JPS5935899B2 - Alpha (4-isobutylphenyl) propionate - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing tetra-isobutylstyrene, a new compound not described in the literature.

The present invention uses α-(4-isobutylphenyl), which is known as a beneficial compound with anti-inflammatory, analgesic and antipyretic properties.
4 as a useful intermediate for the synthesis of propionic acid
isobutylstyrene. The method for producing 4-part isobutylstyrene according to the present invention involves dehydrating or dehydrohalogenating a compound represented by the following general formula (in the formula, one of X and Y represents a hydrogen atom and the other represents a hydroxyl group or a halogen atom). This is a characteristic feature.

The method of the present invention is expressed as a reaction formula as follows.

[In the formula, X and Y represent the same meanings as above.

] The compounds represented by the general formula (I) which are the starting materials of the present invention include α-(4-isobutylphenyl)ethyl alcohol, β-(4-isobutylphenyl)ethyl alcohol, α-(4-isobutylphenyl)ethyl alcohol, and α-(4-isobutylphenyl)ethyl alcohol. (enyl)ethyl halide and β-(4-isobutylphenyl)ethyl halide, and the halogen atoms of X and Y are chlorine, bromine, and iodine. These compounds represented by the general formula (1) can be easily produced in the same manner as general methods for producing aralkyl alcohols and aralkyl halides.

That is, α-(4-isobutylphenyl)ethyl alcohol can be converted to β-(4-isobutylphenyl) by, for example, reduction of 4-isobutylacetophenone or reaction of 4-isobutylphenylmagnesium bromide with valaldehyde. For example, ethyl alcohol can be produced by reduction of 4-isobutylphenyl acetic acid or its ester.
It is produced by the reaction of 4-isobutylbenzyl alcohol, generalized carbon, and hydrogen, or by the reaction of 4-isobutylbenzene and ethylene oxide. α- or β-(4-isobutylphenyl)ethyl halide can be obtained by halogenating the corresponding alcohol with a halogenating agent, or by reacting 4-isobutylbenzene, paraaldehyde, and hydrogen chloride gas in the presence of zinc. Manufactured. 4-isobutylstyrene () by dehydration or dehydrohalogenation of the compound of general formula (1)
can be obtained in accordance with known methods for dehydration of allyl ethyl alcohol and dehydrohalogenation of allyl ethyl halide.

The method will be specifically explained below.

1) α- or β-(4-isobutylphenyl)
A method for obtaining 4-isobutylstyrene from ethyl alcohol.

a) A method in which the alcohol is heated in the liquid phase in dimethyl sulfoxide in the presence of a polymerization inhibitor.

1 mole of alcohol, 1 mole of dimethyl sulfoxide
~20 moles, preferably 3 to 10 moles, and the polymerization inhibitor is present in an amount of 0.1 to 30% by weight, preferably 1 to 15% by weight of the alcohol, at 100 to 250°C, preferably 130 to 190°C. Heat.

Examples of polymerization inhibitors used include hydroquinone,
Examples include m-dinitrobenzene, N-nitrosodiphenylamine, picric acid, and sodium sulfite.

b) Method of heating the alcohol under reduced pressure in the presence of a polymerization inhibitor and a sulfuric acid compound As the sulfuric acid compound, sodium hydrogensulfate, potassium hydrogensulfate, potassium pyrosulfate, etc. are used.

As the polymerization inhibitor, the same one as mentioned in the method a) is used.

In the reaction, the amount of sulfuric acid compound is 0.0% by weight relative to the alcohol.
1-10%, preferably 0.1-5% and a polymerization inhibitor 0.1-30%, preferably 1-15% are added.
100-280°C, preferably 175-250°C under reduced pressure of 600mmHg, preferably 20-400w&MHg
Heat to .

c) Method of bringing the alcohol into contact with activated alumina or caustic alkali and heating under reduced pressure A layer of activated alumina or caustic alkali, such as sodium hydroxide or potassium hydroxide, is heated, and the alcohol is passed therethrough under reduced pressure.

In the case of activated alumina, the temperature is 200 to 400°C under a reduced pressure of 10 to 600 mmHg, preferably 20 to 400 iKmHg.
, preferably at 250 to 350°C. In the case of a caustic alkali, it is appropriate to heat it to 100 to 250°C, preferably 120 to 200°C under a reduced pressure of 2 to 200 mwLHg, preferably 5 to 100 nHg.
). ) A method for obtaining 4-isobutylstyrene from α- or β-(4-isobutylphenyl)ethyl halide.

a) Method of heating the halide in a base Examples of the base used include pyridine, quinoline,
Examples include organic bases such as piperidine, piperazine, aniline, and N,N-dimethylaniline, and inorganic bases such as sodium hydroxide and potassium hydroxide.

The reaction was carried out with a concentration of 1 mole of the halide and a base of 0.8 to 1 mole.
Add 30 moles, preferably 1 to 15 moles, and add 40 to 260 moles.
℃, preferably 60-220℃.

b) A method in which the halide is brought into contact with an amine hydrochloride and heated under reduced pressure.The amine hydrochloride used is secondary and tertiary.
A hydrochloride of an amine, such as diamylamine hydrochloride,
Examples include triamylamine hydrochloride, dihexylamine hydrochloride, trihexylamine hydrochloride, and the like.

The reaction is carried out under reduced pressure of 20 to 760 mmHg, preferably 50 to 200 mHg, and 150 to 300 mHg.
It is carried out in the gas phase by passing the amine hydrochloride in the molten state heated to 170-270°C.

The dehydration or dehydrohalogenation reaction of the present invention proceeds quantitatively, and there are few by-products.The product 4-isobutylstyrene is a stable compound, so purification by simple distillation is sufficient to produce 4-isobutylstyrene of high purity. Styrene can be obtained.

4-isobutylstyrene, which is the object of the method of the present invention, can be carbonylated to form α-(4-isobutylphenyl)propionic acid, which is useful as an anti-inflammatory agent, and its precursor α-(4-isobutylphenyl). ) Propionate ester can be easily synthesized.

The carbonylation reaction can be carried out according to a known carbonylation method in which an olefin-based unsaturated compound is reacted with alcohol or water and carbon monoxide in the presence of a palladium catalyst. The carbonylation reaction, which is carried out using highly pure 4-isobutylstyrene obtained by the method of the present invention, proceeds quantitatively. Enyl) propionic acid has the advantage of being available in extremely high purity.

As a method for synthesizing α-(4-isobutylphenyl)propionic acid, for example, 4-isobutylphenyl acetate, 2-hydroxy-3-(4-alkylphenyl)-3-butenoic acid or 3-methyl-3
Method using -(4-alkylphenyl)glycidylic acid ester as a starting material (Japanese Patent Publication No. 40-7491, JP-A No. 49-95931, 49-95937, 49-9
No. 5938) is known as a typical example, but these starting materials themselves are not easy to synthesize and have to go through complicated intermediate products.

Method using 4-isobutylacetophenone as a starting material (
In Japanese Patent Publications No. 47-18105, No. 47-24550 and Japanese Patent Publication No. 49-108040), the intermediate products are complex compounds and the operations are complicated.

Method using isobutylbenzene as a starting material
-133351 and 50-4040● have an oxidation process, so there is a risk of producing by-products such as incomplete oxides that are not completely oxidized to acid, or excessively oxidized oxides, However, it is still difficult to say that it is sufficient. Method using Grignard reagent as intermediate product (Japanese Patent Application Laid-Open No. 49-39050)
However, this Grignard reagent is unstable, difficult to operate, and expensive.

On the other hand, 4-isobutylstyrene, a new compound obtained by the method of the present invention, is obtained using inexpensive raw materials, is a simple and easy-to-manipulate compound, and has a good effect on α-(4
-isobutylphenyl)propionic acid can be produced, so it has extremely great industrial significance. Next, examples of the method of the present invention will be shown, but the present invention is not limited thereto.

Example 1 α-(4-isobutylphenyl)ethyl alcohol 6θ, dimethyl sulfoxide 121 and m-dinitrobenzene 0.1 as a polymerization inhibitor. ! Add 9 and heat 8 at 160℃
Stir for hours.

The reaction solution was cooled, diluted with water, and extracted with benzene. After drying the obtained organic layer with magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was distilled to obtain 4-isobutylstyrene 4.2f1 having the following physical properties. Reference Example 1 1) 4-isobutylstyrene 4.2y) Ethyl alcohol 40'', bistriphenylphosphine dichloropalladium 0.2f1 and Ξ boron fluoride ether complex 0.2
f1 was placed in an autoclave with an internal volume of 100 kg, carbon monoxide was pressurized at 80 kg/unit, and the reaction was carried out at 70° C. until no absorption of carbon monoxide was observed.

After cooling, the reaction solution was washed with an aqueous calcium chloride solution, the ester layer was dried over magnesium sulfate, and then distilled to reduce the boiling point to 10.
2~104℃/0.8? ! α-(4-
isobutylphenyl) propionic acid ethyl ester 4
．． Obtained 8θ. (2) α-(4-isobutylphenyl)propionic acid ethyl ester 4.89 in 30% NaO
20" of H aqueous solution was added and refluxed for 2 hours.

After cooling, insoluble materials were removed by extraction with ether, and the aqueous layer was acidified with hydrochloric acid and extracted with ether. After washing the ether layer with water and drying with magnesium sulfate, the ether was distilled off under reduced pressure, and the obtained crude crystals were recrystallized from n-hexane to give α-(4
-isobutylphenyl)propionic acid 3.5f1 was obtained. Melting point 75-76°C Example 2 80 mj of pyridine was added to α-(4-isobutylphenyl)ethyl chloride 209 and heated at 115°C for 6 hours.

The product was poured into 130g of concentrated hydrochloric acid and 370g of ice, and extracted with chloroform. After drying the chloroform solution with magnesium sulfate, chloroform was distilled off and further distilled to obtain 11.7 fl of 4-isobutylstyrene.

Reference example 2 (1) 4-isobutylstyrene 10 obtained in Example 2
θ, 12" of 10% hydrogen chloride methyl alcohol solution and 0.29" of bisdichlorotriphenylphosphine palladium were placed in an autoclave with an internal volume of 100 g, and carbon monoxide was pressurized at 300 kg/C7il when cold, and heated to 90°C. After reaching this amount, carbon monoxide was further pressurized to 700 kg/Crll, and the reaction was continued until no absorption of carbon monoxide was observed.

After cooling, the reaction solution was washed with an aqueous calcium chloride solution, extracted with ether, and the ether layer was dried over magnesium sulfate, followed by distillation to obtain α-(4-isobutynolephenylene)propionic acid methyl ester with a boiling point of 99-10 rC/1 nHg. I got .7f1. (2) 9.7y of α-(4-isobutylphenyl)propionate methyl ester in 30%N
40 g of aOH aqueous solution was added and refluxed for 2 hours. After cooling, insoluble matter was removed by extraction with ether, and the aqueous layer was diluted with hydrochloric acid and extracted with ether.

Claims (1)

[Claims] 1 A compound represented by the following general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, one of X and Y represents a hydrogen atom and the other represents a hydroxyl group or a halogen atom) by dehydration or A method for producing 4-isobutylstyrene, which comprises hydrogen halogenation.