JPH0742238B2 - 1- (3-vinylphenyl) -1-phenylethylene - Google Patents

Description

TECHNICAL FIELD The present invention relates to 1- (3-vinylphenyl) -1-phenylethylene represented by the following formula (I).

The 1- (3-vinylphenyl) -1-phenylethylene (formula I) of the present invention is represented by the following formula (II): α- (3-
Via (1-phenylethenyl) phenyl) propionic acid or its alkyl ester, α- (3 represented by the following formula (III), which is useful as a medicine such as an anti-inflammatory agent and an analgesic agent
-Benzoylphenyl) propionic acid (trade name: ketoprofen) is an intermediate for inexpensively producing.

(R is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms) [Prior Art] Various manufacturing methods of ketoprofen have been proposed in the past, and the representative method is as follows.

1) by reacting 3-benzoylpropiophenone with thallium nitrate in the presence of methyl orthoformate,
Obtaining ketoprofen methyl ester (UK Patent No.
2019393 publication).

2) 3-Benzylacetophenone is reacted with ethyl chloroacetate in the presence of a strong base to give a glycidic acid ester. By treating this with an aqueous solution of sodium hydroxide, hydrolyzed and decarboxylated α- (3-benzylphenyl) propionaldehyde is obtained. Further, it is oxidized with potassium permanganate to obtain ketoprofen. (JP-A-55-36
(No. 450 bulletin) [Problems to be Solved by the Invention] In the above method 1), although the reaction step is short, it is difficult to say that toxic thallium is used, and the raw material is easy to synthesize. It's hard to say that it is easy to obtain. As described above, both 1) and 2) are still insufficient as industrial manufacturing methods.

An object of the present invention is to provide an intermediate for synthesizing ketoprofen at low cost and in high yield.

[Means for Solving Problems] The present invention relates to 1- (3-vinylphenyl) -1-phenylethylene represented by the following formula (I).

The 1- (3-vinylphenyl) -1-phenylethylene of the formula (I) can be easily synthesized, for example, as follows.

A method using acetophenone as a starting material will be described. Acetophenone was reacted with Grignard reagent m-vinylphenylmagnesium bromide to prepare 1,1- (3-vinylphenyl) phenylethyl alcohol (formula IV) (hereinafter, referred to as VPA).
And). Thereafter, the product is dehydrated in the presence of potassium hydrogen sulfate to give 1- (3-vinylphenyl) -1-phenylethylene (formula I). This Grignard addition reaction has a temperature of 0 to 100 ° C, preferably 20
Perform at ~ 80 ° C. The dehydration reaction is carried out under reduced pressure conditions at 170 to 250 ° C, preferably 190 to 230 ° C. The Grignard reagent may be 1.0 to 1.2 equivalents relative to acetophenone.

By subjecting the novel reaction product thus obtained, 1- (3-vinylphenyl) -1-phenylethylene, to a known hydroesterification reaction, a carbonyl compound represented by the formula (II) is obtained. An α- (3- (1-phenylethenyl) phenyl) propionic acid or its alkyl ester can be obtained.

(R is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms) The noble metal complex catalyst used for the above carbonylation is a noble metal complex such as Pd, Rh, and Ir, and is particularly a Pd complex. As these noble metals, those containing carbon monoxide or the like as a ligand such as a halogen atom, a trivalent phosphorus compound, or a carbonyl complex compound are used. As the noble metal, for example, palladium, one having a valence of 0 to 2 is used.

Specific examples of the catalyst include bistriphenylphosphine dichloropalladium, bistributylphosphine dichloropalladium, bistridichlorohexylphosphine dichloropalladium, π-allyltriphenylphosphine dichloropalladium, triphenylphosphine piperidine dichloropalladium, bisbunzonitrile dichloropalladium, bis. Cyclohexyl oxime dichloropalladium,
1,5,9-cyclododecatriene dichloropalladium, bistriphenylphosphine dicarbonylpalladium, bistriphenylphosphine palladium acetate, bistriphenylphosphine palladium dinitrate, bistriphenylphosphine palladium sulfate, tetrakistriphenylphosphine palladium, etc. Can be mentioned.

The catalyst may be supplied to the reaction system as a complex for use. It is also possible to separately supply the ligand and generate a complex in the reaction system for use.

The amount of the catalyst is 0.0001 relative to 1 mol of 1- (3-vinylphenyl) -1-phenylethylene represented by the formula (I).
To 0.5 mol, preferably 0.001 to 0.1 mol, and the amount of the compound that can serve as a ligand is 1 noble metal such as Pd, Rh, or Ir.
It is 0.8-10 mol, preferably 1-4 mol, relative to mol.

The hydroesterification reaction is carried out at a reaction temperature of 40 to 150 ° C., preferably 70 to 120 ° C., and a carbon monoxide pressure of 30 to 700 kg / cm ² , preferably 90 to 500 kg / cm ² . An acid such as hydrogen chloride or boron trifluoride may be added for the purpose of promoting the reaction.

In the hydroesterification reaction, when 1- (3-vinylphenyl) -1-phenylethylene represented by the formula (I) is reacted in the presence of water, α- (3- (1-phenylethenyl)) is obtained. A carboxylic acid is obtained in which R in formula (II), which is phenyl) propionic acid or its alkyl ester, corresponds to a hydrogen atom. Further, when the reaction is performed in the presence of an alcohol having an arbitrary alkyl group, an ester in which R in the formula (II) corresponds to the alkyl of the alcohol is obtained, and for example, methyl alcohol gives a methyl ester.

Alcohol is methyl alcohol, ethyl alcohol,
n-propyl alcohol, isopropyl alcohol, n
-Butyl alcohol, sec-butyl alcohol, tert-
It is a lower alcohol having 1 to 4 carbon atoms such as butyl alcohol and isobutyl alcohol, and preferably methyl alcohol.

By oxidizing the carbonyl compound (II) obtained by the above method with an oxidizing agent, ketoprofen represented by the formula (III) and its esterified product, that is, α-(-
Benzoylphenyl) propionic acid or its alkyl ester can be easily obtained. When oxidizing an ester, it can be converted into an acid form by a conventional hydrolysis operation prior to the oxidation. Of course, the ester may be directly oxidized. Examples of the strong oxidant used in the oxidation reaction include permanganate and dichromate. In the reaction, a single or mixed solvent such as glacial acetic acid, acetic acid, isooctane, benzene and chloroform is used, and the reaction temperature is 0 to 200 ° C, preferably 30 to 150 ° C.
Done in. In this way, ketoprofen represented by the formula (III) and its esterified product can be easily produced.

The esterified product of ketoprofen in which R is alkyl is
Ketoprofen can be easily obtained by an ordinary hydrolysis operation.

After oxidation, high-purity ketoprofen can be obtained by separating the oxidizing agent by filtration or by extracting the reaction mixture with an organic solvent such as benzene, ethyl acetate, or chloroform, and then performing ordinary distillation or recrystallization. .

[Effects of the Invention] As described in detail above, by using 1- (3-vinylphenyl) -1-phenylethylene, which is a novel intermediate proposed in the present invention, α- (3- (1-phenylethylene) By passing through tenyl) phenyl) propionic acid or its alkyl ester, ketoprofen can be easily synthesized in a high yield and at low cost via the intermediate. In addition, since the compound of the present invention has a vinyl group substituted at the m-position, if it is used as an intermediate, ketoprofen having a unique anti-inflammatory effect can be produced inexpensively and easily.

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

Example 1 Synthesis of 1- (3-vinylphenyl) -1-phenylethylene (Formula I) 25.5 g (1.05 mol) of metallic magnesium in a two-necked flask equipped with a dropping funnel, a reflux condenser and a stirrer. , Dry nitrogen is flowed, and after sufficiently drying, 50 ml of tetrahydrofuran dried with Molecular Sieve 5A is 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. After that, 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) phenylethyl alcohol. (VPA: Formula (IV))
Was obtained in 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 I) 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, multiplet) 6.65 to 6.80 (1H, quadruple) 5.65 to 5.80 (1H, doublet) 5.45 to 5.50 (2H, doublet) 5.20 to 5.30 (1H, doublet) 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) obtained on the synthesis of propionic acid 43 g of the obtained 1- (3-vinylphenyl) -1-phenylethylene, 5.5 g of bistriphenylphosphine dichloropalladium, 80 g of 10% hydrochloric acid aqueous solution, and 80 ml of toluene as a solvent were placed in an autoclave with a stirrer and an internal volume of 500 ml at room temperature. After pressurizing to 100 kg / cm ^{2 with} carbon monoxide, pressurize while raising the temperature until it reaches 120 ℃, 300 kg
Pressurized to / cm ² . The reaction was continued for 24 hours after the absorption of carbon monoxide disappeared.

After completion of the reaction, the autoclave was cooled to collect the reaction solution, the oil layer and the water layer were separated with a separating funnel, and the oil layer was extracted 3 times with 50 ml of 8% aqueous sodium hydroxide solution. Mix and add pH to 2 with hydrochloric acid. Then, the mixture was extracted 3 times with 500 ml of chloroform, and the extract was decompressed to remove chloroform to obtain 44.7 g of the title compound.

The results of the purified α- (3- (1-phenylethenyl) phenyl) propionic acid are shown below.

In addition, the following analysis results show α obtained in Example 4.
It was the same as that of α- (3- (1-phenylethenyl) phenyl) propionic acid obtained by hydrolyzing methyl- (3- (1-phenylethenyl) phenyl) propionic acid according to a conventional method. .

Properties: Melting point 69.0-71.0 ° C IR: (Neat) cm ^-1 3030, 2750, 2650, 1715, 1610, 1420, 1240, 1070, 91
0 785, 710. ¹ H-NMR: (CCl ₄ , δppm) 12.2 (1H, singlet) 6.80 to 7.50 (9H, multiplet) 5.38 (2H, singlet) 3.45 to 3.90 (1H, quartet) 1.35 to 1.65 (3H, Double line) Elemental analysis: (as C ₁₇ H ₁₆ O ₂ ) Calculated value C: 80.95% H: 6.35% O: 12.70% Measured value C: 80.91% H: 6.32% O: 12.77% Example 3 α- ( Synthesis of 3-benzoylphenyl) propionic acid (ketoprofen) (1) 35 g of α- (3- (1-phenylethenyl) phenyl) propionic acid obtained in Example 2 was dissolved in 250 ml of benzene, and 250 ml of water was further added. In addition, the mixture was vigorously stirred and suspended.
Thereafter, a 2% aqueous solution of potassium permanganate 2 was gradually added dropwise over 1.5 hours, and after completion of the addition, stirring was continued at room temperature for 18 hours. After the reaction was completed, concentrated sulfuric acid was added to acidify the mixture,
After treating with 35 g of sodium sulfite, 500 ml of water was added and the mixture was extracted 3 times with 150 ml of ether. After washing the ether solution with water, it was extracted 3 times with 200 ml of 5% aqueous sodium hydroxide solution,
After that, hydrochloric acid was added to make it acidic. This was again extracted 3 times with 150 ml of ether, washed with water, dried over anhydrous magnesium sulfate, filtered, and the ether was distilled off under reduced pressure.
Finally, recrystallize from benzene / petroleum ether to obtain α- (3
20 g of -benzoylphenyl) propionic acid (ketoprofen) were obtained. The melting point, spectrum, etc. were the same as the standard.

Example 4 Synthesis of α- (3- (1-phenylethenyl) phenyl) propionic acid methyl ester 43-g of 1- (3-vinylphenyl) -1-phenylethylene obtained above, 0.74 g of palladium (II) chloride , Triphenylphosphine 2.19 g, methyl alcohol 13.4 g, and toluene 90 ml as a solvent are put into a 500 ml autoclave with a stirrer, pressurized with carbon monoxide to 150 kg / cm ^{2 at} room temperature, and heated to 125 ° C. And at the same time 400kg / c
The pressure was raised to m ² . 16 after carbon monoxide absorption has ceased
The reaction continued for an hour. After completion of the reaction, the reaction solution was distilled under reduced pressure at 2 to 3 mmHg to obtain α- (3- (1- (1-
Phenylethenyl) phenyl) propionic acid methyl ester was obtained with a yield of 87% [based on 1- (3-vinylphenyl) -1-phenylethylene]. The results of the spectral analysis are shown below.

IR: (Neat) cm ^-1 3040, 2995, 2960, 2880, 2850, 1740, 1610, 1500, 14
^{45,1340,1260,1190,1075,1032,905,785,710 1 H-NMR: (CCl} 4, δppm) 6.70~7.30 (9H, multiplet) 5.32 (2H, 1 doublet) 3.20 to 3.75 (4H , Multiple line) 1.45 to 1.56 (3H, double line) Elemental analysis: (as C ₁₈ H ₁₃ O ₂ ) Calculated value C: 81.20% H: 6.77% O: 12.03% Actual value C: 81.20% H: 6.80% O: 12.00% Example 5 Synthesis of α- (3-benzoylphenyl) propionic acid (ketoprofen) (Part 2) Methyl α- (3- (1-phenylethenyl) phenyl) propionate obtained in Example 4 36 g of the ester was dissolved in 250 ml of benzene, 250 ml of water was added, and the mixture was vigorously stirred and suspended. Then, 2% potassium permanganate aqueous solution 2 was gradually added dropwise over 1.5 hours.
Stirring was continued for 8 hours. After the reaction was completed, concentrated sulfuric acid was added to acidify the solution, and 35 g of sodium sulfite was added for treatment, followed by addition of water 5
00 ml was added and the mixture was extracted 3 times with 150 ml of ether. The ether solution was washed with water and then extracted with a 5% aqueous sodium hydroxide solution, and the aqueous layer was hydrolyzed at reflux temperature for 5 hours. After cooling, the oil layer was extracted with ether, and the aqueous layer was acidified by adding hydrochloric acid, and this was extracted again with ether. The ether layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and ether was distilled off under reduced pressure. Finally, it was recrystallized from benzene / petroleum ether to obtain 23 g of α- (3-benzoylphenyl) propionic acid (ketoprofen). The melting point, spectrum, etc. were the same as the standard.

Claims (1)

[Claims] 1. 1- (3-vinylphenyl) -1-phenylethylene represented by the following formula.