JPH10279518A - Production of 4-biphenylylacetic acid - Google Patents

Abstract

PROBLEM TO BE SOLVED: To easily obtain the subject compound having an excellent antiinflammatory and analgesic action on an industrial scale in high yield by reducing a halogenobiphenylylacetic acid. SOLUTION: The objective compound of formula III can be produced by reacting 4-biphenylaldehyde of formula I with a haloform and a metal alkoxide in a non-aqueous system or with a haloform and an alkali metal hydroxide in a water-containing system in the presence of a phase-transfer catalyst and reducing the resultant halogeno-4-biphenylylacetic acid of formula II (X is a halogen) e.g. by catalytic reduction.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a method for producing 4-biphenylylacetic acid which is useful as an anti-inflammatory and analgesic agent.

[0002]

2. Description of the Related Art 4-Biphenylylacetic acid is a compound widely used clinically as a compound having a powerful anti-inflammatory and analgesic action. As a method for producing 4-biphenylylacetic acid, the following method has been conventionally proposed. (A): A method of producing 4-biphenylylacetic acid by using 4-biphenylaldehyde as a raw material and subjecting it to each step of reduction / halogenation / cyanation / hydrolysis [GermanPate
nt No. 658114 (1936)]. (B): Starting from biphenyl, 4-acetylbiphenyl is obtained by a Friedel-Crafts reaction between acetic anhydride and aluminum chloride, and then is converted to 4-acetylbiphenyl by a Wilgerott reaction.
-Method for producing biphenylyl acetic acid [E. Schwenk & DP
apa: J. Org. Chem., 11 , 798 (1946)]. (C): A method for producing 4-biphenylylacetic acid by reacting biphenyl with chloroacetic acid in the presence of ferric oxide and potassium bromide [Y. Ogata et al.,: J. Org. Chem., 16 , 239
(1951)]. (D): A method for producing 4-biphenylylacetic acid by hydrolyzing a reaction intermediate between an oxazine compound and a Grignard reagent of biphenyl [G. Ray Malone et al.,: J. Org. Chem., 39 ,
618 (1974)]. (E): 4-biphenylaldehyde is reacted with N in the presence of a base.
A method of producing 4-biphenylylacetic acid by subjecting an azlactone derivative obtained by reacting with acylglycine to a hydrolysis / decarboxylation step (JP-A-62-45554).

However, each of the above-described manufacturing methods has the following problems. The method of (A)
It is not preferable as an industrial production method for pharmaceuticals, because it involves many steps, does not necessarily have a high reaction yield, and uses a highly toxic cyanide compound.
In the method (B), there are many by-products in the reaction step, so that it is difficult to obtain a high-purity product, and the reaction yield is necessarily poor. Furthermore, since a sulfur compound is used in the Wilgellot reaction, there is a problem of offensive odor. The method (C) is an attractive method in that the desired 4-biphenylylacetic acid is obtained in a short step, but the method has a large amount of reaction by-products, an extremely low reaction yield, and severe reaction conditions. Which is not suitable for an industrial production method. The method (D) has a problem in that the Grignard reagent is industrially used, and the raw material is expensive. The method (E) involves a large amount of by-products in the reaction step, and therefore requires a complicated operation to obtain a high-purity product. Therefore, at present, it is required to establish a method for producing 4-biphenylylacetic acid which can solve the above problems and can be produced on an industrial scale.

[0004]

SUMMARY OF THE INVENTION In view of the above situation, an object of the present invention is to provide a method capable of producing 4-biphenylylacetic acid with good workability and high yield on an industrial scale.

[0005]

Means for Solving the Problems As a result of intensive studies to solve the above problems, the present inventors have found a method for producing 4-biphenylyl acetic acid from inexpensive raw materials and in good yield. Was completed. That is, the present invention provides the following formula (II):

[0006]

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Wherein X represents a halogen atom, wherein α-halogeno-4-biphenylyl acetic acid is reduced by the following formula (I):

[0008]

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It is another object of the present invention to provide a method for producing 4-biphenylylacetic acid represented by the formula: In this case, α represented by the formula (II)
-Halogeno-4-biphenylylacetic acid is represented by the following formula (II)
I):

[0010]

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The 4-biphenylaldehyde represented by the formula:
It can be obtained by reacting with a haloform and a metal alkoxide in a non-aqueous system, or by reacting with a haloform and an alkali metal hydroxide in the presence of a phase transfer catalyst in a hydrous system.

[0012]

Accordingly, in a specific embodiment of the present invention, 4-biphenylaldehyde represented by the formula (III) is reacted with haloform and a metal alkoxide in a non-aqueous system to obtain a compound represented by the formula (II): An object of the present invention is to provide a method for producing 4-biphenylyl acetic acid by converting α-halogeno-4-biphenylyl acetic acid represented by the following formula, and then reducing this.

[0013] In another specific embodiment of the present invention:
A 4-biphenylaldehyde represented by the formula (III) is
Reaction with haloform and an alkali metal hydroxide in the presence of a phase transfer catalyst in a water-containing system to form α-halogeno-4-biphenylyl acetic acid represented by the formula (II), and then reducing this, 4-biphenylyl An object of the present invention is to provide a method for producing acetic acid. Hereinafter, the production of 4-biphenylylacetic acid of the present invention will be described in detail by describing each step.

The production of 4-biphenylyl acetic acid according to the present invention comprises:
As the first step, first, 4-
It is carried out by reacting biphenylaldehyde with haloform and a base to produce α-halogeno-4-biphenylylacetic acid represented by the formula (II). Typically,
In the reaction between a benzaldehyde derivative and haloform in the presence of an alkali, an α-halogenophenylacetic acid derivative is produced as a reaction intermediate, which is immediately hydrolyzed, and the α-hydroxyphenylacetic acid derivative is obtained as a main product. Α-
Obtaining halogenophenylacetic acid derivatives has proven to be difficult (Synthesis, 1974, 724). However, as a result of earnest studies by the present inventors, in the reaction of 4-biphenylaldehyde with haloform and a base, by appropriately selecting an appropriate reaction condition and an appropriate reaction temperature, an intermediate α-halogeno-4 is formed. The inventors have found that the reaction can be stopped with -biphenylylacetic acid and the production of 4-biphenyl-α-hydroxyacetic acid as a hydrolyzate can be suppressed as much as possible, and the present invention has been completed based on such novel findings.

The reaction of 4-biphenylaldehyde provided by the present invention with haloform and a base is specifically carried out as follows. That is, in a non-aqueous reaction system, 4-biphenylaldehyde is converted into a metal such as chloroform, bromoform, etc. and potassium tert-butoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, sodium methoxide, sodium ethoxide, etc. The reaction can be performed by reacting with an alkoxide. Further, 4-biphenylaldehyde is reacted by reacting a haloform such as chloroform and bromoform with an alkali metal hydroxide such as sodium hydroxide and potassium hydroxide in the presence of a phase transfer catalyst in a water-containing reaction system. Can be. From the viewpoint of an industrial production method, a method based on the reaction of haloform with an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide in the presence of a phase transfer catalyst is particularly preferable. Examples of the haloform used in the reaction include haloforms such as chloroform, bromoform, and iodoform. The amount of these haloforms used is required to be at least equimolar to 4-biphenylaldehyde, and preferably It is preferable to use about 50 times mol.

Examples of the phase transfer catalyst to be present as a catalyst in a water-containing reaction system include ammonium salts such as tetra-n-butylammonium bromide and benzyltriethylammonium bromide, and phosphonium salts such as tetra-n-butylphosphonium bromide and tetraphenylphosphonium bromide. , 18-crown-6, 15
-Crown-5, dicyclohexyl-18-crown-
6, crown ethers such as dibenzo-18-crown-6 are preferably used. The amount used is 1 to 20 mol%, preferably 3 to 10 mol%, based on 4-biphenylaldehyde. When the amount of the catalyst is small, the reaction rate becomes slow, and it is not economical to use too much catalyst. The base used for the reaction in this case is
Alkali metal hydroxides such as sodium hydroxide and potassium hydroxide are preferred, with sodium hydroxide being particularly preferred. The base is used in an amount of at least 3 times the molar amount of 4-biphenylaldehyde, preferably about 4 to 8 times the molar amount.

In the reaction, a mixed solvent of haloform and water is usually used as a reaction reagent, and an organic solvent which does not directly affect the reaction can be used as a diluting solvent. Examples of such organic solvents include halogenated hydrocarbon solvents such as dichloromethane and 1,2-dichloroethane, ether solvents such as tetrahydrofuran and 1,4-dioxane, and acetonitrile. The amount of the solvent used is 5 to 4-biphenylaldehyde.
If the amount of the solvent is too small, it is difficult to ensure uniform stirring of the reaction system, and if the amount is too large, the reaction rate becomes slow, which is not preferable. This reaction is 0
C. to a temperature of about the boiling point of the solvent used, preferably from 10 to 50.degree. C., more preferably from about 20 to 40.degree. When the reaction temperature is too low, the progress of the reaction is insufficient, and when the reaction temperature is too high, α-hydroxy-4-biphenylyl acetic acid in which α-halogeno-4-biphenylyl acetic acid is hydrolyzed produces α-hydroxy-4-biphenylyl acetic acid. This is not preferable because of the possibility of the occurrence. The reaction time is generally from 1 to 24.
The reaction is completed in about an hour, usually about 8 to 16 hours. After completion of the reaction, α-halogeno-4-biphenylyl acetic acid, which is the target substance, can be isolated from the reaction mixture solution by a treatment method known per se.

The thus produced α-halogeno-4-biphenylyl acetic acid represented by the formula (II) is subjected to a reduction reaction, and the desired compound of the present invention, ie, α-halogeno-4-biphenylyl acetic acid, represented by the formula (I):
Biphenylyl acetic acid is produced. This reduction reaction can be preferably carried out by catalytic reduction using a catalyst or reduction using a metal reagent such as zinc, tin or iron. Examples of the catalyst used in the case of the catalytic reduction include palladium-carbon, palladium black, platinum black and the like, and the amount of the catalyst used is preferably 1 to 50% by weight relative to α-halogeno-4-biphenylyl acetic acid, preferably Ranges from 3 to 20% by weight. It should be noted that it is not economical to use too much catalyst, and if the amount of catalyst is small, it takes time to complete the reaction. The reaction temperature cannot be generally limited, but is 0 ° C to 150 ° C.
C., preferably 20 ° C. to 100 ° C., and increasing the reaction temperature is not preferable because even a biphenyl ring forms a reduced bicyclohexyl ring.

The hydrogen pressure in the present catalytic reduction is from normal pressure to 10
It is about 0 kg / cm ² , and usually, catalytic reduction under normal pressure is sufficient. Too high a reaction pressure is not preferable because it requires a special reaction facility and is not practical, and also produces a reduced bicyclohexyl ring up to the biphenyl ring. The reaction time cannot be unconditionally limited by the kind of the catalyst used, the amount of the catalyst, the reaction pressure and the reaction temperature, but usually 0.5 to 8 hours is sufficient. This catalytic reduction can be carried out without using a solvent, but in order to carry out the reaction smoothly, it is preferable to carry out the reaction in an appropriate solvent that does not directly affect the reaction. Such solvents include:
Examples thereof include alcohols such as methanol, ethanol, and isopropanol; ethers such as diethyl ether, 1,4-dioxane and tetrahydrofuran; and organic acids such as formic acid and acetic acid. The amount of the solvent used is less than about 100 ml with respect to 1 g of α-halogeno-4-biphenylylacetic acid to be reduced. If the amount of the solvent is large, the size of the reaction vessel must be increased, which is not economical. In this catalytic reduction reaction, in order to trap hydrogen halide generated by reduction, sodium hydroxide,
It is preferable to coexist a base such as potassium hydroxide.
Instead of using hydrogen gas as described above, it is also possible to use formates such as ammonium formate, sodium formate and potassium formate, and hypophosphites such as sodium hypophosphite and calcium hypophosphite as reducing agents. It is. In this case, the catalyst, solvent and reaction conditions used are the same as those when hydrogen gas is used, and the amount of formates and hypophosphites used is based on 1 mol of α-halogeno-4-biphenylyl acetic acid to be reduced. About 1 to 10 times mol, preferably 3 to 10 times
It is preferable to use about 5 times mol.

In the present catalytic reduction, the α-halogeno-4-biphenylyl acetic acid to be reduced may be in the form of a free acid or in the form of a metal salt such as sodium α-halogeno-4-biphenylyl acetate. Can also be satisfactorily reacted. Therefore, 4-
The alkali metal salt of α-halogeno-4-biphenylylacetic acid produced by the reaction of biphenylaldehyde with haloform and an alkali metal hydroxide such as sodium hydroxide and potassium hydroxide is directly subjected to the present catalytic reduction reaction, To 4-biphenylylacetic acid.

On the other hand, when reduction is carried out using a metal reagent such as zinc, tin or iron, α-halogeno-4-biphenylylacetic acid is dissolved in a suitable solvent, and if necessary, an acid, preferably hydrochloric acid or the like is used. A metal reagent is added to this in the presence of
It can be performed by reacting. In this case, the amount of the metal reagent used is about 1 to 10 moles, preferably about 1.2 to 2.5 moles per mole of α-halogeno-4-biphenylylacetic acid to be reduced. The amount of the mineral acid, such as hydrochloric acid, that can be present in the reaction solution is 0.5 to 20 times, preferably 2 to 5 times, 1 mole of α-halogeno-4-biphenylyl acetic acid to be reduced.
It is preferable that the amount be within the range of about twice the molar amount. As a solvent used in the reaction, a solvent that dissolves α-halogeno-4-biphenylylacetic acid is preferable. As such a solvent, organic acids such as formic acid and acetic acid, and alcohols such as ethanol and isopropanol are preferably used. However, it goes without saying that any solvent that can gradually dissolve 4-biphenylylacetic acid generated during the reaction can be used even in a suspended state. When organic acids are used as the reaction solvent, there is no need to add a mineral acid such as hydrochloric acid. The reaction is carried out at a temperature from room temperature to the reflux temperature of the reaction mixture, preferably in the range of 80 ° C. to 120 ° C., more preferably near the boiling point of the reaction solvent used.

The 4-biphenylylacetic acid produced by the above reaction is isolated by filtering the reaction solution to remove the catalyst, etc., followed by ordinary extraction, concentration and, if necessary, recrystallization. It is performed by a known operation, and 4-biphenylylacetic acid can be obtained as crystals.

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

[0024]

EXAMPLES Example 1 Preparation of α-chloro-4-biphenylylacetic acid: 9.11 g (0.05 mol) of 4-biphenylaldehyde
Was dissolved in 100 ml of chloroform, 0.81 g (0.0025 mol) of tetra-n-butylammonium bromide was added, and then 9.0 g (0.225 mol) of sodium hydroxide was added.
(Mol) at 25 ° C. After completion of the dropwise addition, the mixture was reacted at the same temperature for 16 hours, and the precipitated crystals were collected by filtration. The obtained crystals were converted into free acids with hydrochloric acid, and then extracted with ethyl acetate. The extract was concentrated to dryness under reduced pressure, recrystallized from toluene, and 10.04 g of α-chloro-4-biphenylylacetic acid was obtained as pale yellow crystals (yield: 81.4%).
Obtained. Melting point: 141-144 ° C IR (KBr, cm ^-1 ): 1725, 1408, 127
6,1198,834,753 NMR (270 MHz, CDCl ₃ ), δ: 5.26
(1H, s, -CH-), 7.25-7.77 (9H,
m, aromatic hydrogen), 9.04 (1H, br, -COO
H)

Example 2 Production of α-chloro-4-biphenylylacetic acid: The procedure of Example 1 was repeated, except that benzyltriethylammonium bromide was used instead of tetra-n-butylammonium bromide. After the treatment, 7.89 g (yield: 64.0%) of α-chloro-4-biphenylylacetic acid was obtained as pale yellow crystals. The physical properties of this product completely coincided with those obtained in Example 1.

Example 3 Preparation of α-chloro-4-biphenylylacetic acid: In Example 1, tetra-n-butylphosphonium bromide was used in place of tetra-n-butylammonium bromide, and the other conditions were exactly the same as in Example 1. To give 9.45 g (yield: 77.3%) of α-chloro-4-biphenylylacetic acid as pale yellow crystals. The physical properties of this product completely coincided with those obtained in Example 1.

Example 4 Preparation of α-chloro-4-biphenylylacetic acid: 9.11 g (0.05 mol) of 4-biphenylaldehyde
Is added to 20 ml of chloroform and 80 ml of dichloromethane.
And mixed with 0.81 g (0.0025 mol) of tetra-n-butylammonium bromide, and then 9.0 g (0.225 mol) of sodium hydroxide in 20 m of water.
The solution was added dropwise at 25 ° C. After dropping, 1
After reacting for 6 hours, the precipitated crystals were collected by filtration. The obtained crystals were converted into free acids with hydrochloric acid, and then extracted with ethyl acetate. The extract was concentrated under reduced pressure to dryness and recrystallized from toluene to obtain 10.01 g (yield: 81.2%) of α-chloro-4-biphenylylacetic acid as pale yellow crystals. The physical properties of this product completely coincided with those obtained in Example 1.

Example 5 : Production of α-chloro-4-biphenylylacetic acid: In Example 4, tetrahydrofuran was used in place of dichloromethane as a reaction solvent, and otherwise Example 4
6.29 g (yield: 51.0) of α-chloro-4-biphenylylacetic acid as pale yellow crystals.
%)Obtained. The physical properties of this product completely coincided with those obtained in Example 1.

Example 6 : Production of α-chloro-4-biphenylylacetic acid: In Example 4, acetonitrile was used in place of dichloromethane as the reaction solvent, and the reaction was carried out in the same manner as in Example 4. 7.15 g of -chloro-4-biphenylylacetic acid as pale yellow crystals (yield: 58.0%)
Obtained. The physical properties of this product completely coincided with those obtained in Example 1.

Example 7 Preparation of sodium α-chloro-4-biphenylyl acetate: 9.11 g (0.05 mol) of 4-biphenylaldehyde
Was dissolved in 100 ml of chloroform, 0.81 g (0.0025 mol) of tetra-n-butylammonium bromide was added, and then 9.0 g (0.225 mol) of sodium hydroxide was added.
(Mol) at 25 ° C. After the completion of the dropwise addition, the mixture was reacted at the same temperature for 16 hours, and the precipitated crystals were collected by filtration to obtain 12.29 g of sodium α-chloro-4-biphenylyl acetate as white crystals (yield: 91.5%). . Melting point: 280 ° C. or higher. IR (KBr, cm ^-1 ): 1609, 1398, 122
9,835,794,692 NMR (270 MHz, DMSO-d ₆ ), δ: 5.2
6 (1H, s, -CH-), 7.25-7.77 (9
H, m, aromatic ring hydrogen)

Example 8 Preparation of α-bromo-4-biphenylyl acetic acid: 9.11 g (0.05 mol) of 4-biphenylaldehyde
Was dissolved in 100 ml of bromoform, and after adding 0.81 g (0.0025 mol) of tetra n-butylammonium bromide, 9.0 g (0.225 mol) of sodium hydroxide was added.
(Mol) at 25 ° C. After completion of the dropwise addition, the mixture was reacted at the same temperature for 16 hours, and the precipitated crystals were collected by filtration. The obtained crystals were converted into free acids with hydrochloric acid, and then extracted with ethyl acetate. The extract was concentrated under reduced pressure to dryness and recrystallized from toluene to obtain 5.73 g (yield: 39.4%) of α-bromo-4-biphenylylacetic acid as pale yellow crystals. Melting point: 146-149 ° C IR (KBr, cm ^-1 ): 1717, 1409, 116
8,883,749,693 NMR (270 MHz, CDCl ₃ ), δ: 5.41
(1H, s, -CH-), 7.33-7.65 (9H,
m, aromatic hydrogen), 9.22 (1H, br, -COO
H)

Example 9 : Preparation of 4-biphenylyl acetic acid: 6.7 g (0.12 mol) of potassium hydroxide was dissolved in 125 ml of methanol, and 12.33 g of α-chloro-4-biphenylyl acetic acid was added to this solution. 05 mol) and 5
% Palladium-carbon was added, and a reduction reaction was performed at 20 to 30 ° C. for 2 hours under a hydrogen atmosphere at normal pressure. After completion of the reaction, the catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to dryness. The obtained residue was converted into a free acid with hydrochloric acid, and then extracted with methyl ethyl ketone. The extract was concentrated under reduced pressure to dryness and recrystallized from isopropanol to obtain 8.82 g (yield: 83.1%) of 4-biphenylylacetic acid as white crystals.
Melting point: 163-164 ° C IR (KBr, cm ^-1 ): 3426, 1690, 125
9,929 NMR (270 MHz, DMSO-d ₆ ), δ: 3.6
_{1 (2H, s, -CH 2} -), 7.31-7.66 (9
H, m, aromatic ring hydrogen), 12.29 (1H, br, -C
OOH)

Example 10 Preparation of 4-biphenylyl acetic acid: Sodium α-chloro-4-biphenylyl acetate 13.4
3 g (0.05 mol) were suspended in 125 ml of methanol, and 0.6 g of 5% palladium-carbon was added thereto.
The reduction reaction was performed at 20 to 30 ° C. for 2 hours under a hydrogen atmosphere at normal pressure. After completion of the reaction, the catalyst was removed by filtration, the filtrate was concentrated under reduced pressure to dryness, and recrystallized from isopropanol, and 8.52 g of 4-biphenylylacetic acid was obtained as white crystals (yield: 8).
0.3%). The physical properties of this product completely coincided with those obtained in Example 9.

Example 11 Preparation of 4-biphenylyl acetic acid: α-bromo-4-biphenylyl acetic acid 1 was added to a solution of 6.7 g (0.12 mol) of potassium hydroxide in 125 ml of methanol.
4.56 g (0.05 mol) and 0.6 g of 5% palladium-carbon were added, and 20 to 3 were added under a hydrogen atmosphere at normal pressure.
The reduction reaction was performed at 0 ° C. for 2 hours. After completion of the reaction, the catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to dryness. The obtained residue was converted into a free acid with hydrochloric acid, and then extracted with methyl ethyl ketone. The extract was concentrated under reduced pressure to dryness and recrystallized from isopropanol to give 4-biphenylylacetic acid as white crystals.
75 g (yield: 82.4%) was obtained. The physical properties of this product completely coincided with those obtained in Example 9.

Example 12 : Preparation of 4-biphenylyl acetic acid: 12.33 g of α-chloro-4-biphenylyl acetic acid (0.
(0.5 mol) was dissolved in 60 ml of acetic acid and zinc powder was added.
9 g (0.075 g equivalent) was added and reacted at 110 ° C. for 2 hours. After completion of the reaction, the reaction solution was adjusted to pH 1 with hydrochloric acid, and extracted with methyl ethyl ketone. The extract was concentrated under reduced pressure to dryness, recrystallized from isopropanol, and 8.79 g (yield: 8) of 4-biphenylylacetic acid as white crystals.
2.8%). The physical properties of this product completely coincided with those obtained in Example 9.

Example 13 : Preparation of 4-biphenylyl acetic acid: 12.33 g of α-chloro-4-biphenylyl acetic acid (0.
(0.5 mol) was dissolved in 100 ml of isopropanol, and 7.1 g (0.06 g equivalent) of tin powder was further added, followed by reaction at 80 ° C. for 2 hours. After completion of the reaction, the reaction solution was adjusted to pH 1 with hydrochloric acid, and extracted with methyl ethyl ketone. The extract was concentrated under reduced pressure to dryness, recrystallized from isopropanol,
6.0 g (yield: 56.5%) of 4-biphenylylacetic acid was obtained as white crystals. The physical properties of this product were as described in Example 9
Completely matched what was obtained in.

Example 14 : Preparation of 4-biphenylylacetic acid: 12.33 g of α-chloro-4-biphenylylacetic acid (0.
05 mol) in 60 ml of acetic acid, and further 3.4 parts of iron powder.
g (0.06 g equivalent) was added and reacted at 110 ° C. for 2 hours. After completion of the reaction, the reaction solution was adjusted to pH 1 with hydrochloric acid, and extracted with methyl ethyl ketone. The extract was concentrated under reduced pressure to dryness, recrystallized from isopropanol, and 5.75 g of 4-biphenylylacetic acid as white crystals (yield: 54.2).
%)Obtained. The physical properties of this product completely coincided with those obtained in Example 9.

Example 15 : Preparation of 4-biphenylylacetic acid: Dissolve 12.22 g (0.2 mol) of potassium hydroxide in 125 ml of methanol, and add 9.39 g (0.2%) of 98% formic acid.
Mol), 13.43 g (0.05 mol) of sodium α-chloro-4-biphenylyl acetate are added. Under a nitrogen atmosphere, 0.6 g of 10% palladium-carbon was added, and the mixture was stirred at 20 to 25 ° C for 2 hours. After completion of the reaction, the catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to dryness. The obtained residue was converted into a free acid with hydrochloric acid, and then extracted with methyl ethyl ketone. The extract was concentrated under reduced pressure to dryness and recrystallized from isopropanol to obtain 8.96 g (yield: 84.4%) of 4-biphenylylacetic acid as white crystals. The physical properties of this product completely coincided with those obtained in Example 9.

Example 16 Preparation of 4-biphenylylacetic acid: 12.61 g (0.2 mol) of ammonium formate was dissolved in 125 ml of methanol, and 13.43 g (0.05 mol) of sodium α-chloro-4-biphenylyl acetate was dissolved. Add. Under a nitrogen atmosphere, 10% palladium-carbon 0.6
g was added and the mixture was stirred at 20 to 25 ° C for 2 hours. After completion of the reaction, the catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to dryness. The obtained residue was converted into a free acid with hydrochloric acid, and then extracted with methyl ethyl ketone. The extract was concentrated under reduced pressure to dryness, and recrystallized from isopropanol to obtain 8.74 g (yield: 82.4%) of 4-biphenylylacetic acid as white crystals. The physical properties of this product completely coincided with those obtained in Example 9.

[0040]

As described in detail above, the present invention easily prepares 4-biphenylylacetic acid having an excellent anti-inflammatory and analgesic action,
Further, the present invention provides a method that can be industrially produced with a high yield, is highly useful in that it greatly contributes to a reduction in the price of 4-biphenylylacetic acid, and has a great industrial utility value.

──────────────────────────────────────────────────続 き Continued on front page (51) Int.Cl. ⁶ Identification symbol FI // C07B 61/00 300 C07B 61/00 300 (72) Inventor Toshio Watanabe 1633 Oji-Machiba Kawagoe-shi, Saitama Wako Pure Chemical Industries Co. Inside the Tokyo Research Laboratory

Claims (4)

[Claims] 1. The following formula (II): Wherein X represents a halogen atom, wherein α-halogeno-4-biphenylyl acetic acid represented by the following formula (I) is reduced: A method for producing 4-biphenylylacetic acid represented by the formula: 2. The following formula (III): Is reacted with haloform and a metal alkoxide in a non-aqueous system to obtain the following formula (II): Wherein X represents a halogen atom, wherein α-halogeno-4-biphenylyl acetic acid represented by the following formula (I) is reduced: A method for producing 4-biphenylylacetic acid represented by the formula: 3. The following formula (III): Is reacted with haloform and an alkali metal hydroxide in the presence of a phase transfer catalyst in a water-containing system to obtain the following formula (II): Wherein X represents a halogen atom, wherein α-halogeno-4-biphenylyl acetic acid represented by the following formula (I) is reduced: A method for producing 4-biphenylylacetic acid represented by the formula: 4. The following formula (III): Is reacted with haloform and an alkali metal hydroxide in the presence of a phase transfer catalyst in a water-containing system, the following formula (II): (Wherein, X represents a halogen atom.) A method for producing α-halogeno-4-biphenylyl acetic acid represented by the formula: