JPH0791216B2 - α- (3- (1-phenylethyl) phenyl) propionic acid - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial application] The present invention relates to α- (3- (1-phenylethyl) phenyl) propionic acid.

The compound of the present invention is effective as an intermediate for inexpensively producing α- (3-benzoylphenyl) propionic acid (trade name: ketoprofen), which is useful as a drug such as an anti-inflammatory agent and an analgesic.

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

1) 3-benzoylpropiophenone is reacted with thallium nitrate in the presence of methyl orthoformate to obtain ketoprofen methyl ester (UK Patent 2019
No. 393).

2) 3-Benzylacetophenone is reacted with ethyl chloroacetate in the presence of a strong base to give a glycidic acid ester. This is treated with an aqueous sodium hydroxide solution to hydrolyze and decarboxylate to obtain α- (3-benzylphenyl) propionaldehyde. Further, this is oxidized with potassium permanganate to obtain ketoprofen (JP-A-55)
-36450).

[Problems to be Solved by the Invention] In the method 1) described above, it is difficult to say that toxic thallium is used and the raw material is easily synthesized although the reaction step is short. Also, it is difficult to say that the method 2) makes it easy to obtain the raw materials. As described above, the methods 1) and 2) are still insufficient as industrial manufacturing methods.

An object of the present invention is to provide a novel intermediate for inexpensively synthesizing ketoprofen in high yield.

[Means for Solving the Problems] The present invention relates to α- (3- (1-phenylethyl) phenyl) propionic acid represented by the following formula (I).

The α- (3- (1-phenylethyl) phenyl) propionic acid of the above formula (I) can be easily synthesized, for example, as follows.

(1-Ethyl chloride) benzene [formula (II)] in the presence of a nickel (II) chloride diphosphine complex catalyst, 3-vinylphenyl magnesium bromide (Grignard reagent)
1-phenyl-1- (3-vinylphenyl) ethane (formula IV) is obtained by the coupling reaction of reacting [formula (III)].

The reaction is carried out under a nitrogen atmosphere at atmospheric pressure and at a reaction temperature of 0 to 80 ° C. The (II) / (III) molar ratio may be about 1.0 to 1.5.

The 1-phenyl-1- (3-vinylphenyl) ethane (formula (IV) thus obtained is subjected to a known hydrocarbonylation reaction to give a novel compound represented by the formula (I). It is possible to obtain α- (3- (1-phenylethyl) phenyl) propionic acid or its alkyl ester, which is obtained by hydrolyzing the alkyl ester by a known method.

The noble metal complex catalyst used for the above-mentioned bidrocarbonylation is a noble metal complex such as Pd, Rh, Ir or the like, and 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. A noble metal such as palladium having a valence of 0 to 2 is used.

Specific examples of the catalyst include bistriphenylphosphine dichloropalladium, bistributylphosphine dichloropalladium, bistridichlorohexylphosphine dichloropalladium, π-allyltriphenylphosphine chloropalladium, triphenylphosphine piperidine dichloropalladium, bisbenzonitrile dichloropalladium,
Biscyclohexyl oxime dichloropalladium, 1,5,
9-cyclododecatriene-dichloropalladium, bistriphenylphosphine dicarbonylpalladium, bistriphenylphosphine palladium acetate, bistriphenylphosphine palladium dinitrate, bistriphenylphosphine palladium sulfate, tetrakistriphenylphosphine palladium and the like 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 to 0.5 mol, preferably 0.001 to 0.1 mol, based on 1. mol of 1-phenyl-1- (3-vinylphenyl) ethane, and the amount of the compound that can serve as a ligand is pd 0.8 for 1 mol of noble metal such as Rh, Ir, etc.
-10 mol, preferably 1-4 mol.

The hydrocarbonylation 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 . In addition, an acid such as hydrogen chloride or boron trifluoride may be added for the purpose of promoting the reaction.

In the hydrocarbonylation reaction, 1-phenyl-1
When-(3-vinylphenyl) ethane is reacted with carbon monoxide in the presence of water, the novel compound α- of formula (I)
(3- (1-Phenylethyl) phenyl) propionic acid is obtained. Further, in the presence of an alcohol having an arbitrary alkyl group, when it is reacted with carbon monoxide as well, a corresponding alkyl ester 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, preferably methyl alcohol.

These alkyl esters can be easily hydrolyzed by a known method in the presence of an acid or a base to give a novel compound of the formula (I) in a high yield.

By oxidizing the novel compound (I) obtained by the above method with, for example, a strong oxidant, ketoprofen (trade name) represented by the following formula (V), that is, α- (3-
Benzoylphenyl) propionic acid can be easily obtained.

Examples of the strong oxidant used in the oxidation reaction include permanganate and chromic anhydride. For 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.
It is carried out at -200 ° C, preferably 30-150 ° C. In this way, ketoprofen represented by the formula (V) can be easily produced.

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

[Effects of the Invention] As described in detail above, α- (3- (1-phenylethyl) phenyl) propionic acid, which is a novel intermediate proposed in the present invention, is utilized to facilitate the reaction via an oxidation reaction. It is possible to synthesize ketoprofen at a high yield at low cost.

[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.

Reference Production Example 1 Synthesis of 1-phenyl-1- (3-vinylphenyl) ethane 500 ml dropping funnel, 2 with reflux condenser and stirrer
28 g (1.15 mol) of magnesium metal in a three-necked flask
Then, after thoroughly drying by flowing dry nitrogen, 50 ml of tetrahydrofuran dried with molecular sieve 5A is added dropwise, and vigorously stirred at room temperature. Then, a solution prepared by mixing 183 g (1.0 mol) of 3-vinylbenzenebenzene with 500 m of dried tetrahydrofuran was gradually added dropwise over 2 hours. After the start of the dropping, the temperature was set to 80 ° C., and the stirring was continued for another hour at the same temperature after the dropping, to obtain a Grignard reagent (3-vinylphenylmagnesium bromide). Next, the reagent was mixed with 94 g (0.67 mol) of (1-ethyl chloride) benzene and 5.4 g of 1.3-bis (diphenylphosphino) propane coordinated nickel (II) chloride catalyst in 500 ml of dry ether and stirred. Was gradually added dropwise over 2 hours.
Keep the temperature inside the container at 0 ° C during the dripping.
The temperature was adjusted to ℃ and the stirring was continued for 24 hours. After that, the reaction solution was poured into ice water (1000 g of ice, 500 g of water), and liquid separation was performed to collect an oil layer, and then ether and tetrahydrofuran were distilled off under reduced pressure to obtain 1-phenyl-1- (3-vinylphenyl). Ethane was obtained with a yield of 74%.

The analysis process of the product is as follows.

Boiling point: 123.5-125.0 ° C / 0.5-1.0 mmHg IR: (Neat) cm ^-1 2960, 1600, 1490, 1450, 990, 910, 790, 700 ¹ H-NMR: (CCl ₄ , δppm) 6.80-7.80 (9H , Multiple line) 6.35 ~ 6.75 (1H, quad line) 5.45 ~ 5.75 (1H, double line) 5.00 ~ 5.20 (1H, double line) 3.85 ~ 4.35 (1H, quad line) 1.50 ~ 1.85 (3H, Double line) Example 1 Synthesis of α- (3- (1-phenylethyl) phenyl) propionic acid 43.0 g of 1-phenyl-1- (3-vinylphenyl) ethane obtained in Reference Production Example 1, palladium chloride (II) 0.74
g, triphenylphosphine 2.19g, methyl alcohol 1
3.4 g and 90 ml of toluene as a solvent were placed in a 500 ml autoclave with a stirrer, and carbon monoxide was added at room temperature for 15
The pressure was increased to 0 kg / cm ² , further heated to 125 ° C., and simultaneously increased to 400 kg / cm ² . The reaction was continued for 16 hours after the absorption of carbon monoxide disappeared. After the reaction is complete, add 1
Distilled under reduced pressure at ~ 2mmHg to remove the fraction [α-
47.6 g of (3- (1-phenylethyl) phenyl] propionic acid methyl ester was obtained. The analysis of this fraction showed the following: ¹ H-NMR: (CDCl ₃ , δppm) 6.80 to 7.50 ( 9H, multiple line) 4.00 to 4.30 (1H, quad line) 3.55 to 3.80 (4H, multiple line) 1.40 to 1.70 (6H, quad line) IR: (Neat) cm ^-1 3030, 2980, 1735, 1605, 1492,1453, 900, 765, 705 elemental analysis: (C ₁₈ H ₂₀ as O ₂₎ calculated C: 80.57% H: 7.51% O: 11.92% Found C: 80.53% H: 7.50% O: 11.97% this To the fraction was added 150 g of a 5% aqueous sodium hydroxide solution, and the mixture was hydrolyzed at reflux temperature for 5 hours.After cooling, the oil layer was extracted with chloroform, the aqueous layer was acidified by adding hydrochloric acid, and this was extracted again with chloroform. The chloroform layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and then chloroform was distilled off under reduced pressure to give a colorless transparent viscous liquid α
38.2 g of-(3- (1-phenylethyl) phenyl) propionic acid was obtained. ¹ H-NMR: (CDCl ₃ , δppm) 11.30 (1H, singlet) 6.80 to 7.50 (9H, multiplet) 4.00 to 4.30 (1H, 4t) 3.55 to 3.80 (1H, 4t) 1.40 to 1.70 (6H, 4 ^{doublet) IR: (Neat) cm -1} 2980,1710,1605, 1492,1453,1415, 760, 705 elemental analysis: (as C ₁₇ H ₁₈ O ₂₎ calculated C: 80.29% H : 7.13% O: 12.58% Actual value C: 80.25% H: 7.12% O: 12.63% Reference Production Example 2 Synthesis of α- (3-benzoylphenyl) propionic acid (ketoprofen) α- (obtained in Example 1 3- (1-phenylethyl)
Phenyl) propionic acid 12.7g and glacial acetic acid 200ml mixed solution
Stir at 50 ° C.

Then, a mixed solution of 20 g of chromic anhydride, 16 ml of water and 100 ml of acetic acid was gradually added dropwise at a temperature of 50 ° C. Reaction temperature 50 for an additional hour
It was kept at ℃.

After cooling the solution, methanol was added to decompose excess chromic acid. The reaction solution was then poured into a large excess of ice water and then extracted with benzene. The benzene layer was dried over magnesium sulfate, and then benzene and acetic acid were removed by distillation.

Finally recrystallized from benzene / petroleum ether to give white crystals
21g was obtained. The melting point and spectrum of this product are α- (3
-Benzoylphenyl) propionic acid (ketoprofen) was similar to the standard.

Example 2 Synthesis of α- (3- (1-phenylethyl) phenyl) propionic acid 43.0 g of 1-phenyl-1- (3-vinylphenyl) ethane obtained in Reference Production Example 1, bisdichlorotriphenylphosphine palladium 5.5 g, 80 g of 10% hydrochloric acid aqueous solution and 80 ml of toluene as a solvent are put into an autoclave with a stirrer and an internal volume of 500 ml, and 100 kg of carbon monoxide is added at room temperature /
After pressurizing to cm ^{2, the} temperature was raised until it reached 120 ° C., and the pressure was increased to 300 kg / cm ² . The reaction was continued for 24 hours after the absorption of carbon monoxide was stopped by the reaction.

After completion of the reaction, the autoclave was cooled to collect the reaction liquid, 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 three times with 500 ml of chloroform, the extract was decompressed and the chloroform was distilled off to obtain 42.5 g of α- (3- (1-phenylethyl) phenyl) propionic acid as the title compound. The physical properties such as the spectrum of this product were the same as those obtained in Example 1 above.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification number Office reference number FI technical display location C07C 51/373 59/84 (56) References JP-A-63-230653 (JP, A) JP-A JP-A-63-233948 (JP, A) JP-A-54-141754 (JP, A) JP-A-61-103851 (JP, A)

Claims (1)

[Claims] 1. An α- (3- (1-
Phenylethyl) phenyl) propionic acid.