JP4278938B2 - Process for producing trifluoromethyl-substituted 2-alkoxyacetophenone derivative - Google Patents

Description

[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a method for producing a trifluoromethyl-substituted 2-alkoxyacetophenone derivative that is an important intermediate for pharmaceuticals and agricultural chemicals.
[0002]
[Prior art]
The trifluoromethyl-substituted 2-alkoxyacetophenone derivatives targeted in the present invention are compounds that are important intermediates for pharmaceuticals and agricultural chemicals. Among them, 3′-trifluoromethyl-2-methoxyacetophenone and 4′-trifluoromethyl- Only 2-methoxyacetophenone is known. These production methods are as follows: (1) a reaction of methoxymethyltriphenylphosphonium chlorite with iridium generated from phenyllithium and 4-trifluoromethylbenzonitrile (Non-patent Document 1), (2) methoxyacetonitrile and 3- A method of reacting trifluoromethylphenyl magnesium bromide or 4-trifluoromethylphenyl magnesium bromide (Non-patent Document 2), (3) A method of reacting 4'-trifluoromethyl-2-diasoacetophenone with methanol (Non-patent Document) It is limited to 3), and it is necessary to use an expensive reagent excessively or to use an explosive reagent (Non-patent Document 4), which is difficult to say as an industrial production method.
[0003]
In order to industrially produce a trifluoromethyl-substituted 2-alkoxyacetophenone derivative, the raw material is easy to obtain industrially and the safety of the reagent is relatively high, so that phenacyl halide is reacted with a metal alkoxide. Thus, a method of obtaining a 2-alkoxyacetophenone derivative is considered as a particularly promising method. For example, Non-Patent Document 5 reports a reaction example of 4-methoxyphenacyl bromide or 4-bromophenacyl bromide and sodium methoxide (CH ₃ ONa). However, a reaction example using the trifluoromethyl-substituted phenacyl halide as a target in the present invention has not been reported yet.
[0004]
Also, as a technique related to the present invention, a method for producing α-bromoalkylphenones characterized by reacting alkylphenones with bromine in a lower alcohol and treating the resulting reaction solution with an acid has been reported. (Patent Document 1). Α-Bromoalkylphenones produced by bromination with Br _{2 in} the presence of lower alcohols such as methanol are shifted to the dialkyl acetal side in the reaction system, and α, α-dibromoalkyl by excess reaction is caused. It suppresses by-products of phenones. However, when a lower alcohol such as methanol is used, this equilibrium is not completely biased toward the dialkyl acetal side, and 15 to 17% of α-bromoalkylphenones are present in the reaction solution before treatment with acid. It has been shown. In the detailed description of the invention of Patent Document 1, only methanol, ethanol and propanol are specifically mentioned as lower alcohols, and only examples using methanol are actually reported. A method for producing a brominated acetal by brominating trifluoromethyl-substituted acetophenone with Br _{2 in} the presence of an alkylene diol, which is the subject of the present invention, has not been reported yet.
[0005]
[Patent Document 1]
JP 2001-72638 A [Non-Patent Document 1]
Synthesis, (Germany), 1999, 1999, No. 9, p.1558-1560
[Non-Patent Document 2]
Tetrahedron, (UK), 1979, Vol. 35, No. 15, p. 1807-1815
[Non-Patent Document 3]
J. American Chemical Society, (USA), 1970, Vol. 92, p.311-320
[Non-Patent Document 4]
J. Organometallic Chemistry, (Netherlands), 1990, 390, p.275-292.
[Non-Patent Document 5]
Tetrahedron, (UK), 1994, 50, 35, p.10539-10548
[0006]
[Problems to be solved by the invention]
The objective of this invention is providing the industrial manufacturing method of the trifluoromethyl substituted 2-alkoxy acetophenone derivative used as an important intermediate body of a pharmaceutical and an agricultural chemical.
[0007]
The present inventors initially examined the reaction conditions in detail for the reaction of a trifluoromethyl-substituted phenacyl halide and a metal alkoxide according to the method of Non-Patent Document 5. However, this method hardly yields the desired product, and it has been found that this reaction is greatly influenced by the type of substituent on the aryl group of phenacyl halide. In the substrate substituted with trifluoromethyl group, which is a strong electron withdrawing group, nucleophilic attack to carbonyl group by metal alkoxide and deprotonation at α-position of carbonyl group preferentially occur. It was done.
[0008]
Therefore, the present inventors, when using phenacyl halide substituted with a trifluoromethyl group, in particular phenacyl bromide substituted with a trifluoromethyl group, as a substrate, the carbonyl group is previously an acetal group, particularly an alkylenedioxy group. When it is protected and subsequently reacted with a metal alkoxide, the target substitution reaction proceeds very well, and a trifluoromethyl-substituted 2-alkoxyacetophenone derivative can be obtained in a significantly higher yield than before. Has been filed as Japanese Patent Application No. 2002-232698 (see Scheme 1).
[0009]
However, this production method results in an increase in two steps of protection and deprotection, and it is desired to find a more efficient means for industrial production of trifluoromethyl-substituted 2-alkoxyacetophenone derivatives. It was.
[0010]
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[0011]
[Means for Solving the Problems]
As a result of intensive studies to solve the above-mentioned problems, the present inventors brominated trifluoromethyl-substituted acetophenone with Br _{2 in} the presence of alkylene diol, thereby simultaneously halogenating and protecting in one step. As it progressed, it was clarified that brominated acetal can be produced at a high yield (see Scheme 2).
[0012]
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[0013]
A particularly important point is that the equilibrium is much more biased toward the dialkyl acetal side when alkylene diol is used than when the lower alcohol such as methanol disclosed in Patent Document 1 is used. The crude product contains almost no α-bromoacetophenone. Thereby, the raw material more suitable for the substitution reaction of the next process can be supplied. In other words, when a lower alcohol such as methanol is used, α-bromoacetophenones that are not involved in the substitution reaction in the next step are contained in a considerable amount in the crude product, resulting in a decrease in yield. According to the invention, since brominated acetal is obtained with high yield, the desired trifluoromethyl-substituted 2-alkoxyacetophenone can be obtained with higher yield through subsequent reaction with metal alkoxide and hydrolysis.
[0014]
Further, Br ₂ is not easy to handle due to its physical properties, and the amount charged can not be accurately controlled, and the reaction is often carried out using an excessive amount of Br ₂ for the purpose of increasing the yield. Thus, when an excessive amount of Br ₂ is used, even if a lower alcohol such as methanol disclosed in Patent Document 1 is used, a considerable amount of α-bromoacetophenones are present in the reaction system. The byproduct of α, α-dibromoacetophenones cannot be controlled (see Table 1; Table 1 summarizes the results of Comparative Example 1 and Example 1). However, when an alkylene diol is used, the equilibrium is significantly biased toward the dialkyl acetal side, so that even if an excessive amount of Br ₂ is used, α, α-dibromoacetophenones are hardly produced as a by-product, and the production method is suitable for industrialization. I found out.
[0015]
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[0016]
That is, bromination of trifluoromethyl-substituted acetophenone with Br _{2 in} the presence of alkylene diol, yields a brominated acetal containing almost no α-bromoacetophenones and α, α-dibromoacetophenones all at once. It was found that when this brominated acetal was reacted well with a metal alkoxide, the substitution reaction to the alkoxy group proceeded very smoothly and the corresponding ether was produced in high yield. Next, it was found that the desired trifluoromethyl-substituted 2-alkoxyacetophenone derivative can be produced in good yield by hydrolysis and deprotection in the presence of an acid catalyst.
[0017]
Thus, although this invention consists of three reaction processes, since each reaction process has high selectivity and hardly produces the difficult-to-separate impurity, in order to manufacture a trifluoromethyl substituted 2-alkoxy acetophenone derivative industrially. This proved to be a very useful method.
[0018]
That is, the present invention relates to the general formula [1]
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[Wherein m represents 1 or 2 and takes any substitution position], a trifluoromethyl-substituted acetophenone represented by the general formula [2]
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[Wherein n represents an integer of 2 to 4] and brominated with Br _{2 in} the presence of an alkylene diol represented by the general formula [3]
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[Wherein m represents 1 or 2, takes any substitution position, and n represents an integer of 2 to 4,] and then converted to a brominated acetal represented by the general formula [7]
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[Wherein R represents an alkyl group having 1 to 4 carbon atoms, and M represents Li, Na, or K], by a substitution reaction with a metal alkoxide represented by the general formula [8]
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[Wherein m represents 1 or 2, takes an arbitrary substitution position, n represents an integer of 2 to 4, and R represents an alkyl group having 1 to 4 carbon atoms] Subsequently, it is hydrolyzed and deprotected in the presence of an acid catalyst to give a general formula [9]
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[Wherein m represents 1 or 2, takes an arbitrary substitution position, and R represents an alkyl group having 1 to 4 carbon atoms], and provides a method for producing a trifluoromethyl-substituted 2-alkoxyacetophenone derivative represented by To do.
[0019]
Further, the present invention provides the formula [4]
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A trifluoromethyl-substituted acetophenone represented by the formula: [5]
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Bromination with Br _{2 in} the presence of an alkylene diol represented by formula [6]
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Is converted to a brominated acetal represented by the general formula [10]
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[Wherein M represents Na or K], by a substitution reaction with a metal alkoxide represented by the formula [11]
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Is converted to the ether represented by formula (12), and then hydrolyzed and deprotected in the presence of an acid catalyst to give a compound of the formula [12]
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A method for producing a trifluoromethyl-substituted 2-alkoxyacetophenone derivative represented by the formula:
[0020]
DETAILED DESCRIPTION OF THE INVENTION
Hereinafter, the production method of the trifluoromethyl-substituted 2-alkoxyacetophenone derivative of the present invention will be described in detail. As shown in Scheme 3, this production method comprises three steps: (1) bromination, (2) substitution reaction, and (3) deprotection.
[0021]
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[0022]
First, bromination in the first step will be described in detail.
[0023]
The trifluoromethyl-substituted acetophenone represented by the general formula [1] as a starting material is 2′-trifluoromethylacetophenone, 3′-trifluoromethylacetophenone, 4′-trifluoromethylacetophenone, 2 ′, 3′-. Bis-trifluoromethylacetophenone, 2 ′, 4′-bis-trifluoromethylacetophenone, 2 ′, 5′-bis-trifluoromethylacetophenone, 2 ′, 6′-bis-trifluoromethylacetophenone, 3 ′, 4 Examples include '-bis-trifluoromethylacetophenone, 3', 5'-bis-trifluoromethylacetophenone. The compounds shown here include new compounds, but referring to Patent Document 1 and Tetrahedron Letters No. 53, pp. 4647-4650, (1970), etc., the trifluoromethyl group on the aryl group By using raw material substrates having different substitution positions, it can be produced in the same manner.
[0024]
Examples of the alkylene diol represented by the general formula [2] include ethylene glycol, 1,3-propanediol, and 1,4-butanediol. Among these, ethylene glycol and 1,3-propanediol are preferable, and ethylene glycol is more preferable.
[0025]
The amount of the alkylene diol used may be 1 mole equivalent or more with respect to the trifluoromethyl-substituted acetophenone represented by the general formula [1]. Usually, 1 to 30 mole equivalent is preferable, particularly 1 to 20 mole equivalent. Is more preferable.
[0026]
The amount of Br ₂ used may be 1 molar equivalent or more with respect to the trifluoromethyl-substituted acetophenone represented by the general formula [1], usually 1 to 10 molar equivalents, particularly 1 to 5 molar equivalents. Is more preferable.
[0027]
Br ₂ can be handled after being diluted in a diluent solvent. Examples of the diluting solvent include aliphatic hydrocarbons such as n-pentane, n-hexane, cyclohexane and n-heptane, halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and 1,2-dichloroethane, diethyl Ethers such as ether, tetrahydrofuran, t-butyl methyl ether, 1,4-dioxane, esters such as ethyl acetate and n-butyl acetate, nitriles such as acetonitrile and propionitrile, acetic acid, propionic acid, butyric acid, etc. Examples thereof include carboxylic acid-based compounds. Of these, halogenated hydrocarbons and carboxylic acids are preferred, and halogenated hydrocarbons are more preferred.
[0028]
The method for adding Br ₂ is not particularly limited, and a diluted solution of Br ₂ is usually added dropwise to a mixed solution containing trifluoromethyl-substituted acetophenone and alkylene diol.
[0029]
As the reaction solvent, the same one as the dilution solvent of Br ₂ can be exemplified. Usually, an excessive amount of alkylene diol is used together with the reaction solvent.
[0030]
As temperature conditions, it is -20- + 150 degreeC normally, -10- + 125 degreeC is preferable, and 0- + 100 degreeC is especially more preferable.
[0031]
The reaction time is usually 1 to 48 hours, but since it varies depending on the substrate and reaction conditions, the progress of the reaction is tracked by analytical means such as gas chromatography, liquid chromatography, NMR, etc., and most of the raw materials disappeared. The time point is preferably the end point.
[0032]
The post-treatment is not particularly limited, and usually the reaction completion solution is poured into water or saline, and extracted with an organic solvent such as ethyl acetate or toluene, and the recovered organic layer is made of anhydrous sodium sulfate or anhydrous magnesium sulfate. It can be dried with a desiccant, filtered, concentrated and dried in vacuo to give the crude product. In addition, when the reaction is carried out in combination with a reaction solvent using an excessive amount of alkylene diol, particularly ethylene glycol, the reaction completion liquid is separated into two layers, and the target product can be separated and recovered as a lower layer, and the recovered organic matter is The crude product can be obtained by washing with saline or water, drying with a desiccant such as anhydrous sodium sulfate or anhydrous magnesium sulfate, filtering, and vacuum drying. Obtaining the desired brominated acetal represented by the general formula [3] with high chemical purity by subjecting the crude product to purification operations such as activated carbon treatment, distillation, recrystallization, column chromatography and the like, if necessary. Can do. Also, without performing such an isolation operation, the metal alkoxide in the next step is added directly to the reaction mixture liquid at the end of the reaction, and the bromination in the first step and the substitution reaction in the second step are performed as a one-pot reaction. You can also.
[0033]
Next, the substitution reaction in the second step will be described in detail. The reaction in the second step is achieved by reacting the brominated acetal represented by the general formula [3] obtained in the first step with the metal alkoxide represented by the general formula [7].
[0034]
Examples of the metal alkoxide represented by the general formula [7] include MeOLi, MeONa, MeOK, EtOLi, EtONa, EtOK, n-PrOLi, n-PrONa, n-PrOK, i-PrOLi, i-PrONa, i-PrOK, n. -BuOLi, n-BuONa, n-BuOKi, i-BuOLi, i-BuONa, i-BuOK, sec-BuOLi, sec-BuONa, sec-BuOK, tert-BuOLi, tert-BuONa, tert-BuOK. Here, Me represents a methyl group, Et represents an ethyl group, Pr represents a propyl group, and Bu represents a butyl group. Among these, Na alkoxide and K alkoxide are preferable, and K alkoxide is particularly preferable. Metal alkoxides can be readily prepared from the corresponding alcohol and metal (Li, Na or K). The metal alkoxide can also be used in the substitution reaction in the second step without being isolated from the alcohol solution. In addition, isolated solid metal alkoxides (MeOLi, MeONa, MeOK, etc.) and alcohol solutions of metal alkoxides (28% MeONa methanol solution, 30% MeOK methanol solution, etc.) are commercially available. You can also.
[0035]
The metal alkoxide is used in an amount of 1 molar equivalent or more, preferably 1 to 20 molar equivalents, more preferably 1 to 10 molar equivalents relative to the brominated acetal represented by the general formula [3]. preferable.
[0036]
The reaction in the second step can also be carried out by adding the following additives. Examples of additives include crown ethers such as 12-crown-4, 15-crown-5, and 18-crown-6, ethylene glycol dialkyl ethers such as 1,2-dimethoxyethane, diethylene glycol dimethyl ether, and triethylene glycol dimethyl ether. Examples thereof include iodide ions such as sodium iodide, potassium iodide and tetrabutylammonium iodide. With these additives, the substitution reaction may be able to be performed more smoothly. However, if attention is paid to temperature conditions, these additives may not necessarily be added. The amount of the additive used may be 0.001 molar equivalent or more with respect to the brominated acetal represented by the general formula [3], and is usually preferably 0.005 to 50 molar equivalent, particularly 0.01. ˜30 molar equivalents are more preferred.
[0037]
Examples of the reaction solvent include methanol, ethanol, propanol, isopropanol, butanol, isobutanol, sec-butanol, tert-butanol alcohol, diethyl ether, tetrahydrofuran, t-butyl methyl ether, 1,4-dioxane and the like. Examples include ethers, amides such as hexamethylphosphoric triamide, N, N-dimethylformamide, N, N-dimethylacetamide, and N-methylpyrrolidone. Of these, alcohols and ethers are preferable, and alcohols are particularly preferable.
[0038]
As temperature conditions, it is 0-250 degreeC normally, 25-225 degreeC is preferable, and 50-200 degreeC is especially more preferable. When a temperature condition higher than the boiling point of the reaction solution is required, a pressure glass container can be used.
[0039]
The reaction time is usually 6 to 48 hours, but since it varies depending on the substrate and reaction conditions, the progress of the reaction is traced by analytical means such as gas chromatography, liquid chromatography, NMR, etc., and most of the raw materials disappeared. The time point is preferably the end point.
[0040]
There are no particular limitations on the post-treatment, and the reaction-finished solution is usually poured into water or brine, extracted with an organic solvent such as toluene or ethyl acetate, washed with water, and the recovered organic layer is made of anhydrous sodium sulfate or anhydrous sulfuric acid. It can be dried with a desiccant such as magnesium, filtered, concentrated and dried in vacuo to give the crude product. If necessary, the target ether represented by the general formula [8] can be obtained with high chemical purity by subjecting the crude product to purification operations such as activated carbon treatment, distillation, recrystallization and column chromatography. . Also, without performing such an isolation operation, the aqueous solution of the acid catalyst in the next step is added directly to the reaction mixture liquid at the end of the reaction, so that the substitution reaction in the second step and the deprotection in the third step are performed in a one-pot reaction Can also be done.
[0041]
Finally, the deprotection in the third step will be described in detail. The reaction in the third step is achieved by reacting the ether represented by the general formula [8] obtained in the second step with water in the presence of an acid catalyst.
[0042]
Examples of the acid catalyst include organic acids such as benzenesulfonic acid, p-toluenesulfonic acid, 10-camphorsulfonic acid, trifluoroacetic acid, and trifluoromethanesulfonic acid, and inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid. Can be mentioned. Among these, hydrochloric acid and sulfuric acid are preferable, and hydrochloric acid is more preferable.
[0043]
The amount of the acid catalyst used may be 100 molar equivalents or less with respect to the ether represented by the general formula [8], and is preferably 0.01 to 75 molar equivalents, particularly 0.05 to 50 molar equivalents. Is more preferable.
[0044]
The concentration of the aqueous solution of the acid catalyst may be 0.01N or more, usually 0.05 to 20N, and more preferably 0.1 to 12N.
[0045]
Since this reaction is hydrolysis, it is necessary to dissolve the ether represented by the general formula [8] in an aqueous solution of an acid catalyst, and the reaction can be smoothly carried out by uniformly dissolving using a solubilizing agent. .
[0046]
Examples of the solubilizer include alcohols such as methanol, ethanol, propanol and isopropanol, phase transfer catalysts represented by quaternary ammonium salts, and the like. Among these, methanol and ethanol are preferable, and methanol is more preferable.
[0047]
The amount of solubilizing agent used may be 10 times or less of the volume of the acid catalyst aqueous solution, and is usually preferably 0.001 to 5.0 times the volume, particularly 0.01 to 3.0 times the volume. Is more preferable.
[0048]
As temperature conditions, it is 0-200 degreeC normally, 0-175 degreeC is preferable and especially 0-150 degreeC is more preferable. When a temperature condition higher than the boiling point of the reaction solution is required, a pressure glass container can be used.
[0049]
The reaction time is usually 6 to 48 hours, but since it varies depending on the substrate and reaction conditions, the progress of the reaction is traced by analytical means such as gas chromatography, liquid chromatography, NMR, etc., and most of the raw materials disappeared. The time point is preferably the end point.
[0050]
There are no particular limitations on the post-treatment, and the reaction-finished solution is usually poured into water or brine, extracted with an organic solvent such as toluene or ethyl acetate, washed with water, and the recovered organic layer is made of anhydrous sodium sulfate or anhydrous sulfuric acid. It can be dried with a desiccant such as magnesium, filtered, concentrated and dried in vacuo to give the crude product. If necessary, the trifluoromethyl-substituted 2-alkoxyacetophenone derivative represented by the general formula [9] is obtained by subjecting the crude product to purification operations such as activated carbon treatment, distillation, recrystallization, column chromatography and the like. It can be obtained with high chemical purity.
[0051]
【Example】
Hereinafter, the embodiments of the present invention will be specifically described by way of examples. However, the present invention is not limited to these examples.
[Comparative Example 1]
Methanol 5.6 ml, 4'-trifluoromethyl acetophenone 2.82g (14.99mmol, 1eq) was dissolved, while controlling the internal temperature at _{26~27 ℃, Br 2 3.60g (22.53mmol} , 1 .50 eq) in methanol (dilution amount 1.4 ml) was added and stirred at an internal temperature of 26-28 ° C. for 24 hours. The reaction progress after 3.5 hours and 24 hours was followed by gas chromatography. The analysis results are shown in the table below.
[0052]
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[0053]
[Example 1]
Dissolve 4.82 g (14.99 mmol, 1 eq) of 4′-trifluoromethylacetophenone in 7.5 ml (8.35 g, 134.53 mmol, 8.97 eq) of ethylene glycol, and control the internal temperature to 25 to 28 ° C. Then, a chloroform solution (dilution amount 2.2 ml) of Br ₂ 3.60 g (22.53 mmol, 1.50 eq) was added, and the mixture was stirred at an internal temperature of 25 to 26 ° C. for 24 hours. The reaction progress after 3.5 hours and 24 hours was followed by gas chromatography. The analysis results are shown in the table below.
[0054]
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[0055]
[Example 2]
Ethylene glycol 281ml (313g, 5.04mol, 9.00eq) in, 4'-trifluoromethyl acetophenone 106 g (0.56 mol, 1 eq) was dissolved, while controlling the internal temperature at 28-32 ° C., Br ₂ 108 g A chloroform solution (0.68 mol, 1.21 eq) in chloroform (dilution amount 56 ml) was added, and the mixture was stirred at an internal temperature of 29 to 32 ° C. for 15 hours. The reaction completion liquid was separated and divided into an upper layer and a lower layer. The lower layer was washed with 2% brine, dried over anhydrous sodium sulfate, filtered, and dried under vacuum.
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[0057]
165 g of a brominated acetal crude product represented by the formula: The yield was 94%. The analysis results of the crude product by gas chromatography and the assignment of ¹ H-NMR spectrum are shown below.
[0058]
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[0059]
¹ H-NMR (reference material: TMS, solvent: CDCl ₃ ), δ ppm: 3.64 (s, 2H), 3.83-3.98 (m, 2H), 4.14-4.30 (m , 2H), 7.64 (Ar-H, 4H).
The upper layer was poured into water and extracted with ethyl acetate. The recovered organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and vacuum dried to obtain 6 g of a brominated acetal crude product represented by the above formula. The yield was 3%.
[0060]
In a pressure-resistant glass container, a portion of the crude product of the lower layer of brominated acetal produced by bromination in the first step, 20.11 g (1eq, 64.64 mmol), 75.56 g (323) of 30% MeOK methanol solution .23 mmol, 5.00 eq) and 11,2-dimethoxyethane 11.65 g (129.27 mmol, 2.00 eq) were added, and the mixture was stirred at 140 ° C. for 15 hours. The reaction completed solution was poured into saturated brine and extracted with ethyl acetate. The recovered organic layer is dried over anhydrous sodium sulfate, filtered, concentrated, and vacuum dried.
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[0062]
As a result, 18.12 g of a crude ether product was obtained. The conversion and selectivity of the reaction were determined by gas chromatography and were 99% and 97%, respectively.
¹ H-NMR (reference material: TMS, solvent: CDCl ₃ ), δ ppm: 3.40 (s, 3H), 3.60 (s, 2H), 3.79-3.93 (m, 2H), 4.06-4.20 (m, 2H), 7.55-7.72 (Ar-H, 4H).
In 242.4 ml of methanol, the total amount of the crude ether product produced in the substitution reaction in the second step 18.12 g (64.64 mmol, 1 eq) and 8N hydrochloric acid 242.40 ml (193.20 mmol, 30.00 eq) were added. The mixture was further stirred at room temperature for 36 hours. The reaction completed solution was poured into saturated brine and extracted with ethyl acetate. The recovered organic layer is dried over anhydrous sodium sulfate, filtered, concentrated and dried in vacuo.
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[0064]
15.63 g of a crude product of a trifluoromethyl-substituted 2-alkoxyacetophenone derivative represented by the formula: The conversion of the reaction was determined by GC and was 99%. When the crude product was quantified by ¹⁹ F-NMR internal standard method, it contained 12.07 g of the desired product. The total yield from bromination to deprotection was 83%. Moreover, 9.31 g of purified products were obtained by recrystallizing 15.63 g of the total amount of the crude product from 1.5 times the volume of n-hexane (GC purity> 99.7%).
¹ H-NMR (reference material: TMS, solvent: CDCl ₃ ), δ ppm: 3.52 (s, 3H), 4.70 (s, 2H), 7.75 (d, 8.6 Hz, 2H), 8.06 (d, 8.6 Hz, 2H).
[0065]
【The invention's effect】
Provided is a method for producing a trifluoromethyl-substituted 2-alkoxyacetophenone derivative that is an important intermediate for pharmaceuticals and agricultural chemicals.

Claims (2)

General formula [1]
[Wherein m represents 1 or 2 and takes any substitution position], a trifluoromethyl-substituted acetophenone represented by the general formula [2]
[Wherein n represents an integer of 2 to 4] and brominated with Br _{2 in} the presence of an alkylene diol represented by the general formula [3]
[Wherein m represents 1 or 2, takes any substitution position, and n represents an integer of 2 to 4,] and then converted to a brominated acetal represented by the general formula [7]
[Wherein R represents an alkyl group having 1 to 4 carbon atoms, and M represents Li, Na, or K], by a substitution reaction with a metal alkoxide represented by the general formula [8]
[Wherein m represents 1 or 2, takes an arbitrary substitution position, n represents an integer of 2 to 4, and R represents an alkyl group having 1 to 4 carbon atoms] Subsequently, it is hydrolyzed and deprotected in the presence of an acid catalyst to give a general formula [9]
[Wherein m represents 1 or 2, takes an arbitrary substitution position, and R represents an alkyl group having 1 to 4 carbon atoms], and a method for producing a trifluoromethyl-substituted 2-alkoxyacetophenone derivative represented by the formula: Formula [4]
A trifluoromethyl-substituted acetophenone represented by the formula: [5]
Bromination with Br _{2 in} the presence of an alkylene diol represented by formula [6]
Is converted to a brominated acetal represented by the general formula [10]
[Wherein M represents Na or K], by a substitution reaction with a metal alkoxide represented by the formula [11]
Is converted to the ether represented by formula (12), and then hydrolyzed and deprotected in the presence of an acid catalyst to give a compound of the formula [12]
A method for producing a trifluoromethyl-substituted 2-alkoxyacetophenone derivative represented by the formula: