JPH04356438A - Method for producing acetophenone compounds and intermediate therefor and method for producing the same - Google Patents

Abstract

PURPOSE:To produce an acetophenone compound useful as a raw material for medicines, agricultural chemicals, various chemicals, etc., from a compound such as 2-chloro-4-fluoroanisole as a raw material via a new compound, and further by the reaction of a vinyl ether. CONSTITUTION:The production of an acetophenone compound of formula I (R is H, alkyl) (e.g. 4-chloro-2-fluoro-5-hydroxyacetophenone) comprises halogenating a compound of formula IV (R3 is alkyl, alkoxycarbonyl, alkylsulfonyl, group of formula V; X1, X2 are halogen) (e.g. 2-chloro-4- fluoroanisole), reacting the produced compound of formula III or a new compound of formula III' with a vinyl ether compound of formula II (R1 is alkyl) in the presence of a base and a catalyst, the compound of formula III' being obtained by removing a protecting group from the compound of formula III, and subsequently reacting the reactional product with a mineral acid.

Description

[Detailed description of the invention]

0001

[Industrial Application Field] The present invention relates to the general formula (IV) (wherein,
R3 is a lower alkyl group, a lower alkoxycarbonyl group,
Represents a lower alkylsulfonyl group or (in the formula, X1 and X2 have the meanings below),
X1 and X2 represent halogen atoms which may be the same or different. ) is halogenated in the presence of a halogenating agent, and the compound represented by the general formula (III) (wherein R2 is a lower alkyl group, a lower alkoxycarbonyl group, a lower alkylsulfonyl group, or (wherein, X1 and X2 are Indicates the meaning of the following.)
X1 and X2 are as defined above, and Z represents a halogen atom. ), and the compound (III) or the compound (III) is obtained by deprotecting the general formula (III') (wherein, X1, X2 and Z are the same as above). Compound and general formula (II) CH2=CH-OR1
(II) A general formula characterized by reacting a vinyl ether represented by (wherein R1 represents a lower alkyl group) in the presence of a base and a catalyst, and then reacting with a mineral acid. (I)

0002

[Problem to be Solved by the Invention] As a result of extensive research into a new method for producing acetophenones, the present inventors found that
The present invention was completed by discovering that the manufacturing method of the present invention is a new manufacturing method that has not been described in any literature. Therefore, an object of the present invention is to obtain a new method for producing acetophenones useful as raw materials for medicines, agricultural chemicals, various chemical products, and the like.

[Means for Solving the Problems] The method for producing acetophenones of the present invention is schematically illustrated, for example, as follows. Manufacturing method 1. (In the formula, R, R1, R2, R3, X1, X2 and Z are the same as above.)

A compound represented by general formula (III) is obtained by subjecting the compound represented by general formula (IV) to a halogenation reaction in the presence of an inert solvent and a halogenating agent,
The compound (III) or the general formula (III') obtained by deprotecting the compound (III) is isolated, and then the compound (III) or the compound (III') is combined with the general formula (II). The represented vinyl alcohols are reacted in the presence or absence of an inert solvent and in the presence of a base and a catalyst to obtain a compound represented by the general formula (I''). Acetophenones represented by the general formula (I) can be produced by isolating or not isolating the acetophenones (I) by reacting them with a mineral acid.

■ General formula (IV) → General formula (
III) As the inert solvent that can be used in this reaction, for example, mineral acids such as sulfuric acid, organic acids such as glacial acetic acid, and mixtures thereof can be used. Chlorine as a halogenating agent,
Potassium chlorate, chlorine-silver sulfate, bromine, potassium bromate, bromine-silver sulfate, iodine-silver sulfate, iodine monochloride, etc. can be used, and the amount used depends on the compound represented by general formula (IV). It can be used in an amount of 1 to 1.5 times by mole. In this reaction, for example, it is preferable to use chlorine as a brominating agent at the same time as bromine, and the amount used is in the range of equimolar to excess molar. The reaction temperature may be selected from room temperature to the boiling point of the inert solvent used. The reaction time varies depending on the amount of reaction reagent, reaction temperature, etc., but is in the range of several minutes to 48 hours. After the reaction is completed, it can be isolated by a conventional method and purified if necessary to produce the desired product.

■ General formula (III) → General formula (III') This reaction removes the protecting group from the compound represented by the general formula (III) in the presence of an inert solvent and a base to obtain the desired product. It can be manufactured. Examples of inert solvents that can be used in this reaction include methanol,
Alcohols such as ethanol, propanol, butanol
aromatic hydrocarbons such as benzene, toluene, and xylene, chain ethers such as methyl cellosolve and ethylene glycol dimethyl ether, cyclic ethers such as tetrahydrofuran and dioxane, and nitriles such as acetonitrile. , dimethylformamide, diethylformamide, dimethylacetamide, diethylacetamide, dimethylsulfoxide, 1,3-dimethyl-2-imidazolidinone, etc., and these inert solvents cannot be used alone. They may be used in combination, or they may be used in combination. As the base, for example, an inorganic base such as potassium carbonate or sodium carbonate can be used, and the amount used is appropriately selected from the range of equimolar to excess molar relative to the compound represented by the general formula (III). good. The reaction temperature may be selected from room temperature to the boiling point of the inert solvent used. The reaction time is not constant depending on the reaction scale, reaction temperature, etc., but is in the range of several minutes to 48 hours. After the reaction is completed, the desired product can be produced by isolation by a conventional method and purification if necessary.

[0006] General formula (III) or (I
Representative examples of compounds represented by II') are illustrated in Table 1.

■ General formula (III) or (III'
) → [General formula (I'')] → General formula (I) General formula (III) or (III') A compound represented by general formula (III) or (III') and a vinyl ether represented by general formula (II) are inertized. The reaction is carried out in the presence of a solvent, a base and a catalyst to form a compound represented by the general formula (I''), and the compound (I
Acetophenones represented by the general formula (I) can be produced by isolating or not isolating '') and reacting it with a mineral acid. The inert solvent that can be used in this reaction may be any inert solvent that does not significantly inhibit the progress of this reaction, and inert solvents that can be used in (3) can be used. As the catalyst used in this reaction, a palladium compound and a phosphine compound may be used in combination.
Examples of the palladium compound include palladium metal, palladium carbon, palladium alumina, palladium chloride, palladium bromide, palladium acetate, and the like. Examples of phosphine compounds include trialkylphosphines such as triisopropylphosphine and tributylphosphine, triarylphosphines such as triphenylphosphine, triparafluorophenylphosphine, and triorthomethylphenylphosphine, and 1,1-bis(dimethylphosphine). ) methane, 1,1-bis(diethylphosphino)methane, 1,
2-bis(dimethylphosphino)ethane, 1,2-bis(diethylphosphino)ethane, 1,3-bis(dimethylphosphino)propane, 1,3-bis(diethylphosphino)propane, 1,4- Bis(dialkylphosphino)alkanes such as bis(dimethylphosphino)butane, 1,4-bis(diethylphosphino)butane, 1,2
Examples include bis(diarylphosphino)alkanes such as -bis(diphenylphosphino)ethane, 1,3-bis(diphenylphosphino)propane, and 1,4-bis(diphenylphosphino)butane.

The amount of catalyst used in this reaction is determined by the general formula (
The amount of the phosphine compound used in combination with the palladium compound as a catalyst may be selected as appropriate from the range of 0.001 to equimole relative to the compound represented by III) or (III'). The amount may be selected from the range of 0.01 to 100 times by mole, preferably 0.01 to 50 times by mole. The catalyst for this reaction may be a combination of a phosphine compound and a palladium compound, which may be prepared in advance in the form of a complex in the reaction system, or each may be added separately to the reaction system. Also, in place of the palladium compound used in combination with the phosphine compound,
Metal supports or metal salts such as group II cobalt, platinum, rhodium, ruthenium, iridium or osmium can also be used in combination with the phosphine compounds.

[0009] As the base used in this reaction, an inorganic base or an organic base can be used.
For example, carbonates, oxides, and hydroxides of alkali metals or alkaline earth metals such as sodium carbonate, potassium carbonate, calcium oxide, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydroxide, potassium hydroxide, and calcium hydroxide. Examples include inorganic bases. As the organic base, in addition to organic bases such as triethylamine, tributylamine, pyridine, dimethylaniline, and N-methylpyrrolidone, organic acid salts such as sodium acetate can also be used. The amount of base used in the present invention may be the amount necessary to neutralize the hydrogen halide produced by the reaction, but it can also be used in excess.

In this reaction, the vinyl ether represented by the general formula (II) can be used in an equimolar to an excess molar amount relative to the compound represented by the general formula (III) or (III'). is carried out under normal pressure to increased pressure, preferably 1
It is carried out within the range of ~50 atmospheres. During this reaction, it is preferable to carry out the reaction in a nitrogen atmosphere inside the reaction vessel. The reaction temperature is 20
The temperature may be suitably selected from the range of ~300°C. The reaction vessel used in this reaction may be one that is normally used, for example, and in the case of a pressurized reaction, one that can withstand the pressure is used. For example, reaction vessels made of glass, metal, etc. are exemplified. can do. The reaction time is not constant depending on the reaction scale, reaction temperature, etc., but is in the range of several minutes to 100 hours. After the completion of the reaction, it is sufficient to subject the target product to the next reaction without isolating it from the reaction system containing the target product.
') can be treated from the reaction system by a conventional method such as solvent extraction, and if necessary purified by column chromatography etc. to isolate the target product and use it for the next reaction. .

■ General formula (I'') → General formula (I) After the completion of the previous reaction, the general formula (I'')
By treating a reaction system containing a mineral acid with general formula (I)
Acetophenones represented by can be produced. Examples of mineral acids that can be used in this reaction include hydrochloric acid, sulfuric acid, hydrobromic acid, and hydriodic acid, and the amount used can be as long as it is necessary for the reaction system to show acidity. . In addition, when using the compound represented by the general formula (I'') isolated in the previous reaction, an inert solvent, for example, a compound represented by the general formula (I'')
The mineral acid may be treated in the presence of an alcohol corresponding to the R2 moiety of I''), an ether such as tetrahydrofuran, or an inert solvent such as dimethylformamide. The amount of mineral acid used may be the amount necessary to make the pH of the reaction system acidic. The reaction temperature is selected from the range of 0 to 50°C, preferably room temperature. After completion of the reaction, the desired product can also be produced by processing in a conventional manner and purifying if necessary.

Manufacturing method 2. (In the formula, R', X1, X2 and Q are the same as above.) Acetophenones represented by general formula (I') and general formula (V)
Alternatively, the desired product can be produced by reacting the alkylating agent represented by (V') in the presence of an inert solvent and a base.

Examples of the inert solvent used in this reaction include halogenated hydrocarbons such as methylene chloride, chloroform, and carbon tetrachloride, aromatic hydrocarbons such as benzene, toluene, and xylene, and esters such as ethyl acetate. Examples include nitriles such as , acetonitrile and benzonitrile, chain ethers such as methyl cellosolve and diethyl ether, cyclic ethers such as dioxane and tetrahydrofuran, sulfolane and dimethyl sulfoxide. Examples of the alkylating agent represented by the general formula (V) used in this reaction include lower alkyl halides, lower alkyl sulfonic acid esters, aromatic sulfonic acid alkyl esters, etc. Examples of the alkylating agent include dialkyl sulfates such as dimethyl sulfate and diethyl sulfate.

As the base used in this reaction, for example, the base used in Production Method 1 can be used. Since this reaction is an equimolar reaction, each reactant may be used in equimolar amounts, but one may be used in excess. The reaction temperature may be appropriately selected from the range of 0° C. to the boiling point of the inert solvent used. The reaction time varies depending on the reaction scale, reaction temperature, etc., but is in the range of several minutes to 48 hours. After the reaction is completed, the desired product can be produced by isolation by a conventional method and purification if necessary.

[0015] Typical examples of the present invention will be illustrated below, but the present invention is not limited thereto. Example 1. Production of 5-bromo-2-chloro-4-fluoroanisole 6.79 g (42
．． 4 mmol) in 40 ml of concentrated sulfuric acid, 3 mmol of bromine
1 (55.1 mmol) was added and the reaction was carried out at room temperature for 1.5 hours. After the reaction is complete, the reaction mixture is poured into ice water, the target product is extracted with ether, the organic layer is washed with water, then with an aqueous sodium thiosulfate solution, washed with water, dried, and the extract is concentrated to remove the residue. Purification by silica gel column chromatography yielded 2.74 g of the desired product as crystals. Physical properties m. p. 73.7℃, yield 27%

001
6] Example 2. Preparation of 4-chloro-2-fluoro-5-hydroxyacetophenone 2-1 2.0 g (7.05 mmol) of 5-bromo-2-chloro-4-fluorophenyl methyl carbonate, 8 mg (0.5 mmol) of palladium acetate. 036 mmol), 1,3-bis(diphenylphosphino)propane 58 mg (0.1
4 mmol), 0.8 g (7.55 mmol) of sodium carbonate, 1.1 g (14.9 mmol) of ethyl vinyl ether, and 10 ml of methanol were placed in a 100 ml stainless steel autoclave and placed under a nitrogen atmosphere. Reaction temperature 1
The reaction was stirred at 30° C. for 4 hours. The reaction system was then allowed to cool, acidified with concentrated hydrochloric acid, and reacted for 30 minutes at room temperature. After the reaction is complete, water is added to the reaction system, the target product is extracted with ether, the extract is washed with water, dried, concentrated, and the resulting residue is purified by silica gel column chromatography to obtain the target product 1.
．． 1g was obtained. Physical properties m. p. 112.0℃ Yield 8
3%

2-2 27.5 g (57.6 mmol) of bis(5-bromo-2-chloro-4-fluorophenyl) carbonate, 200 mg (1.15 mmol) of palladium chloride, 1,3-
Bis(diphenylphosphino)propane 700mg (1
．． 70 mmol), 13 g (123 mmol) of sodium carbonate, 30 g (300 mmol) of n-butyl vinyl ether, and 200 ml of n-butyl alcohol in 500 m
The mixture was placed in a 1-liter Erlenmeyer flask and refluxed for 21 hours under a nitrogen atmosphere. Next, the reaction system was allowed to cool, and concentrated hydrochloric acid was added to make it acidic.
The reaction was carried out at room temperature for 30 minutes. After the reaction was completed, water was added to the reaction system and the target product was extracted with ether. The extract was washed with water, dried, and concentrated. The residue was purified by silica gel column chromatography to obtain 18.0 g of the target product. Physical properties m. p. 112.0℃ Yield 7
7%

Example 3. 4-chloro-2-fluoro-5-hydroxyacetophenone and 4-chloro2
-Preparation of fluoro-5-methoxyacetophenone 2.0 g (6.6 mmol) of 5-bromo-2-chloro-4-fluorophenyl methanesulfonate, 20 mg (0.09 mmol) of palladium acetate, 1,3-bis( Diphenylphosphino)propane 120 mg (0.29 mmol), sodium carbonate 800 mg (7.5 mmol)
, 2 g (27.8 mmol) of ethyl vinyl ether and 10 ml of methanol were placed in a 100 ml stainless steel autoclave, and a reaction was carried out at 130° C. for 3 hours under a nitrogen atmosphere. The reaction system was then allowed to cool, made acidic by adding concentrated hydrochloric acid, and reacted at room temperature for 30 minutes. After the reaction was completed, water was added to the reaction system and the target product was extracted with ethyl acetate. The extract was washed with water, dried, and concentrated. The residue was purified by silica gel column chromatography to obtain 4-chloro-2-fluoro-5.
-Hydroxyacetophenone 240 mg (yield 19%)
and 700 mg (yield 52%) of 4-chloro2-fluoro-5-methoxyacetophenone were obtained.

Example 4. 4-chloro2-fluoro-
Preparation of 5-methoxyacetophenone 5-bromo-4-fluoro-2-chloroanisole 0.
5 g (2.1 mmol), palladium chloride 10 mg (0
．． 06 mmol), triphenylphosphine 40 mg (
0.15 mmol) and n-butyl vinyl ether 0.
4 g (4.0 mmol) was dissolved in 20 ml of dimethylformamide, 0.2 g (1.9 mmol) of sodium carbonate was added, and the reaction was carried out at 100 to 120° C. for 9 hours under a nitrogen atmosphere. Next, the reaction solution was allowed to cool, and then the reaction solution was made acidic with concentrated hydrochloric acid, and the reaction was carried out at room temperature for 30 minutes. After the reaction is complete,
Water was added to the reaction solution, and the desired product was extracted with ether. The extract was washed with water, dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 0.26 g of the desired product. Physical properties m. p. 92.4℃, yield 61%

002
0] Example 5. Production of 4-chloro-2-fluoro-5-methoxyacetophenone 5-bromo-4-fluoro-2-chloroanisole 0.
5 g (2.1 mmol), palladium chloride 10 mg (0
．． 06 mmol), triphenylphosphine 40 mg (
0.15 mmol) and n-butyl vinyl ether 0.
4 g (4.0 mmol) was dissolved in 20 ml of dimethylformamide, 0.2 g (1.9 mmol) of sodium carbonate was added, and the reaction was carried out at 100 to 120° C. for 9 hours under a nitrogen atmosphere. After the reaction is complete, water is added to the reaction solution, the target product is extracted with ether, the extract is washed with water, dried, concentrated under reduced pressure, and the residue is purified by column chromatography to remove the intermediate as an oil. .52g was obtained. Physical properties NMR (CDCl3 /TMS, ppm)
0.96 (t, 3H), 1.45 (m, 2H)
, 1.72 (m, 2H), 3.85 (t, 2H
), 3.87 (s, 3H), 4.46 (m, 1H),
4.75 (m, 1H), 7.09 (d, 1H),
7.20 (d, 1H). Add 0.52g of the oily substance obtained above to 20ml of methanol.
The mixture was dissolved in water, acidified with concentrated hydrochloric acid, and reacted at room temperature for 30 minutes. After the reaction was completed, water was added to the reaction solution, the target product was extracted with ether, the extract was washed with water, dried, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 0.26 g of the target product. Obtained. Physical properties m. p. 92.4℃, yield 61%

0
Example 6. 4-chloro-2-fluoro-5
-Production of methoxyacetophenone 7.80g (41.3 mmol) of 4-chloro-2-fluoro-5-hydroxyacetophenone was added to 80ml of acetone.
8.80 g (62.0 mmol) of methyl iodide and 8.52 g (71.7 mmol) of anhydrous potassium carbonate powder were added, and the reaction was carried out under reflux for 1.5 hours. After the reaction was completed, acetone was distilled off under reduced pressure, ice water was added to the residue, and the target product was extracted with ethyl acetate. Wash the extract with water,
After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 7.53 g of the desired product as crystals. Physical properties m. p. 92.4℃, yield 90%

0
Example 7. 5-bromo-2-chloro-4-
Production of fluorophenol A mixed solution of 14.18 g (50 mmol) of 5-bromo-2-chloro-4-fluorophenyl methyl carbonate, 10.35 g (75 mmol) of anhydrous potassium carbonate, and 150 ml of methanol was prepared. The reaction was carried out for 1 hour under stirring and reflux. After the reaction was completed, methanol was distilled off under reduced pressure, 200 ml of ice water was added to the residue, the pH was adjusted to 4 to 5 with concentrated hydrochloric acid, and the target product was extracted with ethyl acetate. The organic layer was washed with water until it became neutral, dried, and the solvent was distilled off under reduced pressure to obtain 10.15 g of the desired product as crystals.

Claims (3)

[Claims] Claim 1: General formula (IV) (wherein R3 is a lower alkyl group, a lower alkoxycarbonyl group, a lower alkylsulfonyl group, or in the formula, X1 and X2 have the meanings given below),
1 and X2 represent halogen atoms which may be the same or different. ) is halogenated in the presence of a halogenating agent, and the compound represented by the general formula (III) (wherein R2 is a lower alkyl group, a lower alkoxycarbonyl group, a lower alkylsulfonyl group, or (wherein, X1 and X2 are Indicates the meaning of the following.)
X1 and X2 are as defined above, and Z represents a halogen atom. ), and the compound (III) or the compound (III) is obtained by deprotecting the general formula (III') (wherein, X1, X2 and Z are the same as above). Compound and general formula (II) CH2=CH-OR1
(II) A general formula characterized by reacting a vinyl ether represented by (wherein R1 represents a lower alkyl group) in the presence of a base and a catalyst, and then reacting with a mineral acid. A method for producing acetophenones represented by (I) (wherein R represents a hydrogen atom or a lower alkyl group, and X1 and X2 are the same as above). Claim 2: General formula (III) or general formula (II)
I') (in the formula, R2 represents a lower alkyl group, a lower alkoxycarbonyl group, a lower alkylsulfonyl group, or (in the formula, X1 and X2 are shown below), and X1 and X2 are halogens which may be the same or different. indicates an atom,
Z represents a halogen atom. ). 3. Acetophenones represented by general formula (I') (wherein X1 and X2 are the same as above) and general formula (V) R'-Q (V) or general formula (V') (R')2SO4 (V')
(In the formula, R' represents a lower alkyl group, and Q represents a halogen atom, a lower alkylsulfonyloxy group, or an arylsulfonyloxy group.) General formula (I') (wherein, R
', X1 and X2 are the same as above. ) A method for producing acetophenones represented by