JPH04356439A - Produciton of difluoromethoxyphenyl alkyl ketone compounds - Google Patents

Abstract

PURPOSE:To provide a novel and excellent method for producing a difluoromethoxyphenyl alkyl ketone compound useful as a raw material for producing medicines and agricultural chemicals. CONSTITUTION:A method for producing a difluoromethoxyphenyl alkyl ketone compound, characterized by reacting a hydroxyphenyl alkyl ketone compound (e.g. 4-hydroxyacetophenone) with chlorodifluoromethane in a solvent containing a quaternary ammonium salt (e.g. tetrabutylammonium bromide) and a base (e.g. potassium hydroxide). The method permits to produce the difluoromethoxyphenyl alkyl ketone compound in a high yield by the reaction using chlorodifluoromethane in an amount less than that by conventional methods at a low temperature.

Description

[Detailed description of the invention]

0001

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for producing difluoromethoxyphenylalkyl ketones useful as raw materials for producing pharmaceuticals and agrochemicals.

0002

[Description of the Prior Art] Conventionally, a method for producing difluoromethoxyphenylalkyl ketones, which is considered to be industrially useful, involves mixing hydroxyphenylalkyl ketones and a large excess of chlorodifluoromethane at a temperature of 80°C or higher in a highly concentrated manner. A method of manufacturing by reacting a water-dioxane system in the presence of a base (JP-A-57-146730, JP-A-58-8035, etc.) is known. However, these methods have the following problems.

[0003] Chlorodifluoromethane is used in large excess. This is a chemical substance that has a negative impact on the natural environment, so if we can reduce its usage in the future, not only at production sites but also from the perspective of preserving the global environment, it would be extremely significant.

■Relatively high temperature (for example, 80°C or higher)
The reaction is carried out using a highly concentrated base (for example, alkali hydroxide). Under such reaction conditions, a commonly used glass tank cannot be used as a reaction tank, and it is necessary to use equipment that takes special care to prevent scattering of chlorodifluoromethane.

(2) The yield of difluoromethoxyphenylalkyl ketones is low. The yield when based on hydroxyalkyl ketones is about 80%, and the yield when based on chlorodifluoromethane is 30% or less.

Therefore, in view of the above-mentioned problems, the amount of chlorodifluoromethane used can be further reduced than before, the reaction can be carried out at a lower temperature, and the target compound can be easily produced industrially with high yield. It was hoped that a method could be developed.

[0007]

SUMMARY OF THE INVENTION An object of the present invention is to provide a novel method for producing difluoromethoxyphenylalkyl ketones useful as raw materials for producing pharmaceuticals and agricultural chemicals.

[0008]

[Means for Solving the Problems] As a result of intensive research to solve the above-mentioned problems, the present inventors have found that the amount of chlorodifluoromethane used can be further reduced than in the conventional technology, and the reaction can be carried out at a lower temperature. The present inventors have discovered a new method that can produce the target compound in high yield and have completed the present invention. That is, the present invention provides compound A of the following formula
:

[0009]

[C4]

A hydroxyphenylalkyl ketone represented by the formula (wherein R represents an alkyl group) and chlorodifluoromethane are combined with a base and a compound B of the following formula:

0011
]

[C5]

(wherein R1, R2, R3 and R4 represent an alkyl group which may be different from each other; X represents a halogen atom) in an organic solvent containing a quaternary ammonium salt. Compound C of the following formula, characterized by:

[0013]

[C6]

(In the formula, R has the same meaning as described above.)
The present invention relates to a method for producing difluoromethoxyphenylalkyl ketones shown in the following.

The present invention will be explained in detail below. In the target compound difluoromethoxyphenylalkyl ketones (compound C), the raw materials for its production hydroxyphenylalkyl ketones (compound A), and the quaternary ammonium salt (compound B), R, R1, R2,
R3, R4 and X are as follows.

Examples of R include linear or branched alkyl groups; preferably linear or branched alkyl groups having 1 to 10 carbon atoms; more preferably linear is preferably an alkyl group having 1 to 4 carbon atoms; more preferably an ethyl group.

R1, R2, R3 and R4 may be straight chain or branched alkyl groups which may be different from each other; preferably straight chain or branched alkyl groups having 1 to 20 carbon atoms. A straight-chain alkyl group having 1 to 10 carbon atoms is more preferable.

Examples of X include halogen atoms (chlorine atom, bromine atom, fluorine atom, iodine atom, etc.); preferably, chlorine atom or bromine atom.

[0019] Compound C (difluoromethoxyphenylalkyl ketones, which is the target compound) is usually synthesized by combining the raw materials Compound A (hydroxyphenylalkyl ketones) and chlorodifluoromethane with a base and the compound, as shown below. This can be carried out by reacting in an organic solvent containing B (quaternary ammonium salt).

[0020]

[C7]

(In the formula, R, R1, R2, R3, R4 and let The amount used is 1.0 to 1.5 times the mole, preferably 1.0 to 1.2 times the mole of compound A (hydroxyphenylalkyl ketones).

The amount of compound B (quaternary ammonium salt) used is 1 to 20 mol%, preferably 5 to 10 mol%, based on compound A.

Examples of the base include alkali metal alkoxides (eg, sodium methoxide, sodium ethoxide, etc.), inorganic bases (eg, sodium amide, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium hydride, etc.). Inorganic bases are preferred; sodium hydroxide, potassium hydroxide, etc. are more preferred.

The solvent is not particularly limited as long as it is not directly involved in this reaction, and various solvents (for example, benzene, toluene, xylene, methylnaphthalene, petroleum ether, ligroin, hexane, chlorobenzene, dichlorobenzene) can be used. Chlorinated or non-chlorinated aromatic, aliphatic, cycloaliphatic hydrocarbons such as , methylene chloride, dichloromethane, dichloroethane, trichlorethylene, cyclohexane, acetone; diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, Ethoxyethane, diethylene glycol dimethyl ether,
ethers such as diethylene glycol diethyl ether, etc.; alcohols such as methanol, ethanol, isopropanol, butanol, etc.; mixtures of said solvents, etc.) can be used; preferably to speed up the reaction rate. It is preferable to use dichloromethane, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, etc., which are economically advantageous because of their production.

The amount of the solvent to be used is preferably 200 to 2000 ml, more preferably 40 to 800 ml per mole of compound A.

The reaction temperature is 0 to 90°C, but is preferably 0 to 20°C since it is necessary to use an excess of chlorodifluoromethane to increase the conversion rate of compound A.
, more preferably 0 to 10°C.

The reaction time varies depending on the above-mentioned concentration, the time for blowing chlorodifluoromethane, and the temperature, but is usually 2 to 8 hours.

Compound A is easily available as a commercial product.

[0029] Such a compound A is 4
-Hydroxyacetophenone, 4-hydroxypropiophenone, 4-hydroxybutyrophenone, 4-hydroxyvalerophenone, 4-hydroxyisobutyrophenone, 3-hydroxyacetophenone, 3-hydroxypropiophenone, 3-hydroxybutyrophenone, 3-
Examples include hydroxyvalerophenone, 3-hydroxyisobutyrophenone, 2-hydroxyacetophenone, 2-hydroxypropiophenone, 2-hydroxybutyrophenone, 2-hydroxyvalerophenone, and 2-hydroxyisobutyrophenone.

Compound B is easily available as a commercial product.

[0031] Such compounds B include those having at least three alkyl groups having 4 or more carbon atoms (for example, tetrabutylammonium chloride,
Tetrabutylammonium bromide, Tetrabutylammonium iodide, Tetraoctylammonium chloride, Tetraoctylammonium bromide,
Tetraoctylammonium iodide, tributylmethylammonium chloride, tributylmethylammonium bromide, tributylmethylammonium iodide, trioctylmethylammonium chloride, trioctylmethylammonium bromide, trioctylmethylammonium iodide, etc.).

The target compound C produced as described above can be obtained by separating and concentrating the organic layer after the completion of the reaction, and further purifying by distillation and purification as necessary.
High purity can be obtained by known means such as various chromatography methods.

Compound C, corresponding to the above compound A, includes, for example, 4-difluoromethoxyacetophenone, 4-difluoromethoxypropiophenone, 4-difluoromethoxybutyrophenone, 4-difluoromethoxyvalerophenone, 4-difluoromethoxy Isobutyrophenone, 3-difluoromethoxyacetophenone, 3
-difluoromethoxypropiophenone, 3-difluoromethoxybutyrophenone, 3-difluoromethoxyvalerophenone, 3-difluoromethoxyisobutyrophenone, 2-difluoromethoxyacetophenone, 2-difluoromethoxypropiophenone, 2-difluoromethoxybutyrophenone, 2-difluoromethoxybutyrophenone Examples include methoxyvalerophenone and 2-difluoromethoxyisobutyrophenone.

[0034]

[Examples] The present invention will be specifically explained below with reference to Examples. Note that these Examples do not limit the scope of the present invention.

Example 1 Potassium hydroxide aqueous solution (56.11 g of 85% KOH dissolved in 60 ml of water), tetrabutylammonium bromide (8.06 g) and dichloromethane (150 ml)
4-Hydroxyacetophenone (34.1 g), which is Compound A, was added to the mixture of ) under a nitrogen atmosphere, and the mixture was cooled to 5°C. Into this, 1.5 chlorodifluoromethane (26.3 g) (1.2 times the mole of compound A) was added under cooling at 5°C.
The mixture was blown into the solution over a period of time, and then stirred for 2.5 hours under cooling at 5° C. (conversion rate of compound A was 92%). After the reaction was completed, water (100 ml) was added to the reaction mixture to separate the organic layer. Then, the aqueous layer was extracted twice with methylene chloride (50 ml), combined with the organic layer, and this was extracted with saturated brine (40 ml).
0 ml), dried over magnesium sulfate, concentrated under reduced pressure, and distilled under reduced pressure to obtain 39.9 g of 4-difluoromethoxyacetophenone (boiling point: 107°C/6 mmHg. Yield is based on compound A. (86% based on chlorodifluoromethane and 72% based on chlorodifluoromethane).

Example 2 The target compound was synthesized in the same manner as in Example 1, except that 4-hydroxypropiophenone (37.5 g) was used as compound A. The conversion rate of 4-hydroxypropiophenone was almost 100%, and 47.5 g of 4-difluoromethoxypropiophenone was obtained (boiling point: 113-115°C/5 mmHg. Yield is based on compound A. and 79% when based on chlorodifluoromethane).

Example 3 The target compound was synthesized in the same manner as in Example 2, except that tetrabutylammonium chloride (6.95 g) was used as compound B. The conversion rate of 4-hydroxypropiophenone was almost 100%, and 45.1g of 4-difluoromethoxypropiophenone was obtained (the yield was 90% based on compound A, (75% based on methane).

Example 4 The target compound was synthesized in the same manner as in Example 1, except that diethylene glycol dimethyl ether (150 ml) was used instead of dichloromethane. The conversion rate of 4-hydroxyacetophenone was almost 100%, and 40.0g of 4-difluoromethoxyacetophenone was
(The yield was 86% based on compound A and 7% when based on chlorodifluoromethane.
2%).

Example 5 The target compound was synthesized in the same manner as in Example 2, except that trioctylmethylammonium bromide (10.03 g) was used as compound B. The conversion rate of 4-hydroxypropiophenone is almost 100%,
46.1g of 4-difluoromethoxypropiophenone
(The yield was 92% based on Compound A and 7% when based on chlorodifluoromethane.
7%).

Example 6 The target compound was synthesized in the same manner as in Example 2, except that tetraethylammonium bromide (5.25 g) was used as compound B. HPLC quantitative analysis of the dichloroethane solution obtained by extracting the reaction solution revealed that 4
The yield of -difluoromethoxypropiophenone was 52% (based on Compound A).

Example 7 The target compound was synthesized in the same manner as in Example 1, except that 2-hydroxyacetophenone was used as compound A. After separating and concentrating the organic layer of the reaction mixture, 11.4 g of 2-difluoromethoxyacetophenone was obtained by silica gel column chromatography (yield: 43.3% based on Compound A).

[0042]

Effects of the Invention According to the novel production method of the present invention, the amount of chlorodifluoromethane used can be reduced compared to the conventional method, the reaction can be carried out at a low temperature, and difluoromethoxyphenylalkyl ketones can be produced in high yield. Obtainable.

Claims (1)

[Claims] [Claim 1] A hydroxyphenylalkyl ketone represented by the following formula: [Chemical 1] (wherein R represents an alkyl group) and chlorodifluoromethane are combined with a base and the following formula: [Chemical formula 2] (Formula (wherein, R1, R2, R3 and R4 represent an alkyl group which may be different from each other; X represents a halogen atom) in an organic solvent containing a quaternary ammonium salt. A method for producing difluoromethoxyphenylalkyl ketones represented by the following formula: [Image Omitted] (wherein R has the same meaning as described above).