JPH0757738B2 - Method for producing 4-isobutylstyrene - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial application] The present invention relates to a method for producing 4-isobutylstyrene. More specifically, the novel compound 1,2-di (4-
Α-, which is useful as a drug having antipyretic, analgesic and anti-inflammatory effects, from isobutylphenyl) ethylene and ethylene
The present invention relates to a method for producing 4-isobutylstyrene, which is an intermediate for efficiently producing (4-isobutylphenyl) propionic acid (trade name: ibuprofen).

[Prior Art and Problems Thereof] α- (4-isobutylphenyl) propionic acid is an excellent drug because it has excellent antipyretic, analgesic and anti-inflammatory effects, and further has few side effects. For this reason, it has been conventionally proposed to synthesize by various methods. As one of them, 4
-A method of producing from isobutylstyrene by a hydroformylation reaction or a Reppe reaction is proposed. Specific examples of these include, for example, British Patent No.
1565235 and JP-A-52-97930 are proposed.

In the method using 4-isobutylstyrene, 4-isobutylstyrene is a simple and stable substance, and α- (4-isobutylstyrene is used by utilizing a reaction that does not use an expensive reagent such as a hydroformylation reaction or a Reppe reaction. Phenyl)
This is an economically superior method because propionic acid can be produced.

However, conventional methods for producing 4-isobutylstyrene either use expensive and unstable reagents such as Grineer's reagent, or expensive starting materials such as p-isobutylacetophenone, as described in the above references. Are using. Therefore, an inexpensive method for producing 4-isobutylstyrene has been desired.

Also, as a method for producing alkyl styrene,
A method for producing 1,1-diarylethane by catalytic decomposition has been conventionally proposed, for example, Industrial and Engineering Chemistry, Vol. 46, No. 4,652 (1954) Journal of Chemical and Engineering Data, Vol. 9, No.1,104 (1964) I & EC Product Research and Development, Vol.3, No.
In the literature such as 1,16 (1964), 1,1 for the purpose of producing methylstyrene, dimethylstyrene, ethylstyrene, isopropylstyrene, and t-butylstyrene as alkylstyrene.
A method for decomposing 1,1-diarylethanes such as -ditolylethane, 1,1-dixylylethane is described. Efforts to industrialize the production of alkylstyrene by decomposition have been continued.

However, when 1,1-diisobutylphenylethane is decomposed using this decomposition method, theoretically equimolar isobutylbenzene is unavoidably produced as a by-product at the same time as the production of the target 4-isobutylstyrene. Therefore, it was necessary to recover the by-produced isobutylbenzene and convert it into a decomposition raw material again.

Against this decomposition method, U.S. Pat.No. 3965206, U.S. Pat.No. 4419526, U.S. Pat.No. 4419527, U.S. Pat.No. 4439627, U.S. Pat.No. 4439628, U.S. Pat. A method for producing styrene by disproportionation is disclosed. However, there is no specific description about 4-isobutylstyrene.

The method of the present invention is a novel compound not described in the literature 1,2-
The use of di (4-isobutylphenyl) ethylene made it possible for the first time to produce 4-isobutylstyrene efficiently and economically.

[Means for Solving the Problem] That is, the present invention is directed to 1,2-di (4-
Isobutylphenyl) ethylene and ethylene are brought into contact with a disproportionation catalyst containing a metal selected from rhenium, tungsten and vanadium, and a method for producing 4-isobutylstyrene. The present invention provides a method for efficiently and economically producing α- (4-isobutylphenyl) propionic acid useful as a pharmaceutical.

The 1,2-di (4-isobutylphenyl) ethylene used in the method of the present invention can be specifically produced by the following method.

That is, isobutylbenzene is converted to di (p-isobutylphenyl) iodonium salt represented by the following formula (II) in concentrated sulfuric acid with potassium periodate and reacted with ethylene in the presence of a palladium catalyst. 1,2-
It can be di (4-isobutylphenyl) ethylene.

(In the formula, X ⁻ represents a counter ion inert to the reaction.) The above-mentioned halogen salt of di (p-isobutylphenyl) iodonium salt is described in JP-A-53-101331 and JP-B-57-53767.
No. 1, British Patent No. 1114950, and the like, and
It can be produced by the method described in J. Amer. Chem. Soc., Vol. 81, 342 (1959). That is, isobutylbenzene and potassium periodate are mixed by stirring in acetic anhydride, then a mixture of acetic anhydride and concentrated sulfuric acid is added dropwise, and then a saturated ammonium chloride aqueous solution is added to precipitate a precipitate, followed by filtration, By recrystallization, a hydrochloride of di (p-isobutylphenyl) iodonium salt is obtained. The formula of the reaction is as follows.

(Wherein R represents an aryl group) The counter ion of Cl ^{− in} the above formula can be mutually ion-exchanged with any anion such as a metal halide anion, but a more preferable counter ion is It is a halogen ion such as chlorine ion or bromine ion.

The other substance reacted with the di (p-isobutylphenyl) iodonium salt is ethylene. This reaction is
This can be achieved by using a transition metal such as palladium as a catalyst in a solvent and introducing ethylene gas in the presence of a basic substance such as potassium acetate. The reaction is described below by equation.

(Here, R represents an aryl group) The amount of the base used may be an amount that neutralizes the acid generated from the counter ion of the reacting di (p-isobutylphenyl) iodonium salt. Therefore, when the amount used is less than the stoichiometric amount, the yield of the target 1,2-di (4-isobutylphenyl) ethylene only decreases. Therefore, the amount can be appropriately selected. As the base that can be used, any base can be used as long as it is soluble in the solvent used. Specifically, tertiary alkylamines such as triethylamine, tripropylamine, tributylamine, dimethylaniline and diethylaniline, alkali metal salts of lower fatty acids such as sodium acetate, potassium acetate and sodium formate, alkalis such as sodium and potassium. Examples include metal carbonates or bicarbonates.

The catalyst used for the reaction with ethylene is VIII in the periodic table.
Group metal transition metal catalysts, such as palladium,
Rhodium, ruthenium, platinum, iridium, osmium, etc. are preferable, and a palladium catalyst is particularly preferable. These transition metal catalysts can be used as catalysts in various forms. That is, it can be used regardless of its oxidation number or complex. Taking palladium as an example, palladium supported on alumina or activated carbon, palladium halides such as palladium chloride, divalent palladium such as palladium oxide and palladium salts of lower fatty acids such as palladium acetate, and other bis (dibenzylideneacetone)
Complexes such as palladium can also be used. For rhodium, a carbonyl complex can also be used.

As the solvent to be used, any solvent can be used as long as it is an organic solvent which dissolves the di (p-isobutylphenyl) iodonium salt in any amount and does not participate in the reaction. For example, in addition to lower alcohols such as methanol and ethanol, ketones such as acetone and methyl ethyl ketone, ethers such as dimethoxyethane and dioxane, various polar solvents such as dimethylformamide, dimethylsulfoxide, acetonitrile and tetrahydrofuran can be appropriately selected. When the base used can also serve as a solvent, it is not necessary to use a solvent.

A reaction time of 0.5 to 10 hours is usually sufficient.

After completion of the reaction, wash the reaction mixture thoroughly with water and cool the reaction mixture
Crystals of 2-di (4-isobutylphenyl) ethylene are deposited. The precipitated crystals are filtered and recrystallized from methanol to obtain 1,2-di (4-isobutylphenyl) ethylene.

The method using the above-mentioned di (p-isobutylphenyl) iodonium salt is a preferable method because the para-position compound has good selectivity.

By reacting 1,2-di (4-isobutylphenyl) ethylene thus obtained with ethylene in the presence of a disproportionation catalyst consisting of a catalyst containing a metal such as rhenium, molybdenum or tungsten, 4 -Isobutylstyrene can be easily obtained. In the disproportionation reaction of the present invention, 1,2-di (4-isobutylphenyl) ethylene in either trans form or cis form can be used. This disproportionation reaction is also called metathesis.

Such a disproportionation catalyst is a catalyst composed of a metal oxide such as rhenium, molybdenum, or tungsten, a metal sulfide, or a mixture thereof. These can be used alone, but as a cocatalyst or a third additive component, rhodium, vanadium, alumina, titanium, manganese, niobium, iridium, tellurium, a metal such as an alkali metal or a mixture thereof, a mixture with a sulfide, Further, an organic metal such as aluminum or tin such as alkylaluminum, hydrogen, carbon monoxide, ammonia, or the like may be used.

These catalysts can be used by supporting them on an appropriate oxide carrier. For example, silica, alumina, silica - addition such as _{alumina, TiO 2, ThO 2, MgO} 2, ZrO 2, TaO 2, Nb
A carrier such as ₂ O ₅ , SnO ₂ or a phosphate of a metal such as Al, Mg, Ca, Zr or Ta is used.

Specific examples of the main catalyst for disproportionation include WO ₃ , MoO ₃ , Re ₂ O _{7 and the} like, as well as ReO ₃ , MoO ₂ , MoS ₃ , WS ₂ and Re ₂ S ₇ .

The disproportionation catalyst is prepared by a known method. For example, it is prepared by impregnating an oxide carrier with an aqueous solution of a metal salt and then calcining. A catalyst obtained by immobilizing the above-mentioned metal carbonyl complex, alkyl complex or the like on an oxide carrier by an appropriate method and then calcining can also be used.

The reaction form is not particularly limited, and may be a liquid phase or a gas phase. The reaction temperature depends strongly on the catalyst. For example,
If a catalyst showing high activity at low temperature such as rhenium oxide is used,
0-100 ° C is sufficient, and 3 for other low activity catalysts.
Can be used at 00-600 ℃. When disproportionated at a low temperature, side reactions such as isomerization and polymerization are difficult to occur, so that it exhibits high selectivity. Considering economical efficiency, a highly active disproportionation catalyst such as Re It is preferable to carry out the liquid phase reaction at a low temperature of 100 ° C. or lower using a system catalyst. The reaction pressure is 1 to 100k.
It can be applied up to g / cm ^2, but 1-10 kg / cm ² is usually sufficient.

Further, even if helium, nitrogen or other inert gas and hydrocarbons such as benzene and hexane which are inert to the disproportionation reaction coexist, there is no problem in the reaction.

After the disproportionation reaction is completed, the desired product, 4-isobutylstyrene, can be obtained by separation by an appropriate separation means such as distillation.

EFFECTS OF THE INVENTION According to the method of the present invention, 4-isobutylstyrene, which is an intermediate for the production of α- (4-isobutylphenyl) propionic acid which is a drug, is efficiently and economically produced. Further, according to the method of the present invention, the isobutyl group is not affected by undesired side reactions such as isomerization and decomposition.
-Isobutylstyrene can be produced.

The present invention will be described in more detail below with reference to examples.

[Reference Experimental Example 1] Production of di (p-isobutylphenyl) iodonium salt A mixture of 107 g of potassium periodate, 134 g of isobutylbenzene and 400 ml of acetic anhydride was placed in a three-necked flask equipped with a cooling tube, and the mixture was heated at a temperature of 5 to 10 ° C. Stir it. In this mixture,
A mixture of 204 g of acetic anhydride and 196 g of concentrated sulfuric acid was gradually added dropwise over 2 hours. The reaction temperature was kept at 5 to 10 ° C. The reaction solution was returned to room temperature and then stirred for 16 hours.

The reaction solution was poured into 600 ml of ice water, and then a saturated aqueous solution of 100 g of potassium bromide was added to precipitate crystals of iodonium salt. The crystals were separated from water by vacuum filtration, washed with water, and filtered again under reduced pressure. this,
It was dried under vacuum at 50 ° C. to obtain 167 g of di (4-isobutylphenyl) iodonium bromide (melting point: 180-182
C).

"Reference Experimental Example 2" Reaction of di (p-isobutylphenyl) iodonium salt with ethylene Di (4-isobutylphenyl) obtained in Reference Experimental Example 1
Iodonium bromide 94.6g, tri-n-butylamine 3
A mixture of 7 g, palladium acetate 2 g and methanol 500 ml,
Place in a flask equipped with a reflux condenser and a stirrer, and blow it with ethylene gas at a flow rate of 100 ml / min for 1 hour at 50 ° C.
Stirred for 6 hours.

After completion of the reaction, methanol was distilled off from the reaction solution under reduced pressure. After adding water 1 to this solution, it was extracted with toluene. The toluene layer was dried over magnesium sulfate, filtered, and toluene was distilled off under reduced pressure. By recrystallizing from this residual liquid using methanol as a recrystallization solvent, a melting point of 10
25 g of crystals at 6 ° C to 108 ° C were obtained.

This crystal had a purity of 98.0%, and it was confirmed by IR analysis and NMR analysis that it was 4-diisobutylstilbene "1,2-di (4-isobutylphenyl) ethylene".

Elemental analysis (as _{C 22 H 28) C: 90.45} % (calcd: 90.35%) H: 9.55% (calcd: 9.65%) IR (KBr ^{method, cm -1) 810, 850,} 970, 1370,1390,1470, 1610, 1910, 2970, 3030.

NMR ( ¹ H-NMR, δ) 0.9 Doublet (12H) 1.8 to 2.0 Multiplet (2H) 2.5 Doublet (4H) 7.0 Singlet (2H) 7.0 to 7.5 Multiplet (8H) "Example 1 Disproportionation by Rhenium Catalyst An aqueous solution of 26.3 g of rhenium heptaoxide was impregnated with 100 g of γ-alumina for a whole day and night, dried at 120 ° C. and then calcined. Firing was carried out in air at 600 ° C. for 5 hours. Α, which is the filling material in the reaction tube
20 ml of catalyst were loaded with alumina. Activation was by heating in a nitrogen stream prior to the reaction. pressure
It was treated at 1 kg / cm ² and 590 ° C. for 2 hours.

After cooling to room temperature, a mixture of 1,2-di (4-isobutylphenyl) ethylene and benzene at a ratio of 1: 3 and ethylene were put in a reaction tube. The molar ratio of 1,2-di (4-isobutylphenyl) ethylene to ethylene is 1: 1.2.
And SV was set to 6. After reacting at 30 ° C for 3 hours, the reaction solution was analyzed by gas chromatography to find that the conversion rate of 1,2-di (4-isobutylphenyl) ethylene was 60%, and
-Isobutylstyrene was obtained.

[Example 2] Disproportionation with a tungsten catalyst 5 g of ammonium paratungstate was dissolved in 200 ml of water, 100 g of silica gel was added thereto, and after mixing well, the mixture was dried at 120 ° C and then baked. Firing at 600 ℃ in air 5
I went on time. 20 ml of the catalyst was charged into the reaction tube together with α-alumina as the packing material. Activation was by heating in a nitrogen stream prior to the reaction. Pressure 1kg / cm ² , 590
Treated for 2 hours at ° C.

The reaction is carried out at a temperature of 400 ° C., and the molar ratio of 1,2-di (4-isobutylphenyl) ethylene to ethylene is 1: 1.2.
Was set to 60. After reaction for 3 hours, the reaction solution was analyzed by gas chromatography to find that 4-isobutylstyrene was obtained with a conversion of 1,2-di (4-isobutylphenyl) ethylene of 40%.

"Example 3" Disproportionation with other catalysts Ammonium molybdate was impregnated into activated alumina,
The mixture was dried at 120 ° C and then baked. It was a catalyst composed of MoO ₃ and Al ₂ O _3, and the atomic ratio of Mo / Al was 1/25. Firing in air 6
It was carried out at 00 ° C for 5 hours. 20 ml of the catalyst was charged into the reaction tube together with α-alumina as the packing material. Activation was by heating in a nitrogen stream prior to the reaction. Pressure 1kg /
cm ^2, for 2 hours at 590 ℃.

Using this catalyst, the same reaction as in Example 1 was carried out to give 1,2
-Di (4-isobutylphenyl) ethylene conversion 30%
Thus, 4-isobutylstyrene was obtained.

"Example 4" Using the catalyst and the reactor of Example (2), 1,2-
A disproportionation reaction of di (4-isobutylphenyl) ethylene and ethylene was performed. The reaction is carried out at a temperature of 400 ° C, 1,2-
The molar ratio of di (4-isobutylphenyl) ethylene to ethylene was 1: 1.2 and the GHSV was 60. After reacting for 3 hours, the reaction solution was analyzed by gas chromatography.
Conversion rate of 2-di (4-isobutylphenyl) ethylene 30
% 4-isobutylstyrene was obtained.

Reference Experimental Example 3 Production of α- (4-isobutylphenyl) propionaldehyde from 4-isobutylstyrene 30 g of 4-isobutylstyrene obtained in Reference Experimental Example 1,
0.3 g of rhodium hydridocarbonyltristriphenylphosphine was placed in a pressure vessel equipped with a stirrer with a capacity of 500 ml, kept at a temperature of 60 ° C., and pressurized to 70 kg / cm ² with an equimolar mixed gas of hydrogen and carbon monoxide. The reaction was carried out for 12 hours. After completion of the reaction, the mixture was cooled, residual gas was released, and the reaction product was finely distilled to
To obtain 26 g of a fraction having a distillation temperature of 70 to 76 at 3 mmHg.
This fraction had a purity of 98.7% and was confirmed by IR analysis and NMR analysis to be α- (4-isobutylphenyl) propionaldehyde as compared with the standard product.

Using this α- (4-isobutylphenyl) propionaldehyde, it was possible to carry out oxidation with potassium permanganate by the method described in J.Org.Chem., And convert it to ibuprofen as a drug. This was also compared with the standard and identified by NMR and IR.

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Claims (4)

[Claims] 1. Contacting 1,2-di (4-isobutylphenyl) ethylene represented by the following formula (I) and ethylene with a disproportionation catalyst containing a metal selected from rhenium, tungsten and molybdenum. And a method for producing 4-isobutylstyrene. 2. The method according to claim 1, wherein the rhenium oxide-based catalyst disproportionates in a liquid phase at a temperature of 100 ° C. or lower.
A method for producing isobutylstyrene. 3. A di (p-isobutylphenyl) iodonium salt represented by the formula (II) in a solvent in which 1,2-di (4-isobutylphenyl) ethylene represented by the formula (I) contains a base. The compound according to claim 1, which is produced by reacting ethylene with ethylene in the presence of a transition metal catalyst.
-Method for producing isobutylstyrene. In the formula, X ⁻ represents a counterion which is inert to the reaction. 4. The method for producing 4-isobutylstyrene according to claim 3, wherein the counterion inert to the reaction is a halogen ion.