Method for producing 2-chloro-3-trifluoromethylpyridine

Abstract

The present invention relates to a method for producing 2-chloro-3-trifluoromethylpyridine in which hydrogen chloride and a liquid mixture that contains 2-chloro-3-trifluoromethylpyridine are reacted with each other and thereby separating out crystals that contain 2-chloro-3-trifluoromethylpyridine hydrochloride produced.

Description

Method for producing 2-chloro-3-trifluoromethylpyridine

[0001] The present invention relates to a method for producing 2-chloro-3-trifluoromethylpyridine, which is useful as an intermediate for pharmaceuticals, agricultural chemicals, etc.

[0002] Patent Documents 1 and 2 disclose methods for producing chloro-β-trifluoromethylpyridine compounds, characterized by reacting a β-methylpyridine compound with chlorine and anhydrous hydrogen fluoride in the vapor phase in the presence of a specific catalyst and an inert diluent. The examples show that the chloro-β-trifluoromethylpyridine compound obtained primarily consists of 2-chloro-5-trifluoromethylpyridine (hereinafter also referred to as 2,5-CTF), with 2-chloro-3-trifluoromethylpyridine (hereinafter also referred to as 2,3-CTF), 2,6-dichloro-3-trifluoromethylpyridine (hereinafter also referred to as 2,3,6-DCTF), and the like.

[0003] Patent Document 3 discloses a method for producing a chloro-3-trifluoromethylpyridine compound by chlorinating 3-trifluoromethylpyridine in the presence of an inert diluent. The examples show that 2,5-CTF is the main chloro-3-trifluoromethylpyridine compound obtained, with 2,3-CTF, 2,3,6-DCTF, and the like also being obtained.

[0004] Patent Documents 4 and 5 disclose methods for producing chloro-β-trifluoromethylpyridine compounds, which are characterized by reacting a β-trichloromethylpyridine compound with anhydrous hydrogen fluoride in the vapor phase in the presence of a specific catalyst. The examples show that 2,5-CTF is the main chloro-β-trifluoromethylpyridine compound obtained.

[0005] Patent Document 6 describes a method in which β-methylpyridine compounds, β-trifluoromethylpyridine compounds, chloro-β-trichloromethylpyridine compounds, or the like are used as raw materials to obtain 2,5-CTF as a main product, while purifying 2,3-CTF from a distillate separated during the distillation process.

[0006] Japanese Patent Application Publication No. 55-147261 Japanese Patent Application Publication No. 56-120667 Japanese Patent Application Publication No. 55-122762 Japanese Patent Application Publication No. 55-124762 Japanese Patent Application Publication No. 56-100764 Japanese Patent Application Publication No. 2020-023489

[0007] 2,3-CTF is a compound useful as an intermediate for agricultural chemicals and pharmaceuticals, and in some cases a method for producing it with high purity is required. However, Patent Documents 1 to 5 do not describe a specific method for purifying 2,3-CTF.

[0008] Patent Document 6 describes a method for obtaining crystals containing 2,3-CTF by melt crystallization. However, it describes that the melt crystallization can usually be carried out in the range of 5 to 25°C, and the temperature range in which the melt crystallization can be carried out is limited. Furthermore, if crystallization is carried out in an industrial production environment, a large amount of energy is required for temperature control. Therefore, when producing 2,3-CTF industrially, melt crystallization, which requires uniform temperature control, poses problems in terms of operation and efficiency.

[0009] Thus, in the industrial production of 2,3-CTF, an efficient production method that does not require strict temperature control is desired. That is, an object of the present invention is to provide a method for producing 2-chloro-3-trifluoromethylpyridine efficiently in the industrial production without requiring strict temperature control.

[0010] As a result of investigations aimed at solving the above problems, the present inventors discovered a method for producing 2,3-CTF by reacting a liquid mixture containing 2,3-CTF with hydrogen chloride to selectively or preferentially convert 2,3-CTF into a hydrochloride salt and crystallize it, and completed the present invention. The present invention also relates to a method for separating, purifying, and producing 2,3-CTF from a liquid mixture containing 2,3-CTF by selectively or preferentially converting 2,3-CTF into a hydrochloride salt and crystallizing it.

[0011] One aspect of the present embodiment provides a method for producing 2-chloro-3-trifluoromethylpyridine, which comprises reacting a liquid mixture containing 2-chloro-3-trifluoromethylpyridine with hydrogen chloride and separating the resulting crystals containing 2-chloro-3-trifluoromethylpyridine hydrochloride.

[0012] One aspect of the present embodiment provides a method for producing 2-chloro-3-trifluoromethylpyridine, comprising: 1) reacting a β-methylpyridine compound with chlorine and hydrogen fluoride in a reaction apparatus, reacting a β-trifluoromethylpyridine compound with chlorine in a reaction apparatus, or reacting a chloro-β-trichloromethylpyridine compound with hydrogen fluoride in a reaction apparatus; 2) separating and collecting a chloro-β-trifluoromethylpyridine compound containing 2-chloro-3-trifluoromethylpyridine produced in the reaction apparatus; 3) reacting the chloro-β-trifluoromethylpyridine compound with hydrogen chloride; and 4) separating and collecting the produced crystals containing 2-chloro-3-trifluoromethylpyridine hydrochloride.

[0013] Hereinafter, in this specification, both of the above aspects are also referred to as the manufacturing method according to this embodiment.

[0014] According to the production method of this embodiment, 2-chloro-3-trifluoromethylpyridine, which is useful as an intermediate for pharmaceuticals, agricultural chemicals, etc., can be efficiently produced industrially without requiring strict temperature control.

[0015] More specifically, in one aspect of this embodiment, by reacting a liquid mixture containing 2,3-CTF with hydrogen chloride, the 2,3-CTF in the liquid mixture is selectively or preferentially converted into a hydrochloride salt and crystallized, thereby enabling a high yield. Furthermore, the obtained crystals can be post-treated appropriately to obtain highly pure 2,3-CTF. Furthermore, in one aspect of this embodiment, the liquid mixture containing 2,3-CTF can be obtained using a β-methylpyridine compound, a β-trifluoromethylpyridine compound, or a chloro-β-trichloromethylpyridine compound as a raw material.

[0016] The manufacturing method according to this embodiment will be described in detail below. Note that the use of "to" to indicate a range of values ​​means that the values ​​before and after it are included as the lower and upper limits.

[0017] One aspect of the production method according to this embodiment includes the following steps 1 to 4 in order: step 1: reacting a β-methylpyridine compound with chlorine and hydrogen fluoride in a reaction apparatus, reacting a β-trifluoromethylpyridine compound with chlorine in a reaction apparatus, or reacting a chloro-β-trichloromethylpyridine compound with hydrogen fluoride in a reaction apparatus, step 2: separating and collecting a chloro-β-trifluoromethylpyridine compound containing 2-chloro-3-trifluoromethylpyridine produced in the reaction apparatus, step 3: reacting the chloro-β-trifluoromethylpyridine compound with hydrogen chloride, and step 4: separating and collecting the produced crystals containing the hydrochloride salt of 2-chloro-3-trifluoromethylpyridine.

[0018] In the above step 1, the reaction in which a β-methylpyridine compound is reacted with chlorine and hydrogen fluoride in a reactor is referred to as reaction 1, the reaction in which a β-trifluoromethylpyridine compound is reacted with chlorine in a reactor is referred to as reaction 2, and the reaction in which a chloro-β-trichloromethylpyridine compound is reacted with hydrogen fluoride in a reactor is referred to as reaction 3. Chloro-β-trifluoromethylpyridine compounds including 2-chloro-3-trifluoromethylpyridine are produced by the methods shown in the above reactions 1 to 3.

[0019] (Reaction 1) Reaction 1 is a reaction between a β-methylpyridine compound and chlorine and hydrogen fluoride in a reactor. The β-methylpyridine compound is preferably a compound represented by the following formula (I):

[0020]

[0021] (In formula (I), X １ and Y １ are each a hydrogen atom or a chlorine atom.

[0022] The reaction (1) in this embodiment, i.e., the reaction of a β-methylpyridine compound with chlorine and hydrogen fluoride, is preferably a reaction of a β-methylpyridine compound represented by formula (I) with chlorine and hydrogen fluoride, more preferably a reaction of a β-methylpyridine compound represented by formula (I) with chlorine and anhydrous hydrogen fluoride, still more preferably a reaction of a β-methylpyridine compound represented by formula (I) with chlorine and anhydrous hydrogen fluoride in the presence of a catalyst and an inert diluent, and particularly preferably a gas-phase reaction of a β-methylpyridine compound represented by formula (I) with chlorine and anhydrous hydrogen fluoride in the presence of a catalyst and an inert diluent.

[0023] That is, in Reaction 1, as shown in the following reaction formula, it is preferable to react a β-methylpyridine compound represented by formula (I) with chlorine and anhydrous hydrogen fluoride in the gas phase in a reactor in the presence of a catalyst and an inert diluent. This produces a chloro-β-trifluoromethylpyridine compound represented by formula (II). In the subsequent Step 2, a liquid mixture containing the chloro-β-trifluoromethylpyridine compound represented by formula (II) is separated from the reactor by distillation. The liquid mixture generally contains 2-chloro-5-trifluoromethylpyridine (2,5-CTF), 2-chloro-3-trifluoromethylpyridine (2,3-CTF), 2,6-dichloro-3-trifluoromethylpyridine (2,3,6-DCTF), and the like.

[0024]

[0025] In formula (I) and formula (II), X １ , X ２ , Y １ and Y ２ are each a hydrogen atom or a chlorine atom, provided that X ２ and Y ２ At least one of the groups is a chlorine atom.

[0026] That is, the above-mentioned reaction 1 is preferably a reaction for producing a chloro-β-trifluoromethylpyridine compound represented by formula (II) by reacting a β-methylpyridine compound represented by formula (I) with chlorine and anhydrous hydrogen fluoride in a gas phase in the presence of a catalyst and an inert diluent.

[0027] Examples of the β-methylpyridine compound represented by formula (I) used in the above reaction 1 include β-picoline as well as chloro-β-picolines such as 2-chloro-β-picoline, 6-chloro-β-picoline, and 2,6-dichloro-β-picoline. In particular, β-picoline is easily available as a raw material in various organic synthetic chemical industries, and the production method according to this embodiment is advantageous in that a chloro-β-trifluoromethylpyridine compound can be directly produced from β-picoline.

[0028] The catalyst used in the above reaction 1 includes metal fluorides. Specific examples of metal fluorides include fluorides of aluminum, chromium, iron, nickel, cobalt, and manganese. More specifically, hydrated aluminum trifluoride (AlF ３ ・3H ２ O), aluminum trifluoride (AlF ３ ), chromium difluoride (CrF ２ ), hydrated chromium trifluoride (CrF ３ ・3H ２ O), chromium trifluoride (CrF ３ ), chromium tetrafluoride (CrF ４ ), hydrated ferrous fluoride (FeF ２ ・8H ２ O), ferrous fluoride (FeF ２ ), ferric fluoride (FeF ３ ), nickelous fluoride (NiF ２ ), hydrated nickelous fluoride (NiF ２ ・3H ２ O), nickel fluoride (NiF ３ ), cobaltous fluoride (CoF ２ ), cobalt(II) fluoride (CoF ３ ), manganese fluoride (MnF ２ ), manganese difluoride (MnF ３ ), manganese tetrafluoride (MnF ４ ) etc.

[0029] The amount of the catalyst used depends on the reaction conditions and cannot be generally defined, but is preferably 0.001 to 3 mol, more preferably 0.01 to 3 mol, per mol of the raw material β-methylpyridine compound. Here, the amount of the catalyst used is preferably 0.001 mol or more, more preferably 0.01 mol or more, and preferably 3 mol or less, per mol of the raw material β-methylpyridine compound.

[0030] Typically, this catalyst is mixed with a carrier such as activated carbon, activated alumina, or aluminum trifluoride, molded into granules or pellets of appropriate size, and then placed in a fixed or fluidized bed. While the catalyst can be placed directly in the form of a fluoride of the above metal in the reaction tube, it is industrially advantageous to place the catalyst in the form of an oxide, chloride, or carbonate of the above metal, or in the form of a hydrate of the above fluoride, and react it with anhydrous hydrogen fluoride to convert it to the fluoride. For example, a molded product of an alumina carrier carrying an oxide or chloride of the above metal, such as chromium trioxide, ferric chloride, or nickel oxide, can be placed in the reaction tube, and anhydrous hydrogen fluoride can be introduced into the reaction tube in advance to react at 200 to 600°C to convert it to the fluoride of the above metal, before the reaction can be carried out.

[0031] Inert diluents include carbon tetrachloride, chloroform, methylene chloride, F-112 (CFCl ２ CFCl ２ ), F-113 (CF ２ Cl・CFCl ２ The diluents used may be halogenated hydrocarbon organic solvents such as toluene, ...

[0032] In carrying out the above-mentioned Reaction 1, the raw materials and the inert diluent can be fed to the reactor separately or in a mixed state, and they can be fed simultaneously or sequentially, or all at once or in portions. For example, a mixture of a β-methylpyridine compound and an inert diluent, or a mixture of chlorine and anhydrous hydrogen fluoride, can be fed separately.

[0033] The amounts of chlorine and anhydrous hydrogen fluoride used cannot be generally defined because they differ depending on the type of the raw material β-methylpyridine compound, the type of the target product, the reaction apparatus, etc., but generally, the amount of chlorine is 2 to 15 moles and the amount of anhydrous hydrogen fluoride is 2 to 60 moles per mole of the raw material β-methylpyridine compound, and the amount of the inert diluent used is preferably 2 to 70 moles per mole of the raw material β-methylpyridine compound.

[0034] The reaction temperature for Reaction 1 is preferably 300 to 600°C. The residence time of the reaction mixture in the reaction zone is preferably 0.5 to 60 seconds, more preferably 3 to 60 seconds. Here, the residence time is preferably 0.5 seconds or more, more preferably 3 seconds or more, and preferably 60 seconds or less. It is more preferable that the reaction temperature for Reaction 1 is 300 to 600°C, and the residence time of the reaction mixture in the reaction zone is 0.5 to 60 seconds.

[0035] Usually, as a result of Reaction 1, gaseous substances containing a fluorinated product mainly composed of a chloro-β-trifluoromethylpyridine compound, unreacted hydrogen fluoride and chlorine, intermediate products, by-product hydrogen chloride, and an inert diluent are discharged from the reactor, but after passing through an appropriate cooling and condensing device, the chloro-β-trifluoromethylpyridine compound is collected as a liquid mixture.

[0036] The liquid mixture generally contains 2,5-CTF, 2,3-CTF, and 2,3,6-DCTF, and the chloro-β-trifluoromethylpyridine compound is obtained at a production rate of, for example, 85% or more. If the collected liquid mixture contains intermediate products that have not yet reached the stage of producing the chloro-β-trifluoromethylpyridine compound, these intermediate products can be separated and recovered together with the unreacted raw materials or the inert diluent, and recycled to the reaction zone.

[0037] The above reaction 1 can be carried out according to the description in Japanese Patent Application Laid-Open No. 55-147261 (Patent Document 1) and Japanese Patent Application Laid-Open No. 56-120667 (Patent Document 2).

[0038] (Reaction 2) Reaction 2 is a reaction between a β-trifluoromethylpyridine compound and chlorine in a reactor. The β-trifluoromethylpyridine compound is preferably a compound represented by the following formula (III):

[0039]

[0040] The reaction (2) in this embodiment, i.e., the reaction of a β-trifluoromethylpyridine compound with chlorine, is preferably a reaction of a β-trifluoromethylpyridine compound represented by formula (II) with chlorine, and more preferably a reaction of a β-trifluoromethylpyridine compound represented by formula (II) with chlorine in a gas phase or a liquid phase.

[0041] In Reaction 2, as shown in the following reaction formula, it is preferable to react a β-trifluoromethylpyridine compound represented by formula (III) with chlorine in a reaction apparatus in the gas phase or liquid phase. This produces a chloro-β-trifluoromethylpyridine compound represented by formula (II) below, and in the subsequent Step 2, a liquid mixture containing the chloro-β-trifluoromethylpyridine compound represented by formula (II) is separated from the reaction apparatus by distillation. The liquid mixture generally contains 2,5-CTF, 2,3-CTF, 2,3,6-DCTF, etc.

[0042]

[0043] In formula (II), X ２ and Y ２ are each a hydrogen atom or a chlorine atom, provided that X ２ and Y ２ At least one of the groups is a chlorine atom.

[0044] One preferred embodiment of the above-mentioned Reaction 2 is a reaction in which a β-trifluoromethylpyridine compound represented by formula (III) is chlorinated in a gas phase in the presence of an inert diluent to produce a chloro-β-trifluoromethylpyridine compound represented by formula (II).

[0045] Generally, the β-trifluoromethylpyridine compound and chlorine are introduced separately into a reactor using an inert diluent as a carrier and subjected to the reaction. The inert diluent has the function of suppressing combustion, carbonization, the production of tar-like by-products, etc., as in the case of a normal gas-phase chlorination reaction. Specific examples of the inert diluent include inert gases such as nitrogen and helium, and halogenated hydrocarbons such as carbon tetrachloride, trichloroethylene, tetrachloroethylene, and tetrachlorodifluoroethane. However, from an industrial perspective, it is desirable to use nitrogen, carbon tetrachloride, or a mixture thereof.

[0046] The amount of the inert diluent used varies depending on other reaction conditions and cannot be generally defined, but is preferably 3 to 70 moles, more preferably 10 to 20 moles, of the inert diluent per mole of the β-trifluoromethylpyridine compound. The amount of the inert diluent used per mole of the β-trifluoromethylpyridine compound is preferably 3 moles or more, more preferably 10 moles or more, and is preferably 70 moles or less, more preferably 20 moles or less.

[0047] The amount of chlorine used varies depending on other reaction conditions and cannot be generally defined, but is preferably 0.5 to 5 mol, more preferably 0.8 to 3 mol, per mol of the β-trifluoromethylpyridine compound. The amount of chlorine used per mol of the β-trifluoromethylpyridine compound is preferably 0.5 mol or more, more preferably 0.8 mol or more, and is preferably 5 mol or less, more preferably 3 mol or less.

[0048] The amounts of the inert diluent and chlorine used vary depending on other reaction conditions and cannot be generally defined. However, it is more preferable that the amount of the inert diluent is 3 to 70 moles and the amount of chlorine is 0.5 to 5 moles per mole of the β-trifluoromethylpyridine compound.

[0049] In this embodiment of Reaction 2, the reaction temperature is preferably 270 to 500°C, more preferably 350 to 450°C. The reaction temperature is preferably 270°C or higher, more preferably 350°C or higher, and is preferably 500°C or lower, more preferably 450°C or lower. The residence time of the reaction mixture in the reaction zone is preferably 0.5 to 60 seconds, more preferably 1 to 20 seconds. The residence time is preferably 0.5 seconds or higher, more preferably 1 second or higher, and is preferably 60 seconds or lower, more preferably 20 seconds or lower. In this embodiment of Reaction 2, the reaction temperature is preferably 270 to 500°C, and the residence time of the reaction mixture in the reaction zone is more preferably 0.5 to 60 seconds.

[0050] The above reaction 2 can be carried out, if desired, in the presence of packings such as porous materials such as silica, alumina, silicon carbide, porcelain, glass beads, or mixtures thereof. In industrial practice, these packings can be present in the reactor as a fixed bed or fluidized bed to improve the reaction efficiency.

[0051] The β-trifluoromethylpyridine compound, chlorine, and inert diluent are usually preheated before being fed into the reactor, but the β-trifluoromethylpyridine compound can be vaporized by introducing it into a high-temperature gaseous inert diluent or by heating a solution of the compound dissolved in a liquid inert diluent. In the reactor, predetermined reaction conditions are maintained, and the desired reaction takes place to produce a chloro-β-trifluoromethylpyridine compound.

[0052] Typically, gaseous substances containing chloro-β-trifluoromethylpyridine compounds, inert diluents, unreacted chlorine, etc. are discharged from the reactor, but after passing through appropriate cooling and condensation equipment, the chloro-β-trifluoromethylpyridine compounds are collected as a liquid mixture. The liquid mixture generally contains 2,5-CTF, 2,3-CTF, and 2,3,6-DCTF. If the collected liquid mixture contains intermediate products that have not yet reached the stage of producing the chloro-β-trifluoromethylpyridine compounds, these intermediate products can be separated and recovered together with the unreacted raw materials or inert diluents and recycled to the reaction zone.

[0053] Another preferred embodiment of the above-mentioned Reaction 2 is a reaction in which a β-trifluoromethylpyridine compound represented by formula (III) is dissolved in an inert diluent and chlorinated in a liquid phase to produce a chloro-β-trifluoromethylpyridine compound represented by formula (II). In this case, the reaction can be promoted by the presence of a radical generator or by irradiation with ultraviolet or visible light.

[0054] Generally, chlorine gas, sulfuryl chloride, etc. are used as the chlorinating agent. Furthermore, organic solvents of halogenated hydrocarbons such as carbon tetrachloride, trichloroethylene, tetrachloroethylene, and tetrachlorodifluoroethane are used as the inert diluent. Examples of radical generators include azobisnitrile compounds such as 2,2'-azobisisobutyronitrile and azobismethylbutyronitrile, as well as benzoyl peroxide compounds such as benzoyl peroxide, O,O'-dichlorobenzoyl peroxide, and P,P'-dimethylbenzoyl peroxide.

[0055] The amounts of the inert diluent and chlorine used vary depending on other reaction conditions and cannot be generally defined, but the amounts used per mole of the β-trifluoromethylpyridine compound are preferably 5 to 30 moles of the inert diluent and 0.5 to 7 moles of chlorine, and more preferably 5 to 30 moles of the inert diluent and 0.5 to 7 moles of chlorine. The radical generator is preferably used in an amount of 0.01 to 5 mass % per mole of the β-trifluoromethylpyridine compound.

[0056] In this embodiment of Reaction 2, the reaction temperature is preferably 35 to 150° C. and the reaction time is preferably 6 to 24 hours, and more preferably the reaction temperature is 35 to 150° C. and the reaction time is 6 to 24 hours.

[0057] Typically, a liquid mixture containing a chloro-β-trifluoromethylpyridine compound is collected from the reactor as a result of Reaction 2. The liquid mixture generally contains 2,5-CTF, 2,3-CTF, and 2,3,6-DCTF. If the collected liquid mixture contains intermediate products that have not yet reached the stage of producing a chloro-β-trifluoromethylpyridine compound, these intermediate products can be separated and recovered together with the unreacted raw materials or the inert diluent, and recycled to the reaction zone.

[0058] The above reaction 2 can be carried out according to the description in Japanese Patent Application Laid-Open No. 55-122762 (Patent Document 3).

[0059] (Reaction 3) Reaction 3 is a reaction between a chloro-β-trichloromethylpyridine compound and hydrogen fluoride in a reactor. The chloro-β-trichloromethylpyridine compound is preferably a compound represented by the following formula (IV):

[0060]

[0061] In formula (IV), X ２ and Y ２ are each a hydrogen atom or a chlorine atom, provided that X ２ and Y ２ At least one of the groups is a chlorine atom.

[0062] The reaction (3) in this embodiment, i.e., the reaction of a chloro-β-trichloromethylpyridine compound with hydrogen fluoride, is preferably a reaction of a chloro-β-trichloromethylpyridine compound represented by formula (IV) with hydrogen fluoride, more preferably a reaction of a chloro-β-trichloromethylpyridine compound represented by formula (IV) with anhydrous hydrogen fluoride, still more preferably a reaction of a chloro-β-trichloromethylpyridine compound represented by formula (IV) with anhydrous hydrogen fluoride in the presence of a catalyst and an inert diluent, and particularly preferably a gas-phase reaction of a chloro-β-trichloromethylpyridine compound represented by formula (IV) with anhydrous hydrogen fluoride in the presence of a catalyst and an inert diluent.

[0063] That is, in Reaction 3, as shown in the following reaction formula, it is preferable to react a chloro-β-trichloromethylpyridine compound represented by formula (IV) with anhydrous hydrogen fluoride in the gas phase in a reactor in the presence of a catalyst and an inert diluent. This produces a chloro-β-trifluoromethylpyridine compound represented by formula (II) below, and in the subsequent Step 2, a liquid mixture containing the chloro-β-trifluoromethylpyridine compound represented by formula (II) is separated from the reactor by distillation. The liquid mixture generally contains 2,5-CTF, 2,3-CTF, 2,3,6-DCTF, etc.

[0064]

[0065] In formulas (IV) and (II), X ２ and Y ２ are each a hydrogen atom or a chlorine atom, provided that X ２ and Y ２ At least one of X in formula (IV) is a chlorine atom. ２ and Y ２ are X in formula (II), respectively. ２ and Y ２ corresponds to:

[0066] The above-mentioned reaction 3 is a reaction for producing a chloro-β-trifluoromethylpyridine compound represented by formula (II) by reacting a chloro-β-trichloromethylpyridine compound represented by formula (IV) with anhydrous hydrogen fluoride in a gas phase in the presence of a catalyst and an inert diluent.

[0067] The catalyst used in the above reaction 3 includes metal fluorides and ammonium fluorides. Specific examples of metal fluorides include those similar to those used in the above reaction 1. Specific examples of ammonium fluorides include ammonium fluoride and acidic ammonium fluoride. Of the catalyst components, chromium, iron, or nickel fluorides are industrially desirable.

[0068] Typically, these catalyst components are mixed with a carrier such as activated carbon or activated alumina, molded into granules or pellets of appropriate size, and then fed to the reaction zone. While the catalyst components may be fed to the reaction tube in the form of the metal fluorides, allowing them to be present directly in the reaction zone, they may also be fed to the reaction tube in the form of metal oxides, chlorides, hydroxides, carbonates, or hydrates thereof, and then reacted with anhydrous hydrogen fluoride gas at high temperatures to convert these substances to the desired fluorine compounds. For example, a molded product of an alumina carrier carrying the metal oxides or chlorides, such as ferric chloride, chromium trioxide, or nickel oxide, may be placed in the reaction tube, and anhydrous hydrogen fluoride may be introduced into the reaction tube to react at 200 to 600°C to convert the metals to fluorides, before the reaction can begin.

[0069] In carrying out the above-mentioned Reaction 3, the raw materials, the chloro-β-trichloromethylpyridine compound and anhydrous hydrogen fluoride, may be supplied to the reaction tube separately or in a mixed state, or may be supplied after being mixed with an inert diluent. The raw materials may be supplied as vaporized materials, or the chloro-β-trichloromethylpyridine compound may be dissolved in an inert solvent and then vaporized and supplied. When supplying the raw materials, it is generally desirable to preheat them to the boiling point or near the reaction temperature of the chloro-β-trichloromethylpyridine compound.

[0070] Examples of inert diluents include carbon tetrachloride, chloroform, methylene chloride, F-112 (CFCl ２ CFCl ２ ), F-113 (CF ２ Cl・CFCl ２ Inert solvents such as halogenated hydrocarbons, such as chloro-β-trichloromethylpyridine, and inert gases such as nitrogen, argon, and helium are used. When an inert diluent is used, the amount used cannot be generally specified, but is preferably 1 to 20 moles, and more preferably 3 to 10 moles, per mole of the chloro-β-trichloromethylpyridine compound. Here, the amount of the inert diluent used per mole of the chloro-β-trichloromethylpyridine compound is preferably 1 mole or more, and more preferably 3 moles or more, and is preferably 20 moles or less, and more preferably 10 moles or less.

[0071] The amount of anhydrous hydrogen fluoride used relative to the chloro-β-trichloromethylpyridine compound cannot be generally defined, but is preferably 3 to 10 moles, more preferably 4 to 9 moles, per mole of the chloro-β-trichloromethylpyridine compound. Here, the amount of anhydrous hydrogen fluoride used per mole of the chloro-β-trichloromethylpyridine compound is preferably 3 moles or more, more preferably 4 moles or more, and is preferably 10 moles or less, more preferably 9 moles or less.

[0072] The amount of catalyst used cannot be generally defined, but the same amount as in Reaction 1 above is suitable.

[0073] Usually, in the reaction zone of the above reaction 3, the raw materials, chloro-β-trichloromethylpyridine compound and anhydrous hydrogen fluoride or an inert diluent, are fed at a constant flow rate, so that the catalyst solid forms a fluidized bed or a fixed bed.

[0074] In Reaction 3, the reaction temperature between the chloro β-trichloromethylpyridine compound and anhydrous hydrogen fluoride is preferably 200 to 700°C, more preferably 300 to 500°C. The reaction temperature is preferably 200°C or higher, more preferably 300°C or higher, and is preferably 700°C or lower, more preferably 500°C or lower. The residence time of the reaction mixture in the reaction zone is preferably 1 to 20 seconds, more preferably 2 to 10 seconds. The residence time is preferably 1 second or higher, more preferably 2 seconds or higher, and is preferably 20 seconds or lower, more preferably 10 seconds or lower. In Reaction 3, the reaction temperature is preferably 200 to 700°C, and the residence time of the reaction mixture in the reaction zone is more preferably 1 to 20 seconds.

[0075] The fluorination reaction described above is completed by Reaction 3, and a gaseous reaction product is discharged from the reactor. This gaseous reaction product contains a fluorination product composed mainly of a chloro-β-trifluoromethylpyridine compound, unreacted hydrogen fluoride, by-product hydrogen chloride, and an inert diluent. This reaction product is cooled and condensed in an appropriate manner, whereby the fluorination product is liquefied to obtain a liquid mixture composed mainly of a chloro-β-trifluoromethylpyridine compound.

[0076] The liquid mixture generally contains 2,5-CTF, 2,3-CTF, and 2,3,6-DCTF, and the chloro-β-trifluoromethylpyridine compound is obtained in a yield of, for example, 80% or more relative to the chloro-β-trichloromethylpyridine compound. If the collected liquid mixture contains intermediate products that have not yet reached the stage of producing the chloro-β-trifluoromethylpyridine compound, these intermediate products can be separated and recovered together with the unreacted raw materials or the inert diluent, and recycled to the reaction zone.

[0077] The above reaction 3 can be carried out according to the description in Japanese Patent Application Laid-Open No. 55-124762 (Patent Document 4) and Japanese Patent Application Laid-Open No. 56-100764 (Patent Document 5).

[0078] Step 2 in this embodiment is a step of separating and collecting chloro-β-trifluoromethylpyridine compounds, including 2-chloro-3-trifluoromethylpyridine, produced in the reaction apparatus. The liquid mixture separated and collected in step 1 contains approximately 30 to 65% 2,5-CTF, approximately 5 to 20% 2,3-CTF, and approximately 10 to 30% 2,3,6-DCTF. The percentages here refer to peak area ratios determined by gas chromatography analysis.

[0079] In step 2 of this embodiment, a fraction containing mainly 2,5-CTF is separated from the liquid mixture by distillation. In industrial practice, this operation is carried out by carrying out the various reactions described in step 1 above to produce chloro-β-trifluoromethylpyridine, and separating a certain fraction during the process of separating a liquid mixture containing chloro-β-trifluoromethylpyridine by distillation.

[0080] In step 2 of this embodiment, it is preferable to separate a liquid mixture containing 2,5-CTF by distillation, and then further perform distillation to separate a liquid mixture containing 2-chloro-3-trifluoromethylpyridine. Then, in the subsequent step 3, it is preferable to react the separated liquid mixture with hydrogen chloride and separate the resulting crystals containing 2-chloro-3-trifluoromethylpyridine hydrochloride, thereby producing 2-chloro-3-trifluoromethylpyridine, a chloro-β-trifluoromethylpyridine-based compound.

[0081] The conditions for distillation to separate a fraction mainly containing 2,5-CTF cannot be generally defined, for example, when performed in a distillation column, because the conditions near the top and near the bottom of the column differ due to the influence of reflux and pressure loss, etc. However, as a condition near the bottom of the column, it is preferably carried out at a temperature of 90 to 130 ° C, more preferably 100 to 120 ° C. Here, the temperature is preferably 90 ° C or higher, more preferably 100 ° C or higher, and also preferably 130 ° C or lower, more preferably 120 ° C or lower. The distillation is preferably carried out under conditions near the bottom of the column, preferably 120 to 147 hPa, more preferably 127 to 140 hPa. Here, the pressure is preferably 120 hPa or higher, more preferably 127 hPa or higher, and also preferably 147 hPa or lower, more preferably 140 hPa or lower. The distillation can be carried out for about 5 to 15 hours. The distillation is more preferably carried out under the conditions of 90 to 130° C. and 20 to 147 hPa near the bottom of the column for about 5 to 15 hours.

[0082] When distillation is carried out under atmospheric pressure, the temperature near the bottom of the column is usually 130 to 160° C. The fraction containing mainly 2,5-CTF can be separated, for example, by appropriately sampling the obtained fraction and analyzing it by gas chromatography, and the separation can be completed when the peak area ratio of 2,5-CTF reaches about 98 to 100%.

[0083] Step 3 in this embodiment is a step of reacting the chloro-β-trifluoromethylpyridine compound separated in Step 2 with hydrogen chloride. Specifically, a liquid mixture containing 2,3-CTF (hereinafter sometimes abbreviated as 2,3-CTF liquid mixture), which is the liquid residue remaining after separating the fraction mainly containing 2,5-CTF in Step 2, is reacted with hydrogen chloride to convert 2,3-CTF into hydrochloride, thereby obtaining crystals containing 2,3-CTF hydrochloride.

[0084] Furthermore, one aspect of the production method according to the present embodiment is a method for producing 2-chloro-3-trifluoromethylpyridine, as described above, by reacting a liquid mixture containing 2-chloro-3-trifluoromethylpyridine with hydrogen chloride and separating the resulting crystals containing 2-chloro-3-trifluoromethylpyridine hydrochloride. Here, the liquid mixture containing 2-chloro-3-trifluoromethylpyridine is synonymous with the 2,3-CTF liquid mixture in Step 3. That is, the 2,3-CTF liquid mixture contains 2-chloro-3-trifluoromethylpyridine, but may also further contain 2-chloro-5-trifluoromethylpyridine, or may be a liquid mixture further containing 2,6-dichloro-3-trifluoromethylpyridine and 2,3-dichloro-5-trifluoromethylpyridine.

[0085] In industrial practice, this operation is carried out in the same manner as in step 2 above, where a liquid mixture containing 2,5-CTF is separated by distillation, followed by subsequent distillation. The distillation conditions, for example, when carried out in a distillation column, cannot be generally defined because the conditions near the top and bottom of the column differ due to factors such as reflux and pressure loss. However, the distillation is preferably carried out at a temperature of 110 to 130°C, more preferably 115 to 125°C, near the bottom of the column. Here, the temperature is preferably 110°C or higher, more preferably 115°C or higher, and preferably 130°C or lower, more preferably 125°C or lower. The distillation is preferably carried out near the bottom of the column under conditions of 120 to 147 hPa, more preferably 127 to 140 hPa. Here, the pressure is preferably 120 hPa or higher, more preferably 127 hPa or higher, and preferably 147 hPa or lower, more preferably 140 hPa or lower. The distillation can be carried out for about 1 to 5 hours. It is more preferable to carry out the distillation for about 1 to 5 hours under conditions of 110 to 130°C and 120 to 147 hPa near the bottom of the column.

[0086] As a combination of the above distillation operations, it is more preferable that the distillation temperature for separating the liquid mixture containing 2-chloro-5-trifluoromethylpyridine is 90 to 130°C under conditions of 120 to 147 hPa, and further the distillation temperature for separating the liquid mixture containing 2-chloro-3-trifluoromethylpyridine by the above distillation operation is 110 to 130°C under conditions of 120 to 147 hPa.

[0087] When distillation is carried out under normal pressure, the temperature near the bottom of the column is usually 160 to 180° C. In this distillation, for example, the obtained fraction is appropriately sampled and analyzed by gas chromatography to obtain a fraction after the peak area ratio of 2,3-CTF reaches about 20 to 85%, preferably 40 to 85%, and more preferably 60 to 85%.

[0088] In the method for purifying 2,3-CTF according to the method described in Patent Document 6, the fraction used in the purification operation needs to have a certain concentration of 2,3-CTF, and specifically, a fraction is obtained after the peak area ratio of 2,3-CTF exceeds 65%, and then crystallized. In contrast, in the production method according to the present embodiment, if the peak area ratio of 2,3-CTF in the fraction is 20% or more, it can be used for the reaction with hydrogen chloride, which is industrially advantageous.

[0089] The 2,3-CTF liquid mixture obtained as described above is reacted with hydrogen chloride to convert 2,3-CTF into hydrochloride, thereby obtaining crystals containing 2,3-CTF hydrochloride preferentially.

[0090] The hydrogen chloride may be in the form of a gas such as hydrogen chloride gas, or may be hydrogen chloride dissolved in a solvent. Preferred examples of the solvent for dissolving hydrogen chloride include hydrocarbon solvents such as benzene, toluene, xylene, normal hexane, and cyclohexane; ether solvents such as diethyl ether; ester solvents such as ethyl acetate, butyl acetate, and isopropyl acetate; aprotic polar solvents such as acetonitrile and N,N-dimethylformamide; and chlorinated hydrocarbon solvents such as dichloromethane, 1,2-dichloroethane, and chloroform.

[0091] The reaction of the 2,3-CTF liquid mixture with hydrogen chloride may be carried out in the absence or presence of a solvent. That is, it is preferable to react a liquid mixture containing 2-chloro-3-trifluoromethylpyridine as a chloro-β-trifluoromethylpyridine compound with hydrogen chloride in the absence or presence of a solvent, and then separate the resulting crystals containing 2-chloro-3-trifluoromethylpyridine hydrochloride.

[0092] "In the absence of a solvent" refers to the case where the 2,3-CTF liquid mixture obtained as described above is reacted with hydrogen chloride as is, without the addition of any new solvent. In this case, the liquid mixture contains liquid compounds such as 2,3,6-DCTF and 2,3-dichloro-5-trifluoromethylpyridine (hereinafter also referred to as 2,3,5-DCTF) in addition to 2,3-CTF. Even in a liquid mixture containing a mixture of 2,3-CTF, 2,3,6-DCTF, and 2,3,5-DCTF, when reacted with hydrogen chloride, 2,3-CTF is selectively converted to its hydrochloride salt, and crystals containing 2,3-CTF hydrochloride can be efficiently obtained.

[0093] "In the presence of a solvent" refers to the case where a solvent is added to the 2,3-CTF liquid mixture obtained as described above and then reacted with hydrogen chloride. The solvent used in this case is not particularly limited, but is preferably a solvent in which 2,3-CTF hydrochloride has a low solubility. In particular, the solvent used in the reaction of the liquid mixture containing 2,3-CTF and 2,5-CTF with hydrogen chloride is preferably a solvent in which the solubility of 2,3-CTF hydrochloride is lower than the solubility of 2,5-CTF hydrochloride.

[0094] Here, the solubility is a numerical value [%] expressed as {(mass of solute [g] / mass of solvent [g]) × 100} in a saturated solution at 20°C and 1 atmospheric pressure. For example, in a saturated 1,2-dichloroethane solution of 2,3-CTF hydrochloride at 20°C and 1 atmospheric pressure, 16.9 g of 2,3-CTF hydrochloride is dissolved in 100 g of 1,2-dichloroethane, so the solubility of 2,3-CTF hydrochloride in 1,2-dichloroethane is 16.9% w / w.

[0095] When the reaction of 2,3-CTF with hydrogen chloride in the production method according to this embodiment is carried out in the presence of a solvent, if a solvent in which 2,3-CTF hydrochloride has a low solubility is used, 2,3-CTF hydrochloride will be preferentially precipitated, thereby increasing the final yield and purity of 2,3-CTF.

[0096] Examples of the solvent having low solubility include isopropyl acetate, toluene, dichloromethane, 1,2-dichloroethane, normal hexane, etc. Among these, it is more preferable to use at least one solvent selected from the group consisting of isopropyl acetate, toluene, dichloromethane, and 1,2-dichloroethane.

[0097] Furthermore, preferred solvents include those in which the solubility of 2,3-CTF hydrochloride is 50% w / w or less.

[0098] More preferred solvents include those in which the solubility of 2,3-CTF hydrochloride is 40% w / w or less.

[0099] Even more desirable solvents include those in which the solubility of 2,3-CTF hydrochloride is 30% w / w or less.

[0100] The most preferred solvents include those in which the solubility of 2,3-CTF hydrochloride is 20% w / w or less.

[0101] Considering operational and cost aspects, it is desirable that the solvent used in the reaction of the 2,3-CTF liquid mixture with hydrogen chloride be the same as the solvent used to dissolve the hydrogen chloride.

[0102] The amount of the solvent used to dissolve hydrogen chloride is not particularly limited, but it is usually preferred to use 10 to 85% by mass of the 2,3-CTF liquid mixture.

[0103] The amount of solvent used in the reaction of the 2,3-CTF liquid mixture with hydrogen chloride is not particularly limited as long as the conversion of 2,3-CTF to hydrochloride proceeds, but is preferably 10 to 85 mass % and more preferably 30 to 60 mass % relative to the 2,3-CTF liquid mixture. The amount used is preferably 10 mass % or more, more preferably 30 mass % or more, and is preferably 85 mass % or less, more preferably 60 mass % or less.

[0104] When reacting the 2,3-CTF liquid mixture with hydrogen chloride, both components can be added simultaneously or in any order, for example, but not limited to, the following methods:

[0105] (1) Add gaseous hydrogen chloride to the 2,3-CTF liquid mixture. (2) Add liquid hydrogen chloride to the 2,3-CTF liquid mixture. (3) Add a solvent to the 2,3-CTF liquid mixture, and then add gaseous hydrogen chloride to the mixture. (4) Add a solvent to the 2,3-CTF liquid mixture, and then add liquid hydrogen chloride to the mixture. (5) Add the 2,3-CTF liquid mixture to the liquid hydrogen chloride. (6) After (1), (2), (3), (4), or (5) above, add more gaseous hydrogen chloride. (7) After (1), (2), (3), (4), or (5) above, add more liquid hydrogen chloride. (8) Simultaneously add the 2,3-CTF liquid mixture and gaseous hydrogen chloride to the solvent. (9) Simultaneously add the 2,3-CTF liquid mixture and liquid hydrogen chloride to the solvent. When gaseous hydrogen chloride, i.e., hydrogen chloride gas, is added, either a method of adding the gas into a reaction vessel or a method of directly adding the gas into a liquid mixture containing 2,3-CTF may be used.

[0106] The amount of hydrogen chloride to be added is not particularly limited, and typically, 1 molar equivalent or more of hydrogen chloride is added relative to 2,3-CTF, preferably 1 to 2 molar equivalents. Hydrogen chloride may be added continuously to the system in which the conversion of 2,3-CTF to hydrochloride is progressing.

[0107] The temperature at which the 2,3-CTF liquid mixture is reacted with hydrogen chloride may be around room temperature as long as the conversion of 2,3-CTF to hydrochloride proceeds, and specifically, the reaction is preferably carried out at a liquid temperature in the range of 0 to 40°C. When 2,3-CTF is purified by utilizing a difference in melting points, as in the melt crystallization method described in Patent Document 6, temperature control is necessary. While uniform temperature control is difficult in an industrial process, the production method according to this embodiment does not require strict temperature control and can be carried out at around room temperature, making it industrially useful.

[0108] The reaction time for reacting the 2,3-CTF liquid mixture with hydrogen chloride may be any time long enough to convert 2,3-CTF into hydrochloride, and can generally be within the range of 0.01 to 24 hours.

[0109] In step 4 of this embodiment, the crystals containing 2,3-CTF hydrochloride produced in step 3 can be separated by filtration. The separated crystals containing 2,3-CTF hydrochloride can be washed, if necessary. This washing can remove reaction residues, such as 2,5-CTF, 2,3-CTF, and 2,3,6-DCTF, adhering to the separated crystals containing 2,3-CTF hydrochloride, and contributes to improving the final yield of 2,3-CTF.

[0110] The solvent used for washing can be the same as the solvent used to dissolve the hydrogen chloride. Considering operational and cost aspects, it is desirable that the solvent used for washing is the same as the solvent used to dissolve the hydrogen chloride or the solvent used in the reaction between the 2,3-CTF liquid mixture and hydrogen chloride.

[0111] The 2,3-CTF hydrochloride obtained by the above procedure can be liberated to 2,3-CTF by neutralizing it with a basic substance. When neutralizing with a basic solution, the basic substance to be used is not particularly limited, but for example, sodium hydroxide (hereinafter referred to as NaOH) can be used.

[0112] According to the production method of this embodiment, 2,3-CTF can be obtained with a purity of 90 to 95 wt % or higher. Furthermore, by performing the above-described washing process, 2,3-CTF can be obtained with an even higher purity. When washing is performed, 2,3-CTF can be obtained with a purity of 95 wt % or higher, or 99 wt % or higher, depending on the conditions of the washing process, such as the solvent used.

[0113] The method described in Patent Document 6 states that melt crystallization can be repeated at least twice, preferably 2 to 4 times, until 2,3-CTF reaches a desired purity. In contrast, the production method according to the present embodiment can purify 2,3-CTF to a high purity in a single operation, which is industrially useful.

[0114] After separating and collecting 2,3-CTF hydrochloride, the remaining filtrate or the washings obtained after washing the crystals containing 2,3-CTF hydrochloride may contain 2,3-CTF. In this case, the obtained filtrate or the washings obtained after washing the crystals can be reused to react the 2,3-CTF liquid mixture with hydrogen chloride. By repeatedly reacting 2,3-CTF with hydrogen chloride, 2,3-CTF can be efficiently converted into the hydrochloride salt, and the yield of 2,3-CTF can be increased.

[0115] The various components in the production method according to this embodiment can be appropriately selected from the examples and conditions described above and can be combined with each other. That is, the type, form of use, or amount of each compound, catalyst, and inert diluent; the temperature of the distillation operation and the hydrochlorination reaction; the reaction time of the hydrochlorination reaction, etc. can be appropriately selected from the examples and conditions in the normal ranges and the examples and conditions in the preferred ranges described above and can be combined with each other.

[0116] Examples of preferred embodiments of the present invention are listed below, but the present invention is not limited thereto. [1] A method for producing 2-chloro-3-trifluoromethylpyridine, comprising reacting a liquid mixture containing 2-chloro-3-trifluoromethylpyridine with hydrogen chloride and separating the resulting crystals containing 2-chloro-3-trifluoromethylpyridine hydrochloride. [2] The method according to [1] above, wherein the liquid mixture further contains 2-chloro-5-trifluoromethylpyridine. [3] The method according to [1] above, wherein the liquid mixture further contains 2,6-dichloro-3-trifluoromethylpyridine and 2,3-dichloro-5-trifluoromethylpyridine. [4] The method according to any one of [1] to [3] above, wherein the reaction temperature between the liquid mixture and the hydrogen chloride is 0°C to 40°C. [5] The method according to any one of [1] to [4] above, wherein the reaction between the liquid mixture and the hydrogen chloride is carried out in the absence or presence of a solvent. [6] The production method according to any one of [1] to [4] above, wherein the reaction between the liquid mixture and the hydrogen chloride is carried out in the presence of a solvent. [7] The production method according to [6] above, wherein the solubility of 2-chloro-3-trifluoromethylpyridine hydrochloride in the solvent is 50 wt% or less. [8] The production method according to [6] above or [7] above, wherein the solvent is at least one selected from the group consisting of isopropyl acetate, toluene, dichloromethane, and 1,2-dichloroethane. [9] A method for producing 2-chloro-3-trifluoromethylpyridine, comprising: 1) reacting a β-methylpyridine compound with chlorine and hydrogen fluoride in a reaction vessel, reacting a β-trifluoromethylpyridine compound with chlorine in a reaction vessel, or reacting a chloro-β-trichloromethylpyridine compound with hydrogen fluoride in a reaction vessel; 2) separating and collecting a chloro-β-trifluoromethylpyridine compound containing 2-chloro-3-trifluoromethylpyridine produced in the reaction vessel; 3) reacting the chloro-β-trifluoromethylpyridine compound with hydrogen chloride; and 4) separating and collecting the produced crystals containing the hydrochloride salt of 2-chloro-3-trifluoromethylpyridine.

[10] The β-methylpyridine compound is represented by the formula (I):

[0117]

[0118] (In formula (I), X １ and Y １ are each a hydrogen atom or a chlorine atom, and the β-trifluoromethylpyridine compound is a compound represented by formula (III):

[0119]

[0120] The chloro β-trichloromethylpyridine compound is a compound represented by formula (IV):

[0121]

[0122] (In formula (IV), X ２ and Y ２ are each a hydrogen atom or a chlorine atom, provided that X ２ and Y ２ At least one of the groups is a chlorine atom, and the chloro-β-trifluoromethylpyridine compound containing 2-chloro-3-trifluoromethylpyridine is a compound represented by formula (II):

[0123]

[0124] (In formula (II), X ２ and Y ２ are each a hydrogen atom or a chlorine atom, provided that X ２ and Y ２wherein at least one of the formula (I) and the formula (III) is a chloro-β-trifluoromethylpyridine compound represented by the formula (II), wherein at least one of the formula (I) and the formula (III) is a chloro-β-trifluoromethylpyridine compound represented by the formula (II), and the reaction in the reaction apparatus is carried out by reacting the β-methylpyridine compound represented by the formula (I) with chlorine and anhydrous hydrogen fluoride in a gas phase in the presence of a catalyst and an inert diluent in the reaction apparatus to produce the chloro-β-trifluoromethylpyridine compound represented by the formula (II), or by reacting the β-trifluoromethylpyridine compound represented by the formula (III) with chlorine in a gas phase or liquid phase in the reaction apparatus to produce the chloro-β-trifluoromethylpyridine compound represented by the formula (II), or by reacting the chloro-β-trichloromethylpyridine compound represented by the formula (IV) with anhydrous hydrogen fluoride in a gas phase in the presence of a catalyst and an inert diluent in the reaction apparatus to produce the chloro-β-trifluoromethylpyridine compound represented by the formula (II).

[12] The production method according to

[11] above, wherein the operation of separating and collecting the chloro-β-trifluoromethylpyridine compound represented by the formula (II) produced in the reaction apparatus is an operation of separating and collecting a liquid mixture containing 2-chloro-5-trifluoromethylpyridine by a distillation operation, and then further performing a distillation operation to separate and collect a liquid mixture containing 2-chloro-3-trifluoromethylpyridine, and the liquid mixture is reacted with hydrogen chloride, and the resulting crystals containing 2-chloro-3-trifluoromethylpyridine hydrochloride are separated, thereby producing 2-chloro-3-trifluoromethylpyridine, a chloro-β-trifluoromethylpyridine compound.

[13] The production method according to

[12] , wherein the reaction temperature of the β-methylpyridine compound represented by formula (I) with chlorine and anhydrous hydrogen fluoride is 300 to 600°C, the reaction temperature of the β-trifluoromethylpyridine compound represented by formula (III) with chlorine in a gas phase is 270 to 500°C, the reaction temperature of the β-trifluoromethylpyridine compound represented by formula (III) with chlorine in a liquid phase is 35 to 150°C, and the reaction temperature of the chloro β-trichloromethylpyridine compound represented by formula (IV) with anhydrous hydrogen fluoride is 200 to 700°C.

[14] The production method according to

[12] or

[13] above, wherein the distillation temperature for separating the liquid mixture containing 2-chloro-5-trifluoromethylpyridine by the distillation operation is 90 to 130° C. under conditions of 120 to 147 hPa, and the distillation temperature for separating the liquid mixture containing 2-chloro-3-trifluoromethylpyridine is 110 to 130° C. under conditions of 120 to 147 hPa.

[15] The production method according to any one of [9] to

[14] above, wherein the liquid mixture containing 2-chloro-3-trifluoromethylpyridine as the chloro-β-trifluoromethylpyridine compound is reacted with hydrogen chloride in the absence or presence of a solvent, and the resulting crystals containing 2-chloro-3-trifluoromethylpyridine hydrochloride are separated.

[16] The production method according to any one of [9] to

[15] above, comprising reacting a liquid mixture containing 2-chloro-3-trifluoromethylpyridine as the chloro-β-trifluoromethylpyridine compound with hydrogen chloride in the presence of a solvent, and separating and collecting the resulting crystals containing 2-chloro-3-trifluoromethylpyridine hydrochloride.

[17] The production method according to

[16] above, wherein the solubility of 2-chloro-3-trifluoromethylpyridine hydrochloride in the solvent is 50 wt% or less.

[18] The production method according to

[16] or

[17] above, wherein the solvent is at least one selected from the group consisting of isopropyl acetate, toluene, dichloromethane, and 1,2-dichloroethane.

[19] The production method according to any one of [9] to

[18] above, wherein the temperature during the reaction of the liquid mixture containing 2-chloro-3-trifluoromethylpyridine as the chloro-β-trifluoromethylpyridine compound with hydrogen chloride is 0°C to 40°C.

[20] A method for producing 2-chloro-3-trifluoromethylpyridine, comprising neutralizing crystals containing the hydrochloride salt of 2-chloro-3-trifluoromethylpyridine separated by the production method according to any one of [1] to

[19] above.

[0125] According to the present invention, by reacting a liquid mixture containing 2,3-CTF with hydrogen chloride, crystals containing 2,3-CTF hydrochloride can be selectively or preferentially obtained, thereby enabling efficient production of 2,3-CTF. For example, even if an attempt is made to selectively obtain 2,3-CTF from a liquid mixture containing a mixture of 2,3-CTF and 2,5-CTF, the boiling points of the two are close (170°C for 2,3-CTF and 152°C for 2,5-CTF), making it difficult to efficiently obtain 2,3-CTF using distillation procedures commonly used in industry. Under these circumstances, the present inventors have discovered a method for efficiently obtaining 2,3-CTF even from a liquid mixture containing 2,5-CTF, which has a similar chemical structure, by converting 2,3-CTF into its hydrochloride salt and separating and collecting the crystals.

[0126] Even if an attempt is made to hydrochloride 2,3-CTF from a liquid mixture containing 2,3-CTF and 2,5-CTF, which have similar chemical structures, and then crystallize and separate the 2,3-CTF, 2,5-CTF itself can be converted to the hydrochloride, and therefore, the conversion of 2,3-CTF to the hydrochloride proceeds and the 2,3-CTF is preferentially crystallized (see Example 7 below), which is not something that a person skilled in the art could have predicted.

[0127] Although it is not possible to say with certainty why crystals containing 2,3-CTF hydrochloride can be obtained selectively or preferentially from a liquid mixture containing 2,3-CTF and 2,5-CTF, the solvent used may have an influence, and desirable results have been obtained with several solvents (see Examples 1 to 4 below). This is one desirable aspect of the present invention, and it is conceivable that when a solvent in which 2,3-CTF hydrochloride has a lower solubility than 2,5-CTF hydrochloride is used, 2,3-CTF hydrochloride will preferentially crystallize. On the other hand, even when a liquid mixture containing 2,3-CTF and 2,5-CTF is reacted with hydrogen chloride without using a solvent, the hydrochloride salt of 2,3-CTF proceeds and crystals containing 2,3-CTF are preferentially produced (see Example 5 below), and the effect is not necessarily dependent solely on the solvent used.

[0128] Thus, although the cause cannot be said to be completely identified, the present inventors have unexpectedly found that, by reacting a liquid mixture containing 2,3-CTF, for example a liquid mixture containing 2,3-CTF and 2,5-CTF, with hydrogen chloride, or by reacting a liquid mixture containing 2,3-CTF, 2,3,6-DCTF, and 2,3,5-DCTF with hydrogen chloride, or by reacting a liquid mixture containing 2,3-CTF, 2,5-CTF, 2,3,6-DCTF, and 2,3,5-DCTF with hydrogen chloride, it is possible to selectively or preferentially obtain crystals containing 2,3-CTF hydrochloride, and to produce 2,3-CTF with high purity and in high yield.

[0129] Next, examples of the present invention will be described to explain the present invention in more detail, but the present invention should not be construed as being limited to these examples.

[0130] Example 1 (1) As a reaction apparatus, an Inconel vertical reactor having a reaction section with a catalyst fluidized bed having an inner diameter of 97.1 mm and a height of 1570 mm was installed, and two Inconel preheating tubes with an inner diameter of 30 mm and a length of 1000 mm were connected to the reactor for the raw materials and the inert diluent. The reaction tube and the preheating tube were covered with an electric heater and a heat insulating material so as to be able to control the temperature.

[0131] 2.2 kg of aluminum trifluoride particles having a particle size of 105 to 250 μm impregnated with 277 g of anhydrous ferric chloride was placed in the catalyst packed section, heated to 200° C., and anhydrous hydrogen fluoride was introduced at a rate of 2.3 L / min for 1 hour to activate the catalyst.

[0132] The reactor was heated to 400°C, and mixed gases of β-picoline at 6.8 g / min and nitrogen gas at 9.9 L / min were introduced through a preheating tube, and chlorine gas at 7.4 L / min and anhydrous hydrogen fluoride at 7.4 L / min were introduced through a preheating tube into the reactor as mixed gases at about 200°C, and the reaction was carried out for about 30 hours. During this time, the activated catalyst was continuously fed and discharged at a rate of 300 g / hr. The residence time of the reaction mixture in the tube was about 3.4 seconds.

[0133] The gas discharged from the reactor was passed through a water washing column and an alkali washing column, and the condensed product was separated and neutralized with aqueous ammonia. 19.11 kg of an oily product was obtained by steam distillation. This oily product was distilled to separate 1.53 kg of a first fraction composed mainly of β-trifluoromethylpyridine and 9.56 kg of a main fraction composed mainly of 2-chloro-5-trifluoromethylpyridine (2,5-CTF). The residue (later fraction) after separating the first fraction and the main fraction contained 3.7% 2-chloro-5-trifluoromethylpyridine (2,5-CTF), 14.5% 2-chloro-3-trifluoromethylpyridine (2,3-CTF), 47.7% 2,6-dichloro-3-trifluoromethylpyridine (2,3,6-DCTF), and 34.1% others. The percentages shown here are based on peak area percentages (GCPA%) determined by gas chromatography analysis.

[0134] (2) From the oily product obtained in accordance with the method described in step (1) above, a fraction containing 2-chloro-5-trifluoromethylpyridine (2,5-CTF) as a main component was separated by distillation, while the remaining fraction was continuously distilled at 110 to 130°C, sampled, and analyzed by gas chromatography to obtain a fraction after the peak area ratio of 2-chloro-3-trifluoromethylpyridine (2,3-CTF) exceeded 65%. According to this operating method, approximately 2,400 kg of the oily product was distilled to obtain approximately 70 kg of a fraction after the area value of 2-chloro-3-trifluoromethylpyridine (2,3-CTF) exceeded 65%.

[0135] (3) A jacketed glass tank (200 L) equipped with a stirrer was charged with 52 kg of isopropyl acetate as a solvent (corresponding to 52% by mass of the 2,3-CTF fraction), and hydrogen chloride gas was added to the isopropyl acetate while cooling to 10 to 15°C and stirring. After the hydrogen chloride concentration in the isopropyl acetate reached 12% by mass, 100 kg of a fraction containing 2-chloro-3-trifluoromethylpyridine (2,3-CTF) obtained in accordance with the method described in steps (1) and (2) above was added dropwise over 10 hours to allow the reaction to proceed. After the dropwise addition was completed, hydrogen chloride gas was continuously added to the reaction solution, and the reaction was continued while 23 kg of hydrogen chloride gas was added to the 2,3-CTF fraction over 2.5 hours. The crystals were collected by filtration using a filter (Nutsche filter) and further washed with 42 kg of isopropyl acetate (corresponding to 42% by mass of the 2,3-CTF fraction) to obtain 65 kg of 2,3-CTF hydrochloride crystals (purity of 99% GCPA or more, crude yield of 72%).

[0136] (4) 64 kg of 2,3-CTF hydrochloride crystals obtained according to the method described in step (3) above and 90 kg of water were charged into a jacketed glass tank (200 L) equipped with a stirrer. Next, 25 kg of a 48% by mass aqueous NaOH solution was added dropwise over 1 hour with stirring to adjust the pH to 13, liberating 2,3-CTF hydrochloride to 2,3-CTF. After that, the mixture was separated to obtain 50.7 kg of 2,3-CTF (purity of 99 wt% or more, crude yield 67%).

[0137] Example 2 (1) 100 g of a fraction containing 2-chloro-3-trifluoromethylpyridine (2,3-CTF), obtained in accordance with the method described in steps (1) and (2) of Example 1 above, was placed in a round-bottom flask (200 mL), followed by 66 g of toluene as a solvent. While cooling to 10-15°C and stirring, 13 g of hydrogen chloride gas, equivalent to 1 equivalent of 2,3-CTF, was added over 1 hour to the reaction vessel containing the fraction and solvent, allowing the reaction to proceed. The crystals were filtered and washed with 37 g of toluene (37% by mass relative to the 2,3-CTF fraction), yielding 61.8 g of 2,3-CTF hydrochloride crystals (purity 95% GCPA, crude yield 74%).

[0138] (2) A round-bottom flask (200 mL) was charged with 61.8 g of the 2,3-CTF hydrochloride crystals obtained in step (1) above and the same weight of water. Next, a 48% by mass aqueous solution of NaOH was added dropwise with stirring to adjust the pH to 13, liberating 2,3-CTF hydrochloride to 2,3-CTF. The resulting mixture was then separated to obtain 49 g of 2,3-CTF (purity of 99 wt% or more, crude yield of 74%).

[0139] Example 3 The same procedure as in Example 2 was carried out except that the solvent and washing liquid were changed to dichloromethane, to obtain 60 g of 2,3-CTF hydrochloride crystals (purity 95 GCPA%, crude yield 72%).

[0140] The obtained 2,3-CTF hydrochloride crystals were liberated in accordance with the method described in step (2) of Example 2 above, to obtain 48 g of 2,3-CTF (purity of 99 wt % or more, crude yield 72%).

[0141] Example 4 60 g of 2,3-CTF hydrochloride crystals (purity 99 GCPA%, crude yield 75%) were obtained in the same manner as in Example 2, except that the solvent and washing liquid were changed to 1,2-dichloroethane.

[0142] The obtained 2,3-CTF hydrochloride crystals were liberated in accordance with the method described in step (2) of Example 2 above, to obtain 47 g of 2,3-CTF (purity of 99 wt % or more, crude yield of 71%).

[0143] Example 5 (1) 95 g of a fraction containing 2-chloro-3-trifluoromethylpyridine (2,3-CTF) obtained in accordance with the method described in steps (1) and (2) of Example 1 was placed in a round-bottom flask (200 mL), and the mixture was cooled to 10 to 15°C and stirred while adding 13 g of hydrogen chloride gas, equivalent to 1 equivalent of 2,3-CTF, to the reaction vessel containing the fraction over 1.5 hours to effect a reaction. The crystals were collected by filtration and washed with 31 g of normal hexane to obtain 54 g of 2,3-CTF hydrochloride crystals (purity 99 GCPA%, crude yield 72%).

[0144] (2) A round-bottom flask (200 mL) was charged with the 2,3-CTF hydrochloride crystals obtained in step (1) above and an equal weight of water. Next, a 48% by mass aqueous solution of NaOH was added dropwise with stirring to adjust the pH to 13, liberating the 2,3-CTF hydrochloride to 2,3-CTF. The resulting mixture was then separated, yielding 45 g of 2,3-CTF (purity of 95 wt% or more, crude yield of 68%).

[0145] Example 6 (1) 100 g of a fraction containing 2-chloro-3-trifluoromethylpyridine (2,3-CTF), obtained in accordance with the method described in steps (1) and (2) of Example 1 above, was placed in a round-bottom flask (200 mL). While cooling to 10-15°C and stirring, 13 g of hydrogen chloride gas, equivalent to 1 equivalent of 2,3-CTF, was added to the reaction vessel containing the fraction over a period of 2 hours to effect a reaction. The crystals were collected by filtration and washed with 37 g of 1,2-dichloroethane (37% by mass relative to the 2,3-CTF fraction), yielding 49.7 g of 2,3-CTF hydrochloride crystals (purity 96% GCPA, crude yield 60%).

[0146] (2) A round-bottom flask (200 mL) was charged with 45.8 g of the 2,3-CTF hydrochloride crystals obtained in step (1) above and the same weight of water. Next, a 48% by mass aqueous solution of NaOH was added dropwise with stirring to adjust the pH to 13, liberating 2,3-CTF hydrochloride to 2,3-CTF. The mixture was then separated to obtain 37.3 g of 2,3-CTF (purity of 96 wt% or more, crude yield of 59%).

[0147] Example 7 50 g of 2-chloro-3-trifluoromethylpyridine (2,3-CTF) (purity 99.6 GCPA%) and 50 g of 2-chloro-5-trifluoromethylpyridine (2,5-CTF) (purity 99.1 GCPA%) were charged into a round-bottom flask (200 mL) and mixed, followed by the addition of 100 g of 1,2-dichloroethane as a solvent. While cooling to 10-15°C and stirring, 10 g of hydrogen chloride gas (1 equivalent to 2,3-CTF) was added over 1.5 hours to the reaction vessel containing the mixture and solvent, allowing the reaction to proceed. The crystals were collected by filtration, yielding 44 g of 2,3-CTF hydrochloride crystals (purity 95 GCPA%, crude yield 70%).

[0148] Example 8 (1) 150 g of a fraction containing 2-chloro-3-trifluoromethylpyridine (2,3-CTF) at a peak area ratio of 22% (gas chromatography analysis), obtained in accordance with the method described in steps (1) and (2) of Example 1 above, was placed in a round-bottom flask (200 mL). While cooling to 10-15°C and stirring, 6 g of hydrogen chloride gas, equivalent to 1 equivalent of 2,3-CTF, was added to the reaction vessel containing the fraction over 1.5 hours to allow the reaction to proceed. The crystals were collected by filtration and washed with 18 g of 1,2-dichloroethane (12% by mass relative to the 2,3-CTF fraction), yielding 12.6 g of 2,3-CTF hydrochloride crystals (purity 98% GCPA, crude yield 31%).

[0149] (2) A round-bottom flask (200 mL) was charged with the 2,3-CTF hydrochloride crystals obtained in step (1) above and an equal weight of water. Next, a 48% by mass aqueous solution of NaOH was added dropwise with stirring to adjust the pH to 13, liberating the 2,3-CTF hydrochloride to 2,3-CTF. The resulting mixture was then separated, yielding 9 g of 2,3-CTF (purity of 99 wt% or more, crude yield of 27%).

[0150] Although the present invention has been described in detail and with reference to specific embodiments, it will be apparent to those skilled in the art that various changes and modifications can be made without departing from the spirit and scope of the present invention. This application is based on a Japanese patent application (Patent Application No. 2024-050405) filed on March 26, 2024, the contents of which are incorporated herein by reference.

Claims

1. A method for producing 2-chloro-3-trifluoromethylpyridine, comprising reacting a liquid mixture containing 2-chloro-3-trifluoromethylpyridine with hydrogen chloride and separating the resulting crystals containing 2-chloro-3-trifluoromethylpyridine hydrochloride.

2. The method of claim 1, wherein the liquid mixture further comprises 2-chloro-5-trifluoromethylpyridine.

3. The method of claim 1, wherein the liquid mixture further comprises 2,6-dichloro-3-trifluoromethylpyridine and 2,3-dichloro-5-trifluoromethylpyridine.

4. The method according to any one of claims 1 to 3, wherein the reaction temperature between the liquid mixture and the hydrogen chloride is 0°C to 40°C.

5. The method according to any one of claims 1 to 3, wherein the reaction of the liquid mixture with the hydrogen chloride is carried out in the absence or presence of a solvent.

6. The method according to any one of claims 1 to 3, wherein the reaction of the liquid mixture with the hydrogen chloride is carried out in the presence of a solvent.

7. The method according to claim 6, wherein the solubility of 2-chloro-3-trifluoromethylpyridine hydrochloride in the solvent is 50 w / w % or less.

8. The method according to claim 7, wherein the solvent is at least one selected from the group consisting of isopropyl acetate, toluene, dichloromethane, and 1,2-dichloroethane.

9. A method for producing 2-chloro-3-trifluoromethylpyridine, comprising: 1) reacting a β-methylpyridine compound with chlorine and hydrogen fluoride in a reactor, reacting a β-trifluoromethylpyridine compound with chlorine in a reactor, or reacting a chloro-β-trichloromethylpyridine compound with hydrogen fluoride in a reactor; 2) separating and collecting a chloro-β-trifluoromethylpyridine compound containing 2-chloro-3-trifluoromethylpyridine produced in the reactor; 3) reacting the chloro-β-trifluoromethylpyridine compound with hydrogen chloride; and 4) separating and collecting the resulting crystals containing the hydrochloride salt of 2-chloro-3-trifluoromethylpyridine.

10. The β-methylpyridine compound has the formula (I): (In formula (I), X １ and Y １ are each a hydrogen atom or a chlorine atom, and the β-trifluoromethylpyridine compound is a compound represented by formula (III): The chloro β-trichloromethylpyridine compound is a compound represented by formula (IV): (In formula (IV), X ２ and Y ２ are each a hydrogen atom or a chlorine atom, provided that X ２ and Y ２ At least one of the groups is a chlorine atom, and the chloro-β-trifluoromethylpyridine compound containing 2-chloro-3-trifluoromethylpyridine is a compound represented by formula (II): (In formula (II), X ２ and Y ２ are each a hydrogen atom or a chlorine atom, provided that X ２ and Y ２ and at least one of the groups is a chlorine atom.

11. The production method according to claim 10, wherein the reaction in the reactor comprises reacting the β-methylpyridine compound represented by formula (I) with chlorine and anhydrous hydrogen fluoride in the gas phase in the presence of a catalyst and an inert diluent in the reactor to produce the chloro-β-trifluoromethylpyridine compound represented by formula (II), or reacting the β-trifluoromethylpyridine compound represented by formula (III) with chlorine in the gas phase or liquid phase in the reactor to produce the chloro-β-trifluoromethylpyridine compound represented by formula (II), or reacting the chloro-β-trichloromethylpyridine compound represented by formula (IV) with anhydrous hydrogen fluoride in the gas phase in the presence of a catalyst and an inert diluent in the reactor to produce the chloro-β-trifluoromethylpyridine compound represented by formula (II).

12. The method according to claim 11, wherein the operation of separating and collecting the chloro-β-trifluoromethylpyridine compound represented by formula (II) produced in the reaction apparatus comprises separating a liquid mixture containing 2-chloro-5-trifluoromethylpyridine by distillation, and then further performing distillation to separate a liquid mixture containing 2-chloro-3-trifluoromethylpyridine, and the liquid mixture is reacted with hydrogen chloride, and the resulting crystals containing 2-chloro-3-trifluoromethylpyridine hydrochloride are separated, thereby producing 2-chloro-3-trifluoromethylpyridine, a chloro-β-trifluoromethylpyridine compound.

13. The production method according to claim 12, wherein the reaction temperature of the β-methylpyridine compound represented by formula (I) with chlorine and anhydrous hydrogen fluoride is 300 to 600°C, the reaction temperature of the β-trifluoromethylpyridine compound represented by formula (III) with chlorine in the gas phase is 270 to 500°C, the reaction temperature of the β-trifluoromethylpyridine compound represented by formula (III) with chlorine in the liquid phase is 35 to 150°C, and the reaction temperature of the chloro β-trichloromethylpyridine compound represented by formula (IV) with anhydrous hydrogen fluoride is 200 to 700°C.

14. The production method according to claim 12, wherein the distillation temperature for separating the liquid mixture containing 2-chloro-5-trifluoromethylpyridine by the distillation operation is 90 to 130°C under conditions of 120 to 147 hPa, and the distillation temperature for separating the liquid mixture containing 2-chloro-3-trifluoromethylpyridine by the distillation operation is 110 to 130°C under conditions of 120 to 147 hPa.

15. The method according to claim 12, comprising reacting a liquid mixture containing 2-chloro-3-trifluoromethylpyridine as the chloro-β-trifluoromethylpyridine compound with hydrogen chloride in the presence or absence of a solvent, and separating the resulting crystals containing 2-chloro-3-trifluoromethylpyridine hydrochloride.

16. The method according to claim 12, comprising reacting a liquid mixture containing 2-chloro-3-trifluoromethylpyridine as the chloro-β-trifluoromethylpyridine compound with hydrogen chloride in the presence of a solvent, and separating the resulting crystals containing 2-chloro-3-trifluoromethylpyridine hydrochloride.

17. The method according to claim 16, wherein the solubility of 2-chloro-3-trifluoromethylpyridine hydrochloride in the solvent is 50 w / w% or less.

18. The method of claim 17, wherein the solvent is at least one selected from the group consisting of isopropyl acetate, toluene, dichloromethane, and 1,2-dichloroethane.

19. The method according to claim 12, wherein the liquid mixture containing 2-chloro-3-trifluoromethylpyridine as the chloro-β-trifluoromethylpyridine compound is reacted with hydrogen chloride at a temperature of 0°C to 40°C.

20. A method for producing 2-chloro-3-trifluoromethylpyridine, comprising neutralizing crystals containing the hydrochloride salt of 2-chloro-3-trifluoromethylpyridine separated by the production method according to any one of claims 1 to 3 and 12.

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