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WO2018123649A1 - Procédé de fabrication de 1,2,2,2- tétrafluoroéthyldifluorométhyléther (desflurane) - Google Patents

Procédé de fabrication de 1,2,2,2- tétrafluoroéthyldifluorométhyléther (desflurane) Download PDF

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WO2018123649A1
WO2018123649A1 PCT/JP2017/045083 JP2017045083W WO2018123649A1 WO 2018123649 A1 WO2018123649 A1 WO 2018123649A1 JP 2017045083 W JP2017045083 W JP 2017045083W WO 2018123649 A1 WO2018123649 A1 WO 2018123649A1
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Prior art keywords
reaction
ether
formula
production method
represented
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Japanese (ja)
Inventor
健史 細井
峰男 渡辺
井村　英明
謙亮 廣瀧
直也 上島
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Central Glass Co Ltd
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Central Glass Co Ltd
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Priority claimed from JP2016257221A external-priority patent/JP6886104B2/ja
Priority claimed from JP2016257223A external-priority patent/JP2018108962A/ja
Priority claimed from JP2016257222A external-priority patent/JP2018108961A/ja
Priority claimed from JP2017234919A external-priority patent/JP6974718B2/ja
Application filed by Central Glass Co Ltd filed Critical Central Glass Co Ltd
Priority to CN201780081257.6A priority Critical patent/CN110139848B/zh
Priority to US16/474,136 priority patent/US10683252B2/en
Publication of WO2018123649A1 publication Critical patent/WO2018123649A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/01—Preparation of ethers
    • C07C41/18—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
    • 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
    • C07C41/28—Preparation of ethers by reactions not forming ether-oxygen bonds from acetals, e.g. by dealcoholysis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/18—Ethers having an ether-oxygen atom bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C07C43/192—Ethers having an ether-oxygen atom bound to a carbon atom of a ring other than a six-membered aromatic ring containing halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/63—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/04—Saturated compounds containing keto groups bound to acyclic carbon atoms
    • C07C49/16—Saturated compounds containing keto groups bound to acyclic carbon atoms containing halogen
    • C07C49/167—Saturated compounds containing keto groups bound to acyclic carbon atoms containing halogen containing only fluorine as halogen

Definitions

  • the present invention relates to a method for producing 1,2,2,2-tetrafluoroethyl difluoromethyl ether (desflurane).
  • 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.
  • Production examples for desflurane include its precursors 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 ) and 1,2,2,2-tetrafluoroethyl dichloromethyl ether (CF 3 CHFOCHCl 2 ) are fluorinated.
  • Patent Document 1 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.
  • Patent Document 8 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.
  • Patent Document 11 As a fluorination reaction for 1,2,2,2-tetrafluoroethyldichloromethyl ether, a method using hydrogen fluoride is known (Patent Document 11).
  • Patent Document 1 is a fluorination reaction under conditions of high temperature and high pressure, so it is difficult to employ industrially and has a low yield.
  • the methods described in Patent Document 2 and Patent Document 3 are also highly toxic and corrosive reagents and are difficult to handle.
  • the methods described in Patent Literature 4 and Patent Literature 5 are intended to achieve a medium yield by performing liquid phase fluorination using hydrogen fluoride in the presence of an antimony pentachloride catalyst in the vicinity of room temperature. You're getting a deathful run.
  • Patent Document 8 has a risk of explosion and is inconvenient to handle. Furthermore, the conversion rate is low (30%), and the target product is also low in yield, so that it is difficult to adopt as 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.
  • 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.
  • Patent Document 11 discloses a reaction example in which liquid phase fluorination of 1,2,2,2-tetrafluoroethyldichloromethyl ether using hydrogen fluoride is performed in the presence of an antimony pentachloride catalyst near room temperature.
  • the yield of the intended desflurane was low (21%).
  • the obtained 1,2,2,2-tetrafluoroethyl methyl ether is subjected to chlorination in the presence of a radical initiator or under light irradiation to obtain a precursor of desflurane, the formula [4]
  • a radical initiator or under light irradiation to obtain a precursor of desflurane
  • the formula [4] To 1,2,2,2-tetrafluoroethyldichloromethyl ether represented by Furthermore, the present inventors have newly found knowledge that can efficiently produce desflurane represented by the formula [5] by reacting the obtained 1,2,2,2-tetrafluoroethyldichloromethyl ether with hydrogen fluoride, The present invention has been completed.
  • 2,2,2-trifluoroacetaldehyde disclosed in the present invention is obtained by performing a fluorination reaction in a gas phase using 2,2,2-trichloroacetaldehyde as a starting material.
  • a method for producing desflurane by efficiently converting to 1,2,2,2-tetrafluoroethyl methyl ether, followed by a chlorination reaction and a fluorination reaction has not been known.
  • the present invention provides a method for producing 1,2,2,2-tetrafluoroethyldifluoromethyl ether (desflurane) described in the following [Invention 1] to [Invention 22].
  • [Invention 1] A process for producing 1,2,2,2-tetrafluoroethyldifluoromethyl ether (desflurane) represented by formula [5], comprising the following four steps.
  • Step 4 By reacting 1,2,2,2-tetrafluoroethyldichloromethyl ether obtained in Step 3 with hydrogen fluoride, 1,2,2 represented by the formula [5] Obtaining 2,2-tetrafluoroethyldifluoromethyl ether (desflurane);
  • the catalyst in the first step is a metal in which a metal compound containing at least one metal selected from the group consisting of chromium, titanium, manganese, iron, nickel, cobalt, magnesium, zirconium, and antimony is supported on a metal oxide or activated carbon
  • the metal compound is at least one metal halide or metal oxyhalide selected from the group consisting of metal fluoride, chloride, fluorinated chloride, oxyfluoride, oxychloride, and oxyfluoride chloride, The manufacturing method of the invention 2.
  • invention 4 The production method according to invention 2 or 3, wherein the metal oxide is at least one selected from the group consisting of alumina, zirconia, titania, chromia, and magnesia.
  • invention 5 The production method according to any one of inventions 1 to 4, wherein the 2,2,2-trifluoroacetaldehyde obtained in the first step is used as it is as a starting material in the second step without performing a purification operation.
  • the radical initiator or light irradiation is at least one selected from the group consisting of a mercury lamp, an ultraviolet LED, an organic EL, an inorganic EL, an ultraviolet laser, and a halogen lamp.
  • a mercury lamp an ultraviolet LED
  • an organic EL an organic EL
  • an inorganic EL an ultraviolet laser
  • a halogen lamp a mercury lamp
  • Fluoride ion scavenger belongs to alkali metal halide, alkali metal sulfate, alkaline earth metal hydroxide, alkaline earth metal halide, alkaline earth metal sulfate, periodic table group 13
  • the invention further includes a step of separating and removing 1,2,2,2-tetrafluoroethyl chloromethyl ether represented by the formula [7] from the mixture by subjecting the mixture to distillation purification. Manufacturing method.
  • invention 15 The production method according to any one of inventions 1 to 14, wherein the reaction is carried out in a gas phase in the fourth step.
  • 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 organic base in “a salt or complex comprising an organic base and hydrogen fluoride” is triethylamine, diisopropylethylamine, tri-n-butylamine, pyridine, and 2,6-lutidine and 1,8-diazabicyclo [5.4.0] undeca.
  • 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 present invention is a manufacturing method including the four steps described above, and the relationship between each step is illustrated as follows.
  • the 2,2,2-trichloroacetaldehyde represented by the formula [1] of the starting material used in this step can be a commercially available product (product of Tokyo Chemical Industry Co., Ltd.). (Tetrahedron Letters, 56 (24), 3758-3761,2015).
  • 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 the present process usually, be of tubular, stainless steel, Hastelloy TM, those or metal such as platinum, tetrafluoroethylene resin, chlorotrifluoroethylene resin, vinylidene fluoride resin, It is preferable to use a reaction vessel in which a PFA resin or the like is lined, and can sufficiently react even under normal pressure or under pressure.
  • the catalyst used in this step is a metal compound in which a metal compound containing at least one metal selected from the group consisting of chromium, titanium, manganese, iron, nickel, cobalt, magnesium, zirconium and antimony is supported on a metal oxide or activated carbon. It is a supported catalyst.
  • the metal compound may be at least one metal halide or metal oxyhalide selected from the group consisting of fluoride, chloride, fluoride chloride, oxyfluoride, oxychloride, and oxyfluoride chloride. is there.
  • the metal oxide is at least one selected from the group consisting of alumina, zirconia, titania, chromia, and magnesia.
  • a fluorinated carrier for example, fluorinated alumina
  • a catalyst in which a chromium compound is supported on a metal oxide or activated carbon is preferable.
  • the supported metal compound When using a catalyst in which the metal compound is supported on a carrier, the supported metal compound is 0.1 to 100 parts by mass, more preferably 1 to 50 parts by mass with respect to 100 parts by mass of the carrier.
  • alumina used as a metal oxide is generally alumina obtained by molding and dehydrating a precipitate generated from an aluminum salt aqueous solution using ammonia or the like.
  • ⁇ -alumina commercially available for catalyst support or for drying is preferably used.
  • the method for preparing the catalyst is not limited, but a soluble compound of at least one metal selected from chromium, manganese, nickel, cobalt, and iron is added to the aluminum oxide such as ⁇ -alumina.
  • the impregnated solution is impregnated or sprayed and then dried.
  • the catalyst is prepared by partially or completely fluorinating the support with a fluorinating agent such as hydrogen fluoride to obtain fluorinated alumina.
  • a fluorinating agent such as hydrogen fluoride to obtain fluorinated alumina.
  • the soluble compound is not particularly limited as long as it is an oxide or salt of a corresponding metal that dissolves in a solvent such as water, ethanol, and acetone, and examples thereof include nitrates, chlorides, sulfates, carbonates, and acetates.
  • a solvent such as water, ethanol, and acetone
  • examples thereof include nitrates, chlorides, sulfates, carbonates, and acetates.
  • chromium nitrate, chromium trichloride, chromium trioxide, potassium dichromate, manganese nitrate, manganese chloride, manganese dioxide, nickel nitrate, nickel chloride, cobalt nitrate, cobalt chloride, iron nitrate, iron chloride, etc. are used. Is preferred.
  • These compounds may be hydrates, and the metal valence may be any valence. It is effective to treat the catalyst prepared by any method in advance with a fluorinating
  • 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 carbon And other synthetic resin systems such as petroleum-based or carbonized polyvinylidene chloride.
  • These activated carbons can be selected and used.
  • the shape and size are usually used in a granular form, but can be used within a normal knowledge range as long as it is suitable for a reactor such as a sphere, fiber, powder, or honeycomb.
  • 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. Further, they may be 800 to 3000 m 2 / g and 0.2 to 1.0 cm 3 / g, respectively.
  • activated carbon when using activated carbon as a support, it is immersed in a basic aqueous solution such as ammonium hydroxide, sodium hydroxide or potassium hydroxide for about 10 hours or more at normal temperature or when activated carbon is used as a catalyst support. It is preferable to perform pretreatment with acid such as nitric acid, hydrochloric acid, hydrofluoric acid, etc., to activate the carrier surface and remove ash in advance.
  • a basic aqueous solution such as ammonium hydroxide, sodium hydroxide or potassium hydroxide for about 10 hours or more at normal temperature or when activated carbon is used as a catalyst support.
  • acid such as nitric acid, hydrochloric acid, hydrofluoric acid, etc.
  • the catalyst according to the present invention loses activity due to the reaction, it can be activated again. That is, the deactivated catalyst can be reactivated by contacting it with an oxidizing substance such as oxygen, air, chlorine, etc. at an elevated temperature.
  • the treatment temperature at that time is 200 to 550 ° C., among which 300 to 500 ° C. is preferable. If it is less than 200 ° C., it remains in an unactivated state, and if it exceeds 550 ° C., the catalyst may be denatured to fail to obtain activity.
  • the reaction temperature in this step is not particularly limited, but is 100 to 500 ° C, preferably 100 to 400 ° C, and more preferably 100 to 350 ° C. Even when the reaction temperature exceeds 500 ° C., the reaction rate is not particularly improved, and a decomposition product is generated, which lowers the selectivity of the fluoral represented by the formula [2].
  • the molar ratio of chloral: hydrogen fluoride supplied to the reaction zone is affected by the reaction temperature, but is usually from 1: 2 to 1:50, preferably from 1: 4 to 1:20. : 6 to 1:15 are more preferable.
  • the conversion rate of reaction may fall and the yield of a target object may fall.
  • chloral supplied to the reaction region can be supplied together with a gas such as nitrogen, helium, or argon that is not involved in the reaction.
  • a gas such as nitrogen, helium, or argon that is not involved in the reaction.
  • hydrogen fluoride can coexist.
  • a gas has a ratio of 100 mol or less per mol of the raw material composed of chloral or a mixture containing the same, and preferably 20 mol or less. Gases that do not participate in the reaction may not be used.
  • the reaction pressure in this step is usually in the range of 0.1 to 6.0 MPa, but the preferable pressure range in this step is preferably 0.1 to 3.0 MPa, more preferably 0.1 to 1.MPa. The range is 5 MPa.
  • the pressure it is desirable to select conditions such that organic substances such as raw materials existing in the system do not liquefy in the reaction system.
  • the contact time in the method of the first 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.
  • 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 product mainly composed of fluoral which is fluorinated by the method of this step and flows out of the reactor can be used in the next step after being purified by a known method.
  • the purification method is not particularly limited, but since fluoral is a water-soluble compound, a deoxidation operation such as washing with water is not preferable.
  • the product mainly composed of fluoral that flows out from the reactor contains hydrogen fluoride, but even if it exists, the fluorinating agent is used in the subsequent second step. Therefore, it is not always necessary to positively remove hydrogen fluoride from the reaction system in this step. Therefore, as shown in the below-mentioned Example, it can be said that it is one of the preferable aspects that the fluoral obtained by this process is used for the next process as it is, without performing special refinement
  • the second step is represented by the formula [3] by reacting the 2,2,2-trifluoroacetaldehyde obtained in the first step with hydrogen fluoride and trimethyl orthoformate. , 2,2,2-Tetrafluoroethyl methyl ether.
  • the product obtained in the previous process and containing fluoral as a main component out of the reactor contains hydrogen fluoride. It can utilize as a fluorinating agent in a process (refer the below-mentioned Example). In this case, since it is substantially synonymous with the embodiment in which hydrogen fluoride is added in this step, even the embodiment using hydrogen fluoride derived from the previous step is included in the scope of this step. .
  • the amount of hydrogen fluoride used in this step is usually 1 equivalent or more with respect to the fluoral obtained in the first step, and using 2 to 10 equivalents is preferable because the reaction proceeds smoothly. Considering the post-treatment surface, 3 to 6 equivalents are particularly preferable.
  • the amount of hydrogen fluoride used in the first step is small, it is necessary to newly add hydrogen fluoride, but sufficient hydrogen fluoride is contained in the organic matter recovered in the first step. If it is, it can be used as it is.
  • Trimethyl orthoformate used in this step can be added to the reaction system, so that the conversion rate of the fluorination reaction can be improved. Therefore, it is mentioned as one of preferred embodiments in the present invention.
  • trimethyl orthoformate a commercially available product (Nichiho Chemical Co., Ltd.) can be used. As shown in the following formula, the fluorination reaction with respect to the fluoroal generates water molecules in addition to the target product as the reaction proceeds.
  • Trimethyl orthoformate is considered to function as a scavenger (scavenger) for water molecules. That is, trimethyl orthoformate is promptly promoted to undergo hydrolysis under the acidic condition of hydrogen fluoride, and is converted into one molecule of methyl formate and two molecules of methanol.
  • alcohol is produced by the reaction of orthoester (trimethyl orthoformate) and water (functions as a dehydrating agent), and at the same time, the ester (methyl formate) obtained is reacted with the desired product (formula It can be easily separated from 1,2,2,2-tetrafluoroethyl methyl ether represented by [3].
  • the amount of trimethyl orthoformate used is 0.2 equivalents or more, usually 1 equivalent of 2,2,2-trifluoroacetaldehyde represented by the formula [2]. It is preferable to use 0.5 to 1.5 equivalents. However, when an amount exceeding 1.5 equivalents of trimethyl orthoformate is used, it is affected by the alcohol (methanol) by-produced by hydrolysis, and the hemi of 2,2,2-trifluoroacetaldehyde, which is an equilibrium compound with fluoral.
  • a solvent having high hydrogen fluoride resistance can be suitably used as the reaction solvent in this step.
  • Aliphatic hydrocarbon type, aromatic hydrocarbon type, halogenated hydrocarbon type, ether type, ester type, amide type, nitrile type, sulfoxide type and the like can be mentioned.
  • n-hexane cyclohexane, n-heptane, benzene, toluene, ethylbenzene, xylene, mesitylene, methylene chloride, chloroform, 1,2-dichloroethane, diethyl ether, tetrahydrofuran, diisopropyl ether, tert-butyl methyl ether
  • Examples include ethyl acetate, n-butyl acetate, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, 1,3-dimethyl-2-imidazolidinone, acetonitrile, propionitrile, dimethyl sulfoxide and the like. It is done.
  • These reaction solvents can be used alone or in combination.
  • the present invention can carry out the reaction without using a reaction solvent.
  • This embodiment is more preferable because the purification operation after the reaction is simple and there is an advantage that the high-purity target product can be obtained only by a washing operation.
  • the temperature condition may be in the range of ⁇ 50 to + 100 ° C., usually ⁇ 20 to + 50 ° C. is preferable, and 0 to + 20 ° C. is particularly preferable.
  • the pressure condition may be in the range of 0.1 MPa to 0.9 MPa, but usually 0.1 MPa to 0.5 MPa is preferable, and 0.1 MPa to 0.2 MPa is more preferable. Therefore, a pressure-resistant reaction vessel made of a material such as stainless steel (SUS) or a resin such as tetrafluoroethylene / perfluoroalkyl vinyl ether copolymer (PFA) or polytetrafluoroethylene (PTFE) having corrosion resistance against hydrogen fluoride.
  • the reaction is preferably performed using a container. For example, when the reaction is performed at a temperature higher than the boiling point of hydrogen fluoride (+ 19.54 ° C.), it is preferable to use a pressure resistant reaction vessel such as stainless steel (SUS).
  • reaction time is usually within 12 hours, the progress of the fluorination reaction is traced by analytical means such as gas chromatography, thin layer chromatography, liquid chromatography, nuclear magnetic resonance, and the starting substrate is almost lost. It is preferred that the time point be the end point of the reaction.
  • the target liquid 1,2,2,2-tetrafluoroethyl methyl ether represented by the formula [3] can be easily obtained by washing the reaction completion solution, which is a normal purification operation. 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.
  • the supply amount of chlorine is from 1.00 equivalent to 4.4 with respect to 1,2,2,2-tetrafluoroethyl methyl ether represented by the formula [3] obtained in the second step. It may be carried out in the range of 00 equivalents, among which 1.25 equivalents to 3.00 equivalents are preferred, with 1.50 equivalents to 2.50 equivalents being particularly preferred.
  • the degree of chlorination of the reaction substrate proceeds according to the amount of chlorine supplied, but by appropriately controlling the amount of chlorine supplied, the target product (1,2,2,2-tetra Byproduct of 1,2,2,2-tetrafluoroethyltrichloromethyl ether (higher chlorinated product) represented by formula [6], which is difficult to separate from (fluoroethyldichloromethyl ether), can be minimized. Obtained knowledge.
  • 1,2,2,2-tetrafluoroethyl chloromethyl ether of formula [7] which is a low-order chlorinated product, is also produced as a mixture with the target product.
  • this mixture can be separated by a normal distillation operation. Further, low-order chlorinated products can be recovered and reused as a raw material for the chlorination reaction.
  • chlorine When supplying chlorine to the reactor, chlorine may be either a gas or a liquid, but is preferably a gas from the viewpoint of easy handling.
  • the method for supplying chlorine is not particularly limited as long as it can supply chlorine into the reaction solution. For example, a method of charging chlorine into the reaction vessel in a batch before starting the chlorination reaction, a method of supplying chlorine sequentially during the chlorination reaction, and a continuous supply of chlorine during the chlorination reaction There are methods. If the reaction is too intense, an inert gas such as argon or nitrogen may be introduced while being mixed with chlorine (that is, “diluting” chlorine with an inert gas).
  • an inert gas such as argon or nitrogen may be introduced while being mixed with chlorine (that is, “diluting” chlorine with an inert gas).
  • a radical initiator in order to further improve the selectivity of the chlorination reaction with respect to 1,2,2,2-tetrafluoroethyl methyl ether, a radical initiator can coexist.
  • organic peroxides include benzoyl peroxide, ketone peroxide, peroxy ketal, hydroperoxide, dialkyl peroxide, diacyl peroxide, peroxy ester, and peroxy dicarbonate.
  • 2,2′-azobis (2-methylpropionitrile) (abbreviation “AIBN”), 2,2′-azobis (4-methoxy-2,4-dimethylvaleronitrile), 2,2′-azobis (2,4-dimethylvaleronitrile), dimethyl 2,2′-azobis (2-methylpropionate), 2,2′-azobis (2-methylbutyronitrile), 2,2 '-Azobis (2- (2-imidazolin-2-yl) propane) dihydrochloride, 2,2'-azobis (2- (2-imidazolin-2-yl) propane) disulfate, 2,2'- An example is azobis (2-methylpropionamidine) dihydrochloride.
  • the amount of the radical initiator used is usually 0.01 to 20 mol with respect to 1.0 mol of 1,2,2,2-tetrafluoroethyl methyl ether represented by the formula [3]. %, Preferably 0.1 to 10 mol%, more preferably 0.5 to 5 mol%. Further, the radical initiator can be added as appropriate by observing the progress of the reaction. If the amount of the radical initiator is less than 0.01 mol% with respect to 1 mol of the raw material, the reaction is likely to stop during the process, and the yield may be lowered. .
  • the light source is at least one selected from the group consisting of a mercury lamp, an ultraviolet LED, an organic EL, an inorganic EL, an ultraviolet laser, and a halogen lamp.
  • a mercury lamp is used. Is preferred.
  • a reaction solvent can be used (the reaction can be carried out without using the reaction solvent, as shown in Examples described later).
  • the reaction solvent include water, aliphatic hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, ethers, esters, amides, nitriles, and sulfoxides.
  • reaction solvents include water, n-hexane, cyclohexane, n-heptane, benzene, toluene, ethylbenzene, xylene, mesitylene, methylene chloride, chloroform, 1,2-dichloroethane, diethyl ether, tetrahydrofuran, diisopropyl ether, tert -Butyl methyl ether, ethyl acetate, n-butyl acetate, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, 1,3-dimethyl-2-imidazolidinone, acetonitrile, propionitrile and Examples thereof include dimethyl sulfoxide, and these reaction solvents can be used alone or in combination of one or more.
  • the amount of the reaction solvent used in this step may be in the range of 10 parts by weight to 1000 parts by weight with respect to 100 parts by weight of 1,2,2,2-tetrafluoroethyl methyl ether. Mass parts are preferred, and a use amount of 25 to 250 parts by mass is particularly preferred.
  • the amount of water used when water is used as the reaction solvent, may be in the range of 10 to 1000 parts by mass with respect to 100 parts by mass of 1,2,2,2-tetrafluoroethyl methyl ether. Of these, 10 to 500 parts by mass are preferable, and 25 to 250 parts by mass is particularly preferable.
  • fluoride ions generated during the reaction can be efficiently collected by adding a fluoride ion scavenger to the reaction system.
  • the fluoride ion scavenger include sodium fluoride, sodium sulfate, calcium hydroxide, calcium chloride, calcium sulfate, aluminum hydroxide, aluminum chloride and aluminum sulfate.
  • calcium chloride is easy to handle and has high solubility in water, so that it can be suitably used.
  • the calcium chloride at least one kind of calcium chloride selected from the group of anhydride, monohydrate, dihydrate, tetrahydrate, and hexahydrate may be used.
  • the fluoride ion scavenger may be added to the reaction system in the form of a solid, but it is more preferable to dissolve it in a solvent such as water because an effective scavenging action of fluoride ions is expected.
  • the amount of the fluoride ion scavenger used may be in the range of 0.1 to 100 parts by weight with respect to 100 parts by weight of 1,2,2,2-tetrafluoroethyl methyl ether, and in particular 0.5 parts by weight. Part to 50 parts by mass is preferable, and an amount of 1 to 25 parts by mass is particularly preferable.
  • the reaction temperature in this step may be usually in the range of ⁇ 50 to + 80 ° C., usually ⁇ 20 to + 50 ° C. is preferable, and ⁇ 10 to + 25 ° C. is particularly preferable.
  • the pressure condition in this step may be in the range of 0.05 MPa to 5.0 MPa, and usually a slight pressure range of about 0.1 MPa to 0.3 MPa is more convenient and preferable.
  • the reaction can be carried out at a pressure exceeding 5.0 MPa. However, since the equipment is loaded under excessive pressure conditions, the reaction in the pressure range and atmospheric pressure is preferred. Therefore, glass containers such as quartz glass and borosilicate glass having corrosion resistance to chlorine and by-product hydrogen chloride, or resins such as tetrafluoroethylene / perfluoroalkyl vinyl ether copolymer (PFA) and polytetrafluoroethylene (PTFE) A container can be used suitably.
  • PFA perfluoroalkyl vinyl ether copolymer
  • PTFE polytetrafluoroethylene
  • 1,2,2,2-tetrafluoroethyl dichloromethyl ether represented by the formula [4], which is the object of this step, is a precursor of desflurane, which is a useful inhalation anesthetic.
  • 1,2,2,2-tetrafluoroethyltrichloromethyl ether represented by the formula [6] with reference to the methods described in Patent Document 2 and Patent Document 3, Proceeds partially to obtain 1,2,2,2-tetrafluoroethyl chlorodifluoromethyl ether (see Reference Example 1 described later).
  • the ether can be a difficult-to-separate impurity when producing desflurane, when considering the production process of desflurane as an inhalation anesthetic, it is represented by the formula [6] at the time of photochlorination of the present invention.
  • 1,2,2,2-tetrafluoroethyl trichloromethyl ether is preferably reduced as much as possible.
  • the reaction time of this step is usually within 12 hours, but the progress of the reaction is traced by analytical means such as gas chromatography, thin layer chromatography, liquid chromatography, nuclear magnetic resonance, etc.
  • analytical means such as gas chromatography, thin layer chromatography, liquid chromatography, nuclear magnetic resonance, etc.
  • the reaction was completed so that the selectivity of 1,2,2,2-tetrafluoroethyltrichloromethyl ether represented by the formula [6], which is a high-order chlorinated product that is difficult to separate, was approximately 10% or less. It is preferable to make it.
  • the post-treatment operation after the completion of the reaction is carried out by subjecting the reaction-terminated liquid to a normal distillation operation, whereby the desired 1,2,2,2-tetrafluoroethyldichloromethyl ether represented by the formula [4] is used. Is obtained. If necessary, it is possible to obtain a target product with higher purity by activated carbon treatment, silica gel column chromatography, or the like.
  • 1,2,2,2-tetrafluoroethyl chloromethyl ether represented by the formula [7], which is a low-order chlorinated product can be easily separated and recovered, and the recovered 1,2,2,2-tetrafluoroethyl is recovered.
  • Chloromethyl ether can be derived into 1,2,2,2-tetrafluoroethyl dichloromethyl ether represented by the formula [4], which is the target product, by chlorinating again.
  • the 1,2,2,2-tetrafluoroethyl chloromethyl ether represented by [7] is reused, the 1,2,2,2-tetrafluoroethyl methyl ether represented by the formula [3] is used.
  • the chlorination reaction can be repeated by re-adding.
  • the fluorination reaction can be carried out in the liquid phase or in the gas phase, but the reaction conditions differ depending on the difference in the liquid phase or the gas phase. Therefore, the case where the fluorination reaction is performed in the liquid phase or in the gas phase will be described step by step.
  • a catalyst can be used when performing the fluorination reaction in the liquid phase.
  • a catalyst is available. These catalysts can be used alone or in combination.
  • tin tetrachloride tin dichloride, tin tetrafluoride and tin difluoride is preferable, and tin tetrachloride is particularly preferably used.
  • the amount of the catalyst used is 0.01 to 50 parts by mass with respect to 100 parts by mass of 1,2,2,2-tetrafluoroethyldichloromethyl ether represented by the formula [4]. Preferably it is 0.1 to 20 parts by mass, and more preferably 0.5 to 10 parts by mass. When the amount of the catalyst exceeds 50 parts by mass, the amount of tar generated from the high boiling point compound increases, which is not preferable. In addition, about the fluorination reaction in a liquid phase, it can also react without using a catalyst (after-mentioned Example).
  • the amount of hydrogen fluoride used in the fluorination reaction in the liquid phase is from 0.1 mol to 1 mol of 1,2,2,2-tetrafluoroethyldichloromethyl ether represented by the formula [4]. 100 moles, preferably 0.5 moles to 50 moles, more preferably 1 moles to 25 moles. When the amount of hydrogen fluoride is less than 0.1 mol, the conversion rate in the reaction is poor. Moreover, it is not preferable from the viewpoint of use and an economical viewpoint that the amount of hydrogen fluoride exceeds 100 mol.
  • hydrogen fluoride is converted to “a salt or complex comprising an organic base and hydrogen fluoride with respect to 1,2,2,2-tetrafluoroethyldichloromethyl ether. It is also possible to produce desflurane which is the target product.
  • the “salt or complex comprising an organic base and hydrogen fluoride” can be prepared by mixing an organic base and hydrogen fluoride.
  • “complex composed of 1 mol of triethylamine and 3 mol of hydrogen fluoride” or “complex composed of 30% of pyridine and 70% of hydrogen fluoride” commercially available from Aldrich (Aldrich, 2012-2014 catalog) Can also be used.
  • the organic base in the “salt or complex comprising an organic base and hydrogen fluoride” is triethylamine, diisopropylethylamine, tri-n-propylamine, tri-n-butylamine, pyridine, 2,6-lutidine, 2,4,6-collidine, Preferred examples include 4-dimethylaminopyridine, 1,5-diazabicyclo [4.3.0] non-5-ene and 1,8-diazabicyclo [5.4.0] undec-7-ene.
  • the organic base generally used in organic synthesis can also be employ
  • 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 [ 5.4.0] undec-7-ene is preferred, and triethylamine, diisopropylethylamine, tri-n-butylamine, pyridine, 2,6-lutidine and 1,8-diazabicyclo [5.4.0] undec-7-ene are preferred.
  • the organic bases can be used alone or in combination.
  • the “salt or complex comprising an organic base and hydrogen fluoride” means that hydrogen fluoride present in the salt or complex reacts with 1,2,2,2-tetrafluoroethyl dichloromethyl ether to generate fluorine.
  • the hydrogenation reaction proceeds (that is, hydrogen fluoride contained in the salt or complex serves as a fluorine source for substituting a chlorine atom for a fluorine atom as in the case of single hydrogen fluoride).
  • the molar ratio of the organic base to hydrogen fluoride in the “salt or complex comprising an organic base and hydrogen fluoride” may be used in the range of 100: 1 to 1: 100. A ratio of 25: 1 to 1:25 is particularly preferable.
  • the amount of hydrogen fluoride contained in the “salt or complex comprising an organic base and hydrogen fluoride” is 1 mol of 1,2,2,2-tetrafluoroethyldichloromethyl ether represented by the formula [1].
  • the amount is 0.1 to 200 mol, preferably 0.5 to 100 mol, and more preferably 1 to 50 mol.
  • the amount of hydrogen fluoride is less than 0.1 mol, the conversion rate in the reaction is poor.
  • the use of an amount of hydrogen fluoride exceeding 200 mol is not preferable from an economical viewpoint.
  • a solvent when the fluorination reaction is performed in the liquid phase, a solvent can be used.
  • the solvent include ether solvents, aliphatic hydrocarbon solvents, aromatic hydrocarbon solvents, halogenated hydrocarbon solvents, ester solvents, amide solvents, nitrile solvents, sulfoxide solvents, and the like.
  • reaction solvents include diethyl ether, diisopropyl ether, dibutyl ether, tert-butyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, tetrahydropyran, cyclopentyl methyl ether, n-hexane, n-heptane, and n-pentane.
  • N-nonane, n-decane toluene, xylene, mesitylene, ethylbenzene, methylene chloride, chloroform, 1,2-dichloroethane, ethyl acetate, n-butyl acetate, N, N-dimethylformamide, N, N-dimethylacetamide, Examples thereof include N-methylpyrrolidone, 1,3-dimethyl-2-imidazolidinone, acetonitrile, propionitrile, dimethyl sulfoxide and the like.
  • tetrahydrofuran N, N-dimethylformamide, N, N-dimethylacetamide, 1,3-dimethyl-2-imidazolidinone, acetonitrile, propionitrile and dimethyl sulfoxide are preferable, and tetrahydrofuran, N, N-dimethyl is preferred. Particularly preferred are formamide and acetonitrile. These reaction solvents can be used alone or in combination.
  • the amount of the solvent used is not particularly limited, but 0.05 L (liter) or more is used with respect to 1 mol of 1,2,2,2-tetrafluoroethyldichloromethyl ether represented by the general formula [1]. Usually, 0.1 to 20 L is preferable, and 0.1 to 10 L is more preferable.
  • the reaction temperature when performing the fluorination reaction in the liquid phase may be in the range of ⁇ 20 ° C. to + 200 ° C., usually ⁇ 10 to + 150 ° C., and particularly preferably 0 to + 100 ° C.
  • the pressure condition for performing the fluorination reaction in the liquid phase may be in the range of 0.1 MPa to 4.0 MPa, preferably 0.1 MPa to 2.0 MPa, and particularly preferably 0.1 MPa to 1.5 MPa. More preferred.
  • the temperature range and the pressure range are 0 ° C. to + 50 ° C. and 0.1 MPa to 1.0 MPa so that the fluorination can be performed at a high conversion rate.
  • the temperature range and pressure range are ⁇ 10 ° C. to + 150 ° C., and By setting the pressure to 1 MPa to 2.0 MPa, the fluorination reaction similarly proceeds with a high conversion rate, and desflurane can be obtained with a high selectivity (see Example 14 described later).
  • a catalyst can be used when performing the fluorination reaction in the gas phase.
  • a metal compound-supported catalyst in which a metal compound containing at least one metal selected from the group consisting of chromium, titanium, manganese, iron, nickel, cobalt, magnesium, zirconium and antimony is supported on a metal oxide or activated carbon.
  • chromium, titanium, manganese, iron, nickel, cobalt, magnesium, zirconium and antimony is supported on a metal oxide or activated carbon.
  • the reaction temperature when performing the fluorination reaction in the gas phase is not particularly limited, but is 100 to 500 ° C, preferably 100 to 400 ° C, and more preferably 100 to 350 ° C.
  • the reaction temperature exceeds 500 ° C., a decomposition product is generated, and the selectivity of the target product may be lowered, which is not preferable.
  • the molar ratio of 1,2,2,2-tetrafluoroethyldichloromethyl ether: hydrogen fluoride supplied to the reaction zone when performing the fluorination reaction in the gas phase is affected by the reaction temperature, but usually 1 : 2 to 1:50, preferably 1: 4 to 1:20, more preferably 1: 5 to 1:15.
  • the conversion rate of reaction may fall and the yield of a target object may fall.
  • the 1,2,2,2-tetrafluoroethyldichloromethyl ether supplied to the reaction zone when performing the fluorination reaction in the gas phase can be supplied together with a gas such as nitrogen, helium, or argon that does not participate in the reaction. it can. Similarly, hydrogen fluoride can coexist. Such a gas has a ratio of 100 mol or less per mol of 1,2,2,2-tetrafluoroethyl dichloromethyl ether, and preferably 20 mol or less. Gases that do not participate in the reaction may not be used.
  • the reaction pressure when performing the fluorination reaction in the gas phase is usually in the range of 0.1 to 6.0 MPa, but the preferred pressure range in this step is preferably 0.1 to 3.0 MPa, more The range is preferably from 0.1 to 1.5 MPa.
  • the pressure it is desirable to select conditions such that organic substances such as raw materials existing in the system do not liquefy in the reaction system.
  • the contact time for carrying out the fluorination reaction in the gas phase 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.
  • the catalyst holding method may be any of fixed bed, fluidized bed, moving bed, etc. However, it is convenient and preferable to use a fixed bed.
  • a pressure resistant reaction vessel made of a material such as stainless steel (SUS), a tetrafluoroethylene / perfluoroalkyl vinyl ether copolymer (PFA) having a corrosion resistance against hydrogen fluoride, or polytetrafluoro
  • SUS stainless steel
  • PFA perfluoroalkyl vinyl ether copolymer
  • the reaction is preferably carried out using a pressure-resistant reaction vessel whose interior is lined with a resin such as ethylene (PTFE).
  • PTFE ethylene
  • the reaction time in this step is usually within 12 hours, but it was caused by the amount of hydrogen fluoride used with 1,2,2,2-tetrafluoroethyldichloromethyl ether represented by the formula [4].
  • the progress of the reaction may be traced by analytical means such as gas chromatography, thin layer chromatography, liquid chromatography, nuclear magnetic resonance, etc., and the end point of the reaction may be the end point of the reaction. preferable.
  • the target desflurane can be obtained in a high yield by carrying out a normal purification operation on the reaction end solution.
  • 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.
  • % of the composition analysis value represents “area%” of the composition obtained by measuring the raw material or the product by gas chromatography (the detector is FID unless otherwise specified).
  • Preparation Example 1 Preparation Example of Catalyst with Chromium Chloride Supported on Alumina
  • 896 g of the special grade reagent CrCl 3 .6H 2 O was dissolved in pure water to make 3.0 L.
  • 400 g of granular alumina was immersed and left for a whole day and night.
  • the alumina was removed by filtration, kept at 100 ° C. in a hot air circulating dryer, and further dried overnight.
  • the obtained chromium-supported alumina was filled in a cylindrical SUS316L reaction tube having a diameter of 4.2 cm and a length of 60 cm equipped with an electric furnace, and the temperature was raised to 300 ° C.
  • Example 1 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 charged with 125 mL of the catalyst prepared in Preparation Example 1 as a catalyst. While flowing air at a flow rate of about 100 mL / min, the temperature of the reaction tube was raised to 305 ° C., and hydrogen fluoride was introduced at a rate of about 0.32 g / min over 1 hour. Next, the supply of chloral as a raw material to the reaction tube was started at a rate of about 0.38 g / min (contact time 15 seconds).
  • the reaction was stable 1 hour after the start of the reaction, the gas flowing out from the reactor was collected in a cylinder with a blow tube cooled with dry ice over 3 hours.
  • the hydrogen fluoride content, the hydrogen chloride content, and the organic matter content are calculated by titration with respect to 70.4 g of the fluoral-containing collected liquid, the hydrogen fluoride content is 41 mass%, the hydrogen chloride content is 11 mass%, and the organic matter content is 49 mass%.
  • the organic matter recovery rate was 90% (based on the number of moles of feedstock chloral).
  • the degree of fluorination is confirmed by 19 F-NMR. It was confirmed.
  • Example 2 A polytetrafluoroethylene (PTFE) stirrer was placed in a 250 ml tetrafluoroethylene / perfluoroalkyl vinyl ether copolymer (PFA) reactor equipped with a thermometer and a condenser for condenser, and contained the fluoral obtained in Example 1. 70.4 g of collected liquid (the number of moles of fluoral: 352 mmol) was quickly charged and cooled. Next, 37.4 g (352 mmol) of trimethyl orthoformate was added while paying attention to the exotherm. Thereafter, after stirring at room temperature for 2 hours, 60 g of water was added to stop the reaction.
  • PFA perfluoroalkyl vinyl ether copolymer
  • the organic substance obtained by separating the reaction solution into two layers was washed with 30 g of a 16% by mass aqueous potassium hydroxide solution, and 25.7 g of organic matter was recovered again by separating into two layers.
  • the two-stage reaction yield from Example 1 was 50%.
  • the amount of 1,2,2,2-tetrafluoroethyl methyl ether represented by the above formula was 91.1%.
  • Example 3 A stirrer of polytetrafluoroethylene (PTFE) was placed in a reaction vessel of borosilicate glass equipped with a condenser and a thermometer, and 40.0 g (303 mmol, 1.0.05) of 1,2,2,2-tetrafluoroethyl methyl ether was placed. 00 equivalents) and 40 g of water were weighed out. In addition, a water trap that absorbs hydrogen chloride by-produced by the reaction and a dry ice strap for the purpose of recovering volatile organic substances were connected to the outlet of the condenser condenser.
  • PTFE polytetrafluoroethylene
  • Example 4 A stirrer of polytetrafluoroethylene (PTFE) is placed in a borosilicate glass reaction vessel equipped with a condenser and a thermometer, and 30 g (227 mmol, 1.00 equivalent) of 1,2,2,2-tetrafluoroethyl methyl ether is placed in the reaction vessel. ), 15 g of water, and 1.5 g of anhydrous calcium chloride. Under cooling, 33 g (465 mmol, 2.00 equivalents) of chlorine was introduced over 4 hours while irradiating UV light from the outside of the reactor with a 400 W high-pressure mercury lamp (USHIO INC.) While paying attention to heat generation. did.
  • PTFE polytetrafluoroethylene
  • Example 5 A stirrer of polytetrafluoroethylene (PTFE) is placed in a borosilicate glass reaction vessel equipped with a condenser and a thermometer, and 30 g (227 mmol, 1.00 equivalent) of 1,2,2,2-tetrafluoroethyl methyl ether is placed in the reaction vessel. ), And 1.5 g of anhydrous calcium chloride was weighed out. Under cooling, 33 g (465 mmol, 2.00 equivalents) of chlorine was introduced over 4 hours while irradiating UV light from the outside of the reactor with a 400 W high-pressure mercury lamp (USHIO INC.) While paying attention to heat generation. did.
  • PTFE polytetrafluoroethylene
  • Example 6 A polytetrafluoroethylene (PTFE) stirrer was placed in a borosilicate glass reaction vessel equipped with a condenser and a thermometer, and 400 g (3.03 mol, 1.00) of 1,2,2,2-tetrafluoroethyl methyl ether was added. Equivalent weight), 285 g of water, and 15 g of anhydrous calcium chloride. While cooling, 379 g (5.35 mol, 1.76 equivalents) of chlorine was heated for 5 hours while irradiating UV light from the outside of the reactor with a 400 W high pressure mercury lamp (USHIO INC.). Introduced.
  • PTFE polytetrafluoroethylene
  • the main fraction contained 1.0% or less of 1,2,2,2-tetrafluoroethyltrichloromethyl ether represented by the formula [6]. From the reaction of the low-order chlorinated product contained in the first fraction, the recovery rate was 29%, and the recovery rate of the target product contained in the main fraction was 37%.
  • Example 7 A polytetrafluoroethylene (PTFE) stirrer was placed in a borosilicate glass reaction vessel equipped with a condenser and a thermometer, and recovered in Example 6, 1, 2, and 2 represented by the formula [7] , 2-tetrafluoroethyl chloromethyl ether (20 g, 120 mmol, 1.00 equivalent) and water (10 g) were weighed out. Under cooling, 8 g (113 mmol, 0.95 equivalents) of chlorine was introduced over 1 hour while paying attention to heat generation while irradiating UV light from the outside of the reactor with a 400 W high pressure mercury lamp (USHIO INC.). did.
  • PTFE polytetrafluoroethylene
  • Example 8 A stirrer of polytetrafluoroethylene (PTFE) was placed in a borosilicate glass reaction vessel equipped with a condenser and a thermometer, and 150 g of 1,2,2,2-tetrafluoroethyl methyl ether represented by the above formula (1. 14 mol, 1.00 equivalent). Then, under cooling, irradiate ultraviolet rays from the outside of the reactor with a 400 W high-pressure mercury lamp (USHIO Co., Ltd.) and take 178 g (2.51 mol, 2.20 equivalents) of chlorine over 5 hours while paying attention to heat generation. Introduced. After the introduction of chlorine, the unreacted chlorine was purged with nitrogen to obtain 199 g of a crude reaction product.
  • PTFE polytetrafluoroethylene
  • Example 9 A polytetrafluoroethylene (PTFE) stirrer was placed in a reaction vessel of borosilicate glass equipped with a condenser and a thermometer, and 50 g (379 mmol, 1,2,2,2-tetrafluoroethyl methyl ether represented by the above formula) 1.00 equivalent) and 1.2 g (7.6 mmol, 2 mol%) of AIBN. After heating the oil bath temperature to 40 ° C., introduction of 107 g (1.52 mol, 4.00 equivalents) of chlorine was started while paying attention to heat generation. During the reaction, the oil bath temperature was raised with the progress of the degree of chlorination of the substrate, and finally the internal temperature was raised to 66 ° C.
  • PTFE polytetrafluoroethylene
  • Example 10 A 100 mL autoclave reaction vessel (manufactured by SUS316L) equipped with a pressure gauge and a cooling condenser was charged with a polytetrafluoroethylene (PTFE) stir bar, and 10 g of 1,2,2,2-tetrafluoroethyldichloromethyl ether represented by the above formula ( 49.8 mmol, 1.00 equivalent), and 1.3 g (4.99 mmol, 10 mol%) of tin tetrachloride were weighed out.
  • PTFE polytetrafluoroethylene
  • Example 11 To a 500 mL autoclave reaction vessel (manufactured by SUS316L) equipped with a stirrer, a pressure gauge, and a cooling condenser, 201 g (1.00 mol, 1.00 equivalent) of 1,2,2,2-tetrafluoroethyldichloromethyl ether represented by the above formula, Then, 2.61 g (10.0 mmol, 1.0 mol%) of tin tetrachloride was weighed. After cooling in an ice bath, 49.8 g (2.49 mol, 2.5 equivalents) of hydrogen fluoride was charged all at once, and the temperature was gradually raised to 20 ° C. while paying attention to sudden heat generation.
  • Example 12 A 100 mL autoclave reaction vessel (manufactured by SUS316L) equipped with a pressure gauge and a cooling condenser was charged with a polytetrafluoroethylene (PTFE) stirrer, and 20 g of 1,2,2,2-tetrafluoroethyldichloromethyl ether represented by the above formula ( 99.5 mmol, 1.00 equivalent), and 0.36 g (1.20 mmol, 1.2 mol%) of antimony pentachloride were weighed out. After cooling in an ice bath, 8.8 g (440 mmol, 4.4 equivalents) of hydrogen fluoride was charged all at once, and the temperature was gradually raised to 15 ° C. while paying attention to sudden heat generation.
  • PTFE polytetrafluoroethylene
  • Example 13 A 100 mL autoclave reaction vessel (manufactured by SUS316L) equipped with a pressure gauge and a cooling condenser was charged with a polytetrafluoroethylene (PTFE) stir bar, and 10 g of 1,2,2,2-tetrafluoroethyldichloromethyl ether represented by the above formula ( 49.8 mmol, 1.00 equivalent). After cooling in an ice bath, 20.0 g (1.00 mol, 20.0 equivalents) of hydrogen fluoride is charged all at once, the temperature is raised to 80 ° C., and a reaction pressure of 1.0 MPa is maintained. The hydrogen was heated and stirred for 8 hours while being removed from the system through a cooling condenser.
  • PTFE polytetrafluoroethylene
  • reaction was stopped by making all the reaction liquids absorb to ice water.
  • the organic matter obtained by the two-layer separation was 7.7 g, and the organic matter recovery rate was 92%. Moreover, the purity of the obtained desflurane (the above formula) was 71.3%.
  • the collected organic matter contained 26.1% of 1,2,2,2-tetrafluoroethylfluorochloromethyl ether represented by the formula [8] (note that this compound contains 1,1 2,2,2-tetrafluoroethyl dichloromethyl ether is a monofluorinated reaction intermediate).
  • SUS stainless steel
  • Example 15 to 17 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 charged with 100 mL of the catalyst prepared in Preparation Example 1 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, the raw material 1,2,2,2-tetrafluoroethyl dichloromethyl ether (91.9 GC%) was fed into the reaction tube at a rate of about 0.1 g / min (contact time 25 seconds).
  • Example 18 Using the same gas phase reactor as in Examples 15 to 17, the temperature of the reaction tube was set to 180 ° C., and hydrogen fluoride was introduced at a rate of about 0.1 g / min over 1 hour. Next, 1,2,2,2-tetrafluoroethyl dichloromethyl ether (94.6 GC%) as a raw material was introduced into the reaction tube at a rate of 0.1 to 0.2 g / min (contact time 20 to 25 seconds). Feeding took place over 4.5 hours. After the gas flowing out from the reactor was blown into water to remove the acidic gas, the organic matter slipped through was collected with a dry ice strap to obtain 23.3 g of organic matter.
  • the 1,2,2,2-tetrafluoroethyl difluoromethyl ether (desflurane) targeted in the present invention can be used as an inhalation anesthetic.

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Abstract

Selon l'invention, un orthoformiate de triméthyle agit sur un fluoral obtenu par réaction de fluoration en phase gazeuse d'un chloral, en présence d'un catalyseur, et un １，２，２，２－tétrafluoroéthylméthyléther constituant un intermédiaire de synthèse d'un desflurane, est facilement obtenu. Le １，２，２，２－tétrafluoroéthylméthyléther ainsi obtenu permet d'induire un 1,2,2,2- tétrafluoroéthyldifluorométhyléther (desflurane) selon un rendement élevé par chloration puis fluoration. Selon ce procédé il est possible de fabriquer efficacement et à échelle industrielle un desflurane avantageux en tant qu'anesthésique par inhalation.
PCT/JP2017/045083 2016-12-29 2017-12-15 Procédé de fabrication de 1,2,2,2- tétrafluoroéthyldifluorométhyléther (desflurane) Ceased WO2018123649A1 (fr)

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WO2019064863A1 (fr) * 2017-09-29 2019-04-04 セントラル硝子株式会社 Procédé de production d'éther 1,2,2,2-tétrafluoroéthyl difluorométhyle (desflurane)
WO2019216163A1 (fr) * 2018-05-09 2019-11-14 セントラル硝子株式会社 Procédé de production d'éther méthylique de 1,2,2,2-tétrafluoroéthyle
WO2020162408A1 (fr) * 2019-02-06 2020-08-13 セントラル硝子株式会社 １，１，１－trifluoro－２，２－bisaryléthane, et procédé de fabrication de celui-ci

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CN115477570A (zh) * 2021-05-30 2022-12-16 山东新时代药业有限公司 一种地氟烷的合成方法
CN117101643A (zh) * 2023-04-06 2023-11-24 风火轮(上海)生物科技有限公司 一种连续制备地氟烷的催化剂

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WO2020162408A1 (fr) * 2019-02-06 2020-08-13 セントラル硝子株式会社 １，１，１－trifluoro－２，２－bisaryléthane, et procédé de fabrication de celui-ci
CN113396137A (zh) * 2019-02-06 2021-09-14 中央硝子株式会社 1,1,1-三氟-2,2-双芳基乙烷的制造方法、和1,1,1-三氟-2,2-双芳基乙烷
JPWO2020162408A1 (ja) * 2019-02-06 2021-12-09 セントラル硝子株式会社 １，１，１−トリフルオロ−２，２−ビスアリールエタンの製造方法、および１，１，１−トリフルオロ−２，２−ビスアリールエタン
JP7460912B2 (ja) 2019-02-06 2024-04-03 セントラル硝子株式会社 １，１，１－トリフルオロ－２，２－ビスアリールエタンの製造方法、および１，１，１－トリフルオロ－２，２－ビスアリールエタン
US12351685B2 (en) 2019-02-06 2025-07-08 Central Glass Company, Limited Polyamide acid, polyimide, optical film, display device and production methods thereof
US12435185B2 (en) 2019-02-06 2025-10-07 Central Glass Company, Limited Method for producing 1,1,1-trifluoro-2,2-bisarylethane, and 1,1,1-trifluoro-2,2-bisarylethane

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