JPS6251251B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a method for producing 4-(meth)allyloxyphenylacetic acids, particularly preferably 3-chloro-4-allyloxyphenylacetic acid. 3-Chloro-4-allyloxyphenylacetic acid is a useful drug that has antipyretic, antiinflammatory, and analgesic effects. However, typical methods for producing acetic acid include (1) 3-chloro-4-allyloxyphenyl acetate produced by reacting 3-chloro-4-hydroxyphenyl acetate with allyl halide; A method of hydrolyzing
7421) (2) 1-(3-chloro-4-hydroxyphenyl)-2,2,2-trihaloethanol and allyl halide are reacted to produce 1-(3-chloro-4-allyloxyphenyl). )-2,2,2-
After producing trihaloethanol and further reacting it with alcohol in the presence of an alkali, for example,
A method of reducing the amount of carbon dioxide (Japanese Unexamined Patent Publication No. 112839/1983) is known. However, upon investigation by the present inventors, it became clear that the above-mentioned known method has the following problems. That is, in the method (1), allyl bromide is used as the allyl halide in terms of yield, but this drug is expensive and has problems due to concerns about corrosivity. Furthermore, method (2) requires three steps from allyl etherification to production of the target product, and the yield in each step is not necessarily satisfactory when implemented on an industrial scale. There's a problem. However, the present inventors have worked hard to solve the problems of such conventional methods and to develop an industrially advantageous method for producing 4-(meth)allyloxyphenylacetic acids such as 3-chloro-4-allyloxyphenylacetic acid. After repeated research, the general formula

[Formula] (where R represents hydrogen, halogen, lower alkyl, lower alkenyl, or lower alkoxy; R ¹ represents hydrogen or lower alkyl) and aromatic sulfonic acid (meth). ) allyl ester in the presence of an alkali hydroxide at a temperature below room temperature to produce 4-(meth)allyloxyphenyl acetate esters, and then by hydrolyzing the ester, the general formula

[Formula] (R is the same as above, X represents hydrogen or methyl)
The present inventors have discovered that 4-(meth)allyloxyphenylacetic acids represented by the formula can be produced in good yields, and have completed the present invention. The characteristics of the present invention are that aromatic sulfonic acid (meth)allyl ester is used as the (meth)allyl etherifying agent, that the reaction is carried out in the presence of alkali hydroxide, and that the reaction is carried out at room temperature or below. , has the following advantages compared to known methods. (b) Aromatic sulfonic acid (meth)allyl ester has no risk of corroding the reaction equipment, and aromatic sulfonic acid produced as a by-product in the (meth)allyl etherification process can be easily recovered from the reaction system. By subsequently converting it into a (meth)allyl ester, it becomes possible to use it again as a (meth)allyl etherifying agent, which is economically extremely advantageous. (b) Since alkali hydroxide is used, aqueous media must also be fully usable. (c) Since the reaction can be carried out at a low temperature below room temperature, no special heat source is required and it is industrially advantageous. In conventional methods, the (meth)allyl etherification reaction is usually carried out at room temperature or above, preferably under reflux, from the viewpoint of yield, but in the present invention, the yield is considerably reduced when the reaction is carried out at room temperature or above, preferably under reflux. This is disadvantageous in practice. That is, the present invention uses a different (meth)allyl etherifying agent compared to the known method (1), and a different starting material compared to the known method (2), so the reaction is significantly different from the conventional method. Temperature conditions must be adopted. In particular, (2) exemplifies P-toluenesulfonic acid allyl ester as an allyl etherification agent, but as mentioned above, the starting material is completely different from that of the present invention, so it is significantly different from (2). It is therefore essential to select the temperature conditions. In the present invention, the method for producing 4-hydroxyphenylacetic acids, which are the raw materials used in the above process, also needs to be devised, and the connection between this process and the allyl etherification process described above is also unique. We also investigated methods for producing enyl acetic acids. That is, 4-substituted phenylacetic acid in which the hydroxyl group of the benzene nucleus is substituted with a functional group such as an alkoxy group.

There are a few documents describing the method for producing [Formula], but there are no documents describing the method for producing 4-hydroxyphenylacetic acids from 4-hydroxymandelic acids. This is thought to be due to the fact that substituting the hydroxyl group of the benzene nucleus with a functional group is advantageous for the reduction treatment. Therefore, when producing 4-hydroxyphenylacetic acids by conventional methods, a step of converting the substituent at the 4-position to a hydroxyl group is always required. Therefore, even if the reaction is similar to the reaction for producing 4-substituted phenylacetic acids and the number of steps is the same, if 4-hydroxyphenylacetic acids can be directly produced, at least one step will be required compared to the conventional method. Since it can be omitted, it can be said that it is advantageous when carried out on an industrial scale. From this point of view, the present inventors used 4-hydroxyphenylacetic acids, particularly preferably 3-chloro-4-
After extensive research on the method of producing hydroxyphenylacetic acid, the general formula

4-hydroxymandelic acids represented by the formula (R ¹ represents hydrogen or lower alkyl, etc.), particularly preferably 3-chloro-
The present inventors have discovered that the desired product can be obtained efficiently when 4-hydroxymandelic acid is reduced, leading to the completion of the present invention. Conventionally, α
Although it is known to convert the hydroxyl group at the - position to hydrogen to produce the corresponding phenylacetic acids, there are no literature examples of a method for reducing the benzene nucleus while leaving the hydroxyl group. However, in the present invention, unlike conventional methods, the desired 4-hydroxyphenylacetic acid can be obtained directly and efficiently by directly carrying out the reduction treatment without replacing the hydroxyl group of the benzene nucleus. I found out. Furthermore, the present inventors continued research on methods for producing 4-hydroxymandelic acids, which are the raw materials mentioned above, and found that the general formula

[Formula] [R represents hydrogen, halogen, lower alkyl, lower alkenyl, lower alkoxy, etc.] Phenols and glyoxylic acid are reacted at a temperature of 40°C to 100°C to produce 4-hydroxymandelic acid. We have also discovered the novel fact that when producing mandelic acids, the mandelic acids can be obtained in highly pure crystalline form. When the crystalline 4-hydroxymandelic acids are subjected to a reduction treatment to produce 4-hydroxyphenylacetic acids, the reduction reaction proceeds extremely smoothly, and the reduction reaction proceeds extremely smoothly, and the aqueous solution or syrupy form obtained by other methods is 4
- There is a significant difference from when using hydroxymandelic acids. As described above, the present invention has a major feature that could not be expected based on conventional knowledge, such as the fact that 4-hydroxymandelic acids can be isolated in crystalline form. In the method of the present invention, in order to convert 4-hydroxymandelic acids into 4-hydroxyphenylacetic acids, it is necessary to dissolve the crystals of 4-hydroxymandelic acids in an appropriate organic solvent and perform a reduction treatment. One of the most promising methods to be implemented on an industrial scale is to obtain 4- as a crystal by reacting substituted phenols with glyoxylic acid. In the case of producing hydroxymandelic acids, there have been few reports on production methods that allow isolation of crystalline 4-hydroxymandelic acids. 4-, which is slightly obtained in the field of vanillin production by reacting substituted phenols with glyoxylic acid.
It has been confirmed that 4-hydroxymandelic acids exist as an intermediate in the series of reaction processes in which vanillin is produced by directly oxidizing the crude reaction solution containing hydroxymandelic acids. There is no need to isolate it as a crystal from the system, so there is no awareness of it at all. However, in the present invention, the general formula

[Formula] [R is the same as above] Phenols, particularly preferably 0-chlorophenol and glyoxylic acid, are combined at 40°C to 100°C, preferably at 60°C.
When reacting at temperatures between ℃ and 90℃, the general formula

[Formula] 4-hydroxymandelic acids represented by [R ¹ is the same as above],
Particularly preferably, crystals of 3-chloro-4-hydroxymandelic acid are easily obtained, and from the crystals, 4-
The above objective of directly producing hydroxyphenylacetic acids can be achieved. The present invention comprises (1) a step of producing 4-hydroxymandelic acids from phenols and glyoxylic acid;
(2) a step of reducing the mandelic acids to produce 4-hydroxyphenylacetic acid; (3) converting the 4-hydroxyphenylacetic acids into (meth)allyl ether and then hydrolyzing the 4-(meth) ) It consists of a process for producing allyloxyphenylacetic acids, and is represented by the following general formula. Among these combinations of steps, the steps considered to be the most industrially practical for producing 3-chloro-4-allyloxyphenylacetic acid, which is the main objective of the present invention, are as follows. It is. (R ² represents an alkyl group) Hereinafter, a detailed explanation will be given step by step from step (1). First, in carrying out the reaction between phenols and glyoxylic acid, the temperature is 40°C to 100°C, preferably 60°C to
The biggest feature is that it is carried out at a fairly high temperature of 90℃. Conventionally, when carrying out a reaction using glyoxylic acid as a raw material, the conventional method is to carry out the reaction at a relatively low temperature below room temperature in order to avoid the decomposition of glyoxylic acid.However, in the reaction with phenols as in the present application, This method is completely different from the conventional method, and even though the reaction is carried out at a considerably high temperature, 4-hydroxymandelic acids are produced in a surprisingly high yield and in a short reaction time, and after the reaction is completed, they precipitate as crystals. The fact that such a unique effect is obtained only in the case of a specific combination of phenols and glyoxylic acid is a novel fact that could not be expected from conventional knowledge. In the present invention, it is particularly preferable to use 0-chlorophenol as the phenol to produce 3-chloro-4-hydroxymandelic acid.

Any compound represented by the formula can be practically used, and the corresponding 4-hydroxymandelic acids can be produced. The position where R is usually present is the 2-position relative to the hydroxyl group, but is not necessarily limited to this. R is hydrogen, halogen (chloro, bromo, etc.), lower alkyl group (methyl, ethyl, propyl, isopropyl, butyl, etc.), lower alkenyl group (allyl, etc.), lower alkoxy group (methoxy,
(ethoxy, propoxy, butoxy, etc.) are exemplified. In addition, glyoxylic acid can be used as it is, usually as a commercially available aqueous solution of about 20 to 50% by weight, but it is not necessarily limited to this, and it can also be used as a diluted or concentrated aqueous solution, or as a powder. Any form of glyoxylic acid hydrate can be used. The reaction between phenols and glyoxylic acid is usually carried out in the presence of an alkali. Examples of the alkali include sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, etc. Among them, sodium hydroxide and potassium hydroxide are preferably used. The ratio of glyoxylic acid, phenols and alkali to be used is selected from the range of glyoxylic acid:phenols:alkali=1:0.8 to 10:1 to 5, preferably from the range of 1:1.2 to 3.5:1.2 to 4.0. desirable. To carry out the reaction, glyoxylic acid, phenols and an alkali are mixed together and heated. There are no particular restrictions on the method of preparation and any method can be adopted, but usually phenols are used as the medium. is dispersed, an aqueous alkaline solution is added thereto, and then a predetermined amount of glyoxylic acid is added as an aqueous solution or an aqueous solution of an alkali salt. Usually the reaction is carried out in an aqueous medium. Glyoxylic acid can be used as an aqueous solution. Although water is the most practical solvent, other organic solvents that are compatible with water may also be used in combination. As mentioned above, the reaction temperature is the most important factor in the present invention, and is preferably 40°C to 100°C, preferably 60°C to 90°C.
It is necessary to strictly adjust the When the reaction is carried out at 40° C. or lower, it is virtually impossible to precipitate the produced 4-hydroxymandelic acids as crystals in the system because the reaction rate is slow.
On the other hand, when carrying out the reaction at a temperature of 100℃ or higher,
The yield of 4-hydroxymandelic acids is greatly reduced, and this method cannot be put to practical use. Since the reaction time varies somewhat depending on the reaction temperature, it cannot be absolutely specified, but in the case of a reaction at 60°C to 90°C, the reaction is usually sufficiently completed in about 2 to 5 hours. It is also one of the features of the present invention that crystals of 4-hydroxymandelic acids can be obtained with good yield in such a short time. Furthermore, when carrying out the reaction, it is desirable to maintain the reaction system in an atmosphere of an inert gas such as nitrogen or argon, since coloring of the crystals of 4-hydroxymandelic acids can be prevented. After the reaction has finished,
After acidification, the end-reacted phenols are extracted and removed from the reaction-completed solution using a suitable organic solvent such as benzene, toluene, or chloroform. 4 from the obtained aqueous layer part
- There are two methods for obtaining crystals of hydroxymandelic acid, as described below, and a preferred method can be carried out as needed. When the obtained aqueous layer is cooled to about 5° C. or lower, crystals of 4-hydroxymandelic acids are precipitated. The crystals are separated from the system by conventional further operations such as centrifugation, straining, etc. 4-Hydroxymandelic acids are extracted and separated from the resulting aqueous layer using an appropriate organic solvent such as esters such as methyl acetate, ethyl acetate, or butyl acetate, or ethers such as diethyl ether, and the solvent is removed from the extract. By removing it, 4-hydroxymandelic acids are precipitated as crystals. The crystals of 4-hydroxymandelic acids obtained by , are commercialized through appropriate steps such as washing and drying. If necessary, it is also possible to further purify by any means such as activated carbon treatment and recrystallization. The crystalline 4-hydroxymandelic acids obtained in this way are white and have extremely high purity, and the yield is also lower than that of glyoxylic acid.
It is nearly 90%, and it can be said that the method of the present invention has extremely great industrial utility. The mandelic acid can also be converted into an alkyl ester if necessary. Next, the process of reducing 4-hydroxymandelic acids will be explained. The reduction is carried out by a catalytic hydrogen reduction method. In carrying out catalytic hydrogen reduction, a nickel-based catalyst such as Raney-nickel, a palladium-based catalyst such as palladium on carbon, or a platinum catalyst can be used. Examples of the solvent include water, acetone, acetic acid, methanol, ethanol, ethyl acetate, hydrocarbon solvents (hexane, etc.), and ether solvents. The reaction can be carried out at normal pressure or under elevated pressure. To improve reaction selectivity, hydrochloric acid,
Mineral acids such as perchloric acid, perbromic acid, and sulfuric acid may also be present. In addition, when performing such a reduction process, usually 4-
Hydroxymandelic acid

[Formula] or 4-hydroxymandelic acid alkyl ester

[Formula] is directly reduced, but in the case of 4-hydroxymandelic acid, if it is necessary to relax the reduction conditions, it is of course possible to modify the hydroxyl group by performing acyloxylation such as acetylation. . Such modification includes, for example, in the case of 3-chloro-4-hydroxymandelic acid, changing the hydroxyl groups at the nucleus and α-positions to acetoxy groups. After the reduction is completed, the catalyst components are removed according to a conventional method, and the 4-hydroxyphenylacetic acids are extracted with a solvent from the reaction solution. By removing the solvent from the extract, crystalline 4-hydroxy Phenyl acetic acids are obtained. Of course, the crystals can be purified if necessary. According to the present invention, 4-hydroxyphenylacetic acids can be obtained at a high yield of 85% or more relative to glyoxylic acid and 95% or more relative to 4-hydroxymandelic acids, and have industrial utility value. can be said to be extremely large. Next, the (meth)allyl etherification step will be explained. The aromatic sulfonic acid (meth)allyl ester used in the present invention includes benzenesulfonic acid allyl ester, benzenesulfonic acid methalyl ester, o-, m-, p-toluenesulfonic acid allyl ester, o-, m-, p- -Toluenesulfonic acid metaallyl ester, or o-, m-, p-
Xylene sulfonic acid allyl ester, o-, m
-, p-xylene sulfonic acid metaallyl ester, etc., but p-toluenesulfonic acid allyl ester is most advantageously used. In addition, the (meth)allyl etherification reaction uses sodium hydroxide,
It is necessary to carry out the reaction in the presence of an alkali hydroxide such as potassium hydroxide. Conventionally, metal alcoholates have often been used in (meth)allyl etherification using aromatic sulfonic acid (meth)allyl esters, but the present invention eliminates the need to use such expensive and inconvenient metal alcoholates. The purpose can be achieved by using inexpensive alkali hydroxide. Furthermore, by using an alkali hydroxide, the reaction proceeds smoothly even if the reaction system is an aqueous medium, and moreover, the hydrolysis reaction can be carried out immediately following the (meth)allyl etherification reaction, and 4-( It is characterized by the ability to produce meth)allyloxyphenylacetic acid. When using a metal alcoholate, it is essential to use a non-aqueous organic solvent, and in comparison, it is necessary to replace the organic solvent with an aqueous solvent prior to the hydrolysis reaction. It can be said that this is an extremely useful method. In carrying out the (meth)allyl etherification reaction, 4-hydroxyphenylacetic acids, aromatic sulfonic acid (meth)allyl ester, and alkali hydroxide are dissolved or dispersed in a solvent and heated at room temperature or below without heating. The reaction is carried out at temperature. For each of the above-mentioned chemicals, a method of feeding them is selected as appropriate, such as batch feeding, divided feeding, continuous feeding, etc. as required. In the (meth)allyl etherification reaction, 4-hydroxyphenylacetic acids may be in the form of free acids, but in that case, the disadvantage is that an extra (meth)allyl aromatic sulfonic acid ester is required. Therefore, it is usually preferable to carry out the (meth)allyl etherification reaction after alkyl esterification of the carboxyl group. The solvents used in the above reaction include water,
and lower alcohols such as methanol, ethanol, isopyropanol, butanol, or mixtures thereof. Further, when a small amount of a hydrocarbon solvent such as benzene is co-existed with the solvent, there is an advantage that the yield can be slightly increased. The molar ratio of the chemicals used is 4-hydroxyphenylacetic acids/aromatic sulfonic acid (meth)allyl ester/alkali hydroxide/solvent from 1/1 to 1/1.
It is preferable to select from the range of 3/1 to 4/3 to 100. In the present invention, it is necessary to carry out the above (meth)allyl etherification reaction at a temperature below room temperature, preferably -5 to 30°C, particularly preferably 0 to 20°C. If the reaction is carried out at a temperature higher than room temperature, the yield of the target product decreases considerably, which poses a practical problem. Conventionally, the (meth)allyl etherification reaction was usually carried out at room temperature or above, preferably under reflux, but in the present invention, the reaction is carried out under temperature conditions that are completely opposite to those of the conventional method, resulting in a unique allyl etherification reaction. I have to say it was a reaction. The reaction is carried out over about 1 to 10 hours. The post-treatment after the reaction and the next hydrolysis step differ slightly depending on the solvent used, and will be explained below. When carrying out the (meth)allyl etherification reaction in an aqueous solvent or an aqueous mixed solvent containing water as the main component, when the reaction-completed solution is allowed to stand, an aqueous layer containing as a by-product an alkali aromatic sulfonic acid salt forms as a main component. And 4-
It separates into two oil layers containing (meth)allyloxyphenyl acetate as the main component. The aqueous layer is recovered for reuse as a (meth)allyl etherification agent, while water and alkali are added to the oil layer to carry out a hydrolysis reaction. After hydrolysis, the generated 4
-(Meth)allyloxyphenyl acetic acid alkali salts are neutralized with acid, and the precipitated 4-(meth)allyloxyphenyl acetic acids are separated to obtain the desired product. Alternatively, the 4-
The target product precipitated by neutralizing the (meth)allyloxyphenyl acetic acid alkali salt is separately obtained. It is also possible to subsequently recover the aromatic sulfonic acid alkali salt from the liquid. When carrying out the (meth)allyl etherification reaction using lower alcohol solvents such as methanol and ethanol, or alcoholic solvents containing these as main components, the initial stage of the reaction is homogeneous, but after the reaction is complete, aromatic Alkaline sulfonic acid salts precipitate. The alkali salts are separately recovered. on the other hand,
Since the liquid contains 4-(meth)allyloxyphenyl acetate, after distilling off the alcohol, water and an alkali are added to hydrolyze the ester. Subsequently generated 4- (meta)
4-allyloxyphenylacetic acids can be easily obtained by neutralizing allyloxyphenylacetic acid alkali salts. In the above, the hydrolysis reaction is carried out according to a conventional method, and the alkali used is sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, etc., and the reaction temperature is usually the reflux temperature. The 4-(meth)allyloxyphenylacetic acid thus obtained, particularly 3-chloro-4-allyloxyphenylacetic acid, is a pale yellow solid and can be obtained in extremely high yield. That is, the yield during allyl etherification is 94-96% based on 4-hydroxyphenyl acetic acid when an alcoholic solvent is used, and the yield in the hydrolysis step is 4-allyloxyphenyl acetic acid. However, it is more than 95%, which is almost quantitative. The above-mentioned 4-(meth)allyloxyphenylacetic acids are subjected to optional purification operations such as activated carbon treatment and recrystallization method, if necessary. On the other hand, the recovered aromatic sulfonic acid alkali salt can be easily converted into aromatic sulfonic acid (meth)allyl ester by reacting with thionyl halide such as thionyl chloride and then treating with (meth)allylic alcohol. Therefore, it can be effectively used again as a (meth)allyl etherifying agent. Next, the method of the present invention will be explained in more detail by giving examples. Example 1 Production of 3-chloro-4-hydroxymandelic acid The inside of a 1000 ml three-necked flask equipped with a stirrer and a thermometer was purged with nitrogen, and thereafter a small amount of nitrogen gas was allowed to flow through it. The flask was charged with a solution of 102.9 g (0.8 mol) of 0-chlorophenol and 50 g (1.25 mol) of sodium hydroxide dissolved in 600 ml of water, followed by 70.2 g (0.5 mol) of a 52.7% glyoxylic acid aqueous solution. Reaction temperature to 70
The reaction was carried out for 3 hours while maintaining the temperature at °C and stirring.
After the reaction was completed, the reaction solution was cooled to room temperature, the pH was adjusted to 2, and unreacted 0-chlorophenol was removed three times with 200 ml of benzene. When the aqueous layer is cooled to 5℃, 3-chloro-4-
White crystals of hydroxymandelic acid precipitated. The crystals were separated, washed and dried to obtain 47.3 g of white crystals. (Melting point: 143-144°C) Subsequently, 3-chloro-4-hydroxymandelic acid dissolved in the mother liquor was extracted and separated with ethyl acetate, and the ethyl acetate was recovered from the extract by evaporation. The overall yield of 3-chloro-4-hydroxymandelic acid was 88% based on glyoxylic acid. The characteristic values of the mandelic acid were as follows. mp142~143℃ IR; 3450cm ^-1 , 3200cm ^-1 , 3000~2500cm ^-1 ,
1755cm ^-1 , 1720cm ^-1 , 1505cm ^-1 , 1190cm
^-1 , 1100cm ^-1 , 820cm ^-1 , 740cm ^-1 , 690cm
^-1 NMR; δ=4.97(s) 1H, δ=6.97(d)
1H, δ = 7.24 (q) 1H, δ = 7.42
(d) 1H, δ = 7.9-11.2 (m) 2H Production of 3-chloro-4-hydroxyphenylacetic acid 10 g (0.049 mol) of 3-chloro-4-hydroxymandelic acid thus obtained was mixed with 60 ml of acetic acid and 95%
Dissolve the mixture by heating in a mixed solution of 4.4 g (0.043 mol) of sulfuric acid, add 4.0 g (palladium equivalent: 0.002 mol) of 5% palladium, and perform catalytic reduction for 10 hours with stirring at 80°C and 30 atmospheres of hydrogen pressure. Ivy. After the reaction was completed, the mixture was cooled, 500 ml of water was added, and the catalyst was separated. The liquid was extracted with 500 ml of ethyl acetate, the extracted layer was washed twice with 300 ml of water, and the ethyl acetate was distilled off to obtain 8 g of crystalline material. (The yield based on 3-chloro-4-hydroxymandelic acid was 87%) The characteristic values of 3-chloro-4-hydroxyphenylacetic acid were as follows. Melting point: 105~107℃ IR: 3450cm ^-1 , 3100~2500cm ^-1 , 1700cm ^-1 ,
1620cm ^-1 , 1500cm ^-1 , 1410cm ^-1 , 1210cm
^-1 , 1200cm ^-1 , 1080cm ^-1 , 940cm ^-1 , 900
cm ^-1 , 875cm ^-1 , 825cm ^-1 , 800cm ^-1 NMR; δ = 3.46 (s) 2H, δ = 7.3 ~ 7 (m)
3H, δ = 8.9-11.0 (Broad) 2H Production of methyl 3-chloro-4-allyloxyphenylacetate 2.0 g (10 mmol) and sodium hydroxide
0.4 g (10 mmol) was dissolved in 10 ml methanol. Next, while maintaining the system at 0 to 5°C, 1.5 g (7 mmol) of allyl P-toluenesulfonic acid was added and thoroughly stirred. After 30 minutes, another 0.2g
4 ml of methanol in which (5 mmol) of sodium hydroxide was dissolved and 0.9 g (4 mmol) of allyl P-toluenesulfonic acid were added, and the reaction was continued with stirring for 2 hours. After the reaction was completed, methanol was distilled off from the reaction solution, and 50 ml of benzene was added to the residue to obtain a slurry liquid. Insoluble matter (sodium P-toluenesulfonate) was removed and benzene was distilled off from the collected liquid to obtain yellow, oily 3-chloro-4-allyloxyphenylacetic acid methyl ester.
2.3g was obtained. (Yield is approximately 96% based on 3-chloro-4-hydroxyphenylacetic acid methyl ester)
Also, the amount of recovered sodium P-toluenesulfonate is
It was 2.5g. The characteristic values of 3-chloro-4-allyloxyphenyl acetic acid methyl ester were as follows. mp33~34℃ IR; 2950cm ^-1 , 1730cm ^-1 , 1650cm ^-1 , 1600cm
^-1 , 1495cm ^-1 , 1430cm ^-1 , 1250cm ^-1 ,
1150cm ^-1 , 1160cm ^-1 , 1100cm ^-1 , 925cm
^-1 , 800cm ^-1 NMR; δ=3.4 (S, 2H), δ=3.55 (S,
3H), δ=4.4-6.3 (M, 5H), δ=6.6
~7.3 (M, 3H) Production of 3-chloro-4-allyloxyphenylacetic acid 2.4 g of 3-chloro-4-allyloxyphenylacetic acid methyl ester was added to 12 ml of 10% aqueous sodium hydroxide solution, and the mixture was refluxed. A hydrolysis reaction was carried out. By adding acid to the reaction completed solution and neutralizing it, 3-chloro-4-allyloxyphenylacetic acid is produced.
2.2g was obtained. (The yield based on methyl ester was 98%) The characteristic values of 3-chloro-4-allyloxyphenylacetic acid were as follows. Melting point: 92℃ (recrystallized from cyclohexane) IR: 3100-2500cm ^-1 , 1700cm ^-1 , 1500cm ^-1 ,
1260cm ^-1 , 1080cm ^-1 , 940cm ^-1 , 800cm
^-1 , 730cm ^-1 , 680cm ^-1 , 600cm ^-1 NMR; δ=3.5 (S, 2H), δ=4.5~6.5
(M, 5H), δ=6.8~7.4 (M, 3H), δ
= 10.9 (S, 1H) Example 2 In the same reaction as in Example 1, 0-chlorophenol and glyoxylic acid were reacted, and unreacted 0-chloro was removed from the reaction solution obtained by adding 200 ml of benzene three times. Phenol was removed. 250 ml of ethyl acetate was added to the resulting aqueous layer for extraction. This extraction operation was performed three times. Next, ethyl acetate was distilled off from the extract to obtain 91 g of pale yellow crystals. (Yield based on glyoxylic acid is 90%) When the same reduction as in Example 1 was carried out using the 3-chloro-4-hydroxymandelic acid as a raw material, 3-chloro-4-hydroxyphenylacetic acid was obtained.
Obtained in a yield of 88% (based on mandelic acid). When 3-chloro-4-allyloxyphenylacetic acid ester and 3-chloro-4-allyloxyphenylacetic acid were produced in the same manner as in Example 1 using the hydroxyphenylacetic acid, the same results as in Example 1 were obtained. The results were obtained. Examples 3 to 8, Reference Examples 1 to 2 Example 1 except that the temperature during the reaction of 0-chlorophenol and glyoxylic acid (first step) and the reaction temperature during allyl etherification were variously changed as shown in the table. The reaction was carried out according to. The results are shown in the table.

【table】

[Table] Example 9 2.01 g (10
0.4 g (10 mmol) of sodium hydroxide in 4 ml of methanol. Next, 1.4 g of P-toluenesulfonic acid allyl ester
(6.6 mmol) and 1 ml of benzene were mixed. After stirring for 20 minutes at a temperature of 0-5℃, 0.1g
1 ml of a methanol solution containing sodium hydroxide (2.5 mmol), 1.0 g (4.7 mmol) of P-toluenesulfonic acid allyl ester, and 1 ml of benzene were added. This solution was reacted for 1 hour with stirring.
After separating the sodium P-toluenesulfonate from the reaction completed solution, the solution was concentrated and 0.8g was added to it.
5 ml of an aqueous solution containing (20 mmol) of sodium hydroxide was added, and a hydrolysis reaction was carried out under reflux for 1 hour. After cooling the reaction solution to room temperature, add 2.5 g of concentrated hydrochloric acid.
The 3-chloro-4-allyloxyphenyl acetic acid precipitated by adding was separately obtained. 3-chloro-4
-The yield for methyl hydroxyphenyl acetate is
95%, and the melting point of the acid was 80-85°C. Example 10 2.0 g (9.8 mmol) of 3-chloro-4-hydroxyphenylacetic acid methyl ester obtained in Example 1, 2.3 g (11 mmol) of P-toluenesulfonic acid allyl ester, and 0.44 g (11 mmol) )
of sodium hydroxide was mixed with 5 ml of water. After stirring at 5°C for 5 hours, 0.9 g (4 mmol) of P-toluenesulfonic acid allyl ester and 1 ml of 10% aqueous sodium hydroxide solution were added, and the reaction was carried out for 5 hours with stirring at 15°C. Chloro-4-allyloxyphenyl acetic acid methyl ester was produced. Next, 10 ml of an aqueous solution containing 1 g of sodium hydroxide was added to the reaction solution, and hydrolysis was carried out under reflux for 1 hour. After the completion of the reaction and cooling to room temperature, 2.7
g of concentrated hydrochloric acid was added to precipitate 3-chloro-4-allyloxyphenylacetic acid, which was separated, washed with water,
It was dried to obtain a slightly brown solid. The yield of the acid based on methyl 3-chloro-4-hydroxyphenylacetate is
85%, and the melting point was 78-83°C.

Claims (1)

[Claims] 1. General formula (Here, R represents hydrogen, halogen, lower alkyl, lower alkenyl, or lower alkoxy, and R ¹ represents hydrogen or lower alkyl) by catalytic hydrogen reduction of the 4-hydroxymandelic acids represented by the general formula 4-Hydroxyphenylacetic acids represented by (R and R ¹ are the same as above) are produced, and the acetic acids and aromatic sulfonic acid (meth)allyl ester are further heated at room temperature or below in the presence of an alkali hydroxide. A general formula characterized by producing 4-(meth)allyloxyphenyl acetate by reacting at a high temperature, and then hydrolyzing the ester. (R is the same as above, and X represents hydrogen or methyl.)
A method for producing 4-(meth)allyloxyphenylacetic acids represented by 2 3-chloro-4-hydroxyphenylacetic acid ester obtained by catalytic reduction of 3-chloro-4-hydroxymandelic acids and P-toluenesulfonic acid allyl ester are reacted to produce 3-chloro-4-
Allyloxyphenyl acetate is produced and then the ester is hydrolyzed to produce 3-chloro-4-
The manufacturing method according to claim 1, characterized in that allyloxyphenylacetic acid is manufactured. 3 3-Chloro-4-hydroxyphenylacetic acid is produced by catalytic hydrogen reduction of 3-chloro-4-hydroxymandelic acid, and after alkyl esterification of this, the ester and allyl P-toluenesulfonic acid are combined. 3-chloro-4- characterized in that 3-chloro-4-allyloxyphenyl acetate is produced by reacting in the presence of an alkali hydroxide at a temperature below room temperature, and then the ester is hydrolyzed. A method for producing allyloxyphenylacetic acid. 4 General formula (Here, R represents hydrogen, halogen, lower alkyl, lower alkenyl, or lower alkoxy) and glyoxylic acid at 40℃
By reacting at a temperature of 100℃, the general formula (R is the same as above, R ¹ is hydrogen or a lower alkyl group) is produced, and the mandelic acid is then catalytically reduced with hydrogen to produce the general formula 4-hydroxyphenylacetic acids represented by (R, R ¹ are the same as above) are produced, and the acid and aromatic sulfonic acid (meth)allyl ester are further mixed in the presence of an alkali hydroxide at a temperature below room temperature. A general formula characterized by producing 4-(meth)allyloxyphenyl acetate esters by reacting with ester and then hydrolyzing the ester. (R is the same as above, X represents hydrogen or methyl)
A method for producing 4-(meth)allyloxyphenylacetic acids represented by 5 Reacting 0-chlorophenol and glyoxylic acid to produce 3-chloro-4-hydroxymandelic acid, followed by catalytic hydrogen reduction of mandelic acid to produce 3-chloro-4-hydroxyphenylacetic acid, After converting this into an alkyl ester, the ester and allyl P-toluenesulfonic acid are reacted in the presence of an alkali hydroxide at a temperature below room temperature to produce 3-chloro-4-allyloxyphenyl acetate. and then hydrolyzing the ester.