JP2006213630A - Method for producing 2-trifluoromethyl-6-fluorobenzaldehyde and its derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a synthetic method of synthesizing 2-trifluoromethyl-6-fluorobenzaldehyde and its derivative which is suited for the production on an industrial scale. <P>SOLUTION: The method for producing 2-trifluoromethyl-6-fluorobenzaldehyde comprises reacting 2,3-dimethylfluorobenzene with chlorine (Cl<SB>2</SB>) to obtain 2-trichloromethyl-6-fluorobenzal chloride (a first step); then reacting the 2-trichloromethyl-6-fluorobenzal chloride with hydrogen fluoride (HF) in the liquid phase to obtain 2-trifluoromethyl-6-fluorobenzal chloride (a second step); and then bringing the 2-trifluoromethyl-6-fluorobenzal chloride into contact with water in the presence of a Lewis acid catalyst to obtain 2-trifluoromethyl-6-fluorobenzaldehyde (a third step). According to this method, 2-trifluoromethyl-6-fluorobenzaldehyde can be produced in a high yield at a high purity by remarkably easier operations than before. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to a process for producing 2-trifluoromethyl-6-fluorobenzaldehyde and its derivatives, which are important intermediates for pharmaceuticals and agricultural chemicals.

  2-Trifluoromethyl-6-fluorobenzaldehyde and its derivatives are useful compounds as intermediates for the production of medical and agricultural chemicals. For example, in Patent Document 1, 2-trifluoromethyl-6-fluorobenzaldehyde is used as one of raw materials for synthesizing a 6-aryl-pyrrolimidazole derivative that can be used as an antihypertensive drug or a sedative. Non-Patent Document 1 also reports the synthesis of fluorine-containing benzothiophene derivatives as part of research on drug development, but 2-trifluoromethyl-6-fluorobenzaldehyde is used as one of the raw materials. Yes. Furthermore, also in Patent Document 2, 2-trifluoromethyl-6-fluorobenzaldehyde is used as one of synthetic raw materials for a prophylactic / therapeutic agent for diabetes (Example 121).

  On the other hand, in Non-Patent Document 2, 2-fluoro-6- (trifluoromethyl) benzylamine is used as one of raw materials for thrombosis inhibitors.

  Non-patent document 1 discloses a specific method for synthesizing the above-mentioned 2-trifluoromethyl-6-fluorobenzaldehyde. That is, 3-trifluoromethyl-1-fluorobenzene (3-fluoro-1- (trifluoromethyl) benzene) is reacted with an organic lithium reagent such as n-butyllithium, and then N, N-dimethylformamide It was reported that 2-trifluoromethyl-6-fluorobenzaldehyde (2-fluoro-6- (trifluoromethyl) benzaldehyde) could be synthesized in 80% yield by contacting with (Entry 3) (Scheme 1).

Even in Patent Document 1, it has been reported that 2-trifluoromethyl-6-fluorobenzaldehyde was synthesized by a method using the same organolithium reagent (column 11).
US Pat. No. 4,046,898 specification International publication 01/090067 pamphlet Tetrahedron Letters, Vol.33, No.49, p.7499〜p.7502 Bioorganic & Medicinal Chemistry Letters, Vol.13, p.1353-p.1357, 2003 (USA)

  Both 2-trifluoromethyl-6-fluorobenzaldehyde and 2-trifluoromethyl-6-fluorobenzylamine targeted by the present invention have different functional groups at three adjacent positions (ortho positions) of the benzene ring. It is a compound bonded one by one. It is generally difficult to synthesize such trisubstituted benzenes.

  As a general method for producing trisubstituted benzene, there is a method in which a difunctional benzene is synthesized in advance and then a third functional group is further introduced into the disubstituted benzene. However, in this method, the selectivity of the object is a big problem. In general, when a third functional group is introduced into a disubstituted benzene, the third functional group is rarely introduced with high selectivity to the target site, and usually a positional isomer or multiple functional groups are introduced. A large amount of the excess reaction product formed is produced. As a result, the yield of the target product decreases, and it becomes difficult to produce a high-purity target product.

  In the above-mentioned Patent Document 1 and Non-Patent Document 1, exceptionally, a disubstituted benzene in which a trifluoromethyl group and a fluorine group are bonded to a meta position is used as a raw material, and a formyl group is efficiently introduced into an intermediate portion thereof. is doing. However, this method uses “organolithium reagent” as an essential reagent, and the organolithium reagent and the intermediate 2-trifluoromethyl-6-fluorophenyllithium are extremely unstable substances. The reaction must be continued at a very low temperature. The reaction itself is accompanied by a strong exotherm, and its control is extremely difficult when handling a large amount. That is, this method is suitable for synthesizing a small amount of 2-trifluoromethyl-6-fluorobenzaldehyde, but is difficult to employ industrially for synthesizing 2-trifluoromethyl-6-fluorobenzaldehyde.

  Thus, a method capable of industrially efficiently synthesizing 2-trifluoromethyl-6-fluorobenzaldehyde and its derivatives has been demanded.

  The present inventors have intensively studied to solve the above problems. As a result, it has been found that the above problem can be solved by using relatively inexpensive 2,3-dimethylfluorobenzene as a starting material and subjecting it to “functional group conversion” in 3 to 4 steps.

That is, when the inventors react 2,3-dimethylfluorobenzene with chlorine (Cl ₂ ), regioselective chlorination occurs, and 2-trichloromethyl-6-fluorobenzal chloride is obtained almost quantitatively. Obtained (first step). When the obtained 2-trichloromethyl-6-fluorobenzal chloride was reacted with hydrogen fluoride (HF) in the liquid phase, 2-trifluoromethyl-6-fluorobenzal chloride was obtained in good yield (No. 1). 2 step), when the obtained 2-trifluoromethyl-6-fluorobenzal chloride is further brought into contact with water under a Lewis acid catalyst, 2-trifluoromethyl-6- 6 which is the first object of the present invention is obtained. It was found that fluorobenzaldehyde can be obtained in good yield (third step).

Further, the 2-trifluoromethyl-6-fluorobenzaldehyde is reacted with hydroxylamine to obtain 2-trifluoromethyl-6-fluorobenzaldoxime, and then in the presence of a transition metal catalyst, hydrogen (H ₂ ) and It was found that 2-trifluoromethyl-6-fluorobenzylamine, which is the second target product of the present application, can be obtained in a high yield when reacted (fourth step).

In the present invention, a particularly important feature is the “chlorination reaction” in the first step. That is, when chlorine (Cl ₂ ) is reacted with 2,3-dimethylfluorobenzene, the methyl group at the meta position as viewed from the fluorine group is converted to the trichloromethyl group, and the methyl group at the ortho position as viewed from the fluorine group is converted. Conversion to a dichloromethyl group gives 2-trichloromethyl-6-fluorobenzal chloride selectively. Through this chlorination reaction, it was found that the isomer 2-trichloromethyl-3-fluorobenzal chloride was virtually not formed (Scheme 2).

  If the isomer 2-trichloromethyl-3-fluorobenzal chloride is significantly produced in this chlorination reaction, its physical and chemical properties are similar to 2-trichloromethyl-6-fluorobenzal chloride. Therefore, purification of the target product becomes extremely difficult. However, in the present invention, since this isomer is not formed in the first step, which is the first step, not only the target product can be obtained in a high yield, but also complicated purification means are not required in the subsequent steps. The target product could be produced with high purity without using it.

In general, when “trisubstituted benzene”, in which two methyl groups and one other group are bonded to a benzene nucleus, is subjected to chlorination, the two methyl groups undergo almost the same chlorination, and two chlorination products. Is obtained. For example, according to Japanese Patent Application No. 2004-189274 already filed by the present applicant, when 3,4-dimethylfluorobenzene is reacted with Cl ₂ , 2-trichloromethyl-5-fluorobenzal chloride and 2-trichloromethyl -4-Fluorobenzal chloride is formed in a ratio of approximately 1: 1 and it is not easy to separate these two isomers (Scheme 3).

  Compared to this, “position selectivity” in the first step (chlorination reaction) of the present invention is a very specific phenomenon. Since a high-purity chlorination product is obtained in the first step, the subsequent steps can also be efficiently performed, and the desired 2-trifluoromethyl-6-fluorobenzaldehyde and 2-trifluoromethyl-6-fluoro are targeted. Benzylamine can be produced in high yield and purity under conditions that are much milder than those of Non-Patent Document 1 and Patent Document 1.

  The present inventors have further found that the production process comprising the above reaction can be achieved particularly preferably by specific conditions and operations, and have completed the present invention.

That is, the present invention provides a method for producing 2-trifluoromethyl-6-fluorobenzaldehyde, which includes the following three steps.
First step: A step of reacting 2,3-dimethylfluorobenzene with chlorine (Cl ₂ ) to obtain 2-trichloromethyl-6-fluorobenzal chloride.
Second step: a step of reacting the 2-trichloromethyl-6-fluorobenzal chloride with hydrogen fluoride (HF) in a liquid phase to obtain 2-trifluoromethyl-6-fluorobenzal chloride.
Third step: A step of bringing 2-trifluoromethyl-6-fluorobenzal chloride into contact with water under a Lewis acid catalyst to obtain 2-trifluoromethyl-6-fluorobenzaldehyde.

The present invention further provides 2-trifluoromethyl-6-fluorobenzylamine obtained by subjecting 2-trifluoromethyl-6-fluorobenzaldehyde obtained by the above method to the following fourth step. A method of manufacturing the same is provided.
Fourth step: 2-trifluoromethyl-6-fluorobenzaldehyde is reacted with hydroxylamine to give 2-trifluoromethyl-6-fluorobenzaldoxime, then the resulting 2-trifluoromethyl-6-fluorobenz A step of reacting aldoxime with hydrogen (H ₂ ) in the presence of a transition metal catalyst to obtain 2-trifluoromethyl-6-fluorobenzylamine.

Further, the present invention is characterized in that the reaction between 2,3-dimethylfluorobenzene and chlorine (Cl ₂ ) in the first step is performed in the presence of a radical initiator or under light irradiation. A method according to any of the above is provided.

  In addition, the present invention provides the method according to any one of the above, wherein the reaction of 2-trichloromethyl-6-fluorobenzal chloride and hydrogen fluoride (HF) in the second step is performed in the absence of a solvent. I will provide a.

  In addition, the present invention uses the reaction mixture obtained after the second step is distilled and purified by distillation to isolate 2-trifluoromethyl-6-fluorobenzal chloride and then used in the subsequent third step. A method as described above is provided, characterized.

  In the present invention, any of the above, wherein the Lewis acid catalyst used in the third step is a Lewis acid catalyst selected from ferric chloride, chromium chloride, aluminum chloride, antimony pentachloride, and boron trifluoride. A method as described above is provided.

  The present invention also provides the method described above, wherein the transition metal catalyst used in the fourth step is at least one transition metal catalyst selected from palladium, platinum, ruthenium, iridium and rhodium. .

In the present invention, 2,3-dimethylfluorobenzene is reacted with chlorine (Cl ₂ ) in the presence of a radical initiator to obtain 2-trichloromethyl-6-fluorobenzal chloride, and then the 2-trichloromethyl- 6-Fluorobenzal chloride is reacted with hydrogen fluoride (HF) in the liquid phase and under solvent-free conditions to obtain a reaction mixture comprising 2-trifluoromethyl-6-fluorobenzal chloride, which is then The reaction mixture is purified by distillation to isolate 2-trifluoromethyl-6-fluorobenzal chloride, and then contacting the 2-trifluoromethyl-6-fluorobenzal chloride with water under a Lewis acid catalyst. A method for producing 2-trifluoromethyl-6-fluorobenzaldehyde is provided.

Further, the present invention was obtained by further reacting 2-trifluoromethyl-6-fluorobenzaldehyde obtained by the above method with hydroxylamine to obtain 2-trifluoromethyl-6-fluorobenzaldoxime, and then obtained. 2-trifluoromethyl-6-fluorobenzaldoxime is reacted with hydrogen (H ₂ ) in the presence of at least one transition metal catalyst selected from palladium, platinum, ruthenium, iridium and rhodium, A process for producing 2-trifluoromethyl-6-fluorobenzylamine is provided.

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

  According to the present invention, 2-trifluoromethyl-6-fluorobenzaldehyde and its derivative 2-trifluoromethyl-6-fluorobenzylamine are produced using 2,3-dimethylfluorobenzene, which is easily available industrially, as a raw material. Can be synthesized by a simple operation at a much lower cost than in the past.

Hereinafter, the present invention will be described in more detail. First, the first step (chlorination of 2,3-dimethylfluorobenzene) will be described in detail. The first step is a step in which 2,3-dimethylfluorobenzene is brought into contact with chlorine (Cl ₂ ) in the reaction region to obtain 2-trichloromethyl-6-fluorobenzal chloride.

As the reaction region, a glass container or a reaction container 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 a glass vessel or a reaction vessel lined with glass, fluororesin or the like 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 2,3-dimethylfluorobenzene charged in a reaction vessel in advance, 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.

  In order to advance this reaction, radical initiators 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 ′ -Azo compounds such as azobis (2-methylpropane), 2,2'-azobis (2-amidinopropane) dihydrochloride, 4,4'-azobis (4-cyanopentanoic acid), benzoyl peroxide, peroxide Dodecanoyl, dilauroyl peroxide, t-butyl peroxypivalate, di-t-butyl hydroperoxide, t-butyl-cumyl-peroxide, 2,5-dimethyl-2,5-bi Radical initiators such as peroxides such as bis (t-butylperoxy) hexyne, isobutyryl peroxide, 3,5,5-trimethylhexanoyl peroxide, red phosphorus, phosphorus pentachloride, phosphorus trichloride, triphenyl Phosphine, phosphorous compounds such as triphenyl phosphite, and the like are used, and light irradiation is performed. Further, these radical initiation methods may be used in appropriate combination. Even if the radical initiator is not added, by heating to a high temperature (approximately 160 ° C. or higher), radicals are generated in the system, and the same radical reaction can be caused. However, in consideration of operational convenience and reaction selectivity, the chlorination in the first step is preferably performed in the presence of a radical initiator or light irradiation, and is performed in the presence of a radical initiator. It is particularly preferred.

  When using a radical initiator, the radical initiator 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, more preferably 0.001 to 0.05 mol. . The radical initiator can be added as appropriate by observing the progress of the reaction. If the amount of the radical initiator is less than 0.0001 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 radical initiator 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.

  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. Therefore, when the chlorination is performed in the presence of a radical initiator or under light irradiation, the initial stage of the reaction (until the degree of chlorination reaches a value in the range of about 3 to 4 (for example, 3.5)) If it is carried out at a relatively low temperature (usually 30 to 150 ° C., preferably 50 to 130 ° C., particularly preferably 60 to 80 ° C.) and the reaction does not proceed easily at this temperature, a higher temperature (usually 150 to 300 ° C., preferably It is effective to carry out at 160 to 250 ° C, particularly preferably 170 to 230 ° C. 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 3-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 and 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 (Cl ₂ ) used in the reaction may be 5 mol or more with respect to 1 mol of 2,3-dimethylfluorobenzene in order to obtain the desired product with a sufficient yield, but is approximately 5 to 10 mol. It is about 5-6 mol by optimizing the reaction apparatus or reaction operation. 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 carried out in the presence of a solvent, but the reaction raw material 2,3-dimethylfluorobenzene is a liquid, and the product 2-trichloromethyl-6. -Fluorobenzal chloride is also a liquid under the reaction conditions, and sufficiently dissolves chlorine and the catalyst and also serves as a solvent. Therefore, it is not necessary to dare to use a separate solvent, which is economically preferable.

  As already mentioned, the main product obtained by chlorination in the first step is 2-trifluoromethyl-6-fluorobenzal chloride, which is the isomer 2-trichloromethyl-3-fluorobensene. It does not produce sarchloride. Under the conditions given above, the yield of this isomer is usually less than 0.1% relative to 2-trifluoromethyl-6-fluorobenzal chloride. Remarkably easy.

  The reaction mixture obtained by the chlorination reaction in the first step is usually 2,3-bis (dichloromethyl) fluorobenzene incompletely chlorinated, 2-chloro-6-fluorobenzal chloride which is excessively chlorinated. And 2-chloro-6-fluorobenzotrichloride are associated as impurities. These impurities can be separated by a purification process such as column chromatography, but their boiling points are close to each other, so that purification by distillation is usually difficult and requires complicated operations. In the present invention, separation can be sufficiently performed by distillation after the next second step. Therefore, in order to take advantage of the present invention, the reaction mixture after the completion of the first step is used as it is without being purified. It is preferable to use it as a raw material for the step (fluorination reaction).

  Hereinafter, the second step (fluorination of 2-trifluoromethyl-6-fluorobenzal chloride) will be described. In the second step, 2-trichloromethyl-6-fluorobenzal chloride obtained in the first step is brought into contact with hydrogen fluoride (HF) in the liquid phase to obtain 2-trifluoromethyl-6-fluorobenzal chloride. It is a process.

  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 200 ° C, preferably 60 to 150 ° C. When the temperature is lower than 40 ° C., the reaction is slow, and when the temperature is higher than 200 ° C., the production of perfluorinated 2-chlorofluoromethyl-3-fluorobenzotrifluoride and 2-difluoromethyl-3-fluorobenzotrifluoride increases. Also, decomposition of the trifluoromethyl group may occur, which is not preferable because the yield and purity of 2-trifluoromethyl-6-fluorobenzal chloride are reduced.

  In the fluorination reaction, hydrogen fluoride is usually used in an amount of 3 to 20 mol, preferably 4 to 15 mol, more preferably 5 to 12 mol, per mol of 2-trichloromethyl-6-fluorobenzal chloride. If the amount is less than 3 moles, the yield decreases, which is not preferable. If it is used in a larger amount than 20 moles, there is no problem in terms of reactivity, but the productivity increases due to an increase in the amount of hydrogen fluoride. Since an industrial problem arises, it is not preferable.

  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 MPa to 10 MPa, preferably 0.5 MPa to 10 MPa, particularly preferably 1 MPa to 5 MPa. Even if the reaction pressure exceeds 10 MPa, there is no problem in terms of reactivity, but an excessive apparatus is required, which is not preferable. On the other hand, when the pressure 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.

  From the above, a particularly preferred combination of reaction temperature and reaction pressure is 60 ° C. to 150 ° 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 toluene, fluorobenzene, difluorobenzene, benzotrifluoride, 1,4-bistrifluoromethylbenzene, and the like. 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 order not to increase the production of perfluorinated 2-chlorofluoromethyl-3-fluorobenzotrifluoride and 2-difluoromethyl-3-fluorobenzotrifluoride, the reaction is not allowed to take longer than necessary in this step. It is preferable. Specifically, the reaction is terminated within 2 hours before or after the 2-chlorodifluoromethyl-6-fluorobenzal chloride, the reaction intermediate in the second step, is completely consumed. It is desirable.

  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 product in 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 reaction product thus obtained can be used as a raw material for the third step as it is, but the components in the reaction mixture at the end of the second step are particularly easy to separate from each other. It is particularly preferable that 2-trifluoromethyl-6-fluorobenzal chloride having a high purity is isolated and used as a raw material for the third step. As this purification operation, distillation is particularly preferred.

  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. Distillation is preferred because it can be achieved at a relatively low temperature when performed under reduced pressure. Although there is no restriction | limiting in the number of stages of the distillation tower | column requested | required for this distillation, 5-100 stages are preferable, More preferably, it is 10-50 stages.

  Hereinafter, the third step (hydrolysis of 2-trifluoromethyl-6-fluorobenzal chloride) will be described. The third step is a step of obtaining 2-trifluoromethyl-6-fluorobenzaldehyde by bringing 2-trifluoromethyl-6-fluorobenzal chloride into contact with water under a Lewis acid catalyst in the reaction region.

  As the reaction region, a glass vessel, a reaction vessel lined with carbon or glass, a 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 hydrogen chloride (hydrochloric acid), so as much as possible glass, glass vessel, fluororesin 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 into 2-trifluoromethyl-6-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.

  Examples of the Lewis acid catalyst for proceeding with this reaction include ferric chloride, chromium chloride, aluminum chloride, antimony pentachloride, boron trifluoride, etc., 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-6-fluorobenzal chloride, but is preferably about 1.05 to 1.2 mol. Use of conventional means for setting the conditions and increasing the contact efficiency, for example, adjustment of the water introduction speed, stirring device, sparger, etc., 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-6-fluorobenzal chloride and the product 2-trifluoromethyl-6-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 performed under reduced pressure conditions. 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. 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, 2-trifluoromethyl-6-fluorobenzaldehyde can be isolated as a colorless liquid fraction.

Hereinafter, the fourth step (amination of 2-trifluoromethyl-6-fluorobenzaldehyde) will be described. In the fourth step, 2-trifluoromethyl-6-fluorobenzaldehyde obtained in the third step is reacted with hydroxylamine to obtain 2-trifluoromethyl-6-fluorobenzaldoxime (referred to as “oximation”). ), And then the obtained 2-trifluoromethyl-6-fluorobenzaldoxime is reacted with hydrogen (H ₂ ) in the presence of a transition metal catalyst to give 2-trifluoromethyl-6-fluorobenzyl alcohol (“ It is a process called “reduction reaction”.

  The hydroxylamine used in the oximation in this step is usually generated by reacting a hydroxylamine salt with an aqueous alkali metal solution in the system. There are no limitations on the type of hydroxylamine salt, but hydroxylamine hydrochloride, hydroxylamine sulfate, etc. are common and are preferably employed. 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. 1-5 times mole is preferable with respect to the sum of the number of moles of an amine salt and the number of moles of a raw material, and 1-3 times mole is more preferable. Less than equimolar is not preferable because the reaction is slow. On the other hand, even if it exceeds 5 mol, there is no problem in terms of reactivity, but the amount of neutralization treatment of excess alkali metal after completion of the reaction increases. 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% by weight to 48% by weight, and particularly preferably 5% by weight to 30% by weight. If the amount is less than 1% by weight, the amount of 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, hydroxylamine salt, alkali metal aqueous solution, 2-trifluoromethyl-6-fluorobenzaldoxime and alkali metal salt of 2-trifluoromethyl-6-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 their low solubility in water.

  Although there is no restriction | limiting in particular in the specific operation procedure of oximation of a 4th process, 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 hydroxylamine 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-6-fluorobenzaldehyde is dropped by using a dropping device such as a dropping funnel or a metering pump. It is preferable to continue the reaction 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. Preferably it is done.

  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-6-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-6-fluorobenzaldoxime may be decomposed into 2-trifluoromethyl-6-fluorobenzaldehyde and hydroxylamine. 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 reaction product obtained by the oximation in this step is not further purified, and it can be used as a raw material for the reduction reaction without adversely affecting the reactivity and selectivity of the reduction reaction. It is preferable to use it as a raw material.

The reduction reaction in this step is a target compound of the present invention by reacting 2-trifluoromethyl-6-fluorobenzaldoxime obtained by the oximation with hydrogen (H ₂ ) in the presence of a transition metal catalyst. In this step, 2-trifluoromethyl-6-fluorobenzylamine is obtained.

  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-6-fluorobenzaldoxime is solid at room temperature, it is preferable to use a solvent. Although there is no restriction | limiting in particular in a solvent, 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 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 used in the reduction reaction is preferably 1 to 20 mol, particularly preferably 1 to 10 mol, per 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 used is usually filled in a gas cylinder, but hydrochloric acid (aqueous hydrogen chloride solution) or a commercially available product dissolved in a solvent (for example, hydrogen chloride 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-6-fluorobenzaldoxime and a solvent are put into an autoclave that can withstand the pressurized condition. As the autoclave, a glass container, a reaction container lined with carbon or glass, a 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, when a predetermined amount of a transition metal catalyst is added and a hydrogen chloride solution dissolved in hydrochloric acid or a solvent is used as a hydrogen chloride source, a hydrogen chloride solution dissolved in a predetermined amount of hydrochloric acid or a solvent is subsequently added. Seal the container and start stirring in the container. When hydrogen chloride gas is added as a hydrogen chloride source instead of hydrochloric acid or a hydrogen chloride solution dissolved in a solvent, a predetermined amount is introduced by connecting a cylinder of hydrogen chloride gas. 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, the solvent is distilled off by evaporation, and neutralized with an alkaline aqueous solution (sodium hydroxide aqueous solution, potassium hydroxide aqueous solution, etc.) to a pH of 9 to 11 to give crude 2-trifluoromethyl. -6-Fluorobenzylamine is separated. This can be washed with water, and then the water can be removed with a desiccant or the like. Moreover, after neutralizing to the range of pH 9-11 with an alkali, and then extracting with an organic solvent such as n-hexane, ethyl acetate, toluene, methylene chloride, washing with water, and removing moisture with a desiccant, etc. The solvent can also be distilled off.

  The product of the fourth step can then be distilled and the colorless and transparent liquid 2-trifluoromethyl-6-fluorobenzylamine is isolated as a fraction by distillation.

  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. 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.

  EXAMPLES Next, examples are shown, but the present invention is not limited to these examples.

[Example 1]
(Example 1-a) Chlorination In a 500 ml four-necked flask equipped with a Dimroth condenser, thermometer, and chlorine blowing tube, 2,3-dimethylfluorobenzene: 248.0 g and 2,2′-azobisbutyronitrile (AIBN): 1.84 g (0.56 mol%) was charged, the internal temperature was raised to 60 ° C. while stirring, and chlorine gas was introduced at a rate of about 1.0 mol / Hr to initiate the reaction. While maintaining the internal temperature at 65 to 72 ° C., chlorine gas was supplied for 7 hours. As a result, the chlorination degree of the reaction solution was 3.65.

Thereafter, the internal temperature was raised to 190 ° C., and the reaction was continued for 12 hours. The composition of the reaction liquid after the reaction was continued was 74.7% of 2-trichloromethyl-6-fluorobenzal chloride, which is the target product, and 2,3-bis ( (Dichloromethyl) fluorobenzene was 1.5%, perchlorinated 2-chloro-6-fluorobenzal chloride was 1.0%, and 2-chloro-6-fluorobenzotrichloride was 17.3%. It was. The weight of the recovered reaction solution was 562.9 g. The isomer 2-trichloromethyl 3-fluorobenzal chloride was not detected. This reaction solution (chlorination mixture) was used in the subsequent Example 1-b (fluorination) without purification.
[Physical property data of 2-trichloromethyl-6-fluorobenzal chloride]
¹ H-NMR (reference material: TMS, solvent: CDCl ₃ )
δ ppm: 7.30 (mlut, 1.2 Hz, 8.3 Hz, 10.6 Hz, 1 H), 7.42 (mlut, 5.4 Hz, 8.3 Hz, 8.3 Hz, 1 H), 7.76 (d 3.6 Hz, 1 H), 7.85 (dd, 1.2 Hz, 8.0 Hz, 1 H)
¹⁹ F-NMR (reference material: CCl ₃ F, solvent: CDCl ₃ )
δ ppm: −102.31 (1F)
GLC-MS
m / z (rel. intensity): 294 (M +, 6.6), 265 (9.9), 263 (47.0), 261 (100), 259 (79.1), 226 (23.8) 224 (25.0), 191 (23.3), 189 (37.9), 156 (15.8), 154 (49.9), 119 (13.3), 118 (15.8), 113 (14.4), 112 (16.6), 99 (13.1), 94 (20.7), 77 (15.9)
Shape: White solid (purified product)
(Example 1-b) Fluorination Obtained in Example 1-a to 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. Then, 556.7 g of chlorinated mixture and 302.6 g of anhydrous hydrogen fluoride were charged and sealed, and the internal temperature was raised to 110 ° C. while stirring to initiate the reaction. The pressure adjustment valve was adjusted so that the internal pressure was 2.9 to 3.0 MPa, and the reaction was performed for 6 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 was 70.7% of 2-trifluoromethyl-6-fluorobenzal chloride, which was the target product, as analyzed by gas chromatography. In addition, 2-chlorofluoromethyl-3-fluorobenzotrifluoride, which is a perfluorinated product, is 0.9%, and 2-difluoromethyl-3-fluorobenzotrifluoride, which is also a perfluorinated product, is 8.9%. %, 2-chloro-6-fluorobenzotrifluoride, which is a perchlorinated fluorinated product, was 16.6%.

  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 417.2 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 1400 to 1500 Pa and a temperature of 76 to 77 ° C. was collected by this distillation, 247.9 g of a target product having a purity of 99.5% was obtained. The overall yield from 2,3-dimethylfluorobenzene as the chlorination raw material was 50.3%.
[Physical property data of 2-trifluoromethyl-6-fluorobenzal chloride]
¹ H-NMR (reference material: TMS, solvent: CDCl ₃ )
δ ppm: 7.03 (d, 3.1 Hz, 1 H), 7.39 (mlut, 1.5 Hz, 8.0 Hz, 10.7 Hz, 1 H), 7.44 (dd, 1.5 Hz, 8.0 Hz) 1H), 7.50 (mlut, 4.8 Hz, 8.0 Hz, 8.0 Hz, 1 H)
¹⁹ F-NMR (reference material: CCl ₃ F, solvent: CDCl ₃ )
δ ppm: −58.35 (3F), −104.21 (1F)
GLC-MS
m / z (rel. intensity): 246 (M +, 7.5), 213 (32.9) 211 (100), 176 (43.1), 161 (8.1), 125 (12.0), 107 (16.5), 88 (13.1)
Shape: colorless transparent liquid (Example 1-c) Hydrolysis 2-trifluoromethyl-6-fluorobenzal chloride (purity 99.5%) in a 500 ml four-necked flask equipped with a Dimroth condenser, thermometer and dropping funnel ): 246.0 g, ferric chloride (anhydrous): 3.2 g (2.0 mol%) and water: 19.8 g were charged into the dropping funnel, 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 105 to 115 ° C., 19.8 g of water was added dropwise over 2 hours. The composition of the reaction solution after the completion of the dropwise addition of water was 99.4% of the target product, 2-trichloromethyl-6-fluorobenzaldehyde, and the starting material, 2-trichloromethyl-5-fluorobenzal chloride, as analyzed by gas chromatography. 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 179.7 g.

  The resulting hydrolysis reaction solution was purified by distillation in a 20 cm distillation column packed with Dixon packing. By fractionating a fraction having a temperature of 1100 to 1200 Pa and a temperature of 73 to 74 ° C. by this distillation, 160.4 g of a target product having a purity of 99.8% was obtained. The overall yield from the hydrolysis raw material 2-trifluoromethyl-6-fluorobenzal chloride was 84.0%.

[Example 2] Amination A 500 ml four-necked flask equipped with a Dimroth condenser, thermometer, and dropping funnel was charged with hydroxylamine hydrochloride: 38.2 g and methanol: 191.1 g in a water or ice bath with stirring. While cooling and maintaining the internal temperature at 20 to 30 ° C., 192.0 g of 25% -aqueous sodium hydroxide solution was dropped over about 1 hour using a dropping funnel. Thereafter, using a dropping funnel while maintaining the internal temperature at 20 to 30 ° C., 2-trifluoromethyl-6-fluorobenzaldehyde synthesized in Example 1 (purity 99.8%): 96.0 g was taken for 1 hour. And dripped. 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-trichloromethyl-5-fluorobenzaldoxime was 96.5% and the raw material 2-trichloromethyl-4-fluorobenzaldehyde was 0.1% (composition ratio excluding the solvent). After completion of the reaction, 35% hydrochloric acid: 66.9 g was added to neutralize to pH = 4. 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 2-trichloromethyl-6-fluorobenzaldoxime obtained by evaporating the solvent of the filtrate by evaporation had a purity of 97.1% and a weight of 98.1 g. The overall yield from the oximation raw material 2-trifluoromethyl-6-fluorobenzaldehyde was 94.8%.

  2-trifluoromethyl-5-fluorobenzaldoxime (purity 97.1%) 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: 98 0.1 g, 5% -Pd / C (50% water-containing product): 3.9 g, 10% -hydrogen chloride methanol solution: 346.0 g (34.6 g as hydrogen chloride content), methanol: 162.5 g (total amount of methanol 473) .9 g) was charged, stirring was started, nitrogen was replaced with hydrogen, hydrogen was introduced, the pressure was adjusted to 0.5 MPa, and the reaction was continued for 10 hours while maintaining the internal temperature of 30 to 32 ° C. The composition of the reaction solution at this time was 97.6% of 2-trifluoromethyl-6-fluorobenzylamine, which was the target product, and 2-trifluoromethyl-6-fluorobenzaldoxime, which was the starting material, based on analysis by gas chromatography. 0.7%, other 2-trifluoromethyl-6-fluorobenzyl alcohol 0.1%, secondary amine (the following formula) 1.0%. 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-6-fluorobenzylamine hydrochloride was obtained, 2-trifluoromethyl-6-fluorobenzylamine was separated by washing with 10% aqueous sodium hydroxide solution to be alkaline. 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, 84.4 g of crude 2-trifluoromethyl-6-fluorobenzylamine was obtained. This was purified by distillation, and fractions of 2500 Pa to 2600 Pa and a temperature of 75 to 76 ° C. were collected to obtain 80.8 g of a target product having a purity of 99.9%. The overall yield from the raw material 2-trifluoromethyl-6-fluorobenzaldoxime was 88.2%.

[Example 3]
(Example 3-a) Chlorination In a 500 ml four-necked flask equipped with a Dimroth condenser, thermometer, and chlorine blowing tube, 2,3-dimethylfluorobenzene: 248.0 g and 2,2′-azobisbutyronitrile (AIBN): 1.84 g (0.56 mol%) was charged, the internal temperature was raised to 60 ° C. while stirring, and chlorine gas was introduced at a rate of about 1.0 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 3.71.

  Thereafter, the internal temperature was raised to 200 ° C., and the reaction was further continued for 7 hours. The composition of the reaction liquid after the reaction was continued was 79.6% of the target product, 2-trichloromethyl-6-fluorobenzal chloride, and 2,3-bis ( Dichloromethyl) fluorobenzene was 0.9%, perchlorinated 2-chloro-6-fluorobenzal chloride was 0.5%, and 2-chloro-6-fluorobenzotrichloride was 13.2%. It was. The isomer 2-trichloromethyl 3-fluorobenzal chloride was not detected. The weight of the reaction solution was 562.2 g. This reaction solution (chlorination mixture) was used in the following Example 3-b (fluorination) without purification.

(Example 3-b) Fluorination A chlorinated mixture obtained in Example 3-a was added to 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. 550.0 g and anhydrous hydrogen fluoride 303.4 g were charged and sealed, and the internal temperature was raised to 110 ° C. while stirring to initiate the reaction. The pressure control valve was adjusted so that the internal pressure became 2.9 to 3.0 MPa, and the reaction was performed for 5 hours while releasing hydrogen chloride generated with the progress of the reaction from the pressure control valve. The composition of the reaction solution (organic phase) at this time was 76.5% of 2-trifluoromethyl-6-fluorobenzal chloride, which was the target product, as analyzed by gas chromatography. In addition, the perfluorinated 2-chlorofluoromethyl-3-fluorobenzotrifluoride is 0.1%, and the perfluorinated 2-difluoromethyl-3-fluorobenzotrifluoride is 4.0%. %, 2-chloro-6-fluorobenzotrifluoride, which is a perchlorinated fluorinated product, was 14.3%.

  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 434.0 g.

  The resulting fluorination reaction solution was purified by distillation in a 45 cm distillation column packed with Dixon packing. When a fraction having a temperature of 2000 to 2150 Pa and a temperature of 81 to 84 ° C. was collected by this distillation, 271.7 g of a target product having a purity of 99.2% was obtained. The overall yield from the chlorinated raw material 2,3-dimethylfluorobenzene was 55.2%.

(Example 3-c) Hydrolysis 2-trifluoromethyl-6-fluorobenzal chloride (purity 99.2%) in a 500 ml four-necked flask equipped with a Dimroth condenser, thermometer and dropping funnel: 246.0 g Ferric chloride (anhydrous): 1.6 g (1.0 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 116 to 122 ° C., 19.8 g of water was added dropwise over 2 hours. The composition of the reaction solution after the completion of the dropwise addition of water was 99.4% of the target product, 2-trichloromethyl-6-fluorobenzaldehyde, and the starting material, 2-trichloromethyl-5-fluorobenzal chloride, as analyzed by gas chromatography. 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 181.0 g.

  The resulting hydrolysis reaction solution was purified by distillation in a 45 cm distillation column packed with Dixon packing. When the fraction having a temperature of 2000 to 2100 Pa and a temperature of 80 to 81 ° C. was collected by this distillation, 151.5 g of a target product having a purity of 99.8% was obtained. The overall yield from the hydrolysis raw material 2-trifluoromethyl-6-fluorobenzal chloride was 78.9%.

[Example 4] Amination A 500 ml four-necked flask equipped with a Dimroth condenser, thermometer, and dropping funnel was charged with hydroxylamine hydrochloride: 38.2 g and water: 200.0 g in a water or ice bath while stirring. While cooling and maintaining the internal temperature at 25-30 ° C., 192.0 g of 25% -aqueous sodium hydroxide solution was dropped over about 1 hour using a dropping funnel. Then, using a dropping funnel while maintaining the internal temperature at 30 to 32 ° C., 2-trifluoromethyl-6-fluorobenzaldehyde produced in Example 3 (purity 99.8%): 96.0 g was taken for 1 hour. And dripped. 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-trichloromethyl-5-fluorobenzaldoxime was 97.2% and the raw material 2-trichloromethyl-4-fluorobenzaldehyde was 0.1% (composition ratio excluding the solvent). After completion of the reaction, 100.0 g of water was added, and 67.8 g of 35% hydrochloric acid was added to neutralize to pH = 3. When neutralized, crystals of 2-trichloromethyl-5-fluorobenzaldoxime were precipitated, and the crystals were collected by filtration. Water: Washed with 50.0 g and then dried in an oven, 2-trichloromethyl-6-fluorobenzaldoxime had a purity of 98.7 and a weight of 98.2 g. The overall yield from the oximation raw material 2-trifluoromethyl-6-fluorobenzaldehyde was 94.9%. This reaction product was used for the subsequent reduction reaction without purification.

  2-trifluoromethyl-5-fluorobenzaldoxime (purity 98.7%) 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: 98 0.2 g, 5% -Pd / C (50% water-containing product): 2.0 g, 10% -hydrogen chloride methanol solution: 346.0 g (34.6 g as hydrogen chloride content), methanol: 162.5 g (total amount of methanol 473) .9 g) was added, stirring was started, nitrogen was replaced with hydrogen, hydrogen was introduced, the pressure was adjusted to 0.5 MPa, and the internal temperature was maintained at 50 to 32 ° C. for 5 hours. The composition of the reaction liquid at this time was 96.0% of the target 2-trifluoromethyl-6-fluorobenzylamine, which was the object of analysis, and the raw material 2-trifluoromethyl-6-fluorobenzaldoxime 0 2%, other 2-trifluoromethyl-6-fluorobenzyl alcohol 0.7%, secondary amine 2.6%. 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-6-fluorobenzylamine hydrochloride was obtained, it was washed with 10% aqueous sodium hydroxide so as to be alkaline, and 2-trifluoromethyl-6-fluorobenzylamine was separated. did. This was extracted with n-hexane, and the organic phase was washed with water. The organic phase after washing was separated, magnesium sulfate was added, and the mixture was stirred and filtered. The filtrate (organic phase) was concentrated again by evaporation to remove n-hexane, whereby 84.3 g of crude 2-trifluoromethyl-6-fluorobenzylamine was obtained. This was purified by distillation, and fractions having a temperature of 2300 Pa to 2400 Pa and a temperature of 71 to 72 ° C. were collected. As a result, 78.6 g of a target product having a purity of 99.8% was obtained. The overall yield from the raw material 2-trifluoromethyl-6-fluorobenzaldoxime was 85.8%.

[Example 5]
(Example 5-a) Chlorination In a 500 ml four-necked flask equipped with a Dimroth condenser, thermometer, and chlorine blowing tube, 2,3-dimethylfluorobenzene: 248.0 g and 2,2′-azobisbutyronitrile (AIBN): 1.84 g (0.56 mol%) was charged, the internal temperature was raised to 60 ° C. while stirring, and chlorine gas was introduced at a rate of about 1.0 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 3.68.

  Thereafter, the internal temperature was raised to 220 ° C., and the reaction was continued for another 5 hours. The composition of the reaction liquid after the reaction was continued was 83.5% of the target product, 2-trichloromethyl-6-fluorobenzal chloride, and 2,3-bis ( (Dichloromethyl) fluorobenzene was 1.0%, perchlorinated 2-chloro-6-fluorobenzal chloride was 0.5%, and 2-chloro-6-fluorobenzotrichloride was 8.6%. It was. The isomer 2-trichloromethyl 3-fluorobenzal chloride was not detected. The weight of the reaction solution was 574.1 g. This reaction solution (chlorination mixture) was used in the following Example 5-b (fluorination) without purification.

(Example 5-b) Fluorination A chlorinated mixture obtained in Example 5-a was added to 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. 572.8 g and anhydrous hydrogen fluoride 380.4 g were charged and sealed, the internal temperature was raised to 100 ° C. while stirring, and the reaction was started. The pressure control valve was adjusted so that the internal pressure was 2.9 to 3.0 MPa, and the reaction was carried out for 10 hours while releasing hydrogen chloride generated with the progress of the reaction out of the system. The composition of the reaction solution (organic phase) at this time was 84.3% of 2-trifluoromethyl-6-fluorobenzal chloride, which was the target product, as analyzed by gas chromatography. In addition, 2-chlorofluoromethyl-3-fluorobenzotrifluoride, which is a perfluorinated product, is 0.6%, and 2-difluoromethyl-3-fluorobenzotrifluoride, which is also a perfluorinated product, is 2.4%. %, 2-chloro-6-fluorobenzotrifluoride, which is a perchlorinated fluorinated product, was 8.8%.

  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 439.6 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 1550 to 1650 Pa and a temperature of 70 to 72 ° C. was collected by this distillation, 294.5 g of a target product having a purity of 99.0% was obtained. The overall yield from 2,3-dimethylfluorobenzene as the chlorination raw material was 59.9%.

(Example 5-c) Hydrolysis In a 500 ml four-necked flask equipped with a Dimroth condenser, thermometer and dropping funnel, 2-trifluoromethyl-6-fluorobenzal chloride (purity 99.0%): 246.0 g Ferric chloride (anhydrous): 1.6 g (1.0 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 dripping of the water was started from the dropping funnel, and the reaction was started. While maintaining the internal temperature at 111 to 106 ° C., 19.8 g of water was added dropwise over 2 hours. The composition of the reaction solution after completion of the dropwise addition of water was 99.4% of the target product, 2-trichloromethyl-6-fluorobenzaldehyde, and the raw material, 2-trichloromethyl-5-fluorobenzal, as analyzed by gas chromatography. 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 181.0 g.

  The resulting hydrolysis reaction solution was purified by distillation in a 20 cm distillation column packed with Dixon packing. When a fraction having a temperature of 1100 to 1000 Pa and a temperature of 69 to 71 ° C. was collected by this distillation, 164.3 g of a target product having a purity of 99.6% was obtained. The overall yield from the hydrolysis raw material 2-trifluoromethyl-6-fluorobenzal chloride was 85.6%.

[Example 6] Amination A 500 ml four-necked flask equipped with a Dimroth condenser, thermometer, and dropping funnel was charged with hydroxylamine hydrochloride: 38.2 g and water: 200.0 g in a water or ice bath with stirring. While cooling and maintaining the internal temperature at 50 ° C. or lower, 192.0 g of 25% -aqueous sodium hydroxide solution was slowly added using a dropping funnel. Then, using a dropping funnel while keeping the internal temperature at 50 ° C. or lower, 2-trifluoromethyl-6-fluorobenzaldehyde (purity 99.4%) produced in Example 5: 96.0 g was applied over 1 hour. It was dripped. 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-trichloromethyl-5-fluorobenzaldoxime was 97.5% and the raw material 2-trichloromethyl-4-fluorobenzaldehyde was 0.1% (composition ratio excluding the solvent). After completion of the reaction, 100.0 g of water was added, and 67.8 g of 35% hydrochloric acid was added to neutralize to pH = 3. When neutralized, crystals of 2-trichloromethyl-5-fluorobenzaldoxime precipitated, and the crystals were collected by filtration. After washing with water: 50.0 g, 2-trichloromethyl-6-fluorobenzaldoxime obtained by drying in an oven had a purity of 99.0% and a weight of 98.6 g. The overall yield from the oximation raw material 2-trifluoromethyl-6-fluorobenzaldehyde was 95.5%. This reaction product was used for the subsequent reduction reaction without purification.

  2-trifluoromethyl-5-fluorobenzaldoxime (purity 99.0%) 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: 98 .6 g, 5% -Pd / C (50% water-containing product): 2.0 g, 35% -hydrochloric acid: 99.3 g (34.8 g as hydrogen chloride content), methanol: 476.3 g, and stirring was started. After substitution with nitrogen and hydrogen, hydrogen was introduced, the pressure was adjusted to 0.5 MPa, and the reaction was continued for 3 hours while maintaining the internal temperature of 50 to 32 ° C. The composition of the reaction solution at this time is 96.8% of 2-trifluoromethyl-6-fluorobenzylamine, which is the target product, and 2-trifluoromethyl-6-fluorobenzaldoxime, which is the raw material, based on analysis by gas chromatography. 0.1%, other 2-trifluoromethyl-6-fluorobenzyl alcohol 2.4%, secondary amine 0.7%. 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-6-fluorobenzylamine hydrochloride was obtained, it was washed with 10% aqueous sodium hydroxide so as to be alkaline, and 2-trifluoromethyl-6-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, 85.0 g of crude 2-trifluoromethyl-6-fluorobenzylamine was obtained. This was purified by distillation, and a fraction having a temperature of 2250 Pa to 2400 Pa and a temperature of 66 to 69 ° C. was collected to obtain 81.4 g of a target product having a purity of 99.9%. The overall yield from the raw material 2-trifluoromethyl-6-fluorobenzaldoxime was 88.8%.

Claims (9)

A method for producing 2-trifluoromethyl-6-fluorobenzaldehyde, comprising the following three steps.
First step: A step of reacting 2,3-dimethylfluorobenzene with chlorine (Cl ₂ ) to obtain 2-trichloromethyl-6-fluorobenzal chloride.
Second step: a step of reacting the 2-trichloromethyl-6-fluorobenzal chloride with hydrogen fluoride (HF) in a liquid phase to obtain 2-trifluoromethyl-6-fluorobenzal chloride.
Third step: A step of bringing 2-trifluoromethyl-6-fluorobenzal chloride into contact with water under a Lewis acid catalyst to obtain 2-trifluoromethyl-6-fluorobenzaldehyde. The 2-trifluoromethyl-6-fluorobenzaldehyde obtained by the method of claim 1 is further subjected to the following fourth step to produce 2-trifluoromethyl-6-fluorobenzylamine Method.
Fourth step: 2-trifluoromethyl-6-fluorobenzaldehyde is reacted with hydroxylamine to give 2-trifluoromethyl-6-fluorobenzaldoxime, then the resulting 2-trifluoromethyl-6-fluorobenz A step of reacting aldoxime with hydrogen (H ₂ ) in the presence of a transition metal catalyst to obtain 2-trifluoromethyl-6-fluorobenzylamine. The reaction of 2,3-dimethylfluorobenzene and chlorine (Cl ₂ ) in the first step is carried out in the presence of a radical initiator or under light irradiation. The method described in 1. The method according to claim 1 or 2, wherein the reaction of 2-trichloromethyl-6-fluorobenzal chloride and hydrogen fluoride (HF) in the second step is performed in the absence of a solvent. After completion of the second step, the reaction mixture obtained is purified by distillation, and 2-trifluoromethyl-6-fluorobenzal chloride is isolated and used in the subsequent third step. Item 5. The method according to Item 4. The Lewis acid catalyst used in the third step is a Lewis acid catalyst selected from ferric chloride, chromium chloride, aluminum chloride, antimony pentachloride, and boron trifluoride. The method described in 1. The method according to claim 2, wherein the transition metal catalyst used in the fourth step is at least one transition metal catalyst selected from palladium, platinum, ruthenium, iridium and rhodium. 2,3-dimethylfluorobenzene is reacted with chlorine (Cl ₂ ) in the presence of a radical initiator to give 2-trichloromethyl-6-fluorobenzal chloride, then the 2-trichloromethyl-6-fluorobenzal The chloride is reacted with hydrogen fluoride (HF) in the liquid phase and under solvent-free conditions to obtain a reaction mixture containing 2-trifluoromethyl-6-fluorobenzal chloride, and then the reaction mixture is purified by distillation 2-trifluoromethyl-6-fluorobenzal chloride, and then contacting the 2-trifluoromethyl-6-fluorobenzal chloride with water under a Lewis acid catalyst. -Method for producing trifluoromethyl-6-fluorobenzaldehyde. The 2-trifluoromethyl-6-fluorobenzaldehyde obtained by the method of claim 8 is further reacted with hydroxylamine to give 2-trifluoromethyl-6-fluorobenzaldoxime, and then the obtained 2-trimethyl Fluoromethyl-6-fluorobenzaldoxime is reacted with hydrogen (H ₂ ) in the presence of at least one transition metal catalyst selected from palladium, platinum, ruthenium, iridium and rhodium. A process for producing fluoromethyl-6-fluorobenzylamine.