JPH0161093B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing an arylacetone derivative represented by the general formula Ar--CH ₂ COCH ₃ ( ), where Ar is a substituted or unsubstituted aromatic group. The arylacetone derivatives represented by the above formula are 2-amino-1-arylpropanol compounds, which are sympathomimetic agents such as efuedrine, and 6-, which is an anticoagulant agent.
It is a substance used as an important intermediate in the production of pharmaceuticals such as aryl-2,3,5-trioxotetrahydropyrans. The present inventors previously succeeded in developing a method for producing 2-arylpropionic acid, which is highly useful as a prophene-based anti-inflammatory analgesic agent, from the compound of the above formula through only two steps (especially Gansho 54-173200),
The present invention further provides an advantageous method for preparing the starting intermediates of the above formula.

The present invention will be explained in detail below.

Up to now, methods for producing the arylacetone derivative of the above formula include 1) reacting an arylacetic acid derivative with acetic acid or acetic anhydride [Org.
Syn. 16 , 47 (1936); U.S. Patent No. 266771 (1954)], 2)
Reacting an arylacetic acid derivative with a metal methyl compound [J.Org.Chem., 15 , 359 (1950)], 3) Dalzens reaction between benzaldehyde and 2-bromopropionic acid ester [German patent]
752328 (1950)] and 4) treating allylbenzene with palladium chloride [US Pat. No. 3,080,425 (1963)], but these methods generally have low yields and require harsh reaction conditions. , It is difficult to separate and purify the target substance due to many by-products.
This method has many disadvantages as an industrial method, such as the need to use expensive reagents and the difficulty in obtaining raw materials, in which case the raw materials themselves must be manufactured.

The present inventors have conducted various studies on the industrial production method of the substance of formula (), and as a result, the general formula: Ar--X () (wherein, Ar has the same meaning as above, and X means halogen). ) A 3-arylacetylacetone derivative represented by the general formula Ar-CH(COCH ₃ ) ₂ () (wherein Ar has the same meaning as above) is obtained by reacting acetylacetone with a halogenated aryl derivative represented by We have succeeded in developing a method for efficiently producing the desired arylacetone derivative of the above formula by producing and then isolating or deacetylating it without isolation.
Therefore, the present invention provides a novel industrial method for producing the arylacetone derivative of the above formula.

According to the method of the present invention, the above-mentioned two-step reaction can be carried out in the same reaction vessel, so it is actually extremely useful industrially in that the compound of the formula can be produced in what can be called a one-step operation. It is a manufacturing method.

Next, the present invention will be explained in detail.

As mentioned above, in the method of the present invention, the compound of the formula is produced by reacting the halogenated aryl derivative of the formula with acetylacetone, and this reaction is carried out in the presence of cuprous halide and a base. In this reaction, the cuprous halide used is, for example, cuprous chloride, cuprous bromide or cuprous iodide, and the base is, for example, potassium carbonate, sodium carbonate, sodium hydride, Potassium etc. are used. Examples of solvents used include acetonitrile, tetrahydrofuran, dioxane, benzene, toluene, dimethylformamide, and hexamethylphosphoric triamide, among which aprotic polar solvents such as dimethylformamide and hexamethylphosphoric triamide are used. is a preferred solvent. It is more preferable that the acetylacetone used in this reaction is prepared separately in advance as a salt such as its sodium salt or potassium salt before use. It was confirmed that the above reaction hardly proceeds in the absence of the cuprous halide mentioned above. Therefore, the presence of cuprous halide is essential in this reaction.

This reaction can be carried out usually by stirring at a temperature of 150°C or lower, preferably 80° to 120°C, for about 1 hour to 30 hours. When stirring for a long time, some deacetylation reaction occurs in the generated compound of formula (), but in any case, this is not a problem as it will be subjected to the next deacetylation reaction. .

The 3-arylacetylacetone derivative () thus obtained can be subjected to the next deacetylation reaction in the same reaction vessel without the need for isolation. That is, the deacetylation reaction is carried out by adding water in an amount equal to or more than the number of moles of the compound of the formula to the above reaction mixture and stirring;
Alternatively, the deacetylation reaction can be carried out simultaneously with the extraction by adding water and a suitable solvent that is immiscible with water.

In either case, the target product can be produced easily, rapidly, and quantitatively without requiring any special heat treatment. This deacetylation reaction is carried out under alkaline conditions, but since the reaction conditions for producing the compound of the formula also satisfy the conditions for the next deacetylation reaction, it is particularly suitable for alkaline conditions. There is no need to add substances. However, it may be added if desired.

As mentioned above, in the method of the present invention, the deacetylation reaction can be carried out simultaneously with the extraction operation, so that the production of the arylacetone derivative of the formula from the halogenated aryl derivative of the formula can actually be done in one step. This can be done by

The method of the present invention has extremely high industrial utility, as the reaction and isolation operations are simple, and the reagents used are inexpensive.

Examples of the present invention will be specifically described below, but the present invention is not limited to these Examples.

Example 1 Production of p-tolylacetone 1.00 g (0.005 mol) of p-bromotoluene was dissolved in 10 ml of dimethylformamide, and 3.05 g (0.025 mol) of sodium salt of acetylacetone was added to this solution at 100°C in a nitrogen stream while stirring. Add. Next, 0.95 g (0.005 mol) of cuprous iodide is added to this and stirred for 23 hours. Add 5 ml of water to the reaction mixture and stir, then add 10 ml of 10% aqueous ammonia and extract twice with 20 ml of benzene. This benzene layer was washed three times with 10 ml of water, dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain a dark brown oil. When this substance is purified by distillation, the boiling point
0.55 g (yield 74.7%) of the title compound was obtained as a colorless oil exhibiting a temperature of 123.0-124.0° (20 mmHg).

IR ν ^liq

Claims (1)

[Claims] 1. A halogenated aryl derivative represented by the general formula Ar-X () (wherein Ar is a substituted or unsubstituted aromatic group and X means a halogen atom) and acetylacetone and react in the presence of cuprous halide,
It is characterized by producing a 3-arylacetylacetone derivative represented by the general formula Ar--CH(COCH ₃ ) ₂ () (wherein Ar has the same meaning as above), and then deacetylating it. A method for producing an arylacetone derivative represented by the general formula Ar--CH ₂ COCH ₃ (in the formula, Ar has the same meaning as above).