KR960009677B1 - Preparation of 4-isobutyl styrene - Google Patents

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Description

Method for preparing 4-isobutylstyrene

The present invention relates to novel compounds 1,2-di (4-isobutylphenyl) ethylene and 1,2-di (4-isobutylphenyl) ethane. This new compound is useful as a medicine with antipyretic, analgesic and anti-inflammatory effects. -(4-Isobutylphenyl) propionic acid (trade name: Ibuprofen) is used as an intermediate for cheaply and economically preparing.

The present invention also relates to a method for preparing Ibuprofen via 4-isobutylstyrene in the novel compound.

-(4-isobutylphenyl) propionic acid is excellent medicine for antipyretic, analgesic, anti-inflammatory effect and less side effects. For this reason, the synthesis | combination by various methods conventionally is proposed. As one of them, a method of producing from 4-isobutylstyrene by hydroformylation reaction or lefe reaction is proposed. As specific examples thereof, for example, British Patent No. 1,565,235 and US Patent No. 4,694,100 are proposed.

This method of using 4-isobutyl styrene is an economically superior method because 4-isobutyl styrene is a simple and stable substance, and hydroformylation reaction or a refepe reaction does not use expensive reagents.

Generally, as a method for producing alkyl styrene, a method of contacting and decomposing 1,1-diarylethane has been conventionally proposed. For example, U.S. Patent No. 4,694,100 discloses a process for producing 4-isobutylstyrene in contact with 1,1-di (4-isobutylphenyl) ethane for decomposition. This US patent publication also discloses the preparation of Ibuprofen in 4-isobutylstyrene and also by hydroesterification or hydroformylation.

However, in this decomposition method, the by-products of equimolar isobutylbenzene are theoretically avoided from occurring simultaneously with the production of the target 4-isobutylstyrene. Therefore, it was necessary to recover this by-product isobutylbenzene and convert it back into decomposition raw materials.

However, when the 1,2-di (4-isobutylphenyl) ethylene and ethylene of this invention are disproportionate, there is no by-product of isobutylbenzene and 4-isobutyl styrene is obtained.

In addition, there was another drawback in the catalytic cracking of 1,1-di (isobutylphenyl) ethane.

That is, in the method by the decomposition reaction, it is inevitable that all of the raw materials are not decomposed and the raw materials are included in the reaction mixture as they are without reaction. This fact is also evident from the 40% to 60% papazcon version in the proposed reactions disclosed above.

In order to economically prepare alkyl styrene by the decomposition reaction, reuse of unreacted 1,1-di (substituted phenyl) ethane becomes an essential condition. In other words, it is necessary to reuse the oil fraction mainly containing 1,1-di (substituted phenyl) ethane separated from the reaction mixture in the decomposition reaction in order to economically industrialize the decomposition reaction.

The present inventors have repeatedly studied the method for producing 4-isobutylstyrene by a decomposition reaction, and according to the conventional method of decomposing 1,1-di (substituted phenyl) ethane, unreacted 1,1-produced by-products are produced. The properties of the oil mainly containing di (substituted phenyl) ethane are changed to properties that are not suitable for re-decomposition, that is, they contain ethylene-based components.The new compound 1,2-di (substituted phenyl) ethane is used as raw material. In this case, it is evident that there is no problem even if the unreacted oil is reused without any by-product of such ethylene components. That is, in the decomposition of conventional 1,1-di (4-isobutylstyrene) ethane, an ethylene component which is dehydrogenated by a decomposition catalyst is included in the unreacted fraction as shown in the following reaction formula, and this ethylene is Since boiling point is near, it is difficult to decompose by distillation. It was found that unreacted 1,1-di (4-isobutylphenyl) ethane fraction containing ethylene as it had an undesirable effect on the catalyst life of the decomposition catalyst.

Ar-CH (-CH ₃ ) -Ar Ar-C (= CH ₂ ) -Ar

The 1,2-di (4-isobutylphenyl) ethane of the present invention does not affect the life of the decomposition catalyst even if the unreacted oil is reused without any by-products of such ethylene components, so there is no problem, 4-isobutylstyrene It is the first time that it is possible to manufacture efficiently.

An object of the present invention is to provide a novel intermediate for producing Ibuprofen economically or efficiently and a novel method for preparing Ibuprofen using the same.

That is, this invention relates to the 1,2-di (4-isobutylphenyl) hydrocarbon represented by the following general formula (I).

here … … Denotes a carbon-carbon single bond or a double bond. Specific compounds are 1,2-di (4-isobutylphenyl) ethylene, tans, cis thereof and 1,2-di (4-isobutylphenyl) ethane.

In the present invention, 1,2-di (4-isobutylphenyl) ethylene can be produced, for example, by the following method.

That is, isobutylbenzene was converted to di (4-isobutylphenyl) iodonium salt using potassium periodate in concentrated sulfuric acid, and then subjected to ethylation reaction in the presence of a palladium catalyst, thereby yielding 1,2-di (4-isobutylphenyl). Ethylene may be used.

The halogen salt of the di (4-isobutylphenyl) iodonium salt is described in Japanese Patent Application Laid-Open No. 53-101331, Japanese Patent Application Laid-Open No. 57-53767, British Patent No. 1,114,950, and J. Amer. Chem. Soc., Vol. 81, 342 (1959).

In other words, isobutylbenzene and potassium periodate were stirred and mixed in acetic anhydride, and then a mixture of acetic anhydride and concentrated sulfuric acid was added dropwise, and then, a saturated ammonium chloride aqueous solution was added to precipitate a precipitate, followed by filtration and recrystallization. Butylphenyl) hydrochloride of iodonium salt is obtained. The summary of the reaction is as follows.

Where R represents an aryl group

Counterions such as Cl ^{− in the} above formula may be ion exchanged with anions inert to any reaction such as, for example, anions made of metal halides, but more suitable counterions are halogen ions such as chlorine ions and bromine ions. .

Another material that reacts with di (4-isobutylphenyl) iodonium salt is ethylene.

This reaction can be achieved by introducing a transition metal such as palladium as a catalyst in a solvent, for example, by introducing ethylene gas in the presence of a base material such as potassium oxide. When the reaction is described by the equation, it is as follows.

Where X Indicates counter ions that are inert to the reaction)

The base may be used in an amount such that the reacted di (4-isobutylphenyl) iodonium salt neutralizes the acid generated from the counterion.

Therefore, when the usage amount is below stoichiometric amount, the yield of the target 1,2-di (4-isobutylphenyl) ethylene only falls. Therefore, the quantity can be selected suitably.

The base which can be used in said reaction can use arbitrary base as long as it is melt | dissolved in the solvent to be used.

Specific examples include tertiary alkylamines such as triethylamine, tripropylamine, tributylamine, dimethylaniline, and diethylarline, alkali metal salts of lower fatty acids such as sodium acetate, potassium acetate, sodium formate, sodium, potassium, and the like. Alkali metal carbonates or bicarbonates.

The catalyst used for the reaction with ethylene is a transition metal catalyst of the Group VIII element in the periodic table, and for example, palladium, rhodium, ruthenium, platinum, iridium, osmium and the like are particularly preferable. These transition metal catalysts can be used as catalysts in various forms.

In other words, it can be used regardless of its oxidation number or complex. Examples of palladium include divalent palladium such as palladium halides such as palladium supported on alumina and activated carbon, palladium chloride, palladium oxide such as palladium oxide, and palladium acetate, and complexes such as bis (dibenzylideneacetone) palladium. Can be used. In rhodium, a carbonyl complex etc. can also be used.

As the solvent to be used, any solvent may be used as long as it dissolves the di (4-isobutylphenyl) iodonium salt even a little 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, dimethyl sulfoxide, acetonitrile and tetrahydrofuran May be appropriately selected. In addition, when the base to be used can also be a solvent, it is not necessary to use a solvent especially.

The reaction time is sufficient as 0.5 to 10 hours in total. After completion of the reaction, the reaction mixture is washed with water sufficiently and the reaction solution is cooled to precipitate 1,2-di (4-isobutylphenyl) ethylene of the target product as crystals. The precipitated crystals are filtered off and recrystallized from methanol to obtain 1,2-di (4-isobutylphenyl) ethylene.

The 1,2-di (4-isobutylphenyl) ethylene obtained in this manner is hydrogenated with an olefinic unsaturated bond of this compound by hydrogenation catalyst, and 1,2-di (4) is another object of the present invention. Isobutylphenyl) ethane.

This hydrogenation can be performed by a conventionally well-known method. However, hydrogenation of the aromatic ring should be avoided. For example, using a noble metal catalyst such as palladium and platinum, a metal catalyst such as nickel, cobalt and molybdenum or a suitable carrier thereof, such as a supported catalyst supported on carbon, reaction temperature: room temperature to 100 ° C, hydrogen pressure: atmospheric pressure Is sufficient in the range of from 50 kg / cm ² . After completion of the reaction, the reaction product is separated by an appropriate method such as distillation to obtain 1,2-di (4-isobutylphenyl) ethane as a target compound.

Next, a method for producing 4-isobutylstyrene using the above two intermediates will be described. That is, 4-isobutylstyrene is prepared by disproportionate with ethylene in 1,2-di (4-isobutylphenyl) ethylene. In 1,2-di (4-isobutylphenyl) ethane, 4-isobutylstyrene is obtained by catalytic decomposition of this with an acid catalyst.

First, the disproportionation method will be described.

4-isobutylstyrene can be easily obtained by reacting the obtained 1,2-di (4-isobutylphenyl) ethylene and ethylene in the presence of a disproportionation catalyst made of a catalyst containing metals such as rhenium and molybdenum tungsten. In the disproportionation reaction of the present invention, 1,2-di (4-isobutylphenyl) ethylene of either trans or cis can be used. This disproportionation reaction is also called metathesis.

Such disproportionation catalysts are catalysts made of metal oxides such as rhenium, molybdenum and tungsten, metal sulfides or mixtures thereof. They may be used alone, but as cocatalysts or third additives, metals such as rhodium, vanadium, aluminum, titanium, manganese, niobium, iridium, delur, alkali metals or mixtures thereof with oxides, sulfides, alkyl Organic metals of metals such as aluminum and tin such as aluminum, hydrogen, carbon monoxide and ammonia can also be used.

These catalysts can also be used on an appropriate oxide carrier. For example, in addition to silica, alumina, silica-alumina, carriers such as phosphates of metals such as TiO ₂ , ThO ₂ , MgO ₂ , ZrO, TaO _u , NbO, SnO, Al, Mg, Ca, Zr, Ta, etc. are used. .

As the primary catalyst of the specific disproportionation, WO _3, MoO _3, etc. _{ReO 3, MoO 2, MoS 3} , WS 2, Re 2 S 7 it is illustrated in Re ₂ O ₇ deungoe.

The disproportionation catalyst is produced by a known method. For example, it is prepared by impregnating a metal salt solution with an oxide carrier and firing it. Carbonyl complexes, alkyl complexes and the like of the above metals may be used as a catalyst formed by firing after immobilization by a method suitable for oxide carriers.

There is no restriction | limiting in particular in reaction form, and it is irrespective of the form of either liquid phase or gaseous phase. Reaction temperature is 0-700 degreeC normally, and has a strong dependence on a catalyst.

For example, when a catalyst showing high activity at low temperatures such as rhenium oxide is used, it is sufficient at 0 to 100 ° C, preferably 5 to 90 ° C, and on other catalysts having low activity, 200 to 700 ° C, preferably It can be used at 300 to 600 ℃.

When disproportionated at low temperature, side reactions such as isomerization and polymerization are less likely to occur, so considering the economical effect of displaying high glossiness, using a highly active heterogeneous catalyst such as a Re-based catalyst, a low temperature of 100 ° C or less In the liquid phase reaction is preferred. In addition, the reaction is carried out by appropriately pressurizing the reaction by introducing ethylene and the reaction pressure may be applied to 1 to 100 kg / cm ² , but usually 1 to 10 kg / cm ² is sufficient.

Moreover, even if hydrocarbons, such as benzene and hexane, which are insoluble in helium, nitrogen, another inert gas, or a disproportionation reaction coexist, there is no interference in reaction.

The molar ratio of 1,2-di (4-isobutylphenyl) ethylene and ethylene supplied to the reaction system can be appropriately selected, but is usually in the range of 1:10 to 10: 1, preferably 1: 5 and 5: 1. Is selected. The reaction format may be either flow or batch. In the distribution formula, the SV (space velocity) is usually selected in the range of 0.01 to 1000, preferably 0.1 to 100.

After disproportionation, 4-isobutylstyrene is obtained by, for example, separating by suitable separation means such as distillation under reduced pressure.

Next, a method for producing 4-isobutylstyrene in which 1,2-di (4-isobutylphenyl) ethane is contacted and decomposed is described.

In this method, 1,2-di (4-isobutylphenyl) ethane is contacted with a solid acid catalyst in an inert gas coexistence and in a diluted state. The inert gas can be used as long as it does not inhibit the acid activity of acid catalysts such as methane, ethane and propane, in addition to inorganic gases such as hydrogen, helium, argon, nitrogen, and water vapor. The inert gas may be used alone or in combination as appropriate. Industrially, as an inert gas, steam is a gas preferable in handling. Dilution with an inert gas is preferably diluted so that the molar ratio represented by the number of moles of inert gas / 1,2-di (4-isobutylphenyl) ethane is 50 or more. There is no particular upper limit to the number of moles of dilution, and the larger the number of moles, the more preferable, but in practice, the upper limit is 500 in molar ratio.

The solid acid catalyst to be connected is an inorganic solid having no acid activity such as silica and alumina, in addition to natural solid acid catalysts such as silica, alumina, silica, magnesium and zeolite, activated clay, acidic clay, kaolin and attapalzite. The protonic acid-supported catalyst in which the protonic acid is impregnated and supported on the porous carrier may be used. Examples of the protonic acid to be impregnated include inorganic protonic acids such as phosphoric acid, sulfuric acid, hydrochloric acid, and heteropolyacids such as silicon tungstic acid and phosphotungstic acid, and organic protonic acids such as benzene sulfonic acid and toluene sulfonic acid.

The temperature to be brought into contact with the solid acid catalyst is a temperature range of 300 to 700 ° C, preferably 400 ° C to 600 ° C, which is a preferable temperature range for the reaction efficiency and the selectivity for decomposition. If the contact temperature is less than 300 DEG C, the efficiency of the reaction becomes low and is not practically preferable. Moreover, when temperature exceeds 700 degreeC, the loss by the thermal polymerization of a target object becomes large and it is unpreferable.

As for the method of vapor phase contact, any of normal pressure, pressure, and reduced pressure may be used as long as the gas phase is maintained under dilute conditions of 1,2-di (4-isobutylphenyl) ethane. As the reaction mode, any of a fixed bed, a mobile bed, and a fluidized bed may be used.

When the decomposition reaction of the present invention is represented by the formula as follows.

Ar-CH ₂ -CH ₂ -Ar --- → Ar-CH = CH ₂ + H-Ar

Wherein Ar represents a p- (iC ₄ H ₉ ) -C ₆ H ₄ ^- group

The unreacted fraction containing 1,2-di (4-isobutylphenyl) ethane does not contain a substituted ethylene component subjected to dehydrogenation, unlike the decomposition of 1,1-di (4-isobutylphenyl) ethane. As the unreacted component, it is possible to recover and decompose it again in the same manner as 1,2-di (4-isobutylphenyl) ethane which is a raw material used for decomposition.

The product by the decomposition reaction can be easily separated by conventionally known physical means, chemical means and the like. For example, as a physical aging step, the solvent extraction separation means using the difference in solubility and distribution coefficient in the solvent, the adsorption separation means using the difference in adsorptivity, the crystallization separation means using the difference in melting point and freezing point, the difference in boiling point Distillation separation means using such may be applied.

Among these means, the distillation separation means is actually the preferred separation means in view of ease of operation. In other words, isobutylbenzene, 4-isobutylstyrene and 1,2-di (4-isobutylphenyl) ethane in the reaction mixture obtained by the method of the present invention can be easily separated by ordinary distillation means.

As described above, a second step is followed by the step of producing 4-isobutylstyrene (hereinafter sometimes referred to as RBS) in the intermediate of the present invention, and related to carbon monoxide and water or alcohol by carboxylation in PBS. By reacting and hydroesterizing -(4-isobutylphenyl) propionic acid (Ibuprofen, sometimes referred to as IPA) or a lower alkyl ester thereof (hereinafter sometimes referred to as IPE) is produced.

In the second step, RBS is carboxylated (hydroformylated) with carbon monoxide and hydrogen. -(4-isobutylphenyl) propionaldehyde (hereinafter sometimes referred to as IPN) is produced. Oxidation of this IPN according to a known method readily yields IPA.

Next, this carbonylation reaction is demonstrated.

As a second step according to the present invention, in step (II), carbonylation of PBS obtained in step (I) described above is carried out to obtain IPA or its ester IPE.

This step can be carried out according to the conventional method of reacting an olefinically unsaturated compound with alcohol or water and carbon monoxide in the presence of a metal complex carbonylation catalyst.

IPA is obtained when water is used and the corresponding ester of IPA is obtained when alcohol is used. Examples of the metal complex carbonylation catalyst include metal complexes of noble metals such as Pd, Rh, Ir, Pt, and Ru with Ni, Co, and Fe. As for the oxidation number of the noble metal, any one of zero to maximum oxidation number can be used and a halogen atom, a trivalent compound, Metal complexes having ligands of allyl groups, amines, nitriles, oximes, olefins and carbon monoxide are effective.

Metal complex carbonylation catalysts include bistriphenyl phosphine dichloro complex, bistributyl phosphine dichloro complex, bistricyclohexyl phosphine dichloro complex, -Allyltriphenylphosphine dichloro complex, triphenyl phosphine piperidine dichloro complex, bisbenzonitrile dichloro complex, biscyclohexyl oxime dichloro complex, 1,5,9-cyclododecartriene dichloro complex, bistriphenyl force Fin dicarbonyl complexes, bistriphenyl phosphine diacetate complexes, bistriphenyl phosphine dinitrate complexes, bistriphenyl phosphine sulfate complexes, tetrakistriphenyl phosphine complexes, and chlorocarbonyl bistriphenyl phosphine complexes And complexes in which some of the ligands are carbon monoxide, such as hydridocarbonyl tristriphenyl phosphine, bischlorotetracarbonyl complex and dicarbonyl acetyl acetonate complex.

Moreover, compounds which produce the metal complexes in the reaction system can also be used. That is, phosphines, nitriles, allyl compounds, amines, oximes, olefins or carbon monoxide, which may be ligands to oxides, sulfates or chlorides such as the noble metals, are simultaneously added to the reaction system in the carbonylation reaction.

Examples of the phosphine include triphenylphosphine, tritolylphosphine, tributylphosphine, tricyclohexylphosphine and triethylphosphine. Nitriles include, for example, benzonitrile, acrylonitrile, propionitrile and benzylnitrile. Examples of the allyl compound include allyl chloride and allyl alcohol. Examples of the amines include benzylamine, pyridine, piperazine and tri-n-butylamine. Oximes are exemplified by cyclohexyl oxime, acetoxime and benzaldoxime. Examples of the olefins include 1,5-cyclooctadiene and 1,5,9-cyclo dodeca triene.

The alcohol used in this step is a lower aliphatic alcohol having 1 to 4 carbon atoms such as methanol, ethanol, propanol and butanol. When higher alcohols than these are used, the boiling point of the resulting IPE becomes too high, which is undesirable because the purification of the IPE is difficult.

The amount of the metal complex or the compound which produces the metal complex to be used as a catalyst in this step is 0.0001 to 0.5 mol, preferably 0.001 to 0.1 mol with respect to 1 mol of RBS. When the compound which produces a metal complex is used, the addition amount of the compound for forming a ligand is 0.8-10 mol, preferably 1-4 mol with respect to 1 mol of compounds to produce a metal complex.

Alcohol and water act as solvents as well as reactants. Their amount is 0.5 to 50 parts by weight and preferably 1 to 20 parts by weight based on 1 part by weight of PBS.

In addition, to improve the reaction rate, it is possible to add inorganic halides such as hydrogen halide and boron trifluoride or organic iodides such as methyl iodide.

When these halides are added, their amount is 0.1 to 30 moles, preferably 1 to 15 moles, as a halogen atom, relative to 1 mole of the complex catalyst or compound for producing the complex. Depending on the type of catalyst, the effect of addition can sometimes not be observed if the addition amount is less than 0.1 mole. If the amount is more than 30 mole times, not only the catalytic activity is lowered, but also halogen atoms are added to the double bond of PBS, which impedes the target reaction.

The amount of carbon monoxide supplied is only required to be excessive relative to the amount of PBS. Depending on the size and shape of the reaction vessel, the termination of the reaction can generally be confirmed by observing the phenomenon in which absorption of carbon monoxide in the reaction vessel under pressure and the pressure drop in the reaction vessel also stop.

The carbonylation reaction is carried out at a temperature in the range 40 to 150 ° C., preferably 60 to 110 ° C. and at a carbon monoxide pressure in the range 5 to 500 kg / cm ² , preferably 30 to 400 kg / cm ² . If the reaction temperature is below 40 ° C., the reaction rate is very low and is not acceptable in the industrial manufacturing process. On the other hand, if the reaction temperature is 150 ° C. or higher, it is not preferable because it causes side reactions of polymerization and decomposition of the complex catalyst. In addition, if the pressure of carbon monoxide is lower than 5kg / cm ² the reaction rate is too slow, the reaction can not be carried out practically.

The upper limit of the pressure is not limited, but from a practical point of view, it is preferable that the pressure is not higher than 500 kg / cm ² .

The reaction is sufficient to continue until the pressure drop due to absorption of carbon monoxide stops. IPA is produced when carbonylation is carried out using water as solvent. When using alcohol as a solvent, IPA can be easily obtained with an alkyl ester, that is, an IPE having an ester group of an alkyl group of alcohol. Since IPE obtained in the presence of an alcoholic solvent is stable, IPE can be easily purified by simple distillation or the like. Further, The final product of (p-isobutyl phenyl) propionic acid can be readily obtained by conventional methods of hydrolysis of esters. For example, IPE is refluxed with aqueous sodium hydroxide solution and the precipitate of acid, IPA, is isolated and recrystallized from n-hexane or petroleum ether. Thus obtained -(p-isobutyl phenyl) propionic acid is very pure.

The metal complex catalyst recovered after the reaction can be used again.

Instead of the above-mentioned step (II), (III) may be performed as the second step. In step (III), PBS is reacted with hydrogen and carbon monoxide in the presence of a metal complex carbonylation catalyst to obtain IPN and then oxidized to produce IPA.

The type, amount and method of use of the metal complex carbonylation catalyst are not repeated here because they are the same as those of step (II) described above. It is also the same that inorganic halides and organic iodides can be added to improve the speed of the reaction.

The carbonylation reaction of step (III) is carried out at a temperature in the range from 40 to 150 ° C, preferably 55 to 110 ° C. If the reaction temperature is below 40 ° C., the reaction rate is very low and is not acceptable in industrial manufacturing processes. On the other hand, if the reaction temperature is 150 ° C. or higher, it is not preferable because side reaction of polymerization and hydrogenation and decomposition of the complex catalyst occur.

The reaction can be determined as appropriate as the pressure is 5 kg / cm ² or more. If the reaction pressure is 5 kg / cm ² or less, the reaction rate is very low and the reaction cannot be practically performed. If the reaction pressure is high enough, the reaction can proceed faster, but too high pressure requires a high pressure resistant reactor, which determines the upper limit of the reaction pressure. Therefore, it is practically sufficient to fix the reaction pressure at a level lower than 500 kg / cm ² .

The reaction continues until no pressure drop is observed due to absorption of the mixture of carbon monoxide and hydrogen. A reaction time of 4 to 20 hours is generally sufficient.

The carbon monoxide and hydrogen required for the reaction can be supplied separately or by mixing them in advance. The molar ratio of carbon monoxide to hydrogen supplied to the reaction system can be arbitrarily selected. In this carbonylation reaction of step (III) of the reaction, carbon monoxide and hydrogen are consumed (absorbed) in a precise ratio of 1: 1.

Thus, because excess gas remains unreacted, the reaction proceeds again if another drop of gas is supplied when the pressure drop stops and the reactant still remains. Depending on the size of the reaction vessel and the mode of reaction, it is generally the most effective to feed in a molar ratio of carbon monoxide to hydrogen 1: 1.

It is possible to use an inert solvent for carbonylation to remove the heat of reaction in the carbonylation of this stage of the invention. Examples of solvents inert to carbonylation include polar solvents such as ethers, ketones and alcohols, and nonpolar solvents such as paraffins, cycloparaffins and aromatic hydrocarbons. However, satisfactory results can generally be obtained with no solvent.

The reaction product thus obtained is then distilled under reduced pressure to very easily separate the IPN and the catalyst. The recovered complex catalyst can be used again in the next carbonylation reaction.

In this step of the invention, carbonylation is carried out by using the stable and highly pure PBS obtained in step (I). Thus, the IPN obtained contains only a small amount of β- (p-isobutylphenyl) propion aldehyde (NPN) and it is easily purified to produce highly pure IPN.

Since IPN can be prepared in very pure form by the process of the present invention, -(p-isobutylphenyl) propionic acid (IPN) can be readily obtained.

Oxidation has IPN It is carried out in relatively mild conditions because it has an aldehyde group and a hydrogen atom in the -position. For example, IPN is oxidized by aqueous calcium permanganate solution, alkaline aqueous suspension of silver oxide or mild oxidizing agent of bromine water. A particularly preferred oxidation method is to oxidize to hypohalogenic acid under acidic conditions. The hypohalogenic acid is exemplified by the sodium, potassium and calcium salts of hypochlorous acid or hypobromic acid. Oxidation is carried out with cooling at a temperature in the range from -10 to 30 ° C.

The highly pure PBS obtained in the above step is then carbonylated in the subsequent step to produce IPA, IPE or IPN. In the carbonylation of PBS a highly pure product can be obtained which contains little impurities. IPE obtained with alcohol solvent can be easily hydrolyzed to IPA, while IPA is produced directly when water is used as solvent. IPA is also easily converted to IPA by oxidation.

In other words, the process for preparing IPA or its ester IPE is achieved by turning the attention to a new compound and by using a lower cost material compared to the conventional method and by using the intermediate compound of the present invention which is simply and easily handled. It became. Therefore, the method of the present invention can be said to be breakthrough.

In the following the invention will be described in more detail with reference to several embodiments.

Example 1

Preparation of di (4-isobutylphenyl) iodonium salt.

A mixture of 107 g of potassium periodate, 134 g of isobutylbenzene, and 400 ml of acetic anhydride is placed in a three-necked flask equipped with a cooling tube, and stirred at a temperature of 5 to 10 ° C. A mixture of 204 g of acetic anhydride and 196 g of concentrated sulfuric acid was slowly added dropwise to the mixture over 2 hours. The reaction temperature was maintained at 5 to 10 ℃. The reaction solution was returned to room temperature and stirred for another 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 diisobutylphenyl iodonium salt. The result was separated from the water by filtration under reduced pressure, washed with water, and then filtered again under reduced pressure. This was dried under vacuum at 50 ° C. to obtain 167 g of di (4-isobutylphenyl) iodonium bromide (melting point: 180 to 182 ° C.).

Example 2

Reaction of di (4-isobutylphenyl) iodonium salt with ethylene.

A mixture of 94.6 g of di (4-isobutylphenyl) iodonium bromide, 37 g of tri-n-butylamine, 2 g of palladium acetate, and 500 ml of methanol was added to a 1 L flask equipped with a reflux condenser and a dispenser, and 100 ml / min of ethylene gas was added. It stirred at 50 degreeC for 16 hours, blowing in the flow volume of.

After completion of the reaction, methanol was distilled off under reduced pressure from the reaction solution. 1 liter of this solution was added, and then extracted with toluene. The toluene layer was dried over magnesium sulfate and filtered again, and then toluene was distilled off under reduced pressure. Recrystallization from this residue using methanol as a recrystallization solvent yielded 25 g of crystals at 108 ° C and 108 ° C.

This crystal was 98.0% pure and confirmed by 1R analysis and NMR analysis to be paradiasobutyl stilbene "1,2-di (4-isobutylphenyl) ethylene".

Elemental analysis (as C ₂₂ H ₂₆ ); C: 90.45% (calculated: 90.35%), H: 0.55% (calculated: 9.65%).

IR (KBr method, cm ^-1 ): 810, 850, 970, 1370, 1390, 1470, 1610, 1910, 2970, 3030.

NMR ( ¹ H-NMR, : 0.9 doublet (12H), 1.8 ~ 2.0 multiplet (2H), 2.5 doublet (4H), 7.0 singlet (2H), 7.0 ~ 7.5 multiplet (8H).

Example 3

Preparation of 1,2-di (4-isobutylphenyl) ethane by hydrogenation.

5 g of 1,2-di (4-isobutylphenyl) ethylene, 200 ml of diethyl ether and 0.5 g of Pd-carbon (5% supported product: manufactured by Nippon Engelhard Co., Ltd.) were placed in a 1 liter autoclave, followed by 10 kg of pure hydrogen. Pressurized to / cm ² . It stirred at room temperature for 16 hours as it maintained the pressure. After completion of the reaction, unreacted hydrogen gas was removed and returned to atmospheric pressure, and the catalyst was filtered to obtain an ether solution. Distilling off the ether gave 4.8 g of crystals. Furthermore, 4.3 g of two-sided crystals were obtained by recrystallization with methanol.

Next, the analysis result is displayed.

Melting Point 29 ° C to 31 ° C

Elemental analysis (as C ₂₂ H ₃₄ ); C: 89.71% (calculated; 89.73%), H: 10.29 (calculated: 10.27%).

IR (KBt method, cm ^-1 ): 795, 840, 1020, 1110, 1170, 1370, 1390, 1470, 1510, 1620, 1680, 1790, 1900, 2970, 3030.

NMR ( ¹ H-NMR, ): 0.8 ~ 1.0 doublet (12H), 1.8 ~ 2.0 multitight (2H), 2.4 ~ 2.6 doublet (4H), 2.9 singlet (4H), 7.0 ~ 7.3 multitight (8H).

Example 4

Disproportionation due to rhenium catalyst.

100 g of gamma -alumina was impregnated into the aqueous solution of 26.3 g of rhenium oxide for one week, and baked after drying at 120 degreeC. Firing was carried out at 600 ° C in air for 5 hours. Filling in the reaction tube 20 ml of catalyst were charged simultaneously with alumina. Activation was by heating in a nitrogen stream prior to the reaction. The treatment was performed at a pressure of 1 kg / cm ² at 590 ° C. for 2 hours.

After cooling to room temperature, 1,2-di (4-isobutylphenyl) ethylene and benzene were mixed at a ratio of 1: 3 and ethylene was charged in a reaction tube. The molar ratio of 1,2-di (4-isobutylphenyl) ethylene and ethylene was 1: 1.2 and SV was 6. After reacting at 30 ° C. for 3 hours, the reaction solution was analyzed by gas chromatography to obtain 4-isobutylstyrene at a conversion rate of 1,2-di (4-isobutylphenyl) ethylene at 60%.

Example 5

Disproportionation by tungsten catalyst.

5 g ammonium paratungstate was dissolved in 200 ml of water, 100 g of silica gel was added thereto, mixed well, and calcined after drying at 120 ° C. Firing was performed at 600 ° C. for 5 hours in air. Filling in the reaction tube Charge 20 ml of catalyst with alumina. Activation was by heating in a nitrogen stream prior to the reaction. Treatment was performed at a pressure of 1 kg / cm ² at 590 ° C. for 2 hours.

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

Example 6

Disproportionation by other catalysts.

Ammonium molybdate was impregnated into activated alumina and calcined after drying at 120 ° C. A catalyst consisting of MoO ₃ and Al ₂ O _3, the atomic ratio of Mo / Al was 1/25. Firing was performed at 600 ° C. for 5 hours. Filling in the reaction tube Charge 20 ml of catalyst with alumina. Activation was by heating in a nitrogen stream prior to the reaction. The treatment was performed at a pressure of 1 kg / cm ² at 590 ° C. for 2 hours.

Using this catalyst, the same reaction as in Example 4 was carried out, whereby 4-isobutylstyrene was obtained at a conversion ratio of 1,2-di (4-isobutylphenyl) ethylene 30%.

Example 7

The disproportionation reaction of 1,2-di (4-isobutylphenyl) ethylene and ethylene was performed in the gaseous phase using the catalyst and reaction apparatus of Example (5). The reaction was carried out at a temperature of 400 ° C., and the GHVS was 60 at a molar ratio of 1,2-di (4-isobutylphenyl) ethylene and ethylene of 1: 1.2. After reacting for 3 hours, the reaction solution was analyzed by gas chromatography to obtain (4-isobutylphenyl) styrene at a conversion rate of 1,2-di (4-isobutylphenyl) ethylene at 30%.

Example 8

Decomposition of 1,2-di (4-isobutylphenyl) ethane.

A silica-alumina catalyst N-631-L manufactured by Nikki Chemical Co., Ltd. having 15 to 25 mesh was filled in a stainless steel reaction tube having an inner diameter of 12 mm to a height of 135 mm. This was heated by the electric furnace at the temperature of 500 degreeC, and the decomposition was performed by continuously supplying 1,2- (4-isobutylphenyl) ethane in the ratio of 15 ml / hr, and water in the ratio of 150 ml / h, respectively. After cooling the reactor outlet, the oil layer was analyzed by gas chromatogram separated from 6 hours to 54 hours after the start of the reaction.

Gas Chromatogram Analysis Results -1

weight%

Light oil 0.6

Isobutylbenzene Oil 13.3

4-isobutylbenzene oil 1.8

4-isobutylstyrene oil

Unreacted 1,2-di (4-isobutylphenyl) ethane fraction 72.3

Heavy oil 0.7

The distillation product obtained in the decomposition was precisely distilled to obtain a 4-isobutylstyrene fraction (recovery rate 88%) of 74 ° C to 89 ° C and a distillation temperature range of 178 ° C to 185 under a reduced pressure of 74mm to 89 ° C under reduced pressure of 30mmHg to 34mmHg. Unreacted 1, 2- diphenyl ethane recovery fraction (recovery rate 92%) was obtained at degreeC.

The bromine value of 1,2-di (4-isobutylphenyl) ethane fraction corresponding to the recovered unreacted fraction is 0.20, and m / e = 292 (1,1-di (4-isobutylphenyl) according to mass spectrometry. ) M / e = 294) of the ethane content of the component was 0.3%.

Comparative Example 1

Decomposition of 1,1-di (4-isobutylphenyl) ethane.

4-isobutylbenzene and acetaldehyde were reacted with a sulfuric acid catalyst. The decomposition was carried out in the same manner as in Example 8 with respect to 1,1-di (4-isobutylphenyl) ethane (bromine value = 0.16) at an outlet temperature of 177 ° C to 184 ° C at 2mmHg to 3mmHg.

Gas chromatogram analysis result-2

weight%

Light oil 2.7

Isobutylbenzene Oil 24.6

4-isobutylethylbenzene fraction 2.3

4-isobutylstyrene oil 24.8

Unreacted 1,1-di (4-isobutylphenyl) ethane fraction44.3

Heavy oil 1.3

The obtained decomposition product was precisely distilled and unreacted 1,1-di (4-isobutylphenyl) ethane having a distillation temperature range of 175 ° C to 185 ° C under reduced pressure of 2mmHg to 3mmHg of 4-isobutyl styrene fraction (73% recovery). Recovered fraction (91% recovery) was obtained.

The bromine value of the recovered 1,1-di (4-isobutylphenyl) ethane fraction was 3.5, and m / e = 292 (m / e of 1,1-di (4-isobutylphenyl) ethane according to the quantitative analysis. = 294), and the content of the component was 6.0%.

Example 9

Reassembly of recovered oil.

Diaryl ethane fraction which was collected on the unreacted raw material fractions recovered in Example 8 and Comparative Example 1 was decomposed as in Example 8, respectively, and the change over time of the decomposition rate in the decomposition reaction was compared.

Note (* 1) Relative value at the decomposition rate of 1.00 6 hours after the start of the reaction.

Content of substituted ethylene component in a main (* 2) diphenyl ethane oil fraction.

The numerical value which showed the intensity | strength of the substituted ethylenes component which is m / e-2 when the intensity of m / e of diaryl ethane is 100 by mass spectrometry.

As is apparent from the above results, in Example 8, the change in the catalytic decomposition rate is small in comparison with Comparative Example 1.

Example 10

Using the catalyst shown in the table below, 1,2-di (4-isobutylphenyl) ethane was decomposed in the same manner as in Example 8. The results are shown in the table below.

Example 11

Preparation of IPA or IPE by Carbonylation of PBS.

Into a 500 ml autoclave with a stirrer was added 30 g of PBS obtained in Example 8, 100 ml of ethyl alcohol, 1 g of bistriphenylphosphine dichloro palladium and 0.2 g of a 30% boron trifluoride solution in ethyl ether. The reaction was carried out together with carbon monoxide at 80 kg / cm ² until the absorption of carbon monoxide was stopped.

After the reaction, the autoclave was cooled and the unreacted gas was evacuated. By adding 1 g of potassium carbonate powder to the contents, a 90-115 ° C / mmHg fraction was obtained by simple distillation, thereby separating the catalyst. According to this fraction of gas chromatographic analysis, its composition was 1.0 wt% PBE (isobutylethylbenzene), 0.3 wt% PBS, 93.6 wt% IPE (ethyl ester) and ethyl of β- (p-isobutylphenyl) propionic acid. It was 0.6 weight% (five components) of ester.

The fraction was again distilled off under reduced pressure to obtain 38 g of IPE (ethyl ester) having 119 to 121 ° C / mmHg. The purity of the product was 99.7% according to gas chromatography analysis. Furthermore, the chemical structure of the product was confirmed by IR analysis in comparison with the true sample.

Example 12

In a 500 ml autoclave, 30 g of PBS obtained in Example 8, 150 ml of 5% hydrogen chloride solution in methyl alcohol and 1 g of bistychloro triphenyl phosphine palladium were added. It was pressurized to 350 kg / cm ² with carbon monoxide at room temperature and heated to 95 ° C., then further to 700 kg / cm ² with carbon monoxide. The reaction was continued until absorption of carbon monoxide was stopped.

After the reaction, the reaction product was treated in the same manner as in Example 11 to obtain 21 g of IPE (ethyl ester) having a boiling point of 119 to 121 ° C / mmHg.

Example 13

In a 500 ml autoclave, 30 g of PBS obtained in Example 8, 75 g of 10% aqueous hydrochloric acid solution, 0.8 g of bisdichlorotriphenyl phosphine palladium, 80 ml of benzene and 1 g of acetofetone were added as a reaction solvent. It was pressurized to 100 kg / cm ² with carbon monoxide at room temperature. After heating it to 100 ° C., it was further pressurized together with carbon monoxide to 300 kg / cm ² and the reaction was continued until absorption of carbon monoxide was stopped.

After the reaction, the autoclave was cooled, the benzene layer was separated and extracted three times with 50 ml of 5% aqueous sodium hydroxide solution.

Next, hydrochloric acid was added until the sodium hydroxide solution reached pH 2 and extracted with chloroform. Chloroform was removed by evaporation under reduced pressure to give 36 g of pale yellow crude crystals. This crude crystal was recrystallized from n-heptane to obtain a white crystal of IPA having a melting point of 75.5 to 76.5 ° C. The recovery by redistillation was 81%. The maximum absorption of the ethanol solution of the white crystals in the ultraviolet absorption was 220 mμ, and light absorption at 257 mμ, 263 mμ and 272 mμ was observed. Furthermore, it was confirmed by IR analysis that the obtained crystal was like a true sample.

Example 14

The reaction was carried out in the same manner as in Example 11, using 0.37 g of palladium chloride and 0.63 g of triphenylphosphine instead of bisphenylphosphine dichloropalladium, and obtained results similar to those of Example 11.

Example 15

Example 11 and 3 ml of trifluoroacetic acid using 0.7 ml of palladium dibenzylidene acetone and 1.2 g of dipentyl neopentylphosphine in place of bisphenylphosphine dichloropalladium, and 3 ml of trifluoroacetic acid in place of the solution of ethyl ether boron trifluoride. The reaction was carried out in the same manner to obtain 29 g of IPE (ethyl ester) having 99.4% purity.

Reference Example

Hydrolysis of Ethyl Ester

A mixture of 10 g of IPE obtained in Example 11 and 200 ml of 12% aqueous sodium hydroxide solution was prepared and hydrolysis of IPE was performed at reflux for 3 hours.

After cooling, the oily component was extracted with ethyl ether, rinsed with water and hydrochloric acid added until the aqueous layer was at pH2. Then extracted with carbon tetrachloride and carbon tetrachloride was removed under reduced pressure to give 8.1 g of a pale yellow crude crystal. The crude crystals were recrystallized from n-heptane to give 6.7 g of white crystals having a melting point of 75 to 76 ° C.

This crystal was compared to a true sample and the result was understood to be the same IPA as Example 13.

Example 16

from p-isobutylstyrene (PBS) Preparation of-(p-isobutylphenyl) propionaldehyde (IPN).

30 g of PBS obtained in Example 4 and 0.4 g of rhodium hydrido carbonyl tristriphenyl phosphine were added to a 500 ml autoclave equipped with a stirrer. It was heated to 70 ° C. and pressurized to 50 kg / cm ² with an equimolar gas mixture of hydrogen and carbon monoxide. The reaction was continued until absorption of the mixed gas was stopped. After the reaction, the autoclave was cooled and the remaining mixed gas was evacuated. The contents were transferred to a simple distillation distillation to obtain 33 g of crude IPN fraction having a distillation range of 65 to 91 ° C./2 mmHg. The composition of the obtained fraction was as follows.

(Composition of crude IPN fraction)

0.2% by weight of PBE

0.1% by weight of PBS

IPN 90.8 wt%

NPN 8.9 wt%

This crude IPN fraction was again treated by distillation under reduced pressure to obtain 25 g of IPN having a boiling point range of 71 to 75 ° C / 3mmHg. The purity of this IPN was 99.7%.

(Oxidation)

In a flask equipped with a thermometer, condenser, dropping funnel and stirrer, 19.03 g of IPN, 100 ml of acetone and 10.0 g of acetic acid obtained in the above method were added. The reaction was carried out by adding dropwise 68.8 g of sodium hypochlorite (11% aqueous solution) for 2 hours while maintaining the temperature in the range of -5 to -10 DEG C by cooling and stirring. Stirring was continued for 1 hour, which participated.

The reaction mixture was then rinsed with water and extracted with benzene. The benzene layer was rinsed with water and neutralized with aqueous sodium hydroxide solution. It was then acidified with hypochlorous acid while cooling and further cooled to precipitate crystals. After recrystallization, 48% yield IPA was obtained. Its chemical structure was confirmed in comparison with the true sample.

Example 17

The reaction was carried out in the same manner as in Example 16 using 0.2 g of rhodium oxide and 1.5 g of triphenylphosphine instead of hydridocarbonyl tristriphenylphosphine. As a result, a crude IPN fraction of 30 g containing 0.3 wt% PBE, 0.2 wt% PBS, 82.2 wt% IPN, and 17.6 wt% NPN was obtained.

This crude IPN fraction was then oxidized in the same manner as in Example 16 to obtain IPA.

Examples 18 and 19

Hydroformylation

Instead of rhodium hydridocarbonyl tristriphenylphosphine, the complex catalyst shown in Table 1 was used, and the reaction was carried out in the same manner as in Example 16 at a reaction temperature of 95 ° C. and a reaction pressure of 170 kg / cm ² .

The results are shown in Table 1 below.

TABLE 1

Claims (2)

4-isobutylstyrene characterized by contacting 1,2-di (4-isobutylphenyl) ethylene and ethylene represented by the following formula (I) with a disproportionation catalyst containing a metal selected from rhenium, tungsten and molybdenum Manufacturing method. The method for producing 4-isobutylstyrene according to claim 1, wherein the rhenium oxide catalyst disproportionates in the liquid phase at a temperature of 100 ° C or lower.