JPH0742242B2 - α- (3- (1-phenylethenyl) phenyl) propionaldehyde - Google Patents

Description

TECHNICAL FIELD The present invention relates to α- (3- (1-phenylethenyl) phenyl) propionaldehyde represented by the following formula (II).

α- (3- (1-Phenylethenyl) phenyl) propionaldehyde is an α- (3-benzoylphenyl) propionic acid (trade name) represented by the following formula (I), which is useful as a medicine such as an anti-inflammatory agent and an analgesic. : Ketoprofen) is an intermediate for inexpensively producing.

[Prior Art] Various manufacturing methods of ketoprofen have been proposed in the past, and the representative method is as follows.

1) 3-vinylbenzophenone is reacted with carbon monoxide in dilute hydrochloric acid using palladium as a catalyst to obtain ketoprofen in high yield. (JP-A-60-45171) 2) 3-acetylbenzophenone and chloroform,
After reacting in the presence of a quaternary ammonium salt under basic conditions to obtain α-arylpropenoic acid, catalytic hydrogenation reduction is further performed using palladium carbon as a catalyst to obtain ketoprofen. (JP-A-55-7225) [Problems to be Solved by the Invention] In both the above 1) and 2), the target product can be obtained in a high yield with few reaction steps, but it is difficult to say that the raw material is easily synthesized, and it is industrially difficult. It is still not sufficient from the viewpoint of manufacturing method.

An object of the present invention is to provide an intermediate for easily and inexpensively synthesizing ketoprofen in a high yield using readily available raw materials.

[Means for Solving Problems] The present invention relates to α- (3- (1-phenylethenyl) phenyl) propionaldehyde represented by the following formula (II). The compound of the following formula also includes an optically active isomer.

The α- (3- (1-phenylethenyl) phenyl) propionaldehyde of the formula (II) can be easily synthesized, for example, as follows.

The method of using acetophenone as a starting material is as follows. Acetophenone was reacted with m-vinylphenylmagnesium bromide, which is a Grignard reagent, to give 1,1- (3-vinylphenyl) phenylethyl alcohol (hereinafter referred to as “VPA”). To do. Thereafter, the product is dehydrated in the presence of potassium hydrogen sulfate to give 1- (3-vinylphenyl) -1-phenylethylene (formula III). This Grignard addition reaction has a temperature of 0 to 100 ° C, preferably 20 to 8 ° C.
Perform at 0 ° C. The dehydration reaction is 170 to 250 ° C, preferably 1
Perform at 90-230 ° C under reduced pressure. The Grignard reagent may be 1.0 to 1.2 equivalents relative to acetophenone.

(Hydroformylation) If the obtained 1- (3-vinylphenyl) -1-phenylethylene is hydroformylated by a conventional method, α-
(3- (1-Phenylethenyl) phenyl) propionaldehyde is obtained.

This method is represented by 1- (3-
Vinylphenyl) -1-phenylethylene as a raw material is reacted with hydrogen and carbon monoxide at a temperature of 40 to 150 ° C. in the presence of a transition metal carbonylation catalyst to give a compound of formula (I
This leads to α- (3- (1-phenylethenyl) phenyl) propionaldehyde represented by I).

Complex catalysts used include Ni, Co, Fe, Mo, Pt, R
Complexes of transition metals such as h, Ir, Ru, Re, preferably Pt, R
It is a complex of a noble metal such as h, Ir, Ru, and Re. As the transition metal, an acid value of 0 to the highest acid value can be used, and a halogen atom, a trivalent phosphorus compound, a π-allyl group, an amine,
Those containing nitrile, oxime, olefin, hydrogen or carbon monoxide as a ligand are used.

Specific examples of the transition metal complex catalyst include bistriphenylphosphine dichloro complex, bistributylphosphine dichloro complex, bistricyclohexylphosphine dichloro complex, π-allyltriphenylphosphine dichloro complex, triphenylphosphine piperidine dichloro complex,
Bisbenzonitrile dichloro complex, biscyclohexyl oxime dichloro complex, 1,5,9-cyclododecatriene dichloro complex, bistriphenylphosphine dicarbonyl complex, bistriphenylphosphine acetate complex,
Bistriphenylphosphine dinitrate complex, bistriphenylphosphine sulfate complex, tetrakistriphenylphosphine complex, and chlorocarbonylbistriphenylphosphine complex, which has carbon monoxide as a part of the ligand, hydridocarbonyltristriphenylphosphine complex, Examples thereof include bischlorotetracarbonyl complex and dicarbonylacetylacetonate complex.

A compound capable of forming the above complex in the reaction system can also be used by supplying it to the reaction system. That is, a compound that can serve as a ligand for the above-mentioned transition metal oxide, sulfate, chloride, etc., that is, phosphine, nitrile, allyl compound, amine, oxime, olefin, or carbon monoxide is present in the reaction system at the same time. It is a method to let.

Examples of the phosphine as a compound that can be the above ligand include, for example, triphenylphosphine, tritolylphosphine, tributylphosphine, tricyclohexylphosphine, triethylphosphine, and the like, and examples of the nitrile include benzonitrile, acrylonitrile, propionitrile, and the like. Examples of allylic compounds such as benzyl nitrile include allyl chloride and allyl alcohol, examples of amines include benzylamine, pyridine, piperazine and tri-n-butylamine, and examples of oximes include cyclohexyl oxime and acetoxime.
Examples of olefins such as benzaldoxime and the like include 1,5-cyclooctadiene and 1,5,9-cyclodecatriene.

The amount of the complex catalyst or the compound capable of forming a complex is 1
-(3-Vinylphenyl) -1-phenylethylene (formula
III) 0.0001 to 0.5 mol, preferably 0.00
It is 1 to 0.1 mol. When a compound capable of forming a complex is used, the amount of the compound capable of becoming a ligand is 0.8 to 10 mol, preferably 1 to 4 mol, per 1 mol of the compound capable of forming a complex.

Further, for the purpose of improving the reaction rate, an inorganic halide such as hydrogen chloride or boron trifluoride or an organic iodide such as methyl iodide can be added.

When these halides are added, the halogen atom is used in an amount of 0.1 to 30 times mol, preferably 1 to 15 times mol, relative to 1 mol of the complex catalyst or the compound capable of forming a complex. If the amount added is less than 0.1 mol, the effect of the addition may not be seen, although it depends on the type of catalyst. Further, when it exceeds 30 times by mole, the catalytic activity is rather decreased and the desired reaction such as addition of halogen to the double bond of 1- (3-vinylphenyl) -1-phenylethylene (formula III) is suppressed. To be done.

The hydroformylation reaction is carried out at a reaction temperature of 40 to 150 ° C, preferably 55 to 110 ° C. If the reaction temperature is below 40 ° C,
The reaction rate becomes remarkably slow and it cannot be practically carried out. Further, if the temperature exceeds 150 ° C, side reactions such as polymerization and hydrogenation and decomposition of the complex catalyst may occur, which is not preferable.

The reaction pressure can be appropriately selected as long as it is 5 kg / cm ² or more. 5 kg
If it is less than / cm ² , the reaction becomes so slow that it cannot be practically carried out. Further, the higher the pressure is, the faster the reaction proceeds, which is preferable. However, too high a pressure naturally has a limit in terms of a manufacturing apparatus, such that the pressure resistance of the reactor needs to be extremely high. Therefore, a pressure of 500 kg / cm ² or less is practically sufficient.

The reaction may be carried out until the pressure decrease due to the absorption of the mixed gas of carbon monoxide and hydrogen is no longer observed, usually 4 to 20.
Reaction times of hours are sufficient.

Carbon monoxide and hydrogen required for the reaction may be supplied in the state of a mixed gas in which they are mixed in advance or separately to the reactor. When supplied to the reaction system, the molar ratio of carbon monoxide and hydrogen can be appropriately selected. That is, in the hydroformylation reaction, carbon monoxide and hydrogen are absorbed and consumed in an exact 1: 1 molar ratio. Therefore, since the excessively supplied component remains without reacting, if the other component is supplied when the pressure decrease is no longer recognized, the reaction proceeds again. Therefore, although it depends on the size of the reactor and the type of reaction, it is most efficient if the molar ratio of carbon monoxide to hydrogen is 1: 1.

In the above hydroformylation method, a solvent inert to the reaction may be used for the purpose of removing reaction heat. As a solvent inert to hydroformylation, ether,
Examples thereof include polar solvents such as ketone and alcohol, and nonpolar solvents such as paraffin, cycloparaffin, and aromatic hydrocarbon. However, generally, a sufficiently favorable result can be obtained in a solvent-free state.

After completion of the hydroformylation reaction, the reaction product is easily separated by distillation, preferably under reduced pressure, to obtain the desired product α
It can be separated into-(3- (1-phenylethenyl) phenyl) propionaldehyde (Formula II) and the catalyst. The recovered complex catalyst can be used again for hydroformylation.

The thus obtained product of the hydroformylation reaction, α- (3- (1-phenylethenyl) phenyl) propionaldehyde (formula II), is optionally treated simultaneously or sequentially with an oxidizing agent in the same manner. When oxidized, α-of formula (I)
(3-Benzoylphenyl) propionic acid, ie ketoprofen, is easily obtained.

Next, this oxidation will be described.

Oxidation of α- (3- (1-phenylethenyl) phenyl) propionaldehyde (formula II) is carried out on the vinylidene and formyl groups it has. At that time, the vinylidene group and the formyl group may be simultaneously oxidized by a one-step reaction. In addition, after the vinylidene group is oxidized, the reaction of further oxidizing the formyl group may be combined, or vice versa.

If the vinylidene group is first oxidized, α- (3-benzoylphenyl) propionaldehyde is obtained. In this case, the aldehyde group can be blocked by a known method with an appropriate blocking agent, for example, as an acetal group. If the formyl group is first oxidized, α-
(3- (1-Phenylethenyl) phenyl) propionic acid is obtained. When these are subsequently oxidized, α- (3-benzoylphenyl) propionic acid, ie, ketoprofen, which is the object of the present invention, can be obtained.

A known oxidation method is applied to the above-mentioned oxidation method, for example, oxidation with molecular oxygen in the presence of an oxidation catalyst, or permanganate, manganese dioxide, chromate, lead tetraacetate, periodate as an oxidizing agent. Oxidation using an oxidant consisting of salts, ruthenium tetroxide, osmium tetroxide, hydrogen peroxide, selenium dioxide, ozone and mixtures thereof.

One-step oxidation by one of these oxidation methods, namely simultaneous oxidation,
Alternatively, α- (3- (1-phenylethenyl) phenyl) propionaldehyde (formula II) to α- (3-benzoylphenyl) can be obtained by oxidation using a two-step oxidation method that combines two, that is, sequential oxidation. Propionic acid (Formula I:
Ketoprofen) can be obtained.

The catalyst for oxidation by molecular oxygen is the VI in the periodic table.
-B, VII-B, a metal selected from the group VIII, for example,
Chromium, manganese, tungsten, molybdenum, platinum,
Palladium, cobalt, nickel, iron, rhodium, ruthenium salts and mixtures thereof may be mentioned, and particularly preferred are cobalt, iron, manganese and chromium salts. As the salt, for example, a salt of naphthenic acid is preferable.
The amount of the catalyst used is, for example, 0.05 to 10% by weight based on the raw material. Molecular oxygen may be supplied as pure oxygen or air, or may be mixed with pure oxygen and another inert gas and supplied to the reaction system.

The reaction temperature for the oxidation with molecular oxygen is 30 to 250 ° C, preferably 50 to 200 ° C. If the reaction temperature is lower than 30 ° C., the reaction rate will be remarkably low, and if it exceeds 250 ° C., the selectivity of the target product will be remarkably lowered, which is not preferable.

In addition, a solvent may be used to improve the contact efficiency with the oxidizing agent, and examples of such a solvent include water,
Acetone, alcohols such as t-butyl alcohol, glacial acetic acid, acetic acid, isooctane, benzene, chloroform,
A single or mixed solvent such as pyridine is used.

The oxidizing agent such as permanganate is required to be at least 1 equivalent or more, preferably 1.5 equivalents or more based on the raw material. The upper limit of the amount used is not particularly limited, but if it exceeds 10 equivalents, it is not preferable because it is uneconomical. The reaction temperature for the oxidation with the oxidizing agent is 0 to 200 ° C, preferably 30 to 150 ° C. At a reaction temperature of less than 0 ° C, the reaction does not proceed and
If the temperature exceeds 0 ° C, by-products and the like are generated and the selectivity of the target substance is remarkably reduced, so that both are not preferable.

After the oxidation, the oxidizing agent or the oxidation catalyst is separated by filtration or the like, or the reaction mixture is extracted with an organic solvent such as benzene, ethyl acetate, chloroform and the like, followed by ordinary distillation or recrystallization to obtain a high-purity product. α-
Ketoprofen, which is (3-benzoylphenyl) propionic acid, is obtained.

[Effects of the Invention] As described in detail above, the novel intermediate proposed in the present invention. By using α- (3- (1-phenylethenyl) phenyl) propionaldehyde, ketoprofen can be easily produced at a high yield at a low cost via the intermediate. Since the compound of the present invention has specified substituents, use of the compound as an intermediate produces ketoprofen having a specific anti-inflammatory effect.

[Examples] Hereinafter, the present invention will be described in more detail with reference to Examples.
The invention is not limited to these examples only.

Example 1 Synthesis of 1- (3-vinylphenyl) -1-phenylethylene (formula III) 25.5 g (1.05 mol) of magnesium metal in a two-necked flask equipped with a dropping funnel, a reflux condenser and a stirrer. , Dry nitrogen was flowed, and after sufficiently drying, 50 ml of tetrahydrofuran dried with Molecular Sieve 5A was added and vigorously stirred. After that, 183 g of 3-vinylbenzene bromide
A solution of (1.0 mol) in 500 ml of dry tetrahydrofuran was gradually added dropwise over 2 hours. The reaction temperature was kept at 75 ° C to 80 ° C, and the stirring was continued for another hour as it was after the dropping of the solution. The Grignard reagent thus obtained, 3-bromide
In a solution of vinylphenylmagnesium, further acetophenone 122.6g (1.02mol) of dry tetrahydrofuran 500m
The solution was gradually added dropwise over 2 hours. Reaction temperature is 75-8
The temperature was kept at 0 ° C., and stirring was continued for another hour as it was after the dropping was completed. Then, the reaction solution was poured into an aqueous solution 3 of 75 g of ammonium chloride and allowed to stand for 20 hours, then the oil layer was separated and recovered, and tetrahydrofuran was distilled off to give 1,1- (3-vinylphenyl) phenyl. Ethyl alcohol (VPA) was obtained with a yield of 89% (based on acetophenone).

81 g of potassium hydrogen sulfate was placed in a 300 ml three-necked flask equipped with a distillation column and a dropping funnel, the pressure was reduced to 15 to 20 mmHg, and the produced alcohol was added dropwise over 2 hours. The water and oil flowing out from the top of the distillation column after the dehydration reaction were collected and separated to obtain 1- (3-vinylphenyl) -1-phenylethylene in the oil layer with a yield of 100% (VPA standard). Dehydration reaction temperature
It was carried out at 200 to 250 ° C.

The analysis results of the produced 1- (3-vinylphenyl) -1-phenylethylene (formula III) are shown below.

Boiling point: 134.0-135.5 ° C / 2.0-3.0 mmHg IR: (Neat) cm ^-1 3050, 1690, 1495, 1260, 995, 900, 810, 780, 700 ¹ H-NMR: (CCl ₄ , δppm) 7.10-7.70 (9H, multiple line) 6.65 ~ 6.80 (1H, double line) 5.65 ~ 5.80 (1H, double line) 5.45 ~ 5.50 (2H, double line) 5.20 ~ 5.30 (1H, double line) Elemental analysis: ( C ₁₆ as H ₁₄₎ calculated C: 93.20% H: 6.80% Found C: 93.24% H: 6.76% example 2 α- (3- (1- phenylethenyl) phenyl) preparation example of propionaldehyde 1 1- (3-vinylphenyl) -1- obtained in
50 g of phenylethylene and 0.6 g of rhodium hydridocarbonyltristriphenylphosphine, with an internal volume of 500 m
The mixture was placed in an autoclave equipped with a stirrer of 1, and pressurized to 60 kg / cm ^{2 with} a mixed gas of hydrogen and carbon monoxide (molar ratio 1: 1), and reacted until absorption of the mixed gas by the reaction disappeared. The reaction temperature was 60 ° C. After completion of the reaction, the mixture was cooled to room temperature to remove unreacted mixed gas, and then the reaction product was recovered and subjected to distillation under reduced pressure to a distillation temperature of 125.5 to 126.5 ° C /
0.5-1 mmHg of α- (3- (1-phenylethenyl) phenyl) propionaldehyde was obtained with a yield of 73% [1- (3-vinylphenyl) -1-phenylethylene standard].
As a result of GC analysis, it was 96% as α- (3- (1-phenylethenyl) phenyl) propionaldehyde. The results of the spectrum analysis are shown below.

IR: (Neat) cm ^-1 3055, 2995, 2850, 2730, 1740, 1620, 1500, 1445, 1380, 1060, 900, 750, 700 ¹ H-NMR: (CCl ₄ , δppm) 9.80 (1H, single line) 6.90-7.45 (9H, multiplet) 3.05~3.55 (1H, 4 doublet) 5.09 (2H, 1 doublets) from 1.30 to 1.47 (3H, 2 doublets) elemental analysis: as (C ₁₇ H ₁₆ O) Calculated value C: 86.44% H: 6.78% O: 6.78% Actual value C: 86.50% H: 6.80% O: 6.70% Example 3 Production of α- (3-benzoylphenyl) propionic acid (ketoprofen) (No. 1) 15 g of α- (3- (1-phenylethenyl) phenyl) propionaldehyde obtained in Example 2, 0.03 g of cobalt naphthenate and 100 ml of acetic acid as a solvent, 300 m with a stirrer.
lPut it in the reactor and keep the pure oxygen at 150ml / min at the reaction temperature of 120 ℃.
I kept blowing it in for 16 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, and the obtained solid was washed 5 times with 500 ml of water and washed with ether 5
After dissolving in 00 ml and further washing with water three times, the ether was distilled off under reduced pressure and finally recrystallized from benzene / petroleum ether to obtain 10 g of α- (3-benzoylphenyl) propionic acid (ketoprofen). The melting point, spectrum, etc. were the same as the standard.

Example 4 Production of α- (3-benzoylphenyl) propionic acid (No. 2) 200 ml / mi of air dried with silica gel instead of pure oxygen
The same procedure as in Example 3 was carried out except that n was used and the reaction temperature was 150 ° C., to obtain 8.6 g of ketoprofen. The melting point, spectrum, etc. were the same as the standard.

Claims (1)

[Claims] 1. An α- (3- (1-phenylethenyl) phenyl) propionaldehyde represented by the following structural formula.