KR970000934B1 - PROCESS FOR THE PREPARATION OF Ñß-(4-ISOBUTYLPHENYL) PROPIONIC ACID - Google Patents

Abstract

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Description

Method for preparing α- (4-isobutylphenyl) propionic acid

The present invention relates to novel compounds 1,2-di (4-isobutylphenyl) ethylene and 1,2-di (4-isobutylphenyl) ethane.

This novel compound is used as an intermediate for inexpensively and economically preparing α- (4-isobutylphenyl) propionic acid (trade name: Ibuprofen), which is useful as a medicine having antipyretic analgesic anti-inflammatory effect.

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

α- (4-isobutylphenyl) propionic acid is an excellent medicine because it has excellent antipyretic, analgesic and anti-inflammatory effects and fewer side effects.

For this reason, synthesis | combination by various methods conventionally is proposed.

As one of them, a method of producing from 4-isobutylstyrene by a hydroformylation reaction or a lefe reaction or the like has been 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 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-product of theoretically equimolar isobutylbenzene is inevitably avoided at the same time as 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 apparent in the above-described proposed method, the papazcon version is about 40% to 60% in the reaction.

In order to economically manufacture alkyl styrene by the decomposition reaction, the use 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 (substitutedphenyl) ethane separated from the reaction mixture in the decomposition reaction in order to make the industrialization of the decomposition reaction economical.

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. 1,2-di (substitutedphenyl) ethane which is a novel compound for changing the properties of an oil mainly containing di (substituted phenyl) ethane to an unsuitable property for re-decomposition, that is, containing ethylene components. When using as a raw material, 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-isobutylphenyl) ethane, an ethylene component subjected to dehydrogenation by a decomposition catalyst is included in the unreacted fraction as shown in the following reaction formula, and the ethylene has a boiling point. Since it is close, disassembly by a kind is difficult.

It was found that unreacted 1,1-di (4-isobutylphenyl) ethane fraction containing this 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 present invention has no problem because 1,2-di (4-isobutylphenyl) ethane does not affect the life of the decomposition catalyst even if the unreacted oil is recycled without any by-product of such ethylene components. This makes it possible for the first time to efficiently produce styrene.

It is an object of the present invention 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 Indicates carbon-carbon single bond or double bond.

Specific compounds are 1,2-di (4-isobutylphenyl) ethylene tans, cis and 1,2-di (4-isobutylphenyl) ethane thereof.

The 1,2-di (4-isobutenphenyl) ethylene of the present invention can be produced, for example, specifically by the following method.

Namely, 1,2-di (4-isobutylphenyl) ethylene is converted into isobutylbenzene in concentrated sulfuric acid using potassium periodate to di (4-isobutylphenyl) iodonium salt and ethyleneized in the presence of a palladium catalyst. You can do

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 precipitated by adding saturated aqueous ammonium chloride solution, followed by filtration and recrystallization. Hydrochloride of isobutylphenyl) 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 which are inert to any reaction, such as anions made of metal halides, for example, but more suitable counterions are halogen ions such as chlorine 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 into the solvent and 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.

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 diethylarylene, 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, a palladium-based catalyst is particularly preferable as palladium, rhodium, ruthenium, platinum, iridium, osmium, or the like. These transition metal catalysts can be used as various types of catalysts.

In other words, it can be used regardless of its oxidation number or complex.

As an example of palladium, a complex such as bivalent palladium such as palladium such as palladium halogenated palladium supported on alumina or activated carbon, palladium chloride, palladium salt of lower fatty acids such as palladium acetate, palladium acetate, and other complexes such as bis (dibenzylideneacetone) Can be.

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 any di (4-isobutylphenyl) iodonium salt and does not participate in the reaction.

For example, various polar solvents such as dimethylformamide, dimethyl sulfoxide, acetonitrile and tetrahydrofuran, in addition to low alcohols such as methanol and ethanol, ketones such as acetone and methyl ethyl ketone, ethers such as dimethoxyethane and dioxane 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 solution is sufficiently washed with water to cool the reaction solution to precipitate 1,2-di (4-isobutylphenyl) ethylene as a crystal.

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 olefinically unsaturated bond of this compound with a hydrogenation catalyst, which is another object of the present invention, 1,2-di (4- Isobutylphenyl) ethane is obtained.

This hydrogenation can be performed by a conventionally well-known method.

However, hydrogenation of aromatic rings should be avoided. For example, noble metal catalysts such as palladium and platinum, metal catalysts such as nickel, cobalt and molybdenum, or a suitable carrier thereof, for example, using a supported catalyst supported on carbon, reaction temperature: room temperature to 100 ° C hydrogen pressure: atmospheric pressure to 50 It is sufficient in the range of kg / cm 2.

After completion of the reaction, the compound 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 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, 40 isobutyl styrene 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, molybdenum and 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 co-catalysts or third additives, metals such as rhodium, vanadium, aluminum, titanium, manganese, niobium, iridium, tellurium, alkali metals or mixtures thereof with oxides and sulfides, such as alkyl aluminum Organic metals of metals such as aluminum and tin, hydrogen, carbon monoxide and ammonia can also be used.

These catalysts can also be used on an appropriate oxide carrier.

For example, phosphates of metals such as TiO ₂ , ThO ₂ , MgO ₂ , ZrO ₂ , TaO ₂ , Nb ₂ O ₅ , SnO ₂ , Al, Mg, Ca, Zr, Ta, in addition to silica, alumina, silica-alumina, etc. Carriers such as these are used.

Specific main catalysts for disproportionation include WO ₃ , M ₀ O ₃ , Re ₂ O ₇ , and the like, ReO ₃ , M ₀ 0 ₂ , MOS ₃ , WS ₂ , Re ₂ S _7, and the like.

Disproportionation catalysts are prepared by known methods. For example, it is prepared by impregnating an aqueous metal salt solution into an oxide carrier and then firing.

The carbonyl complex, alkyl complex, and the like of the metal may be used as a catalyst formed by firing after immobilization in an appropriate manner to the oxide carrier.

The reaction form is not particularly limited and may be in any form of liquid gas 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 other catalysts having low activity are 200 to 700 ° C., preferably 300 to 600. It can be used at ℃.

Since disproportionation at low temperature is unlikely to cause side reactions such as isomerization and polymerization, it is difficult to generate high selectivity, and considering economic feasibility, a highly active heterogeneous catalyst such as a Re-based catalyst is used for liquid phase reaction at a low temperature of 100 ° C. or lower. It is preferable to make it.

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 heterogeneous 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 in the range of conventional 1:10 to 10: 1 preferably 1: 5 and 5: 1. Is selected.

The reaction type may be either a flow type or a batch type.

In flow-through formula, SV (space velocity) is usually selected in the range of 0.01 to 1000, preferably 0.1 to 100.

After the end of disproportionation, for example, 4-isobutylstyrene is obtained by separation by appropriate separation means such as vacuum distillation.

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

In this process, an inert gas is present in contact with the 1,2-di (4-isobutylphenyl) ethanol solid acid catalyst 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, propane, in addition to inorganic gases such as hydrogen, helium, argon, nitrogen, steam, and the like.

Inert gas may be used independently and may be mixed and used suitably.

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 carpenter of the limestone, and the larger the number of moles, the more preferable, but in practice, the upper limit is 500.

The solid acid catalyst to be contacted is inorganic which does not have acid activity such as silica and alumina, in addition to natural solid acid catalysts such as silica, alumina, silica magnesium, zeolite, and the like, and solid solid acid catalysts such as activated clay, acidic clay, kaolin and attapalzite. The protonic acid-supported solid catalyst which impregnated and supported the protonic acid on the porous carrier may be sufficient.

Proton acids to be impregnated include inorganic protonic acids such as phosphoric acid, sulfuric acid, hydrochloric acid and heteropolyacids such as silicon tungstic acid and phosphorus tungstic acid, and organic protonic acids such as benzenesulfonic acid and toluenesulfonic acid.

The temperature for contacting the solid acid catalyst is in the range of temperatures 300 to 700 ° C., preferably 400 ° C. to 600 ° C., in terms of efficiency of the reaction and selectivity for decomposition.

If the contact temperature is less than 300 DEG C, the efficiency of the reaction is low, which is not practical.

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 gas phase contact method, any of normal pressure, pressure, and reduced pressure may be used as long as the gas phase is maintained under conditions in which 1,2-di (4-isobutylphenyl) ethane is diluted.

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.

The unreacted fraction containing 1,2-di (4-isobutylphenyl) ethane does not contain substituted ethylene components subjected to dehydrogenation, unlike the decomposition of 1,1-di (4-isobutylphenyl) ethane. As a reaction component, it is possible to collect | recover and decompose | disassemble again, considering it the same thing 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 physical means, solvent extraction separation means using different solubility distribution coefficients for solvents, adsorptive separation means using different adsorptive differences, crystallization separation means using different melting point freezing points, and distillation using different boiling points. Separation means or the like can be applied.

Among these means, the distillation separation means is actually the preferred separation means in view of ease of operation.

That is, 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 conventional distillation means.

As described above, after the process for preparing 4-isobutylstyrene (sometimes referred to as PBS) in the intermediate of the present invention, as a second process, carbon monoxide in PBS and carbon or water or alcohol By reacting and hydroesterizing, (alpha)-(4-isobutylphenyl) propionic acid (Ibuprofen may be called IPA below) or its lower alkyl ester (hereinafter may be called IPE) is manufactured.

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

Next, this carbonylation reaction is demonstrated.

In step (II) according to the present invention, 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 a conventional method of reacting with alcohol or water and carbon monoxide in the presence of a metal complex carbonylation catalyst of an olefinically unsaturated compound.

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, and Ru with Ni, Co, and Fe.

As regards the oxidation number of the noble metal, any of zero to maximum oxidation number can be used and metal complexes having ligands of halogen atom trivalent compound, π-allyl group, amine, nitrile, oxime, olefin and carbon monoxide are effective.

Metal complex carbonylation catalysts include bistriphenylphosphine dichloro complex, bistributylphosphine dichloro complex, bistricyclohexanephosphine dichloro complex, π-allyltriphenylphosphine dichloro complex, triphenyl Phosphine piperidine dichloro complex, bisbenzonitrile dichloro complex, biscyclohexyl oxime dichloro complex, 1,5,9-cyclododecatriene dichloro complex, bistriphenylphosphine dicarbonyl complex, bistriphenylphosphine di Acetate complexes, bistriphenylphosphine dinitrate complexes, bistriphenylphosphine sulfate complexes, tetrakistriphenyl phosphine complexes and chlorocarbonyl bistriphenyl phosphine complexes, hydridocarbonyl tristriphenyl phosphines, bis Examples of complexes in which some of the ligands, such as the chlorotetracarbonyl complex and the dicarbonyl acetyl acetonate complex, are carbon monoxide Can be mentioned.

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 ambicides 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 are used than these, 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 mole, preferably 0.001 to 0.1 mole per 1 mole of PBS.

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.

Alcohols 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.

It is also possible to add inorganic halides such as hydrogen halide and boron trifluoride or organic iodides such as methyl iodide to improve the reaction rate.

When adding these halides, their amount is from 0.1 to 30 moles, preferably from 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 only needs to be in excess of the amount of PBS.

Depending on the size and shape of the reaction vessel, termination of the reaction can generally be confirmed by observing a phenomenon in which the absorption of carbon monoxide in the reaction vessel under pressure and the pressure drop in the reaction vessel also stops.

The carbonylation reaction is carried out at a temperature in the range 40 to 150 ° C. preferably 60 to 110 ° C. and carbon monoxide pressure in the range 5 to 500 kg / cm 2 preferably 30 to 400 kg / cm 2.

If the reaction temperature is less than 40 ℃ reaction rate is very low is not acceptable in the industrial manufacturing process, whereas if the reaction temperature is more than 150 ℃ it is not preferable because it causes the side reaction of polymerization and decomposition of the complex catalyst.

In addition, if the carbon monoxide pressure is lower than 5 kg / ㎠ 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 a solvent.

When the alcohol is used as the solvent, IPE having an alkyl ester, i.e., an ester group of an alkyl group of alcohol, can be easily obtained.

Since IPE obtained in the presence of an alcoholic solvent is stable, IPE can be easily purified by simple distillation or the like.

Furthermore, the final product of α- (p-isobutylphenyl) propionic acid can be easily obtained by conventional methods of hydrolysis of esters.

For example, IPE is refluxed with aqueous sodium hydroxide solution and the precipitate IPA of the acid is isolated and recrystallized from n-hexane or petroleum ether.

The α- (p-isobutylphenyl) propionic acid thus obtained is very pure.

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

Instead of the above-described step (II), step (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 amounts and methods of use of the metal complex carbonylation catalysts are the same as those of step (II) described above, and thus are not described here again.

It is also the same that inorganic halides and organic iodides may be added to improve the rate of reaction.

In step (III), the carbonylation reaction is carried out at a temperature in the range from 40 to 150 ° C, preferably from 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 more than 150 ℃ is undesirable because it causes the side reaction of polymerization and hydrogenation and decomposition of the complex catalyst.

The pressure of the reaction can be suitably determined as long as it is at least 5 kg / cm 2.

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 premixing them.

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 molar ratio of exactly 1: 1.

Therefore, since the excess of the supplied gas remains unreacted, the pressure stops and the reaction proceeds again if another gas is supplied when 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 a solvent which is inert 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.

But satisfactory results can generally be obtained with no solvents.

The reaction product thus obtained is then distilled off 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 the carbonylation is carried out by using the stable and highly pure PBS obtained in step (I).

The IPN thus obtained contains only a small amount of β- (p-isobutylphenyl) propionaldehyde (NPN) and it is easily purified to produce highly pure IPN.

Since IPN can be prepared in a very pure form by the method of the present invention, α- (p-isobutylphenyl) propionic acid (IPA) can be easily obtained by oxidizing IPN.

Oxidation is performed under relatively mild conditions because IPN has an aldehyde group and a hydrogen atom in the α-position. For example, IPN is oxidized by aqueous potassium permanganate solution, alkaline aqueous suspension of silver oxide or mild oxidizer 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 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.

IPN is also easily converted to IPA by oxidation.

In other words, the process for preparing IPA or its ester IPE has been achieved by turning attention to new compounds and by using lower cost materials compared to conventional methods and by using the intermediate compounds of the present invention which are simply and easily handled. .

Therefore, the method of the present invention can be said to be innovative.

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 with a cooling tube and left to stir 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 6 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 again, and then separated under filtration 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, 37 g, 2 g of palladium acetate, and 500 ml of methanol was placed in a 1 L flask with a reflux condenser and stirrer, and ethylene gas was 100 ml / min. It stirred at 50 degreeC for 16 hours, blowing at the flow volume of.

After the reaction was completed, methanol was distilled off under reduced pressure in the reaction solution.

1 liter of water was added to the solution, followed by extraction 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 a melting point of 106 ° C and 108 ° C.

This crystal was found to be 98.0% pure and 1D, 4-di (4-isobutylphenyl) ethylene paradiisobutyl stilbene by 1R analysis and NMR analysis.

Elemental Analysis (as C ₂₂ H ₂₈ )

C: 90.45% (calculated: 90.35%)

H: 9.55% (calculated: 9.65%)

IR (KBr method, cm ^-1 )

810, 850, 970, 1370, 1470, 1610, 1910, 2970, 3030.

NMR ( ¹ H-NMR, δ)

0.9 double line (12H)

1.8 to 2.0 multiplet (2H)

2.5 Double Line (4H)

7.0 singlet (2H)

7.0 ~ 7.5 multiple line (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 L autoclave, followed by Pressurized to kg / cm 2.

It stirred at room temperature for 16 hours as it maintained the pressure.

After completion | finish of reaction, after removing unreacted hydrogen gas and returning to atmospheric pressure, the catalyst was filtered and obtained the ether solution. 4.8 g of crystals were obtained by distilling off the ether by distillation. Furthermore, 4.3 g of flaky 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 ₂₈ )

C: 89.71% (calculated: 89.73%)

H: 10.29% (calculated: 10.27%)

IR (KBr method, cm ^-1 )

NMR ( ¹ H-NMR, δ)

0.8 ~ 1.0 double wire (12H)

1.8 to 2.0 multiplet (2H)

2.4 ~ 2.6 double wire (4H)

2.9 Single Line (4H)

7.0 ~ 7.3 multiple wire (8H)

Example 4 Disproportionation by Rhenium Catalyst

100 g of an aqueous solution γ-alumina of 26.3 g of rhenium oxide was impregnated for one week, and fired after drying at 120 ° C. Firing was carried out at 600 ° C in air for 5 hours.

Into the reaction tube, 20 ml of the catalyst was simultaneously charged with α-alumina as a filler.

Activation was by heating in a nitrogen stream prior to the reaction.

Treatment was performed at a pressure of 1 kg / cm 2 and 590 ° C. for 2 hours.

After cooling to room temperature, 1,2-di (4-isobutylphenyl) ethylene and benzene were mixed in the ratio of 1: 3, and ethylene was charged to the reaction tube.

The 1,2-di (4-isobutylphenyl) ethylene and ethylene molar ratio was 1: 1.2 and SV was 6.

After 3 hours of reaction at 30 ° C, 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 with Tungsten Catalysts

5 g ammonium paratungstate was dissolved in 20 ml of water, 100 g of silica gel was added thereto, mixed well, and then calcined after drying at 120 ° C.

Firing was performed at 600 ° C. for 5 hours in air.

20 ml of catalyst was charged in the reaction tube together with α-alumina as a filler.

Activation was by heating in a nitrogen stream prior to the reaction.

Treatment was performed at a pressure of 1 kg / cm 2 and 590 ° C. for 2 hours.

Reaction was performed at the temperature of 400 degreeC, GHSV was set to 60 with molar ratio of 1,2-di (4-isobutylphenyl) ethylene and ethylene of 1: 1.2.

After reacting for 3 hours and analyzing the reaction liquid by gas chromatography, 4-isobutylstyrene was obtained at the conversion ratio of 1,2-di (4-isobutylphenyl) ethylene at 40%.

Example 6 Disproportionation with Other Catalysts

Ammonium molybdate was impregnated into activated alumina and dried at 120 ° C. and then calcined.

The catalyst made of a M _O O ₃ and Al ₂ O _3, the atomic ratio of M _O / Al was 1/25.

Firing was carried out at 600 ° C in air for 5 hours. 20 ml of catalyst was charged in the reaction tube together with α-alumina as a filler. Activation was by heating in a nitrogen stream prior to the reaction. Treatment was performed at a pressure of 1 kg / cm 2 and 590 ° C. for 2 hours.

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

Example 7 The disproportionation reaction of 1,2-di (4-isobutylphenyl) ethylene and ethylene in the gas phase was carried out using the catalyst and the reaction apparatus of Example (5). The GHSV was 60 at a molar ratio of 1,2-di (4-isobutylphenyl) ethylene and ethylene of 1: 1.2.

After reacting for 3 hours and analyzing the reaction liquid by gas chromatography, (4-isobutylphenyl) styrene was obtained at the conversion ratio of 1,2-di (4-isobutylphenyl) ethylene at 30%.

Example 8 Decomposition of 1,2-di (4-isobutylphenyl) ethane.

Nishiki Chemical Co., Ltd. silica alumina catalyst N-631-L with 15-25 mesh was filled in the stainless reaction tube of 12 mm of internal diameter to 135 mm in height.

This was heated to the temperature of 500 degreeC by the electric furnace, and the decomposition was performed by continuously supplying 1,2-di (4-isobutylphenyl) ethane in the ratio of 15 ml / hr, and water in the ratio of 150 ml / hr, respectively.

After cooling the reactor outlet, the oil layer from 6 hours to 54 hours after the start of the reaction was analyzed by gas chromatography.

Gas Chromatogram Analysis Result-1

weight%

Hard milk powder 0.6

Isobutylbenzene Oil 13.3

4-isobutylbenzene oil 1.8

4-isobutylstyrene oil 11.3

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

Heavy oil 0.7

The distillation products obtained in the decomposition were precisely distilled to obtain 4-isobutylstyrene fraction (recovery rate 88%) from 74 ° C. to 89 ° C. under a reduced pressure of 30 mm Hg to 34 mm Hg, and an outlet temperature range of 178 ° C. to 185 ° C. under reduced pressure of 203 mmHg. A reaction 1,2-diphenyl ethane recovery fraction (92% recovery) was obtained.

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

"Comparative Example 1" Decomposition of 1,1-di (4-isobutylphenyl) ethane

The reaction was carried out by 4-isobutylbenzene and acetaldehyde sulfate 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) having an outflow temperature of 177 ° C to 184 ° C at 2mmHg to 3mmHg.

Gas Chromatogram Analysis Result-2

weight%

Hard Powdered Milk 2.7

Isobutylbenzene Oil 24.6

4-isobutylbenzene fraction 2.3

4-isobutylstyrene oil 24.8

Unreacted 1,2-di (4-isobutylphenyl) ethane fraction 44.3

Heavy Oil 1.3

The obtained decomposition product was precisely distilled to recover unreacted 1,1-di (4-isobutylphenyl) ethane having a distillation temperature range of 175 ° C to 185 ° C under reduced pressure of 2 mmHg to 40 mmHg of 40 isobutyl styrene oil (73% recovery). An oil (91% recovery) was obtained.

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

Example 9 Reassembly of Recovery Oil.

Diaryl ethane oil corresponding to the unreacted crude oil recovered in Example 8 and Comparative Example 1 was decomposed in the same manner as in Example 8, and the change in decomposition rate over time was compared in the decomposition reaction.

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

Content of substituted ethylene component in a main (* 2) diphenyl ethane fraction. The numerical value which showed the intensity | strength of the substituted ethylene component of m / e-2 when the intensity of m / e of diaryl ethane is 100 by mass spectrometry.

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

"Example 10"

Using the catalyst shown in the table, 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

To a 500 ml autoclave with a stirrer was placed 30 g of PBS obtained in Example 8, 1 g of ethyl alcohol 100 ml bistriphenylphosphine dichloro palladium and 0.2 g of a 30% boron trifluoride solution in ethyl ether.

The reaction was carried out at 80 kg / cm 2 with carbon monoxide 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./1 mmHg fraction was obtained by simple distillation under reduced pressure, thereby separating the catalyst.

According to this fraction of gas chromatographic analysis, its composition is 1.0 wt% PBE (isobutylethylbenzene), 0.3 wt% PBS, 93.6 wt% IPE (ethyl ester) and ethyl ester of β- (p-isobutylphenyl) propionic acid 0.6 wt% (five components).

The fraction was distilled off again under reduced pressure to obtain 38 g of 119 to 121 ° C / 1mmHgIPE (ethyl ester). The purity of the product was 99.7% according to gas chromatography analysis.

Furthermore, the chemical structure of the product was confirmed by comparison with a true sample by IR analysis.

"Example 12"

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 bisdichloro triphenylphosphine palladium were added.

It was pressurized to 350 kg / cm 2 with carbon monoxide at room temperature and heated to 95 ° C., and further to 700 kg / cm 2 with carbon monoxide.

The reaction continued 4 *** 47 until the absorption of carbon monoxide was 7 * /.

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 / 1 mmHg.

"Example 13"

In a 500 ml autoclave, 80 ml of benzene and 1 g of acetophenone were added as 30 g of PBS obtained in Example 8, 75 g of 10% aqueous hydrochloric acid solution, and 0.8 g of bisdichloro triphenylphosphine palladium.

It was pressurized to 100 kg / cm 2 with carbon monoxide at room temperature. After heating it to 100 degreeC, it pressurized further with 300 kg / cm <2> with carbon monoxide, and 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 60 ml of 5% aqueous sodium hydroxide solution.

Hydrochloric acid was then added until the sodium hydroxide solution reached pH2 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 IPA white crystal having a melting point of 75.5 to 76.5 ° C.

The recovery by redistillation was 81%.

In ultraviolet absorption, the maximum absorption of the ethanol solution of white crystal was 220 micrometers, and the light absorption at 247 micrometers, 263 micrometers, and 272 micrometers was observed.

Furthermore, the obtained crystals were confirmed by IR analysis as if they were true samples.

"Example 14"

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

"Example 15"

Example 11 using 3 ml of trifluoroacetic acid instead of boron trifluoride ethyl ether solution using 0.7 g of palladium dibenzylidene acetone and 1.2 g of dipentyl neopentylphosphine in place of bisphenylphosphine dichloro palladium; 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 h of IPE obtained in Example 11 and 200 ml of 12% sodium hydroxide demand was prepared and performed at a hydrolyzate reflux temperature of IPE for 3 hours.

After cooling, the oily component was extracted with ethyl ether, rinsed with water and hydrochloric acid was added until the aqueous layer reached pH 2.

Then extracted with carbon tetrachloride and carbon tetrachloride 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 Preparation of α- (P-isobutylphenyl) propionaldehyde (IPN) from p-isobutylstyrene (PBS).

30 g of PBS obtained in Example 4 and 0.4 g of rhodium hydridocarbonyl tristriphenylphosphine 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 okoclav was cooled and the residual mixed gas was removed.

The contents were transferred to a simple distillation to obtain 33 g of crude IPN fraction with distillation range 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%

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

(Oxidation)

In a flask equipped with a thermometer, condenser, funnel and stirrer, 19.03 g of IPN obtained from the above method, 100 ml of acetone and 10.0 g of acetic acid 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 after addition.

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, IPA was obtained with a yield of 84%.

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 hydrocarbonyl tristriphenylphosphine.

The result was 30 g of a crude IPN fraction containing 0.3 wt% PBE, 0.2 wt% PBS, 82.2 wt% IPN, and 17.6 wt% NPN.

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.

Claims (3)

Catalytic cracking 1,2-di (4-isobutylphenyl) ethane with 4-isobutylstyrene and isobutylbenzene in a temperature ranging from 300 to 700 ° C in the presence of an acid catalyst, and then obtaining 4-isobutylcitre Reacting with carbon monoxide and water in the presence of a metal complex carbonylation catalyst at a temperature ranging from 40 to 150 ° C. under a pressure of 5 to 500 kg / cm 2 to obtain α- (4-isobutylphenyl) propionic acid. The manufacturing method of (alpha)-(4-isobutylphenyl) pyrionic acid which is used. Catalytic cracking 1,2-di (4-isobutylphenyl) ethane with 4-isobutylstyrene and isobutylbenzene in the presence of an acid catalyst at a temperature in the range from 300 to 700 ° C, and then obtaining 4-isobutylstyrene Reacting with carbon monoxide and low alcohol in the presence of a metal complex carbonylation catalyst at a temperature in the range of 40 to 150 ° C. under a pressure of 5 to 500 kg / cm 2 and then hydrolyzing the product in a conventional manner to produce α- (4 -Obtaining isobutylphenyl) propionic acid, The manufacturing method of (alpha)-(4-isobutylphenyl) pyrionic acid characterized by the above-mentioned. Catalytic cracking of 1,2-di (4-isobutylphenyl) ethane with 4-isobutylstyrene and isobutylbenzene in a temperature ranging from 300 to 700 ° C in the presence of an acid catalyst. Reacting with carbon monoxide and hydrogen in the presence of a metal complex carbonylation catalyst at a temperature in the range from 40 to 150 ° C. under a pressure of from 500 kg / cm 2 and then oxidizing the product by the method of conversion to α- (4-isobutyl A method for producing α- (4-isobutylphenyl) propionic acid, comprising the step of obtaining phenyl) propionic acid.