JPH0220619B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the general formula () (In the formula, R ₁ is a hydrogen atom, a lower alkyl group, an alkoxy group, a hydroxyl group, an alkylcarbonyl group, R ₂
and R ₃ are selected from a hydrogen atom and a lower alkyl group, and both may be the same or different, m
represents an integer of 1 or 2, and l and n represent an integer of 0, 1 or 2. However, this excludes the case where m is 1 and l and n are 0. ) The present invention relates to a method for producing hydroxyphenyl-substituted fatty acids represented by: Hydroxyphenyl-substituted fatty acids of formula () are known as useful intermediates in the synthesis of choleretic active pharmaceuticals and pesticides. Several methods are known for synthesizing hydroxyphenyl-substituted fatty acids. For example, 2-methoxyacetophenone is converted to 2-methoxyphenylacetic acid, which is then treated with hydrobromic acid to produce 2-hydroxyphenylacetic acid (J.
Org.Chem.11 (1946) 798), a method for reducing nitrophenyl acetic acid to aminophenyl acetic acid, which is then diazotized and hydrolyzed to convert it to hydroxyphenylacetic acid (J.Chem.Soc. (London) 1948),
150), a method for hydrolyzing 2-bromophenyl acetic acid in an aqueous morpholine solution in the presence of a catalyst such as bis(ethylenediamine) copper salt (JOC
(USSR) 1971, 2666-2668), and a method of reacting a halogenated phenylacetic acid such as 2-chlorophenylacetic acid with a caustic alkali in the presence of metallic copper and a copper salt to give 2-hydroxyphenylacetic acid (especially Publication No. 47-4870) is known.
Among these known methods, the method described in JP-A-47-4870 is said to be superior in that 2-hydroxyphenylacetic acid can be obtained with a relatively high yield. (According to the same publication, the yield of 2-hydroxyphenylacetic acid is 82 to 95%.) However, in this method, the reaction is carried out under high temperature and high pressure conditions of 220 to 250°C and 20 to 60 atm. This is not an industrially advantageous method. An object of the present invention is to produce hydroxyphenyl-substituted fatty acids represented by the general formula () in high yield under conditions that are milder than the temperature and pressure conditions described in JP-A No. 47-4870. We are here to provide you with the technology that makes it possible. That is, the present invention provides a method for preparing general formula (I) in the presence of a catalyst. ₍ In _the formula _, R ₄ is selected from a hydrogen atom and a monovalent hydrocarbon group, m is an integer of 1 or 2, and l and n are integers of 0, 1 or 2. , except when m is 1 and l and n are 0) are reacted with an alkali to form the general formula () (In the formula, R ₁ , R ₂ , R ₃ , l, m and n have the same meanings as above.) In the method for producing hydroxyphenyl-substituted fatty acids represented by the formula:

Bis(8-quinolinolato)copper () represented by [Formula]
This method is characterized by using. Bis(8-quinolinolato) used as catalyst
Copper() is prepared by converting 8-quinolinol ( _C9H7NO ) into copper() salts, _{e.g. CuSO4.5H2O , CuCl2} ,
Cu (NO ₃ ) ₂・3H ₂ O, Cu (ClO ₄ ) ₂・6H ₂ O, Cu
It can be easily prepared by reacting with (C ₂ H ₃ O ₂ )・H ₂ O, etc. (The manufacturing method is, for example, JC
Fanning and H.B.Jonassen: J.Inorg.Nucl.
Chem., 1963, Vol. 25, pp 29-35. ) The preferred amount of the catalyst to be used varies depending on the reaction temperature, reaction time, halogenophenyl-substituted fatty acids, type of starting compound, etc., but is usually 0.001 to 0.3 mol, more preferably 0.01 to 0.3 mol per mol of halogenophenyl-substituted fatty acids. It can be selected within the range of 0.2 mol. The catalyst used in the hydrolysis reaction can be neutralized by adding an acid to the reaction mixture after the completion of the reaction to precipitate the catalyst as crystals, which can be collected by filtration and reused. Regarding the halogenophenyl-substituted fatty acids represented by the general formula (I) used as starting materials in the method of the present invention, X represents a halogen atom, and those in which the halogen is chlorine are particularly advantageous for use in the method of the present invention. It is a raw material. This is because, in general, chlorine substituents are difficult to hydrolyze unless under high temperature conditions. Furthermore, even if halogenophenyl-substituted fatty acids are free acids (R ₄ =H), they are esters (R ₄ =
(hydrocarbon group). Examples of the hydrocarbon group serving as R ₄ include alkyl groups such as methyl, ethyl and n-butyl, and aralkyl groups such as benzyl and phenethyl. Specific examples of halogenophenyl-substituted fatty acids include 4-chloro-3-methylphenylacetic acid, 3-chloro-4,6
-dimethylphenylacetic acid, 3-chloro-4,5-
Dimethylphenylacetic acid, 2-(4'-chloro-3'-
methylphenyl)butanoic acid, 2-(2'-chloro-
4'-methylphenyl)-2-methylpropanoic acid,
2-chloro-3-methoxyphenylacetic acid, 4-chloro-3-methoxyphenylacetic acid, 3-chloro-
6-methoxyphenylacetic acid, 2-chloro-5-acetylphenylacetic acid, 2-chloro-4-hydroxyphenylacetic acid, 2,5-dichlorophenylacetic acid, 3-(2'-chlorophenyl)propanoic acid, 4
- Free acids such as (4'-chlorophenyl)butanoic acid and esters such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-octyl, benzyl, α-phenethyl, β-phenethyl, etc. Examples include compounds. As the alkali to be reacted with the halogenophenyl-substituted fatty acids, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, etc. are used. The amount of alkali used is 1 to 10 mol, preferably 2 to 7 mol, per mol of halogenophenyl-substituted fatty acids. These alkalis are used as aqueous solutions, and the concentration is usually 50% by weight.
The content is preferably 5 to 30% by weight. If the concentration of the alkaline aqueous solution exceeds about 50% by weight, it becomes difficult to stir the reaction mixture uniformly, and a heterogeneous reaction tends to occur. The hydrolysis reaction is generally carried out at 100-300°C, preferably
Carry out at a temperature of 150-250 ° C. Reaction time is negatively correlated with reaction temperature, typically requiring several hours or more at relatively low temperatures such as 150-170°C and 2 hours or more at relatively high temperatures such as 230-250°C.
It may take an hour or less. In this way, the reaction time may be determined depending on the reaction temperature, catalyst, starting materials, etc. The hydrolysis reaction is conveniently carried out under autogenous pressure in a pressure-resistant reactor such as an autoclave, and generally,
Reaction temperatures of 150-250°C correspond to pressures of about 4 to about 35 Kg/cm ² . Hereinafter, the present invention will be specifically explained with reference to Examples. Example 1 13% sodium hydroxide aqueous solution in an autoclave
124 g (0.4 mol), 18.4 g (0.1 mol) of 4-chloro-3-methylphenylacetic acid, and 3.51 g (0.01 mol) of bis(8-quinolinolato) copper () were charged and reacted under pressure at 170°C for 2 hours. Reaction pressure is 6.5-7
It was Kg/ ^cm2 . After the reaction was completed, the obtained reaction mixture was allowed to cool, concentrated hydrochloric acid was added to neutralize it, and the produced copper bis(8-quinolinolato) was filtered off. The obtained filtrate was concentrated under reduced pressure, concentrated hydrochloric acid was added, and the precipitated crystals were collected by filtration, washed with water, and dried to give white plate-like crystals, melting point 109-110.
4-Hydroxy-3-methylphenylacetic acid at °C
15.8g (yield 95.4%) was obtained. Comparative example 1 13% sodium hydroxide aqueous solution in autoclave
124 g (0.4 mol), 18.4 g (0.1 mol) of 4-chloro-3-methylphenylacetic acid and copper sulfate ( _CuSO4 .
5H ₂ O) 2.5g (0.01mol) and heated at 170℃ under pressure.
The mixture was reacted for 6 hours. Reaction pressure is 6.5-7Kg/cm ²
It was hot. After the reaction was completed, the resulting reaction mixture was allowed to cool, acidified with concentrated hydrochloric acid, and the precipitated crystals were collected by filtration, washed with water, and dried. White plate-like crystals, melting point 109-110℃ 4
-Hydroxy-3-methylphenylacetic acid 4.1g (yield 25%) was obtained. Comparative example 2 13% sodium hydroxide aqueous solution in autoclave
124g (0.4mol), 4-chloro-3-methylphenylacetic acid 18.4g (0.1mol), copper powder 0.42g (0.0067mol)
and 0.44 g (0.0033 mol) of cupric chloride were charged and reacted under pressure at 170° C. for 6 hours. Reaction pressure is 6.5 ~
It was 7Kg/ ^cm2 . After the reaction was completed, the resulting reaction mixture was allowed to cool, and undissolved copper powder was filtered off. The obtained filtrate was concentrated under reduced pressure, then made acidic by adding concentrated hydrochloric acid, and the precipitated crystals were collected by filtration, washed with water, and dried. white plate crystals,
4.3 g (yield 26%) of 4-hydroxy-3-methylphenylacetic acid having a melting point of 109-110°C was obtained. Example 2 Following the same procedure as in Example 1, 2-(4'-chloro-3'-methylphenyl)butanoic acid was reacted with sodium hydroxide in the presence of copper bis(8-quinolinolato)(). The amount of 2-(4′-chloro-3′-methylphenyl)butanoic acid used was 21.2 g (0.1 mol).
Other than that, the reaction conditions were the same as in Example 1. The reaction product was treated in substantially the same manner as in Example 1 to obtain 19.2 g of 2-(4'-hydroxy-3'-methylphenyl)butanoic acid as a white amorphous powder with a melting point of 82-85°C (yield: 99°C).
%) was obtained. The above procedure was repeated with different reaction temperatures (and therefore reaction pressures) and reaction times. The results were as follows.

[Table] Example 3 2-(4'-Hydroxy-3'-methylphenyl)butanoic acid was synthesized according to the same method as in Example 2. However, the reaction temperature and reaction pressure are
The temperature was 170° C. and 6.5 to 7 Kg/cm ² , and the amount of catalyst and reaction time were changed as follows. The yield was as follows.

[Table] Examples 4 to 12 The same procedure as in Example 1 was carried out except that the halogenophenyl-substituted fatty acids and the catalyst were changed. The results are shown in the table below.

【table】

【table】

Claims (1)

[Claims] 1. General formula (I) in the presence of a catalyst ₍ In _the formula _, R ₄ is selected from a hydrogen atom and a monovalent hydrocarbon group, m is an integer of 1 or 2, and l and n are integers of 0, 1 or 2. , except when m is 1 and l and n are 0) are reacted with an alkali to form the general formula () (In the formula, R ₁ , R ₂ , R ₃ , l, m and n have the same meanings as above.) In the method for producing hydroxyphenyl-substituted fatty acids represented by the formula [Formula] as a catalyst, Bis(8-quinolinolato)copper() represented by
A method characterized by using.