure gauge, thermometer, PTFE stirrer, 5 g (33.9 mmol) of chloral, 13.6 g (680 mmol) of hydrogen fluoride, 8.1 g of chloroform ( 68.0 mmol), and 0.481 g (3.39 mmol) of boron trifluoride diethyl ether complex were weighed out. After raising the internal temperature to 150 ° C., the reaction pressure was controlled at around 4.0 MPa while purging the by-produced hydrogen chloride gas, and the reaction was continued for 12 hours. After completion of the reaction, the reaction pressure was purged to 0.1 MPa, and the reaction solution was sampled.
  • SUS stainless steel
  • Example 3 In a 50 ml stainless steel (SUS) autoclave reactor equipped with a pressure gauge, thermometer, PTFE stirrer, 5 g (33.9 mmol) of chloral, 13.6 g (680 mmol) of hydrogen fluoride, 8.1 g of chloroform ( 68.0 mmol), and 1.01 g (3.39 mmol) of antimony pentachloride were weighed out. After the temperature was raised to an internal temperature of 150 ° C., the reaction pressure was controlled at around 4.0 MPa while purging the by-produced hydrogen chloride gas, and the reaction was continued for 8 hours. After completion of the reaction, the reaction pressure was purged to 0.1 MPa, and the reaction solution was sampled.
  • SUS stainless steel
  • Example 4 A gas phase reactor (made of SUS316L, diameter 2.5 cm, length 40 cm) composed of a cylindrical reaction tube equipped with an electric furnace was filled with 50 mL of the catalyst prepared in the preparation example as a catalyst. While flowing chlorine gas at a flow rate of about 3 mL / min, the temperature of the reaction tube was raised to 120 ° C., and hydrogen fluoride was introduced at a rate of about 0.1 g / min over 1 hour. Next, 1-fluoro-2,2,2-trichloroethyl difluoromethyl ether (90.2 GC area%) as a raw material was started to be supplied to the reaction tube at a rate of about 0.1 g / min (contact time 15 seconds).
  • a gas phase reactor (made of SUS316L, diameter 2.5 cm, length 40 cm) composed of a cylindrical reaction tube equipped with an electric furnace was filled with 50 mL of aluminum fluoride (AlF 3 ) as a catalyst. While flowing nitrogen gas at a flow rate of about 10 mL / min, the temperature of the reaction tube was raised to 180 ° C., and hydrogen fluoride was introduced at a rate of about 0.1 g / min over 1 hour. Next, 1-fluoro-2,2,2-trichloroethyl difluoromethyl ether (90.2 GC%) as a raw material was started to be fed to the reaction tube at a rate of about 0.1 g / min (contact time 14 seconds).
  • AlF 3 aluminum fluoride
  • 1,2,2,2-tetrafluoroethyl difluoromethyl ether can be used as an inhalation anesthetic.

Abstract

Provided is a method by which 1-fluoro-2,2,2-trichloroethyl difluoromethyl ether, which is useful as an intermediate for the synthesis of desflurane, is conveniently obtained using inexpensive chloral as a starting material and reacting with chloroform and hydrogen fluoride in the presence of a Lewis acid catalyst. The obtained 1-fluoro-2,2,2-trichloroethyl difluoromethyl ether is then derived to desflurane by reaction with hydrogen fluoride in the gas phase in the presence of a supported metal halide catalyst in which metal halide containing at least one metal selected from the group consisting of antimony, tantalum, niobium, molybdenum, tin, and titanium is supported on active carbon. This method can efficiently produce desflurane by a short process.

Description

１，２，２，２－テトラフルオロエチルジフルオロメチルエーテル（デスフルラン）の製造方法Method for producing 1,2,2,2-tetrafluoroethyl difluoromethyl ether (desflurane)
　本発明は、１，２，２，２－テトラフルオロエチルジフルオロメチルエーテル（デスフルラン）の製造方法に関する。 The present invention relates to a method for producing 1,2,2,2-tetrafluoroethyl difluoromethyl ether (desflurane).
　１，２，２，２－テトラフルオロエチルジフルオロメチルエーテルはデスフルランとして知られている重要な吸入麻酔薬である。該吸入麻酔薬は、極めて低い生体内代謝率を有しており、生体に優しく安全性の高い薬剤として広く使用されている。 1,2,2,2-tetrafluoroethyl difluoromethyl ether is an important inhalation anesthetic known as desflurane. The inhalation anesthetic has a very low in vivo metabolic rate and is widely used as a safe and gentle drug for the living body.
　デスフルランに関する製造例は、それの前駆体として１－クロロ－２，２，２－トリフルオロエチルジフルオロメチルエーテル（ＣＦ3ＣＨＣｌＯＣＨＦ2；イソフルラン）、２，２，２－トリフルオロエチルジフルオロメチルエーテル（ＣＦ3ＣＨ2ＯＣＨＦ2）、または１，２，２，２－テトラフルオロエチルジクロロメチルエーテル（ＣＦ3ＣＨＦＯＣＨＣｌ2）に対して、フッ素化する方法が挙げられる。 Preparation examples for desflurane are 1-chloro-2,2,2-trifluoroethyl difluoromethyl ether (CF 3 CHClOCHF 2 ; isoflurane), 2,2,2-trifluoroethyl difluoromethyl ether (CF 3 CH 2 OCHF 2 ) or 1,2,2,2-tetrafluoroethyl dichloromethyl ether (CF 3 CHFOCHCl 2 ) may be fluorinated.
　イソフルランのハロゲン交換フッ素化反応として、アルカリ金属フッ化物を使用する方法（特許文献１）、三フッ化臭素を使用する方法（特許文献２や特許文献３）、フッ化水素を使用する方法（特許文献４、特許文献５、特許文献６、特許文献７）が知られている。２，２，２－トリフルオロエチルジフルオロメチルエーテルを、直接フッ素化する反応としては、フッ素ガスを使用する方法（特許文献８）、高次金属フッ素化合物を使用する方法（特許文献９や特許文献１０）が知られている。 As a halogen exchange fluorination reaction of isoflurane, a method using an alkali metal fluoride (Patent Document 1), a method using bromine trifluoride (Patent Document 2 and Patent Document 3), a method using hydrogen fluoride (Patent Document 1) Document 4, Patent Document 5, Patent Document 6, and Patent Document 7) are known. As a reaction for directly fluorinating 2,2,2-trifluoroethyldifluoromethyl ether, a method using a fluorine gas (Patent Document 8), a method using a higher-order metal fluorine compound (Patent Document 9 and Patent Documents) 10) is known.
　１，２，２，２－テトラフルオロエチルジクロロメチルエーテルに対するフッ素化反応は、フッ化水素を使用する方法が知られている（特許文献１１）。 As a fluorination reaction for 1,2,2,2-tetrafluoroethyldichloromethyl ether, a method using hydrogen fluoride is known (Patent Document 11).
米国特許４８７４９０１号明細書US Pat. No. 4,874,901 米国特許４７６２８５６号明細書US Pat. No. 4,762,856 米国特許５０１５７８１号明細書US Pat. No. 5,157,781 特開平２－２７９６４６号公報JP-A-2-279646 米国特許６８００７８６号明細書US Pat. No. 6,800,786 国際公開第２００６－０７６３２４号International Publication No. 2006-076324 特表２０１０－５３３２１１号明細書Special table 2010-533211 specification 米国特許３８９７５０２号明細書US Pat. No. 3,897,502 特開平４－２７３８３９号公報JP-A-4-273739 特開平６－１９２１５４号公報JP-A-6-192154 西独国特許２３６１０５８号明細書West German Patent No. 2361058
　デスフルランの製造方法については、デスフルラン等のエーテル部位（「－Ｏ－」）を持つ化合物の物性上、過酷な条件下にてフッ素化反応を行った場合、エーテル部位の開裂に伴った分解物の副生が問題となってくる。従来からの方法は、高価な出発原料を採用する割に変換率が悪く、効率の良い方法ではなかった。また、これらの高価な出発原料を合成する方法は、環境負荷の大きい試薬や、取り扱いの難しい試薬を用いるものが多く、工業的に好ましい製法とは言い難い。 Regarding the method for producing desflurane, when a fluorination reaction is performed under severe conditions due to the physical properties of a compound having an ether moiety (“—O—”) such as desflurane, the decomposition product accompanying the cleavage of the ether moiety By-product comes into question. The conventional method is not an efficient method because the conversion rate is poor while employing expensive starting materials. In addition, many of the methods for synthesizing these expensive starting materials use a reagent with a large environmental load or a reagent that is difficult to handle, and it is difficult to say that this is an industrially preferable production method.
　特許文献１に記載の方法は、フッ化カリウムを用いたフッ素化反応を開示しているが、反応条件は高温かつ高圧である為、工業的な製法として採用しにくく、かつ低収率である。特許文献２や特許文献３に記載の方法についても、使用している三フッ化臭素は、毒性と腐食性の強い試薬であり、取り扱いが困難な点が挙げられる。特許文献４や特許文献５に記載の方法は、五塩化アンチモン触媒の存在下、室温付近の条件でフッ化水素を用いた液相フッ素化を行うことにより、目的とするデスフルランを得ている。しかし、フッ化水素自身、酸性物質でもあり、また、一般的に反応活性が高いとされる五塩化アンチモンを使用しているため、原料であるイソフルランや目的物であるデスフルランのエーテル部位の開裂に由来した不純物の副生が多く生じていた。 Although the method described in Patent Document 1 discloses a fluorination reaction using potassium fluoride, since the reaction conditions are high temperature and high pressure, it is difficult to adopt as an industrial production method and has a low yield. . Also for the methods described in Patent Document 2 and Patent Document 3, bromine trifluoride used is a reagent that is highly toxic and corrosive, and is difficult to handle. In the methods described in Patent Document 4 and Patent Document 5, target desflurane is obtained by performing liquid phase fluorination using hydrogen fluoride under the condition of room temperature in the presence of an antimony pentachloride catalyst. However, hydrogen fluoride itself is an acidic substance, and antimony pentachloride, which is generally considered to have a high reaction activity, is used, so that it can cleave the ether moiety of isoflurane as the raw material and desflurane as the target product. Many by-products of derived impurities were generated.
　特許文献６に記載の方法は、クロミア触媒の存在下での気相フッ素化反応を行っているが、変換率は中程度であり、満足な結果を得ていない。特許文献７に記載の方法は、活性炭に担持したアンチモン触媒の存在下での気相フッ素化反応を行っているが、こちらも変換率は必ずしも高いとは言えなかった。 Although the method described in Patent Document 6 performs a gas phase fluorination reaction in the presence of a chromia catalyst, the conversion rate is moderate and satisfactory results have not been obtained. Although the method described in Patent Document 7 performs a gas phase fluorination reaction in the presence of an antimony catalyst supported on activated carbon, the conversion rate is not necessarily high.
　特許文献８に記載の方法は、爆発の危険もあり、また、取り扱いが不便で目的物が低収率ということもあり、工業的な製造としては採用しにくい。特許文献９や特許文献１０に記載の方法は、反応を円滑に行うためには、大過剰の高次金属フッ素化合物が必要であり、経済的な観点から好ましくない。また、特許文献１１に記載の方法は、何れも低収率～中程度の収率であり、吸入麻酔剤としての製造方法としては採用しにくく、何れの方法も課題が残されたままである。 The method described in Patent Document 8 has a risk of explosion, is inconvenient to handle and has a low yield of the target product, and is difficult to adopt for industrial production. The methods described in Patent Document 9 and Patent Document 10 require a large excess of higher-order metal fluorine compound in order to carry out the reaction smoothly, which is not preferable from an economical viewpoint. In addition, any of the methods described in Patent Document 11 has a low yield to a medium yield, and is difficult to employ as a production method as an inhalation anesthetic, and any method still has problems.
　特許文献１１に記載の方法によれば、五塩化アンチモン触媒の存在下、室温付近にてフッ化水素を用いた液相フッ素化を行うことにより、目的とするデスフルランを得ているが、低収率（２１％）であった。これらの反応例により、１，２，２，２－テトラフルオロエチルジクロロメチルエーテルに対するフッ素化反応によるデスフルランの合成には、低収率という課題が残されていた。 According to the method described in Patent Document 11, the desired desflurane is obtained by performing liquid phase fluorination using hydrogen fluoride at around room temperature in the presence of an antimony pentachloride catalyst. Rate (21%). According to these reaction examples, the problem of low yield remained in the synthesis of desflurane by fluorination reaction with 1,2,2,2-tetrafluoroethyldichloromethyl ether.
　以上のように、原料の入手が容易な出発原料を用い、取り扱いが安全なフッ素化試薬を用いて、効率的にデスフルランを製造する方法が強く望まれていた。 As described above, there has been a strong demand for a method for efficiently producing desflurane using a starting material that is easily available and using a fluorinating reagent that is safe to handle.
　本発明者らは、上記の問題点を鑑み、鋭意検討を行った。その結果、ルイス酸触媒の存在下、式［１］で表される２，２，２－トリクロロアセトアルデヒド（クロラール、本明細書では式［１］で表される２，２，２－トリクロロアセトアルデヒドを単に「クロラール」と言うことがある。）に対し、クロロホルム及びフッ化水素を反応させることにより、デスフルランの中間体として有用な、式［２］で表される１－フルオロ－２，２，２－トリクロロエチルジフルオロメチルエーテルが得られ、続いて、得られた２，２，２－トリクロロ－１－フルオロエチルジフルオロメチルエーテルに対し、気相中、アンチモン、タンタル、ニオブ、モリブデン、スズ、及びチタンからなる群より選ばれる少なくとも１種の金属を含む金属ハロゲン化物を活性炭に担持した金属ハロゲン化物担持触媒の存在下、フッ化水素を用いたフッ素化反応により、式［３］で表される１，２，２，２－テトラフルオロエチルジフルオロメチルエーテル（デスフルラン）へ誘導できる製造方法を新たに見出した。
Figure JPOXMLDOC01-appb-C000005
Figure JPOXMLDOC01-appb-C000006
Figure JPOXMLDOC01-appb-C000007
 In view of the above problems, the present inventors have conducted intensive studies. As a result, in the presence of the Lewis acid catalyst, 2,2,2-trichloroacetaldehyde represented by the formula [1] (chloral, in this specification, 2,2,2-trichloroacetaldehyde represented by the formula [1] 1-fluoro-2,2,2 represented by the formula [2], which is useful as an intermediate of desflurane by reacting chloroform and hydrogen fluoride. -Trichloroethyl difluoromethyl ether is obtained, followed by antimony, tantalum, niobium, molybdenum, tin and titanium in the gas phase with respect to the obtained 2,2,2-trichloro-1-fluoroethyl difluoromethyl ether In the presence of a metal halide-supported catalyst in which activated carbon is supported on a metal halide containing at least one metal selected from the group consisting of The fluorination reaction using hydrogen fluoride was newly found a manufacturing method that can be induced to be expressed by the formula [3] 1,2,2,2-tetrafluoroethyl difluoromethyl ether (Desflurane).
Figure JPOXMLDOC01-appb-C000005
Figure JPOXMLDOC01-appb-C000006
Figure JPOXMLDOC01-appb-C000007
　本発明者らは、特定の反応条件（反応基質、反応試剤、触媒）を採用することで、意外にも、従来の製造方法と比べて極めて少ない工程でデスフルランを合成できる、大変有用な知見を得た。本発明らは、デスフルランを合成する際、出発原料としてフルオラール（２，２，２－トリフルオロアセトアルデヒド）またはそれの等価体を用い、触媒の存在下、クロロホルム及びフッ化水素を反応させることで、デスフルランを製造する検討を行ってみたところ、デスフルランが全く生成せず、目的とする反応は進行しなかった（後述の比較例１参照）。 Surprisingly, the present inventors have obtained very useful knowledge that, by adopting specific reaction conditions (reaction substrate, reaction reagent, catalyst), desflurane can be synthesized in an extremely small number of steps as compared with conventional production methods. Obtained. The present inventors used fluoral (2,2,2-trifluoroacetaldehyde) or an equivalent thereof as a starting material when synthesizing desflurane, and by reacting chloroform and hydrogen fluoride in the presence of a catalyst, When examination which manufactures desflurane was performed, desflurane was not produced | generated at all and the target reaction did not advance (refer the below-mentioned comparative example 1).
　そこで、鋭意検討した結果、出発原料としてフルオラールと類似化合物であるクロラールを用い、かつ、特定の条件で反応を試みたところ、意外にも、デスフルランを少ない工程で簡便に製造できる知見を得た。安価に入手できるクロラールを出発原料とした本発明は、工業的スケールで製造できる、極めて有利な製造方法である。 Thus, as a result of diligent investigation, when chloral, which is a similar compound to fluoral, was used as a starting material and a reaction was attempted under specific conditions, surprisingly, it was found that desflurane can be easily produced with few steps. The present invention using chloral which can be obtained at low cost as a starting material is a very advantageous production method which can be produced on an industrial scale.
　このように、ルイス酸触媒存在下、クロラールにクロロホルム及びフッ化水素を反応させることで２，２，２－トリクロロ－１－フルオロエチルジフルオロメチルエーテルに誘導し、次いでフッ素化を行うことによりデスフルランを製造する方法は、今まで知られていなかった。 In this manner, chloral is reacted with chloroform and hydrogen fluoride in the presence of a Lewis acid catalyst to induce 2,2,2-trichloro-1-fluoroethyldifluoromethyl ether, followed by fluorination to produce desflurane. The manufacturing method has not been known so far.
　すなわち、本発明は、以下の［発明１］から［発明６］に記載する、１，２，２，２－テトラフルオロエチルジフルオロメチルエーテル（デスフルラン）の製造方法を提供する。 That is, the present invention provides a method for producing 1,2,2,2-tetrafluoroethyldifluoromethyl ether (desflurane) described in [Invention 1] to [Invention 6] below.
　［発明１］
　以下の工程を含む、１，２，２，２－テトラフルオロエチルジフルオロメチルエーテル（デスフルラン）の製造方法。
　第１工程：ルイス酸触媒の存在下、式［１］で表される２，２，２－トリクロロアセトアルデヒドに、クロロホルム及びフッ化水素を反応させることにより、式［２］で表される１－フルオロ－２，２，２－トリクロロエチルジフルオロメチルエーテルを得る工程。
　第２工程：第１工程にて得られた、式［２］で表される１－フルオロ－２，２，２－トリクロロエチルジフルオロメチルエーテルに対し、気相中、アンチモン、タンタル、ニオブ、モリブデン、スズ、及びチタンからなる群より選ばれる少なくとも１種の金属を含む金属ハロゲン化物を活性炭に担持した金属ハロゲン化物担持触媒の存在下、フッ化水素を反応させることにより、式［３］で表される１，２，２，２－テトラフルオロエチルジフルオロメチルエーテル（デスフルラン）を得る工程。 [Invention 1]
A process for producing 1,2,2,2-tetrafluoroethyldifluoromethyl ether (desflurane), comprising the following steps.
First step: By reacting 2,2,2-trichloroacetaldehyde represented by formula [1] with chloroform and hydrogen fluoride in the presence of a Lewis acid catalyst, 1-form represented by formula [2] Obtaining fluoro-2,2,2-trichloroethyl difluoromethyl ether.
Second step: Antimony, tantalum, niobium, molybdenum in the gas phase with respect to 1-fluoro-2,2,2-trichloroethyldifluoromethyl ether represented by the formula [2] obtained in the first step Represented by the formula [3] by reacting hydrogen fluoride in the presence of a metal halide-supported catalyst in which a metal halide containing at least one metal selected from the group consisting of tin, titanium and titanium is supported on activated carbon. To obtain 1,2,2,2-tetrafluoroethyl difluoromethyl ether (desflurane).
　［発明２］
　第１工程で用いるルイス酸触媒が、ホウ素（ＩＩＩ）、スズ（ＩＩ）、スズ（ＩＶ）、チタン（ＩＶ）、亜鉛（ＩＩ）、アルミニウム（ＩＩＩ）、アンチモン（ＩＩＩ）、及びアンチモン（Ｖ）からなる群より選ばれる少なくとも１種の金属を含む金属ハロゲン化物である、発明１に記載の製造方法。 [Invention 2]
The Lewis acid catalyst used in the first step is boron (III), tin (II), tin (IV), titanium (IV), zinc (II), aluminum (III), antimony (III), and antimony (V). The manufacturing method of the invention 1 which is a metal halide containing at least one metal selected from the group consisting of:
　［発明３］
　第１工程で用いるルイス酸触媒が、三フッ化ホウ素（ＩＩＩ）、四塩化スズ（ＩＶ）、及び五塩化アンチモン（Ｖ）からなる群より選ばれる少なくとも一種の金属ハロゲン化物である、発明１または２に記載の製造方法。 [Invention 3]
Invention 1 or the Lewis acid catalyst used in the first step is at least one metal halide selected from the group consisting of boron trifluoride (III), tin tetrachloride (IV), and antimony pentachloride (V) 2. The production method according to 2.
　［発明４］
　第２工程において、反応を、五塩化アンチモンを活性炭に担持した触媒の存在下で行う、発明１乃至３の何れかに記載の製造方法。 [Invention 4]
The production method according to any one of Inventions 1 to 3, wherein in the second step, the reaction is carried out in the presence of a catalyst in which antimony pentachloride is supported on activated carbon.
　［発明５］
　第２工程において、式［２］で表される１－フルオロ－２，２，２－トリクロロエチルジフルオロメチルエーテル１００モルに対し、０．１から１０モルの塩素（Ｃｌ2）を反応系に導入させる工程を含む、発明１乃至４の何れかに記載の製造方法。 [Invention 5]
In the second step, 0.1 to 10 mol of chlorine (Cl 2 ) is introduced into the reaction system with respect to 100 mol of 1-fluoro-2,2,2-trichloroethyldifluoromethyl ether represented by the formula [2]. The manufacturing method in any one of invention 1 thru | or 4 including the process to make.
　［発明６］
　式［２］で表される１－フルオロ－２，２，２－トリクロロエチルジフルオロメチルエーテル。 [Invention 6]
1-fluoro-2,2,2-trichloroethyl difluoromethyl ether represented by the formula [2].
　本発明によれば、入手が容易なクロラールを出発原料とし、取り扱いが安全な各種試剤を用いて、前記で記載した工程を経由することにより、１，２，２，２－テトラフルオロエチルジフルオロメチルエーテル（デスフルラン）を効率的に製造できるという効果を奏する。 According to the present invention, 1,2,2,2-tetrafluoroethyldifluoromethyl is obtained by using the easily described chloral as a starting material and passing through the steps described above using various reagents that are safe to handle. The effect is that ether (desflurane) can be produced efficiently.
　以下、本発明を詳細に説明する。本発明は以下の実施態様に限定されるものではなく、本発明の趣旨を損なわない範囲で、当業者の通常の知識に基づいて、適宜実施することができる。 Hereinafter, the present invention will be described in detail. The present invention is not limited to the following embodiments, and can be appropriately implemented based on the ordinary knowledge of those skilled in the art without departing from the spirit of the present invention.
　本発明の１，２，２，２－テトラフルオロエチルジフルオロメチルエーテル（デスフルラン）の製造方法は、以下の工程（第１工程から第２工程）を含む。
　第１工程：ルイス酸触媒の存在下、式［１］で表される２，２，２－トリクロロアセトアルデヒドに、クロロホルム及びフッ化水素を反応させることにより、式［２］で表される１－フルオロ－２，２，２－トリクロロエチルジフルオロメチルエーテルを得る工程。
　第２工程：第１工程にて得られた、式［２］で表される１－フルオロ－２，２，２－トリクロロエチルジフルオロメチルエーテルに対し、気相中、アンチモン、タンタル、ニオブ、モリブデン、スズ、及びチタンからなる群より選ばれる少なくとも１種の金属を含む金属ハロゲン化物を活性炭に担持した金属ハロゲン化物担持触媒の存在下、フッ化水素を反応させることにより、式［３］で表される１，２，２，２－テトラフルオロエチルジフルオロメチルエーテル（デスフルラン）を得る工程。
　これら各工程の関係を図示すると、以下の通りとなる。
Figure JPOXMLDOC01-appb-C000008
 The method for producing 1,2,2,2-tetrafluoroethyldifluoromethyl ether (desflurane) of the present invention includes the following steps (from the first step to the second step).
First step: By reacting 2,2,2-trichloroacetaldehyde represented by formula [1] with chloroform and hydrogen fluoride in the presence of a Lewis acid catalyst, 1-form represented by formula [2] Obtaining fluoro-2,2,2-trichloroethyl difluoromethyl ether.
Second step: Antimony, tantalum, niobium, molybdenum in the gas phase with respect to 1-fluoro-2,2,2-trichloroethyldifluoromethyl ether represented by the formula [2] obtained in the first step Represented by the formula [3] by reacting hydrogen fluoride in the presence of a metal halide-supported catalyst in which a metal halide containing at least one metal selected from the group consisting of tin, titanium and titanium is supported on activated carbon. To obtain 1,2,2,2-tetrafluoroethyl difluoromethyl ether (desflurane).
The relationship between these steps is illustrated as follows.
Figure JPOXMLDOC01-appb-C000008
　［第１工程］
　最初に第１工程について説明する。第１工程は、ルイス酸触媒の存在下、式［１］で表される２，２，２－トリクロロアセトアルデヒドに、クロロホルム及びフッ化水素を反応させることにより、式［２］で表される１－フルオロ－２，２，２－トリクロロエチルジフルオロメチルエーテルを得る工程である。 [First step]
First, the first step will be described. The first step is a reaction represented by the formula [2] by reacting 2,2,2-trichloroacetaldehyde represented by the formula [1] with chloroform and hydrogen fluoride in the presence of a Lewis acid catalyst. This is a step of obtaining fluoro-2,2,2-trichloroethyl difluoromethyl ether.
　本工程において使用する原料のクロラールは、市販品（例えば、東京化成工業株式会社品）を用いることができるが、その他にも文献記載（Tetrahedron Letters, 56(24), 3758-3761, 2015）の方法等により、水和物である抱水クロラールの脱水反応により、調製可能である。 The raw material chloral used in this step can be a commercial product (for example, a product of Tokyo Kasei Kogyo Co., Ltd.), but in addition to the literature description (TetrahedronedLetters, 56 (24),) 3758-3761, -2015) It can be prepared by a dehydration reaction of chloral hydrate as a hydrate by a method or the like.
　本工程において、フッ化水素の使用量は、クロラールに対し、通常、３当量以上あれば良く、反応を円滑に進行させる為には、５当量から４０当量用いるのが好ましい。さらに、反応後の処理操作を考慮すると、５当量から２０当量が特に好ましい。 In this step, the amount of hydrogen fluoride used is usually 3 equivalents or more relative to chloral, and it is preferably used in an amount of 5 equivalents to 40 equivalents in order to allow the reaction to proceed smoothly. Furthermore, in view of the processing operation after the reaction, 5 to 20 equivalents are particularly preferable.
　本工程におけるクロロホルムの使用量は、クロラールに対し、通常、１．０当量以上あれば良く、反応を円滑に進行させる為には、１．０当量から２０．０当量を用いるのが好ましい。反応後の処理操作を考慮すると、１．０当量から３．０当量が特に好ましい。 The amount of chloroform used in this step is usually 1.0 equivalent or more with respect to chloral, and in order to allow the reaction to proceed smoothly, it is preferable to use 1.0 equivalent to 20.0 equivalent. In view of the treatment operation after the reaction, 1.0 equivalent to 3.0 equivalent is particularly preferable.
　本工程で用いるルイス酸触媒としては、ホウ素、スズ、チタン、亜鉛、アルミニウム、及びアンチモンからなる群より選ばれる少なくとも１種の金属を含む金属ハロゲン化物である。なお、用いる金属ハロゲン化物としては、高原子価金属ハロゲン化物、すなわち、通常取りうる最高の原子価を有する金属のハロゲン化物が好ましい。 The Lewis acid catalyst used in this step is a metal halide containing at least one metal selected from the group consisting of boron, tin, titanium, zinc, aluminum, and antimony. The metal halide to be used is preferably a high valence metal halide, that is, a metal halide having the highest possible valence.
　該ハロゲン化物における高原子価金属としては、ホウ素（III：酸化数をいう。以下同じ）、スズ（ＩＩ）、スズ（ＩＶ）、チタン（ＩＶ）、亜鉛（II）、アルミニウム（III）、アンチモン（III）、及びアンチモン（Ｖ）からなる群より選ばれる少なくとも１種の金属である。これらの金属を用いた金属ハロゲン化物のうち、三フッ化ホウ素（III）、四塩化スズ（IＶ）、及び五塩化アンチモン（Ｖ）が特に好ましい。 As the high-valent metal in the halide, boron (III: refers to the oxidation number; the same shall apply hereinafter), tin (II), tin (IV), titanium (IV), zinc (II), aluminum (III), antimony (III) and at least one metal selected from the group consisting of antimony (V). Of the metal halides using these metals, boron trifluoride (III), tin tetrachloride (IV), and antimony pentachloride (V) are particularly preferable.
　本工程は、熱的または化学的にも安定な溶媒を反応溶媒として好適に用いることができる。例えば、パーフルオロブタン、パーフルオロペンタン、パーフルオロヘキサン、パーフルオロヘプタン等のフルオラス溶媒が使用できる。これらの反応溶媒は、単独または組み合わせて用いることができる。 In this step, a thermally or chemically stable solvent can be suitably used as the reaction solvent. For example, fluorous solvents such as perfluorobutane, perfluoropentane, perfluorohexane, and perfluoroheptane can be used. These reaction solvents can be used alone or in combination.
　本工程では、反応基質であるクロロホルムを過剰量用いることにより、反応試剤として用いるのと同時に、反応を円滑に進める反応溶媒としての働きが期待できる。なお、反応基質でもあるクロロホルムは、本工程において、反応系内で、一時的にフッ素化されるといった、副反応が生じる場合がある。但し、クロロホルムのフッ素化物であるジクロロフルオロメタン（ＨＣＦＣ－２１）やクロロジフルオロメタン（ＨＣＦＣ－２２）が仮に生成することがあっても、クロラールとの反応が進行し、最終的に本工程の目的物である２，２，２－トリクロロ－１－フルオロエチルジフルオロメチルエーテルへ収束すると考えられるため、本工程におけるクロロホルムの副反応は特段、問題ではない。 In this step, by using an excessive amount of chloroform as a reaction substrate, it can be used as a reaction reagent, and at the same time, it can be expected to function as a reaction solvent that facilitates the reaction. In this step, side reaction such as temporary fluorination may occur in the reaction system of chloroform which is also a reaction substrate. However, even if chlorofluoromethane (HCFC-21) or chlorodifluoromethane (HCFC-22), which are fluorinated products of chloroform, may be produced temporarily, the reaction with chloral proceeds and the purpose of this process is finally reached. Since it is thought that it converges to 2,2,2-trichloro-1-fluoroethyldifluoromethyl ether, which is a product, the side reaction of chloroform in this step is not particularly a problem.
　一方、本工程において、反応溶媒を用いずに反応を実施することが可能である。中でも、反応溶媒を共存させない条件で反応を行うことは、反応後の精製操作が簡便となり、より好ましい。 On the other hand, in this step, it is possible to carry out the reaction without using a reaction solvent. Among these, it is more preferable to carry out the reaction under the condition that the reaction solvent does not coexist because the purification operation after the reaction becomes simple.
　本工程における温度条件は、＋２５から＋２００℃の範囲で行えば良く、通常は＋５０から＋１８０℃が好ましく、中でも＋１００から＋１５０℃が特に好ましい。 The temperature condition in this step may be performed in the range of +25 to + 200 ° C., usually +50 to + 180 ° C., and particularly preferably +100 to + 150 ° C.
　本工程における圧力条件は、０．１ＭＰａ（絶対圧。以下、本明細書で同じ）から１０．０ＭＰａの範囲で行えば良く、通常は１．０ＭＰａから７．０ＭＰａが好ましく、特に１．０ＭＰａから５．０ＭＰａがより好ましい。従って、ステンレス鋼（ＳＵＳ）の様な材質でできた耐圧反応容器やフッ化水素に対する防食性能を有するテトラフルオロエチレン・パーフルオロアルキルビニルエーテル共重合体（ＰＦＡ）やポリテトラフルオロエチレン（ＰＴＦＥ）等の樹脂でライニングした耐圧反応容器を用いることができる。 The pressure condition in this step may be in the range of 0.1 MPa (absolute pressure, hereinafter the same in the present specification) to 10.0 MPa, usually 1.0 MPa to 7.0 MPa, particularly 1.0 MPa. 5.0 MPa is more preferable. Therefore, a pressure resistant reaction vessel made of a material such as stainless steel (SUS), a tetrafluoroethylene / perfluoroalkyl vinyl ether copolymer (PFA) or a polytetrafluoroethylene (PTFE) having anticorrosion performance against hydrogen fluoride, etc. A pressure-resistant reaction vessel lined with resin can be used.
　本工程における反応時間は、通常は４８時間以内であるが、クロラールと使用したフッ化水素の使用量に起因した反応条件の違いにより、ガスクロマトグラフィー、薄層クロマトグラフィー、液体クロマトグラフィー、核磁気共鳴等の分析手段により反応の進行状況を追跡し、出発基質が殆ど消失した時点を反応の終点とすることが好ましい。 The reaction time in this step is usually within 48 hours, but depending on the reaction conditions due to the amount of chloral and hydrogen fluoride used, gas chromatography, thin layer chromatography, liquid chromatography, nuclear magnetics It is preferable that the progress of the reaction is traced by an analytical means such as resonance, and the point of time when the starting substrate has almost disappeared is the end point of the reaction.
　本工程の後処理操作は、反応終了液に対して通常の精製操作を実施することにより、目的とする式［２］の２，２，２－トリクロロ－１－フルオロエチルジフルオロメチルエーテルを容易に得ることができる。目的物は、必要に応じて、活性炭処理、蒸留、再結晶、カラムクロマトグラフィー等により、さらに高い化学純度品へ精製することができる。 In the post-treatment operation in this step, the target 2,2,2-trichloro-1-fluoroethyldifluoromethyl ether of the formula [2] can be easily obtained by carrying out a normal purification operation on the reaction end solution. Obtainable. The target product can be purified to a higher chemical purity product by activated carbon treatment, distillation, recrystallization, column chromatography and the like, if necessary.
　［第２工程］
　次に、第２工程について説明する。第２工程は、第１工程にて得られた、式［２］で表される１－フルオロ－２，２，２－トリクロロエチルジフルオロメチルエーテルに対し、気相中、アンチモン、タンタル、ニオブ、モリブデン、スズ、及びチタンからなる群より選ばれる少なくとも１種の金属を含む金属ハロゲン化物を活性炭に担持した金属ハロゲン化物担持触媒の存在下、フッ化水素を反応させることにより、式［３］で表される１，２，２，２－テトラフルオロエチルジフルオロメチルエーテル（デスフルラン）を得る工程である。 [Second step]
Next, the second step will be described. In the second step, antimony, tantalum, niobium, 1-fluoro-2,2,2-trichloroethyldifluoromethyl ether represented by the formula [2] obtained in the first step is used in the gas phase. By reacting hydrogen fluoride in the presence of a metal halide-supported catalyst in which a metal halide containing at least one metal selected from the group consisting of molybdenum, tin, and titanium is supported on activated carbon, the formula [3] In this step, 1,2,2,2-tetrafluoroethyldifluoromethyl ether (desflurane) is obtained.
　本工程は、フッ化水素に対して実質的に不活性な材質で造られた反応器を用い、温度調節の下、触媒の充填された反応領域へクロラールを導入することで行なわれる。本工程で用いる反応容器としては、通常、管状のものであって、ステンレス鋼、ハステロイTM、白金等の金属製のものや、四フッ化エチレン樹脂、クロロ－トリフルオロエチレン樹脂、フッ化ビニリデン樹脂、ＰＦＡ樹脂等を内部にライニングしたものであり、常圧又は加圧下でも十分反応を行うことができる反応容器を用いるのが好ましい。 This step is performed by using a reactor made of a material substantially inert to hydrogen fluoride and introducing chloral into the reaction zone filled with the catalyst under temperature control. The reaction vessel used in this step is usually tubular and made of metal such as stainless steel, Hastelloy ™ , platinum, tetrafluoroethylene resin, chloro-trifluoroethylene resin, vinylidene fluoride resin It is preferable to use a reaction vessel that is lined with a PFA resin or the like and can sufficiently react even under normal pressure or under pressure.
　本工程で用いる触媒は、アンチモン、タンタル、ニオブ、モリブデン、スズ、及びチタンからなる群より選ばれる少なくとも１種の金属を含む金属ハロゲン化物を活性炭に担持した金属ハロゲン化物担持触媒である。 The catalyst used in this step is a metal halide-supported catalyst in which activated carbon supports a metal halide containing at least one metal selected from the group consisting of antimony, tantalum, niobium, molybdenum, tin, and titanium.
　触媒調製に用いる前記金属ハロゲン化物としては、高原子価金属ハロゲン化物、すなわち、通常取りうる最高の原子価を有するハロゲン化物が好ましい。したがって、該ハロゲン化物における高原子価金属としては、アンチモン（Ｖ：酸化数をいう。以下同じ））、スズ（ＩＶ）、チタン（ＩＶ）、ニオブ（Ｖ）、タンタル（Ｖ）、モリブテン（Ｖ）であるのが好ましい。これらの金属のうち、アンチモン、タンタルは好ましく、アンチモンが特に好ましい。 The metal halide used for catalyst preparation is preferably a high-valence metal halide, that is, a halide having the highest valence that can be usually obtained. Therefore, as the high valent metal in the halide, antimony (V: an oxidation number; the same applies hereinafter)), tin (IV), titanium (IV), niobium (V), tantalum (V), molybdenum (V ) Is preferred. Of these metals, antimony and tantalum are preferable, and antimony is particularly preferable.
　なお、金属ハロゲン化物を担体に担持した後に、通常取りうる最高の酸化数に塩素などで酸化すること、さらには金属化合物を担持し、次いでハロゲン化および／または高次酸化することで高原子価金属ハロゲン化物を担持した触媒としても良い。金属ハロゲン化物は、ＳｂＸ5（Ｘはそれぞれ独立にフッ素、塩素、臭素、ヨウ素を表す。以下同じ）、ＴａＸ5、ＮｂＸ5、ＭｏＸ5、ＳｎＸ4、ＴｉＸ4の構造等の金属ハロゲン化物が挙げられる。 In addition, after supporting a metal halide on a support, it is oxidized with chlorine or the like to the highest oxidation number that can normally be obtained, and further, a metal compound is supported and then halogenated and / or higher-order oxidized to achieve a high valence. A catalyst carrying a metal halide may be used. Examples of the metal halide include metal halides such as SbX 5 (X independently represents fluorine, chlorine, bromine and iodine; the same applies hereinafter), TaX 5 , NbX 5 , MoX 5 , SnX 4 and TiX 4. It is done.
　触媒調製に用いる金属ハロゲン化物として、具体的にはアンチモン化合物としては、五塩化アンチモン、三塩化二フッ化アンチモン、三塩化アンチモン、五臭化アンチモン、三臭化アンチモン、五フッ化アンチモン、三フッ化アンチモン、三沃化アンチモン等が挙げられる。これらのうち、五塩化アンチモンが特に好ましい。同様に、スズ化合物としては、四塩化スズ、二塩化スズ等が、チタン化合物としては、四塩化チタン、三塩化チタン等が、ニオブ化合物としては、五塩化ニオブ等が、タンタル化合物としては、五塩化タンタル等が、モリブテン化合物としは、五塩化モリブデン等が挙げられる。 As metal halides used for catalyst preparation, specifically, antimony compounds include antimony pentachloride, antimony trichloride, antimony trichloride, antimony trichloride, antimony pentabromide, antimony tribromide, antimony pentafluoride, trifluoride. And antimony trioxide and antimony triiodide. Of these, antimony pentachloride is particularly preferred. Similarly, as the tin compound, tin tetrachloride, tin dichloride, etc., as the titanium compound, titanium tetrachloride, titanium trichloride, etc., as the niobium compound, niobium pentachloride, etc., as the tantalum compound, Examples of the molybdenum compound such as tantalum chloride include molybdenum pentachloride.
　調製方法としては特に限定されず金属ハロゲン化物が活性炭に付着しておればよい。常温付近で液体である化合物、例えば、五塩化アンチモン、四塩化スズまたは四塩化チタンなどの場合、後述する塩基性水溶液、酸または熱水による処理や脱水処理の前処理を必要に応じて施した活性炭に、そのまま滴下、スプレー、浸漬等の方法で直接付着させることができる。また、常温で液体または固体の化合物である場合には、化合物を溶媒に溶解した溶液へ活性炭を浸漬し含浸させるか、スプレーなどの方法で活性炭に付着させる。次に、このようにして得られた金属化合物の付着した活性炭を加熱または／および減圧して乾燥した後、金属ハロゲン化物が付着した活性炭を加熱下においてフッ化水素、塩素、塩化水素、塩化フッ化炭化水素等と接触させることで触媒を調製する。特に五塩化アンチモンを担持した場合、１００℃以上で１当量以上の塩素により処理することが、触媒の活性化に望ましい。 Preparation method is not particularly limited as long as the metal halide adheres to the activated carbon. In the case of a compound that is liquid near room temperature, for example, antimony pentachloride, tin tetrachloride, or titanium tetrachloride, a treatment with a basic aqueous solution, acid or hot water described below, or a pretreatment for dehydration treatment was performed as necessary. It can be directly attached to the activated carbon by a method such as dropping, spraying or dipping. Further, when the compound is a liquid or solid compound at room temperature, the activated carbon is immersed in a solution in which the compound is dissolved in a solvent, or impregnated, or attached to the activated carbon by a method such as spraying. Next, the activated carbon attached with the metal compound thus obtained is dried by heating or / and reducing the pressure, and then the activated carbon attached with the metal halide is heated under hydrogen fluoride, chlorine, hydrogen chloride, fluoride chloride. A catalyst is prepared by contacting with a hydrocarbon or the like. In particular, when antimony pentachloride is supported, treatment with 1 equivalent or more of chlorine at 100 ° C. or higher is desirable for activating the catalyst.
　本工程で用いる溶媒としては金属ハロゲン化物を溶解でき、その際、金属ハロゲン化物を分解しない溶媒であれば良い。具体的には、例えば、低級アルコール類（炭素数１～６の直鎖もしくは分岐鎖状のアルキル基を有するアルコール、または炭素数３～６の環式のアルキル基を有するアルコールのことを言う）、エーテル類、ケトン類、芳香族化合物、エステル類、塩素系溶剤、フッ素系溶剤などが挙げられる。具体的には、メタノール、エタノール、イソプロパノール、ジエチルエーテル、アセトン、メチルエチルケトン、ベンゼン、トルエン、キシレン、酢酸エチル、酢酸ブチル、塩化メチレン、クロロホルム、テトラクロロエチレン、テトラクロロエタン、１，３－ビス（トリフルオロメチル）ベンゼン、トリフルオロメチルベンゼン等が挙げられる。 The solvent used in this step may be any solvent that can dissolve the metal halide and does not decompose the metal halide. Specifically, for example, lower alcohols (referred to as alcohols having a linear or branched alkyl group having 1 to 6 carbon atoms or alcohols having a cyclic alkyl group having 3 to 6 carbon atoms) , Ethers, ketones, aromatic compounds, esters, chlorinated solvents, fluorinated solvents, and the like. Specifically, methanol, ethanol, isopropanol, diethyl ether, acetone, methyl ethyl ketone, benzene, toluene, xylene, ethyl acetate, butyl acetate, methylene chloride, chloroform, tetrachloroethylene, tetrachloroethane, 1,3-bis (trifluoromethyl) Examples thereof include benzene and trifluoromethylbenzene.
　例えば、五塩化アンチモン、五塩化ニオブ、五塩化タンタル、五塩化モリブデンなどの溶剤としては１，３－ビス（トリフルオロメチル）ベンゼン、トリフルオロメチルベンゼンなど、フッ素系溶剤は好適である。これらの溶媒を使用する際、または溶媒を用いない場合でも水などのハロゲン化物と反応性を有する物質を溶媒および処理系から除去し、実質的に水の非存在下において担持させることが好ましい。 For example, as a solvent such as antimony pentachloride, niobium pentachloride, tantalum pentachloride, and molybdenum pentachloride, fluorine-based solvents such as 1,3-bis (trifluoromethyl) benzene and trifluoromethylbenzene are suitable. When these solvents are used or even when no solvent is used, it is preferable to remove substances having reactivity with halides such as water from the solvent and the treatment system and to carry them substantially in the absence of water.
　本工程で使用する触媒の、該触媒の調製に用いる金属ハロゲン化物の活性炭への担持量は、活性炭１００質量部に対し０．１から５００質量部であり、好ましくは１から２５０質量部である。また、２種以上の金属を併せて触媒活性を調節することもできる。この場合、アンチモンハロゲン化物（特に五塩化アンチモン）を主成分として、他のニオブ化合物（特に五塩化ニオブ）またはタンタル化合物（特に五塩化タンタル）、スズ、チタン、ニオブ、タンタル、モリブテンのハロゲン化物を組み合わせるのが良い。副成分金属／主成分金属の原子比は、副成分金属を含まない場合でも良いが、５０／５０～０／１００とすることができ、３０／７０～０／１００が好ましい。 The amount of the metal halide used in the preparation of the catalyst used in this step on the activated carbon is 0.1 to 500 parts by mass, preferably 1 to 250 parts by mass with respect to 100 parts by mass of the activated carbon. . Moreover, catalyst activity can also be adjusted combining 2 or more types of metals. In this case, antimony halide (especially antimony pentachloride) as a main component, other niobium compounds (especially niobium pentachloride) or tantalum compounds (especially tantalum pentachloride), tin, titanium, niobium, tantalum, molybdenum halides. It is good to combine. The atomic ratio of the minor component metal / major component metal may not include the minor component metal, but may be 50/50 to 0/100, and preferably 30/70 to 0/100.
　担体として用いる活性炭は、木材、木炭、椰子殻炭、パーム核炭、素灰等を原料とする植物系、泥炭、亜炭、褐炭、瀝青炭、無煙炭等を原料とする石炭系、石油残滓、オイルカ－ボン等を原料とする石油系または炭化ポリ塩化ビニリデン等の合成樹脂系がある。これら市販の活性炭から選択し使用することができ、例えば、瀝青炭から製造された活性炭（東洋カルゴン製ＢＰＬ粒状活性炭）、椰子殻炭（武田薬品工業製粒状白鷺ＧＸ、ＳＸ、ＣＸ、ＸＲＣ、東洋カルゴン製ＰＣＢ）等が挙げられるが、これらに限定されない。形状、大きさも通常粒状で用いられるが、球状、繊維状、粉体状、ハニカム状等反応器に適合すれば良い。 Activated carbon used as a carrier is plant based on wood, charcoal, coconut shell charcoal, palm kernel charcoal, bare ash, etc., coal based on peat, lignite, lignite, bituminous coal, anthracite, etc., petroleum residue, oil car There are petroleum-based or synthetic resin-based such as carbonized polyvinylidene chloride using Bonn as a raw material. For example, activated carbon manufactured from bituminous coal (BPL granular activated carbon manufactured by Toyo Calgon), coconut shell charcoal (granular white birch GX, SX, CX, XRC manufactured by Takeda Pharmaceutical Co., Ltd., Toyo Calgon). PCB) and the like, but is not limited thereto. The shape and size are usually used in a granular form, but may be adapted to a reactor such as a sphere, fiber, powder or honeycomb.
　本発明において使用する活性炭は比表面積の大きな活性炭が好ましい。活性炭の比表面積ならびに細孔容積は、市販品の規格の範囲で十分であるが、それぞれ４００ｍ2／ｇより大きく、０．１ｃｍ3／ｇより大きいことが望ましい。またそれぞれ８００から３０００ｍ2／ｇ、０．２から１．０ｃｍ3／ｇであればよい。さらに、活性炭は、水酸化アンモニウム、水酸化ナトリウム、水酸化カリウム等の塩基性水溶液に常温付近で１０時間程度またはそれ以上の時間浸漬するか、活性炭を触媒担体に使用する際に慣用的に行われる硝酸、塩酸、フッ酸等の酸による前処理を施し、予め担体表面の活性化ならびに灰分の除去を行うことが望ましい。さらに、本工程での触媒は、何れの方法により前処理される場合も、金属ハロゲン化物を担持処理する際に加水分解等により劣化しないよう前もって加熱し、その後、減圧乾燥等することで水分除去を可及的に行うのが好ましい。何れの方法で調製した触媒も、使用の前に予めフッ化水素、フッ素化またはフッ素化塩素化炭化水素などのフッ素化剤と接触させておき、反応中の触媒の組成変化、短寿命化、異常反応などを防止することが有効である。 The activated carbon used in the present invention is preferably activated carbon having a large specific surface area. The specific surface area and pore volume of the activated carbon are sufficient within the range of the specifications of commercially available products, but are desirably larger than 400 m 2 / g and larger than 0.1 cm 3 / g, respectively. They may be 800 to 3000 m 2 / g and 0.2 to 1.0 cm 3 / g, respectively. Further, activated carbon is immersed in a basic aqueous solution such as ammonium hydroxide, sodium hydroxide or potassium hydroxide for about 10 hours or longer at room temperature, or conventionally used when activated carbon is used as a catalyst support. It is desirable to perform pretreatment with an acid such as nitric acid, hydrochloric acid, hydrofluoric acid, etc. to activate the carrier surface and remove ash in advance. Furthermore, the catalyst used in this step is pretreated by any method, and when the metal halide is supported, the catalyst is heated in advance so as not to deteriorate due to hydrolysis, etc., and then dehydrated by drying under reduced pressure. Is preferably performed as much as possible. The catalyst prepared by any method is contacted with a fluorinating agent such as hydrogen fluoride, fluorinated or fluorinated chlorinated hydrocarbon in advance before use to change the composition of the catalyst during the reaction, shorten the life, It is effective to prevent abnormal reactions.
　また、本工程で使用する触媒はフッ化水素および／または塩素と接触させておくことは同様の理由で好ましい。また、反応中に、塩素、フッ素化塩素化または塩素化炭化水素などを反応器中に供給することは触媒寿命の延長、反応率、反応収率の向上に有効である。特に塩素の導入は触媒活性の向上、維持に好ましく、原料である２，２，２－トリクロロ－１－フルオロエチルジフルオロメチルエーテル１００モルに対し、０．１から１０モル程度同伴させることが望ましい。 Further, it is preferable for the same reason that the catalyst used in this step is in contact with hydrogen fluoride and / or chlorine. Further, supplying chlorine, fluorinated chlorinated or chlorinated hydrocarbon into the reactor during the reaction is effective for extending the catalyst life, improving the reaction rate, and the reaction yield. In particular, introduction of chlorine is preferable for improving and maintaining the catalytic activity, and it is desirable to bring about 0.1 to 10 mol with respect to 100 mol of 2,2,2-trichloro-1-fluoroethyldifluoromethyl ether as a raw material.
　本工程では、気相中、フッ化水素を流通させることでフッ素化反応を進行させるが、このような流通形式では、触媒の保持方法は固定床、流動床、移動床等、いずれの形式でもかまわないが、固定床で行うのが簡便であり、好ましい。 In this step, the fluorination reaction proceeds by circulating hydrogen fluoride in the gas phase. In such a flow format, the catalyst retention method can be any type such as fixed bed, fluidized bed, moving bed, etc. Although it does not matter, it is convenient and preferable to carry out on a fixed bed.
　本工程における反応温度は特に限定されないが、１００から５００℃であり、１００から３００℃が好ましく、１００から２００℃がさらに好ましい。反応温度が５００℃を超えても特に反応率は向上せず、その一方、分解生成物が生成して式［３］に示すデスフルランの選択率が低下するので好ましくない。 The reaction temperature in this step is not particularly limited, but is 100 to 500 ° C, preferably 100 to 300 ° C, and more preferably 100 to 200 ° C. Even if the reaction temperature exceeds 500 ° C., the reaction rate is not particularly improved. On the other hand, a decomposition product is generated, and the selectivity of desflurane shown in the formula [3] is lowered, which is not preferable.
　本工程において、反応領域へ供給する１－フルオロ－２，２，２－トリクロロエチルジフルオロメチルエーテル：フッ化水素のモル比は反応温度により変わり得るが、１：５０から１：２であり、１：３０から１：４が好ましく、１：２０から１：５がより好ましい。フッ化水素が過剰量である場合、有機物処理量の減少ならびに反応系から排出された未反応フッ化水素と生成物との混合物の分離に支障をきたす。一方で、フッ化水素が少ないと反応変換率は低下し、目的物の収率が低下する。 In this step, the molar ratio of 1-fluoro-2,2,2-trichloroethyldifluoromethyl ether: hydrogen fluoride supplied to the reaction zone can vary depending on the reaction temperature, but is from 1:50 to 1: 2. : 30 to 1: 4 is preferable, and 1:20 to 1: 5 is more preferable. When the hydrogen fluoride is in an excessive amount, the reduction of the organic matter throughput and the separation of the mixture of the unreacted hydrogen fluoride discharged from the reaction system and the product are hindered. On the other hand, when there is little hydrogen fluoride, reaction conversion rate falls and the yield of a target object falls.
　本工程の方法は、圧力については特に限定されないが、例えば気相反応として行う場合は、特に加圧または減圧などの圧力調節をすることなく行うことができる。装置の機械的な側面から０．１ＭＰａ～１．０ＭＰａで行うのが好ましい。なお、操作圧力を設定する場合、系内に存在する原料などの有機物が反応系内で液化しないような条件を選ぶことが望ましい。 The method of this step is not particularly limited with respect to pressure, but for example, when it is performed as a gas phase reaction, it can be performed without particularly adjusting pressure such as pressurization or decompression. It is preferable to carry out at 0.1 MPa to 1.0 MPa from the mechanical side of the apparatus. When setting the operation pressure, it is desirable to select conditions so that organic substances such as raw materials existing in the system do not liquefy in the reaction system.
　本工程の方法での接触時間は、標準状態において、通常０．１から２００秒、好ましくは３から１００秒である。接触時間が短いと反応率が低下し、接触時間が長すぎると副反応が起こるので好ましくない。 The contact time in the method of this step is usually 0.1 to 200 seconds, preferably 3 to 100 seconds, in the standard state. If the contact time is short, the reaction rate decreases, and if the contact time is too long, side reactions occur, which is not preferable.
　本工程の方法により、反応器から流出する、デスフルランを主成分とする生成物は、公知の方法で精製することができる。後処理は、反応終了液に対して通常の蒸留操作を実施することにより、目的とするデスフルランの単体を高純度に得ることができる。目的生成物は、必要に応じて、活性炭処理、シリカゲルカラムクロマトグラフィー等により、さらに高い化学純度へ精製することができる。 The product containing desflurane as a main component flowing out of the reactor by the method of this step can be purified by a known method. In the post-treatment, the intended desflurane simple substance can be obtained with high purity by performing a normal distillation operation on the reaction end solution. The target product can be purified to a higher chemical purity by activated carbon treatment, silica gel column chromatography or the like, if necessary.
　以下、実施例により本発明を詳細に説明するが、これらの実施態様に限られない。ここで、組成分析値の「％」は、原料または生成物をガスクロマトグラフィー（以下ＧＣと記す、検出器はＦＩＤ）によって測定して得られた組成の「面積％」を表す。第２工程に用いる触媒は後述した調製例により調製したものを用いて、フッ素化反応に供した。なお、後述するスキーム中、Ｅｔはエチル基を表す。 Hereinafter, the present invention will be described in detail by way of examples. However, 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 product by gas chromatography (hereinafter referred to as GC, the detector is FID). The catalyst used in the second step was subjected to the fluorination reaction using one prepared according to the preparation example described later. In the scheme described later, Et represents an ethyl group.
　［調製例］
　１リットルガラス製フラスコに、表面積１１５０から１２５０ｍ2／ｇ、細孔径１５から２０オングストロームの粒状活性炭（東洋カルゴンＰＣＢ、４×１０メッシュ）０．２５リットルを入れ１３０から１５０℃に加温した後真空ポンプにより水分を除去した。水分の留出が認められなくなった時点でフラスコ内に窒素を導入して常圧とし、１２５ｇの五塩化アンチモンを滴下ロートにて１時間にわたり撹拌しながら活性炭層に導入した。五塩化アンチモンを含浸した活性炭は約１時間、１５０℃に保持して熟成した。 [Preparation Example]
Into a 1 liter glass flask, 0.25 liter of granular activated carbon (Toyo Calgon PCB, 4 × 10 mesh) having a surface area of 1150 to 1250 m 2 / g and a pore diameter of 15 to 20 angstrom was placed, heated to 130 to 150 ° C. and then vacuumed. Water was removed by a pump. When no water was observed to be distilled, nitrogen was introduced into the flask to normal pressure, and 125 g of antimony pentachloride was introduced into the activated carbon layer while stirring with a dropping funnel for 1 hour. The activated carbon impregnated with antimony pentachloride was aged by holding at 150 ° C. for about 1 hour.
　[実施例１]
Figure JPOXMLDOC01-appb-C000009
 　圧力計、温度計、攪拌モーターを備えた３００ｍｌのステンレス鋼製（ＳＵＳ）オートクレーブ反応器内にクロラール５０ｇ（３３９ｍｍｏｌ）、フッ化水素１３６ｇ（６．８ｍｏｌ）、クロロホルム８０．９ｇ（６７８ｍｍｏｌ）、そして四塩化スズ１７．７ｇ（６７．８ｍｍｏｌ）を量り取った。内温１５０℃まで昇温後、副生する塩化水素ガスをパージしながら、反応圧力を４．０ＭＰａ前後でコントロールして２４時間反応を継続させた。反応終了後、０．１ＭＰａまで反応圧力をパージし、発熱に注意しながらイオン交換水２００ｇを反応液へ添加して反応を停止させた。次いで水洗浄後、２層分離を行うことで９９ｇの反応粗体を得た。得られた反応粗体に関しては、ビス－１，４－トリフルオロベンゼンを内部標準に用い、19Ｆ－ＮＭＲによる目的物の定量値を算出したところ、２５．８ｇの１－フルオロ－２，２，２－トリクロロエチルジフルオロメチルエーテルが含有していることを確認した。この場合の目的物の定量収率は３５％であった。
［物性データ］
１－フルオロ－２，２，２－トリクロロエチルジフルオロメチルエーテル：
1Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ3）δ（ｐｐｍ）：５．９７（１Ｈ，ｄ，Ｊ＝５６．６３Ｈｚ），６．５１（１Ｈ，ｔ，Ｊ＝７０．６８Ｈｚ）
19Ｆ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ3，ＣＦＣｌ3）δ（ｐｐｍ）：－１２６．７（１Ｆ，ｄ，Ｊ＝５４．９１Ｈｚ），－８５．８（１Ｆ，ｄｄ，Ｊ＝６９．４Ｈｚ，Ｊ＝１５６．１Ｈｚ），－８４．７（１Ｆ，ｄｄ，Ｊ＝６９．４Ｈｚ，Ｊ＝１５８．９Ｈｚ） [Example 1]
Figure JPOXMLDOC01-appb-C000009
 In a 300 ml stainless steel (SUS) autoclave reactor equipped with a pressure gauge, thermometer, stirring motor, chloral 50 g (339 mmol), hydrogen fluoride 136 g (6.8 mol), chloroform 80.9 g (678 mmol), and four 17.7 g (67.8 mmol) of tin chloride was weighed out. After the temperature was raised to an internal temperature of 150 ° C., the reaction pressure was controlled at around 4.0 MPa while purging the by-produced hydrogen chloride gas, and the reaction was continued for 24 hours. After completion of the reaction, the reaction pressure was purged to 0.1 MPa, and 200 g of ion exchanged water was added to the reaction solution while paying attention to heat generation to stop the reaction. Subsequently, after washing with water, separation of two layers was performed to obtain 99 g of a crude reaction product. With respect to the obtained reaction crude product, bis-1,4-trifluorobenzene was used as an internal standard, and the quantitative value of the target product by 19 F-NMR was calculated. As a result, 25.8 g of 1-fluoro-2,2 , 2-trichloroethyl difluoromethyl ether was confirmed to be contained. In this case, the quantitative yield of the target product was 35%.
[Physical property data]
1-Fluoro-2,2,2-trichloroethyl difluoromethyl ether:
1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 5.97 (1H, d, J = 56.63 Hz), 6.51 (1H, t, J = 70.68 Hz)
19 F-NMR (400 MHz, CDCl 3 , CFCl 3 ) δ (ppm): −126.7 (1F, d, J = 54.91 Hz), −85.8 (1F, dd, J = 69.4 Hz, J = 156.1 Hz), -84.7 (1F, dd, J = 69.4 Hz, J = 158.9 Hz)
　[実施例２]
Figure JPOXMLDOC01-appb-C000010
 　圧力計、温度計、ＰＴＦＥ製の攪拌子を備えた５０ｍｌのステンレス鋼製（ＳＵＳ）オートクレーブ反応器内にクロラール５ｇ（３３．９ｍｍｏｌ）、フッ化水素１３．６ｇ（６８０ｍｍｏｌ）、クロロホルム８．１ｇ（６８．０ｍｍｏｌ）、そして三フッ化ホウ素ジエチルエーテル錯体０．４８１ｇ（３．３９ｍｍｏｌ）を量り取った。内温１５０℃まで昇温後、副生する塩化水素ガスをパージしながら、反応圧力を４．０ＭＰａ前後でコントロールして１２時間反応を継続させた。反応終了後、０．１ＭＰａまで反応圧力をパージし、反応液をサンプリングした。サンプリング液中に含まれる過剰のフッ化水素はフッ化ナトリウムで吸着後、ＧＣ分析に供すると９．８％の目的物（１－フルオロ－２，２，２－トリクロロエチルジフルオロメチルエーテル）の存在を確認した。 [Example 2]
Figure JPOXMLDOC01-appb-C000010
 In a 50 ml stainless steel (SUS) autoclave reactor equipped with a pressure gauge, thermometer, PTFE stirrer, 5 g (33.9 mmol) of chloral, 13.6 g (680 mmol) of hydrogen fluoride, 8.1 g of chloroform ( 68.0 mmol), and 0.481 g (3.39 mmol) of boron trifluoride diethyl ether complex were weighed out. After raising the internal temperature to 150 ° C., the reaction pressure was controlled at around 4.0 MPa while purging the by-produced hydrogen chloride gas, and the reaction was continued for 12 hours. After completion of the reaction, the reaction pressure was purged to 0.1 MPa, and the reaction solution was sampled. Excess hydrogen fluoride contained in the sampling solution is adsorbed with sodium fluoride and then subjected to GC analysis, and 9.8% of the target product (1-fluoro-2,2,2-trichloroethyl difluoromethyl ether) is present. It was confirmed.
　[実施例３]
Figure JPOXMLDOC01-appb-C000011
 　圧力計、温度計、ＰＴＦＥ製の攪拌子を備えた５０ｍｌのステンレス鋼製（ＳＵＳ）オートクレーブ反応器内にクロラール５ｇ（３３．９ｍｍｏｌ）、フッ化水素１３．６ｇ（６８０ｍｍｏｌ）、クロロホルム８．１ｇ（６８．０ｍｍｏｌ）、そして五塩化アンチモン１．０１ｇ（３．３９ｍｍｏｌ）を量り取った。内温１５０℃まで昇温後、副生する塩化水素ガスをパージしながら、反応圧力を４．０ＭＰａ前後でコントロールして８時間反応を継続させた。反応終了後、０．１ＭＰａまで反応圧力をパージし、反応液をサンプリングした。サンプリング液中に含まれる過剰のフッ化水素はフッ化ナトリウムで吸着後、ＧＣ分析に供すると６．２％の目的物（１－フルオロ－２，２，２－トリクロロエチルジフルオロメチルエーテル）の存在を確認した。 [Example 3]
Figure JPOXMLDOC01-appb-C000011
 In a 50 ml stainless steel (SUS) autoclave reactor equipped with a pressure gauge, thermometer, PTFE stirrer, 5 g (33.9 mmol) of chloral, 13.6 g (680 mmol) of hydrogen fluoride, 8.1 g of chloroform ( 68.0 mmol), and 1.01 g (3.39 mmol) of antimony pentachloride were weighed out. After the temperature was raised to an internal temperature of 150 ° C., the reaction pressure was controlled at around 4.0 MPa while purging the by-produced hydrogen chloride gas, and the reaction was continued for 8 hours. After completion of the reaction, the reaction pressure was purged to 0.1 MPa, and the reaction solution was sampled. Excess hydrogen fluoride contained in the sample solution is adsorbed with sodium fluoride and then subjected to GC analysis. 6.2% of the target product (1-fluoro-2,2,2-trichloroethyl difluoromethyl ether) is present. It was confirmed.
　[実施例４]
Figure JPOXMLDOC01-appb-C000012
 　電気炉を備えた円筒形反応管からなる気相反応装置（ＳＵＳ３１６Ｌ製、直径２．５ｃｍ・長さ４０ｃｍ）に触媒として調製例で調製した触媒を５０ｍＬ充填した。約３ｍＬ／分の流量で塩素ガスを流しながら、反応管の温度を１２０℃に上げ、フッ化水素を約０．１ｇ／分の速度で１時間にわたり導入した。次いで、原料である１－フルオロ－２，２，２－トリクロロエチルジフルオロメチルエーテル（９０．２ＧＣ面積％）を約０．１ｇ／分（接触時間１５秒）の速度で反応管へ供給開始した。反応開始１時間後には反応は安定したので、反応器から流出するガスを水中に吹き込んで酸性ガスを除去した後、生成物をＧＣにて分析したところ、１，２，２，２－テトラフルオロエチルジフルオロメチルエーテル（デスフルラン）が３４．１％であった。
［物性データ］
１，２，２，２－テトラフルオロエチルジフルオロメチルエーテル（デスフルラン）：
1Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ3）δ（ｐｐｍ）：５．９１（１Ｈ，ｄｑ，Ｊ＝２．８Ｈｚ，５４．２Ｈｚ），６．４３（１Ｈ，ｔ，Ｊ＝７０．５Ｈｚ）
19Ｆ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ3，ＣＦＣｌ3）δ（ｐｐｍ）：－１４６．５（１Ｆ，ｄ，Ｊ＝５４．８Ｈｚ），－８６．８（１Ｆ，ｄｄ，Ｊ＝６９．３Ｈｚ，Ｊ＝１６１．７Ｈｚ），－８５．５（１Ｆ，ｄｄ，Ｊ＝６９．３Ｈｚ，Ｊ＝１６１．７Ｈｚ），－８４．６（３Ｆ，ｓ） [Example 4]
Figure JPOXMLDOC01-appb-C000012
 A gas phase reactor (made of SUS316L, diameter 2.5 cm, length 40 cm) composed of a cylindrical reaction tube equipped with an electric furnace was filled with 50 mL of the catalyst prepared in the preparation example as a catalyst. While flowing chlorine gas at a flow rate of about 3 mL / min, the temperature of the reaction tube was raised to 120 ° C., and hydrogen fluoride was introduced at a rate of about 0.1 g / min over 1 hour. Next, 1-fluoro-2,2,2-trichloroethyl difluoromethyl ether (90.2 GC area%) as a raw material was started to be supplied to the reaction tube at a rate of about 0.1 g / min (contact time 15 seconds). Since the reaction was stable 1 hour after the start of the reaction, the gas discharged from the reactor was blown into water to remove the acidic gas, and then the product was analyzed by GC. As a result, 1,2,2,2-tetrafluoro Ethyl difluoromethyl ether (desflurane) was 34.1%.
[Physical property data]
1,2,2,2-tetrafluoroethyl difluoromethyl ether (desflurane):
1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 5.91 (1H, dq, J = 2.8 Hz, 54.2 Hz), 6.43 (1H, t, J = 70.5 Hz)
19 F-NMR (400 MHz, CDCl 3 , CFCl 3 ) δ (ppm): -146.5 (1F, d, J = 54.8 Hz), −86.8 (1F, dd, J = 69.3 Hz, J = 161.7 Hz), -85.5 (1F, dd, J = 69.3 Hz, J = 161.7 Hz), -84.6 (3F, s)
　［比較例１］
Figure JPOXMLDOC01-appb-C000013
 　圧力計、温度計、ＰＴＦＥ製の攪拌子を備えた２００ｍｌのステンレス鋼製（ＳＵＳ）オートクレーブ反応器内にフッ化水素４０．８ｇ（２．０４ｍｏｌ）、クロロホルム２４．４ｇ（２０４ｍｍｏｌ）、そして四塩化スズ２．６６ｇ（１０．２ｍｍｏｌ）を量り取った。ドライアイスアセトンによる反応器の冷却後、公知の方法（有機合成化学協会誌（日本）、１９９９年、５７巻、１０号、１０２－１０３ページ）で調製したフルオラール１０．０ｇ（１０２ｍｍｏｌ）を添加した。その後、内温１００℃まで昇温して反応圧力１．０ＭＰａ前後にてコントロールしながら１２時間反応を行った。反応終了後、０．１ＭＰａまで反応圧力をパージし、反応液をサンプリングした。サンプリング液中に含まれる過剰のフッ化水素はフッ化ナトリウムで吸着後、ＧＣ分析に供すると目的物のデスフルランは未検出であった。ＧＣ分析上はクロロホルムのフッ素化物であるクロロジフルオロメタン（ＨＣＦＣ－２２）やジクロロフルオロメタン（ＨＣＦＣ－２１）が主に新規ピークとして検出されるのみであった。 [Comparative Example 1]
Figure JPOXMLDOC01-appb-C000013
 In a 200 ml stainless steel (SUS) autoclave reactor equipped with a pressure gauge, thermometer, PTFE stirrer 40.8 g (2.04 mol) hydrogen fluoride, 24.4 g (204 mmol) chloroform, and tetrachloride 2.66 g (10.2 mmol) of tin was weighed out. After cooling the reactor with dry ice acetone, 10.0 g (102 mmol) of fluoral prepared by a known method (Journal of Synthetic Organic Chemistry (Japan), 1999, Vol. 57, No. 10, pp. 102-103) was added. . Thereafter, the reaction was carried out for 12 hours while raising the internal temperature to 100 ° C. and controlling the reaction pressure at around 1.0 MPa. After completion of the reaction, the reaction pressure was purged to 0.1 MPa, and the reaction solution was sampled. Excess hydrogen fluoride contained in the sampling solution was adsorbed with sodium fluoride, and when subjected to GC analysis, the target desflurane was not detected. In GC analysis, chlorodifluoromethane (HCFC-22) and dichlorofluoromethane (HCFC-21), which are fluorinated products of chloroform, were mainly detected as new peaks.
　［比較例２］
Figure JPOXMLDOC01-appb-C000014
 　電気炉を備えた円筒形反応管からなる気相反応装置（ＳＵＳ３１６Ｌ製、直径２．５ｃｍ・長さ４０ｃｍ）に触媒としてフッ化アルミニウム（ＡｌＦ3）を５０ｍＬ充填した。約１０ｍＬ／分の流量で窒素ガスを流しながら、反応管の温度を１８０℃に上げ、フッ化水素を約０．１ｇ／分の速度で１時間にわたり導入した。次いで、原料である１－フルオロ－２，２，２－トリクロロエチルジフルオロメチルエーテル（９０．２ＧＣ％）を約０．１ｇ／分（接触時間１４秒）の速度で反応管へ供給開始した。反応開始１時間後には反応は安定したので、反応器から流出するガスを水中に吹き込んで酸性ガスを除去した後、生成物をガスクロマトグラフィーにて分析した。その結果、目的物の１，２，２，２－テトラフルオロエチルジフルオロメチルエーテル（デスフルラン）は得られず、複雑な分解物と原料回収のみであった。 [Comparative Example 2]
Figure JPOXMLDOC01-appb-C000014
 A gas phase reactor (made of SUS316L, diameter 2.5 cm, length 40 cm) composed of a cylindrical reaction tube equipped with an electric furnace was filled with 50 mL of aluminum fluoride (AlF 3 ) as a catalyst. While flowing nitrogen gas at a flow rate of about 10 mL / min, the temperature of the reaction tube was raised to 180 ° C., and hydrogen fluoride was introduced at a rate of about 0.1 g / min over 1 hour. Next, 1-fluoro-2,2,2-trichloroethyl difluoromethyl ether (90.2 GC%) as a raw material was started to be fed to the reaction tube at a rate of about 0.1 g / min (contact time 14 seconds). Since the reaction was stable 1 hour after the start of the reaction, the gas flowing out from the reactor was blown into water to remove the acidic gas, and then the product was analyzed by gas chromatography. As a result, the target 1,2,2,2-tetrafluoroethyl difluoromethyl ether (desflurane) was not obtained, and only complicated decomposition products and raw material recovery were obtained.
　本発明における対象化合物である１，２，２，２－テトラフルオロエチルジフルオロメチルエーテル（デスフルラン）は、吸入麻酔剤として利用できる。 The target compound in the present invention, 1,2,2,2-tetrafluoroethyl difluoromethyl ether (desflurane) can be used as an inhalation anesthetic.

Claims (6)

  1. 　以下の工程を含む、１，２，２，２－テトラフルオロエチルジフルオロメチルエーテル（デスフルラン）の製造方法。
    　第１工程：ルイス酸触媒の存在下、式［１］で表される２，２，２－トリクロロアセトアルデヒドに、クロロホルム及びフッ化水素を反応させることにより、式［２］で表される１－フルオロ－２，２，２－トリクロロエチルジフルオロメチルエーテルを得る工程。
    Figure JPOXMLDOC01-appb-C000001
    Figure JPOXMLDOC01-appb-C000002
     　第２工程：第１工程にて得られた、式［２］で表される１－フルオロ－２，２，２－トリクロロエチルジフルオロメチルエーテルに対し、気相中、アンチモン、タンタル、ニオブ、モリブデン、スズ、及びチタンからなる群より選ばれる少なくとも１種の金属を含む金属ハロゲン化物を活性炭に担持した金属ハロゲン化物担持触媒の存在下、フッ化水素を反応させることにより、式［３］で表される１，２，２，２－テトラフルオロエチルジフルオロメチルエーテル（デスフルラン）を得る工程。
    Figure JPOXMLDOC01-appb-C000003
         A process for producing 1,2,2,2-tetrafluoroethyldifluoromethyl ether (desflurane), comprising the following steps.
    First step: By reacting 2,2,2-trichloroacetaldehyde represented by formula [1] with chloroform and hydrogen fluoride in the presence of a Lewis acid catalyst, 1-form represented by formula [2] Obtaining fluoro-2,2,2-trichloroethyl difluoromethyl ether.
    Figure JPOXMLDOC01-appb-C000001
    Figure JPOXMLDOC01-appb-C000002
     Second step: Antimony, tantalum, niobium, molybdenum in the gas phase with respect to 1-fluoro-2,2,2-trichloroethyldifluoromethyl ether represented by the formula [2] obtained in the first step Represented by the formula [3] by reacting hydrogen fluoride in the presence of a metal halide-supported catalyst in which a metal halide containing at least one metal selected from the group consisting of tin, titanium and titanium is supported on activated carbon. To obtain 1,2,2,2-tetrafluoroethyl difluoromethyl ether (desflurane).
    Figure JPOXMLDOC01-appb-C000003
  2. 　第１工程で用いるルイス酸触媒が、ホウ素（ＩＩＩ）、スズ（ＩＩ）、スズ（ＩＶ）、チタン（ＩＶ）、亜鉛（ＩＩ）、アルミニウム（ＩＩＩ）、アンチモン（ＩＩＩ）、及びアンチモン（Ｖ）からなる群より選ばれる少なくとも１種の金属を含む金属ハロゲン化物である、請求項１に記載の製造方法。 The Lewis acid catalyst used in the first step is boron (III), tin (II), tin (IV), titanium (IV), zinc (II), aluminum (III), antimony (III), and antimony (V). The manufacturing method of Claim 1 which is a metal halide containing the at least 1 sort (s) of metal chosen from the group which consists of.
  3. 　第１工程で用いるルイス酸触媒が、三フッ化ホウ素（ＩＩＩ）、四塩化スズ（ＩＶ）、及び五塩化アンチモン（Ｖ）からなる群より選ばれる少なくとも一種の金属ハロゲン化物である、請求項１または２に記載の製造方法。 The Lewis acid catalyst used in the first step is at least one metal halide selected from the group consisting of boron trifluoride (III), tin tetrachloride (IV), and antimony pentachloride (V). Or the manufacturing method of 2.
  4. 　第２工程において、反応を、五塩化アンチモンを活性炭に担持した触媒の存在下で行う、請求項１乃至３の何れかに記載の製造方法。 The production method according to any one of claims 1 to 3, wherein in the second step, the reaction is performed in the presence of a catalyst in which antimony pentachloride is supported on activated carbon.
  5. 　第２工程において、式［２］で表される１－フルオロ－２，２，２－トリクロロエチルジフルオロメチルエーテル１００モルに対し、０．１から１０モルの塩素（Ｃｌ2）を反応系に導入させる工程を含む、請求項１乃至４の何れかに記載の製造方法。 In the second step, 0.1 to 10 mol of chlorine (Cl 2 ) is introduced into the reaction system with respect to 100 mol of 1-fluoro-2,2,2-trichloroethyldifluoromethyl ether represented by the formula [2]. The manufacturing method in any one of Claims 1 thru | or 4 including the process to make.
  6. 　式［２］で表される１－フルオロ－２，２，２－トリクロロエチルジフルオロメチルエーテル。
    Figure JPOXMLDOC01-appb-C000004
         1-fluoro-2,2,2-trichloroethyl difluoromethyl ether represented by the formula [2].
    Figure JPOXMLDOC01-appb-C000004
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CN105753638A (en) * 2014-12-13 2016-07-13 西安近代化学研究所 2,3,3,3-tetrafluoropropene synthetic method

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HUDLICKY, TOMAS ET AL.: "Practical preparation of potentially anesthetic fluorinated ethyl methyl ethers by means of bromine trifluoride and other methods", JOURNAL OF FLUORINE CHEMISTRY, vol. 102, 2000, pages 363 - 367, XP004193168 *
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