JPS5811415B2 - Method for producing substituted acetophenone - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing a known substituted acetophenone represented by the following general formula I.

(In the formula, R represents a para-lower alkoxy group or an ortho-substituted anilino group (the substituent is a halogen group)) The substituted acetophenone represented by the general formula I is one of a series of known phenylacetic acid derivatives that are important as anti-inflammatory and analgesic agents. Precursor ['Compt'es RenclusHe'
b'doma'dair'es de's' 5ea
nc'es"deL'academie des
5sciences, 261°22'59 (1965)
].

- Conventionally, substituted acetophenones represented by general formula I have been synthesized as follows.

(4) Method of using phenol and alkyloxybenzene as precursors Friedelkraff reaction (wherein R has the same meaning as above) (2) Method of using benzoic acid derivatives as precursors (a) ) [In the formula, R represents a Grignard reagent or methyllithium; R has the same meaning as above; R′ represents a lower alkyl group] (In the formula, R has the same meaning as above) However, these In the case of (1), the position of the substituent cannot be selected in the reaction, resulting in a mixture of compounds substituted at different positions, which is extremely difficult to separate.

(2) In the case of (a), if a Grignard reagent is used, a tertiary alcohol will be produced as a by-product in addition to the target compound, and if methyllithium is used, it must be kept at a low temperature because of its high reactivity. A product is formed.

In addition, the raw materials are expensive and there are other problems such as being uneconomical.

(2) In the case of (b), a method of treatment with aluminum amalgam (Journal of the Ame
ricanChemical 5ociety 8
6,1639 (1964) and 87.1345 (196
5)] uses a mercury alloy, so pollution prevention measures must be taken in case of commercial production.
he American Chemical 5ocie
ty 88, 5498 (1966)) is not suitable for compounds that are sensitive to acids, and on the other hand, it has problems such as the possibility that rearrangement products of the target compound may be produced as by-products under severe conditions such as high temperatures.

The present invention provides a method that does not have the drawbacks of the prior art, and the method of the present invention provides a method for preparing a β-ketosulfo compound represented by the general formula side in a two-phase solvent,
It consists of obtaining a substituted acetophenone of the general formula I: (wherein R has the same meaning as above) in a high yield by reacting it with aluminum under alkaline conditions.

When the substituent R is a para-lower alkoxy group, the β-ketosulfoxide represented by the general formula
m, Soc, 86.1639 (1964).

One set, 1345 (1965), 88, 5498 (196
It is synthesized by the same method as described in 6).

On the other hand, when the substituent R is an ortho-substituted anilino group,
In the above method, the general formula ■: (wherein, R is a substituted anilino group (the substituent is a halogen group),
It is produced by reacting a substituted benzoic acid ester represented by (R' represents a lower alkyl group) with dimsyl sodium (CH3SOCH2Na).

Dimcil sodium is prepared by heating sodium hydride together with dry dimethyl sulfoxide at 60°C to 70°C under a nitrogen stream.
It may be formed on the spot by heating with C until the bubbling of hydrogen gas subsides.

In the present invention, "alkaline conditions" refers to the pH of the reaction mixture being 7 to 14, and preferably the alkali concentration of the aqueous layer of the reaction system is 2N or more.

Alkali that can be added to the reaction system to achieve this condition are alkali metal hydroxides, such as sodium hydroxide and potassium hydroxide.

Aluminum is required in an amount of 1 gram atom or more, preferably 2 gram atom or more per mole of β-ketosulfoxide.

Further, it may be in any form such as powder, granule, or cocoon, but powder is preferable.

In the invention filed in Japanese Patent Application No. 53-133950, a similar reaction proceeds using zinc or tin in place of aluminum.

In this case, β-
There is an advantage that substituted acetophenone (I) can be synthesized by generating ketosulfoxide (II)' and reacting with zinc or tin without isolating it.

In the case of the present invention, it is necessary to once extract and separate β-ketosulfoxide (1) and then apply the action of aluminum to Ramura. (1) Aluminum is cheaper than zinc and tin; (2) ) Aluminum has a smaller atomic weight than zinc and tin, so it only needs a small amount; (3) While zinc is divalent when it becomes an ion,
Since aluminum is trivalent, if equimolar amounts of both are used, the amount of β-ketosulfoxide (■) reduced is greater when aluminum is used; Since the reaction activity is higher than that of aluminum, the reaction proceeds more quickly and the reaction time can be shortened by using aluminum; this is an advantage.

The method of the invention is carried out in a biphasic solvent.

Here, the term "two-phase solvent" refers to a mixed solvent of water and an organic solvent (eg, benzene) that dissolves the reaction product and is immiscible with water.

The capacity ratio between the former and the latter is not an absolute condition, but the former is 1~
5 and 6, it is preferable to use the latter 1.

The product, the substituted acetophenone represented by the above general formula I, is soluble in organic solvents but not in water.

On the other hand, the opposite is true for β-ctosulfoxide anion, which is a reaction intermediate, so the reaction takes place only in the aqueous layer, and once the reaction is completed, the product moves to the organic layer, so the reaction does not proceed any further. Therefore, there is no concern that by-products will be produced.

Post-treatment consists only of separating the aqueous and organic layers and removing the solvent from the organic layer.

Therein lies the advantage of using a biphasic solvent in carrying out the method of the invention.

Also, for this reason, the amount of organic solvent should theoretically be sufficient to dissolve the substituted acetophenone produced.

However, in reality, it is preferable to use 5.01 or more per mole of substituted acetophenone produced.

Generally, a mixture of an aqueous alkaline solution and the organic solvent, such as benzene, is often emulsified by vigorous stirring or shaking, but in the method of the present invention, such an emulsification phenomenon does not occur because a metal salt is present in the reaction system. No.

This is another advantage of the invention. The process of the invention can be carried out at ambient temperature, but may also be carried out at reflux temperature to reduce reaction time.

The reaction time is about 10 minutes to 5 hours depending on the reaction temperature and the type of reactants.

The pressure is normal pressure. Isolation and purification of the product can be achieved by conventional methods.

For example, the reaction mixture may be distilled under reduced pressure and then recrystallized from ethanol.

The method for producing the starting materials used in the present invention is illustrated by the following production examples.

Production example l Para-n-butoxy-ω-(methylsulfinyl)-acetophenone 60% After thoroughly washing 2.10 g of oily sodium hydride with petroleum ether, 17 ml of dry dimethyl sulfoxide was added and the mixture was heated under a nitrogen stream. 60-70 while stirring
Heated at ℃.

Heating was continued until the bubbling of hydrogen gas subsided.

It took 1.5 hours. Next, a solution of 4.40 g of ethyl para-n-butoxybenzoate in dimethyl sulfoxide (10 ml) was added dropwise under water cooling, and the mixture was stirred at ambient temperature for 1 hour.

By distillation under reduced pressure, 5.00 g of para-n-butoxy-ω-(methylsulfinyl)-acetophenone was obtained (yield: 99.
3%).

m, p, 74°C. Production Example 2 Para-methoxy-ω-(methylsulfinyl)-acetophenone Para-methoxy-ω was prepared by using the method of Example 1 but using methyl para-methoxybenzoate instead of ethyl para-n-butoxybenzoate. -(methylsulfinyl)-
4.10 g (yield 97.3%) of acetophenone was obtained.

m, p, to: 3-103.5°C. Production Example 3 o-(2,6-dichloroanilino)-ω-(methylsulfinyl)-acetophenone After thoroughly washing 3.68 g of 63% oily sodium hydride with petroleum ether, 50 ml of dry dimethyl sulfoxide was added. 60-7 while stirring under a nitrogen stream.
Heated at 0°C.

Heating was continued until the foaming subsided.

It took 1.5 hours. Next, 20 mL of tetrahydrofuran was added, and a solution of 8.00 g of methyl N-(2,6-dichlorophenyl)-anthranilate in tetrahydrofuran (20 ml) was added dropwise under water cooling, followed by stirring at ambient temperature for 1 hour.

After adding 800ml of water under water cooling, add hydrochloric acid to adjust the pH.
I gave it around 3.

After extraction with 400ml of ethyl acetate three times and drying with anhydrous sodium sulfate, the solvent was distilled off to obtain o-(2,
6-dichloroanilino)-ω-(methylsulfinyl)
- 9.20 g (yield 99.5%) of acetophenone was obtained.

m, p, l l 4-115°c.

Hereinafter, the present invention will be explained in more detail with reference to the following examples.

Example l Para-methoxyacetophenone 0.500 g of para-methoxy-ω-(methylsulfinyl)-acetophenone and 0.110 g of aluminum powder are mixed well, then 12 m of benzene is added, and 8.75N sodium hydroxide is added while stirring well. Aqueous solution 6- was added dropwise.

After dropping, the mixture was heated in a 60°C water bath for 10 minutes.

Thereafter, the separated organic layer was washed with water and dried over anhydrous magnesium sulfate.

Then, the solvent was distilled off and recrystallized from ethanol to obtain 0.340 g of para-methoxyacetophenone (yield: 96.1
%) was obtained.

m, p, 34.5-36.5°C.

Example 2 Para-n-butoxyacetophenone 0.500 g of para-n-butoxy-ω-(methylsulfinyl)-acetophenone and 0.112 g of aluminum powder
Mix well, then add 10ml of benzene,
While stirring well, add 5 m of 5N aqueous sodium hydroxide solution.
1 was added dropwise.

After the addition, the mixture was stirred at ambient temperature for about 0.5 hours and heated to reflux for an additional 4 hours.

Thereafter, the dispersed organic layer was washed with water and dried over anhydrous sodium sulfate.

Then, the solvent was distilled off to obtain 0.356 g (yield: 94.2%) of para-n-butoxyacetophenone.

b, p, 179-180°C/25 mHg.

Example 3 2-(2,6-dichloroanilino)-acetophenone Mix 0.841 g of 2-(2,6-dichloroanilino)-ω-methyl-acylinyl-acetophenone and 0.330 g of aluminum powder thoroughly. , then benzene 15-
was added, and 3.3N aqueous sodium hydroxide solution 16- was added dropwise while stirring well.

After the addition, the mixture was heated under reflux for 5 hours.

Thereafter, the separated organic layer was washed with water and dried over anhydrous magnesium sulfate.

Then, the solvent was distilled off and recrystallized from ethanol to obtain 2-
(2,6-dichloroanilino)-acetophenone 0.6
30S' (yield 91.7%) was obtained.

Claims (1)

[Scope of Claims] 1 A method for producing a substituted acetophenone represented by the general formula I [wherein R represents a para-lower alkoxy group or an ortho-substituted anilino group (the substituent is a halogen group]) (wherein R has the same meaning as above) The reaction product of β-ketosulfoxide is dissolved in a mixed solvent of water and an organic solvent that is immiscible with water,
A method characterized by reacting with aluminum under alkaline conditions.