JP2805342B2 - Process for producing (3-ethylphenyl) phenylmethanol and intermediate therefor - Google Patents

Description

The present invention relates to a novel process for producing (3-ethylphenyl) phenylmethanol and a novel intermediate (3-ethylphenyl) phenylmethane hydroperoxide. It is.

In addition, (3-ethylphenyl) phenylmethanol is useful as a medicine such as an anti-inflammatory agent and an analgesic.
Benzoylphenyl) propionic acid (trade name: ketoprofen) is an intermediate used for inexpensive production.

[Prior Art] Various methods for producing ketoprofen have been conventionally proposed, and the following methods are typical.

(1) 3-Methylbenzophenone is brominated to form 3-bromomethylbenzophenone, and further reacted with potassium cyanide to form 3-cyanomethylbenzophenone.
Next, 3-cyanomethylbenzophenone is methylated with methyl iodide in the presence of a base, and further subjected to alkali hydrolysis to obtain ketoprofen (Japanese Patent Application Laid-Open No.
51-115452).

(2) 3-chlorobenzoic acid is reacted with propionitrile in the presence of a strong base to give (3-hydroxycarbonylphenyl) propionitrile, and then (3-chlorocarbonylphenyl) using thionyl chloride. Propionitrile. Next, a Friedel-Crafts reaction is performed with benzene in the presence of aluminum chloride to give 3- (1-cyanoethyl) benzophenone, which is further subjected to alkaline hydrolysis to obtain ketoprofen (Japanese Patent Publication No. 52-83).
No. 01).

(3) The benzophenone is subjected to Friedel-Crafts alkylation using diethyl sulfate in the presence of aluminum chloride to give 3-ethylbenzophenone. 3-Ethylbenzophenone is brominated using N-bromosuccinimide to give 3- (1-bromoethyl) benzophenone, and then alkali-hydrolyzed to give 3- (1-hydroxyethyl) benzophenone. This is further reacted with carbon monoxide to obtain ketoprofen (Spanish Patent 45
2500 publication).

[Problems to be Solved by the Invention] However, the method (1) is not preferable as an industrial production method because toxic potassium cyanide is used when synthesizing 3-cyanomethylbenzophenone. In addition, the method (2) has a drawback that the yield is low when synthesizing (3-hydroxycarbonylphenyl) propionitrile and the method (3) when synthesizing 3-ethylbenzophenone. Not enough.

Therefore, an object of the present invention is to synthesize ketoprofen at low cost and in high yield.

Means for Solving the Problems The present invention provides a method for producing (3-ethylphenyl) phenylmethanol and a novel intermediate (3-ethylphenyl) phenylmethanehydrogen represented by the following formula (I) used in the method: It relates to peroxide.

(3-Ethylphenyl) phenylmethane hydroperoxide represented by the formula (I) is synthesized in a high yield as follows, and ketoprofen can be further synthesized using the same.

That is, by oxidizing (3-ethylphenyl) phenylmethane with molecular oxygen in the presence of a base, an oil containing peroxide is obtained. It is sufficient that the reaction temperature is in the range of 40 to 165 ° C and the pressure is normal pressure or about 5 atm. If the reaction temperature is lower than 40 ° C., the oxidation reaction does not proceed sufficiently, and if it exceeds 165 ° C., side reactions such as decomposition occur, which is not preferable.

By separating the obtained oil by chromatography, (3-ethylphenyl) phenylmethane hydroperoxide is obtained. Silica gel or the like can be used as a packing material for chromatography.

The oxygen may be pure oxygen or oxygen diluted with an inert gas such as air. The oxidation is performed in the presence of a base to be carried out in a basic state. An appropriate base such as sodium carbonate can be used as the base. It is preferable to use an appropriate radical generator such as azobisisobutyronitrile as a reaction initiator. The reaction time is not particularly limited, but is usually from 10 minutes to several hours.

That is, the reaction is, for example, molybdenum, titanium, vanadium, tungsten, rhenium, cerium,
The reaction of a lower olefin such as propylene, ethylene or isobutylene with a hydroperoxide in the presence of a metal catalyst containing a metal such as niobium or tellurium converts the olefin to an epoxide and the hydroperoxide to the corresponding alcohol. Therefore, (3-ethylphenyl) phenylmethane hydroperoxide becomes (3-ethylphenyl) phenylmethanol. The metal as the catalyst may be in various forms such as inorganic salts and organic salts. For example, it can be used as naphthenate, stearate, octoate, carbonyl and the like. Chelates, enol salts, such as acetoacetonate, may also be used.
Further, oxides, sulfides, and halides may be used.

The olefin is used in an amount of 2 to 10 times the molar amount of the hydroperoxide. The amount of the catalyst is 0.005 to 5
Molar% is appropriate. The reaction temperature is 0 to 150 ° C, preferably 50 to 120 ° C. If the reaction temperature is lower than 0 ° C., the reaction does not proceed, and if it exceeds 150 ° C., it is not preferable because the yield of the desired product is reduced by side reactions. The pressure is normal pressure or under pressure, and the reaction is carried out under conditions of temperature and pressure at which the reaction system can maintain a liquid phase. Reaction times range from 10 minutes to several hours. An inert reaction solvent can be used for the reaction.

The resulting alcohol of the formula (II) is dehydrogenated by oxidation according to a conventional method, and is converted into 3-ethylbenzophenone of the formula (III).

This oxidation may be, for example, a metal catalyst such as platinum-carbon, platinum black or cerium, a catalytic oxygen oxidation reaction using molecular oxygen using sodium pyrazolide or a base, or chromium oxide, chlorine, permanganate, ruthenium oxide. Oxidation reaction using an oxidizing agent such as hypohalite or selenium oxide.

The 3-ethylbenzophenone represented by the formula (III) obtained as described above is obtained by the above-mentioned Spanish Patent No. 4525.
It is a starting material of ketoprofen in JP-A-00. Therefore, ketoprofen can be obtained by reacting according to the method described in the Spanish patent.

[Effects of the Invention] As described in detail above, if (3-ethylphenyl) phenylmethane hydroperoxide, which is a novel intermediate proposed in the present invention, is used, via the intermediate,
Ketoprofen can be easily produced at a high yield and at low cost.

EXAMPLES Hereinafter, the present invention will be described more specifically with reference to Examples, but the present invention is not limited to these Examples.

[Synthesis of (3-ethylphenyl) phenylmethane hydroperoxide (I)] 39.2 g of (3-ethylphenyl) phenylmethane (200 mm
ol), 0.12 g of sodium stearate, 0.77 g of azobisisobutyronitrile as a reaction initiator and 150 ml of 1% aqueous sodium carbonate solution at 85 ° C. with vigorous stirring at a rate of 4 / hr with pure oxygen. Time introduced. After cooling to room temperature, the oil layer was separated and dehydrated with anhydrous magnesium sulfate to obtain 36 g of an oil.

[Isolation of (3-ethylphenyl) phenylmethane hydroperoxide (I)] The above oil was separated by column chromatography.
N-hexane / ethyl acetate (volume ratio: 8/2) as developing solution
A column packed with silica gel (trade name: Wakogel C-300) using a mixed solvent of was used. When the developing solvent was distilled off from the fraction containing only the spot having an _Rf value of 0.31 at reduced pressure at room temperature, 4.2 g of oil remained.

About this oil, infrared absorption spectrum, proton
Analyzes such as NMR, ¹³ C NMR, elemental analysis and iodometry were performed. The results are as follows.

IR (νcm ^-1): 3200~3550 (broad absorption) 2880~3070 1670,1605,1490 1450,1370,1270 1150,1040,1020 800, 740 , 700 NMR (1 H) :( ppm) 9.98 (1H) Singlet 7.12 to 7.25 (9H) Multiplet 5.86 (1H) Singlet 2.52 (2H) Quadruple 1.12 (3H) Triplet NMR ( ^13C )-decoupled-(ppm) 144.3, 139.4, 139.2 128.9, 128.4, 128.0 127.6, 127.1, 124.9 89.4, 32.7, 27.8 Iodometry: Peroxide content = 0.00404 mol / g Elemental analysis: (as C ₁₅ H ₁₆ O ₂ ) C% H% O% Actual 78.85 7.05 14.10 Calculated 78.92 7.06 14.02 [Synthesis of 3-ethylbenzophenone (III) via (3-ethylphenyl) phenylmethanol (II)] In an autoclave, (3-ethylphenyl) phenylmethane hydroperoxide (I) 6.9 g, propylene 9.0 g And molybdenum naphthenate-sodium naphthenate catalyst (Mo / Na = 2) .5 g was added and heated at 120 ° C. for 2 hours. After cooling to room temperature, gas was released. From the residual liquid,
Propylene oxide was removed by distillation so that the liquid temperature did not exceed 100 ° C. The thus obtained (3-
After removing the catalyst from the distillation residue containing (ethylphenyl) phenylmethanol (II), the mixture was transferred to a 100 ml reactor equipped with a stirrer. Further, 250 mg of platinum black and 50 ml of n-heptane as a solvent were added, and pure oxygen was blown at a reaction temperature of 40 ° C. at a flow rate of 30 ml / min for 20 hours.After the completion of the reaction, the catalyst was filtered, and the reaction solution was analyzed by iodometry. It was found that no peroxide was contained (peroxide conversion rate 100
%). Further, when gas chromatography and MASS analysis were performed, the yield of 3-ethylbenzophenone was found to be
75%.

[Synthesis of 3- (1-bromoethyl) benzophenone] 60 ml of carbon tetrachloride and 10 g of 3-ethylbenzophenone (III) are placed in a 200 ml reactor equipped with a reflux condenser and a stirrer, and stirred at room temperature. 8.6 g of n-bromosuccinimide and 0.14 g of benzoyl peroxide were added thereto, and the reaction solution was heated and refluxed for 8 hours while stirring. After cooling the reaction solution to room temperature, succinimide was filtered, and carbon tetrachloride was distilled off from the filtrate under reduced pressure. Each spectrum data of the obtained product was consistent with that of 3- (1-bromoethyl) benzophenone.

[Synthesis of 3- (1-hydroxyethyl) benzophenone] 100 ml of water, 3.3 g of calcium carbonate and 10 g of 3- (1-bromoethyl) benzophenone were put in an autoclave and heated at 120 ° C. for 6 hours. After extracting the reaction solution with benzene and drying the benzene layer with anhydrous sodium sulfate,
The solvent was distilled off under reduced pressure. Each spectrum data of the obtained product was consistent with that of 3- (1-hydroxyethyl) benzophenone.

(Synthesis of ketoprofen)

3- (1) is added to 50 ml of anhydrous methanol containing 1.5% of hydrogen chloride.
(Hydroxyethyl) benzophenone (10 g) was dissolved, and to this was added a solution of [P (CH ₃ ) ₃ ] PdCl _{2 (} 0.1 g) in anhydrous methanol. This solution was put in an autoclave and heated at 500 atm and 95 ° C. for 5 hours in a carbon monoxide atmosphere. The reaction solution was transferred to a 200 ml reactor equipped with a reflux condenser and a stirrer, 5 ml of concentrated hydrochloric acid was added, and the mixture was refluxed for 4 hours under a nitrogen atmosphere. Water was added to the reaction solution, extracted with ether,
The ether layer was washed with water and extracted with a 5% aqueous potassium hydroxide solution. The ether layer was washed with water, dried over anhydrous sodium sulfate, and the ether was distilled off under reduced pressure. By recrystallization from benzene / petroleum ether, 2- (3
White crystals of -benzoylphenyl) propionic acid (ketoprofen) were obtained.

 The spectrum, melting point, etc. were the same as the standard.

────────────────────────────────────────────────── ─── Continued on the front page (72) Inventor Koichi Iwamoto 105 Toko Market, Saiwai-ku, Kawasaki City, Kanagawa Prefecture (56) References Can. J. Chem. , Vol. 9, p. 1555-1559 (1968) Kinetica kataliz, Vol. 14, No. 2, P. 341-345 (1973) (58) Fields investigated (Int. Cl. ⁶ , DB name) C07C 33/24 C07C 29/132 C07C 409/04-409/12 CA (STN) REGISTRY (STN)

Claims (2)

(57) [Claims] 1. Production of (3-ethylphenyl) phenylmethane hydroperoxide by oxidizing (3-ethylphenyl) phenylmethane with molecular oxygen in the presence of a base at a reaction temperature of 40 to 165 ° C. And then the reaction temperature
A process for producing (3-ethylphenyl) phenylmethanol, comprising reacting (3-ethylphenyl) phenylmethane hydroperoxide with a lower olefin in the presence of a metal catalyst in the range of 150 ° C. 2. A (3-ethylphenyl) phenylmethane hydroperoxide represented by the following formula (I).