JP4287814B2 - Process for producing 2-trifluoromethyl-5-fluorobenzaldehyde and derivatives thereof - Google Patents

Description

  The present invention relates to a process for producing 2-trifluoromethyl-5-fluorobenzaldehyde and its derivatives, which are important intermediates for pharmaceuticals and agricultural chemicals.

  2-trifluoromethyl-5-fluorobenzaldehyde and its derivatives are useful compounds as intermediates for pharmaceuticals and agricultural chemicals, and various fluorine-containing compounds can be synthesized using this compound as a key compound. For example, in Non-Patent Document 1, 2-trifluoromethyl-5-fluorobenzylamine is used as one of raw materials for a thrombosis inhibitor. Patent Document 1 discloses an example in which 2-trifluoromethyl-5-fluorobenzoic acid is used as a raw material for an anticancer agent (Compound 233). In Patent Document 2, 2-trifluoromethyl-5-fluorobenzoic acid and 2-trifluoromethyl-5-fluorobenzaldehyde are used as a building block of an LPL activity enhancer.

The 2-trifluoromethyl-5-fluorobenzaldehyde and derivatives thereof targeted in the present invention are a trifluoromethyl (—CF ₃ ) group at the 2-position of the benzene ring, a fluorine (—F) group at the 5-position, and a 1-position. It can be synthesized by introducing a carbon chain such as a formyl (—CHO) group. However, there are few documents that specifically disclose the synthesis methods of these compounds.

According to Non-Patent Document 2 (chemical abstract of Zhurnal Obshchei Khimii (1963) (AN: 1963: 475140)), 5-aminophthalide is dissolved in HBF ₄ solution, treated with aqueous NaNO ₂ , and converted into 5-fluorophthalide. After conversion, this compound is reacted with PCl ₅ dissolved in POCl ₃ to give 5-fluoro-1,1,3,3-tetrafluorophthalane, which is further reacted with SbF ₃ , It is described that 2-trifluoromethyl-5-fluorobenzamide is formed by reaction with ammonia after purification, and 2-trifluoromethyl-5-fluorobenzoic acid can be obtained by heating this compound with sulfuric acid. (Scheme 1).

  In Examples 16 and 19 of Patent Document 2, 2-trifluoromethyl-5-fluorobenzyl alcohol is reacted with lithium aluminum hydride to react 2-trifluoromethyl-5-fluorobenzyl alcohol. Furthermore, it is described that 2-trifluoromethyl-5-fluorobenzaldehyde can be obtained by oxidizing this compound with manganese dioxide (Scheme 2).

  On the other hand, as a technique related to the present invention, according to Patent Document 3, when excess hydrofluoric acid (HF) is allowed to act on p-fluorotrichloromethylbenzene, p-fluorotrifluoromethylbenzene is the main component. It is known that a reaction mixture is obtained (Scheme 3).

  According to Non-Patent Document 3, it is reported that dichloromethylbenzotrichloride can be obtained by chlorinating xylene and then fluorinated with hydrogen fluoride to obtain dichloromethylbenzotrifluoride (Scheme 4).

  Furthermore, Non-Patent Document 4 shows that 4-trifluoromethyl-3-methylfluorobenzene can be synthesized by mixing 3-methylfluorobenzene with an excess amount of carbon tetrachloride and hydrogen fluoride and continuing heating. (Scheme 5).

International Publication No. 02/70494 Pamphlet WO 01/27088 pamphlet JP 60-51127 A Bioorganic & Medicinal Chemistry Letters, (USA), 2003, 13 (7), 1353-1357 Zhurnal Obshchei Khimii, (Soviet Union), 1963 Chemical Abstract (AN: 1963: 475140) Journal of Chemical Society, (UK), 1960, p. 4003 to 4007 Journal of Fluorine Chemistry, (Netherlands), 1981, Vol. 18, p. 281-291

  The target compound of the present invention, 2-trifluoromethyl-5-fluorobenzaldehyde and its derivatives, has a carbon chain such as a formyl group at the 1-position of the benzene nucleus, a trifluoromethyl group at the 2-position, and a fluorine group at the 5-position. Introduced compound. In the prior art, it has been difficult to produce such benzene substituted at a specific site on an industrial scale.

  The method disclosed in Non-Patent Document 2 (Scheme 1) is advantageous for carrying out on a small scale, but requires a large number of complicated steps and has a low selectivity for the target product. It is unsuitable for producing trifluoromethyl-5-fluorobenzoic acid. The same applies to the case where 2-trifluoromethyl-5-fluorobenzoic acid thus produced is converted into various derivatives by the method disclosed in Patent Document 2 (Scheme 2) and the like.

  Synthesis of benzene having two substitutions containing a trifluoromethyl group by the method described in Patent Document 3 (Scheme 3) is an industrially established technique. However, in order to convert these disubstituted benzenes into the trisubstituted benzenes that are the subject of the present invention, a third group (carbon side chain) must be introduced into the adjacent site (ortho position) of the trifluoromethyl group. I must. Since the trifluoromethyl group has a strong meta-orientation property, it is difficult to selectively introduce a functional group at such an ortho position.

The method (Scheme 4) for producing disubstituted benzene disclosed in Non-Patent Document 3 is also an industrially established technique. If the dichloromethyl (—CHCl ₂ ) group of the obtained compound is converted into a formyl (—CHO) group and a fluorine (—F) group can be introduced as a third group in the para position of the trifluoromethyl group, the target compound Can be synthesized. However, it is difficult to introduce a fluorine group at the para position of the trifluoromethyl group due to the meta-orientation of the trifluoromethyl group.

According to the method of Non-Patent Document 4 (Scheme 5), the target 4-trifluoromethyl-3-methylfluorobenzene can be synthesized in one step. If the methyl group at the 3-position of this compound is further chlorinated to convert it to a dichloromethyl (—CHCl ₂ ) group, and then this group is converted to a formyl group by hydrolysis, 2-trifluoro which is the object of the present invention. It is believed that methyl-5-fluorobenzaldehyde can be produced. However, in the reaction of Scheme 5, carbon tetrachloride, which is a chlorofluorocarbon-regulated substance, must be used in large quantities. Carbon tetrachloride is a substance that needs to be used in a closed system and requires special care when used. Furthermore, since the reaction of this method is low in reactivity, it requires a large excess of carbon tetrachloride and hydrogen fluoride, resulting in a large capacity and low productivity. The starting material 3-methylfluorobenzene is also an expensive compound. Therefore, although this method is a suitable method for synthesizing a small amount of sample, it is difficult to say that it is advantageous in industrially producing a large amount of an object.

  Thus, 2-trifluoromethyl-5-fluorobenzaldehyde and its derivatives are difficult to produce industrially according to existing methods, and more efficient means have been demanded.

  The present inventors have intensively studied to solve the above problems, and surprisingly, by using relatively inexpensive 3,4-dimethylfluorobenzene as a starting material, this is subjected to a two-step reaction. It has been found that 2-trifluoromethyl-5-fluorobenzal chloride having a high purity can be easily obtained. By further subjecting the 2-trifluoromethyl-5-fluorobenzal chloride thus obtained to hydrolysis, 2-trifluoromethyl-5-fluorobenzaldehyde is obtained in high yield, and various derivatives starting from this compound are obtained. Has been found to be able to be synthesized, and the solution to the problem of the present invention has been achieved.

That is, when 3,4-dimethylfluorobenzene is reacted with chlorine (Cl ₂ ), this reaction has poor regioselectivity, so that the regioisomers (2-trichloromethyl-5-fluorobenzal chloride and 2-trichloromethyl- A mixture containing 4-fluorobenzal chloride) (this mixture is also referred to as “chlorination reaction mixture”) is obtained (first step). Here, the inventors have found that there is a significant difference between the isomers in the reaction rate of fluorination using hydrogen fluoride (HF) in the liquid phase. That is, when the “chlorination reaction mixture” is brought into contact with HF in a liquid phase, one of the isomers, 2-trichloromethyl-5-fluorobenzal chloride, is preferentially fluorinated, and 2-trifluoro It was found that methyl-5-fluorobenzal chloride can be obtained with high selectivity (second step). Surprisingly, while this liquid phase fluorination reaction proceeds significantly (until the conversion of 2-trichloromethyl-5-fluorobenzal chloride reaches 99% or more), the isomer 2-trichloromethyl-4 -Fluorobenzal chloride does not undergo fluorination or only "incomplete fluorination". That is, from the isomer, two compounds of 2-dichlorofluoromethyl-4-fluorobenzal chloride and 2-chlorodifluoromethyl-4-fluorobenzal chloride are formed stepwise, but further fluorinated 2- It was found that trifluoromethyl-4-fluorobenzal chloride (the regioisomer of 2-trifluoromethyl-5-fluorobenzal chloride) was not formed significantly.

In general, when isomers having methyl groups at different positions form a mixture, it is difficult to replace only the methyl group of a specific compound with a CF ₃ group, and isomers that have similar physical properties and are difficult to separate. Making the production of high purity fluorinated products significantly difficult. On the other hand, in the second step of the present invention, 2-trifluoromethyl-5-fluorobenzal chloride can be selectively synthesized, and hardly separated impurities (such as isomers) are hardly generated. That is, the target product 2-trifluoromethyl-5-fluorobenzal chloride, 2-trichloromethyl-4-fluorobenzal chloride remaining without being fluorinated, and “incomplete fluorination product” Their physical properties are very different and they are easy to separate from each other.

  In the second step of the present invention, it is important to carry out the reaction “in the liquid phase”. Here, the “reaction in the liquid phase” means a reaction performed at a combination of temperature and pressure that keeps the reaction mixture in the liquid phase, and the reaction is performed under the condition that HF having a low boiling point among the reaction components maintains the liquid state. Just do. By performing the “fluorination in the liquid phase”, the selectivity of the target product in the second step is improved.

  The inventors subsequently subject the 2-trifluoromethyl-5-fluorobenzaldehyde obtained in the second step to hydrolysis to give 2-trifluoromethyl which is one of the target compounds of the present invention. It has been found that it can be converted to methyl-5-fluorobenzaldehyde with good yield (third step).

  It was found that the obtained 2-trifluoromethyl-5-fluorobenzaldehyde can be derived into various derivatives by the following “fourth steps (a) to (d)”.

(1) Fourth step (a): 2-trifluoromethyl-5-fluorobenzaldehyde is reacted with hydrogen (H ₂ ) in the presence of a transition metal catalyst to give 2-trifluoromethyl-5-fluorobenzyl alcohol. Obtaining step.

(2) Fourth step (b): 2-trifluoromethyl-5-fluorobenzaldehyde is reacted with hydroxylamine or a salt thereof to obtain 2-trichloromethyl-5-fluorobenzaldoxime, and further the 2-trichloromethyl A step of reacting 5-fluorobenzaldoxime with hydrogen (H ₂ ) in the presence of a transition metal catalyst to obtain 2-trifluoromethyl-5-fluorobenzylamine.

(3) Fourth step (c): A step of obtaining 2- trifluoromethyl -5-fluorobenzoyl chloride, characterized by reacting 2-trifluoromethyl-5-fluorobenzaldehyde with a chlorinating agent.

  (4) Fourth step (d): a step of reacting 2-trifluoromethyl-5-fluorobenzaldehyde with an oxidizing agent to obtain 2-trifluoromethyl-5-fluorobenzoic acid.

  The above reaction in each step is not only a reaction that proceeds under mild conditions, but also does not generate impurities that are difficult to separate, and industrially synthesizes 2-trifluoromethyl-5-fluorobenzaldehyde and its derivatives. , Proved to be an excellent method.

  The inventors have found that the reactions in the above steps proceed particularly advantageously under specific conditions, and have completed the present invention.

That is, the present invention provides a method for producing 2-trifluoromethyl-5-fluorobenzaldehyde, which includes the following three steps.
First step: A step of reacting 3,4-dimethylfluorobenzene with chlorine (Cl ₂ ) to obtain a chlorination reaction mixture.
Second step: The step of reacting the chlorination reaction mixture with hydrogen fluoride (HF) in a liquid phase to obtain a reaction mixture containing 2-trifluoromethyl-5-fluorobenzal chloride.
Third step: a step of obtaining 2- trifluoromethyl -5- fluorobenzaldehyde by bringing the 2- trifluoromethyl -5-fluorobenzal chloride into contact with water in the presence of a Lewis acid catalyst.

The present invention also provides 2-trifluoromethyl-5-fluorobenzaldehyde obtained by the above-described method, which is reacted with hydrogen (H ₂ ) in the presence of a transition metal catalyst. A process for producing methyl-5-fluorobenzyl alcohol is provided.

In addition, the present invention provides 2-trifluoromethyl-5-fluorobenzaldehyde obtained by the above-described method and hydroxylamine or a salt thereof to give 2- trifluoromethyl -5-fluorobenzaldoxime, the 2-trifluoromethyl-5-fluoro-benzaldoxime, the presence of a transition metal catalyst, wherein the reaction with hydrogen (H _2), a method for producing 2-trifluoromethyl-5-fluoro-benzylamine provide.

The present invention also provides a process for producing 2- trifluoromethyl -5-fluorobenzoyl chloride, characterized by reacting 2-trifluoromethyl-5-fluorobenzaldehyde obtained by the above method with a chlorinating agent. I will provide a.

  The present invention also provides a method for producing 2-trifluoromethyl-5-fluorobenzoic acid, characterized by reacting 2-trifluoromethyl-5-fluorobenzaldehyde obtained by the above method with an oxidizing agent. provide.

  In addition, the present invention provides the method according to any one of the above, wherein the reaction in the first step is performed in the presence of a radical initiator or under light irradiation.

  Moreover, this invention provides the method in any one of the said characterized by performing reaction of the said 2nd process on pressurization conditions.

  In addition, the present invention purifies the reaction mixture obtained in the second step and isolates 2-trifluoromethyl-5-fluorobenzal chloride, and then converts the 2-trifluoromethyl-5-fluorobenzal chloride. The method according to any one of the above, wherein the reaction of the third step is carried out.

  The outline of the present invention is shown in the following scheme 6.

  According to the present invention, using 3,4-dimethylfluorobenzene, which is easily available industrially, as a raw material, 2-trifluoromethyl-5-fluorobenzaldehyde and its derivatives can be easily operated at a much lower cost than before. Can be synthesized.

In the present invention, the first to third steps are essential components, and the fourth steps (a) to (d) are added thereto depending on the type of the object.

First, the first step will be described in detail. The first step is a step of bringing 3,4-dimethylfluorobenzene into contact with chlorine (Cl ₂ ) in the reaction region to obtain 2-trichloromethyl-5-fluorobenzal chloride. In this step, normally, 2-trichloromethyl-4-fluorobenzal chloride, which is an isomer, is also produced at the same time, so that the target product is obtained as an “isomer mixture”. The reaction formula is shown below (Scheme 7).

As the reaction region, glass, or a reaction vessel lined with glass, fluororesin or the like is preferably employed. In the case of a reaction vessel having stainless steel, iron, etc. as its inner wall, the reaction itself proceeds, but the metal is converted into chloride (FeCl _{3 in} the case of Fe), which becomes the Lewis acid catalyst and becomes a Friedel-Crafts-type secondary container. Since a reaction may occur and a compound in which Cl is directly bonded to the benzene nucleus may be generated, it is better to use glass or a reaction vessel lined with glass or fluororesin as much as possible.

  A contact method is not specifically limited, It can carry out by a distribution system, a batch type, or a semibatch type. For example, it is generally performed by blowing chlorine gas into 3,4-dimethylfluorobenzene previously charged in a reaction vessel, and is preferably employed. Hydrogen chloride gas generated by the reaction can be discharged from the reaction region together with unreacted chlorine gas and trapped with water, an alkaline aqueous solution or the like.

  To proceed with this reaction, a catalyst such as 2,2′-azobis (4-methoxy-2,4-dimethylvaleronitrile), 2,2′-azobis (2,4-dimethylvaleronitrile), (1 -Phenylethyl) azodiphenylmethane, 2,2'-azobisisobutyronitrile, dimethyl 2,2'-azobisisobutyrate, 1,1'-azobis (1-cyclohexanecarbonitrile), 2,2'-azobis Azo compounds such as (2-methylpropane), 2,2′-azobis (2-amidinopropane) dihydrochloride, 4,4′-azobis (4-cyanopentanoic acid), benzoyl peroxide, dodecanoyl peroxide, Dilauroyl peroxide, t-butyl peroxypivalate, di-t-butyl hydroperoxide, t-butyl-cumyl-peroxide, 2,5-dimethyl-2,5-bis (t-butyl Tilperoxy) radical initiators such as peroxides such as hexyne, isobutyryl peroxide, 3,5,5-trimethylhexanoyl peroxide, red phosphorus, phosphorus pentachloride, phosphorus trichloride, triphenylphosphine, phosphorous acid Phosphorus compounds such as triphenyl are used, and light irradiation is performed. Further, these radical initiation methods may be used in appropriate combination. Even if the above radical initiator is not added, it is possible to generate radicals in the system by heating to a high temperature (approximately 160 ° C. or higher) and cause the same radical reaction. From the viewpoint of keeping, it is preferable to use an initiator.

  The catalyst is usually added in an amount of 0.0001 to 1 mol per mol of the raw material, preferably 0.001 to 0.1 mol, and more preferably 0.001 to 0.05 mol. The catalyst can be added as appropriate by observing the progress of the reaction. If the amount of the radical initiator is less than 0.0001 mol with respect to 1 mol of the raw material, the reaction is likely to stop in the middle, and the yield may be lowered. Moreover, a catalyst can also be added in the middle of reaction as needed.

  The light source for light irradiation in carrying out this chlorination reaction is at least one selected from the group consisting of a high-pressure mercury lamp, a low-pressure mercury lamp, various halogen lamps, a tungsten lamp, a light-emitting diode, and the like. Lamps and tungsten lamps are preferred.

  Although reaction temperature changes with kinds of catalyst to be used, it is about 0-250 degreeC, 30-200 degreeC is preferable and 50-180 degreeC is more preferable. Further, the reaction hardly proceeds at a temperature lower than 0 ° C., and the reaction yield is decreased at a temperature higher than 250 ° C.

  The chlorination of the present invention has a relatively fast reaction until 3 atoms of Cl are introduced into the raw material substrate, and the subsequent chlorination tends to be slow. For this reason, the initial stage of the reaction (until the degree of chlorination reaches a value in the range of about 3 to 4 (eg 3.5)) is relatively low (usually 30 to 100 ° C., preferably 50 to 80 ° C., particularly preferably When the reaction is difficult to proceed at this temperature, a catalyst is added or a higher temperature (usually 150 to 250 ° C, preferably 160 to 200 ° C, particularly preferably 170 to 180 ° C). This is effective. Here, “degree of chlorination” means the average value of the number of chlorine atoms introduced per aromatic ring, calculated from the composition of the reaction mixture at that time.

  In the case of the reaction substrate of the present invention, since two methyl groups are adjacent to each other, a compound in which both methyl groups are converted to a trichloromethyl group has a large steric hindrance, and 6 Cl atoms are introduced. There is usually no risk of 4-bis (trichloromethyl) fluorobenzene being the main product.

  Since the chlorination reaction is exothermic, the reaction temperature can be adjusted by heating or cooling from the outside, changing the chlorine introduction rate, or diluting the chlorine gas with an inert gas. Since the reaction pressure hardly affects the reaction, it is not particularly necessary to pressurize, and it is usually 0.05 to 1 MPa (absolute pressure, hereinafter the same in this specification), and 0.1 to 0.3 MPa. It can be carried out.

  The amount of chlorine used in the reaction may be 5 mol or more with respect to 1 mol of 3,4-dimethylfluorobenzene, but is about 5 to 10 mol, and 5 to 5 by optimizing the reaction apparatus or reaction operation. It can be about 6 mol. Since optimization sets reaction conditions and the chlorination reaction is a gas-liquid contact reaction, conventional means for increasing contact efficiency, for example, adjustment of gas introduction speed, stirring device, gas blowing device, It is effective to use a method such as a sparger or a method using a multistage chlorination reactor as appropriate.

  The chlorination in the first step of the present invention can also be performed in the presence of a solvent. The solvent used can dissolve raw materials and products, is an inert solvent in the chlorination reaction, and preferably has a sufficient boiling point difference with the product, such as carbon tetrachloride, chloroform, Tetrachloroethane, monochlorobenzene, o-, m-, p-dichlorobenzene, trichlorobenzene, monobromobenzene, dibromobenzene, 2,3-, 2,4-, 2,5-, 2,6-, 3,4 -, 3,5-dichlorobenzotrifluoride, 3,4,5-trichlorobenzotrifluoride or bistrifluoromethylbenzene. However, the reaction raw material 3,4-dimethylfluorobenzene and the products 2-trichloromethyl-5-fluorobenzal chloride and 2-trichloromethyl-4-fluorobenzal chloride are both liquid, and chlorine and catalyst are sufficient. Therefore, it is not necessary to use a separate solvent, which is economically preferable.

  The 2-trichloromethyl-5-fluorobenzal chloride obtained by the chlorination reaction in the first step is usually accompanied by the isomer 2-trichloromethyl-4-fluorobenzal chloride as an impurity. The reaction mixture can be separated into each isomer by subjecting it to a purification treatment such as column chromatography, but purification by distillation is extremely difficult. In the present invention, in the next second step, separation is possible by utilizing the difference in reactivity of isomers. Therefore, in order to take advantage of the present invention, the reaction mixture after the completion of the first step should be purified. Instead, it is preferable to use it as it is as a raw material for the second step (fluorination reaction).

  Hereinafter, the second step will be described. In the second step, 2-trichloromethyl-5-fluorobenzal chloride obtained in the first step is brought into contact with hydrogen fluoride (HF) in the liquid phase to obtain 2-trifluoromethyl-5-fluorobenzal chloride. It is a process. As described above, in this second step, even if 2-trichloromethyl-4-fluorobenzal chloride, which is an isomer, coexists in 2-trichloromethyl-5-fluorobenzal chloride as a raw material. A major feature is that the former is preferentially fluorinated and 2-trifluoromethyl-5-fluorobenzal chloride is obtained as the main product (Scheme 8).

  On the other hand, coexisting 2-trichloromethyl-4-fluorobenzal chloride also undergoes fluorination, but the reaction is slow and 2-dichlorofluoromethyl-4-fluorobenzal chloride into which one atom of F has been introduced, Only 2-chlorodifluoromethyl-4-fluorobenzal chloride into which F has been introduced is mainly produced (see Scheme 9).

  The reaction mixture obtained by the fluorination in the second step is also referred to as “fluorination reaction mixture”. 2-Trichloromethyl-4-fluorobenzal chloride or “incompletely fluorinated compound” in the “fluorination reaction mixture” has a higher boiling point than 2-trifluoromethyl-5-fluorobenzal chloride. Therefore, the separation is easy. That is, 2-trifluoromethyl-5-fluorobenzal chloride can be efficiently isolated with high purity from the “fluorination reaction mixture”.

  In the liquid phase fluorination reaction in the second step, a metal halide commonly used in the liquid phase fluorination reaction, for example, antimony pentachloride, tin tetrachloride, etc. can be used as a catalyst, but it may be non-catalyzed. When a catalyst is used, it reacts at a temperature of 0 ° C. or higher and the reaction speeds up. For example, it may be necessary to carry out the reaction at room temperature or lower. In the case of no catalyst, the reaction temperature is usually 40 to 150 ° C, preferably 50 to 100 ° C. If it is less than 40 ° C, the reaction is slow, and if it exceeds 150 ° C, the fluorination of the isomer 2-trichloromethyl-4-fluorobenzal chloride may be difficult to control, and decomposition of the trifluoromethyl group may also occur. This is not preferable because the yield and purity of 2-trifluoromethyl-5-fluorobenzal chloride are reduced.

In the fluorination reaction, hydrogen fluoride is usually used in an amount of 3 to 20 mol, preferably 4 to 12 mol, more preferably 5 to 10 mol, relative to 1 mol of 2-trichloromethyl-5-fluorobenzal chloride. If the amount is less than 3 mol, the yield is unfavorable, and if it is used in a larger amount than 20 mol, the isomer 2-trichloromethyl-4-fluorobenzal chloride is likely to be fluorinated, and the dichloromethyl group (-CHCl ₂ group) is also unfavorable because it may undergo fluorination to produce 2-chlorofluoromethyl-4-fluorobenzotrifluoride and the like.

  The liquid phase fluorination reaction is carried out using a stirrer in a pressure vessel lined with fluoric resin such as Monel, Hastelloy, nickel or these metals, polytetrafluoroethylene, perfluoropolyether resin, etc. , Continuous or semi-continuous reactions are used.

  The reaction pressure is usually 0.1 to 10 MPa due to restrictions on the apparatus. The inventors have found that the reaction in the second step preferably proceeds under pressurized conditions. In particular, when the raw material 2-trichloromethyl-5-fluorobenzal chloride contains the isomer 2-trichloromethyl-4-fluorobenzal chloride, it is preferably in the range of 0.5 MPa to 10 MPa, more preferably When carried out at a pressure of 1 MPa to 5 MPa, the production rate of the desired 2-trifluoromethyl-5-fluorobenzal chloride is sufficiently large, and the production of 2-trifluoromethyl-4-fluorobenzal chloride is suppressed, Particularly preferred. Conversely, if it is less than 0.1 MPa (normal pressure), hydrogen fluoride is not liquefied at the reaction temperature described above, and the reaction may not proceed, which is not preferable.

  From the above, a particularly preferable combination of reaction temperature and reaction pressure is 50 ° C to 100 ° C and 1 MPa to 5 MPa.

  In carrying out the fluorination reaction, an inert solvent can also be used. Examples of such a solvent include 1,4-bistrifluoromethylbenzene. However, since the raw material and product of this step are both liquid and the reaction proceeds smoothly even if no solvent is present, the absence of solvent is preferred from the viewpoint of economy and operability.

  The time required for the fluorination reaction depends on temperature, pressure, the presence or absence of a solvent, and the like. However, in the case where the isomer 2-trichloromethyl-4-fluorobenzal chloride coexists in the raw material 2-trichloromethyl-5-fluorobenzal chloride, the reaction takes longer than necessary in this step. It is important not to let them. Specifically, it is desirable to finish the reaction within 2 hours before or after the 2-trichloromethyl-5-fluorobenzal chloride, which is the raw material in the second step, is completely consumed. . By doing so, the production of 2-trifluoromethyl-4-fluorobenzal chloride, which is difficult to separate, can be effectively suppressed.

  Therefore, the reaction time in the second step is preferably optimized by those skilled in the art while observing the composition of the reaction solution by means such as gas chromatography. Under the above-mentioned conditions of “particularly preferable combination of reaction temperature and reaction pressure”, a reaction time of about 5 hours to 10 hours is preferably employed.

  The reaction mixture of the second step can be worked up by a usual method. That is, unreacted hydrogen fluoride is separated and removed, followed by washing with water and washing with an alkaline aqueous solution (sodium carbonate aqueous solution, sodium hydrogen carbonate aqueous solution, etc.) to remove hydrogen fluoride from the system. Thereafter, moisture can be removed with a desiccant or the like.

  The “fluorination reaction mixture” obtained in the second step can be purified by distillation, whereby 2-trifluoromethyl-5-fluorobenzal chloride is preferably isolated. Such distillation purification is preferably performed under reduced pressure conditions (for example, the boiling point of 2-trifluoromethyl-5-fluorobenzal chloride at 2100 Pa is 72 ° C.). In the case of performing distillation, one obtained by removing hydrogen fluoride by the post-treatment is usually used. In this case, the material of the distillation column is not limited, and glass, stainless steel, tetrafluoroethylene resin, chlorotrifluoroethylene resin, vinylidene fluoride resin, PFA resin, glass, etc. are lined inside. Things can be used. During distillation or the like, a filler can be packed. The number of stages required for this distillation is not limited, but is preferably 5 to 100 stages, more preferably 10 to 50 stages. By this distillation operation, a colorless transparent liquid 2-trifluoromethyl-5-fluorobenzal chloride is isolated as a fraction. The boiling point of 2-trichloromethyl-4-fluorobenzal chloride or a compound in which it is incompletely fluorinated is significantly higher than this (the boiling point of 2-trichloromethyl-4-fluorobenzal chloride is 127 ° C. (1470 Pa), 2-chloro-difluoromethyl-4-fluorobenzal chloride has a boiling point of 100 ° C. (2400 Pa), and therefore can be easily separated as a distillation residue (bottle residue).

  Hereinafter, the third step will be described. The third step is a step of obtaining 2-trifluoromethyl-5-fluorobenzaldehyde by bringing 2-trifluoromethyl-5-fluorobenzal chloride into contact with water under a Lewis acid catalyst in the reaction region.

  As the reaction region, a reaction vessel lined with glass, carbon, glass, fluororesin or the like is preferably employed. In the case of a reaction vessel with stainless steel, iron, etc. as the inner wall, the reaction itself proceeds, but the metal may be corroded by hydrogen chloride (hydrochloric acid), so glass, glass, fluororesin, etc. as much as possible It is better to use a reaction vessel lined with.

  A contact method is not specifically limited, It can carry out by a gaseous phase (flow system) or a liquid phase (batch type), and can be performed by contact with water vapor or contact with water.

  For example, it is common to drop water onto 2-trifluoromethyl-5-fluorobenzal chloride previously charged in a reaction vessel, which is preferably employed. Hydrogen chloride gas generated by the reaction can be discharged from the reaction region and trapped with water, an alkaline aqueous solution or the like.

  In order to proceed with this reaction, a catalyst such as a Lewis acid such as ferric chloride, chromium chloride, aluminum chloride, antimony pentachloride or boron trifluoride is used, and these catalysts are used as a support such as activated carbon. You may carry and use. Even if the above catalyst is not added, it is possible to cause hydrolysis by heating to high temperature with concentrated sulfuric acid, but there is also a concern about side reactions to carboxylic acids, etc. From the viewpoint of keeping, it is preferable to use a catalyst.

  The catalyst is usually added in an amount of 0.0001 to 0.5 mol per mol of the raw material, preferably 0.001 to 0.2 mol, and more preferably 0.005 to 0.1 mol. The catalyst can be added as appropriate by observing the progress of the reaction. If the amount of the catalyst is less than 0.0001 mol with respect to 1 mol of the raw material, the reaction tends to stop in the middle and the yield may be lowered, and it is not preferable if it exceeds 1 mol. Moreover, a catalyst can also be added in the middle of reaction as needed.

  Although reaction temperature changes with kinds of catalyst to be used, it is about 100-250 degreeC normally, 100-200 degreeC is preferable and 100-150 degreeC is more preferable. If the temperature is lower than 100 ° C., water accumulates in the system to deactivate the catalyst and the reaction hardly proceeds. If the temperature exceeds 250 ° C., the reaction yield decreases due to decomposition or the like.

  Since the reaction pressure hardly affects the reaction, it is not particularly necessary to pressurize, and it is usually 0.05 to 1 MPa (absolute pressure, hereinafter the same in this specification), and 0.1 to 0.3 MPa. It can be carried out.

  The amount of water used in the reaction may be 1 mol or more with respect to 1 mol of 2-trifluoromethyl-5-fluorobenzal chloride, but is preferably about 1.05 to 1.2 mol, and optimization is the reaction. Use of conventional means for setting the conditions and increasing the contact efficiency, for example, adjustment of the water introduction speed, water introduction method, stirring device, sparger and the like is effective.

  The hydrolysis in the third step of the present invention can also be performed in the presence of a solvent. The solvent used can dissolve raw materials and products, is an inert solvent in the hydrolysis reaction, and preferably has a sufficient boiling point difference with the product. For example, toluene, o-, m -, P-xylene, 1,3,5-mesitylene, trifluorobenzene, o-, m-, p-, bistrifluoromethylbenzene and the like. However, the reaction raw material 2-trifluoromethyl-5-fluorobenzal chloride and the product 2-trifluoromethyl-5-fluorobenzaldehyde are both liquid, and the product is sufficiently dissolved to serve as a solvent. Therefore, it is not necessary to dare to use a separate solvent, and this is more economical.

  The reaction mixture obtained in the third step can be worked up by a usual method. That is, washing with water and washing with an alkaline aqueous solution (sodium carbonate aqueous solution, sodium hydrogen carbonate aqueous solution, etc.) are performed to remove hydrogen chloride from the system. Thereafter, moisture can be removed with a desiccant or the like.

  The product of the third step can then be distilled, and such distillation purification is preferably carried out under reduced pressure conditions (for example, the boiling point of 2-trifluoromethyl-5-fluorobenzaldehyde at 3000 Pa is 65 ° C.). In the case of carrying out distillation, those from which hydrogen chloride has been removed by the above-mentioned post-treatment are usually used. In this case, the material of the distillation column is not limited, and glass, stainless steel, tetrafluoroethylene resin, chlorotrifluoroethylene resin, vinylidene fluoride resin, PFA resin, glass, etc. are lined inside. Things can be used. A filler can also be packed in the distillation column. The number of stages required for this distillation is not limited, but is preferably 3 to 100 stages, more preferably 3 to 50 stages.

  By distillation, 2-trifluoromethyl-5-fluorobenzaldehyde can be isolated as a colorless liquid fraction.

Hereinafter, the fourth step (a) (reduction of 2-trifluoromethyl-5-fluorobenzaldehyde) will be described. The fourth step (a) is a target compound of the present invention by reacting 2-trifluoromethyl-5-fluorobenzaldehyde obtained in the third step with hydrogen (H ₂ ) in the presence of a transition metal catalyst. In this step, 2-trifluoromethyl-5-fluorobenzyl alcohol is obtained. In addition, this step can be performed by either a gas phase method or a liquid phase method.

  As the transition metal of the transition metal catalyst used in this reaction, palladium, platinum, ruthenium, iridium, or rhodium is preferable because it is not easily corroded under the reaction conditions and has high catalytic activity. Of these, palladium is particularly preferred because it is easy to handle and has high activity. Multiple types of metals may be used simultaneously. The transition metal catalyst is preferably used by being supported on a carrier. As the carrier, activated carbon, silica, or alumina can be used, and activated carbon is preferred. The supporting method is not particularly limited, but the carrier is immersed in the above metal compound solution, or the solution is sprayed onto the carrier, then dried, and reduced with hydrogen gas while being heated to about 150 ° C. to 350 ° C. Obtained by. The obtained catalyst may be used as it is, but it is preferable to use it as a “water-containing catalyst (wet product)” mixed with an appropriate amount of water. Moreover, as a transition metal catalyst which can be prepared in this way, you may use a commercially available thing (for example, palladium / activated carbon catalyst).

  The total value of the amount of transition metal supported on the carrier in this reaction (amount converted to metal atoms) is not particularly limited, but is preferably 0.1 g to 10 g, particularly preferably 0.2 g to 5 g, relative to 100 g of the carrier. If it is less than 0.1 g, the reaction rate is slow, and if it exceeds 10 g, it is not economically preferable. The transition metal catalyst thus prepared is preferably used in an amount of 0.1 to 30% by weight (weight excluding moisture) based on the raw material compound obtained in the third step, and 1 to 10% by weight (excluding moisture). (Weight) is more preferable. In addition, since these transition metal catalysts are solid-phase catalysts, they can be separated and reused by an operation such as filtration after being used for the reaction.

  In this reaction, an additive other than the transition metal catalyst is not necessary, but the addition of an acid is preferable because the reaction proceeds rapidly by adding an acid. As the acid used, sulfuric acid, hydrochloric acid, acetic acid and the like are used, but the acid is not particularly limited. Among these, sulfuric acid is preferable because it is easy to handle.

  The amount of the protonic acid used in this reaction is preferably 0.01 g to 20 g, particularly preferably 0.1 g to 5 g, relative to 100 g of the substrate. If the amount is less than 0.01 g, the effect becomes small, and if it exceeds 20 g, it is not economically preferable.

  Although there is no restriction | limiting in particular in the specific operation procedure of a 4th process (a), For example, it can implement by the following procedure. 2-trifluoromethyl-5-fluorobenzaldehyde is charged into an autoclave that can withstand the pressurized conditions. As the material inside the autoclave, a reaction vessel lined with glass, carbon or glass, fluororesin, or the like is preferably employed. In the case of a reaction vessel whose inner wall is made of stainless steel, iron, etc., the reaction itself proceeds, but the metal may be corroded by acid, so it was lined with glass or glass or fluororesin as much as possible. It is better to use a reaction vessel. Subsequently, a predetermined amount of transition metal catalyst is added, the container is sealed, and stirring in the container is started. Connect to a hydrogen gas cylinder and pressurize and heat. Thereafter, heating or cooling is performed so as to maintain a predetermined temperature, and hydrogen gas may be supplied continuously or intermittently so that the system is maintained at a predetermined pressure. It is preferable to carry out the reaction while sampling appropriately during the reaction and measuring the progress of the reaction by an analytical method such as NMR or gas chromatography. The reaction is continued until the raw material is sufficiently converted into the target product or hydrogen gas is no longer absorbed.

  The reaction temperature is preferably 40 to 150 ° C, particularly preferably 50 to 100 ° C. The pressure of hydrogen in the system is preferably normal pressure (0.1 MPa) or more and 10 MPa or less, particularly preferably 0.3 to 2.0 MPa. It is not preferable to carry out at a very high pressure because there is no problem in terms of reactivity, but an industrial problem such as an excessive strength required for the reactor occurs. For example, when a glass container is used as the reactor, the upper limit of the pressure is usually about 2 MPa, so it is necessary to set the pressure while paying attention to the strength of the reactor.

  The purification treatment of the reaction mixture after the completion of the fourth step (a) may be performed based on a usual organic synthesis treatment method, and is not particularly limited. That is, washing with water or alkaline aqueous solution (sodium carbonate aqueous solution, sodium hydrogen carbonate aqueous solution, etc.) is performed to remove the acid content from the system. Thereafter, moisture can be removed with a desiccant or the like.

  The product 2-trifluoromethyl-5-fluorobenzyl alcohol of the fourth step (a) can then be distilled, and such distillation purification is preferably performed under reduced pressure conditions. In the case of performing distillation, a product obtained by removing acid from the post-treatment is usually used. In this case, the material of the distillation column is not limited, and glass, stainless steel, tetrafluoroethylene resin, chlorotrifluoroethylene resin, vinylidene fluoride resin, PFA resin, glass, etc. are lined inside. Things can be used. During distillation or the like, a filler can be packed. The number of stages required for this distillation is not limited, but is preferably 3 to 100 stages, more preferably 3 to 50 stages.

  By distillation, a colorless and transparent liquid 2-trifluoromethyl-5-fluorobenzyl alcohol is isolated as a fraction.

Hereinafter, the fourth step (b) (amination of 2-trifluoromethyl-5-fluorobenzaldehyde) will be described. In the fourth step (b), 2-trifluoromethyl-5-fluorobenzaldehyde obtained in the third step is reacted with hydroxyamine to obtain 2-trifluoromethyl-5-fluorobenzaldoxime (“oxime”). Then, the obtained 2-trifluoromethyl-5-fluorobenzaldoxime is reacted with hydrogen (H ₂ ) in the presence of a transition metal catalyst to give 2-trifluoromethyl-5-fluorobenzyl alcohol. This is a process of obtaining (referred to as “reduction reaction”).

  The hydroxyamine used in the oximation in this step is usually generated by reacting a hydroxyamine salt with an alkali metal aqueous solution in the system. Although there is no restriction | limiting in the kind of hydroxyamine salt, Hydroxyamine hydrochloride, a sulfated amine, etc. are common and are employ | adopted suitably. Moreover, although there is no restriction | limiting in the kind of alkali metal of alkali metal aqueous solution, Sodium hydroxide, potassium hydroxide, etc. are common and are employ | adopted suitably.

  In the oximation method of the present invention, the amount of alkali metal in the aqueous alkali metal solution is usually equimolar or more with respect to the sum of the number of moles of the hydroxylamine salt used and the number of moles of the raw material, but the mole of the hydroxylamine salt used. 1-5 times mole is preferable with respect to the sum of the number and the mole number of a raw material, and 1-3 times mole is more preferable. The equimolar or less is not preferable because the reaction becomes slow. On the other hand, there is no problem in terms of reactivity even if it is used in an amount of 5 moles or more, but the amount of excess alkali metal neutralized after the reaction is increased. Further, an increase in the amount of the alkali metal aqueous solution is not preferable because an industrial problem such as deterioration of productivity occurs.

  In the oximation method of this step, the concentration of the aqueous alkaline solution is not limited, but is preferably 1% to 48% by weight, and particularly preferably 5% to 30% by weight. If the amount is 1% by weight or less, the aqueous alkali solution increases and the productivity is deteriorated. If the amount exceeds 48% by weight, there is no problem in terms of reactivity, but operability problems such as solidification and precipitation of alkali metal occur.

  The oximation of this reaction is generally performed in a solvent. As solvent, hydroxyamine salt, alkali metal aqueous solution, 2-trifluoromethyl-5-fluorobenzaldoxime and alkali metal salt of 2-trifluoromethyl-5-fluorobenzaldoxime are dissolved and inactive for oximation As the solvent, alcohol, water or the like is used. As the alcohol, lower alcohols such as methanol, ethanol, propanol, isopropanol, butanol, and tert-butanol are preferable, and higher alcohols having a large number of carbon atoms are not preferable because of poor solubility in water.

  Although there is no restriction | limiting in particular in the specific operation procedure of oximation of a 4th process (b), For example, it can implement by the following procedure. Water or a solvent or a mixture of water and a solvent is put into a reaction vessel. Subsequently, a predetermined amount of hydroxyamine salt is charged. As the material inside the reaction vessel, a reaction vessel lined with glass, carbon or glass, fluororesin or the like is preferably employed. The reaction itself proceeds even in the case of a reaction vessel whose inner wall is made of stainless steel, iron, etc., but since the metal uses hydrochloric acid during neutralization after the reaction, it can be corroded by this hydrochloric acid. It is better to use glass or a reaction vessel lined with glass, fluororesin or the like. Stirring in the container is started, and a predetermined amount of an aqueous alkali metal solution is added while cooling. There are methods for charging the alkali metal aqueous solution such as batch charging, divided charging, and dropping charging, but there is no particular limitation, and the charging should be performed with care so as not to exceed the set temperature. Subsequently, a predetermined amount of 2-trifluoromethyl-5-fluorobenzaldehyde is dropped by using a dropping device such as a dropping funnel or a metering pump. The reaction is continued until the raw material is sufficiently converted into the target product even after dropping. During the reaction, it is cooled or heated so as to maintain a predetermined temperature. It is preferable to carry out the reaction while appropriately sampling during the reaction and measuring the progress of the reaction by an analytical method such as NMR or gas chromatography.

  The reaction temperature is preferably -50 to 150 ° C, particularly preferably 0 to 100 ° C. Since the reaction pressure hardly affects the reaction, it is not particularly necessary to pressurize, and it is usually 0.05 to 1 MPa (absolute pressure, hereinafter the same in this specification), and 0.1 to 0.3 MPa. It can be carried out.

  The purification of the reaction product after the completion of the oximation in this step may be performed based on a general organic synthesis method. For example, when neutralized with hydrochloric acid to pH 9 to 3, crystals of 2-trifluoromethyl-5-fluorobenzaldoxime are precipitated. When the pH is 9 or more, the yield is decreased, and when the pH is 3 or less, the produced 2-trifluoromethyl-5-fluorobenzaldoxime may be decomposed into 2-trifluoromethyl-5-fluorobenzaldehyde and hydroxyamine. Absent. The crystals are collected by filtration and dried. Further, neutralize with hydrochloric acid until the pH is in the range of 9 to 3, then pour with an organic solvent such as ethyl acetate, toluene, methylene chloride, and wash with water to remove the acid content from the system. After removal of the solvent, the solvent can be distilled off.

  The reactant obtained by the oximation in this step is preferably used as it is as a raw material for the reduction reaction without further purification.

In the reduction reaction in this step, 2-trifluoromethyl-5-fluorobenzaldoxime obtained by oximation in this step is reacted with hydrogen (H ₂ ) in the presence of a transition metal catalyst, and the target compound of the present invention is used. This is a step of obtaining certain 2-trifluoromethyl-5-fluorobenzylamine.

  As the transition metal of the transition metal catalyst used in this reaction, palladium, platinum, ruthenium, iridium, or rhodium is preferable because it is not easily corroded under the reaction conditions and has high catalytic activity. Of these, palladium is particularly preferred because it is easy to handle and has high activity. Multiple types of metals may be used simultaneously. The transition metal catalyst is preferably used by being supported on a carrier. As the carrier, activated carbon, silica, or alumina can be used, and activated carbon is preferred. The supporting method is not particularly limited, but the carrier is immersed in the above metal compound solution, or the solution is sprayed onto the carrier, then dried, and reduced with hydrogen gas while being heated to about 150 ° C. to 350 ° C. Obtained by. The obtained catalyst may be used as it is, but it is preferable to use it as a “water-containing catalyst (wet product)” mixed with an appropriate amount of water. Moreover, as a transition metal catalyst which can be prepared in this way, you may use a commercially available thing (for example, palladium / activated carbon catalyst).

  In the method of the present invention, the total value of the amount of transition metal supported on the support (amount converted to metal atoms) is not particularly limited, but is preferably 0.1 g to 10 g, particularly 0.2 g to 5 g, relative to 100 g of the support. preferable. If it is less than 0.1 g, the reaction rate is slow, and if it exceeds 10 g, it is not economically preferable. The transition metal catalyst thus prepared is preferably used in an amount of 0.1 to 30% by weight (weight excluding moisture) based on the raw material compound obtained in the third step, and 1 to 10% by weight (excluding moisture). (Weight) is more preferable. In addition, since these transition metal catalysts are solid-phase catalysts, they can be separated and reused by an operation such as filtration after being used for the reaction.

  In the reduction reaction method of the present invention, since the starting material 2-trifluoromethyl-5-fluorobenzaldoxime is solid at room temperature, it is preferable to use a solvent. Although there is no restriction | limiting in particular in a solvent, Ethyl acetate, toluene, methanol, ethanol, propanol, isopropanol etc. are common, and are employ | adopted suitably.

  In this reaction, an additive other than the transition metal catalyst is not necessary, but hydrogen chloride or ammonia can be added to suppress the formation of a secondary amine represented by the following formula, which is usually preferred.

  The amount of hydrogen chloride or ammonia used in the reduction reaction is preferably 1 to 20 mol, particularly preferably 1 to 10 mol, relative to 1 mol of the substrate. If the amount is less than 1 mol, the effect is small, and if it exceeds 20 mol, it is not economically preferable. The hydrogen chloride or ammonia to be used is usually one filled in a gas cylinder, but a commercially available one dissolved in a solvent (for example, hydrogen chloride methanol solution, ammonia methanol solution) may be used.

  Although there is no restriction | limiting in particular in the specific operation procedure of the reduction reaction of this process, For example, it can implement by the following procedure. 2-Trifluoromethyl-5-fluorobenzaldoxime and a solvent are put into an autoclave that can withstand pressure conditions. As the material inside the autoclave, a reaction vessel lined with glass, carbon or glass, fluororesin, or the like is preferably employed. Although the reaction itself proceeds even in the case of a reaction vessel having an inner wall of stainless steel, iron or the like, the use of hydrogen chloride as an additive is not preferable because the metal may be corroded by hydrogen chloride. Subsequently, a predetermined amount of transition metal catalyst is added, the container is sealed, and stirring in the container is started. In the case of adding hydrogen chloride or ammonia, a predetermined amount is introduced by connecting a cylinder of hydrogen chloride gas or ammonia. Subsequently, it is connected to a hydrogen gas cylinder and pressurized and heated. Thereafter, heating or cooling is performed so as to maintain a predetermined temperature, and hydrogen gas may be supplied continuously or intermittently so that the interior of the system is maintained at a predetermined pressure. It is preferable to carry out the reaction while sampling appropriately during the reaction and measuring the progress of the reaction by an analytical method such as NMR or gas chromatography. The reaction is continued until the raw material is sufficiently converted into the target product or hydrogen gas is no longer absorbed.

  The reaction temperature is preferably 0 to 150 ° C, particularly preferably 10 to 100 ° C. The pressure of hydrogen in the system is preferably normal pressure (0.1 MPa) or more and 10 MPa or less, particularly preferably 0.3 to 2.0 MPa. It is not preferable to carry out at a very high pressure because there is no problem in terms of reactivity, but an industrial problem such as an excessive strength required for the reactor occurs. For example, when a glass container is used as the reactor, the upper limit of the pressure is usually about 2 MPa, so it is necessary to set the pressure while paying attention to the strength of the reactor.

  The purification treatment of the reaction mixture after completion of the reduction reaction in this step may be performed based on a normal organic synthesis treatment method, and is not particularly limited. That is, after removing the catalyst by filtration, washing with water or an alkaline aqueous solution (such as an aqueous sodium carbonate solution or an aqueous sodium hydrogen carbonate solution) can be performed, and then moisture can be removed with a desiccant or the like.

  The distillation purification in this step is preferably carried out under reduced pressure conditions. When distillation is carried out, usually, the acid content removed by the above-mentioned post-treatment is used. In this case, the material of the distillation column is not limited, and glass, stainless steel, tetrafluoroethylene resin, chlorotrifluoroethylene resin, vinylidene fluoride resin, PFA resin, glass, etc. are lined inside. Things can be used. A filler can also be packed in the distillation column. The number of stages required for this distillation is not limited, but is preferably 3 to 100 stages, more preferably 3 to 50 stages.

  The product of the fourth step (b) can then be distilled, and such distillation purification is preferably performed under reduced pressure conditions. The colorless and transparent liquid 2-trifluoromethyl-5-fluorobenzylamine is isolated as a fraction by distillation.

  Hereinafter, the fourth step (c) (chlorination of 2-trifluoromethyl-5-fluorobenzaldehyde) will be described.

  The fourth step (c) is a step of contacting 2-trifluoromethyl-5-fluorobenzaldehyde obtained in the third step with a chlorinating agent in the reaction region to obtain 2-trifluoromethyl-5-fluorobenzoyl chloride. It is.

Examples of the chlorinating agent in this reaction include chlorine (Cl ₂ ), POCl ₃ , PCl ₃ , PCl ₅ , (CO) ₂ Cl ₂ , SO ₂ Cl ₂ , and chlorine (Cl ₂ ) is preferable. It is particularly preferable to carry out by a radical reaction with a radical initiator, heat, light or the like.

As the reaction region, glass, or a reaction vessel lined with glass, fluororesin or the like is preferably employed. In the case of a reaction vessel having stainless steel, iron, etc. as its inner wall, the reaction itself proceeds, but the metal is converted to chloride (FeCl _{3 in} the case of Fe), which becomes a Lewis acid catalyst and becomes a Friedel-Crafts-type secondary container. Since a reaction may occur and a compound in which Cl is directly bonded to the benzene nucleus may be generated, it is better to use glass or a reaction vessel lined with glass or fluororesin as much as possible.

  A contact method is not specifically limited, It can carry out by a distribution system, a batch type, or a semibatch type. For example, it is generally carried out by blowing chlorine gas into 2-trifluoromethyl-5-fluorobenzaldehyde previously charged in a reaction vessel, which is preferably employed. Hydrogen chloride gas generated by the reaction can be discharged from the reaction region together with unreacted chlorine gas and trapped with water, an alkaline aqueous solution or the like.

  To proceed with this reaction, a catalyst such as 2,2′-azobis (4-methoxy-2,4-dimethylvaleronitrile), 2,2′-azobis (2,4-dimethylvaleronitrile), (1 -Phenylethyl) azodiphenylmethane, 2,2'-azobisisobutyronitrile, dimethyl 2,2'-azobisisobutyrate, 1,1'-azobis (1-cyclohexanecarbonitrile), 2,2'-azobis Azo compounds such as (2-methylpropane), 2,2′-azobis (2-amidinopropane) dihydrochloride, 4,4′-azobis (4-cyanopentanoic acid), benzoyl peroxide, dodecanoyl peroxide, Dilauroyl peroxide, t-butyl peroxypivalate, di-t-butyl hydroperoxide, t-butyl-cumyl-peroxide, 2,5-dimethyl-2,5-bis (t-butyl Tilperoxy) radical initiators such as peroxides such as hexyne, isobutyryl peroxide, 3,5,5-trimethylhexanoyl peroxide, red phosphorus, phosphorus pentachloride, phosphorus trichloride, triphenylphosphine, phosphorous acid Phosphorus compounds such as triphenyl are used, and light irradiation is performed. Further, these radical initiation methods may be used in appropriate combination. Even if the above radical initiator is not added, it is possible to generate radicals in the system by heating to a high temperature (approximately 160 ° C. or higher) and cause the same radical reaction. From the viewpoint of keeping, it is preferable to use an initiator.

  The catalyst is usually added in an amount of 0.0001 to 1 mol per mol of the raw material, preferably 0.001 to 0.1 mol, and more preferably 0.001 to 0.05 mol. The catalyst can be added as appropriate by observing the progress of the reaction. If the amount of the radical initiator is less than 0.0001 mol with respect to 1 mol of the raw material, the reaction is likely to stop in the middle, and the yield may be lowered. Moreover, a catalyst can also be added in the middle of reaction as needed.

  The light source for light irradiation in carrying out this chlorination reaction is at least one selected from the group consisting of a high-pressure mercury lamp, a low-pressure mercury lamp, various halogen lamps, a tungsten lamp, a light-emitting diode, and the like. Lamps and tungsten lamps are preferred.

  Although reaction temperature changes with kinds of catalyst to be used, it is about 0-250 degreeC, 30-200 degreeC is preferable and 50-180 degreeC is more preferable. Further, the reaction hardly proceeds at a temperature lower than 0 ° C., and the reaction yield is decreased at a temperature higher than 250 ° C.

  Since the chlorination reaction is exothermic, the reaction temperature can be adjusted by heating or cooling from the outside, changing the chlorine introduction rate, or diluting the chlorine gas with an inert gas. Since the reaction pressure hardly affects the reaction, it is not particularly necessary to pressurize, and it is usually 0.05 to 1 MPa (absolute pressure, hereinafter the same in this specification), and 0.1 to 0.3 MPa. Can be done.

  The amount of chlorine used in the reaction may be 1 mol or more per mol of 2-trifluoromethyl-5-fluorobenzaldehyde, but is about 1 to 1.5 mol, and the reaction apparatus or reaction operation is optimized. By doing so, it can be made about 1-1.2 mol. Since optimization sets reaction conditions and the chlorination reaction is a gas-liquid contact reaction, conventional means for increasing contact efficiency, for example, adjustment of gas introduction speed, stirring device, gas blowing device, It is effective to use a method such as a sparger or a method using a multistage chlorination reactor as appropriate.

  The chlorination in the fourth step (c) of the present invention can also be performed in the presence of a solvent. The solvent used can dissolve raw materials and products, is an inert solvent in the chlorination reaction, and preferably has a sufficient boiling point difference with the product, such as carbon tetrachloride, chloroform, Tetrachloroethane, monochlorobenzene, o-, m-, p-dichlorobenzene, trichlorobenzene, monobromobenzene, dibromobenzene, 2,3-, 2,4-, 2,5-, 2,6-, 3,4 -, 3,5-dichlorobenzotrifluoride, 3,4,5-trichlorobenzotrifluoride or bistrifluoromethylbenzene. However, the reaction raw material 2-trifluoromethyl-5-fluorobenzaldehyde and the product 2-trifluoromethyl-5-fluorobenzoyl chloride are both liquids, and sufficiently dissolve chlorine and catalyst, and also serve as a solvent. Therefore, it is not necessary to dare to use a separate solvent, and this is more economical.

  The purification process of the reaction product after the completion of the fourth step (c) may be performed based on a normal organic synthesis method, and is not particularly limited. That is, washing with water or alkaline aqueous solution (sodium carbonate aqueous solution, sodium hydrogen carbonate aqueous solution, etc.) is performed to remove the acid content from the system. Thereafter, moisture can be removed with a desiccant or the like.

  The product of the fourth step (c) can then be distilled, and such distillation purification is preferably performed under reduced pressure conditions. In the case of performing distillation, a product obtained by removing acid from the post-treatment is usually used. In this case, the material of the distillation column is not limited, and glass, stainless steel, tetrafluoroethylene resin, chlorotrifluoroethylene resin, vinylidene fluoride resin, PFA resin, glass, etc. are lined inside. Things can be used. A filler can also be packed in the distillation column. The number of stages required for this distillation is not limited, but is preferably 3 to 100 stages, more preferably 3 to 50 stages.

  By distillation, a colorless and transparent liquid 2-trifluoromethyl-5-fluorobenzyl alcohol is isolated as a fraction.

  Hereinafter, the fourth step (d) (oxidation of 2-trifluoromethyl-5-fluorobenzaldehyde) will be described. The fourth step (d) is a step of obtaining 2-trifluoromethyl-5-fluorobenzoic acid by bringing the 2-trifluoromethyl-5-fluorobenzaldehyde obtained in the third step into contact with an oxidizing agent.

There are no particular restrictions on the oxidizing agent used in this process, but manganese dioxide, sodium permanganate, potassium permanganate, sodium chromate, potassium chromate, sodium dichromate, potassium dichromate, chlorite Sodium, potassium chlorite, sodium perchlorate, potassium perchlorate, peracetic acid, sulfuric acid, nitric acid, hydrogen peroxide, ozone, silver oxide, silver nitrate, cupric oxide, cupric hydroxide, selenium dioxide, etc. Can be mentioned. Among them, it is industrially particularly preferable to react with oxygen (O ₂ ) in a basic aqueous solution from the viewpoint of excellent reactivity and excellent post-treatment, waste, and economic efficiency.

  When oxygen is used as the oxidizing agent, the base constituting the basic aqueous solution is not particularly limited as long as it can dissolve 2-trifluoromethyl-5-fluorobenzoic acid, which is a product, but an alkali metal salt, Examples include alkali metal hydroxides, alkaline earth metal salts, alkaline earth metal hydroxides (calcium hydroxide, etc.), organic bases (trimethylamine, triethylamine, pyridine, lutidine, etc.), among which alkali metal salts, alkali metal waters Oxides are preferred. Among these, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, trisodium phosphate, tripotassium phosphate, sodium acetate, potassium acetate and the like are preferably used. Among these, sodium hydroxide and potassium hydroxide are water. It is particularly preferable because of its high solubility in water and easy handling.

  Although the quantity of the base which comprises basic aqueous solution is 1 mol or more normally with respect to the raw material manufactured at the 3rd process, 1-5 mol is preferable and 1-3 mol is more preferable. If it is 1 mol or less, 2-trifluoromethyl-5-fluorobenzoic acid to be produced cannot be sufficiently dissolved, and even if 5 mol or more is used, there is no problem in terms of reactivity, but it is produced by increasing the volume of the basic aqueous solution. This is not preferable because it causes industrial problems such as worsening the properties.

  In the method of the present invention, the concentration of the basic aqueous solution is not limited, but is preferably 1% by weight to 30% by weight, and particularly preferably 5% by weight to 20% by weight. If the amount is less than 1% by weight, the volume of the basic aqueous solution becomes large and the productivity is deteriorated. If the amount exceeds 30% by weight, the cannaro reaction proceeds to generate a large amount of by-products, which is not preferable. .

  Although there is no restriction | limiting in particular in the specific operation procedure of 4th process (d), For example, it can implement by the following procedure. 2-trifluoromethyl-5-fluorobenzaldehyde is charged into an autoclave that can withstand the pressurized conditions. As the material inside the autoclave, a reaction vessel lined with glass, carbon or glass, fluororesin, or the like is preferably employed. In the case of a reaction vessel with stainless steel, iron, etc. as the inner wall, the reaction itself proceeds, but the metal may be corroded by hydrochloric acid, so it was lined with glass or glass or fluororesin as much as possible. It is better to use a reaction vessel. Subsequently, a predetermined amount of a basic aqueous solution such as an aqueous alkali metal solution is added, the container is sealed, and stirring in the container is started. Connect to an oxygen gas cylinder and pressurize and heat. Thereafter, heating or cooling is performed so as to maintain a predetermined temperature, and oxygen gas may be supplied continuously or intermittently so that the inside of the system is maintained at a predetermined pressure. It is preferable to carry out the reaction while appropriately sampling during the reaction and measuring the progress of the reaction by an analytical method such as NMR or gas chromatography. The reaction is continued until the raw material is sufficiently converted into the target product or oxygen gas is no longer absorbed.

  The reaction temperature is preferably 50 to 150 ° C, particularly preferably 60 to 100 ° C. The pressure of oxygen in the system is preferably normal pressure (0.1 MPa) or more and 10 MPa or less, particularly preferably 0.3 to 2.0 MPa. It is not preferable to carry out at a very high pressure because there is no problem in terms of reactivity, but an industrial problem such as an excessive strength required for the reactor occurs. For example, when a glass container is used as the reactor, the upper limit of the pressure is usually about 2 MPa, so it is necessary to set the pressure while paying attention to the strength of the reactor.

  The purification process of the reaction product after the completion of the fourth step (d) may be performed based on a normal organic synthesis method, and is not particularly limited. For example, when neutralization with hydrochloric acid to pH 3 to 1, crystals of 2-trifluoromethyl-5-fluorobenzoic acid are precipitated. The crystals are collected by filtration and dried. Moreover, after neutralizing to pH 3 to 1 with hydrochloric acid, it was poured into an organic solvent such as ethyl acetate, toluene, and methylene chloride, washed with water, acid content was removed from the system, and moisture was removed with a desiccant or the like. Thereafter, the solvent can be distilled off.

  The purification in this step can be performed by recrystallization with an organic solvent. When recrystallization is performed, the crystal obtained by the post-treatment is usually used. In this case, the material of the container used for recrystallization is not limited, and glass, stainless steel, tetrafluoroethylene resin, chlorotrifluoroethylene resin, vinylidene fluoride resin, PFA resin, glass, etc. It is possible to use one that has been lined. The solvent used for recrystallization is not particularly limited as long as 2-trifluoromethyl-5-fluorobenzoic acid can be dissolved by heating and can be precipitated by cooling, but saturated hydrocarbons such as hexane and heptane are not limited. preferable.

  When the recrystallized crystals are dried, white crystalline 2-trifluoromethyl-5 fluorobenzoic acid is isolated.

  EXAMPLES Hereinafter, although an Example demonstrates this invention in detail, the embodiment of this invention is not restricted to this. Unless otherwise noted, “%” in the examples represents the area% of the gas chromatograph of each component in the organic phase excluding the solvent.

[Example 1]
(Example 1-1) Chlorination (first step)
In a 500 ml four-necked flask equipped with a Dimroth tube, a thermometer and a chlorine blowing tube, 248.0 g of 3,4-dimethylfluorobenzene and 0.93 g of 2,2′-azobisbutyronitrile (AIBN) ( 0.28 mol%) was added, the internal temperature was raised to 60 ° C. while stirring, and chlorine gas was introduced at a rate of about 1.0 to 1.1 mol / Hr to initiate the reaction. While maintaining the internal temperature at 65 to 70 ° C., chlorine gas was supplied for 7 hours. As a result, the chlorination degree of the reaction solution was 3.51.

  Thereafter, the internal temperature was raised to 180 ° C., and the reaction was further continued for 5 hours. The composition of the reaction liquid after the reaction was continued was determined by gas chromatography analysis to show that the target product, 2-trichloromethyl-5-fluorobenzal chloride was 52.2% and the isomer 2-trichloromethyl-4-fluoroben 44.2% sarchloride, 0.3% 3,4-bis (dichloromethyl) fluorobenzene as other by-products, 2-chloro-5-fluorobenzal chloride and 2-chloro-4-fluoroben The sum of sarchloride was 0.9%, and the sum of 2-chloro-4-fluorobenzotrichloride and 2-chloro-5-fluorobenzotrichloride was 2.2%. The weight of the reaction solution was 585.0 g. This reaction solution (chlorination reaction mixture) was used in the following (Example 1-2) without purification.

(Example 1-2) Fluorination (second step) and distillation purification To a metal 1L autoclave equipped with a stirrer, a cooling reflux pipe equipped with a pressure regulating valve, a thermocouple, a pressure gauge, and a sampling pipe, 579.4 g of the chlorination reaction mixture obtained in (Example 1-1) and 169.3 g of anhydrous hydrogen fluoride were charged and hermetically sealed, the internal temperature was raised to 80 ° C. while stirring, and the reaction was started. The pressure adjustment valve was adjusted so that the internal pressure was 2.0 to 2.1 MPa, and the reaction was performed for 8 hours while releasing hydrogen chloride generated from the pressure adjustment valve to the outside of the system. The composition of the reaction solution (organic phase) at this time is 52.6% of 2-trifluoromethyl-5-fluorobenzal chloride, which is the target product, and 2-trifluoromethyl, which is an isomer, based on analysis by gas chromatography. -4-Fluorobenzal chloride was 0.7%. In addition, 2.4% of 2-chlorofluoromethyl-4-fluorobenzotrifluoride, which is the perfluorinated product, and 2-chlorofluoromethyl-5-fluorobenzo, which is the perfluorinated product of the isomer, are also present. 1.6% of trifluoride, 1.1% of 2-chlorodifluoromethyl-5-fluorobenzal chloride as an intermediate of the target product, 2-chlorodifluoro which is a compound in which the isomer is incompletely fluorinated 21.9% of methyl-4-fluorobenzal chloride, 11.7% of 2-dichlorofluoromethyl-4-fluorobenzal chloride, which is a compound in which the isomer was incompletely fluorinated, and unreacted isomerism The product 2-trichloromethyl-4-fluorobenzal chloride was 1.4%.

  After completion of the reaction, the recovered reaction solution was washed with water, washed with an aqueous sodium hydrogen carbonate solution, and further washed with water. Magnesium sulfate was added to the reaction solution after washing, followed by filtration after stirring. The weight of the reaction solution obtained from the filtrate was 445.1 g.

  The resulting fluorination reaction mixture was purified by distillation in a 45 cm distillation column (10 theoretical plates) packed with Dixon packing.

A fraction having a temperature of 72 to 76 ° C. was collected by this distillation, and 164.5 g of a target product having a purity of 95.3% was obtained. The overall yield from 3,4-dimethylfluorobenzene as the chlorination raw material was 33.3%.
[Physical property data of 2-trifluoromethyl-5-fluorobenzal chloride]
¹ H-NMR (reference material: TMS, solvent: CDCl ₃ )
δ ppm: 7.04 (d, 1.7 Hz, 1 H), 7.18 (mlut, 2.7 Hz, 7.4 Hz, 8.8 Hz, 1 H), 7.64 (dd, 5.4 Hz, 8.8 Hz) 1H), 7.82 (dd, 2.7 Hz, 9.3 Hz, 1H)
¹⁹ F-NMR (reference material: CCl ₃ F, solvent: CDCl ₃ )
δ ppm: −58.36 (3F), −105.13 (1F)
GLC-MS
m / z (rel. intensity): 246 (M ⁺ , 11.4), 211 (100), 176 (46.6), 107 (12.3), 88 (17.4)
Shape: colorless and transparent liquid.

[Example 2]
(Example 2-1) Chlorination (first step)
A 500 ml four-necked flask equipped with a Dimroth, thermometer and chlorine blowing tube was charged with 248.0 g of 3,4-dimethylfluorobenzene and 0.93 g (0.28 mol%) of AIBN, and the internal temperature was adjusted to 60 with stirring. The temperature was raised to ° C., and chlorine gas was introduced at a rate of about 1.0 to 1.1 mol / Hr to initiate the reaction. While maintaining the internal temperature at 65 to 70 ° C., chlorine gas was supplied for 7 hours. The chlorination degree of the reaction liquid after 7 hours was 3.60. Thereafter, 1.46 g (0.50 mol%) of di-t-butyl peroxide was added and the temperature was raised to 130 ° C., and the reaction was continued for 10 hours. The composition of the reaction solution after 10 hours was determined by gas chromatography analysis to be 52.6% of 2-trichloromethyl-5-fluorobenzal chloride as a target product and 2-trichloromethyl-4-fluoro as an isomer. 44.9% benzal chloride, 1.4% 3,4-bis (dichloromethyl) fluorobenzene as other by-products, 2-chloro-5-fluorobenzal chloride and 2-chloro-4-fluoro The sum of benzal chloride was 0.3%, and the sum of 2-chloro-5-fluorobenzotrichloride and 2-chloro-5-fluorobenzotrichloride was 0.4%. The weight of the reaction solution was 591.2 g. This reaction solution (chlorination reaction mixture) was used in the subsequent (Example 2-2) without purification.

(Example 2-2) Fluorination (second step) and distillation purification A metal 1 L autoclave equipped with a stirrer, a cooling reflux pipe equipped with a pressure control valve, a thermocouple, a pressure gauge, and a sampling pipe was used. The reaction was started by charging 587.3 g of the chlorination reaction mixture obtained in (Example 2-1) and 237.3 g of anhydrous hydrogen fluoride and sealing it, raising the internal temperature to 70 ° C. while stirring. The pressure regulating valve was adjusted so that the internal pressure became 2.0 to 2.1 MPa, and the reaction was performed for 9 hours while releasing hydrogen chloride generated from the pressure regulating valve to the outside of the system. The composition of the reaction solution after 9 hours was measured by gas chromatography. As a result, the target product, 2-trifluoromethyl-5-fluorobenzal chloride, was 57.2%, and the isomerized fluorinated product, 2-trifluoro. Methyl-4-fluorobenzal chloride was 0.2%. In addition, 2.4% of 2-chlorofluoromethyl-4-fluorobenzotrifluoride, 2-chlorofluoromethyl-5-fluorobenzotrifluoride which is a perfluorinated isomer, and 2 which is an intermediate of the target product -Chlorodifluoromethyl-5-fluorobenzal chloride 1.1%, incompletely fluorinated 2-chlorodifluoromethyl-4-fluorobenzal chloride 16.9% The fully fluorinated 2-dichlorofluoromethyl-4-fluorobenzal chloride was 15.5% and the unreacted isomer 2-trichloromethyl-4-fluorobenzal chloride was 3.2%. After completion of the reaction, the recovered reaction solution was washed with water, an aqueous sodium hydrogen carbonate solution, and further washed with water. Magnesium sulfate was added to the reaction solution after washing, followed by filtration after stirring. The weight of the reaction solution obtained from the filtrate was 483.6 g.

  The resulting fluorination reaction solution was purified by distillation in a 45 cm distillation column packed with Dixon packing. When the fraction having a temperature of 2270 to 2400 Pa and a temperature of 77 to 81 ° C. was collected by this distillation, 224.5 g of a target product having a purity of 97.6% was obtained. The overall yield from the chlorinated raw material 3,4-dimethylfluorobenzene was 45.4%.

[Example 3]
(Example 3-1) Chlorination (first step)
A 500 ml four-necked flask equipped with a Dimroth tube, thermometer, and chlorine blowing tube was charged with 248.0 g of 3,4-dimethylfluorobenzene and 0.93 g (0.28 mol%) of AIBN, and the internal temperature was adjusted to 60 with stirring. The temperature was raised to 0 ° C., and chlorine gas was introduced at a rate of about 1.0 to 1.1 mol / Hr to initiate the reaction. While maintaining the internal temperature at 65 to 70 ° C., chlorine gas was supplied for 7 hours. The chlorination degree of the reaction liquid after 7 hours was 3.55. Thereafter, 0.93 g (0.28 mol%) of AIBN was added every hour, and the reaction was continued for 5 hours. The composition of the reaction solution after 5 hours was determined by gas chromatography analysis to be 55.1% of the target product, 2-trichloromethyl-5-fluorobenzal chloride, and the isomer of 2-trichloromethyl-4-fluoro. 42.4% benzal chloride, 1.0% 3,4-bis (dichloromethyl) fluorobenzene as other by-products, 2-chloro-5-fluorobenzal chloride and 2-chloro-4-fluoroben The sum of sarchloride was 0.1% and the sum of 2-chloro-5-fluorobenzotrichloride and 2-chloro-5-fluorobenzotrichloride was 0.2%. The weight of the reaction solution was 592.8 g. This reaction solution (chlorination reaction mixture) was used in the subsequent (Example 3-2) without purification.

(Example 3-2) Fluorination (second step) and distillation purification To a metal 1 L autoclave equipped with a stirrer, a cooling reflux pipe equipped with a pressure regulating valve, a thermocouple, a pressure gauge, and a sampling pipe, The reaction was started by charging 589.8 g of the chlorination reaction mixture obtained in (Example 3-1) and 238.7 g of anhydrous hydrogen fluoride and sealing it, raising the internal temperature to 70 ° C. while stirring. The pressure control valve was adjusted so that the internal pressure became 3.0 to 3.1 MPa, and the reaction was performed for 8 hours while releasing hydrogen chloride generated with the progress of the reaction out of the system. The composition of the reaction solution after 8 hours is determined by gas chromatography analysis to be 58.5% of 2-trifluoromethyl-5-fluorobenzal chloride, which is the target product, and 2-trifluoro, which is a fluorinated product of the isomer. Methyl-4-fluorobenzal chloride was 0.1%. In addition, 2.4% of 2-chlorofluoromethyl-4-fluorobenzotrifluoride, which is a perfluorinated product, and 2-chlorofluoromethyl-5-fluorobenzotrifluoride, which is a perfluorinated product of an isomer. 0.3%, 2-chlorodifluoromethyl-5-fluorobenzal chloride, which is the intermediate of the target product, 1.2%, 2-chlorodifluoromethyl-4-fluoro incompletely fluorinated isomer 13.9% of benzal chloride, 17.0% of 2-dichlorofluoromethyl-4-fluorobenzal chloride, which is also incompletely fluorinated isomer, and unreacted isomer 2-trichloromethyl-4- Fluorobenzal chloride was 5.1%. After completion of the reaction, the recovered reaction solution was washed with water, an aqueous sodium hydrogen carbonate solution, and further washed with water. Magnesium sulfate was added to the reaction solution after washing, followed by filtration after stirring. The weight of the reaction solution obtained from the filtrate was 485.8 g.

  The resulting fluorination reaction mixture was purified by distillation in a 45 cm distillation column packed with Dixon packing. By fractionating a fraction having a temperature of 2270-2400 Pa and a temperature of 77-80 ° C. by this distillation, 233.5 g of a target product having a purity of 98.4% was obtained. The overall yield from 3,4-dimethylfluorobenzene as the chlorination raw material was 47.3%.

[Example 4] Hydrolysis of 2-trifluoromethyl-5-fluorobenzal chloride (Synthesis of 2-trifluoromethyl-5-fluorobenzaldehyde: third step)

(Example 4-1)
In a 500 ml four-necked flask equipped with a Dimroth tube, thermometer and dropping funnel, 246.0 g of 2-trifluoromethyl-5-fluorobenzal chloride (purity 98.4%) and ferric chloride (anhydrous) 3.2 g (2.0 mol%) and a dropping funnel were charged with 19.8 g of water, and the internal temperature was raised to 110 ° C. while stirring. The dropping of water was started from the dropping funnel, and the reaction was started. While maintaining the internal temperature at 105 to 115 ° C., 19.8 g of water was added dropwise over 2 hours. After the dropwise addition of water, the internal temperature was raised to 120 ° C., and the reaction was continued for another hour. The composition of the reaction solution after the reaction continues from the analysis of gas chromatography, the desired product 2-trifluoromethyl-5-fluoro-benzaldehyde 99.1%, the starting material 2-trifluoromethyl-5-fluoro-benzal Chloride was 0.1%.

  After completion of the reaction, the recovered reaction solution was washed twice with water. Magnesium sulfate was added to the reaction solution after washing, followed by filtration after stirring. The weight of the reaction solution obtained from the filtrate was 179.6 g.

  The resulting hydrolysis reaction solution was purified by distillation in a 45 cm distillation column (10 theoretical plates) packed with Dixon packing.

  By fractionating a fraction having a temperature of 3000 to 3100 Pa and a temperature of 69 to 72 ° C. by this distillation, 152.7 g of a target product having a purity of 99.8% was obtained. The overall yield from the hydrolysis raw material 2-trifluoromethyl-5-fluorobenzal chloride was 85.0%.

(Example 4-2)
In a 500 ml four-necked flask equipped with a Dimroth tube, thermometer and dropping funnel, 246.0 g of 2-trifluoromethyl-5-fluorobenzal chloride (purity 98.4%), and ferric chloride (anhydrous) 3.2 g (2.0 mol%) and a dropping funnel were charged with 19.8 g of water, and the internal temperature was raised to 120 ° C. while stirring. The dripping of the water was started from the dropping funnel, and the reaction was started. While maintaining the internal temperature at 115 to 125 ° C., 19.8 g of water was added dropwise over 2 hours. The composition of the reaction liquid after completion of the dropwise addition of water, from the analysis of gas chromatography, the desired product 2-trifluoromethyl-5-fluoro-benzaldehyde 98.9% as the starting material 2-trifluoromethyl-5- Fluorobenzal chloride was 0.1%.

  After completion of the reaction, the recovered reaction solution was washed twice with water. Magnesium sulfate was added to the reaction solution after washing, followed by filtration after stirring. The weight of the reaction solution obtained from the filtrate was 176.5 g.

  The resulting hydrolysis reaction solution was purified by distillation in a 15 cm distillation column (3 to 4 theoretical plates) packed with Dixon packing.

  When the fraction having a temperature of 2800 to 2900 Pa and a temperature of 64 to 65 ° C. was collected by this distillation, 150.0 g of a target product having a purity of 99.5% was obtained. The overall yield from the hydrolysis raw material 2-trifluoromethyl-5-fluorobenzal chloride was 78.1%.

(Example 4-3)
In a 500 ml four-necked flask equipped with a Dimroth tube, a thermometer and a dropping funnel, 246.0 g of 2-trifluoromethyl-5-fluorobenzal chloride (purity 98.4%) and ferric chloride (anhydrous) 6. 4 g (4.0 mol%) and 19.8 g of water were charged into a dropping funnel, and the internal temperature was raised to 110 ° C. while stirring. The dripping of the water was started from the dropping funnel, and the reaction was started. While maintaining the internal temperature at 105 to 115 ° C., 19.8 g of water was added dropwise over 2 hours. The composition of the reaction liquid after completion of the dropwise addition of water, from the analysis of gas chromatography, the desired product 2-trifluoromethyl-5-fluoro-benzaldehyde 98.9% as the starting material 2-trifluoromethyl-5- Fluorobenzal chloride was 0.1%.

  After completion of the reaction, the recovered reaction solution was washed twice with water. Magnesium sulfate was added to the reaction solution after washing, followed by filtration after stirring. The weight of the reaction solution obtained from the filtrate was 174.3 g. The resulting hydrolysis reaction solution was purified by distillation in a 15 cm distillation column (3 to 4 theoretical plates) packed with Dixson packing.

  When a fraction having a temperature of 3200 to 3300 Pa and a temperature of 65 to 66 ° C. was collected by this distillation, 161.6 g of a target product having a purity of 99.5% was obtained. The overall yield from the hydrolysis raw material 2-trifluoromethyl-5-fluorobenzal chloride was 84.2%.

[Example 5] Reduction of 2-trifluoromethyl-5-fluorobenzaldehyde (Synthesis of 2-trifluoromethyl-5-fluorobenzyl alcohol: Fourth Step (a))

(Example 5-1)
In a 500 ml autoclave made of glass equipped with a stirrer, thermocouple, pressure gauge, hydrogen inlet tube, and degassing valve, 192.0 g of 5-trifluoromethyl-5-fluorobenzaldehyde (purity 99.6%), 5%- 3.84 g of Pd / C (50% water-containing product) was charged, stirring was started, and after nitrogen and hydrogen substitution, hydrogen was introduced, the pressure was 0.5 MPa, and the internal temperature was 80 ° C. and reacted for 10 hours. The composition of the reaction solution at this time was determined by gas chromatography analysis to be 98.5% of 2-trifluoromethyl-5-fluorobenzyl alcohol as the target product, and 2-trifluoromethyl-5-fluorobenzaldehyde as the raw material in an amount of 0. 4%.

  After completion of the reaction, the recovered reaction solution was filtered while maintaining the temperature at 60 ° C. to remove the catalyst, and the weight of the reaction solution obtained from the filtrate was 191.2 g. The organic substance in the filtrate was purified by distillation, and a fraction having a temperature of 85 to 86 ° C. was collected at 1600 Pa. As a result, 160.8 g of a target product having a purity of 99.9% was obtained. The overall yield from the reduction reaction raw material 2-trifluoromethyl-5-fluorobenzaldehyde was 82.3%.

(Example 5-2)
In a glass 500 ml autoclave equipped with a stirrer, thermocouple, pressure gauge, hydrogen inlet tube, and degassing valve, 192.0 g of 2-trifluoromethyl-5-fluorobenzaldehyde (purity 99.4%), concentrated sulfuric acid 1 .9 g, 5% -Pd / C (50% water-containing product) 3.84 g was charged, and stirring was started. After substitution with nitrogen and hydrogen, hydrogen was introduced, the pressure was 0.5 MPa, and the internal temperature was 60 ° C., followed by reaction for 5 hours. The composition of the reaction solution after the reaction was analyzed by gas chromatography, and the target 2-trifluoromethyl-5-fluorobenzyl alcohol 98.2%, the raw material 2-trifluoromethyl-5-fluorobenzaldehyde 0.8%. 4%.

  After completion of the reaction, the recovered reaction solution was filtered while maintaining 60 ° C. to remove the catalyst, and 200 ml of ethyl acetate was added and washed with water. The organic phase was separated, magnesium sulfate was added, the mixture was stirred and filtered, and the filtrate was evaporated to remove the solvent. The weight of the obtained crude 2-trifluoromethyl-5-fluorobenzyl alcohol was 188.9 g. The organic matter in the filtrate was purified by distillation, and a fraction having a temperature of 2000 to 1800 Pa and a temperature of 90 to 91 ° C. was collected to obtain 156.6 g of a target product having a purity of 99.8%. The overall yield from the reduction reaction starting material 2-trifluoromethyl-5-fluorobenzaldehyde was 80.7%.

(Example 5-3)
In a glass 500 ml autoclave equipped with a stirrer, thermocouple, pressure gauge, hydrogen inlet tube, and degassing valve, 96.0 g of 2-trifluoromethyl-5-fluorobenzaldehyde (purity 99.4%), ethanol (Solvent) 96.0 g, concentrated sulfuric acid 1.0 g, 5% -Pd / C (50% water-containing product) 1.92 g were charged, stirring was started, and after nitrogen and hydrogen substitution, hydrogen was introduced and pressure 0.5 MPa In addition, the reaction was carried out at an internal temperature of 60 ° C. for 2 hours. The composition of the reaction solution after the reaction was analyzed by gas chromatography, and the target product, 2-trifluoromethyl-5-fluorobenzyl alcohol, 91.3%, the raw material, 2-trifluoromethyl-5-fluorobenzaldehyde, 0.8%. 1% (composition ratio excluding solvent).

  After completion of the reaction, the recovered reaction solution was filtered to remove the catalyst, and 200 ml of ethyl acetate was added, followed by washing with water. The organic phase was separated, magnesium sulfate was added, the mixture was stirred and filtered, and the filtrate was evaporated to remove the solvent. The weight of the obtained crude 2-trifluoromethyl-5-fluorobenzyl alcohol was 94.2 g. The organic substance in the reaction solution was purified by distillation, and a fraction having a temperature of 1600 to 1700 Pa and a temperature of 86 to 87 ° C. was collected. The overall yield from the reduction reaction raw material 2-trifluoromethyl-5-fluorobenzaldehyde was 65.9%.

  [Example 6] Oxidation and reduction of 2-trifluoromethyl-5-fluorobenzaldehyde (synthesis of 2-trifluoromethyl-5-fluorobenzylamine: fourth step (b))

(Example 6-1)
A 500 ml four-necked flask equipped with a Dimroth tube, a thermometer, and a dropping funnel was charged with 38.2 g of hydroxyamine hydrochloride and 191.1 g of methanol, and cooled with a water or ice bath while stirring, so that the internal temperature was 20-30. While maintaining the temperature at 19 ° C., 192.0 g of 25% aqueous sodium hydroxide solution was dropped over about 1 hour using a dropping funnel. Thereafter, 96.0 g of 2-trifluoromethyl-5-fluorobenzaldehyde (purity 99.6%) was dropped over 1 hour using a dropping funnel while maintaining the internal temperature at 20 to 30 ° C. The composition of the reaction solution after the dropping was the target product from gas chromatography analysis (partly sampled, neutralized with hydrochloric acid to pH = 5-3 and then extracted with ethyl acetate). The amount of 2- trifluoromethyl -5-fluorobenzaldoxime was 98.1%, and the raw material 2- trifluoromethyl -4-fluorobenzaldehyde was 0.1% (composition ratio excluding the solvent). After completion of the reaction, 35% hydrochloric acid: 64.3 g was added to neutralize to pH = 5. After further extraction with 200 ml of ethyl acetate, the organic phase was separated, magnesium sulfate was added, and the mixture was stirred and filtered. The filtrate was evaporated to give 100.3 g of 2- trifluoromethyl -5-fluorobenzaldoxime. The overall yield from the reduction reaction raw material 2-trifluoromethyl-5-fluorobenzaldehyde was 95.1%. This reaction solution was used for the subsequent reduction reaction without purification.

2- trifluoromethyl -5-fluorobenzaldoxime (purity 98.1% product) 100 manufactured in the previous step was added to a glass 1 L autoclave equipped with a stirrer, thermocouple, pressure gauge, hydrogen inlet tube, and degassing valve. .3 g, 5% -Pd / C (containing 50% water) 8.4 g, hydrogen chloride 34.7 g, methanol 475.6 g were charged, stirring was started, and after nitrogen and hydrogen substitution, hydrogen was introduced, The pressure was 0.5 MPa and the internal temperature was 60 ° C., and the reaction was carried out for 10 hours. 88.4% the desired product 2-trifluoromethyl-5-fluorobenzylamine from the analysis of the composition of the reaction solution at this time gas chromatography, the starting material 2-trifluoromethyl-5-fluoro-benzaldoximes 1 0.1%, other 2-trifluoromethyl-5-fluorobenzyl alcohol 6.2%, secondary amine 3.1%. After completion of the reaction, the recovered reaction solution was filtered to remove the catalyst, and methanol and excess hydrogen chloride were removed by evaporation. Since 2-trifluoromethyl-5-fluorobenzylamine hydrochloride was obtained, it was washed with 10% aqueous sodium hydroxide so as to be alkaline, and 2-trifluoromethyl-5-fluorobenzylamine was separated. did. This was extracted with n-hexane, and the organic matter was washed with water. The organic phase after washing was separated, magnesium sulfate was added, and the mixture was stirred and filtered. When n-hexane was removed from the organic matter of the filtrate again by evaporation, 62.8 g of crude 2-trifluoromethyl-5-fluorobenzylamine was obtained. This was purified by distillation, and a fraction having a temperature of 3200 Pa to 3500 Pa and a temperature of 84 to 85 ° C. was collected. As a result, 50.1 g of a target product having a purity of 99.0% was obtained. The yield of the reduction reaction was 54.5% (total yield from the raw material 2-trifluoromethyl-5-fluorobenzaldehyde was 51.9%).

(Example 6-2)
A 500 ml four-necked flask equipped with a Dimroth tube, a thermometer, and a dropping funnel is charged with 38.2 g of hydroxyamine hydrochloride and 200.0 of water and cooled in a water or ice bath while stirring to an internal temperature of 20-30 ° C. While maintaining, 192.0 g of 25% sodium hydroxide aqueous solution was dropped over about 1 hour using a dropping funnel. Thereafter, 96.0 g of 2-trifluoromethyl-5-fluorobenzaldehyde (purity 99.6%) was dropped over 1 hour using a dropping funnel while maintaining the internal temperature at 20 to 30 ° C. The composition of the reaction solution after the dropping was the target product from gas chromatography analysis (partly sampled, neutralized with hydrochloric acid to pH = 5-3 and then extracted with ethyl acetate). The amount of 2- trifluoromethyl -5-fluorobenzaldoxime was 98.7%, and the raw material 2- trifluoromethyl -4-fluorobenzaldehyde was 0.2% (composition ratio excluding the solvent). After completion of the reaction, 65.0 g of 35% hydrochloric acid was added to neutralize to pH = 5. After further extraction with 200 ml of ethyl acetate, the organic phase was separated, magnesium sulfate was added, and the mixture was stirred and filtered. The filtrate was evaporated to remove the solvent. The weight of the obtained 2- trifluoromethyl -5-fluorobenzaldoxime was 100.1 g. The overall yield from the reduction reaction raw material 2-trifluoromethyl-5-fluorobenzaldehyde was 93.4%. This reaction solution was used for the subsequent reduction reaction without purification.

2- trifluoromethyl -5-fluorobenzaldoxime (purity 98.1% product) 100 manufactured in the previous step was added to a glass 1 L autoclave equipped with a stirrer, thermocouple, pressure gauge, hydrogen inlet tube, and degassing valve. .3 g, 5% -Pd / C (50% water-containing product) 4.1 g, ammonia 16.2 g, methanol 476.2 g were charged, stirring was started, hydrogen was introduced after nitrogen and hydrogen substitution, and pressure 0.5 MPa And an internal temperature of 30 ° C. was reacted for 3 hours. 96.9% the desired product 2-trifluoromethyl-5-fluorobenzylamine from the analysis of the composition of the reaction solution at this time gas chromatography, the starting material 2-trifluoromethyl-5-fluoro-benzaldoximes 0 0.2%, other 2-trifluoromethyl-5-fluorobenzyl alcohol 0.8%, secondary amine 1.3%. After completion of the reaction, the recovered reaction solution was filtered to remove the catalyst, and methanol and excess hydrogen chloride were removed by evaporation. Since 2-trifluoromethyl-5-fluorobenzylamine hydrochloride was obtained, it was washed with 10% aqueous sodium hydroxide solution so as to be alkaline, and 2-trifluoromethyl-5-fluorobenzylamine was separated. did. This was extracted with n-hexane, and the organic matter was washed with water. The organic phase after washing was separated, magnesium sulfate was added, and the mixture was stirred and filtered. When n-hexane was removed from the organic matter in the filtrate again by evaporation, 84.7 g of crude 2-trifluoromethyl-5-fluorobenzylamine was obtained. This was purified by distillation, and a fraction having a temperature of 3000 to 3200 Pa and a temperature of 82 to 83 ° C. was collected to obtain 78.6 g of a target product having a purity of 99.0%. The yield of the reduction reaction was 85.5% (the overall yield from the raw material 2-trifluoromethyl-5-fluorobenzaldehyde was 81.5%).

(Example 6-3)
A 500 ml four-necked flask equipped with a Dimroth tube, a thermometer, and a dropping funnel is charged with 38.2 g of hydroxyamine hydrochloride and 200.0 of water and cooled in a water or ice bath while stirring to an internal temperature of 30-40 ° C. While maintaining, 192.0 g of 25% sodium hydroxide aqueous solution was dropped over about 1 hour using a dropping funnel. Thereafter, 96.0 g of 2-trifluoromethyl-5-fluorobenzaldehyde (purity 99.6%) was dropped over 1 hour using a dropping funnel while maintaining the internal temperature at 45 to 55 ° C. The composition of the reaction solution after the dropping was the target product from gas chromatography analysis (partly sampled, neutralized with hydrochloric acid to pH = 5-3 and then extracted with ethyl acetate). The amount of 2- trifluoromethyl -5-fluorobenzaldoxime was 99.0% and the raw material 2- trifluoromethyl -4-fluorobenzaldehyde was 0.1% (composition ratio excluding the solvent). After completion of the reaction, 64.6 g of 35% hydrochloric acid was added to neutralize to pH = 5. After further extraction with 200 ml of ethyl acetate, the organic phase was separated, magnesium sulfate was added, and the mixture was stirred and filtered. The weight of 2- trifluoromethyl -5- fluorobenzaldoxime obtained by evaporating the solvent of the filtrate by evaporation was 99.6 g. The overall yield from the reduction reaction raw material 2-trifluoromethyl-5-fluorobenzaldehyde was 95.3%. This reaction solution was used for the subsequent reduction reaction without purification.

2- trifluoromethyl -5-fluorobenzaldoxime (purity 99.0% product) 99 produced in the previous step was added to a glass 1 L autoclave equipped with a stirrer, thermocouple, pressure gauge, hydrogen inlet tube, and degassing valve. .6 g, 5% -Pd / C (50% water-containing product) 4.0 g, methanol: 476.3 g were charged, stirring was started, hydrogen was introduced after nitrogen and hydrogen substitution, and the pressure was adjusted to 0.5 MPa. Together with the internal temperature of 30 ° C., the reaction was carried out for 3 hours. 95.3% the desired product 2-trifluoromethyl-5-fluorobenzylamine from the analysis of the composition of the reaction solution at this time gas chromatography, the starting material 2-trifluoromethyl-5-fluoro-benzaldoximes 0 0.5%, other 2-trifluoromethyl-5-fluorobenzyl alcohol 0.1%, secondary amine 2.9%. After completion of the reaction, the recovered reaction solution was filtered to remove the catalyst, and methanol and excess hydrogen chloride were removed by evaporation. Since 2-trifluoromethyl-5-fluorobenzylamine hydrochloride was obtained, it was washed with 10% aqueous sodium hydroxide solution so as to be alkaline, and 2-trifluoromethyl-5-fluorobenzylamine was separated. did. This was extracted with n-hexane, and the organic matter was washed with water. The organic phase after washing was separated, magnesium sulfate was added, and the mixture was stirred and filtered. When n-hexane was removed from the organic matter of the filtrate again by evaporation, 86.1 g of crude 2-trifluoromethyl-5-fluorobenzylamine was obtained. This was purified by distillation, and a fraction having a temperature of 3000 to 3200 Pa and a temperature of 82 to 83 ° C. was fractionated to obtain 74.0 g of a target product having a purity of 99.5%. The yield of the reduction reaction was 78.8% (the total yield from the raw material 2-trifluoromethyl-5-fluorobenzaldehyde was 76.7%).

[Example 7] Chlorination of 2-trifluoromethyl-5-fluorobenzaldehyde (synthesis of 2-trifluoromethyl-5-fluorobenzoyl chloride: fourth step (c))
(Example 7-1)
Charged 192.0 g of 2-trifluoromethyl-5-fluorobenzaldehyde (purity 99.6%) and 0.82 g (0.5 mol%) of AIBN to a 300 ml four-necked flask equipped with a Dimroth tube, a thermometer, and a chlorine blowing tube. While stirring, the internal temperature was raised to 60 ° C., and chlorine gas was introduced at a rate of about 0.3 to 0.35 mol / Hr to initiate the reaction. While maintaining the internal temperature at 65 to 70 ° C., chlorine gas was supplied for 3 hours. The composition of the reaction solution after 3 hours was determined by gas chromatography analysis to be 96.6% of 2- trifluoromethyl -5-fluorobenzoyl chloride as a target product and 2- trifluoromethyl -5-fluoro as a raw material. Benzaldehyde was 0.2%.

  After completion of the reaction, the recovered reaction solution was washed with water, washed with an aqueous sodium hydrogen carbonate solution, and further washed with water. Magnesium sulfate was added to the reaction solution after washing, followed by filtration after stirring. The weight of the reaction solution obtained from the filtrate was 220.4 g.

  The resulting fluorination reaction solution was purified by distillation using a 45 cm distillation column (theoretical plate number: 10) filled with Dixon packing. When a fraction having a temperature of 1700 to 1900 Pa and a temperature of 73 to 74 ° C. was collected by this distillation, 191.3 g of a target product having a purity of 99.3% was obtained. The overall yield from the chlorinated raw material 2-trifluoromethyl-5-fluorobenzaldehyde was 83.9%.

(Example 7-2)
In a 300 ml four-necked flask equipped with a Dimroth, thermometer, and chlorine blowing tube, 192.0 g of 2-trifluoromethyl-5-fluorobenzaldehyde (purity 99.6%) and 3.23 g of niper BW (benzoyl peroxide) (1.0 mol%) was added, the internal temperature was raised to 70 ° C. while stirring, and chlorine gas was introduced at a rate of about 0.3 to 0.35 mol / Hr to initiate the reaction. While maintaining the internal temperature at 75 to 85 ° C., chlorine gas was supplied for 3 hours. The composition of the reaction solution after 3 hours was determined by gas chromatography analysis to be 94.9% of the target 2- trifluoromethyl -5-fluorobenzoyl chloride and the starting material 2-trifluoromethyl-5-fluoro. Benzaldehyde was 0.2%.

  After completion of the reaction, the recovered reaction solution was washed with water, washed with an aqueous sodium hydrogen carbonate solution, and further washed with water. Magnesium sulfate was added to the reaction solution after washing, followed by filtration after stirring. The weight of the reaction solution obtained from the filtrate was 224.7 g.

  The resulting fluorination reaction solution was purified by distillation using a 45 cm distillation column (theoretical plate number: 10) filled with Dixon packing. By fractionating a fraction having a temperature of 1300 to 1400 Pa and a temperature of 69 to 70 ° C. by this distillation, 200.2 g of a target product having a purity of 99.0% was obtained. The overall yield from the chlorinated raw material 2-trifluoromethyl-5-fluorobenzaldehyde was 87.8%.

(Example 7-3)
In a 300 ml four-necked flask equipped with a Dimroth tube, a thermometer, and a chlorine blowing tube, 192.0 g of 2-trifluoromethyl-5-fluorobenzaldehyde (purity 99.6%) and perbutyl D (t-butyl peroxide) 46 g (1.0 mol%) was charged, the internal temperature was raised to 120 ° C. while stirring, and chlorine gas was introduced at a rate of about 0.3 to 0.35 mol / Hr to initiate the reaction. While maintaining the internal temperature at 125 to 130 ° C., chlorine gas was supplied for 3 hours. The composition of the reaction solution after 3 hours was determined by gas chromatography analysis to be 95.6% of 2- trifluoromethyl -5-fluorobenzoyl chloride as a target product and 2- trifluoromethyl -5-fluoro as a raw material. Benzaldehyde was 0.4%.

  After completion of the reaction, the recovered reaction solution was washed with water, washed with an aqueous sodium hydrogen carbonate solution, and further washed with water. Magnesium sulfate was added to the reaction solution after washing, followed by filtration after stirring. The weight of the reaction solution obtained from the filtrate was 220.6 g.

  The resulting fluorination reaction solution was purified by distillation using a 45 cm distillation column (theoretical plate number: 10) filled with Dixon packing.

  When a fraction having a temperature of 1700 to 1900 Pa and a temperature of 72 to 73 ° C. was collected by this distillation, 198.3 g of a target product having a purity of 99.3% was obtained. The overall yield from the chlorinated raw material 2-trifluoromethyl-5-fluorobenzaldehyde was 87.0%.

[Example 8] Oxidation of 2-trifluoromethyl-5-fluorobenzaldehyde (synthesis of 2-trifluoromethyl-5-fluorobenzoic acid: fourth step (d))
(Example 8-1)
To a metal 1 L autoclave equipped with a stirrer, thermocouple, pressure gauge, oxygen inlet tube, and deaeration valve, 194.0 g of 2-trifluoromethyl-5-fluorobenzaldehyde (purity 99.8% product), 533.3 g of 15% sodium hydroxide aqueous solution was charged, stirring was started, oxygen was introduced after oxygen substitution, the pressure was adjusted to 0.5 MPa, and the internal temperature was raised to 80 ° C. The reaction was performed for 6 hours while maintaining the reaction temperature at 75 to 85 ° C. The composition of the reaction solution at this time was analyzed by gas chromatography (partially sampled, adjusted to pH = 1 with hydrochloric acid, and extracted with ethyl acetate), and the target 2-trifluoromethyl was analyzed. It was 94.3% of -5-fluorobenzoic acid, 1.1% of 2-trifluoromethyl-5-fluorobenzaldehyde as a raw material, and 3.5% of other 2-trifluoromethyl-5-fluorobenzyl alcohol. After completion of the reaction, the recovered reaction solution was adjusted to pH = 1 by adding 250.3 g of 35% aqueous hydrochloric acid solution. After extraction with 500 ml of ethyl acetate, the organic matter in the filtrate separated into two layers was further washed with water. Magnesium sulfate was added to the reaction solution after washing, followed by filtration after stirring, and then ethyl acetate was removed by evaporation to obtain 193.6 g of crude 2-trifluoromethyl-5-fluorobenzoic acid. The crude 2-trifluoromethyl-5-fluorobenzoic acid and 400 ml of n-hexane were charged into a 1 L four-necked flask equipped with a Dimroth tube and a thermometer, heated and completely dissolved, and then cooled to 10 ° C. or lower in an ice bath. Cooled and recrystallized. The precipitated 2-trifluoromethyl-5-fluorobenzoic acid crystals were collected by filtration and dried with a dryer to obtain 160.8 g of 2-trifluoromethyl-5-fluorobenzoic acid having a purity of 99.6%. . The yield based on 2-trifluoromethyl-5-fluorobenzaldehyde was 76.6%.

(Example 8-2)
To a metal 1 L autoclave equipped with a stirrer, thermocouple, pressure gauge, oxygen inlet tube, and deaeration valve, 194.0 g of 2-trifluoromethyl-5-fluorobenzaldehyde (purity 99.8% product), The mixture was charged with 640.0 g of a 7.5% aqueous sodium hydroxide solution, stirring was started, oxygen substitution was performed, oxygen was introduced, the pressure was adjusted to 0.5 MPa, and the internal temperature was raised to 60 ° C. The reaction was carried out for 3 hours while maintaining the reaction temperature at 60 to 70 ° C. The composition of the reaction solution at this time was analyzed by gas chromatography (partially sampled, adjusted to pH = 1 with hydrochloric acid, and extracted with ethyl acetate), and the target 2-trifluoromethyl was analyzed. It was 99.3% of -5-fluorobenzoic acid and 0.7% of 2-trifluoromethyl-5-fluorobenzaldehyde as a raw material. After completion of the reaction, the recovered reaction solution was adjusted to pH = 1 by adding 156.4 g of 35% hydrochloric acid aqueous solution. After extraction with 500 ml of ethyl acetate, the organic matter in the filtrate separated into two layers was further washed with water. Magnesium sulfate was added to the reaction solution after washing, followed by filtration after stirring, and then ethyl acetate was removed by evaporation to obtain 202.6 g of crude 2-trifluoromethyl-5-fluorobenzoic acid. The crude 2-trifluoromethyl-5-fluorobenzoic acid and 400 ml of n-hexane were charged into a 1 L four-necked flask equipped with a Dimroth tube and a thermometer, heated and completely dissolved, and then cooled to 10 ° C. or lower in an ice bath. Cooled and recrystallized. The precipitated crystals of 2-trifluoromethyl-5-fluorobenzoic acid are collected by filtration and dried with a dryer to obtain 185.4 g of 2-trifluoromethyl-5-fluorobenzoic acid having a purity of 99.6%. It was. The yield based on 2-trifluoromethyl-5-fluorobenzaldehyde was 88.3%.

(Example 8-3)
To a metal 1 L autoclave equipped with a stirrer, thermocouple, pressure gauge, oxygen inlet tube, and deaeration valve, 194.0 g of 2-trifluoromethyl-5-fluorobenzaldehyde (purity 99.8% product), 800.0 g of 5% aqueous sodium hydroxide solution was added, stirring was started, oxygen was introduced, oxygen was introduced, the pressure was adjusted to 0.5 MPa, and the internal temperature was raised to 80 ° C. The reaction was performed for 3 hours while maintaining the reaction temperature at 75 to 85 ° C. The composition of the reaction solution at this time was analyzed by gas chromatography (partially sampled, adjusted to pH = 1 with hydrochloric acid, and extracted with ethyl acetate), and the target 2-trifluoromethyl was analyzed. It was 99.5% of -5-fluorobenzoic acid and 0.5% of 2-trifluoromethyl-5-fluorobenzaldehyde as a raw material. After completion of the reaction, the recovered reaction solution was adjusted to pH = 1 by adding 155.0 g of 35% aqueous hydrochloric acid solution. After extraction with 500 ml of ethyl acetate, the organic matter in the filtrate separated into two layers was further washed with water. Magnesium sulfate was added to the reaction solution after washing, and the mixture was stirred and filtered. Then, ethyl acetate was removed by evaporation to obtain 199.2 g of crude 2-trifluoromethyl-5-fluorobenzoic acid. The crude 2-trifluoromethyl-5-fluorobenzoic acid and 400 ml of n-hexane were charged into a 1 L four-necked flask equipped with a Dimroth tube and a thermometer, heated and completely dissolved, and then cooled to 10 ° C. or lower in an ice bath. Cooled and recrystallized. The precipitated crystals of 2-trifluoromethyl-5-fluorobenzoic acid were collected by filtration and dried with a dryer to obtain 184.8 g of 2-trifluoromethyl-5-fluorobenzoic acid having a purity of 99.8%. It was. The yield based on 2-trifluoromethyl-5-fluorobenzaldehyde was 88.0%.

Claims (8)

A method for producing 2-trifluoromethyl-5-fluorobenzaldehyde, comprising the following three steps.
First step: A step of reacting 3,4-dimethylfluorobenzene with chlorine (Cl ₂ ) to obtain a chlorination reaction mixture.
Second step: The step of reacting the chlorination reaction mixture with hydrogen fluoride (HF) in a liquid phase to obtain a reaction mixture containing 2-trifluoromethyl-5-fluorobenzal chloride.
Third step: a step of obtaining 2- trifluoromethyl -5- fluorobenzaldehyde by bringing the 2- trifluoromethyl -5-fluorobenzal chloride into contact with water in the presence of a Lewis acid catalyst. 2-Trifluoromethyl-5 obtained by reacting 2-trifluoromethyl-5-fluorobenzaldehyde obtained by the method of claim 1 with hydrogen (H ₂ ) in the presence of a transition metal catalyst. -Method for producing fluorobenzyl alcohol. The 2-trifluoromethyl-5-fluorobenzaldehyde obtained by the method of claim 1 is reacted with hydroxylamine or a salt thereof to obtain 2- trifluoromethyl -5-fluorobenzaldoxime, trifluoromethyl-5-fluoro-benzaldoxime, the presence of a transition metal catalyst, wherein the reaction with hydrogen (H _2), method for producing a 2-trifluoromethyl-5-fluorobenzylamine. A method for producing 2- trifluoromethyl -5-fluorobenzoyl chloride, comprising reacting 2- trifluoromethyl -5-fluorobenzaldehyde obtained by the method of claim 1 with a chlorinating agent. A process for producing 2-trifluoromethyl-5-fluorobenzoic acid, comprising reacting 2-trifluoromethyl-5-fluorobenzaldehyde obtained by the method of claim 1 with an oxidizing agent. The method according to any one of claims 1 to 5, wherein the reaction in the first step is performed in the presence of a radical initiator or under light irradiation. The method according to any one of claims 1 to 6, wherein the reaction in the second step is performed under a pressurized condition. After purifying the reaction mixture obtained in the second step and isolating 2-trifluoromethyl-5-fluorobenzal chloride, the second step was conducted using this 2-trifluoromethyl-5-fluorobenzal chloride. The method according to claim 1, wherein the reaction is carried out.