Process for the production of 2-chloro-3-trifluoromethylpyridine

Abstract

The present invention relates to a process for producing 2-chloro-3-trifluoromethylpyridine, wherein a liquid mixture containing 2-chloro-3-trifluoromethylpyridine is reacted with hydrogen chloride, and the crystals of the resulting 2-chloro-3-trifluoromethylpyridine hydrochloride are separated.

Description

Technical Field

[0001] This invention relates to a method for manufacturing 2-chloro-3-trifluoromethylpyridine, which is useful as an intermediate in pharmaceuticals, pesticides, etc. Background Technology

[0002] Patent Documents 1 and 2 disclose a method for manufacturing chloro-β-trifluoromethylpyridine compounds, characterized in that the β-methylpyridine compound is reacted with chlorine and anhydrous hydrogen fluoride in the gas phase in the presence of a specific catalyst and an inactive diluent. Examples show that, as the chloro-β-trifluoromethylpyridine compound, 2-chloro-5-trifluoromethylpyridine (hereinafter also referred to as 2,5-CTF) is mainly obtained, along 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), etc.

[0003] Patent document 3 discloses a method for producing chloro-3-trifluoromethylpyridine compounds by chlorinating 3-trifluoromethylpyridine in the presence of an inactive diluent. Its examples show that 2,5-CTF is mainly obtained as this chloro-3-trifluoromethylpyridine compound, along with 2,3-CTF, 2,3,6-DCTF, etc.

[0004] Patent documents 4 and 5 disclose a method for producing chloro-β-trifluoromethylpyridine compounds, characterized in that the β-trichloromethylpyridine compound is reacted with anhydrous hydrogen fluoride in the gas phase in the presence of a specific catalyst. Examples show that 2,5-CTF is primarily obtained as the chloro-β-trifluoromethylpyridine compound.

[0005] Patent document 6 describes the following method: using β-methylpyridine compounds, β-trifluoromethylpyridine compounds, chloro-β-trichloromethylpyridine compounds, etc. as raw material compounds to obtain 2,5-CTF as the main product, and purifying 2,3-CTF from the distillate separated during the distillation process.

[0006] Existing technical documents

[0007] Patent documents

[0008] Patent Document 1: Japanese Patent Application Publication No. 55-147261

[0009] Patent Document 2: Japanese Patent Application Publication No. 56-120667

[0010] Patent Document 3: Japanese Patent Application Publication No. 55-122762

[0011] Patent Document 4: Japanese Patent Application Publication No. 55-124762

[0012] Patent Document 5: Japanese Patent Application Publication No. 56-100764

[0013] Patent Document 6: Japanese Patent Application Publication No. 2020-023489 Summary of the Invention

[0014] The problem the invention aims to solve

[0015] 2,3-CTF is a useful compound as an intermediate in pesticides and pharmaceuticals. Depending on the circumstances, a method for manufacturing it with high purity is required, but specific purification methods for 2,3-CTF are not described in patent documents 1-5.

[0016] Patent document 6 describes a method for obtaining crystals containing 2,3-CTF by melt crystallization. However, it describes that this melt crystallization can typically be carried out in the range of 5 to 25°C, which is a limited temperature range. Furthermore, if crystallization is carried out in an industrial manufacturing setting, a large amount of energy is required to control the temperature. Therefore, in the industrial manufacturing of 2,3-CTF, melt crystallization, which requires uniform temperature control, presents challenges in terms of operation and efficiency.

[0017] In the industrial manufacturing of 2,3-CTF, a manufacturing method that does not require strict temperature control and is highly efficient is desired.

[0018] That is, the objective of this invention is to provide a method for efficiently manufacturing 2-chloro-3-trifluoromethylpyridine without strict temperature control in industrial manufacturing.

[0019] Solution for solving the problem

[0020] In order to solve the above-mentioned problems, the inventors conducted research and discovered the following method: a method for manufacturing 2,3-CTF by reacting a liquid mixture containing 2,3-CTF with hydrogen chloride to selectively or preferentially hydrochlorinate / crystallize 2,3-CTF, thereby completing the present invention.

[0021] In addition, the present invention relates to a method for separating, purifying, and manufacturing 2,3-CTF by selectively or preferentially hydrochlorinating / crystallizing 2,3-CTF from a liquid mixture containing 2,3-CTF.

[0022] One embodiment of this invention provides a method for manufacturing 2-chloro-3-trifluoromethylpyridine, wherein a liquid mixture containing 2-chloro-3-trifluoromethylpyridine is reacted with hydrogen chloride, and the resulting crystals containing 2-chloro-3-trifluoromethylpyridine hydrochloride are separated.

[0023] Additionally, one embodiment of this invention provides a method for manufacturing 2-chloro-3-trifluoromethylpyridine, comprising:

[0024] 1) React β-methylpyridine compounds with chlorine and hydrogen fluoride in a reaction apparatus, react β-trifluoromethylpyridine compounds with chlorine in a reaction apparatus, or react chloro-β-trichloromethylpyridine compounds with hydrogen fluoride in a reaction apparatus;

[0025] 2) Take off the chloro-β-trifluoromethylpyridine compounds containing 2-chloro-3-trifluoromethylpyridine generated in the reaction apparatus;

[0026] 3) Reacting the chloro-β-trifluoromethylpyridine compound with hydrogen chloride; and

[0027] 4) Take the crystals of the hydrochloride containing 2-chloro-3-trifluoromethylpyridine that are generated.

[0028] Hereinafter, in this specification, the two methods described above will also be referred to as the manufacturing methods of this embodiment.

[0029] The effects of the invention

[0030] According to the manufacturing method of this embodiment, when 2-chloro-3-trifluoromethylpyridine, which is useful as an intermediate in pharmaceuticals, pesticides, etc., is manufactured industrially, strict temperature control is not required, and it can be manufactured efficiently.

[0031] More specifically, in one embodiment of this invention, by reacting a liquid mixture containing 2,3-CTF with hydrogen chloride, the 2,3-CTF in the liquid mixture is selectively or preferentially hydrochlorinated / crystallized, thus achieving a high yield. Furthermore, the resulting crystals, through appropriate post-processing, can yield 2,3-CTF with high purity.

[0032] In another embodiment, β-methylpyridine compounds, β-trifluoromethylpyridine compounds, or chloro-β-trichloromethylpyridine compounds can be used as raw materials to obtain a liquid mixture containing the above-mentioned 2,3-CTF. Detailed Implementation

[0033] The manufacturing method of this embodiment will now be described in detail. It should be noted that the "~" symbol, which indicates a numerical range, is used to mean that the values ​​before and after it are both lower and upper limits.

[0034] One embodiment of the manufacturing method includes the following steps 1 to 4 in sequence.

[0035] Step 1: A step of reacting β-methylpyridine compounds with chlorine and hydrogen fluoride in a reaction apparatus; a step of reacting β-trifluoromethylpyridine compounds with chlorine in a reaction apparatus; or a step of reacting chloro-β-trichloromethylpyridine compounds with hydrogen fluoride in a reaction apparatus.

[0036] Step 2: The step of separating the chloro-β-trifluoromethylpyridine compounds containing 2-chloro-3-trifluoromethylpyridine generated in the above reaction apparatus;

[0037] Step 3: The step of reacting the above-mentioned chloro-β-trifluoromethylpyridine compound with hydrogen chloride; and

[0038] Step 4: The step of separating the generated crystals of hydrochloride containing 2-chloro-3-trifluoromethylpyridine.

[0039] In the above step 1, the reaction that will cause the β-methylpyridine compound to react with chlorine and hydrogen fluoride in the reaction apparatus is called reaction 1, the reaction that will cause the β-trifluoromethylpyridine compound to react with chlorine in the reaction apparatus is called reaction 2, and the reaction that will cause the chloro-β-trichloromethylpyridine compound to react with hydrogen fluoride in the reaction apparatus is called reaction 3.

[0040] Chloro-β-trifluoromethylpyridine compounds containing 2-chloro-3-trifluoromethylpyridine are produced by the method shown in reactions 1 to 3 above.

[0041] (Reaction 1)

[0042] Reaction 1 is a reaction of a β-methylpyridine compound with chlorine and hydrogen fluoride in a reaction apparatus. The β-methylpyridine compound is preferably a compound represented by the following formula (I).

[0043]

[0044] (In formula (I), X) 1 and Y 1 These are either hydrogen atoms or chlorine atoms.

[0045] In this embodiment, reaction (1), namely the reaction of β-methylpyridine compound with chlorine and hydrogen fluoride, is preferably the reaction of β-methylpyridine compound of formula (I) with chlorine and hydrogen fluoride, more preferably the reaction of β-methylpyridine compound of formula (I) with chlorine and anhydrous hydrogen fluoride, even more preferably the reaction of β-methylpyridine compound of formula (I) with chlorine and anhydrous hydrogen fluoride in the presence of a catalyst and an inactive diluent, and particularly preferably the reaction of β-methylpyridine compound of formula (I) with chlorine and anhydrous hydrogen fluoride in the gas phase in the presence of a catalyst and an inactive diluent.

[0046] That is, in reaction 1, as shown in the following reaction formula, it is preferable to react the β-methylpyridine compound represented by formula (I) with chlorine and anhydrous hydrogen fluoride in the gas phase within the reaction apparatus in the presence of a catalyst and an inactive diluent. This produces the chloro-β-trifluoromethylpyridine compound represented by formula (II), and in the following step 2, a liquid mixture containing the chloro-β-trifluoromethylpyridine compound represented by formula (II) is separated from the reaction apparatus by distillation.

[0047] The liquid mixtures mentioned above typically contain 2-chloro-5-trifluoromethylpyridine (2,5-CTF), 2-chloro-3-trifluoromethylpyridine (2,3-CTF), 2,6-dichloro-3-trifluoromethylpyridine (2,3,6-DCTF), etc.

[0048]

[0049] In equations (I) and (II), X 1 X 2 Y 1 and Y 2 They are either hydrogen atoms or chlorine atoms, where X 2 and Y 2 At least one of them is a chlorine atom.

[0050] That is, the above reaction 1 is suitable as the following reaction: in the presence of a catalyst and an inactive diluent, the β-methylpyridine compound of formula (I) is reacted with chlorine and anhydrous hydrogen fluoride in the gas phase, thereby producing the chloro-β-trifluoromethylpyridine compound of formula (II).

[0051] As for the β-methylpyridine compounds represented by formula (I) used in reaction 1 above, in addition to β-methylpyridine, examples include chloro-β-methylpyridines such as 2-chloro-β-methylpyridine, 6-chloro-β-methylpyridine, or 2,6-dichloro-β-methylpyridine. In particular, β-methylpyridine is readily available as a raw material in various organic synthetic chemical industries, and according to the manufacturing method of this embodiment, chloro-β-trifluoromethylpyridine compounds can be directly manufactured from it, which is therefore advantageous.

[0052] Metal fluorides can be listed as catalysts used in reaction 1 above.

[0053] As metallic fluorides, examples include fluorides of aluminum, chromium, iron, nickel, cobalt, and manganese. More specifically, examples include hydrated aluminum trifluoride (AlF3·3H2O), aluminum trifluoride (AlF3), chromium difluoride (CrF2), hydrated chromium trifluoride (CrF3·3H2O), chromium trifluoride (CrF3), chromium tetrafluoride (CrF4), hydrated ferrous fluoride (FeF2·8H2O), ferrous fluoride (FeF2), ferric fluoride (FeF3), nickel fluoride (NiF2), hydrated nickel fluoride (NiF2·3H2O), nickel fluoride (NiF3), cobalt fluoride (CoF2), cobalt fluoride (CoF3), manganese fluoride (MnF2), manganese fluoride (MnF3), and manganese tetrafluoride (MnF4), etc.

[0054] The amount of catalyst used varies depending on the reaction conditions, but is preferably 0.001 to 3 moles, more preferably 0.01 to 3 moles, relative to 1 mole of the β-methylpyridine compound. Here, the amount of catalyst used relative to 1 mole of the β-methylpyridine compound is preferably 0.001 moles or more, more preferably 0.01 moles or more, and preferably 3 moles or less.

[0055] Typically, the catalyst is mixed with supports such as activated carbon, activated alumina, and aluminum trifluoride, and shaped into granules or pellets of appropriate size, then present in a fixed bed or fluidized bed. Alternatively, the catalyst can be placed directly into the reaction tube as a fluoride of the aforementioned metal. However, industrially, it is advantageous to place the catalyst in the reaction tube as an oxide, chloride, or carbonate of the aforementioned metal, or as a hydrate of the aforementioned fluoride, allowing it to react with anhydrous hydrogen fluoride to convert it into a fluoride.

[0056] For example, the molded article obtained by loading the oxides or chlorides of the above-mentioned metals such as chromium trioxide, ferric chloride, and nickel oxide onto an alumina carrier can be placed in a reaction tube, and anhydrous hydrogen fluoride can be introduced in advance to react it at 200~600°C to convert it into the fluoride of the above-mentioned metals before the reaction is carried out.

[0057] As inactive diluents, organic solvents containing halogenated hydrocarbons such as carbon tetrachloride, chloroform, dichloromethane, F-112 (CFCl2·CFCl2), and F-113 (CF2Cl·CFCl2) can be used; as well as inactive gases such as nitrogen, helium, and argon. These inactive diluents have the function of inhibiting combustion, carbonization, and the formation of tar-like byproducts.

[0058] When carrying out reaction 1 above, the raw materials and inactive diluent can be supplied to the reactor separately, or they can be supplied in a mixed state. In addition, they can be supplied simultaneously or sequentially, together or separately. For example, a mixture of β-methylpyridine compound and inactive diluent, or a mixture of chlorine and anhydrous hydrogen fluoride can be supplied separately.

[0059] The amounts of chlorine and anhydrous hydrogen fluoride vary depending on the type of β-methylpyridine compound used as the raw material, the type of target compound, and the reaction apparatus. Generally, relative to 1 mole of the β-methylpyridine compound, the amount of chlorine is 2 to 15 moles, and the amount of anhydrous hydrogen fluoride is 2 to 60 moles. The amount of inactive diluent relative to 1 mole of the β-methylpyridine compound is preferably 2 to 70 moles.

[0060] The reaction temperature for reaction 1 is preferably 300-600°C. Furthermore, the residence time of the reaction mixture in the reaction zone is preferably 0.5-60 seconds, more preferably 3-60 seconds. Here, the residence time is preferably 0.5 seconds or more, more preferably 3 seconds or more, and preferably 60 seconds or less.

[0061] More preferably, reaction 1 is carried out at a reaction temperature of 300-600°C and the residence time of the reaction mixture in the reaction zone is 0.5-60 seconds.

[0062] Typically, through reaction 1, a gaseous substance containing fluorinated products, mainly composed of chloro-β-trifluoromethylpyridine compounds, unreacted hydrogen fluoride and chlorine, intermediate products, by-product hydrogen chloride, and inactive diluent is discharged from the reaction apparatus. After passing through a suitable cooling and condensation device, the chloro-β-trifluoromethylpyridine compounds are collected in the form of a liquid mixture.

[0063] The aforementioned liquid mixture typically contains 2,5-CTF, 2,3-CTF, and 2,3,6-DCTF, from which chloro-β-trifluoromethylpyridine compounds are obtained, for example, at a formation rate of over 85%. When the collected liquid mixture contains intermediates that have not yet formed chloro-β-trifluoromethylpyridine compounds, these intermediates can be separated and recovered along with unreacted raw materials or inactive diluents and recycled within the reaction zone.

[0064] Furthermore, the above-mentioned reaction 1 can be carried out in accordance with the records in Japanese Patent Application Publication No. 55-147261 (Patent Document 1) and Japanese Patent Application Publication No. 56-120667 (Patent Document 2).

[0065] (Reaction 2)

[0066] Reaction 2 is a reaction between a β-trifluoromethylpyridine compound and chlorine in a reaction apparatus. The β-trifluoromethylpyridine compound is preferably the compound shown in formula (III) below.

[0067]

[0068] In this embodiment, reaction (2), namely the reaction of β-trifluoromethylpyridine compound with chlorine, is preferably the reaction of β-trifluoromethylpyridine compound with chlorine as shown in formula (II), and more preferably the reaction of β-trifluoromethylpyridine compound with chlorine as shown in formula (II) in the gas phase or liquid phase.

[0069] In reaction 2, as shown in the following reaction formula, it is preferable to react the β-trifluoromethylpyridine compound represented by formula (III) with chlorine in the gas or liquid phase within the reaction apparatus. This produces the chloro-β-trifluoromethylpyridine compound represented by formula (II), and in the next step 2, a liquid mixture containing the chloro-β-trifluoromethylpyridine compound represented by formula (II) is separated from the reaction apparatus by distillation.

[0070] The liquid mixtures mentioned above typically contain 2,5-CTF, 2,3-CTF, 2,3,6-DCTF, etc.

[0071]

[0072] In equation (II), X 2 and Y 2 They are either hydrogen atoms or chlorine atoms, where X 2 and Y 2 At least one of them is a chlorine atom.

[0073] A suitable way to produce the chloro-β-trifluoromethylpyridine compound of formula (II) is by chlorinating the β-trifluoromethylpyridine compound of formula (III) in the gas phase in the presence of an inactive diluent.

[0074] Typically, β-trifluoromethylpyridine compounds and chlorine are introduced into the reaction apparatus using an inactive diluent as a carrier for reaction.

[0075] Inactive diluents, like those used in typical gas-phase chlorination reactions, have the function of inhibiting combustion, carbonization, and the formation of tar-like byproducts. Specific examples of inactive diluents include inactive gases such as nitrogen and helium; and halogenated hydrocarbons such as carbon tetrachloride, trichloroethylene, tetrachloroethylene, and tetrachlorodifluoroethane. However, in industry, the use of nitrogen, carbon tetrachloride, or mixtures thereof is preferred.

[0076] The amount of inactive diluent varies depending on other reaction conditions and cannot be generalized. Relative to 1 mole of the β-trifluoromethylpyridine compound, the amount of inactive diluent is preferably 3 to 70 moles, more preferably 10 to 20 moles. Here, the amount of the aforementioned inactive diluent relative to 1 mole of the β-trifluoromethylpyridine compound is preferably 3 moles or more, more preferably 10 moles or more, and further preferably 70 moles or less, more preferably 20 moles or less.

[0077] The amount of chlorine used varies depending on other reaction conditions and cannot be generalized. Relative to 1 mole of the β-trifluoromethylpyridine compound, the amount of chlorine is preferably 0.5 to 5 moles, more preferably 0.8 to 3 moles. Here, the amount of chlorine relative to 1 mole of the β-trifluoromethylpyridine compound is preferably 0.5 moles or more, more preferably 0.8 moles or more, and preferably 5 moles or less, more preferably 3 moles or less.

[0078] The amounts of inactive diluent and chlorine vary depending on other reaction conditions and cannot be generalized. More preferably, for every 1 mole of β-trifluoromethylpyridine compound, the amount of inactive diluent is 3 to 70 moles and the amount of chlorine is 0.5 to 5 moles.

[0079] The reaction temperature for reaction 2 in this embodiment is preferably 270~500°C, more preferably 350~450°C. Here, the above-mentioned reaction temperature is preferably 270°C or higher, more preferably 350°C or higher, and preferably 500°C or lower, more preferably 450°C or lower.

[0080] Furthermore, the residence time of the reaction mixture in the reaction zone is preferably 0.5 to 60 seconds, more preferably 1 to 20 seconds. Here, the aforementioned residence time is preferably 0.5 seconds or more, more preferably 1 second or more, and preferably 60 seconds or less, more preferably 20 seconds or less.

[0081] More preferably, the reaction temperature of reaction 2 in this manner is 270~500°C, and the residence time of the reaction mixture in the reaction zone is 0.5~60 seconds.

[0082] The above reaction 2 can be carried out in the presence of porous materials such as silica, alumina, and silicon carbide, as well as fillers such as ceramics, glass spheres, or mixtures thereof, as needed. In industrial implementation, these fillers can also be present in the reactor in the form of a fixed bed or fluidized bed to improve reaction efficiency.

[0083] β-trifluoromethylpyridine compounds, chlorine, and inactive diluents are usually supplied to the reaction apparatus after preheating. However, when supplying β-trifluoromethylpyridine compounds, they can be supplied by introducing them into a high-temperature gaseous inactive diluent or by heating the solution dissolved in the liquid inactive diluent to vaporize it.

[0084] Within the reaction apparatus, under specified reaction conditions, the desired reaction proceeds to generate chloro-β-trifluoromethylpyridine compounds.

[0085] Typically, gaseous substances containing chloro-β-trifluoromethylpyridine compounds, inactive diluents, and unreacted chlorine are discharged from the reaction apparatus. After passing through appropriate cooling and condensation devices, the chloro-β-trifluoromethylpyridine compounds are collected in the form of a liquid mixture.

[0086] The liquid mixture typically contains 2,5-CTF, 2,3-CTF, and 2,3,6-DCTF. When the collected liquid mixture contains intermediates that have not yet formed chloro-β-trifluoromethylpyridine compounds, these intermediates can be separated and recovered along with unreacted raw materials or inactive diluents and recycled within the reaction zone.

[0087] Another suitable mode of reaction 2 above is the following reaction: dissolving the β-trifluoromethylpyridine compound of formula (III) in an inactive diluent and chlorinating it in the liquid phase, thereby producing the chloro-β-trifluoromethylpyridine compound of formula (II).

[0088] At this point, the presence of a free radical generator or exposure to ultraviolet or visible light can promote the reaction.

[0089] Typically, chlorine gas and sulfonyl chloride are used as chlorinating agents. Additionally, organic solvents containing halogenated hydrocarbons such as carbon tetrachloride, trichloroethylene, tetrachloroethylene, and tetrachlorodifluoroethane are used as inactive diluents.

[0090] As free radical generators, examples include azobisisobutyronitrile compounds such as 2,2'-azobisisobutyronitrile and azobismethylbutyronitrile; or peroxide benzoyl compounds such as benzoyl peroxide, O,O'-dichlorobenzoyl peroxide and P,P'-dimethylbenzoyl peroxide.

[0091] The amounts of inactive diluent and chlorine vary depending on other reaction conditions and cannot be generalized. Regarding the amount of 1 mole of β-trifluoromethylpyridine compound, the inactive diluent is preferably 5 to 30 moles and the chlorine is preferably 0.5 to 7 moles. More preferably, the inactive diluent is 5 to 30 moles and the chlorine is 0.5 to 7 moles.

[0092] In addition, the free radical generator is preferably used at 0.01 to 5% by mass relative to the β-trifluoromethylpyridine compound.

[0093] In this method, the reaction temperature of reaction 2 is preferably 35℃~150℃, and the reaction time is preferably 6 hours~24 hours. More preferably, the reaction temperature is 35℃~150℃ and the reaction time is 6 hours~24 hours.

[0094] Typically, reaction 2 is used to collect a liquid mixture containing chloro-β-trifluoromethylpyridine compounds from the reaction apparatus.

[0095] The liquid mixture typically contains 2,5-CTF, 2,3-CTF, and 2,3,6-DCTF. When the collected liquid mixture contains intermediates that have not yet formed chloro-β-trifluoromethylpyridine compounds, these intermediates can be separated and recovered along with unreacted raw materials or inactive diluents and recycled within the reaction zone.

[0096] Furthermore, the above-mentioned reaction 2 can be carried out in accordance with the description in Japanese Patent Application Publication No. 55-122762 (Patent Document 3).

[0097] (Reaction 3)

[0098] Reaction 3 is a reaction between a chloro-β-trichloromethylpyridine compound and hydrogen fluoride in a reaction apparatus. The chloro-β-trichloromethylpyridine compound is preferably the compound shown in formula (IV) below.

[0099]

[0100] In equation (IV), X 2 and Y 2 They are either hydrogen atoms or chlorine atoms, where X 2 and Y 2 At least one of them is a chlorine atom.

[0101] In this embodiment, reaction (3), namely the reaction of chloro-β-trichloromethylpyridine compound with hydrogen fluoride, is preferably the reaction of chloro-β-trichloromethylpyridine compound of formula (IV) with hydrogen fluoride, more preferably the reaction of chloro-β-trichloromethylpyridine compound of formula (IV) with anhydrous hydrogen fluoride, even more preferably the reaction of chloro-β-trichloromethylpyridine compound of formula (IV) with anhydrous hydrogen fluoride in the presence of a catalyst and an inactive diluent, and particularly preferably the reaction of chloro-β-trichloromethylpyridine compound of formula (IV) with anhydrous hydrogen fluoride in the gas phase in the presence of a catalyst and an inactive diluent.

[0102] That is, in reaction 3, preferably, as shown in the following reaction formula, the chloro-β-trichloromethylpyridine compound represented by formula (IV) is reacted with anhydrous hydrogen fluoride in the gas phase within the reaction apparatus in the presence of a catalyst and an inactive diluent. Thus, the chloro-β-trifluoromethylpyridine compound represented by formula (II) is produced, and in the next step 2, a liquid mixture containing the chloro-β-trifluoromethylpyridine compound represented by formula (II) is separated from the reaction apparatus by distillation.

[0103] Liquid mixtures typically contain 2,5-CTF, 2,3-CTF, 2,3,6-DCTF, etc.

[0104]

[0105] In equations (IV) and (II), X 2 and Y 2 They are either hydrogen atoms or chlorine atoms, where X 2 and Y 2 At least one of them is a chlorine atom. It should be noted that X in formula (IV) 2 and Y 2 Corresponding to X in equation (II) 2 and Y 2 .

[0106] The above reaction 3 is the following reaction: in the presence of a catalyst and an inactive diluent, the chloro-β-trichloromethylpyridine compound shown in formula (IV) is reacted with anhydrous hydrogen fluoride in the gas phase, thereby producing the chloro-β-trifluoromethylpyridine compound shown in formula (II).

[0107] Catalysts used in reaction 3 above can include metal fluorides and ammonium fluorides.

[0108] As fluorides of metals, specifically, fluorides of the same metals as those in reaction 1 above can be listed.

[0109] As ammonium fluorides, specifically, ammonium fluoride, acidic ammonium fluoride, etc. can be listed.

[0110] In industry, the catalyst composition is preferably a fluoride of chromium, iron, or nickel.

[0111] Typically, these catalyst components are mixed with supports such as activated carbon and activated alumina, shaped into granules or pellets of appropriate size, and then supplied to the reaction zone. Alternatively, the catalyst components can be supplied to the reaction tube in the form of fluorides of the aforementioned metals, thus existing directly in the reaction zone. They can also be supplied to the reaction tube in the form of oxides, chlorides, hydroxides, carbonates, or their hydrates, followed by the flow of anhydrous hydrogen fluoride gas at high temperature, thereby causing these substances to react with the hydrogen fluoride and transform into the desired fluorine compound.

[0112] For example, the molded product obtained by loading the oxides or chlorides of the above-mentioned metals such as ferric chloride, chromium trioxide, and nickel oxide onto an alumina carrier can be placed in a reaction tube, and anhydrous hydrogen fluoride can be introduced in advance to react it at 200~600°C to convert it into the fluoride of the above-mentioned metals before the reaction is carried out.

[0113] In carrying out reaction 3 above, the chloro-β-trichloromethylpyridine compound and anhydrous hydrogen fluoride, as raw materials, can be supplied to the reaction tube separately or in a mixed state. Alternatively, they can be supplied after being mixed with an inactive diluent. The raw materials can be supplied by direct vaporization, or the chloro-β-trichloromethylpyridine compound can be supplied by vaporization after temporary dissolution in an inactive solvent. When supplying the raw materials, it is generally desirable to preheat them to near the boiling point or reaction temperature of the chloro-β-trichloromethylpyridine compound.

[0114] As inactive diluents, inactive solvents such as carbon tetrachloride, chloroform, dichloromethane, F-112 (CFCl2·CFCl2), F-113 (CF2Cl·CFCl2), nitrogen, argon, and helium are used.

[0115] When using an inactive diluent, the amount used cannot be generalized. It is preferably 1 to 20 moles, more preferably 3 to 10 moles, relative to 1 mole of the chloro-β-trichloromethylpyridine compound. Here, the amount of the aforementioned inactive diluent relative to 1 mole of the chloro-β-trichloromethylpyridine compound is preferably 1 mole or more, more preferably 3 moles or more, and further preferably 20 moles or less, more preferably 10 moles or less.

[0116] The amount of anhydrous hydrogen fluoride relative to the chloro-β-trichloromethylpyridine compound is not fixed; it is preferably 3 to 10 moles, more preferably 4 to 9 moles, relative to 1 mole of the chloro-β-trichloromethylpyridine compound. Here, the amount of anhydrous hydrogen fluoride relative to 1 mole of the chloro-β-trichloromethylpyridine compound is preferably 3 moles or more, more preferably 4 moles or more, and preferably 10 moles or less, more preferably 9 moles or less.

[0117] The amount of catalyst used cannot be generalized either; for example, it may be suitable to use the same amount as in reaction 1 above.

[0118] Typically, in the reaction zone of reaction 3 above, the raw material chloro-β-trichloromethylpyridine compound and anhydrous hydrogen fluoride or inactive diluent are supplied at a certain flow rate, thus forming a fluidized bed or fixed bed of catalyst solids.

[0119] The reaction temperature of the chloro-β-trichloromethylpyridine compound in reaction 3 with anhydrous hydrogen fluoride is preferably 200~700°C, more preferably 300~500°C. Here, the above reaction temperature is preferably 200°C or higher, more preferably 300°C or higher, and preferably 700°C or lower, more preferably 500°C or lower.

[0120] Furthermore, the residence time of the reaction mixture in the reaction zone is preferably 1 to 20 seconds, more preferably 2 to 10 seconds. Here, the aforementioned residence time is preferably 1 second or more, more preferably 2 seconds or more, and more preferably 20 seconds or less, more preferably 10 seconds or less.

[0121] More preferably, reaction 3 is carried out at a reaction temperature of 200-700°C and the residence time of the reaction mixture in the reaction zone is 1-20 seconds.

[0122] Reaction 3 completes the aforementioned fluorination reaction within the reaction apparatus, discharging the gaseous reaction products. These gaseous products contain fluorinated products, primarily composed of chloro-β-trifluoromethylpyridine compounds, unreacted hydrogen fluoride, byproduct hydrogen chloride, and an inactive diluent. After passing through a suitable cooling and condensation device, the fluorinated products are liquefied, yielding a liquid mixture primarily composed of chloro-β-trifluoromethylpyridine compounds.

[0123] The liquid mixture typically contains 2,5-CTF, 2,3-CTF, and 2,3,6-DCTF, and chloro-β-trifluoromethylpyridine compounds are obtained, for example, in yields of chloro-β-trifluoromethylpyridine compounds exceeding 80%. When the collected liquid mixture contains intermediates that have not yet formed chloro-β-trifluoromethylpyridine compounds, these intermediates can be separated and recovered along with unreacted starting materials or inactive diluents and recycled within the reaction zone.

[0124] Furthermore, the above reaction 3 can be carried out in accordance with the records in Japanese Patent Application Publication No. 55-124762 (Patent Document 4) and Japanese Patent Application Publication No. 56-100764 (Patent Document 5).

[0125] Step 2 in this embodiment is the process of separating the chloro-β-trifluoromethylpyridine compound containing 2-chloro-3-trifluoromethylpyridine generated in the reaction apparatus. The liquid mixture separated in step 1 contains approximately 30-65% 2,5-CTF, 5-20% 2,3-CTF, and 10-30% 2,3,6-DCTF. These proportions represent peak area fractions based on gas chromatography analysis.

[0126] In step 2 of this embodiment, a fraction mainly containing 2,5-CTF is separated from the liquid mixture by distillation. This operation is carried out as follows: In an industrial implementation, various reactions described in step 1 are carried out to produce chloro-β-trifluoromethylpyridine, and a certain fraction is separated during the process of separating the liquid mixture containing chloro-β-trifluoromethylpyridine by distillation.

[0127] Furthermore, in step 2 of this embodiment, it is preferable to further perform a distillation operation after separating the liquid mixture containing 2,5-CTF by distillation to separate the liquid mixture containing 2-chloro-3-trifluoromethylpyridine. Then, in the next step 3, it is preferable to separate the generated crystals containing 2-chloro-3-trifluoromethylpyridine hydrochloride by reacting the separated liquid mixture with hydrogen chloride, thereby producing 2-chloro-3-trifluoromethylpyridine as a chloro-β-trifluoromethylpyridine compound.

[0128] Regarding the distillation conditions for separating the fraction mainly containing 2,5-CTF, for example, when carried out in a distillation column, the conditions near the top and bottom of the column differ due to the effects of reflux, pressure loss, etc., and therefore cannot be generalized. As for the conditions near the bottom of the column, it is preferable to carry out the distillation at a temperature of 90°C to 130°C, more preferably 100°C to 120°C. Here, the above-mentioned temperature is preferably 90°C or higher, more preferably 100°C or higher, and preferably 130°C or lower, more preferably 120°C or lower.

[0129] As for the conditions near the bottom of the column, the above distillation is preferably carried out at 120-147 hPa, more preferably at 127-140 hPa. Here, the pressure is preferably 120 hPa or more, more preferably 127 hPa or more, and preferably 147 hPa or less, more preferably 140 hPa or less.

[0130] The above distillation can be carried out in about 5 to 15 hours.

[0131] As for the conditions near the bottom of the column, the above distillation is more preferably carried out at 90°C to 130°C and 20hPa to 147hPa for about 5 to 15 hours.

[0132] When distilling at atmospheric pressure, the conditions near the bottom of the column are typically maintained at a temperature of 130–160 °C. Regarding the fraction primarily containing 2,5-CTF, for example, the resulting fraction can be appropriately sampled and analyzed by gas chromatography, ending when the peak area of ​​2,5-CTF reaches approximately 98–100%.

[0133] Step 3 of this embodiment is a step of reacting the chloro-β-trifluoromethylpyridine compound separated in step 2 with hydrogen chloride. Specifically, the liquid residue after separating the fraction mainly containing 2,5-CTF in step 2, i.e., a liquid mixture containing 2,3-CTF (hereinafter sometimes simply referred to as the 2,3-CTF liquid mixture), is reacted with hydrogen chloride to hydrochloride the 2,3-CTF, thereby obtaining crystals containing 2,3-CTF hydrochloride.

[0134] Furthermore, as described above, one embodiment of the manufacturing method is a method for manufacturing 2-chloro-3-trifluoromethylpyridine as follows: reacting a liquid mixture containing 2-chloro-3-trifluoromethylpyridine with hydrogen chloride, and then separating the resulting crystals containing 2-chloro-3-trifluoromethylpyridine hydrochloride. Here, the liquid mixture containing 2-chloro-3-trifluoromethylpyridine mentioned above has the same meaning as the 2,3-CTF liquid mixture in step 3 of this process.

[0135] That is, the 2,3-CTF liquid mixture contains 2-chloro-3-trifluoromethylpyridine, and may also contain 2-chloro-5-trifluoromethylpyridine, or may be a liquid mixture containing 2,6-dichloro-3-trifluoromethylpyridine and 2,3-dichloro-5-trifluoromethylpyridine.

[0136] Regarding this operation, in an industrial implementation, in the distillation operation described for step 2 above, after the liquid mixture containing 2,5-CTF is separated by distillation, a distillation operation is then performed.

[0137] Regarding the distillation conditions described above, for example, when carried out in a distillation column, the conditions near the top and bottom of the column differ due to factors such as reflux and pressure loss, and therefore cannot be generalized. As for the conditions near the bottom of the column, it is preferable to carry out the distillation at a temperature of 110-130°C, more preferably 115-125°C. Here, the aforementioned temperature is preferably 110°C or higher, more preferably 115°C or higher, and further preferably 130°C or lower, more preferably 125°C or lower.

[0138] As for the conditions near the bottom of the column, the distillation is preferably carried out at 120-147 hPa, more preferably 127-140 hPa. Here, the pressure is preferably 120 hPa or more, more preferably 127 hPa or more, and preferably 147 hPa or less, more preferably 140 hPa or less.

[0139] The above distillation can be carried out in about 1 to 5 hours.

[0140] As for the conditions near the bottom of the column, the above distillation is more preferably carried out at 110~130°C and 120~147hPa for about 1~5 hours.

[0141] As a combination of the above distillation operations, it is more preferable to set the distillation temperature for separating the liquid mixture containing 2-chloro-5-trifluoromethylpyridine at 90-130°C under conditions of 120-147 hPa, and further, to set the distillation temperature for separating the liquid mixture containing 2-chloro-3-trifluoromethylpyridine by the aforementioned distillation operation at 110-130°C under conditions of 120-147 hPa.

[0142] When distilling at atmospheric pressure, the conditions near the bottom of the column are typically maintained at a temperature of 160–180 °C. During this distillation, for example, a suitable sample of the resulting fraction is taken and analyzed by gas chromatography to obtain a fraction with a 2,3-CTF peak area of ​​approximately 20–85%, preferably 40–85%, and more preferably 60–85%.

[0143] In the 2,3-CTF purification method based on the method described in Patent Document 6, the concentration of 2,3-CTF in the fraction used for purification needs to be at a certain level. Specifically, a fraction with a 2,3-CTF peak area ratio exceeding 65% is used for crystallization. In contrast, in the manufacturing method of this embodiment, if the 2,3-CTF peak area ratio in the fraction is 20% or more, it can be used for reaction with hydrogen chloride, which is industrially advantageous.

[0144] The 2,3-CTF liquid mixture obtained by the above operation is reacted with hydrogen chloride to hydrochloride the 2,3-CTF, thereby preferentially obtaining crystals containing 2,3-CTF hydrochloride.

[0145] Hydrogen chloride can be a gas like hydrogen chloride gas, or it can be a substance formed by dissolving hydrogen chloride in a solvent. Ideal solvents for dissolving hydrogen chloride include hydrocarbon solvents such as benzene, toluene, xylene, n-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.

[0146] The reaction of 2,3-CTF liquid mixtures with hydrogen chloride can be carried out in the absence of solvent or in the presence of solvent.

[0147] That is, preferably, under conditions where no solvent is present or where a solvent is present, a liquid mixture containing 2-chloro-3-trifluoromethylpyridine, which is a chloro-β-trifluoromethylpyridine compound, is reacted with hydrogen chloride, and the resulting crystals containing 2-chloro-3-trifluoromethylpyridine hydrochloride are collected.

[0148] The absence of solvent refers to the situation where the 2,3-CTF liquid mixture obtained by the above operation is reacted directly with hydrogen chloride without the addition of new solvent. In this case, the liquid mixture contains, in addition to 2,3-CTF, liquid compounds such as 2,3,6-DCTF and 2,3-dichloro-5-trifluoromethylpyridine (hereinafter also referred to as 2,3,5-DCTF).

[0149] Even when 2,3-CTF, 2,3,6-DCTF and 2,3,5-DCTF are mixed in such a liquid mixture, 2,3-CTF can be selectively hydrochlorinated by reacting with hydrogen chloride, and crystals containing 2,3-CTF hydrochloride can be obtained efficiently.

[0150] The presence of a solvent refers to the situation where a solvent is added to the 2,3-CTF liquid mixture obtained as described above, causing it to react with hydrogen chloride. There are no particular restrictions on the solvent used in this case, but a solvent with low solubility in 2,3-CTF hydrochloride is preferred. In particular, it is desirable that the solvent used in the reaction of the liquid mixture containing 2,3-CTF and 2,5-CTF with hydrogen chloride has a lower solubility in 2,3-CTF hydrochloride than in 2,5-CTF hydrochloride.

[0151] Here, solubility refers to the value [%] expressed as {(mass of solute [g] / mass of solvent [g]) × 100} in a saturated solution at 20°C and 1 atmosphere.

[0152] For example, at 20°C and 1 atmosphere, 16.9 g of 2,3-CTF hydrochloride dissolves in 1,2-dichloroethane relative to 100 g of 1,2-dichloroethane in a saturated solution of 1,2-dichloroethane. Therefore, the solubility of 2,3-CTF hydrochloride in 1,2-dichloroethane is 16.9% w / w.

[0153] When the reaction of 2,3-CTF with hydrogen chloride is carried out in the manufacturing method of this embodiment in the presence of a solvent, if a solvent with low solubility of 2,3-CTF hydrochloride is used, 2,3-CTF hydrochloride will precipitate preferentially, which can improve the final yield and purity of 2,3-CTF.

[0154] Examples of solvents with low solubility include isopropyl acetate, toluene, dichloromethane, 1,2-dichloroethane, and n-hexane. More preferably, at least one solvent selected from the group consisting of isopropyl acetate, toluene, dichloromethane, and 1,2-dichloroethane is used.

[0155] In addition, as a desired solvent, solvents with a solubility of 2,3-CTF hydrochloride of less than 50% w / w can be listed.

[0156] As a more desirable solvent, solvents with a solubility of 2,3-CTF hydrochloride of less than 40% w / w can be listed.

[0157] As a further desired solvent, solvents with a solubility of 2,3-CTF hydrochloride of less than 30% w / w can be listed.

[0158] As the most desirable solvents, solvents with a solubility of 2,3-CTF hydrochloride of less than 20% w / w can be listed.

[0159] Considering operational and cost aspects, the solvent used in the reaction of the 2,3-CTF liquid mixture with hydrogen chloride is expected to be the same solvent used to dissolve the aforementioned hydrogen chloride.

[0160] There is no particular limitation on the amount of solvent used to dissolve hydrogen chloride; generally, 10 to 85 by mass is preferred relative to the 2,3-CTF liquid mixture.

[0161] Regarding the amount of solvent used in the reaction of the 2,3-CTF liquid mixture with hydrogen chloride, there are no particular limitations as long as the 2,3-CTF hydrochlorination is carried out. It is preferable to use 10 to 85% by mass relative to the 2,3-CTF liquid mixture, more preferably 30 to 60% by mass. Here, the above-mentioned amount is preferably 10% by mass or more, more preferably 30% by mass or more, and preferably 85% by mass or less, more preferably 60% by mass or less.

[0162] When reacting a 2,3-CTF liquid mixture with hydrogen chloride, the two components can be added simultaneously or in any order, as can be listed below, but are not limited to these methods.

[0163] (1) Add gaseous hydrogen chloride to the 2,3-CTF liquid mixture.

[0164] (2) Add liquid hydrogen chloride to the 2,3-CTF liquid mixture.

[0165] (3) Add solvent to the 2,3-CTF liquid mixture and add gaseous hydrogen chloride to it.

[0166] (4) Add solvent to the 2,3-CTF liquid mixture and add liquid hydrogen chloride to it.

[0167] (5) Add 2,3-CTF liquid mixture to liquid hydrogen chloride.

[0168] (6) After (1), (2), (3), (4) or (5) above, further add gaseous hydrogen chloride.

[0169] (7) After (1), (2), (3), (4) or (5) above, liquid hydrogen chloride is added.

[0170] (8) Add 2,3-CTF liquid mixture and gaseous hydrogen chloride to the solvent simultaneously.

[0171] (9) Add 2,3-CTF liquid mixture and liquid hydrogen chloride to the solvent simultaneously.

[0172] In the case of adding gaseous hydrogen chloride, i.e., hydrogen chloride gas, the method can be either adding the gas into the reaction vessel or adding the gas directly into a liquid mixture containing 2,3-CTF; it can be any method.

[0173] There is no particular limit to the amount of hydrogen chloride added; generally, adding more than 1 molar equivalent of hydrogen chloride relative to 2,3-CTF is sufficient, with 1 to 2 molar equivalents being desirable. Hydrogen chloride can also be continuously added to the system undergoing 2,3-CTF hydrochlorination.

[0174] Regarding the temperature at which the 2,3-CTF liquid mixture reacts with hydrogen chloride, as long as the 2,3-CTF hydrochlorination is carried out, it can be done near room temperature, specifically preferably in the range of 0°C to 40°C.

[0175] As described in Patent Document 6, when purifying 2,3-CTF using the melting point difference, temperature control is required. Uniform temperature control is difficult to achieve in industrial processes, but the manufacturing method of this embodiment does not require strict temperature control and can be carried out near room temperature, thus making it industrially useful.

[0176] Regarding the reaction time for reacting the 2,3-CTF liquid mixture with hydrogen chloride, it is sufficient to perform the hydrochlorination of 2,3-CTF, which can usually be carried out in the range of 0.01 to 24 hours.

[0177] In step 4 of this embodiment, the crystals containing 2,3-CTF hydrochloride generated in step 3 can be separated by filtration. The separated crystals containing 2,3-CTF hydrochloride can be cleaned as needed. This cleaning can remove reaction residues, such as 2,5-CTF, 2,3-CTF, 2,3,6-DCTF, etc., adhering to the separated crystals containing 2,3-CTF hydrochloride, which helps to improve the final yield of 2,3-CTF.

[0178] The solvent used for cleaning can be the same solvent used to dissolve the aforementioned hydrogen chloride. However, considering operational / cost factors, it is desirable to use the same solvent used for cleaning as the solvent used to dissolve the aforementioned hydrogen chloride or the solvent used in the reaction of the 2,3-CTF liquid mixture with hydrogen chloride.

[0179] The 2,3-CTF hydrochloride obtained through the above operations can be liberated by neutralization with an alkaline substance to produce 2,3-CTF. There are no particular restrictions on the alkaline substance used for neutralization with an alkaline solution; for example, sodium hydroxide (hereinafter referred to as NaOH) can be used.

[0180] According to the manufacturing method of this embodiment, 2,3-CTF can be obtained with a purity of 90-95 wt% or higher. Furthermore, by performing the above-described cleaning process, 2,3-CTF can be obtained with even higher purity. While the purity of 2,3-CTF depends on the solvent and other conditions used in the cleaning process, it is possible to obtain 2,3-CTF with a purity of 95 wt% or higher, or 99 wt% or higher.

[0181] The method described in Patent Document 6 involves repeated melting and crystallization until 2,3-CTF reaches the desired purity, but this process can be repeated at least twice, and ideally two to four times. In contrast, the manufacturing method according to this embodiment can purify 2,3-CTF to a high purity in a single operation, which is also useful industrially.

[0182] After separating 2,3-CTF hydrochloride, the remaining filtrate or the washing solution after washing the crystals containing 2,3-CTF hydrochloride sometimes contains 2,3-CTF. In this case, the obtained filtrate or washing solution after washing the crystals can be reused for the reaction of the 2,3-CTF liquid mixture with hydrogen chloride. By repeatedly reacting 2,3-CTF with hydrogen chloride, the hydrochlorination of 2,3-CTF can be effectively carried out, thereby improving the yield of 2,3-CTF.

[0183] The various constituent elements in the manufacturing method of this embodiment can be appropriately selected from the foregoing examples and conditions, and combined with each other. That is, the types, usage forms or amounts of each compound, catalyst and inactive diluent; the temperatures of the distillation operation and the hydrochlorination reaction; the reaction time in the hydrochlorination reaction, etc., can be appropriately selected from the foregoing examples and conditions within the general range and the examples and conditions within the preferred range, and combined with each other.

[0184] The following is an example of a preferred embodiment of the present invention, but the present invention is not limited to these embodiments. [1]

[0186] A method for producing 2-chloro-3-trifluoromethylpyridine, wherein a liquid mixture containing 2-chloro-3-trifluoromethylpyridine is reacted with hydrogen chloride, and the resulting crystals containing 2-chloro-3-trifluoromethylpyridine hydrochloride are separated. [2]

[0188] According to the manufacturing method described above [1], the liquid mixture further comprises 2-chloro-5-trifluoromethylpyridine. [3]

[0190] According to the manufacturing method described above [1], the liquid mixture further comprises 2,6-dichloro-3-trifluoromethylpyridine and 2,3-dichloro-5-trifluoromethylpyridine. [4]

[0192] According to any one of the manufacturing methods described above [1] to [3], the reaction temperature of the liquid mixture with the hydrogen chloride is 0°C to 40°C. [5]

[0194] According to any one of the manufacturing methods described above [1] to [4], the reaction of the liquid mixture with the hydrogen chloride is carried out under conditions where no solvent is present or in the presence of a solvent. [6]

[0196] According to any one of the manufacturing methods described above [1] to [4], the reaction of the liquid mixture with the hydrogen chloride is carried out in the presence of a solvent. [7]

[0198] According to the manufacturing method described above [6], the solubility of 2-chloro-3-trifluoromethylpyridine hydrochloride in the solvent is less than 50 w / w% relative to the solvent. [8]

[0200] According to the manufacturing method described above [6] or [7], the solvent is at least one selected from the group consisting of isopropyl acetate, toluene, dichloromethane and 1,2-dichloroethane. [9]

[0202] A method for manufacturing 2-chloro-3-trifluoromethylpyridine, comprising:

[0203] 1) React β-methylpyridine compounds with chlorine and hydrogen fluoride in a reaction apparatus, react β-trifluoromethylpyridine compounds with chlorine in a reaction apparatus, or react chloro-β-trichloromethylpyridine compounds with hydrogen fluoride in a reaction apparatus;

[0204] 2) Take off the chloro-β-trifluoromethylpyridine compounds containing 2-chloro-3-trifluoromethylpyridine generated in the reaction apparatus;

[0205] 3) Reacting the chloro-β-trifluoromethylpyridine compound with hydrogen chloride; and

[0206] 4) Take the crystals of the hydrochloride containing 2-chloro-3-trifluoromethylpyridine that are generated.

[10]

[0208] According to the manufacturing method described above [9], wherein the β-methylpyridine compound is a compound represented by formula (I), the β-trifluoromethylpyridine compound is a compound represented by formula (III), and the chloro-β-trichloromethylpyridine compound is a compound represented by formula (IV).

[0209] The chloro-β-trifluoromethylpyridine compounds containing 2-chloro-3-trifluoromethylpyridine are those shown in formula (II).

[0210]

[0211] (In formula (I), X) 1 and Y 1 These are either hydrogen atoms or chlorine atoms.

[0212]

[0213]

[0214] (In formula (IV), X) 2 and Y2 They are either hydrogen atoms or chlorine atoms, where X 2 and Y 2 (At least one of them is a chlorine atom.)

[0215]

[0216] (In formula (II), X) 2 and Y 2 They are either hydrogen atoms or chlorine atoms, where X 2 and Y 2 (At least one of them is a chlorine atom.)

[11]

[0218] According to the manufacturing method described above

[10] , the reaction within the reaction apparatus is:

[0219] The β-methylpyridine compound of formula (I) is reacted with chlorine and anhydrous hydrogen fluoride in the gas phase within the reaction apparatus in the presence of a catalyst and an inactive diluent to produce the chloro-β-trifluoromethylpyridine compound of formula (II), or

[0220] The β-trifluoromethylpyridine compound of formula (III) is reacted with chlorine in the gas or liquid phase within the reaction apparatus to produce the chloro-β-trifluoromethylpyridine compound of formula (II), or

[0221] The chloro-β-trichloromethylpyridine compound of formula (IV) is reacted with anhydrous hydrogen fluoride in the gas phase in the presence of a catalyst and an inactive diluent within the reaction apparatus to produce the chloro-β-trifluoromethylpyridine compound of formula (II).

[12]

[0223] According to the manufacturing method described above

[11] , the operation of separating the chloro-β-trifluoromethylpyridine compound of formula (II) generated in the reaction apparatus is as follows: after separating the liquid mixture containing 2-chloro-5-trifluoromethylpyridine by distillation, a further distillation operation is performed to separate the liquid mixture containing 2-chloro-3-trifluoromethylpyridine.

[0224] The liquid mixture is reacted with hydrogen chloride.

[0225] The resulting crystals containing 2-chloro-3-trifluoromethylpyridine hydrochloride were isolated, thereby producing 2-chloro-3-trifluoromethylpyridine as a chloro-β-trifluoromethylpyridine compound.

[13]

[0227] According to the manufacturing method described above

[12] , the reaction temperature of the β-methylpyridine compound represented by formula (I) with chlorine and anhydrous hydrogen fluoride is 300~600℃.

[0228] The reaction temperature of the β-trifluoromethylpyridine compound represented by formula (III) with chlorine in the gas phase is 270~500℃.

[0229] The reaction temperature of the β-trifluoromethylpyridine compound represented by formula (III) with chlorine in the liquid phase is 35~150℃.

[0230] The reaction temperature of the chloro-β-trichloromethylpyridine compound shown in formula (IV) with anhydrous hydrogen fluoride is 200~700℃.

[14]

[0232] According to the manufacturing method described above

[12] or

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

[15]

[0234] According to any one of the manufacturing methods described above [9] to

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

[16]

[0236] According to any one of the manufacturing methods described above [9] to

[15] , in the presence of a solvent, a liquid mixture containing 2-chloro-3-trifluoromethylpyridine, which is the chloro-β-trifluoromethylpyridine compound, is reacted with hydrogen chloride.

[0237] The resulting crystals containing 2-chloro-3-trifluoromethylpyridine hydrochloride were isolated.

[17]

[0239] According to the manufacturing method described above

[16] , the solubility of 2-chloro-3-trifluoromethylpyridine hydrochloride in the solvent is less than 50 w / w% relative to the solvent.

[18]

[0241] According to the manufacturing method described above

[16] or

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

[19]

[0243] According to any one of the manufacturing methods described above [9] to

[18] , the temperature at which the liquid mixture containing 2-chloro-3-trifluoromethylpyridine, which is the chloro-β-trifluoromethylpyridine compound, is reacted with hydrogen chloride is 0°C to 40°C.

[20]

[0245] A method for manufacturing 2-chloro-3-trifluoromethylpyridine, comprising neutralizing crystals of 2-chloro-3-trifluoromethylpyridine hydrochloride obtained by any of the manufacturing methods described above [1] to

[19] to manufacture 2-chloro-3-trifluoromethylpyridine.

[0246] 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, enabling efficient production of 2,3-CTF. For example, even when it is desired to selectively obtain 2,3-CTF from a liquid mixture containing both 2,3-CTF and 2,5-CTF, their boiling points are close (170°C for 2,3-CTF and 152°C for 2,5-CTF), making efficient production of 2,3-CTF difficult using industrially common distillation methods. In such cases, the inventors have discovered a method that, by hydrochlorinating 2,3-CTF and separating it in crystalline form, 2,3-CTF can be efficiently obtained even from a liquid mixture containing 2,5-CTF, which has a similar chemical structure.

[0247] Even if one wanted to hydrochloride 2,3-CTF from a liquid mixture containing chemically similar 2,3-CTF and 2,5-CTF, and preferentially crystallize and separate it, 2,5-CTF itself is a hydrochlorideable compound, and hydrochloride 2,3-CTF and preferentially crystallize it (see Example 7 below) would not have been predicted by those skilled in the art.

[0248] The main reason why crystals containing 2,3-CTF hydrochloride can be selectively or preferentially obtained from liquid mixtures containing 2,3-CTF and 2,5-CTF is, while not definitively known, the effect of the solvent used, for example, is that the desired results were obtained when several solvents were used (see Examples 1-4 described below).

[0249] This is one of the desired aspects of the present invention. When using a solvent in which the solubility of 2,3-CTF hydrochloride is lower than that of 2,5-CTF hydrochloride, it is conceivable that 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 the use of a solvent, 2,3-CTF hydrochlorination will occur, and crystals containing 2,3-CTF will be preferentially generated (see Example 5 described later), which is not necessarily dependent on the solvent used.

[0250] As such, although it cannot be said that the main reason has been determined, the inventors have discovered that by reacting hydrogen chloride with a liquid mixture containing 2,3-CTF, such as a liquid mixture containing 2,3-CTF and 2,5-CTF, and by reacting hydrogen chloride with a liquid mixture containing 2,3-CTF, 2,3,6-DCTF and 2,3,5-DCTF, and further by reacting hydrogen chloride with a liquid mixture containing 2,3-CTF, 2,5-CTF, 2,3,6-DCTF and 2,3,5-DCTF, crystals containing 2,3-CTF hydrochloride can be obtained selectively or preferentially, and 2,3-CTF can be produced with high purity and high yield.

[0251] Example

[0252] Next, embodiments of the present invention will be described in detail, but the present invention is not to be construed as limiting thereto.

[0253] Example 1

[0254] (1) As a reaction apparatus, a vertical reaction tube made of Inconel alloy with a catalyst fluidized bed having an inner diameter of 97.1 mm and a height of 1570 mm is set up in the reaction section. Two Inconel alloy preheating tubes with an inner diameter of 30 mm and a length of 1000 mm for raw materials and inactive diluents are connected for use. The reaction tube and the preheating tube are covered with electric heaters and heat insulation materials so that the temperature can be controlled.

[0255] The substance obtained by impregnating 277g of anhydrous ferric chloride with 2.2kg of aluminum trifluoride with a particle size of 105~250μm was placed in the catalyst packing section, heated to 200℃, and anhydrous hydrogen fluoride was introduced at a ratio of 2.3L / min for 1 hour to activate the catalyst.

[0256] The reaction apparatus was heated to 400°C. β-methylpyridine was introduced into the preheating tube at a rate of 6.8 g / min, nitrogen at a rate of 9.9 L / min, chlorine at a rate of 7.4 L / min, and anhydrous hydrogen fluoride at a rate of 7.4 L / min, all as a mixed gas at approximately 200°C, and the reaction was carried out for approximately 30 hours. During this period, an activation catalyst was continuously supplied and discharged at a rate of 300 g / h. The residence time of the reaction mixture in the tube was approximately 3.4 seconds.

[0257] The gas discharged from the reaction apparatus was passed through a water washing tower and an alkaline washing tower to separate the condensed products. The products were neutralized with ammonia solution and then steam distilled to obtain 19.11 kg of an oily substance. This oily substance was distilled to separate a 1.53 kg initial fraction mainly composed of β-trifluoromethylpyridine and a 9.56 kg main fraction mainly composed of 2-chloro-5-trifluoromethylpyridine (2,5-CTF). The residual components (later fraction) after separating the initial and main fractions 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% other components. The percentages here are based on peak area percentage (GCPA%) obtained using gas chromatography.

[0258] (2) By distillation, a fraction mainly composed of 2-chloro-5-trifluoromethylpyridine (2,5-CTF) is separated from the oil obtained according to the method described in step (1) above. At the same time, the residual components are further distilled and sampled at 110~130℃ and analyzed by gas chromatography to obtain a fraction with a peak area of ​​2-chloro-3-trifluoromethylpyridine (2,3-CTF) exceeding 65%. According to this operation method, about 2400 kg of the above oil is distilled to obtain about 70 kg of a fraction with an area value of 2-chloro-3-trifluoromethylpyridine (2,3-CTF) exceeding 65%.

[0259] (3) 52 kg of isopropyl acetate (equivalent to 52% by mass relative to the 2,3-CTF fraction) as a solvent was added to a jacketed glass tank (200 L) equipped with a stirrer. While cooling and stirring to 10°C~15°C, hydrogen chloride gas was added to the isopropyl acetate. After the hydrogen chloride concentration in the isopropyl acetate reached 12% by mass, 100 kg of the fraction containing 2-chloro-3-trifluoromethylpyridine (2,3-CTF) obtained by the method described in steps (1) and (2) above was added dropwise over 10 hours to allow it to react. After the dropwise addition was completed, hydrogen chloride gas was continued to be added to the reaction solution. Then, 23 kg of hydrogen chloride gas was added to the 2,3-CTF fraction over 2.5 hours to allow it to react. The crystals were filtered using a filter (Nouchi filter), and the resulting crystals were further washed with 42 kg of isopropyl acetate (equivalent to 42% by mass relative to the 2,3-CTF fraction) to obtain 65 kg of 2,3-CTF hydrochloride crystals (purity above 99% GPA, crude yield 72%).

[0260] (4) Add 64 kg of 2,3-CTF hydrochloride crystals obtained according to the method described in step (3) above and 90 kg of water to a jacketed glass jar (200 L) equipped with a stirrer. Then, while stirring, add 25 kg of 48% NaOH aqueous solution dropwise over 1 hour to adjust the pH to 13, thereby ionizing the 2,3-CTF hydrochloride into 2,3-CTF. Then, separate the liquid to obtain 50.7 kg of 2,3-CTF (purity of ≥99 wt%, crude yield of 67%).

[0261] Example 2

[0262] (1) 100g of the fraction containing 2-chloro-3-trifluoromethylpyridine (2,3-CTF) obtained by the method described in steps (1) and (2) of Example 1 above was placed into a round-bottom flask (200mL), followed by 66g of toluene as a solvent. While cooling and stirring to 10°C~15°C, 13g of hydrogen chloride gas, equivalent to 1 equivalent of 2,3-CTF, was added to the reaction vessel containing the above fraction and solvent over 1 hour to allow the reaction to proceed. The crystals were filtered off, and the obtained crystals were washed with 37g of toluene (37% by mass relative to the 2,3-CTF fraction) to obtain 61.8g of 2,3-CTF hydrochloride crystals (purity 95% GCP, crude yield 74%).

[0263] (2) Add 61.8 g of 2,3-CTF hydrochloride crystals obtained in step (1) above and the same weight of water to a round-bottom flask (200 mL). Then, while stirring, add 48% NaOH aqueous solution dropwise to adjust the pH to 13, thereby ionizing the 2,3-CTF hydrochloride into 2,3-CTF. Then, separate the liquid to obtain 49 g of 2,3-CTF (purity above 99 wt%, crude yield 74%).

[0264] Example 3

[0265] The solvent and cleaning solution were replaced with dichloromethane, and the procedure was otherwise the same as in Example 2 above, to obtain 60 g of 2,3-CTF hydrochloride crystals (purity 95 GCP, crude yield 72%).

[0266] Using the obtained 2,3-CTF hydrochloride crystals, the method described in step (2) of Example 2 above was used to ionize them to obtain 48g of 2,3-CTF (purity of 99wt% or more, crude yield of 72%).

[0267] Example 4

[0268] The solvent and cleaning solution were replaced with 1,2-dichloroethane, and the procedure was otherwise the same as in Example 2 above, to obtain 60 g of 2,3-CTF hydrochloride crystals (purity 99 GCP, crude yield 75%).

[0269] Using the obtained 2,3-CTF hydrochloride crystals, the method described in step (2) of Example 2 above was used to ionize them to obtain 47g of 2,3-CTF (purity of 99wt% or more, crude yield of 71%).

[0270] Example 5

[0271] (1) 95 g of the fraction containing 2-chloro-3-trifluoromethylpyridine (2,3-CTF) obtained by the method according to steps (1) and (2) of Example 1 was added to a round-bottom flask (200 mL). While cooling and stirring to 10°C~15°C, 13 g of hydrogen chloride gas, equivalent to 1 equivalent of 2,3-CTF, was added to the reaction vessel containing the above fraction over 1.5 hours to allow the reaction to proceed. The crystals were filtered off and washed with 31 g of n-hexane to obtain 54 g of 2,3-CTF hydrochloride crystals (purity 99 GCP, crude yield 72%).

[0272] (2) Add the 2,3-CTF hydrochloride crystals obtained in step (1) above and the same weight of water to a round-bottom flask (200 mL). Then, while stirring, add 48% by mass NaOH aqueous solution dropwise to adjust the pH to 13, thereby ionizing the 2,3-CTF hydrochloride into 2,3-CTF. Then, separate the liquid to obtain 45 g of 2,3-CTF (purity of ≥95 wt%, crude yield of 68%).

[0273] Example 6

[0274] (1) 100g of the fraction containing 2-chloro-3-trifluoromethylpyridine (2,3-CTF) obtained by the method described in steps (1) and (2) of Example 1 above was placed into a round-bottom flask (200mL). While cooling and stirring to 10°C~15°C, 13g of hydrogen chloride gas, equivalent to 1 equivalent of 2,3-CTF, was added to the reaction vessel containing the above fraction over 2 hours to allow it to react. The crystals were filtered off, and the obtained crystals were washed with 37g of 1,2-dichloroethane (37% by mass relative to the 2,3-CTF fraction) to obtain 49.7g of 2,3-CTF hydrochloride crystals (purity 96GCP, crude yield 60%).

[0275] (2) Add 45.8 g of 2,3-CTF hydrochloride crystals obtained in step (1) above and the same weight of water to a round-bottom flask (200 mL). Then, while stirring, add 48% NaOH aqueous solution dropwise to adjust the pH to 13, thereby ionizing the 2,3-CTF hydrochloride into 2,3-CTF. Then, separate the liquid to obtain 37.3 g of 2,3-CTF (purity of ≥96 wt%, crude yield 59%).

[0276] Example 7

[0277] 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 placed in a 200 mL round-bottom flask and mixed. Then, 100 g of 1,2-dichloroethane was added as a solvent. While cooling and stirring to 10-15°C, 10 g of hydrogen chloride gas (equivalent to one equivalent of 2,3-CTF) was added to the reaction vessel containing the mixture and solvent over 1.5 hours to allow the reaction to proceed. The crystals were filtered off, yielding 44 g of 2,3-CTF hydrochloride crystals (purity 95 GCPA%, crude yield 70%).

[0278] Example 8

[0279] (1) 150 g of a fraction containing 2-chloro-3-trifluoromethylpyridine (2,3-CTF) with a peak area of ​​22% (gas chromatographic analysis) obtained by the method described in steps (1) and (2) of Example 1 above was placed into a round-bottom flask (200 mL). While cooling and stirring to 10°C~15°C, 6 g of hydrogen chloride gas, equivalent to 1 equivalent of 2,3-CTF, was added to the reaction vessel containing the above fraction over 1.5 hours to allow the reaction to proceed. The crystals were filtered off and washed with 18 g of 1,2-dichloroethane (12% by mass relative to the 2,3-CTF fraction) to obtain 12.6 g of 2,3-CTF hydrochloride crystals (purity 98% GCP, crude yield 31%).

[0280] (2) Add the 2,3-CTF hydrochloride crystals obtained in step (1) above and the same weight of water to a round-bottom flask (200 mL). Then, while stirring, add 48% by mass NaOH aqueous solution dropwise to adjust the pH to 13, thereby ionizing the 2,3-CTF hydrochloride into 2,3-CTF. Then, separate the liquid to obtain 9 g of 2,3-CTF (purity of ≥99 wt%, crude yield of 27%).

[0281] Although the present invention has been described in detail 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 invention. This application is based on Japanese Patent Application No. 2024-050405, filed on March 26, 2024, the contents of which are incorporated herein by reference.

Claims

1. A method for manufacturing 2-chloro-3-trifluoromethylpyridine, wherein, A liquid mixture containing 2-chloro-3-trifluoromethylpyridine is reacted with hydrogen chloride, and the resulting crystals containing 2-chloro-3-trifluoromethylpyridine hydrochloride are collected.

2. The manufacturing method according to claim 1, wherein, The liquid mixture also contains 2-chloro-5-trifluoromethylpyridine.

3. The manufacturing method according to claim 1, wherein, The liquid mixture also contains 2,6-dichloro-3-trifluoromethylpyridine and 2,3-dichloro-5-trifluoromethylpyridine.

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

5. The manufacturing 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 of a solvent or under conditions where a solvent is present.

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

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

9. A method for manufacturing 2-chloro-3-trifluoromethylpyridine, comprising: 1) React β-methylpyridine compounds with chlorine and hydrogen fluoride in a reaction apparatus, react β-trifluoromethylpyridine compounds with chlorine in a reaction apparatus, or react chloro-β-trichloromethylpyridine compounds with hydrogen fluoride in a reaction apparatus; 2) Take off the chloro-β-trifluoromethylpyridine compounds containing 2-chloro-3-trifluoromethylpyridine generated in the reaction apparatus; 3) Reacting the chloro-β-trifluoromethylpyridine compound with hydrogen chloride; and 4) Take the crystals of the hydrochloride containing 2-chloro-3-trifluoromethylpyridine that are generated.

10. The manufacturing method according to claim 9, wherein, The β-methylpyridine compound is the compound represented by formula (I), the β-trifluoromethylpyridine compound is the compound represented by formula (III), and the chloro-β-trichloromethylpyridine compound is the compound represented by formula (IV). The chloro-β-trifluoromethylpyridine compounds containing 2-chloro-3-trifluoromethylpyridine are those represented by formula (II). In formula (I), X 1 and Y 1 They are either hydrogen atoms or chlorine atoms, respectively; In equation (IV), X 2 and Y 2 They are either hydrogen atoms or chlorine atoms, where X 2 and Y 2 At least one of them is a chlorine atom; In equation (II), X 2 and Y 2 They are either hydrogen atoms or chlorine atoms, where X 2 and Y 2 At least one of them is a chlorine atom.

11. The manufacturing method according to claim 10, wherein, The reaction within the reaction apparatus is: The β-methylpyridine compound of formula (I) is reacted with chlorine and anhydrous hydrogen fluoride in the gas phase within the reaction apparatus in the presence of a catalyst and an inactive diluent to produce the chloro-β-trifluoromethylpyridine compound of formula (II), or The β-trifluoromethylpyridine compound of formula (III) is reacted with chlorine in the gas or liquid phase within the reaction apparatus to produce the chloro-β-trifluoromethylpyridine compound of formula (II), or The chloro-β-trichloromethylpyridine compound of formula (IV) is reacted with anhydrous hydrogen fluoride in the gas phase in the presence of a catalyst and an inactive diluent within the reaction apparatus to produce the chloro-β-trifluoromethylpyridine compound of formula (II).

12. The manufacturing method according to claim 11, wherein, The operation of separating the chloro-β-trifluoromethylpyridine compound of formula (II) generated in the reaction apparatus is as follows: after separating the liquid mixture containing 2-chloro-5-trifluoromethylpyridine by distillation, a further distillation operation is performed to separate the liquid mixture containing 2-chloro-3-trifluoromethylpyridine. The liquid mixture is reacted with hydrogen chloride. The resulting crystals containing 2-chloro-3-trifluoromethylpyridine hydrochloride were isolated, thereby producing 2-chloro-3-trifluoromethylpyridine as a chloro-β-trifluoromethylpyridine compound.

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

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

15. The manufacturing method according to claim 12, wherein, Under conditions of the absence of a solvent or the presence of a solvent, a liquid mixture containing 2-chloro-3-trifluoromethylpyridine, which is a chloro-β-trifluoromethylpyridine compound, is reacted with hydrogen chloride. The resulting crystals containing 2-chloro-3-trifluoromethylpyridine hydrochloride were isolated.

16. The manufacturing method according to claim 12, wherein, In the presence of a solvent, a liquid mixture containing 2-chloro-3-trifluoromethylpyridine, which is the chloro-β-trifluoromethylpyridine compound, is reacted with hydrogen chloride. The resulting crystals containing 2-chloro-3-trifluoromethylpyridine hydrochloride were isolated.

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

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

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

20. A method for manufacturing 2-chloro-3-trifluoromethylpyridine, comprising neutralizing crystals of a 2-chloro-3-trifluoromethylpyridine hydrochloride obtained by the manufacturing method according to any one of claims 1 to 3 and 12 to manufacture 2-chloro-3-trifluoromethylpyridine.

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