JPH10251190A - Aromatic ketone compound, its production and intermediate thereof - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain an aromatic ketone compound useful as an intermediate for a medicine, an agrochemical material, etc. SOLUTION: This aromatic ketone compound is a compound of formula I (R is phenyl, biphenyl or naphthyl), e.g. 3-hydroxyl-1-(4'-methoxybiphenyl)-4- chloro-4,4-difluoro-1-butanone. The compound of formula I is obtained by reacting β-chlorodifluoromethyl-β-propiolactone of formula II with an aromatic compound expressed by the formula: RH is the presence of a lewis acid. Also, the compound of formula II is a new compound and is obtained by reacting chlorodifluoroacetoaldehyde with ketone in the response of a lewis acid. As the lewis acid, magnesium dibromide diethyletherate, etc., are cited and used by 0.01-1mol fold amount based on the compound of the formula II.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to an aromatic ketone compound, a method for producing the same, and an intermediate thereof.

[0002]

2. Description of the Related Art In the field of medical and agricultural chemicals, it is useful to easily convert a functional group and to introduce a functional group, which has a high possibility of expressing a biological activity or improving a biological activity. The creation of new compounds is desired.

[0003]

Under these circumstances, the present inventors have conducted intensive studies to develop compounds that can be useful intermediates such as useful medicinal and agricultural chemicals, methods for producing the same, and intermediates thereof. The present inventors have found an aromatic ketone compound represented by the general formula (1), and have reached the present invention. That is, the present invention
General formula (1) (In the formula, R represents a phenyl group, a biphenylyl group, or a naphthyl group. Here, the phenyl group, the biphenylyl group, or the naphthyl group may be substituted with a lower alkyl group, a lower alkoxy group, or a halogen atom.) The present invention provides an aromatic ketone compound represented by the formula (I), a method for producing the same, and an intermediate thereof.

[0004]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail. The aromatic ketone compound represented by the general formula (1) of the present invention has the formula (2) Β-chlorodifluoromethyl-β-propiolactone represented by the general formula (3) RH (3) (wherein R represents a phenyl group, a biphenylyl group or a naphthyl group. Here, a phenyl group, a biphenylyl group) Alternatively, the naphthyl group may be substituted with a lower alkyl group, a lower alkoxy group or a halogen atom) in the presence of a Lewis acid.

In the present invention, β-chlorodifluoromethyl-β represented by the general formula (2) used as a raw material
-Propiolactone is a novel compound and can be obtained by reacting chlorodifluoroacetaldehyde with ketene in the presence of a Lewis acid. The Lewis acid used in this reaction is not particularly limited, and examples thereof include aluminum compounds such as magnesium dibromide / diethyl etherate, aluminum chloride, aluminum bromide, triphenoxyaluminum, and triisopropoxyaluminum; Zinc chloride, zinc compounds such as zinc bromide, titanium compounds such as titanium chloride and titanium bromide, boron compounds such as boron chloride, boron bromide and boron fluoride, and silicon compounds such as tetramethylsilyl chloride. it can. The amount of the Lewis acid to be used is usually from 0.01 to chlorodifluoroacetaldehyde.
It is about 1 mole times, preferably about 0.1 to 0.5 mole times. The amount of ketene used is usually about 0.8 to 5 times, preferably about 1 to 2 times the mole of chlorodifluoroacetaldehyde.

[0006] The above reaction is usually carried out in the presence of an organic solvent. Such organic solvents include diethyl ether,
Ethers such as tetrahydrofuran, dioxane and methyl-t-butyl ether; aromatics such as benzene, toluene, xylene and chlorobenzene; hydrocarbons such as hexane, heptane and cyclohexane; halogenated hydrocarbons such as chloroform and carbon tetrachloride Or a mixture thereof. The amount of the organic solvent used is not particularly limited, but is usually about 0.5 to 20 times by weight based on chlorodifluoroacetaldehyde.

The above-mentioned reaction is usually carried out in the presence of the above-mentioned solvent, and the order of charging ketene and chlorodifluoroacetaldehyde is not particularly limited, and either one may be charged first or the two may be charged in parallel. The reaction temperature of the above reaction is -78 ° C to 50 ° C, preferably -60 ° C.
-30 ° C. For example, it can be performed by adding chlorodifluoroacetaldehyde while introducing ketene into a solution obtained by adding a Lewis acid to an organic solvent.

Thus, β-chlorodifluoromethyl-
β-propiolactone (2) is produced, but after the reaction,
The reaction can be stopped by adding hydrochloric acid or the like, and isolated by extraction with a solvent such as diethyl ether. If necessary, it can be purified by subjecting it to purification means such as distillation and various types of chromatography.

Next, β-chlorodifluoromethyl-β-propiolactone (2) obtained by the above reaction is reacted with an aromatic compound represented by the general formula (3) in the presence of a Lewis acid to obtain an aromatic ketone. The reaction for obtaining the compound (1) will be described below.

The lower alkyl group which is a substituent of R in the aromatic ketone compound represented by the general formula (1) includes, for example, methyl, ethyl and propyl. The lower alkoxy group includes, for example, methoxy and ethoxy. , Propoxy and the like, and the halogen atom includes chloro, bromo, fluoro and the like.

The substituent of the aromatic compound (3) as the raw material is the same as R in the aromatic ketone compound (1),
For example, benzene, toluene, biphenyl, methoxybiphenyl, naphthalene, β-methoxynaphthalene, o, m,
p-xylene, mesitylene, anisole, chlorobenzene, o, m, p-dichlorobenzene, o, m, p-dimethoxybenzene and the like.

The Lewis acids used in the above reaction include:
Although not particularly limited, for example, aluminum compounds such as magnesium dibromide / diethyl etherate, aluminum chloride, aluminum bromide, triphenoxyaluminum, triisopropoxyaluminum, zinc compounds such as zinc chloride and zinc bromide , Titanium compounds such as titanium chloride and titanium bromide, boron compounds such as boron chloride, boron bromide and boron fluoride, and silicon compounds such as tetramethylsilyl chloride. The amount of the Lewis acid to be used is generally about 0.01 to 1 mol, preferably about 0.1 to 0.5 mol, relative to β-chlorodifluoromethyl-β-propiolactone (2). Also,
The amount of the aromatic compound (3) to be used is usually based on β-chlorodifluoromethyl-β-propiolactone (2).
It is about 1 to 50 mole times, preferably about 1 to 20 mole times.

The above reaction is usually carried out in the presence of an organic solvent. Such organic solvents include diethyl ether,
Ethers such as tetrahydrofuran, dioxane and methyl-t-butyl ether; alcohols such as methanol, ethanol, propanol and isopropanol; aromatics such as benzene, toluene, xylene and chlorobenzene; hydrocarbons such as hexane, heptane and cyclohexane; Halogenated hydrocarbons such as chloroform and carbon tetrachloride, and mixtures thereof. The amount of the organic solvent to be used is not particularly limited, but is usually 0.5 to chlorodifluoroacetaldehyde.
It is about 20 times by weight.

The above reaction is usually carried out in the presence of the above solvent, and the order of charging the aromatic compound (3) and β-chlorodifluoromethyl-β-propiolactone (2) is not particularly limited. May be charged first, or may be charged in parallel. For example, β-chlorodifluoromethyl-β-propiolactone (2) can be added to a solution in which a Lewis acid and an aromatic compound (3) are added to an organic solvent. The reaction temperature of the above reaction is −78 ° C. to 5
0 ° C, preferably -50 ° C to 30 ° C.

The above reaction produces the aromatic ketone compound (1), which is the target compound. After the reaction, the reaction is stopped by adding hydrochloric acid or the like, and isolated by extraction with a solvent such as diethyl ether. can do. If necessary, it can be purified by subjecting it to purification means such as distillation and various types of chromatography.

[0016]

The aromatic ketone compound (1) obtained by the present invention and its intermediate β-chlorodifluoromethyl-β-propiolactone (2) are extremely useful compounds as intermediates for medicinal and agricultural chemicals. And can be used for various applications.

[0017]

The present invention will be described in more detail with reference to the following examples.
Although described, the present invention is limited to these examples.
There is no. Example 1 of β-chlorodifluoromethyl-β-propiolactone
Synthesis: Under a nitrogen atmosphere, dibromide was added to a 300 ml
Gnesium diethyl etherate (402mg, 1.566m
mol) and diethyl ether (20 ml) and dichlorometh
Dissolved in a mixture of tan (3 ml). Cool solution to -55 ° C
And pyrolysis of diketene separately (electric ring furnace 600 ° C)
While introducing ketene generated by
Die of oacetaldehyde (869 g, 7.6 mmol)
Dissolution of chill ether (10 ml) and dichloromethane (1.5 ml)
The solution was added dropwise over one hour. 14 hours from -55 ° C to room temperature
The reaction was stopped by adding 1N hydrochloric acid. Reaction solution
Extract with dichloroether and saturate the diethyl ether layer
Wash with brine, dry with magnesium sulfate, and evaporate the solvent
This gave a crude product. Crude product is silica gel
Column chromatography using Merck 938 (Merck938
5.1 g, eluent diethyl ether) 411 mg, 3
The desired product was obtained in a yield of 5%. β-chlorodifluoromethyl-β-propiolactone:
¹H NMR (CDCl_Three) 3.60 (dd, 1H, J = 4.19, 16.74 H
z), 3.77 (dd, 1H, J = 5.94, 16.74 Hz), 4.60-4.76
(m, 1H): Exact Mass found 156.9841; Calcd for C _FourH
 _FourO_TwoF_TwoCl, 156.9868

Example 2 3-Hydroxy-1- (4'-methoxybiphenyl)-
Synthesis of 4-chloro-4,4-difluoro-1-butanone: -30 ° C in a 50 ml eggplant flask under a nitrogen atmosphere.
Methoxybiphenyl (552 mg, 3 mmol) Aluminum trichloride (120 mg, 0.9 mmol), dichloromethane (4 m
l) A solution of β-chlorodifluoromethyl-β-propiolactone (47 mg, 0.3 mmol) in dichloromethane (2 m
l) The solution was slowly added dropwise, and the mixture was stirred from -30 ° C to 0 ° C for 2 hours. The reaction was terminated with 1N hydrochloric acid, extracted with diethyl ether, the diethyl ether layer was washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off to obtain a crude product (872 mg). The crude product was subjected to silica gel column chromatography (Merck9385.20 g, eluent hexane: ethyl acetate 20/1 to 5/1) to give a crude product of 72%.
mg, 70% yield of the desired compound.

Example 3 Synthesis of 3-hydroxy-1-p-methoxyphenyl-4-chloro-4,4-difluoro-1-butanone: Aluminum trichloride (120 mg) was placed in a 50 ml eggplant flask under a nitrogen atmosphere. , 0.9 mmol) of anisole (1.08 g, 10 mm
The solution was cooled to −30 ° C., and β-chlorodifluoromethyl-β-propiolactone (47 mg, 0.3 mg) was added.
mmol) of anisole (540 mg) was slowly added dropwise, followed by stirring at −30 ° C. for 1 hour. The reaction was terminated with 1N hydrochloric acid, extracted with diethyl ether, the diethyl ether layer was washed with saturated saline, and dried over magnesium sulfate.
The solvent was distilled off to obtain a crude product. Silica gel chromatography of the crude product (silica gel Merck9385,
58 mg, 73% by eluent hexane: ethyl acetate system)
The target compound was obtained in a yield of

Example 4 Synthesis of 3-hydroxy-1- (2 ′, 6′-dimethylphenyl) -4-chloro-4,4-difluoro-1-butanone: In a 50 ml eggplant flask under a nitrogen atmosphere. , A solution of aluminum trichloride (120 mg, 0.9 mmol) in n-xylene (1.06 g, 10 mmol must be confirmed) was cooled to -30 ° C, and β-chlorodifluoromethyl-β-propiolactone (47 mg, 0.3 mmol) was added. ) Was slowly added dropwise, and the mixture was stirred from -30 ° C to 0 ° C for 1 hour. The reaction was terminated with 1N hydrochloric acid, extracted with diethyl ether, the diethyl ether layer was washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off to obtain a crude product. The crude product was subjected to silica gel column chromatography (silica gel Merck9385, eluent hexane: ethyl acetate system) to give the product in a yield of 62 mg and 78%.

Example 5 Synthesis of 3-hydroxy-1- (2 ', 4', 6'-trimethylphenyl) -4-chloro-4,4-difluoro-1-butanone: 50 ml eggplant under nitrogen atmosphere In a flask, a solution of aluminum trichloride (120 mg, 0.9 mmol) in mesitylene (1.20 g, 10 mmol must be confirmed) was placed at -30 ° C.
And β-chlorodifluoromethyl-β-propiolactone (47 mg, 0.3 mmol) in anisole (600 m
g) The solution was slowly added dropwise, and the mixture was stirred from -30 ° C to 0 ° C for 1 hour. The reaction was terminated with 1N hydrochloric acid, extracted with diethyl ether, the diethyl ether layer was washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off to obtain a crude product. The crude product was subjected to silica gel column chromatography (silica gel Merck9385, eluent hexane: ethyl acetate system) to give the product in a yield of 65 mg and 78%.

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Claims (4)

[Claims] 1. The general formula (1) (In the formula, R represents a phenyl group, a biphenylyl group, or a naphthyl group. Here, the phenyl group, the biphenylyl group, or the naphthyl group may be substituted with a lower alkyl group, a lower alkoxy group, or a halogen atom.) An aromatic ketone compound represented by the formula: Expression (2) Β-chlorodifluoromethyl-β-propiolactone represented by the general formula (3) RH (3) (wherein R represents a phenyl group, a biphenylyl group or a naphthyl group. Here, a phenyl group, a biphenylyl group) Or a naphthyl group which may be substituted with a lower alkyl group, a lower alkoxy group or a halogen atom) in the presence of a Lewis acid. A method for producing an aromatic compound represented by the formula: 3. A β-chlorodifluoromethyl-β-propiolactone represented by the formula (2). 4. A β-chlorodifluoromethyl-β-formula represented by the formula (2), wherein chlorodifluoroacetaldehyde and ketene are reacted in the presence of a Lewis acid.
A method for producing propiolactone.