JP2001302582A - Method for producing trifluoromethylphenylacetic acid - Google Patents

Abstract

PROBLEM TO BE SOLVED: To produce bis(trifluoromethyl)phenylacetaldehyde having useful applications by a simple operation by using an easily available compound as a raw material. SOLUTION: Trifluoromethylphenylacetic acid is produced by reacting a halogen-substituted trifluoromethyl compound with a vinyl ether or ethanamide in the presence of a palladium compound, a phosphine and a base to obtain a trifluoromethylstylene derivative subsequently hydrolyzing the derivative to obtain trifluoromethylphenylacetldehyde and oxidizing the aldehyde.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a process for producing trifluoromethylphenylacetic acids useful as intermediates for producing pharmaceuticals, pesticides, insecticides, dyes, and fragrances and as a reagent for introducing a fluorine-containing group. The present invention relates to trifluoromethylphenylacetaldehyde derivatives and trifluoromethylstyrene derivatives, which are simple intermediates, and a method for producing the same.

[0002]

BACKGROUND ART When a specific aryl halide (containing no trifluoromethyl group) or aryl trifluoromethanesulfonate is reacted with a specific olefin in the presence of a palladium compound, phosphine or bidentate amine, or a base, Reactions to produce styrene derivatives are known (eg, J. Org. Chem., 58,7421 (1993), J. Org. Che.
m, 52, 3529 (1987), Tetrahedron Letters, 32, 1753 (199
1)). Here, when a vinyl ether such as n-butyl vinyl ether is used as the olefin, a mixture of 1-alkoxystyrene and 2-alkoxystyrene is generally obtained. For example, according to J. Org. Chem., 52, 3529-3536 (1987), when bromobenzene and n-butyl vinyl ether are heated at 100 ° C. for 16 hours in acetonitrile in the presence of palladium acetate and triphenylphosphine, 1- 34% butoxystyrene, 22% 2-butoxystyrene
% (Total of cis and trans isomers).

The product 1-alkoxystyrene, 1-
Amidostyrene is converted to acetophenone by hydrolysis.
It has been reported that 2-alkoxystyrene and 2-amidostyrene are converted to phenylacetaldehyde by hydrolysis (Tetrahedron, 50, 285 (1994)).

[0004]

An industrially suitable method for producing highly useful trifluoromethylphenylacetaldehyde and trifluoromethylphenylacetic acid by a simple operation from a readily available compound as a raw material. I will provide a.

[0005]

The present inventors have made studies to solve the above-mentioned problems, and found that the corresponding trifluoromethylhalogenobenzene was converted to a vinyl ether compound in the presence of a palladium compound, a phosphine and a base. Alternatively, when the ethaneamides are reacted, the corresponding trifluoromethylstyrene derivative is found to be formed under mild conditions, and trifluoromethylphenylacetaldehyde can be produced by hydrolyzing the trifluoromethylstyrene derivative. The inventors have found that oxidization gives trifluoromethylphenylacetic acid, and completed the present invention.

That is, the present invention is a process for producing trifluoromethylphenylacetic acids represented by the general formula (7), comprising the following three steps. General formula (1),

[0007]

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Wherein X is a halogen atom (chlorine, bromine or iodine) or a trifluoromethanesulfonate group, Y is a hydrogen atom or an inert group, and n represents 1 or 2. In the presence of a palladium compound and a phosphine or bidentate amine and a base, a methyl compound is reacted with a compound represented by the following general formula (2): CH ₂ ＣＨCH—OR ¹ (2) (wherein R ¹ is a C ₁ -C ₈ alkyl group) , C ₁ haloalkyl group -C _8, C alkenyl group ₂ -C _8, haloalkenyl groups C ₁ -C _8, cycloalkyl radical of C ₃ -C _6, an aryl group, an -C ₁ -C ₂ alkyl Group, a heteroaryl group or a C _{1 to} C ₈ acyl group) or a general formula (3), CH ₂ ＣＨCH—N (R ² ) —CO—R ³ (3) Wherein R ² and R ³ are each independently C ₁ -C ₈ alkyl, C ₁ haloalkyl group -C _8, C alkenyl group ₂ -C _8, haloalkenyl groups C ₁ -C _8, cycloalkyl radical of C ₃ -C _6, an aryl group, Aryl-C ₁ -C ₂ alkyl group heteroaryloxy group or C ₁ -C ₈ acyl group) represented by the general formula (4)

[0009]

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Wherein Y, R ¹ and n are the same as defined above, or a trifluoromethylstyrene derivative represented by the general formula (5):

[0011]

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Wherein Y, R ² , R ³ and n are the same as above.
Obtaining a trifluoromethylstyrene derivative represented by the following formula (first step). By hydrolyzing any of the trifluoromethylstyrene derivatives represented by the general formula (4) or (5), the general formula (6)

[0013]

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A step of obtaining a trifluoromethylphenylacetaldehyde represented by the formula (where Y and n are the same as described above) (second step). The trifluoromethylphenylacetaldehyde represented by the general formula (6) is oxidized to obtain a compound represented by the general formula (7)

[0015]

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A step of obtaining trifluoromethylphenylacetic acid represented by the formula (where Y and n are the same as described above) (third step).

Another invention is a method for producing trifluoromethylphenylacetaldehydes represented by the general formula (6) comprising a first step and a second step, and a method represented by a general formula (7) in a third step. And a trifluoromethylphenylacetaldehyde represented by the general formula (8).

The general formula (1) as a starting material of the present invention,

[0019]

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(Wherein X is a halogen atom (chlorine, bromine or iodine) or a trifluoromethanesulfonate group, Y is a hydrogen atom or an inert group, and n represents 1 or 2). The methyl compound is
It is a compound having at least one trifluoromethyl group and a halogen atom serving as a reaction site on a benzene ring. Y
May be independently different hydrogen atoms or inert groups.

Specifically, although not particularly limited, compounds having one trifluoromethyl group, for example, 1-bromo-2-trifluoromethylbenzene, 1-iodo-2
-Trifluoromethylbenzene, 1-bromo-3-trifluoromethylbenzene, 1-iodo-3-trifluoromethylbenzene, 1-bromo-4-trifluoromethylbenzene, 1-iodo-4-trifluoromethylbenzene, Compounds having two trifluoromethyl groups, for example, 1-bromo-2,4-bis (trifluoromethyl) benzene, 1-iodo-2,4-bis (trifluoromethyl) benzene, 1-bromo-3 , 5-bis (trifluoromethyl) benzene [3,5-bis (trifluoromethyl) bromobenzene], 1-iodo-3,5-bis (trifluoromethyl) benzene [3,5-bis (trifluoromethyl) ) Iodobenzene], 2-bromo-
1,3-bis (trifluoromethyl) benzene, 2-iodo-1,3-bis (trifluoromethyl) benzene,
2-bromo-1,4-bis (trifluoromethyl) benzene, 2-iodo-1,4-bis (trifluoromethyl) benzene, 4-bromo-1,2-bis (trifluoromethyl) benzene, and the like. Can be

The trifluoromethyl compound represented by the general formula (1) used in the present invention may be a compound having an alkyl group, an alkoxy group, a nitro group or the like as an inert group. For example, 1-bromo-2-methoxy-3,5-bis (trifluoromethyl) benzene,
1-iodo-2-methoxy-3,5-bis (trifluoromethyl) benzene, 2-bromo-1-nitro-3,5
-Bis (trifluoromethyl) benzene and the like.

As the trifluoromethyl compound represented by the general formula (1), 3,5-bis (trifluoromethyl) bromobenzene or 3,5-bis (trifluoro Most preferred is methyl) iodobenzene.

The vinyl ether represented by the general formula (2) CH ₂ ＣＨCH—OR ¹ (2) or CH ₂ ＣＨCH—N (R ² ) —CO— used in the method of the present invention. In the ethanamide represented by R ³ (3), R ¹ , R ² , and R ³ may be any groups as long as they do not adversely affect the reaction. Examples thereof include C ₁ -C ₈ alkyl groups and C ₁ -C ₈ alkyl groups. haloalkyl group ₁ -C _8, an alkenyl group of C ₂ -C _8, haloalkenyl groups C ₁ -C _8, cycloalkyl radical of C ₃ -C _6, an aryl group, an -C ₁ -C ₂ alkyl group, Examples include a heteroaryl group or a C ₁ -C ₈ acyl group. Also,
These may have a substituent appropriately. R ¹ , R ² , R
^{In the} present invention, any of ³ is a group which is eliminated in the second step, so that an alkyl group is usually sufficient. Of these,
A vinyl ether represented by the general formula (10) CH ₂ ＝ CH—OR ⁴ (10) (wherein R ⁴ represents a C ₁ -C ₆ alkyl group), for example, methyl vinyl ether, ethyl vinyl ether, propyl vinyl ether; Isopropyl vinyl ether, n-butyl vinyl ether, s
Preferred examples include ec-butyl vinyl ether, tert-butyl vinyl ether, and n-pentyl vinyl ether.

In the present invention, palladium is a palladium salt such as palladium acetate, palladium chloride, palladium bromide, palladium trifluoroacetate, or a palladium complex such as [3,5-bis (trifluoromethyl) benzoato] 3. ', 5'-bis (trifluoromethyl) phenylbis (triphenylphosphine) palladium (II), [Pd (PPh ₃ ) ₄ ], bis (dibenzalacetone) palladium, PdCl ₂ [P (Ph) ₂ CH ₂ C
H ₂ P (Ph) ₂ ], PdCl ₂ [P (Ph) ₂ CH ₂ CH ₂
CH ₂ P (Ph) ₂ ], PdCl ₂ [P (Ph) ₂ CH ₂ C
H ₂ CH ₂ CH ₂ P (Ph) ₂ ], PdCl ₂ (dpp
b), PdCl ₂ (dppf), PdCl ₂ [P (o-M
_{e-Ph) 3] 2,} PdCl 2 [P (m-Me-Ph) 3]
₂ , PdCl ₂ [P (p-Me-Ph) ₃ ] ₂ , PdCl ₂
(PMe ₃ ) ₂ , PdCl ₂ (PPh ₃ ) ₂ , PdBr ₂ (P
Ph ₃ ) ₂ , Pd (PPh ₃ ) ₄ , Pd (CO) (PP
_{h 3) 3, PhPdI (PPh} 3) 2, PhPdBr (PP
_{h 3) 2, PhPdBr (PMePh} 2) 2, PdCl
₂ (PMePh ₂ ) ₂ , PdCl ₂ (PEt ₂ Ph) ₂ , Pd
Cl ₂ (PMe ₂ Ph) ₂ , Pd ₂ Br ₄ (PPh ₃ ) ₂ , P
dCl ₂ (PEt ₃ ) ₂ , Pd (OAc) ₂ (PPh ₃ ) ₂ ,
PdCl ₂ (acetonitrile) ₂ , PdCl ₂
(Benzonitrile) ₂ , PdCl ₂ (bpy)
And the like. Here, Me represents a methyl group, Et represents an ethyl group, Ph represents a phenyl group, and OAc represents an acetato ligand. Of these, palladium salts such as palladium acetate and palladium chloride are used as palladium salts, and PdCl is used as a complex.
₂ (dppb), PdCl ₂ (PPh ₃ ) ₂ , Pd (OA
c) ₂ (PPh ₃ ) _{2 and the} like are particularly preferred.

The phosphine used as a ligand in the method of the present invention is not particularly limited, but specific examples include 1,1'-bis (diphenylphosphino) ferrocene (dppf) and 1,4-bis (Diphenylphosphino) butane (dppb), 1,3-bis (diphenylphosphino) propane (dppp), 1,2-bis (diphenylphosphino) ethane (dppe), triphenylphosphine, methyldiphenylphosphine, tri- o-
Tolyl phosphine, tri-m-tolyl phosphine, tri-p-tolyl phosphine, tri-n-butyl phosphine, triethyl phosphine and the like can be mentioned. These phosphines may be added as free phosphines, or may be added in a form contained in a Pd complex such as PdCl ₂ (PPh ₃ ) ₂ .

Further, bidentate amines can be used in place of phosphines. Examples of these bidentate amines are 2,2'-bipyridyl, 1,10-phenanthroline, 1,2-diaminobenzene, N, N, N ', N'-
Tetramethylethylenediamine and the like can be mentioned.

The amount of palladium used is 0.00001 to 0.5 mol, preferably 0.001 mol, per mol of the trifluoromethyl compound represented by the general formula (1) as a raw material.
005 to 0.1 mol, more preferably 0.0001 to
0.1 mol. If the amount is less than 0.00001 mol, the progress of the reaction is too slow to be practical, and it is not preferable.

The phosphine (or bidentate amine) is added so that the coordinated phosphorus atom (or nitrogen atom) is about 0.5 to 4 moles, preferably about 1 to 3 moles per mole of palladium. Phosphine (or bidentate amine)
If too much is used, the reaction rate will decrease,
-The selectivity of the substituted product may decrease. Also, if phosphine (or bidentate amine) is not added more than necessary,
Palladium black may precipitate and the reaction may not proceed sufficiently, which is not preferable.

The reaction according to the first step of the present invention is carried out in a solvent. As the solvent, an aprotic polar solvent is used,
Examples include propylene carbonate, anisole, N-methyl-2-pyrrolidone, N, N-dimethylacetamide, dimethylformamide, tetramethylurea, γ-butyrolactone, N, N-dimethylimidazolidinone, dimethylsulfoxide and the like.

Since the reaction may be accelerated by adding water to these aprotic polar solvents, water may be appropriately added to the system. The amount of addition is not particularly limited, but if added in too large an amount, the reaction may be suppressed or a side reaction may be accelerated. Specifically, the addition amount range is preferably not more than half of the aprotic polar solvent.

Examples of the base include amines; triethylamine, triethylenediamine, cyclohexylamine, N
-Cyclohexyl-N, N-diethylamine, pyridine, 4- (N, N-dimethylamino) pyridine, N-methylmorpholine, 1,8-diazabicyclo [5.4.
0] Undec-5-ene (DBU), alkali metal, alkaline earth metal hydroxide, carbonate, hydrogen carbonate, phosphate, for example, potassium hydroxide, carbonate, hydrogen carbonate, phosphorus Acid Salts: Carboxylates, for example, alkali metal salts of C ₂ -C ₄ carboxylic acids and the like. Among them, triethylamine, potassium hydroxide, potassium carbonate, potassium hydrogen carbonate, potassium phosphate and sodium acetate are particularly preferred.

The reaction temperature of the reaction of the first step of the present invention is 30.
To 200 ° C, preferably about 70 to 150 ° C.

The operation of the first step is not particularly limited, and may be performed by a general procedure of organic synthesis. For example, a predetermined amount of a trifluoromethyl compound represented by the general formula (1), a reaction solvent, a base , A palladium compound and phosphine (or bidentate amine) are charged into a reaction vessel, and the inside is replaced with an inert gas, for example, nitrogen, argon, hydrogen, helium, etc., and the temperature is raised to a predetermined temperature while stirring. Thereafter, a predetermined amount of the compound represented by the general formula (2) or (3) is added at one time, continuously or intermittently. A predetermined amount of the compound represented by the general formula (2) or (3) may be charged into the reactor together with other reagents before the temperature is raised. After completion of the charging, the reaction is further continued as necessary. After the reaction is completed or completed, the contents are taken out and subjected to a purification operation.

In the second step, any one of the trifluoromethylstyrene derivatives represented by the general formula (4) or (5) obtained in the first step is hydrolyzed to obtain a compound of the general formula (6) And trifluoromethylphenylacetaldehydes represented by General formula (4)
Alternatively, the trifluoromethylstyrene derivative represented by the general formula (5) has a cis isomer and a trans isomer, but in the reaction of the second step, the product represented by the general formula (6) is obtained in any case. Can be

The second step of the present invention comprises hydrolyzing the compound represented by the general formula (4) or (5) to obtain an aldehyde compound represented by the general formula (6). . This hydrolysis reaction is carried out by bringing the product represented by the general formula (4) or (5) obtained in the first step into contact with an aqueous acid solution at about 0 to 100 ° C. At this time, a solvent may be allowed to coexist. As the acid, for example, hydrochloric acid, sulfuric acid, acetic acid and the like can be used, and the solvent is not particularly limited as long as it can dissolve the product. For example, acetone, N,
Examples include N-dimethylformamide (DMF), N, N-dimethylacetamide (DMAC), and acetonitrile. It is preferable to use a solvent, since the selectivity of trifluoromethylphenylacetaldehydes generally increases as compared with the case without a solvent.

In the first step, together with the compound (2-substituted) represented by the general formula (4) or (5), an isomer (1) in which an aryl group is substituted at the 1-position of vinyl ether or ethanamide -Substituted) may be obtained. When the 1-substituted product is hydrolyzed in the second step, the compound represented by the general formula (9):

[0038]

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(Where Y and n are the same as those described above), so that the aldehyde compound represented by the general formula (6), which is formed by hydrolysis of the 2-substituted product, is obtained. Known methods, for example, distillation, solvent extraction,
It can be separated and removed by recrystallization, column chromatography or the like. When the 2-substituted product is more susceptible to a hydrolysis reaction than the 1-substituted product, the 2-substituted product is obtained under relatively mild conditions.
It is also possible to hydrolyze only the substituted product to obtain an aldehyde compound represented by the general formula (6), and to separate and purify the aldehyde compound from the unreacted 1-substituted product. On the other hand, when the 1-substituted product is more susceptible to hydrolysis than the 2-substituted product, the 1-substituted product is removed in advance before the hydrolysis in the second step in order to avoid complicated purification of the aldehyde compound. You can also keep. As a method for removal, a method such as distillation, solvent extraction, recrystallization, or column chromatography may be employed. Alternatively, only the 1-substituted product can be reacted in advance and converted to another substance, and then separated and removed by known means. For example, the compound is converted into an acetophenone derivative represented by the general formula (6) under the condition that only the 1-substituted product can be hydrolyzed and removed from the compound represented by the general formula (4) or (5). This is the preferred method.

The reaction product obtained in the second step can be purified by a known method, for example, distillation, solvent extraction, recrystallization, column chromatography or the like. For example, in the case of 3,5-bis (trifluoromethyl) phenylacetaldehyde, since this compound is a solid at ordinary temperature, after the hydrolysis reaction is completed, the organic component is extracted with a suitable organic solvent, and then concentrated and washed. Can be easily isolated as crystals. This 3,5-bis (trifluoromethyl) phenylacetaldehyde is sufficiently stable under ordinary conditions.

Furthermore, the present inventors can easily produce the corresponding trifluoromethylphenylacetic acid having high utility by subjecting the aldehyde compound represented by the general formula (6) obtained as described above to an oxidation treatment. Was found.

In the reaction relating to the third step, the aldehyde compound represented by the general formula (6) is reacted with a specific oxidizing agent together with a solvent.
The contact is performed at a temperature of about 50 to 100 ° C. As the aldehyde compound represented by the general formula (6), an isolated and purified aldehyde compound may be used, but it is not always necessary, and the organic phase is separated from the reaction product obtained in the second step. It may be used without purification. Oxidizing agents include oxygen, ozone, chromium trioxide (CrO ₃ ), potassium dichromate (K ₂ Cr ₂ O ₇ ), potassium permanganate (KMnO ₄ ), active manganese, manganese dioxide, silver monoxide, etc. A general-purpose oxidizing agent such as a heavy metal salt, sodium hypochlorite, sodium chlorite, sodium chlorate, sodium perchlorate and peroxide such as hydrogen peroxide may be used. Further, as the solvent, water, acetone, acetic acid and the like are preferable.

The purification of trifluoromethylphenylacetic acid after the completion of the reaction may be carried out by a conventional organic synthesis method, and is not particularly limited. For example, solvent extraction, column chromatography, distillation, recrystallization and the like may be appropriately combined.

[0044]

EXAMPLES The present invention will be described in detail below with reference to examples, but the present invention is not limited to these embodiments.

[Preparation of Complex 1] [3,5-bis (trifluoromethyl) benzoato] Synthesis of 3 ', 5'-bis (trifluoromethyl) phenylbis (triphenylphosphine) palladium (II) Stainless steel autoclave 65.3 g of 3,5-bis (trifluoromethyl) bromobenzene, 100 ml of tetrahydrofuran, 50.0 g of palladium acetate, 175.5 g of triphenylphosphine, 57.6 g of 3,5-bis (trifluoromethyl) benzoic acid, 25 60.8 g of an aqueous ammonia solution was charged. Nitrogen replacement is performed twice, the stirring is started at a nitrogen pressure of 3 kg / cm ² , and the internal temperature becomes about 50 ° C.
Rose. Thereafter, the oil bath temperature was set to 120 ° C. and heating was started. About 2 hours later, when the internal temperature reached 95.6 ° C, the oil bath was removed and the system was cooled. 200 ml of water and 600 ml of toluene were added to the reaction solution, and the mixture was stirred for several minutes. The obtained treatment liquid was subjected to suction filtration, the organic layer (upper layer) of the filtrate was separated, washed twice with a saturated saline solution, dried over anhydrous magnesium, and concentrated by evaporation of volatile components. The solid precipitated at the initial stage of concentration was separated by filtration, and the filtrate was further concentrated. Then, n-hexane was added and the mixture was cooled, and the precipitated solid was filtered to obtain 187.5 g of a crude product. The crude product was recrystallized from toluene to give pale yellow crystals.
3.0 g were obtained.

[3,5-bis (trifluoromethyl) benzoato] 3 ', 5'-bis (trifluoromethyl) phenylbis (triphenylphosphine) palladium (II) Melting point: 168-170 ° C (decomp.) IR (KBr: cm ^-1 ): 3060,2926,1637,1437,1321,1277,1173,
1127,748,697,518 ¹ H-NMR (reference substance: TMS solvent: CDCl ₃ ): δ ppm 6.97 (s, 1
H), 7.09 (s, 2H), 7.20-7.32 (m, 18H), 7.40-7.50 (m, 12H), 7.
53 (s, 2H), 7.62 (s, 1H) ³¹ P-NMR (reference substance: 85% H ₃ PO ₄ solvent: CDCl ₃ ): δ ppm 2
5.73 (s) [Preparation of complex 2] Preparation of PdCl ₂ (dppb) is performed by a known method [J. Coord. Chem. (Engl. Edit), 22 (1996), 563-5].
67]. That is, 100 ml of acetonitrile was put into a 300 ml Erlenmeyer flask containing a stirrer, 0.574 g of palladium chloride was put therein, and 7
The mixture was stirred while warming to 0 ° C. After dissolving the palladium chloride, 1.382 g of 1,4-bis (diphenylphosphino) butane was added, and pale yellow crystals precipitated. After continuing stirring for about 3 hours, the crystals were filtered and washed with acetonitrile to obtain PdCl ₂ (dppb).

Example 1-1 In a 1-liter SUS autoclave, 3,5- (bistrifluoromethyl) was added.
150 g (0.51) of bromobenzene (purity 97.0%)
2mol), 102.6 g of n-butyl vinyl ether
(1.024 mol), 62.2 g of triethylamine
(0.615 mol), PdCl ₂ (dppb)
5462 g (0.00256 mol), 360 ml of N, N-dimethylacetamide and 90 ml of water were added. After closing the reactor and purging with nitrogen several times, the internal temperature was raised to 105 ° C. with an oil bath while stirring. Thereafter, 105-110 ° C
For 12 hours.

The reaction product was allowed to cool to room temperature, and water was added to the reaction product to form a two-phase transparent liquid. The lower phase was separated and washed twice with water. Remove 3,5-bis (trifluoromethyl)-
1-n-butoxystyrene = 22.6%, 3,5-bis (trifluoromethyl) -2-n-butoxystyrene (cis) = 31.1%, 3,5-bis (trifluoromethyl) -2 -N-butoxystyrene (trans) =
138.6 g of a brown liquid containing 25.9% and 3,5-bis (trifluoromethyl) acetophenone = 2.0%
Obtained.

In the same manner, two batches of the first step were carried out, and 380.5 g of the obtained styrene derivative mixture was used in Example 2.

Examples 1-2 to 1-6 5.0 g of 3,5-bis (trifluoromethyl) bromobenzene was placed in a 100 ml pressure-resistant glass autoclave.
ol), 3.42 g (0.0%) of n-butyl vinyl ether.
341 mol), a base (0.0205 mol), a solvent,
The Pd catalyst and phosphine ligand were added as shown in Table 1, respectively. After replacing the inside of the reactor several times with nitrogen gas,
The reactor was closed, the temperature was raised to a predetermined temperature in an oil bath, and stirring was continued for a predetermined time. After completion of the reaction, the product was washed with water, extracted with diethyl ether, and analyzed for composition by gas chromatography. The result was as shown in Table 1.

[0051]

[Table 1]

Example 2 To 380.5 g of the styrene derivative mixture obtained in Example 1-1, 760 g of acetone and 20%
380.5 g of hydrochloric acid was added, and the mixture was shaken at 25 ° C. for about 10 seconds using a separating funnel. After standing, the mixture was separated into two phases. The lower phase was separated and washed with water to remove acetone and hydrochloric acid. The organic phase was treated with an aqueous solution of NaHCO ₃ to remove the acid component, and then dried over MgSO ₄ to remove water. As a fraction, 3,5 (bistrifluoromethyl) acetophenone (colorless liquid, purity 98.6%) ) Is 50.7g
And 8,5-bis (trifluoromethyl) 2-n-butoxystyrene (ci) having a purity of 89.4% as a distillation residue.
s, trans) were obtained.

Example 3 Of the distillation residue obtained in Example 2, 107 g was added to 252 g of acetone and 84 g of 20% hydrochloric acid.
Was added and stirred at 40 ° C. for 1 hour. The reaction product was washed with water, and the organic component was concentrated. As a result, a solid precipitated. This solid was collected on a funnel, washed several times with toluene and hexane, and dried under vacuum. As a result, 59.9 g of white crystals were obtained. The crystals were 3,5-bis (trifluoromethyl) phenylacetaldehyde, and no impurities were detected by gas chromatography.

Physical properties of 3,5-bis (trifluoromethyl) phenylacetaldehyde White crystal Molecular weight (GC-MASS) 256 (M ⁺ ) Main fragment 227, 208, 177,159 Melting point 57-58 ° C. ¹ H-NMR ( Reference substance: TMS, solvent: CDCl ₃ ): δ ppm; 3.89 (d, J = 1.3 Hz, 2H),
7.65 (s, 2H), 7.81 (s, 1H), 9.8
2 (t, J = 1.3 Hz, 1H) ¹⁹ F-NMR (reference substance: CCl ₃ F, solvent: CDC
l ₃ ) δ ppm; -63.43 (s).

Example 4 The 3,5- obtained in Example 3
0.3744 g of sodium dihydrogen phosphate in 11.7 ml of acetonitrile solution of 3.0 g (0.0117 mol) of bis (trifluoromethyl) phenylacetaldehyde
(0.00312 mol) 4.7 ml of aqueous solution and 1.17 ml of 35% hydrogen peroxide solution were added, and the mixture was stirred and the internal temperature was reduced to 5 to 10%.
1.872 g of sodium chlorite while maintaining at
(0.0163 mol) of an aqueous solution (16.4 ml) was added dropwise over 3 hours. After completion of the dropwise addition, stirring was continued under the same conditions for another 2 hours.

After the completion of the reaction, 20% hydrochloric acid and sodium sulfite were added to the reaction product. Then, the organic matter was washed with water and extracted with diethyl ether. When this ether phase was analyzed by gas chromatography, the composition excluding diethyl ether was 3,5-bis (trifluoromethyl) phenylacetic acid 9
2.7% and 3.2% of 3,5-bis (trifluoromethyl) phenylacetaldehyde.

Example 5 120 g of the distillation residue obtained in Example 2 was hydrolyzed in the same manner as in Example 3 to obtain unpurified 3,5-bis (trifluoromethyl) phenylacetaldehyde. To 385 ml of the solution, an aqueous solution of 12.3 g (0.1025 mol) of sodium dihydrogen phosphate 1
54 ml and 38.5 ml of 35% hydrogen peroxide solution were added, and while stirring and maintaining the internal temperature at 5 to 10 ° C., an aqueous solution of 538 m of 61.54 g (0.537 mol) of sodium chlorite was added.
1 was added dropwise over 3 hours. 2 hours after dropping,
Stirring was continued under the same conditions.

After completion of the reaction, 100 g of a 20% aqueous sodium hydroxide solution was added to the reaction product, and the reaction product was washed three times with 100 ml of toluene. Then, 20% hydrochloric acid and sodium sulfite were added, and the precipitated organic matter was extracted into toluene and concentrated by an evaporator, whereby crystals were precipitated.
The crystals were washed with toluene and dried under vacuum to obtain 60.5 g of white crystals. As a result of analysis by gas chromatography, the crystals were found to be 3,5-bis (trifluoromethyl) phenylacetic acid having a purity of 98.9%.

Physical properties data 3,5-bis (trifluoromethyl) phenylacetic acid White crystal Molecular weight (GC-MASS) 272 (M ⁺ ) Main fragments 253, 227, 208, 177,
159 melting point 120-123 ° C ¹ H-NMR (reference substance: TMS, solvent: CDCl ₃ ) δ ppm; 3.79 (s, 2H), 7.74 (s, 2)
H), 7.80 (s, 1H) ¹⁹ F-NMR (reference substance: CCl ₃ F, solvent: CDC
l ₃ ) δ ppm; -63.41 (s).

[0060]

According to the method of the present invention, highly useful trifluoromethylphenylacetaldehydes can be industrially produced from readily available compounds as raw materials. This produces an effect that a useful derivative of can be produced.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI theme coat ゛ (reference) // C07B 61/00 300 C07B 61/00 300 F term (reference) 4H006 AA01 AA02 AB84 AC12 AC24 AC43 AC45 AC46 AC53 BA02 BA25 BA29 BA32 BA37 BA48 BA51 BA53 BB15 BB17 BB24 BB25 BB41 BC10 BC34 BM10 BM71 BS10 4H039 CA61 CA62 CA71 CC30 CG20

Claims (6)

[Claims] 1. A method for producing trifluoromethylphenylacetic acids represented by the general formula (7), comprising the following three steps. General formula (1), (Where X is a halogen atom (chlorine, bromine or iodine)
Or a trifluoromethanesulfonate group, Y is a hydrogen atom or an inert group, and n represents 1 or 2. ) In the presence of a palladium compound and phosphines or bidentate amines and a base in the presence of a base of the general formula (2) CH ₂ ＣＨCH—OR ¹ (2) (wherein R ¹ is C alkyl group of ₁ -C _8, C ₁ haloalkyl group -C _8, C alkenyl group ₂ -C _8, haloalkenyl groups C ₁ -C _8, cycloalkyl radical of C ₃ -C _6, an aryl group, an aryl -C ₁ -C ₂ alkyl group, heteroaryl group or C ₁ -C ₈ acyl group) or a vinyl ether represented by the general formula (3): CH ₂ ＣＨCH—N (R ² ) —CO— R ³ (3) (wherein, R ² and R ³ are each independently a C ₁ -C ₈ alkyl group, a C ₁ -C ₈ haloalkyl group, a C ₂ -C ₈ alkenyl group, a C ₁ -C _{8 8} haloalkenyl group, a cycloalkyl group of C ₃ -C _6, an aryl group, an aryl - ₁ -C ₂ alkyl group, a heteroaryl group or a C ₁ represents an acyl group -C ₈₎ the Etanamido compound represented by is reacted general formula (4), ## STR2 ## Wherein Y, R ¹ and n are as defined above, or a trifluoromethylstyrene derivative represented by the general formula (5): (Wherein, Y, R ² , R ³ , and n are the same as those described above). Either the trifluoromethylstyrene derivative represented by the general formula (4) or the general formula (5) is hydrolyzed to obtain a compound represented by the general formula (6): (Wherein, Y and n are the same as those described above). The trifluoromethylphenylacetaldehyde represented by the general formula (6) is oxidized to form a compound represented by the general formula (7): (Wherein, Y and n are the same as described above). 2. A method for producing trifluoromethylphenylacetaldehyde represented by the general formula (6), comprising the following two steps. The trifluoromethyl compound represented by the general formula (1) is converted to a vinyl ether represented by the general formula (2) or a general formula (3) in the presence of a palladium compound and a phosphine or a bidentate amine and a base. A step of reacting ethanamide to obtain a trifluoromethylstyrene derivative represented by the general formula (4) or (5). A step of hydrolyzing any of the trifluoromethylstyrene derivatives represented by the general formula (4) or (5) to obtain trifluoromethylphenylacetaldehydes represented by the general formula (6). 3. Production of a trifluoromethylphenylacetaldehyde represented by the general formula (6) by hydrolyzing either a trifluoromethylstyrene derivative represented by the general formula (4) or (5). how to. 4. Oxidizing a trifluoromethylphenylacetaldehyde represented by the general formula (6) to obtain a compound of the general formula (7)
A method for producing trifluoromethylphenylacetic acid represented by the formula: 5. A compound represented by the general formula (8): (Wherein, Y represents a hydrogen atom or an inert group, and m represents 0 to
Represents an integer of 3. ). 6. A 3,5-bis (trifluoromethyl) phenylacetaldehyde