JP2011088841A - MANUFACTURING METHOD OF alpha,alpha-DIFLUOROACETOPHENONES - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a manufacturing method of α,α-difluoroacetophenones using an industrially available compound bearing a difluoromethyl group that does not require an extreme temperature condition to be applied to mass production. <P>SOLUTION: The manufacturing method of α,α-difluoroacetophenones represented by general formula (2) includes causing an aromatic compound represented by general formula (1) (wherein R's are each independently a hydrogen atom, a halogen atom, an alkyl group or a fluoroalkyl group; and n is an integer of 0-2) to react with difluoroacetic fluoride in the presence of a catalyst. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

  The present invention relates to a method for producing α, α-difluoroacetophenones used as pharmaceutical and agrochemical intermediates and reaction reagents, and to a substitution reaction of aromatic ring hydrogen with difluoroacetic acid fluoride.

As a method for producing α, α-difluoroacetophenones, (1) ethyl difluoroacetate is allowed to act on magnesium phenyl bromide, (2) together with 10% PhCOCHFOCF _{3 by} reaction of α-diazoacetophenone with CF ₃ OF 14 % PhCOCHF ₂ (3) obtained by refluxing difluoromethylacyltriazole in benzene with aluminum chloride as catalyst, (4) argon atmosphere o-MeC6H4Li is reacted with F ₂ CHCONEt ₂ in ether at −75 ° C. 65.7% o-MeC ₆ H ₄ COCHF ₂ is obtained, and p-isomer is obtained in the same manner. (5) Lithium in ether prepared by reacting 2,5-difluorobromobenzene with ethyllithium 40% 2,5-F ₂ C ₆ H ₃ COCHF ₂ with difluoroacetic acid (6) Obtained from benzene and chlorodifluoroacetic acid chloride in carbon disulfide using AlCl ₃ as a catalyst. (7) Steam distillation by reacting 1,1,2,2-tetrafluoroethylbenzene or its nuclear substitute with an aqueous sulfuric acid solution. Many methods have been proposed, such as the method of obtaining them.

Further, Friedel-Craft acylation of aromatic compounds and fluorocarboxylic acid halides using a Lewis acid catalyst such as aluminum chloride or an acid such as hydrogen fluoride is widely performed. Fluorocarboxylic acid halides include acid chlorides such as fluoroacetic acid chloride and trifluoroacetic acid chloride, and acid fluorides having a relatively large molecular weight such as (CF ₃ —CF ₂ —CF ₂ —O—) (CF ₃ ) FCCOF (non-patented) There is also a report on the acid fluoride of literature 1).

Journal of Fluorine Chemistry, 14 (3), 243-52; 1979

  Although the production method of α, α-difluoroacetophenone is various, it is not necessarily satisfactory for industrial application. For example, in the above example, the raw materials or intermediates are difficult to obtain or handle in large quantities, the organic metal compound requires a very low temperature, the use of flammable toxic auxiliary materials, etc. Any improvement can be found.

  Therefore, the present invention provides a method for producing α, α-difluoroacetophenones that can be applied to mass production since a compound having a difluoromethyl group that can be obtained industrially is used and extreme temperature conditions are not required.

  As a method for introducing an acyl group into an aromatic compound, the present inventors searched for prior literature on acylation by the Fluidel Crafts reaction. As a raw material, fluorocarboxylic acid chlorides such as trifluoroacetic acid chloride and fluoroacetic acid chloride are used as raw materials. Although a method for introducing a fluorine-containing acetyl group could be found, no corresponding acid chloride was introduced for a difluoroacetyl group. Furthermore, even when searching for introduction of a fluorine-containing acetyl group by acid fluoride, there was no use example of fluorine-containing carboxylic acid fluoride having a low molecular weight such as difluoroacetic acid fluoride.

  The reason why such low molecular weight fluorine-containing carboxylic acid fluoride is not used is not clear, but under such circumstances, difluoroacetic acid fluoride, which is a low molecular weight fluorine-containing carboxylic acid fluoride, is catalyzed by Lewis acid such as aluminum chloride. As a result, it was surprisingly found that α, α-difluoroacetophenones can be produced in good yield when reacted with an aromatic compound.

That is, the present invention is as follows.
[Invention 1] Formula (1)

(In the formula, each R independently represents a hydrogen atom, a halogen atom, an alkyl group or a fluorine-containing alkyl group, and n represents an integer of 0 to 2). General formula (2) for reacting with fluoride

The manufacturing method of (alpha), (alpha)-difluoro acetophenone represented by these.
[Invention 2] A process for producing α, α-difluoroacetophenone according to Invention 1, wherein the catalyst is a Lewis acid.
[Invention 3] A process for producing α, α-difluoroacetophenone according to Invention 2, wherein the Lewis acid is aluminum chloride or aluminum bromide.
[Invention 4] A process for producing α, α-difluoroacetophenone according to Invention 1, wherein the catalyst is hydrogen fluoride.
[Invention 5] Difluoroacetic acid fluoride heats 1-alkoxy-1,1,2,2-tetrafluoroethane represented by CHF ₂ CF ₂ OR ′ (R ′ represents a monovalent organic group). A method for producing α, α-difluoroacetophenone according to any one of inventions 1 to 4, which is a thermal decomposition product obtained by decomposition.

  The method of the present invention is a production method with good yield, since α, α-difluoroacetophenone can be produced on a large scale because difluoroacetic acid fluoride capable of mass production is used as a building block of a difluoroacetyl group.

  The present invention relates to a general formula (1)

(In the formula, each R independently represents a hydrogen atom, a halogen atom, an alkyl group or a fluorine-containing alkyl group, and n represents an integer of 0 to 2). General formula (2) for reacting with fluoride

It is a manufacturing method of (alpha), (alpha)-difluoro acetophenone represented by these.

  The difluoroacetyl group of α, α-difluoroacetophenone represented by the general formula (2) is preferentially introduced into the p- (para) position with respect to at least one substituent R.

  The substituted benzene used for this invention can use what was manufactured by the well-known method. Moreover, what can be obtained as an industrial product or a commercial item may be sufficient. As a halogen atom of General formula (1), they are a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. As an alkyl group, the C1-C8 alkyl group which may have a substituent, the cycloalkyl group which may have an alkyl group as a substituent can be mentioned, A lower alkyl group is more preferable. In the present specification, the “alkyl group” refers to linear, branched, and cyclic unless otherwise specified. The lower alkyl group means a linear or branched alkyl group having 1 to 4 carbon atoms and an alicyclic group having 3 to 7 carbon atoms.

  Examples of the alkyl group having 1 to 8 carbon atoms that may have a substituent include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, s-butyl group, t-butyl group, and n-pentyl. Group, isopentyl group can be mentioned as an example. Specific examples of the lower alkyl group include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, s-butyl group, t-butyl group. Examples include groups.

  Examples of the cycloalkyl group that may have an alkyl group as a substituent include a cyclobutyl group, a cyclopentyl group, a 2-methylcyclopentyl group, a 3-methylcyclopentyl group, a 2-ethylcyclopentyl group, a 3-ethylcyclopentyl group, a cyclohexyl group, and 2 -Methylcyclohexyl group, 3-methylcyclohexyl group, 4-methylcyclohexyl group, 2-ethylcyclohexyl group, 3-ethylcyclohexyl group, 4-ethylcyclohexyl group, cycloheptyl group, 2-methylcyclohexyl group, 3-methylcyclohexane A heptyl group, 3-methylcycloheptyl group, 4-methylcycloheptyl group, etc. can be mentioned.

  As a fluorine-containing alkyl group, C1-C8 is preferable and C1-C4 is more preferable. Specifically, the fluorine-containing alkyl group includes a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a chlorofluoromethyl group, a chlorodifluoromethyl group, a bromodifluoromethyl group, a dibromofluoromethyl group, 2,2,2 Examples include -trifluoroethyl group, pentafluoroethyl group, 2,2,3,3,3-pentafluoropropyl group, n-hexafluoropropyl group, hexafluoroisopropyl group, and the like. Of these, a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, and a 2,2,2-trifluoroethyl group are preferable, and a trifluoromethyl group and a difluoromethyl group are more preferable.

  Among these, as R, a fluorine atom, a chlorine atom, a C1-C4 alkyl group which may have a substituent, or a fluorine-containing alkyl group is preferable.

  Specific examples of the aromatic compound used in the present invention include benzene, fluorobenzene, chlorobenzene, bromobenzene, toluene, ethylbenzene, n-propylbenzene, cumene, n-butylbenzene, s-butylbenzene, and t-butyl. Benzene, trifluoromethylbenzene, pentafluoroethylbenzene, 2,2,2-trifluoroethylbenzene, n-heptafluoropropylbenzene, i-heptafluoropropylbenzene, α-trifluoromethyl-β, β, β-trifluoroethylbenzene , O-, m-, p-difluorobenzene, o-, m-, p-dichlorobenzene, o-, m-, p-dibromobenzene, o-, m-, p-xylene, mesitylene, durene, o- , M-, p-bistrifluoromethylbenzene, o-, m P-fluorotoluene, o-, m-, p-chlorotoluene, o-, m-, p-bromotoluene, o-, m-, p-iodotoluene, o-, m-, p-fluoroethylbenzene, o-, m-, p-chloroethylbenzene, o-, m-, p-bromoethylbenzene, o-, m-, p-iodoethylbenzene, o-, m-, p-bromoiodobenzene, o-, m- P-chloroiodobenzene, o-, m-, p-fluoroiodobenzene, o-, m-, p-bromofluorobenzene, o-, m-, p-chlorofluorobenzene, o-, m-, p -Bromochlorobenzene and the like.

  These aromatic compounds are preferably used with the lowest possible water content. For this purpose, it is preferable to perform dehydration distillation, dehydration with a solid adsorbent such as zeolite, phosphorus pentoxide, silica gel or the like prior to use. The zeolite may be a natural product or a synthetic product, and may be 3A, 4A, 5A, 10X, 13Y or other crystal forms, but the 4A type is preferred.

The difluoroacetic acid fluoride may be produced by any method. For example, (1) a method in which difluoroacetic acid is reacted with phosphorus pentoxide, thionyl chloride, etc. and then fluorinated with a metal fluoride such as potassium fluoride, (2) 1-alkoxy- represented by CHF ₂ CF ₂ OR A method of decomposing 1,1,2,2-tetrafluoroethane in the presence of sulfur trioxide and fluorosulfuric acid (J. Am. Chem. Soc., 1956 78, 2608-10), (3) 1-alkoxy- A method of reacting 1,1,2,2-tetrafluoroethane in the presence of a catalyst such as antimony halide or titanium halide (JP-A-8-53388), (4) 1-alkoxy-1,1,2, A method of producing difluoroacetic acid fluoride by thermally decomposing 2-tetrafluoroethane in the presence of a catalyst (Japanese Patent Laid-Open No. 2007-8930) is known.

  In the method of the present invention, difluoroacetic acid fluoride obtained by thermally decomposing 1-alkoxy-1,1,2,2-tetrafluoroethane in the presence of a catalyst is preferably used. This reaction is represented by the following formula.

CHF ₂ CF ₂ OR '→ CHF ₂ COF + R'F
R of 1-alkoxy-1,1,2,2-tetrafluoroethane represented by the general formula CHF ₂ CF ₂ OR ′ (R ′ represents a monovalent organic group) which is a starting material for this reaction. 'Is a leaving group and is not particularly limited. However, it may have a branched alkyl group having 1 to 8 carbon atoms, a cycloalkyl group that may have an alkyl group as a substituent, a fluorine-containing alkyl group, an aryl group, An aralkyl group can be mentioned, and among these, an alkyl group or a fluorine-containing alkyl group is preferable, an alkyl group is more preferable, and a lower alkyl group is more preferable.

  Examples of the alkyl group having 1 to 8 carbon atoms that may have a branch include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, s-butyl group, t-butyl group, and n-pentyl group. An isopentyl group can be given as an example. Specific examples of the lower alkyl group include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an s-butyl group, and a t-butyl group. Is applicable.

  Examples of the cycloalkyl group that may have an alkyl group as a substituent include a cyclobutyl group, a cyclopentyl group, a 2-methylcyclopentyl group, a 3-methylcyclopentyl group, a 2-ethylcyclopentyl group, a 3-ethylcyclopentyl group, a cyclohexyl group, and 2 -Methylcyclohexyl group, 3-methylcyclohexyl group, 4-methylcyclohexyl group, 2-ethylcyclohexyl group, 3-ethylcyclohexyl group, 4-ethylcyclohexyl group, cycloheptyl group, 2-methylcyclohexyl group, 3-methylcyclohexane A heptyl group, 3-methylcycloheptyl group, 4-methylcycloheptyl group, etc. can be mentioned.

  As the aryl group, phenyl group, 2-methylphenyl group, 3-methylphenyl group, 4-methylphenyl group, 2,3-dimethylphenyl group, 2,4-dimethylphenyl group, 2,5-dimethylphenyl group, 2,6-dimethylphenyl group, 3,4-dimethylphenyl group, 3,5-dimethylphenyl group, 3,6-dimethylphenyl group, 2-methoxyphenyl group, 3-methoxyphenyl group, 4-methoxyphenyl group, Examples include 1-naphthyl group, 2-naphthyl group and the like.

  The fluorine-containing alkyl group includes a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a chlorofluoromethyl group, a chlorodifluoromethyl group, a bromofluoromethyl group, a dibromofluoromethyl group, and a 2,2,2-trifluoroethyl group. And pentafluoroethyl group, 2,2,3,3,3-pentafluoropropyl group, n-hexafluoropropyl group, hexafluoroisopropyl group and the like.

  Examples of the aralkyl group include phenethyl group, 2-methylphenylmethyl group, 3-methylphenylmethyl group, 4-methylphenylmethyl group, 2,3-dimethylphenylmethyl group, 2,4-dimethylphenylmethyl group, 2,5 -Dimethylphenylmethyl group, 2,6-dimethylphenylmethyl group, 3,4-dimethylphenylmethyl group, 3,5-dimethylphenylmethyl group, 3,6-dimethylphenylmethyl group, 4-ethylphenylmethyl group, 4 Examples include-(n-propyl) methylphenylmethyl group and 4- (n-butyl) methylphenylmethyl group.

  1-alkoxy-1,1,2,2-tetrafluoroethane can be obtained by a known production method. For example, it can be synthesized by a method in which alcohol (R′OH) and tetrafluoroethylene are reacted in the presence of a base.

  Specifically, 1-methoxy-1,1,2,2-tetrafluoroethane can be synthesized by a method in which methanol and tetrafluoroethylene are reacted in the presence of potassium hydroxide (J. Am. Chem. Soc. 73, 1329 (1951)).

Specific examples of the fluorine-containing ether that can be used in the present invention include, but are not limited to, the following.
1-methoxy-1,1,2,2-tetrafluoroethane (CHF ₂ CF ₂ OMe), 1-ethoxy-1,1,2,2-tetrafluoroethane (CHF ₂ CF ₂ OEt), 1- (n -Propoxy) -1,1,2,2-tetrafluoroethane, 1-isopropoxy-1,1,2,2-tetrafluoroethane, 1- (n-butoxy) -1,1,2,2-tetra Fluoroethane, 1- (s-butoxy) -1,1,2,2-tetrafluoroethane, 1- (t-butoxy) -1,1,2,2-tetrafluoroethane, 1-trifluoromethoxy-1 , 1,2,2-tetrafluoroethane, 1-difluoromethoxy-1,1,2,2-tetrafluoroethane, 1- (2,2,2-trifluoroethoxy) -1,1,2,2- Tetrafluoroethane, 1-pen Fluoroethoxy-1,1,2,2-tetrafluoroethane, 1- (2,2,2,3,3-pentafluoropropoxy) -1,1,2,2-tetrafluoroethane, 1-hexafluoroiso Examples thereof include propoxy-1,1,2,2-tetrafluoroethane.

The catalyst used for the thermal decomposition according to the present invention is a solid catalyst, and metal oxides and metal fluorinated oxides described in JP-A-8-92162 can be used as the catalyst. Phosphate can also be used as the catalyst. The phosphate may be supported on a carrier.
As phosphoric acid, any of orthophosphoric acid, polyphosphoric acid, and metaphosphoric acid may be used. Examples of polyphosphoric acid include pyrophosphoric acid. Phosphate is the metal salt of these phosphoric acids. Since it is easy to handle, orthophosphoric acid is preferred. Phosphate refers to a metal salt of these phosphoric acids. In this specification, an acid in which a metal is substituted with a hydrogen atom is also referred to as a metal salt.

  The phosphate is not particularly limited, but is composed of hydrogen, aluminum, boron, alkaline earth metal, titanium, zirconium, lanthanum, cerium, yttrium, rare earth metal, vanadium, niobium, chromium, manganese, iron, cobalt, nickel. And at least one metal phosphate selected from the group. Preferably, the main component is aluminum phosphate, cerium phosphate, boron phosphate, titanium phosphate, zirconium phosphate, chromium phosphate, or the like. It is also preferable that the metal of a subsidiary component is included. As specific subcomponents, cerium, lanthanum, yttrium, chromium, iron, cobalt, nickel and the like are preferable, but cerium, iron and yttrium are more preferable. Of these, aluminum phosphate, cerium phosphate, and phosphates composed of these two types are more preferable.

  The method for preparing the catalyst is not particularly limited, and a commercially available phosphate may be used as it is, or a general precipitation method may be used. As a specific preparation method of the precipitation method, for example, diluted ammonia water is added dropwise to a mixed aqueous solution of metal nitrate (in the case of a plurality of raw material salts, each raw material salt solution is prepared) and phosphoric acid to adjust the pH. To adjust to precipitate and leave to mature as necessary. Then, it is washed with water and it is confirmed that it has been sufficiently washed with the conductivity of the washing water. In some cases, alkali metal containing a portion of the slurry is measured. It is then filtered and dried. There is no particular limitation on the drying temperature. Preferably 80 to 150 degreeC is good. More preferably, it is 100 degreeC-130 degreeC. The obtained dried product is pulverized to uniform particle size, or further pulverized and molded. Thereafter, firing is performed in an air or nitrogen atmosphere at 200 ° C. to 1500 ° C. The firing is preferably performed at 400 to 1300 ° C, more preferably 500 to 900 ° C.

  Although depending on the temperature, the firing time is about 1 to 50 hours, preferably about 2 to 24 hours. Since the calcination treatment is a treatment necessary for stabilizing the phosphate, if the treatment is performed at a temperature lower than the above temperature range or the treatment time is short, the catalyst activity may not be sufficiently exhibited at the initial stage of the reaction. . In addition, it is not preferable to perform the calcination treatment at a temperature higher than the above temperature range or for a long time because not only excessive heating energy is required but also crystallization of the catalyst may occur.

The operation of adding a metal component other than the main component is preferably performed with a metal salt, and nitrates, chlorides, oxides, phosphates, and the like of the metal are preferable. Among them, nitrate is preferable because it is easy to prepare. Although there is no restriction | limiting in particular in addition amount, Generally it is 1 gram atom or less with respect to 1 gram atom of phosphorus, Preferably it is 0.5 gram atom or less. More preferably, it is 0.3 gram atom or less. The addition of these metal components may be performed at the time of catalyst preparation, or may be performed on the phosphate after the catalyst is calcined. The obtained catalyst has different physical properties depending on the type of metal salt and the preparation method and conditions. The catalyst may be used as it is, but it can also be used in a state of being supported on a carrier. As support, alumina, titania, zirconia, zirconia sulfate (ZrO (SO ₄ ))
Examples thereof include metal oxides such as metal oxides, silicon carbide, silicon nitride, activated carbon, etc., and activated carbon having a large specific surface area is particularly preferable.

  Activated carbon carrying phosphoric acid or phosphate can be prepared by immersing it in phosphoric acid and impregnating it, or drying and coating or adsorbing it by spraying. In the case of loading a compound, it can be prepared by impregnating a solution of the compound to be loaded, or drying a coating or adsorbed by spraying. In addition, a second compound is allowed to act on activated carbon impregnated with a solution of the compound, or coated or adsorbed by spraying, thereby causing a precipitation reaction or the like on the activated carbon surface to carry a compound different from the first compound. You can also. Further, the phosphate-carrying catalyst can also be prepared by carrying out the above-described phosphate preparation method in the presence of a support such as activated carbon. As an example, activated carbon supporting aluminum phosphate is shown in the examples.

  Activated carbon is made from plant-based, peat, lignite, lignite, bituminous coal, anthracite, etc. that are made from wood, charcoal, coconut husk, palm kernel charcoal, raw ash, etc. Any of petroleum type or synthetic resin type such as carbonized polyvinylidene chloride may be used. These activated carbons can be selected and used. For example, activated carbon produced from bituminous coal (BPL granular activated carbon manufactured by Toyo Calgon), coconut shell charcoal (granular white birch GX, SX, CX, XRC manufactured by Nippon Enviro Chemicals), Toyo Calgon PCB) and the like, but is not limited thereto. 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 as the carrier for the thermal decomposition reaction is preferably activated carbon having a large specific surface area. The specific surface area of the activated carbon is sufficient in a range of commercially available standards, are each 400m ² / g~3000m ² / g, preferably 800m ² / g~2000m ² / g. Furthermore, when using activated carbon as a support, it is usually immersed in a basic aqueous solution such as ammonium hydroxide, sodium hydroxide, potassium hydroxide or the like for about 10 hours or longer at room temperature or when activated carbon is used as a catalyst support. It is desirable to perform pretreatment with acid such as nitric acid, hydrochloric acid, hydrofluoric acid, etc. to activate the carrier surface and remove ash in advance.

  Further, the carrier such as an oxide of the present invention may contain a metal component and an atom other than oxygen, and the other atom is preferably a fluorine atom or a chlorine atom. For example, partially fluorinated alumina, partially chlorinated alumina, partially fluorinated chlorinated alumina, partially fluorinated zirconia, partially fluorinated titania and the like may be used. The ratio of chlorine atoms and fluorine atoms in the oxide catalyst is not particularly limited.

  In the present specification and claims, unless otherwise specified, partially fluorinated or chlorinated oxides such as alumina and zirconia as described above are oxides such as “alumina” and “zirconia”. Display by name.

These supports include at least one metal oxide selected from the group consisting of alumina (Al ₂ O ₃ ), zirconia (ZrO ₂ ), titania (TiO ₂ ), zirconia sulfate, and partially fluorinated oxides thereof. Catalysts are preferred, and alumina and partially fluorinated alumina are more preferred in terms of reactivity and catalyst life.

These partially fluorinated oxides can be used as a support for a difluoroacetic acid fluoride synthesis catalyst, and can also be used as a catalyst. Preparation, pretreatment, use, etc. as a catalyst can be applied as described in the present specification for preparation, pretreatment, use, etc. as a carrier as it is or according to common general technical knowledge. That is, when a metal oxide such as alumina (Al ₂ O ₃ ), zirconia (ZrO ₂ ), titania (TiO ₂ ) or the like is used as a catalyst, it can be handled in the same manner as a supported catalyst on which a metal compound or the like is supported. Good.

  The catalyst is usually used in the form of particles or granules. The diameter of the particles or the granulated body (all may be referred to as “particle diameter”) is not particularly limited, and is usually about 20 μm to 10 mm. When the catalyst contains a chlorine atom or a fluorine atom, the chlorine atom or the fluorine atom may exist only on the surface of the metal oxide.

  Before use, the catalyst is partially fluorinated by contacting with a fluorine-containing compound such as hydrogen fluoride, fluorinated hydrocarbon or fluorinated chlorinated hydrocarbon in advance to change the composition of the catalyst during the reaction, shorten the life, It is effective to prevent abnormal reactions.

  In particular, treatment with hydrogen fluoride can significantly increase the activity of the reaction. The fluorination treatment with hydrogen fluoride is preferably performed by contacting with hydrogen fluoride at least at a temperature higher than the reaction temperature of the reaction according to the present invention. Specifically, in the case of a phosphate simple substance, it is about 200 to 700 ° C, preferably about 250 to 600 ° C, and more preferably 300 to 550 ° C. On the other hand, in the case of a supported catalyst using an oxide or activated carbon as a carrier, the temperature is about 200 to 600 ° C, preferably about 250 to 500 ° C, more preferably 300 to 400 ° C. In any case, if the temperature is lower than 200 ° C., it takes time for the treatment, and it is not preferable to perform the treatment beyond the maximum temperature range because excessive heating energy is required. The treatment time is also related to the treatment temperature and cannot be limited, but it is about 1 hour to 10 days, preferably about 3 hours to 3 days.

  In the case of activated carbon not supporting phosphoric acid, even if it is treated with hydrogen fluoride, it shows little activity. However, when activated carbon treated with phosphoric acid is treated with hydrogen fluoride, the conversion rate is 96. under the same reaction conditions. The catalyst activity was 1% and selectivity: 98.0%. Also from this, the effect of the hydrogen fluoride treatment can be easily seen.

  Furthermore, it is preferable to perform an activation treatment prior to the reaction. As the activation treatment, it is sufficiently dehydrated in a nitrogen stream at about 250 ° C. to 300 ° C., and an organic fluorine compound such as dichlorodifluoromethane or chlorodifluoromethane, or a gas or catalyst treatment such as hydrogen fluoride or chlorine trifluoride. It is preferable to activate with an inorganic fluorine compound showing a sufficient vapor pressure in the state. Of these, hydrogen fluoride is particularly preferred. This activation treatment is considered to generate an active catalyst containing fluorine atoms on the entire surface of the catalyst.

Further, when R ′ of 1-alkoxy-1,1,2,2-tetrafluoroethane (CHF ₂ CF ₂ OR ′), which is a raw material for thermal decomposition, is a group having 2 or more carbon atoms, R′F produced Is decomposed in the reaction region to generate hydrogen fluoride, which may have an effect of increasing the activity of the catalyst.

  The thermal decomposition reaction is recommended as a most preferable form of the gas phase flow continuous system, but is not limited thereto. The type of the reactor is preferably a fixed bed type or a fluidized bed type, and the dimensions and shape of the reactor can be appropriately changed according to the amount of the reactants and the like.

  In pyrolysis, an inert gas may exist in the reaction conditions. Examples of the inert gas include nitrogen or rare gases, and nitrogen or helium is preferable from the viewpoint of ease of handling and availability. The amount in the presence of the inert gas is not particularly limited, but if it is too much, there is a possibility that the recovery rate is lowered. Therefore, in the usual case, the raw material 1-alkoxy-1,1,2,2-tetrafluoro An amount less than the ethane feed rate is preferred.

  The reaction temperature for thermal decomposition varies depending on the type of catalyst and the raw material. Usually, it is 100-400 degreeC, about 150-350 degreeC is preferable and 180-280 degreeC is more preferable. If the reaction temperature is less than 100 ° C., the conversion tends to be low, which is not preferable. When the reaction temperature exceeds 400 ° C., severe heat resistance is required for the reaction apparatus, and excessive heating energy is required, which is not economically preferable.

  The reaction time (contact time) is usually 0.1 to 300 seconds, preferably 0.5 to 200 seconds, and more preferably 1 to 60 seconds. If the reaction time is too short, the conversion rate may be lowered. On the other hand, if the reaction time is too long, productivity is lowered, which is not preferable. The reaction pressure is not particularly limited and may be normal pressure, reduced pressure, or increased pressure. A pressure of about 0.05 to 0.5 MPa (0.5 to 5 atmospheres) is preferable, and usually a pressure in the vicinity of atmospheric pressure that facilitates operation is preferable.

  In the catalyst, coking may occur over time, and the activity of the catalyst may decrease. The catalyst having reduced activity can be easily regenerated by contacting with oxygen at 200 ° C. to 1200 ° C., preferably 400 ° C. to 800 ° C. It is convenient to perform the oxygen treatment while it is loaded in the reaction tube or in an external device. This is done by circulating oxygen there. As a method of circulating oxygen, other gas may coexist, and air diluted with nitrogen or air is economically preferable. Further, a gas having oxidizing power such as chlorine and fluorine can be used.

  In the thermal decomposition reaction, in addition to the desired difluoroacetic acid fluoride, as a by-product, a compound obtained by further decomposing alkyl fluoride (R′F) or alkyl fluoride is generated. For example, when ethyl fluoride is generated as the alkyl fluoride, ethylene and hydrogen fluoride may be formed. A crude product containing a by-product obtained by the reaction can be used as a raw material for difluoroacetic acid fluoride of the present invention without containing purification alkyl fluoride, and is obtained mainly by removing alkyl fluoride. Crude products can also be used, and further purified and highly purified difluoroacetic acid fluorides can be used, or these variously purified gases can be cooled or compressed and stored in containers. . Difluoroacetic acid fluoride can be purified by distillation.

The process of the present invention is carried out in the presence of an acid catalyst such as a Lewis acid. Examples of the Lewis acid include AlCl ₃ , SbCl ₅ , FeCl ₃ , TeCl ₂ , SnCl ₄ , TiCl ₄ , TeCl ₄ , BiCl ₃ , ZnCl ₂ or a part or all of them substituted with bromine or fluorine, BF ₃ Etc. Further, hydrogen fluoride, sulfuric acid, phosphorus pentoxide, and phosphoric acid can also be used. Of these, aluminum chloride and aluminum bromide are particularly preferred.

  In the method of the present invention, since the reaction between the aromatic compound and difluoroacetic acid fluoride is an equimolar reaction, usually 0.01 to 100 mol of difluoroacetic acid fluoride is used with respect to 1 mol of the aromatic compound. .1 to 10 mol is preferable, and 0.3 to 3 mol is more preferable. Even if difluoroacetic acid fluoride is used in excess of 100 moles, an excess amount is not involved because it is not involved in the reaction, and treatment as a waste is required, which is not preferable. Since the excess aromatic compound functions as difluoroacetic acid fluoride or a solvent for the catalyst, excess aromatic compound can be used with respect to difluoroacetic acid fluoride. Since it is low and inferior in productivity, it is preferable to avoid it.

  In the method of the present invention, 1 mol or more of Lewis acid as a catalyst is used for 1 mol of α, α-difluoroacetophenone to be formed. The Lewis acid as the catalyst is usually used in an amount of 1 to 5 mol, preferably 1 to 3 mol, more preferably 1 to 2 mol, based on 1 mol of the minor component of the aromatic compound or difluoroacetic acid fluoride. . If the amount is less than 1 mol, the progress of the reaction is slow and the conversion rate is not sufficiently increased. If the amount exceeds 5 mol, the loss in recovery of the product is large, which is not preferable. Hydrogen fluoride also functions as a solvent, and an arbitrary amount can be added to the Lewis acid.

  In the method of the present invention, a solvent can also be used. In particular, it is necessary when a solid substituted benzene is used as a reaction raw material under reaction temperature conditions, but it can also be used in the case of a liquid aromatic compound. Such a solvent may be any solvent as long as it does not affect the reaction. For example, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and dichloroethane, ethers such as diethyl ether, diisopropyl ether and tetrahydrofuran, carbon disulfide, and the like can be used as the solvent. Among these solvents, aromatic hydrocarbons are more preferable, and dichloromethane or dichloroethane is preferable for suppressing the production of by-products and improving the yield of the target compound.

  The method of the present invention is carried out at −78 to 100 ° C., preferably −20 to 30 ° C. Implementation at -78 ° C is not preferable because a special apparatus is required for cooling, and at 100 ° C, side reactions occur and the yield is lowered. Since it does not depend on the reaction pressure, it can be carried out under any pressure, but it is usually performed at about 0.1 to 1 MPa. The reaction time depends on the reaction temperature, the apparatus scale, and the amount of catalyst, but is usually about 10 minutes to 30 hours, and about 30 minutes to 10 hours is preferable from the viewpoint of throughput and ease of operation.

  The α, α-difluoroacetophenone produced by the method of the present invention can be purified from the reaction mixture by a method generally used as a post-treatment of a reaction using aluminum chloride. Usually, water is added to the reaction mixture to stop the activity of the catalyst and transfer to the aqueous layer, and the target product is obtained as an organic layer. The organic layer can be further washed with a saturated salt aqueous solution or water. This solution is dried with calcium chloride or zeolite. Moreover, when it contains a solvent, it can be distilled, and further a high-purity target product can be obtained by precision distillation.

  Although the method of this reaction may be a flow type or a batch type, it is usually preferable to use a batch type tank reactor. The reactor is preferably stainless steel, Monel (registered trademark), Inconel (registered trademark), Hastelloy (registered trademark), fluororesin, or a container lined with these. Since difluoroacetic acid fluoride has a boiling point of 2 ° C., it is preferably a pressure-resistant container that can be sealed, or preferably provided with a means for preventing distillation such as a reflux tower.

  Next, the case where the method of the present invention is carried out in batch mode will be described. However, it is easy for those skilled in the art to appropriately change the reaction conditions and operation when adopting the flow type.

  A predetermined amount of catalyst and aromatic compound are charged into the reactor while stirring and substituted with an inert gas, and then cooled to a predetermined temperature. Mole of difluoroacetic acid fluoride is introduced and stirring is continued for about 10 minutes to 5 hours, and then a predetermined amount of difluoroacetic acid fluoride required for the reaction is added. Thereafter, the reaction is continued at room temperature (25 ° C.) for 2 to 30 hours. Thereafter, the reaction product is put into a container charged with water to obtain an organic layer. The organic layer is washed with brine or a saturated aqueous solution of acidic sodium carbonate, and further washed with water. The desired α, α-difluoroacetophenone can be obtained by distillation after drying.

EXAMPLES Hereinafter, although an Example demonstrates this invention, this does not limit the embodiment of this invention.

  In Examples, the composition of organic components such as ethyl difluoroacetate, ethanol, and difluoroacetic acid was measured by FID gas chromatography (GC), and the content of inorganic acids such as hydrogen fluoride was measured by ion chromatography (IC). Thus, moisture was measured by the Karl Fischer (KF) method.

[Synthesis Example 1]
Aluminum phosphate manufactured by Aldrich was tableted into 5 mmφ × 5 mmL pellets and calcined in a nitrogen stream at 700 ° C. for 5 hours to prepare an aluminum phosphate catalyst. 200 cc of this was filled into a stainless steel reaction tube with a vaporizer (inner diameter: 37.1 mmφ × 500 mmL). While flowing nitrogen at 15 cc / min, the reaction tube was heated in an electric furnace provided outside. When the catalyst temperature reached 50 ° C., hydrogen fluoride (HF) was introduced through the vaporizer at a rate of 0.6 g / min. Slowly raise the temperature to 300 ° C with HF flowing, hold at 300 ° C for 5 hours, lower the heater set temperature to 200 ° C, stop the flow of HF when the temperature reaches 200 ° C, Was increased to 200 cc / min and held for 2 hours, after which 1-methoxy-1,1,2,2-tetrafluoroethane (HFE-254pc) was introduced through the vaporizer at a rate of 0.13 g / min. After 30 minutes, the nitrogen was stopped, and only HFE-254pc was circulated, gas sampling was performed in a steady state, and analysis was performed with a gas chromatograph. As a result, CHF2COF and CH3F were quantitatively generated at a conversion rate of 99.8%. After collecting this crude gas with a dry ice strap, CHF2COF was isolated by distillation.

[Example 1]
An anhydrous aluminum chloride (AlCl ₃ , 20.5 g, 0.153 mol) was added to a 500-cc three-necked PFA flask equipped with a condenser cooled with ethanol / dry ice and sealed with nitrogen at the outlet side, an inlet tube, and a thermometer. And benzene (55.7 g, 0.715 mol) were charged and ice-cooled from the outside while stirring with a stirrer. First, CHF ₂ COF corresponding to one-tenth of a predetermined amount was introduced to activate the catalyst. That is, the purified CHF ₂ COF gas (0.98 g, 0.01 mol) obtained in Synthesis Example 1 was introduced at a rate of 0.1 g / min through the blowing tube after nitrogen substitution, and stirring was continued for 1 hour. Thereafter, the remaining CHF ₂ COF (9.03 g, 0.092 mol) was fed at a rate of 0.1 g / min. After completion of the supply, the ice bath was removed, the temperature was slowly returned to room temperature (about 25 ° C.) and the reaction was continued for 2 hours. The reaction solution was sampled and analyzed by a gas chromatograph (FID detector). As a result, the crude yield was 96 area% (CHF ₂ COF standard). Therefore, ice (50 g) and water (99 g) were added to the reactor to recover 59.3 g of the organic layer. Diisopropyl ether (86.6 g) was added to this aqueous layer (168.3 g) to extract organic matter. The extract (85.7 g) and the organic layer (59.3 g) were combined and washed with saturated acidic sodium carbonate (NaHCO ₃ ) water. This organic layer (144.2 g) was washed with water (106.0 g) to obtain 156.1 g of a crude product, dried over MgSO ₄ , distilled under reduced pressure, and 2,2-difluoro-1 as the target compound. -Phenylethanone (2,2-difluoro-1-phenylethane) was obtained in an isolated yield of 71%.

[Example 2]
Experiments were conducted in the same manner as in Example 1 using chlorobenzene (80.5 g, 0.715 mol) and AlCl ₃ (20.5 g, 0.153 mol) instead of benzene. As a result, the crude yield immediately after the reaction (CHF ₂ COF standard) was 37 area%, and the target compound 1- (4-chlorophenyl) -2,2-difluoroethanone (1- (4-chlorophenyl) -2, 2-difluoroethanone) was obtained in an isolated yield of 19%.

[Example 3]
The same experiment as in Example 1 was performed using toluene (65.9 g, 0.715 mol) instead of benzene. As a result, the crude yield immediately after the reaction (CHF ₂ COF standard) was 96 GC%, and the target compound 2,2-difluoro-1-p-tolylethanone (2,2-difluoro-1-p-tolythanone) was isolated. Obtained in 67% yield.

[Example 4]
The experiment was conducted in the same manner as in Example 1 using orthoxylene (75.9 g, 0.715 mol) instead of benzene. As a result, the crude yield immediately after the reaction (CHF ₂ COF standard) was 89 area%, and the target compound 1- (3,4-dimethylphenyl) -2,2-difluoroethanone (1- (3,4- dimethylphenyl) -2,2-difluoroethane)) was obtained in an isolated yield of 61%.

[Example 5]
The experiment was performed in the same manner as in Example 1 except that the crude product containing methyl fluoride was used as it was without purifying the pyrolyzate of HFE-254pc produced in Synthesis Example 1 by distillation. Instead of 10.0 g of purified CHF ₂ COF, 13.2 g of HFE-254pc pyrolyzed crude gas was blown through the air-cooled spiral tube without isolation of CHF ₂ COF. As a result, the crude yield after completion of the reaction (CHF ₂ COF standard) was 95 area%, and 2,2-difluoro-1-phenylethanone was obtained in an isolated yield of 66%.

  Α, α-Difluoroacetophenone useful as a pharmaceutical and agrochemical intermediate can be supplied on an industrial scale.

Claims (5)

General formula (1)

(In the formula, each R independently represents a hydrogen atom, a halogen atom, an alkyl group or a fluorine-containing alkyl group, and n represents an integer of 0 to 2). General formula (2) for reacting with fluoride

The manufacturing method of (alpha), (alpha)-difluoro acetophenone represented by these. The method for producing α, α-difluoroacetophenone according to claim 1, wherein the catalyst is a Lewis acid. The method for producing α, α-difluoroacetophenone according to claim 2, wherein the Lewis acid is aluminum chloride or aluminum bromide. The method for producing α, α-difluoroacetophenone according to claim 1, wherein the catalyst is hydrogen fluoride. Difluoroacetic acid fluoride is obtained by thermally decomposing 1-alkoxy-1,1,2,2-tetrafluoroethane represented by CHF ₂ CF ₂ OR ′ (R ′ represents a monovalent organic group). The method for producing α, α-difluoroacetophenone according to any one of claims 1 to 4, which is a thermal decomposition product obtained.