JPH08259507A - Nitration of acetophenone derivative - Google Patents

Abstract

PURPOSE: To nitrate acetophenone derivative useful as an intermediate for organic chemicals such as pharmaceuticals in high reaction rate and yield by using an extremely small amount of a metal and/or a metal compound or an inorganic acid. CONSTITUTION: (A) An acetophenone derivative the formula (R<1> to R<3> are each H or a halogen; at least one of R<1> to R<3> is a halogen; R<4> is H, a halogen, an alkyl, amino or an alkoxy; (n) is 1-4) (e.g. acetophenone) is nitrated with (B) oxygen or air containing a nitrogen oxide and ozone by using a catalyst consisting of (C) a metal (preferably at least one kind of metal selected from among transition metals, tin, antimony, lead and bismuth, especially iron) and/or a compound of the metal or (D) an inorganic acid (preferably sulfuric acid and/or sulfur trioxide).

Description

Detailed Description of the Invention

[0001]

[Industrial application] Nitroacetophenone derivatives are
In recent years, it has become important as an intermediate for organic chemicals represented by medicines and agricultural chemicals.

[0002]

2. Description of the Related Art In the conventional nitration method of a halogenoacetophenone derivative, when the conventional mixed acid method of nitric acid and sulfuric acid was used, hydrolysis was easily carried out and the yield of the desired product was low. Among them, Journal of the Chemical Society Tea Perkin Transactions 1903 (1994)
(J. Chem. Soc. Perkin Trans.
1, 903 (1994)), a method of inhibiting this hydrolysis and nitrating by using nitrogen oxide and ozone has been reported. However, here, methanesulfonic acid is used as the additive. Methanesulfonic acid is practically expensive and has a problem in economic efficiency. Further, nitrogen oxide is used in a large excess, and ozone is used in 3 equivalents.

On the other hand, in Japanese Unexamined Patent Publication (Kokai) No. 6-247904, there is seen an example of using a metal and / or the metal compound in a nitration method using nitrogen oxide and ozone. Further, in JP-A-6-293709, an example in which an inorganic acid is added can be seen. However, in any case, the examples of the raw material are only anthraquinone, and the acetophenone derivative is not mentioned as the target compound.

[0004]

DISCLOSURE OF THE INVENTION The present inventors have earnestly studied an economically inexpensive catalyst which replaces the methanesulfonic acid of the above-mentioned literature when nitrating an acetophenone derivative with nitrogen oxide and ozone. As a result, they have found that the reaction is accelerated by using a trace amount of metal and / or the metal compound or the inorganic acid, and accordingly, the amounts of ozone and nitrogen oxide used are also reduced, and the present invention has been completed.

An object of the present invention is to provide a method for nitration by reacting nitrogen oxides and oxygen containing ozone or air.
Another object of the present invention is to provide a method for producing a nitrohalogenoacetophenone derivative capable of nitrating a halogenoacetophenone derivative in a high yield using an inexpensive catalyst.

[0006]

That is, the present invention provides an acetophenone derivative represented by the general formula (I):

[0007]

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(R ¹ , R ² and R ³ represent hydrogen or a halogen atom and may be the same, provided that at least one of them contains a halogen atom. R ⁴ represents a hydrogen atom, a halogen atom or an alkyl group. Represents a group, an amino group and an alkoxy group, n is an integer of 1 to 4, and when n is 2 to 4, R ⁴ may be the same or different.) Oxygen or air containing nitrogen oxide and ozone A method for nitrating an acetophenone derivative, which comprises using a metal and / or a compound of the metal or an inorganic acid as a catalyst in the method for nitrating.

The starting halogenoacetophenone derivative used in the present invention includes acetophenone, 2-fluoroacetophenone, 2,2-difluoroacetophenone,
2,2,2-trifluoroacetophenone, 2-chloroacetophenone, 2,2-dichloroacetophenone,
2,2,2-trichloroacetophenone, 2-bromoacetophenone, 2,2-dibromoacetophenone, 2,
2,2-tribromoacetophenone, 2'-methylacetophenone, 3'-methylacetophenone, 4'-methylacetophenone, 2'-aminoacetophenone, 3 '
-Aminoacetophenone, 4'-aminoacetophenone, 2'-fluoroacetophenone, 3'-fluoroacetophenone, 4'-fluoroacetophenone, 2'-
Chloracetophenone, 3'-Chloracetophenone,
4'-chloroacetophenone, 2'-bromoacetophenone, 3'-bromoacetophenone, 4'-bromoacetophenone, 2'-methoxyacetophenone, 3'-methoxyacetophenone, 4'-methoxyacetophenone, 2,2,2-trifluoro -2'-methylacetophenone, 2,2,2-trifluoro-3'-methylacetophenone, 2,2,2-trifluoro-4'-methylacetophenone, 2,2,2-trifluoro-2'-amino Acetophenone, 2,2,2-trifluoro-3 '
-Aminoacetophenone, 2,2,2-trifluoro-
4'-aminoacetophenone, 2,2,2-trifluoro-2'-fluoroacetophenone, 2,2,2-trifluoro-3'-fluoroacetophenone, 2,2,2
-Trifluoro-4'-fluoroacetophenone, 2,
2,2-trifluoro-2'-chloroacetophenone,
2,2,2-trifluoro-3'-chloroacetophenone, 2,2,2-trifluoro-4'-chloroacetophenone, 2,2,2-trifluoro-2'-bromoacetophenone, 2,2,2 -Trifluoro-3'-bromoacetophenone, 2,2,2-trifluoro-4'-bromoacetophenone, 2,2,2-trifluoro-2 '
-Methoxyacetophenone, 2,2,2-trifluoro-3'-methoxyacetophenone, 2,2,2-trifluoro-4'-methoxyacetophenone and the like.

As the metal used as the catalyst, transition metals such as copper, zinc, iron, cobalt, nickel, ruthenium and palladium, and metals such as tin, antimony, lead and bismuth are also used. As a catalyst, it is used as a simple metal, and a compound of the metal is also used as a catalyst. Examples of the metal compound used as a catalyst include oxides, hydroxides and salts. Examples of the metal salts include halides such as chlorides and bromides, and salts such as nitrates and sulfates. Further, a metal complex or the like may be used. These catalysts can be used alone or in admixture of two or more. In the case of complexes and salts, it is desirable to avoid those that are nitrated with nitric acid or nitrogen oxides, or organic compounds that are oxidized.

Of these metals and metal compounds, iron is preferable because it is low in cost and economical, and the reaction accelerating effect is very good. As an iron compound,
Inorganic salts such as ferrous chloride, ferric chloride, ferrous nitrate, ferric nitrate, ferrous sulfate, and ferric sulfate; organics such as iron (III) acetylacetonate and iron (III) phthalocyanine And the iron compound.

The amount of the metal and / or the compound of the metal used is 5 mol% or less with respect to the raw materials, and in the case of the iron compound, even 0.01 mol% exhibits a high catalytic effect. On the other hand, examples of the inorganic acid include sulfur trioxide, chlorosulfonic acid, fuming sulfuric acid, sulfuric acid, nitric acid, hydrogen chloride, and the like, with sulfur trioxide, chlorosulfonic acid, fuming sulfuric acid, and sulfuric acid being particularly preferable.

The amount used is 10 mol% or less with respect to the raw materials to promote the reaction sufficiently. NO for nitrogen oxides,
_{NO 2, N 2 O 3,} N 2 O 4, N 2 O 5 or the like alone or in combination can be used. The amount of the nitrogen oxide used varies slightly depending on the type of the nitrogen oxide or the mixture composition ratio thereof, but it is sufficient that the amount is 2 to 5 mole times in terms of nitrogen atom with respect to the raw material.

Ozone is obtained by passing oxygen or air through a silent discharge tube, and is used in a method of blowing the mixed gas into the reaction system. The amount of ozone used is 1 for the raw materials
~ 2 molar times is sufficient. When the starting material is solid, it is desirable to use an organic solvent. Examples of the organic solvent include those that are stable under the reaction conditions of the present invention, such as halogenated aliphatic compounds, sulfolane, acetonitrile, and aliphatic hydrocarbons.

The halogenated aliphatic compounds include methylene chloride, chloroform, carbon tetrachloride, 1,1-dichloroethane, 1,2-dichloroethane, 1,1,2-trichloroethane, 1,1,2,2-tetrachloroethane. , Pentachloroethane, 1,2-dichloropropane, 1,3
-Dichloropropane, 1,2,3-trichloropropane, 1,1,2,3-tetrachloropropane, 1,1,
3,3-tetrachloropropane, 1,1,1,2,2
3,3-heptachloropropane, 1,1,1,2,3
3,3-heptachloropropane, 1,2-dichlorobutane, 1,4-dichlorobutane and the like can be mentioned.

Examples of the aliphatic hydrocarbon include n-pentane, n-hexane, n-heptane, n-octane, cyclopentane, cyclohexane and the like. These may be used alone or in admixture of two or more, and are usually 1 to 200 times by weight, preferably 3 to 100 times by weight of the raw material. The reaction temperature is -30 ° C to 100 ° C, preferably -20 ° C to 30 ° C. The reaction time differs depending on the reaction conditions and cannot be specified, but can be determined by analyzing the reaction solution by gas chromatography, liquid chromatography or the like. The reaction may be atmospheric pressure, pressurized, batchwise or continuous. The reaction is performed as follows, for example. Oxygen or air containing nitrogen oxide and ozone is continuously blown into a reaction vessel containing raw materials, a catalyst and, if necessary, an organic solvent. In the case of this method, in order to use ozone more effectively, it is preferable to adjust the blowing composition of nitrogen oxide and ozone so that the nitrogen oxide is 2 mol or more in terms of nitrogen atom per mol of ozone. .

Alternatively, a method may be employed in which nitrogen oxides are charged in advance in a reaction vessel containing raw materials, a catalyst and, if necessary, an organic solvent, and then oxygen or air containing ozone is continuously blown. After the reaction, if necessary, the reaction solution is neutralized, and then the purity of the desired product can be efficiently increased by a usual method such as washing with water, distillation, crystallization and the like.

[0018]

The present invention will be described in more detail with reference to the following examples. The present invention is not limited to these.

Example 1 (Synthesis of 2,2,2-trifluoro-3'-nitroacetophenone (TFNA))

[0020]

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2,2,2-Trifluoroacetophenone (TFA) 5.2 g (30 mmol), N ₂ O ₄ 2.8
g (30 mmol), 1,2-dichloroethane (ED
26 g of C) and 0.02 g of FeCl ₃ were charged into a 4-neck reaction flask, and oxygen gas containing 10 mmol / h of ozone was fed at −10 ° C. for 2.5 hours. Here N ₂ O ₄ 2.
After adding 8 g (30 mmol), 10 mmol /
Oxygen gas containing h of ozone was fed in for 2 h. [Total N ₂
O ₄ 2 equivalent, O ₃ 1.5 equivalent] Here, when the reaction liquid was analyzed by gas chromatography, the raw material disappeared and an almost single peak appeared. The reaction solution was washed with water and then concentrated to obtain 6.27 g of crude crystals. When this crystal was recrystallized from a mixed solvent of n-heptane: ethyl acetate = 5: 1, 4.68 g of pure white crystal having a purity of 100% was obtained by gas chromatography.

The analysis of this crystal was as follows. MASS (m / e (%)): 219 (5), 150
(100), 104 (38), 76 (28), 50 (1
0) ¹ H-NMR (CDCl ₃ , δppm): 7.93 (1
H, t, J = 8.1), 8.47 (1H, d, J = 7.
5), 8.63 (1H, d, J = 8.3), 8.89
(1H, s) m. p. (° C) (DSC): 54.5-55.5 [Note, literature value (J. Chem. Soc. Perkin
Trans. 1 903 (1994)); 54-55.
° C] From the above, the present compound is 2,2,2-trifluoro-3 '
-It was confirmed to be nitroacetophenone (TFNA).

Then, as a result of quantifying the above-mentioned crude crystal using this pure product, it was found that the purity was 97.6%. Therefore, the yield of TFNA was 93.1%.

Example 2 0.87 g of 2,2,2-trifluoroacetophenone
(5 mmol), N₂O _Four2.3 g (25 mmol),
20 g of 1,2-dichloroethane (EDC) and FeCl
₃Charge 0.05 g into a 4-neck reaction flask, 10 mmo
Oxygen gas containing 1 / h ozone is fed at -10 ° C for 1 hour.
did. When the reaction solution is analyzed by gas chromatography,
The charge disappeared and the peak of TFNA appeared. The reaction solution is water
After washing and concentration, 1.06 g of an oily substance was obtained. this
The oily material solidified shortly at room temperature. Quantify this crystal
As a result, it was found that the TFNA purity was 96.4%.
Was. Therefore, the yield of TFNA was 93.3%.

Examples 3 to 7 and Comparative Examples 1 to 2 Tables show the results of the same operations as in Example 2 except that the reaction conditions were changed.

[0026]

[Table 1]

[0027]

EFFECTS OF THE INVENTION According to the present invention, in a method for nitrating nitrogen oxide and oxygen or ozone containing ozone, the halogenoacetophenone derivative is nitrated in high yield using an inexpensive catalyst. You can

Claims (4)

[Claims] 1. An acetophenone derivative represented by the general formula (I): (R ¹ , R ² and R ³ represent hydrogen or a halogen atom,
It may be the same. However, at least one of R ¹ , R ² and R ³ contains a halogen atom, R ⁴ represents a hydrogen atom, a halogen atom, an alkyl group, an amino group and an alkoxy group, n is an integer of 1 to 4, and n And R ⁴ are 2 to 4, R ⁴ may be the same or different. ) A method for nitrating an acetophenone derivative, characterized by using a metal and / or a compound of the metal or an inorganic acid as a catalyst in a method for nitrating by reacting nitrogen oxides with oxygen or air containing ozone. . 2. The method for nitrating an acetophenone derivative according to claim 1, wherein the metal is at least one metal selected from transition metals, tin, antimony, lead and bismuth. 3. The method for nitrating an acetophenone derivative according to claim 1, wherein the metal is iron. 4. The method for nitrating an acetophenone derivative according to claim 1, wherein the inorganic acid is sulfuric acid and / or sulfur trioxide.