JPH083087A - Production of alcohol having trifluoromethyl group at alpah-site - Google Patents

Abstract

PURPOSE:To produce the subject compound useful as a raw material or intermediate for pharmaceuticals, agrochemicals, liquid crystals, etc., on an industrial scale in high yield at a low cost by reacting an aldehyde with a trifluoromethyl halide in the presence of a nitrogen-containing aromatic compound and Zn and separating the produced alcohol from the reaction liquid. CONSTITUTION:This alcohol having a trifluoromethyl group on the alpha-site can be produced by reacting (A) a nitrogen-containing aromatic compound such as pyridine or 2-methylpyridine with (B) an aldehyde and (C) a trifluoromethyl halide in the presence of (D) metallic Zn and separating the produced alcohol from the reaction liquid. The amounts of the component D and the component C are 1.5-5 equivalent and 1.5-10 equivalent based on 1 equivalent of the formyl group of the component B, respectively and the amount of the component A is 1-10 equivalent based on 1 equivalent of the component D.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing an alcohol having a trifluoromethyl group at the α-position. More specifically, the present invention relates to an improvement in the method for producing an alcohol having a trifluoromethyl group at the α-position using aldehyde as a raw material.

[0002]

2. Description of the Related Art Alcohols having a trifluoromethyl group at the α-position have been attracting attention as important raw materials or intermediates in the production of fluorine-containing drugs, agricultural chemicals, liquid crystals and the like. As one of the methods for producing this compound, a method of using a reaction of introducing a trifluoromethyl group into a carbonyl group of a carbonyl compound has been proposed, but an industrially practical and practical production utilizing this reaction is proposed. The method has not been established yet.

For example, a method of reacting an aldehyde with trifluoromethyl iodide in the presence of copper has been conventionally known. However, this method requires extremely high temperature and high pressure as reaction conditions, and is practically used. Is hard to say. Also, J.
Am. Chem. Soc. , 1985 [Vol. 107]
(US) pp. 5186-5191 discloses a method of reacting an aldehyde with a perfluoroalkyl halide in the presence of zinc under a special condition of ultrasonic irradiation, but a special method of ultrasonic irradiation is disclosed. This method of using is not practical from the viewpoint of industrial practice and is not satisfactory.

[0004]

DISCLOSURE OF THE INVENTION The present invention is intended to solve the above-mentioned problems of the prior art, and is capable of synthesizing a target trifluoromethylated alcohol under mild reaction conditions, The present invention is intended to provide a method for producing an alcohol having a trifluoromethyl group at the α-position, which can be carried out with advantage.

[0005]

Means for Solving the Problems As a result of intensive studies to solve the above problems, the present inventors have found that the reaction between an aldehyde and trifluoromethyl halide is carried out in the presence of a nitrogen-containing aromatic compound and metallic zinc. It was found that the target alcohol compound can be easily synthesized by carrying out the method described in 1. above, and the present invention has been completed based on this finding.

In order to solve the above-mentioned problems, in the present invention, an aldehyde and a trifluoromethyl halide are reacted in the presence of a nitrogen-containing aromatic compound and metallic zinc, and a trifluoromethyl halide is added to the α-position from the resulting reaction solution. A measure is taken to separate the alcohol having a fluoromethyl group.

Hereinafter, the present invention will be described in detail. According to the present invention, aldehyde and trifluoromethyl halide are used as raw materials. The aldehyde used as a raw material in the present invention is not particularly limited as long as it has at least one formyl group in the molecule, and may be an aliphatic aldehyde, an aromatic aldehyde, or an alicyclic aldehyde. . Further, these aldehydes may have a substituent, the kind of the substituent,
There is no particular restriction on the position. Specific examples of the aliphatic aldehyde include acetaldehyde, propionaldehyde, and butyroaldehyde, and various saturated or unsaturated aliphatic aldehydes. Specific examples of the aromatic aldehyde include benzaldehyde, 4
-Chlorobenzaldehyde, 4-fluorobenzaldehyde, 4-trifluoromethylbenzaldehyde, 2-
Mention may be made of various aromatic aldehydes such as naphthyl aldehyde and 9-anthryl aldehyde.

The reaction of the starting aldehyde with trifluoromethyl halide is usually preferably carried out in a liquid phase. As the starting aldehyde, a nitrogen-containing aromatic compound to be present in the reaction system or a nitrogen-containing aromatic compound It is preferable to use a solvent that is soluble or has good miscibility in a mixed solvent with an inert solvent. From this viewpoint, the aliphatic aldehyde preferably has 2 to 20 carbon atoms.

The trifluoromethyl halide used as a raw material in the present invention is trifluoromethyl iodide (CF).
₃ I), trifluoromethyl bromide (CF ₃ Br), trifluoromethyl chloride (CF ₃ Cl), and tetrafluoromethane (CF ₄ ). But,
Considering the reactivity with the raw material aldehyde, CF ₃ I, C
F ₃ Br and CF ₃ Cl are preferred, and CF ₃ I is most preferred.

In the present invention, the above two raw materials are reacted in the presence of a nitrogen-containing aromatic compound and metallic zinc. In the present invention, the nitrogen-containing aromatic compound means a compound having a nitrogen atom in or between aromatic rings, and the nitrogen-containing aromatic compound used in the production method of the present invention has the above-mentioned molecular structure. There is no particular limitation as long as it is one. Specific examples of the nitrogen-containing aromatic compound that can be used include pyridine and 2-
Methylpyridine, 3-methylpyridine, 4-methylpyridine, 4-N, N-dimethylaminopyridine, 2-ethylpyridine, 3-ethylpyridine, 4-ethylpyridine, quinoline, isoquinoline, quinazoline, quinoxaline, pyrrole, imidazole, Oxazole, thiazole, pyridazine, indole, phenazine, 1,10-
Phenanthroline, azobenzene, xanthine, 1,
Examples thereof include 2,4-benzotriazine, benzotriazole, and m-anthrazoline, but are not limited to those exemplified here. Among these,
Pyridines are preferable, and pyridine and 2-methylpyridine are particularly preferable because they are liquid at normal reaction temperatures, have good mixing properties in the reaction system, and are easily available. The nitrogen-containing aromatic compound is preferably dried by molecular sieve or the like. This is because the desired reaction product can be obtained in a higher yield by using a nitrogen-containing aromatic compound having a low water content.

The metallic zinc used in the present invention is not particularly limited in its shape as long as it has been generally used in organic chemical reactions, and a particle size of about 100 to 325 mesh which is commercially available as zinc powder. The thing of a grade can be used conveniently.

Next, the reaction conditions in the production method of the present invention will be described. First, the proportion of trifluoromethyl halide used is generally in the range of 1 to 20 equivalents, preferably 1.5, relative to 1 equivalent of the formyl group of the raw material aldehyde.
The range is preferably 10 to 10 equivalents, more preferably 2 to 7 equivalents. If the usage rate is less than 1 equivalent,
The reaction rate is slow, the yield of the desired reaction product is low, and even if it is used in excess of 20 equivalents, the yield of the reaction product cannot be increased, and the cost is high. Not preferable.

The proportion of metallic zinc used is generally in the range of 1 to 20 equivalents, preferably 1.5 to 5 equivalents, and more preferably 2 to 5 equivalents, relative to 1 equivalent of the formyl group of the raw material aldehyde. It is good to set the range. The usage rate is 1
When the amount is less than the equivalent, the yield of the desired reaction product decreases, and even when the amount exceeds 20 equivalents, the yield of the reaction product cannot be increased and only the cost increases. Absent. Here, 1 equivalent of metallic zinc means 1 mol thereof.

The proportion of the nitrogen-containing aromatic compound used is generally in the range of 1 to 30 equivalents, preferably 1 to 10 equivalents, based on 1 equivalent of the metal zinc used.
More preferably, the range is 2 to 4 equivalents. If the usage ratio is less than 1 equivalent, the yield of the desired reaction product will be low, and even if it is used in excess of 30 equivalents, the yield of the reaction product cannot be increased and the cost will increase. However, neither is preferable. Here, 1 equivalent of the nitrogen-containing aromatic compound with respect to 1 equivalent of metallic zinc means 1 mol of the nitrogen-containing aromatic compound with respect to 1 mol of metallic zinc.

In the production method of the present invention, the reaction between the starting aldehyde and trifluoromethyl halide must be carried out in the presence of a nitrogen-containing aromatic compound and metallic zinc. An inert solvent can be added. As the inert solvent that can be used, hexane, cyclohexane, toluene, xylene, tetrahydrofuran, diethyl ether, dichloromethane, chloroform, acetonitrile, dimethylformaldehyde,
Examples thereof include dimethylacetamide and dimethylsulfoxide, but are not limited to those exemplified here. Among these, nonpolar hydrocarbons such as hexane and toluene are preferable. And
As this inert solvent, it is preferable to use a solvent dried by a molecular sieve or the like. This is because the intended reaction product can be obtained in a higher yield by using an inert solvent containing less water. The amount of these inert solvents used is not particularly limited, but it is usually preferable to set it in the range of 2 to 10 ml per 1 mmol of the formyl group of the raw material aldehyde.

The above-mentioned reaction between the raw material aldehyde and the trifluoromethyl halide is below a temperature at which none of the raw material aldehyde, trifluoromethyl halide, and nitrogen-containing aromatic compound charged into the reaction system are decomposed when an inert solvent is not used. If the temperature is, the reaction temperature is not particularly limited,
It can be performed at any temperature. However, the reaction temperature in this case is preferably selected from a temperature range in which at least one of the raw material aldehyde and the nitrogen-containing aromatic compound exhibits a liquid phase. When at least one is liquid, other components can be dissolved, mixed or dispersed in it, and the reaction system as a whole can be handled as a liquid phase, so that stirring, mixing, temperature control of the reaction system, etc. are easy. And is preferable. This reaction temperature is generally -78 to in order to avoid ultra-low temperature and special high temperature.
Although it can be selected from the range of 200 ° C, it is usually preferable to select from the range of 0 to 100 ° C in consideration of the reaction rate and the thermal stability of each component constituting the reaction system. When an inert solvent is used, the reaction temperature is usually
It is preferable that the temperature is not higher than the boiling point of the inert solvent used, but if the pressure reactor is used, the temperature can be higher than the boiling point of the inert solvent.

In the production method of the present invention, the raw material aldehyde, trifluoromethyl halide, and
A nitrogen-containing aromatic compound, metallic zinc, and optionally an inert solvent are charged into a reactor, and the trifluoromethylation reaction of a raw material aldehyde is easily progressed only by adjusting the reaction temperature to a predetermined reaction temperature and stirring. be able to. This reaction proceeds at a practical rate, and a reaction solution containing the desired reaction product can be obtained in a sufficiently high yield, but it may be supplemented with ultrasonic waves.

In the production method of the present invention, the reaction solution is obtained as described above, and the desired reaction product, that is, an alcohol having a trifluoromethyl group at the α-position is separated and purified from the reaction solution. As a result, a product having a desired purity can be easily obtained. Separation and purification of the target reaction product from the reaction solution are carried out by conventional methods such as addition of protic acid such as hydrochloric acid, filtration, distillation, silica gel chromatography, and purification by recrystallization. be able to. As an example of a specific method for separating and purifying a desired reaction product, (a) about 1N hydrochloric acid is added to the above reaction solution to stop the reaction, and a reaction mixture solution is obtained. The metallic zinc suspended in the reaction solution can be dissolved as zinc chloride by adding hydrochloric acid. Then, (b)
The target product is extracted into the organic phase by organic extraction of the reaction mixture. In this case, as the organic extractant, ethyl acetate,
Ethyl ether, chloroform, methylene chloride and the like are used. (C) Extracting and removing hydrogen chloride bonds of nitrogen-containing aromatic compounds and inorganic compounds such as hydrochloric acid and zinc chloride from the organic phase to the aqueous phase side by washing with water several times and washing with saturated sodium chloride solution. To obtain a crude product, and then (d) the obtained crude product is dried over magnesium sulfate and then subjected to a distillation treatment under reduced pressure to remove unreacted aldehyde, trifluoromethyl halide and the like. Can be mentioned. Unreacted aldehyde can also be separated and removed by column purification using silica gel chromatography.

[0019]

EXAMPLES Next, the present invention will be explained more specifically with reference to Examples and Comparative Examples, but the present invention is not limited to the description of these Examples unless it exceeds the gist.

Example 1 A volume of 50 so that stirring was possible with a stirrer under a nitrogen atmosphere.
A mixed solution of 7 ml of hexane and 1 ml of pyridine (manufactured by Kishida Chemical Co., Ltd., special grade reagent) was placed in a 2-necked flask of ml, and trifluoromethyl iodide 1176 mg and benzaldehyde 212 mg were added thereto, and the mixture was stirred at room temperature for about 10 minutes. , Zinc powder for reaction system (Aldrich, 325 ~ 100 mesh
) Add 260 mg and stir at room temperature for 20 hours,
A reaction solution was obtained. Next, 1N hydrochloric acid was added to this reaction solution for about 5 m.
1 was added to stop the reaction to obtain a reaction mixture. The obtained reaction mixture was transferred to a separating funnel, and about 8 wt.
0 ml was added thereto for extraction and liquid separation to collect a crude product as an organic phase. Transfer the collected organic phase to the separating funnel again,
It was washed twice with about 10 ml of demineralized water and once with about 10 ml of a saturated aqueous solution of sodium chloride. further,
About 10 g of magnesium sulfate (drying agent) was added to the organic phase washed in this way to dry it. After filtering the drying agent, the solvent and trifluoromethyl iodide were distilled off using an evaporator to obtain a crude product. A product was obtained, and the obtained crude product was subjected to vacuum distillation under the conditions of 96 to 98 ° C. and 15 mmHg to remove light-boiling components such as unreacted aldehyde to obtain 1 -Phenyl-2,2,2-trifluoroethyl alcohol (target compound) was obtained. The yield of the obtained target compound was 76% based on the raw material aldehyde used. These are collectively shown in Table 1 below.

Examples 2 to 9 In the example described in Example 1, the type and amount of the solvent and the nitrogen-containing aromatic compound used, the amount of trifluoromethyl iodide, and the type and amount of the raw material aldehyde were used. Table 1
Alternatively, reaction liquids were obtained in the same manner as in the same example except that the reaction liquids were changed as shown in Table 2, and 1N hydrochloric acid was added to each of these reaction liquids to obtain a reaction liquid mixture. Then, each reaction mixture obtained as described above was treated in the same manner as in Example 1 to obtain the target compound described in the yield column of Table 1 or Table 2 from each of the tables. Obtained in yield. In addition, in these examples, the stirring time after adding the zinc powder was 24 in Examples 3 to 6.
The time was changed to 7 hours in Examples 7 to 8 respectively. Further, in Example 9, the stirring time after adding the zinc powder was changed to 4 hours, and during this period, the reaction system was irradiated with ultrasonic waves.

[0022]

[Table 1]

[0023]

[Table 2]

Comparative Examples 1 to 8 In the examples described in Examples 1 to 8, the same aldehyde as in these examples was used, respectively, and the nitrogen-containing aromatic compound (pyridine or 2- (Methyl pyridine) was added, and the stirring time after the zinc powder was added was changed to 48 hours, but the same reaction as in these examples was tried, but obtained in Examples 1 to 8. The desired compound could not be obtained at all.

From the above-mentioned examples, the production method of the present invention does not require extremely high temperature and high pressure as reaction conditions, and does not use a special technique such as ultrasonic irradiation, and under mild reaction conditions. It is apparent that the alcohol having a trifluoromethyl group at the α-position can be easily synthesized with, and the target compound can be produced in good yield by separating and purifying the alcohol from the reaction solution.

[0026]

INDUSTRIAL APPLICABILITY According to the production method of the present invention, the desired alcohol having a trifluoromethyl group at the α-position can be easily synthesized under mild reaction conditions, and the resulting reaction solution is separated and purified. As a result, there is an advantageous effect that the desired compound can be produced in good yield and industrially advantageously.

Claims (8)

[Claims] 1. A method of reacting an aldehyde with trifluoromethyl halide in the presence of a nitrogen-containing aromatic compound and metallic zinc to separate an alcohol having a trifluoromethyl group at the α-position from the resulting reaction solution. Characteristic α-
For producing an alcohol having a trifluoromethyl group at the position. 2. The nitrogen-containing aromatic compound is pyridine or 2-methylpyridine.
The manufacturing method described. 3. The production method according to claim 1, wherein trifluoromethyl halide is reacted in the range of 1.5 to 10 equivalents with respect to 1 equivalent of formyl group of the raw material aldehyde. 4. The method according to claim 1, wherein metallic zinc is present in the range of 1.5 to 5 equivalents relative to 1 equivalent of formyl group of the raw material aldehyde. 5. The nitrogen-containing aromatic compound is present in the range of 1 to 10 equivalents relative to 1 equivalent of metallic zinc present in the reaction system, according to any one of claims 1 to 4. Production method. 6. The production method according to claim 1, wherein an appropriate amount of an inert solvent is added to the reaction system. 7. The production method according to claim 6, wherein the inert solvent is hexane or toluene. 8. The production method according to claim 1, wherein an aqueous solution of a protonic acid is added to the obtained reaction solution.