JPS63422B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a novel method for producing phenylacetic acids, particularly 4-hydroxyphenylacetic acid or its alkyl ester, which are useful as intermediates for antibiotic modifiers or anti-inflammatory analgesics. As a method for producing 4-hydroxyphenylacetic acids, P-hydroxybenzaldehyde method, P
-Hydroxyacetophenone method, P-hydroxyphenyl malonic acid ester method, etc. are described in the literature, but they are not always suitable for industrial use due to the expensive raw materials and low yield of the target product. I'm not satisfied. However, the present inventors have conducted extensive research with the aim of solving this problem and industrially advantageously producing phenylacetic acids such as 4-hydroxyphenylacetic acid, and as a result, the general formula

[Formula] [where X; halogen, R ₁ , R ₂ ; hydrogen or lower alkyl group, Y;
OH is shown respectively. halogen-substituted phenyl acetic acid derivatives, especially 3-chloro-
A catalytic hydrogenation reaction is carried out while introducing hydrogen gas into a lower carboxylic acid and/or lower alcohol solution of 4-hydroxymandelic acid, and water is added to the system when hydrogen gas absorption substantially reaches equilibrium,
If the catalytic hydrogenation reaction is continued further, the general formula

The present inventors have discovered the novel fact that phenylacetic acids, particularly 4-hydroxyphenylacetic acid, represented by the formula [R ₁ and R ₂ are the same as above] can be obtained, and have completed the present invention. The present invention is characterized in that the dehalogenation of benzene nuclei and the hydrogenation of α-position carbon proceed smoothly through a simple operation called catalytic hydrogenation reaction, and the desired phenylacetic acids can be easily obtained. This technical content is completely new and previously unknown. In the reaction of the present invention, a lower carboxylic acid solvent (especially an acetic acid solvent), a lower alcohol solvent (especially a methanol or ethanol solvent), or a mixed solvent of both is used in the first half of the reaction, so that absorption of hydrogen gas is substantially balanced. After that point, that is, in the latter half of the reaction, by adding water to the system and continuing the reaction in a mixed solvent of lower carboxylic acid-water, lower alcohol-water, or lower carboxylic acid-lower alcohol-water. It is implemented efficiently. Even if a solvent other than a lower carboxylic acid, a lower alcohol, or a mixture of both is used, the reaction hardly occurs or an extremely long reaction time is required, which is impractical. Furthermore, if water is not added during the reaction, the reaction may stop at intermediates and the yield of the target product may decrease. It is necessary to add water around the time when the absorption of hydrogen gas is substantially in equilibrium. That is, when the reaction is started, absorption of hydrogen gas progresses, and usually gas absorption occurs up to a theoretical amount equivalent to the equimolar amount of the raw material. Near this stoichiometric amount of hydrogen gas absorption, gas absorption becomes very slow, so that virtually no absorption is observed or only very slight absorption is observed. Add water at this point. Adding water too early before the equilibrium point will reduce the yield of the target product, while adding water too late after the equilibrium point will prolong the reaction time. This is disadvantageous in practical terms. The point at which the absorption of hydrogen gas reaches equilibrium is probably the point at which an intermediate in which the substituent at the benzyl position of the halogen-substituted phenylacetic acid derivative is eliminated by hydrogenolysis is mainly produced. In this method, absorption of hydrogen gas substantially reaches equilibrium during the reaction, and the reaction appears to stop. If water is added to the system at this point, hydrogen gas will be absorbed again and the reaction will continue to proceed. It is believed that in this latter half of the reaction, dehalogenation of the intermediate described above occurs predominantly to produce the object of the present invention. The raw materials used in the present invention have the general formula as described above.

A halogen-substituted phenylacetic acid derivative represented by the formula: X, R ₁ ,
R ₂ and Y represent OH. Although there is no difference in the effects of the present invention with any of these combinations of compounds,
3-chloro-4-hydroxymandelic acid to 4-
The production of hydroxyphenyl acetic acid or its alkyl ester is preferably carried out. In such a case, 3-chloro-4-hydroxymandelic acid can be easily prepared by reacting glyoxylic acid and O-chlorophenol, and the method of the present invention is less expensive than the conventional method in terms of raw material costs and the desired product. It has an advantage in terms of yield, and its usefulness is extremely high. In carrying out the method of the present invention, a halogen-substituted phenyl acetic acid derivative is dissolved in a lower carboxylic acid solvent or a lower alcohol solvent, and hydrogen gas is introduced into the solution under normal pressure or increased pressure to perform a catalytic hydrogenation reaction. The solvent is used in an amount of 3 times or more by weight, preferably 4 to 7 times the weight of the halogen-substituted phenylacetic acid derivative as the raw material. Further, two or more of these solvents may be used in combination. During the hydrogenation reaction, it is necessary to use a nickel-based catalyst such as Raney nickel, a palladium-based catalyst such as palladium on carbon, or a platinum-based catalyst. Furthermore, in the present invention, it is necessary to coexist a strong acid during the reaction, and the use of such a strong acid is also a major feature of the present invention. That is, apart from the reduction of the α-position carbon, it is well known that when a nuclear halogen is eliminated by a catalytic hydrogenation reaction, the presence of a base in the system accelerates the dehalogenation reaction. Nevertheless, in the present invention, contrary to such conventional knowledge, the presence of a base inhibits the reaction, and the dehalogenation reaction does not proceed efficiently unless in the presence of a strong acid. Examples of strong acids include inorganic acids such as hydrochloric acid, sulfuric acid, orthophosphoric acid, polyphosphoric acid, perchloric acid, perbromic acid, and hydrobromic acid, and organic acids such as methanesulfonic acid, benzenesulfonic acid, and toluenesulfonic acid. Among such strong acids, sulfuric acid is preferably used. The strong acid is used in an amount of 0.05 to 0.5 mol per 1 mol of the halogen-substituted phenylacetic acid derivative. A suitable reaction temperature is 30 to 120°C, preferably 40 to 90°C. The reaction is carried out under the supply of hydrogen either under normal pressure or under increased pressure, and a practical hydrogen pressure in the reactor is selected to be 2 to 15 kg/cm ² . As the reaction progresses, the absorption of hydrogen gas eventually reaches an equilibrium, and the reaction appears to stop. At this point, when water is added to the system, hydrogen gas absorption starts again and the reaction progresses. The appropriate amount of water to be added is 0.1 times or more by weight, preferably 1 to 10 times the weight of the raw material halogen-substituted phenylacetic acid derivative; if it is less than 0.1 times the reaction, the reaction will not substantially proceed, but on the other hand, if it is 10 times or more by weight or more This is disadvantageous in terms of economic efficiency such as equipment efficiency.
Water may be supplied in any form, either liquid or heated steam. The reaction temperature after adding water is suitably in the range of 40 to 90°C. There is no particular restriction on the means for supplying hydrogen gas from the start to the end of the reaction, and any method such as a continuous method or a divided method may be employed. The reaction pressure can be either normal pressure or increased pressure, but a range of 2 to 15 kg/cm ² is suitable. Further, the reaction time varies depending on the activity of the catalyst, the reaction pressure, etc., but 2 hours or more is required. Furthermore, in carrying out the method of the present invention, in addition to lower carboxylic acids, lower alcohols, and water, solvents that are compatible with these, such as esters, acetone, acetic acid esters, hydrocarbons, and ethers, are added to the system. There is no harm in adding a small amount. After the reaction is completed, the catalyst component is removed according to a conventional method, and the target product such as 4-hydroxyphenylacetic acid is extracted from the reaction solution with a solvent. By removing the solvent from the extract, the desired product in the form of crystals or oil can be obtained. Purification treatment may then be performed as necessary. According to the present invention, for example, 4-hydroxyphenylacetic acid or its alkyl ester is
- It can be obtained with a yield of 70% or more based on hydroxymandelic acid, and its industrial utility value can be said to be extremely large. Next, the method of the present invention will be explained in more detail by giving examples. Example 1 After dissolving 2.5 g of 3-chloro-4-hydroxymandelic acid in 10 ml of acetic acid in a shaking pressure reactor,
0.175 ml of 95% sulfuric acid was added. Next, 125 mg of 5% palladium/carbon catalyst was added,
Raise the temperature to 65℃. Next, hydrogen gas was replaced, and while the hydrogen pressure was maintained at 4 kg/cm ^{2 ,} a catalytic hydrogenation reaction was carried out at a temperature of 63 to 67° C. with stirring for 1 hour. Further, 10 ml of water was introduced under pressure, and the catalytic hydrogenation reaction was continued at a hydrogen pressure of 4 kg/cm ² and a temperature of 63 to 67° C. for 4 hours. After the reaction was completed, the reactor was cooled to room temperature, hydrogen gas was purged, and the catalyst was separated. The liquid was concentrated under reduced pressure to remove acetic acid and water, and 10 ml of saturated brine was added to the residue, followed by extraction with 50 ml of ethyl acetate. When ethyl acetate was distilled off, 1.74 g of colorless needle crystals were obtained. When the gas chromatogram, infrared absorption spectrum, and NMR spectrum of the obtained crystals were measured, they matched those of the standard 4-hydroxyphenylacetic acid. The yield of 4-hydroxyphenylacetic acid was 92.7% based on 3-chloro-4-hydroxymandelic acid. Example 2 The same experiment as in Example 1 was conducted except that the amount of water used was changed to 5 ml. The yield of 4-hydroxyphenylacetic acid was 70.2%. Example 3 In the same reactor as Example 1, 10 ml of methanol
After dissolving 2.5 g of -chloro-4-hydroxymandelic acid, 0.215 ml of 95% sulfuric acid was added. Next 5
Add 250 mg of % palladium/carbon catalyst and raise the temperature to 100°C. Next, replace the hydrogen gas and reduce the hydrogen pressure to 8.5
The catalytic hydrogenation reaction was carried out for 24 hours with stirring at a temperature of 98 to 102° C. while maintaining the temperature at Kg/cm ² . Further, 10 ml of water was pressurized and the catalytic hydrogenation reaction was continued for 4 hours under the conditions of hydrogen pressure of 8.5 Kg/cm ² and temperature of 98 to 102°C. After the reaction was completed, the reactor was cooled to room temperature, hydrogen gas was purged, and the catalyst was separated. The liquid was concentrated under reduced pressure to remove methanol and water, and 10 ml of saturated brine was added to the residue, followed by extraction with 50 ml of ethyl acetate. When ethyl acetate was distilled off, 1.7g of light brown oil was obtained.
Obtained. The gas chromatogram, infrared absorption spectrum, and NMR spectrum of the obtained oil were measured, and the results matched those of the standard products 4-hydroxyphenylacetic acid and methyl 4-hydroxyphenylacetate. 4-hydroxyphenylacetic acid and 4
-The overall yield of methyl hydroxyphenylacetate is 3
-for chloro-4-hydroxymandelic acid
It was 83.0%. Example 4 In the same reactor as Example 1, 2.5 g of 3-chloro-4-hydroxymandelic acid was dissolved in 10 ml of acetic acid and 5 ml of methanol, and then 0.175 ml of 95% acetic acid was added. Next, 135 mg of 5% palladium/carbon catalyst is added and the temperature is raised to 65°C. Next, hydrogen gas was replaced and a catalytic hydrogenation reaction was carried out at a temperature of 62 to 66° C. for 2 hours with stirring while maintaining the hydrogen pressure at 10 Kg/cm ² . 5 more
ml of water was injected under pressure and the catalytic hydrogenation reaction was continued for 4 hours under the conditions of a hydrogen pressure of 10 Kg/cm ² and a temperature of 62 to 65°C. After the reaction was completed, the reactor was cooled to room temperature, hydrogen gas was purged, and the catalyst was separated. The liquid was concentrated under reduced pressure to remove acetic acid, methanol and water, and 10 ml of saturated brine was added to the residue, followed by extraction with 50 ml of ethyl acetate. When ethyl acetate was distilled off, 2.3 g of light brown oil was obtained. The gas chromatogram, infrared absorption spectrum, and NMR spectrum of the obtained oil were measured, and the results were consistent with those of standard 4-hydroxyphenylacetic acid and methyl 4-hydroxyphenylacetate. 4-hydroxyphenylacetic acid and 4
-The overall yield of methyl hydroxyphenylacetate is 3
-for chloro-4-hydroxymandelic acid
It was 78.9%.

Claims (1)

[Claims] 1 General formula [Formula] [where X: halogen, R ₁ , R ₂ ; hydrogen or lower alkyl group, Y: OH, respectively. ] A catalytic hydrogenation reaction is carried out while introducing hydrogen gas into a lower carboxylic acid and/or lower alcohol solution of a halogen-substituted phenylacetic acid derivative, and when hydrogen gas absorption substantially reaches equilibrium, the system A method for producing phenylacetic acids represented by the general formula [Formula] [R ₁ and R ₂ are the same as above], which comprises adding water to the mixture and continuing the catalytic hydrogenation reaction. 2. The manufacturing method according to claim 1, wherein the lower carboxylic acid is acetic acid. 3. The manufacturing method according to claim 1, wherein the lower alcohol is methanol.