United States Patent (19) (11) 4,337,355 Nakajima Et Al

United States Patent (19) (11) 4,337,355 Nakajima et al. 45) Jun. 29, 1982

54 PROCESS FOR PREPARING 4-HYDROXYPHENYLACETIC ACID FOREIGN PATENT DOCUMENTS (75) Inventors: Kazuhisa Nakajima, Mino; Kazuaki 3825 2/1979 European Pat. Off...... 562/478 Gohgi, Nishinomiya; Toshio Primary Examiner-Paul J. Killos Yamamoto, Suita, all of Japan Attorney, Agent, or Firm-Armstrong, Nikaido, 73) Assignee: Nippon Gohsei Kagaku Kogyo Marmelstein & Kubovcik Kabushiki Kaisha, Osaka, Japan (57) ABSTRACT 21 Appl. No.: 161,592 A process for preparing 4-hydroxyphenylacetic acid by 22 Filed: Jun. 20, 1980 reducing 4-hydroxymandelic acid in a reaction medium (51) Int. Cl...... C07C 65/01 of a lower aliphatic carboxylic acid or a water-contain (52) U.S. C...... 562/478; 562/470 ing lower aliphatic carboxylic acid. When the crystal 58) Field of Search ...... 562/478,470 line 4-hydroxymandelic acid is employed as the staring material, 4-hydroxyphenylacetic acid of high quality is 56) References Cited obtained in high yields. U.S. PATENT DOCUMENTS 4,198,526 4/1980 Edwards ...... 562/475 9 Claims, No Drawings 4,337,355 1. 2 reaction mixture is extracted with a solvent and the PROCESS FOR PREPARING solvent is distilled away from the extract, 4-hydroxy 4-HYDROXYPHENYLACETIC ACID mandelic acid can be readily obtained in the form of crystal in a short period of time in high yields. BACKGROUND OF THE INVENTION 5 The preferable embodiment of the process of the The present invention relates to a process for prepar present invention consists of (1) a step for preparing ing 4-hydroxyphenylacetic acid. 4-hydroxymandelic acid from phenol and glyoxylic 4-Hydroxyphenylacetic acid is useful as an intermedi acid and (2) a step for preparing 4-hydroxyphenylacetic ate of pharmaceuticals and agricultural chemicals. acid by the reduction of the 4-hydroxymandelic acid in As an industrially advantageous process for the prep 10 a definite condition, and these steps are explained be aration of 4-hydroxyphenylacetic acid, there is pro low; posed a process by catalytic reduction of 4-hydroxy The preparation of 4-hydroxymandelic acid accord mandelic acid, and one of the most preferable embodi ing to the present invention is characterized by (1) con ment of the process is the catalytic reduction of 4 ducting the reaction of phenol and glyoxylic acid at a hydroxymandelic acid, especially the sodium salt 15 relatively high temperature region such as a tempera thereof with palladium catalyst in water medium in the ture of 40° to 70° C., preferably 40' to 65° C. and (2) presence of a large amount of hydrochloric acid. How subjecting the obtained reaction mixture to extraction ever, such a process involves problems that (1) the yield with a solvent and then distilling away the solvent from of 4-hydroxyphenylacetic acid is at most 85% by mole to 4-hydroxymandelic acid, and that (2) because of the 20 the extract to give crystals. Reactions of glyoxylic acid use of a large amount of hydrochloric acid, the desired at a high temperature has hitherto been considered to be product is contaminated with a large amount of a neu undesirable, because glyoxylic acid would convert into tralized salt and the purification is troublesome, and an oxalic acid and glycolic acid by Cannizzaro reaction, apparatus is in danger of corrosion. For these reasons, and such reactions have been generally conducted at a further improvements are desired in the operation and 25 relatively low temperature region such as room temper the quality of the product in the industrial production. ature. In the present invention, 4-hydroxymandelic acid Accordingly, it is an object of the present invention is obtained unexpectedly in a short reaction time in high to provide an improved process for preparing 4-hydrox yields by the reaction of a high temperature contrary to yphenylacetic acid. the usual practice. The reaction temperature of 40' to A further object of the invention is to provide a pro 30 70° C. is an important factor in the reaction of phenol cess for preparing 4-hydroxyphenylacetic acid of high and glyoxylic acid. When the reaction temperature is quality in high yields. raised too much, i.e. to more than 70° C., by-product, These and other objects of the invention will become 2-hydroxymandelic acid is remarkable and the desired apparent from the description hereinafter. product is contaminated therewith to result in lowering 35 of its quality. In order to avoid the by-production, the SUMMARY OF THE INVENTION amount of an aqueous medium must be increased. This In accordance with the present invention, there is is also not practical in points of the extraction efficiency provided a process for preparing 4-hydroxyphenyla of the desired product from the reaction mixture and cetic acid which comprises reducing 4-hydroxyman the apparatus efficiency. delic acid in a reaction medium of a lower aliphatic 40 Commercially available glyoxylic acid is in the form carboxylic acid, or a water-containing lower aliphatic of an aqueous solution in concentrations of about 20 to carboxylic acid, and recovering the resulting 4-hydrox about 50% by weight, but there may also be employed yphenylacetic acid. glyoxylic acid in various forms such as an aqueous solu There is also provided a process for preparing 4 tion diluted or concentrated and a solid glyoxylic acid hydroxyphenylacetic acid which comprises reacting 45 hydrate. glyoxylic acid with phenol in the presence of an alkali at The reaction of phenol and glyoxylic acid is usually a temperature of 40' to 70° C., reducing the obtained carried out in an aqueous medium in the presence of an 4-hydroxymandelic acid, and recovering the resulting alkali such as sodium hydroxide, potassium hydroxide, 4-hydroxyphenylacetic acid. sodium carbonate or potassium carbonate. Sodium and 50 potassium hydroxides are particularly preferred as the DETAILED DESCRIPTION alkali. Water is the most practical as the medium, but a In the present invention, the reduction of 4-hydroxy mixture of water and an organic solvent miscible with mandelic acid is carried out in a reaction medium of a water may also be employed. lower aliphatic carboxylic acid or an aqueous solution The ratio of glyoxylic acid, phenol and an alkali is of a lower aliphatic carboxylic acid. It is advantageous 55 selected from glyoxylic acid:phenol:alkali = 1:0.8 to to use 4-hydroxymandelic acid of high quality as the 10:1 to 5, preferably 1:1.2 to 3.5:1.2 to 4. The aqueous starting material, because impurities in 4-hydroxyman medium is employed suitably in an amount of not more delic acid disturb the reduction. When crystalline 4 than 80 times the number of moles of glyoxylic acid, hydroxymandelic acid is employed, the reduction pro The water in an aqueous solution of glyoxylic acid and ceeds very smoothly and 4-hydroxyphenylacetic acid of 60 water in an aqueous solution of an alkali are also esti high quality is produced in high yields, e.g. in yields of mated as the amount of the aqueous medium. The use of 90 to 95% by mole based on the 4-hydroxymandelic the aqueous medium in an amount of more than the acid. above is not practical in points of the extraction effi The present inventors have investigated on a process ciency and apparatus efficiency. of the synthesis of crystalline 4-hydroxymandelic acid, 65 Admixing of glyoxylic acid, phenol and an alkali in an and found that when phenol and glyoxylic acid are aqueous medium and heating of the mixture are suffi reacted in the presence of an alkali at a temperature of cient for conducting the reaction. Any means may be 40' to 70° C., preferably 40' to 65. C., the resulting adopted for charging these materials, and there is usu 4,337,355 3 4. ally adopted a manner in which phenol is first dispersed further purified by a suitable means such as treatment into a medium, and after adding an aqueous solution of with active carbon or recrystallization. an alkali to the medium, a prescribed amount of glyox The crystal of 4-hydroxymandelic acid so obtained is ylic acid is added in the form of an aqueous solution white or light yellow, and the purity is very high. The thereof or an aqueous solution of its alkali metal salt. melting point is about 100-105” C. The yield of the The reaction temperature is one of the important crystal to glyoxylic acid is at least 70% by mole and, factors in the present step as mentioned before, and it is therefore, the step for preparing 4-hydroxymandelic necessary to adjust the temperature exactly within the acid is industrially useful. range of 40' to 70° C., preferably 40' to 65° C. By carry The step for preparing 4-hydroxyphenylacetic acid ing out the reaction of phenol and glyoxylic acid at such 10 by the reduction of 4-hydroxymandelic acid is then a high temperature, 4-hydroxymandelic acid can be explained below. obtained in a very short time in high yields. When the The reduction may be carried out in any known man reaction temperature is lower than 40 C., the reaction ners such as catalytic reduction and reduction with a rate is very slow. Therefore, in case of obtaining the chemical reagent. Catalylic reduction is industrially desired product in a practical yield, the reaction takes 15 advantageous. several days and is impractical in industrial production. It is essential to conduct the catalytic reduction in a On the other hand, when the reaction temperature is reaction medium of a lower aliphatic carboxylic acid higher than 70° C., the quality of the obtained 4 such as acetic acid, propionic acid or butyric acid, or a hydroxymandelic acid is remarkably decreased. The water-containing lower aliphatic carboxylic acid. reaction time varies to some extent depending on the 20 Acetic acid is particularly preferred as the aliphatic reaction temperature. In general, the reaction at a tem carboxylic acid. When a reaction medium other than perature of 40 to 65° C. is sufficiently completed in the carboxylic acid, e.g. water alone, is employed, a about 3 hours. large amount of a mineral acid is required and the ob In order to prevent the coloration of the obtained tained 4-hydroxyphenylacetic acid is colored to lower 4-hydroxymandelic acid crystal, it is desirable to carry 25 its quality. Addition of water to the carboxylic acid out the reaction in an atmosphere of an inert gas such as greatly prevents the 4-hydroxymandelic acid from nitrogen or argon. changing to a viscous oily material of high molecular After the completion of the reaction, the reaction weight and, therefore, it is possible to increase the yield mixture is acidified, and the unreacted phenol is re and quality of 4-hydroxyphenylacetic acid. The water moved from the reaction mixture by extraction with a content of the reaction medium is selected from 5 to suitable organic solvent such as benzene, toluene or 50% by weight, preferably 10 to 30% by weight. The chloroform. The secondary important factor in this step use of water in an amount of less than 5% by weight is for preparing 4-hydroxymandelic acid is to extract the not effective for increasing the reduction rate and the obtained aqueous phase with a solvent to recover the yield, and on the other hand, the use of water more than crystal of 4-hydroxymandelic acid from the aqueous 35 50% by weight makes the reduction rate and the yield phase. The crystal cannot be substantially obtained by a of 4-hydroxyphenylacetic acid remarkably decrease. separation method other than extraction, e.g. by a cool The presence of a proper amount of water is very ad ing method in which the obtained aqueous phase is vantageous for the present invention. The amount of the cooled to less than 5 C. Also, in case of a concentration aliphatic carboxylic acid or the water-containing ali method, decomposition of the desired product may take 40 phatic carboxylic acid is at least 3 times the weight of place, and in case of a salting-out method, the desired 4-hydroxymandelic acid, and is employed preferably in product is contaminated with a neutralization salt. an amount of 4 to 12 times, more preferably 6 to 10 4-Hydroxymandelic acid is thus obtained in the form times the weight of 4-hydroxymandelic acid. of an alkali metal salt, and it should be changed to the In the catalytic reduction, there may be employed a free acid by acidifying the aqueous phase. An alkali 45 palladium, nickel or platinum catalyst. These catalysts metal salt of 4-hydroxymandelic acid cannot be sepa may be supported on a suitable carrier such as active rated from the aqueous phase by the solvent extraction. carbon, aluminum or silica. In order to conduct efficiently the extraction operation, The reaction may be carried out under atmospheric the aqueous phase may be concentrated previously. In pressure or under a pressure, and it is desirable to carry that case, the concentration is conducted at pH 2 to 8.5, 50 out the reaction under a pressure of several kilograms preferably pH 3 to 8, and at a temperature of at most 80 per square centimeter from viewpoint of practical reac C., preferably at most 60° C., so that the stability of tion rate. The reaction temperature is selected from 50 4-hydroxymandelic acid is not impaired. It is sufficient to 120° C., preferably 70 to 100° C. Addition of a min to concentrate to 10% by weight in the concentration of eral acid such as sulfuric acid or hydrochloric acid is 4-hydroxymandelic acid. As the solvent for extraction, 55 desired for increasing the reaction rate and yield. Al there are employed organic solvents substantially im though the amount of the acid to be added varies de miscible with water, e.g. a lower alkyl ester of acetic pending on the kind of the acid, it is particularly desir acid such as methyl acetate, ethyl acetate or butyl ace able to employ the acid in an amount of 0.05 to 1.0 mole, tate, an ether such as diethyl ether, and an aliphatic preferably 0.1 to 0.5 mole, per mole of 4-hydroxyman ketone such as methyl isobutyl ketone. A lower alkyl 60 delic acid. The use of sulfuric acid is the most preferable ester of acetic acid such as ethyl acetate and an aliphatic among the mineral acids. Sulfuric acid produces a spe ketone such as methyl isobutyl ketone are preferred. A cific effect in this step for preparing 4-hydroxyphenyla solvent such as benzene or chloroform is poor in extrac cetic acid, and it is necessary to control exactly its tion effect and is impractical. 4-Hydroxymandelic acid amount. The use of sulfuric acid in an amount within a is separated from the aqueous phase by extraction with 65 very narrow range, i.e. in an amount of 0.1 to 0.5 mole the solvent, and the solvent is removed from the extract per mole of 4-hydroxymandelic acid, produces a good to precipitate 4-hydroxymandelic acid as the crystal. result that 4-hydroxyphenylacetic acid is obtained in The obtained crystal of 4-hydroxymandelic acid may be high yields. Such a phenomenon is peculiar to the cata 4,337,355 5 6 lytic reduction of 4-hydroxymandelic acid. For in was dissolved 66.7 g (0.269 mole) of the above 4 stance, in case of the reduction of 3-chloro-4-hydroxy hydroxymandelic acid monohydrate. After adding 2.5 mandelic acid, the amount of sulfuric acid used is not so g. of a 5% palladium/carbon catalyst to the solution, critical as in the present invention. It is considered that the catalytic reduction was carried out at a temperature sulfuric acid is complicatedly, organically, connected of 85’ to 90° C. for 2.0 hours under a pressure of 4 with the kind of a nuclear substituent in the mandelic kg/cm.2 G of hydrogen with stirring. After the com acid, the kind of a solvent and the like. , pletion of the reaction, the reaction mixture was cooled As mentioned above, the factors affecting the yield of and the catalyst was removed by filtration. The filtrate 4-hydroxyphenylacetic acid are (1) a lower aliphatic was neutralized with an equivalent amount of sodium carboxylic acid solvent, (2) water content in the sol 10 vent, (3) kind of a mineral acid and its amount, and (4) hydroxide to the charged sulfuric acid, and the solvent reaction temperature. The most preferable embodiment was distilled away to give 69.3 g of crystal of 4-hydrox is the catalytic reduction with a palladium catalyst char yphenylacetic acid. The yield to 4-hydroxymandelic acterized by (1) employing the water-containing acetic acid monohydrate was 95% by mole. The infrared spec acid as a reaction medium in an amount of 4 to 12 times 15 trum and nuclear magnetic resonance spectrum of the the weight of 4-hydroxymandelic acid, (2) containing 10 recrystallized product agreed with those of the authen to 30% by weight of water in the reaction medium, (3) tic 4-hydroxyphenylacetic acid. The product was white using sulfuric acid in an amount of 0.1 to 0.5 mole per crystal and its quality was very good. The melting point mole of 4-hydroxymandelic acid and (4) maintaining the was 151-153 C. reaction temperature within the range of 70 to 100° C. 20 EXAMPLE 2 It is desirable to avoid the use of water alone as: the reaction medium and the use of hydrochloric acid as the Reaction of phenol and glyoxylic acid was carried mineral acid from viewpoint of the yield of the desired out in the same manner as in Example 1. The resulting product and of the coloration of the product and corro reaction mixture was adjusted to pH 6.0 with 61 g of sion of apparatus, resulting from the use of a large 25 conc. hydrochloric acid, and was then extracted with amount of hydrochloric acid. three 100 ml. portions of ethyl acetate to remove the After the completion of the reduction, the catalyst is unreacted phenol. removed in a usual manner, and 4-hydroxyphenylacetic After making the obtained aqueous layer strong acid is obtained in the form of crystal by neutralizing a acidic by adding 65 g. of conc. hydrochloric acid, the mineral acid and distilling away the solvent from the 30 extraction of the aqueous layer with ethyl acetate was reaction mixture, or by adding water to the reaction carried out in the same manner as in Example 1 to give mixture and extracting with a solvent and removing the 67.9 g, of light yellow crystal of 4-hydroxymandelic solvent from the extract. The crystal may be further acid monohydrate. The yield to glyoxylic acid was 73% purified as occasion demands. by mole. According to the present invention, 4-hydroxy 35 In a mixture of 390 g. of acetic acid containing 15% phenylacetic acid can be obtained in a yield of at least of water and 6.5 g (0.063 mole) of conc. hydrochloric 60% by mole to glyoxylic acid, and in a yield of at least acid was dissolved in 66.7 g (0.269 mole) of 4-hydroxy 90% by mole to 4-hydroxymandelic acid. mandelic acid monohydrate. After adding 3.2 g of a 5% The present invention is more particularly described palladium/carbon catalyst to the solution, the catalytic and explained by means of the following Examples, in 40 reduction was carried out at a temperature of 86 to 90' C. for 1.25 hours under a pressure of 4 kg/cm2 G of which all % are by weight unless otherwise noted. hydrogen with stirring. After the completion of the EXAMPLE 1 reaction, the reaction mixture was treated in the same After replacing the air with nitrogen gas, a one liter manner as in Example 1 to give 51.5 g. of violet 4 three neck flask equipped with a stirrer and a thermom 45 hydroxyphenylacetic acid. The yield to 4-hydroxyman eter was charged with 75.2 g (0.8 mole) of phenol and delic acid monohydrate was 89.8% by mole. an aqueous solution of 75.7 g. of potassium hydroxide EXAMPLES3 TO 5 AND COMPARATIVE dissolved in 600 ml. of water. To the flask was then added 74.1 g of a 50% aqueous solution of glyoxylic EXAMPLES AND 2 acid (0.5 mole). The reaction was carried out at 55 C. 50 The procedures of Example 1 were repeated except for 2.0 hours with stirring in a nitrogen stream. After that upon the preparation of 4-hydroxymandelic acid the completion of the reaction, the reaction mixture was monohydrate, potassium hydroxide was employed in an cooled to room temperature and was acidified with 120 amount of 72.8 g. and the reaction of phenol and glyox g. of a conc. hydrochloric acid, and then extracted with ylic acid was conducted at a temperature shown in the four 200 ml. portions of benzene to remove the unre 55 following Table. acted phenol. The results are shown in the Table, in which the The obtained aqueous layer was then extracted with yields are based on glyoxylic acid. 250 ml. of ethyl acetate. This extraction procedure was repeated 5 times. Ethyl acetate was distilled away from Yield (mole %) the resulting extract to give 68.5g. of light yellow crys 60 4-Hydroxy tal of 4-hydroxymandelic acid monohydrate. The yield Reaction mandelic 4-Hydroxy to glyoxylic acid was 74% by mole, and the melting Reaction time acid mono- phenylacetic point was 100-105 C. temp. (C.) (hour) hydrate acid The infrared spectrum and nuclear magnetic reso Ex. 3 50 3 73 68 nance spectrum of the crystal agreed with those of 65 Ex... 4 60 1.5 72 69 Ex. 5 65 .2 70 67 authentic 4-hydroxymandelic acid. Con. In a mixture of 400g. of acetic acid containing 18% Ex. 0 160 66 63 of water and 5.5 g (0.053 mole) of conc. sulfuric acid Com. 4,337,355 8 9), 75% by mole (Example 10) and 63% by mole (Exam -continued ple 11). Yield (mole %) 4-Hydroxy EXAMPLES 12 TO 14 Reaction mandelic 4-Hydroxy Reaction time acid mono- phenylacetic 5 The catalytic reduction was carried out in the same temp. (C.) (hour) hydrate acid manner as in Example 1 except that acetic acid contain ing 16% of water (Example 12), 8% of water (Example Ex. 2 25 24 69 66 13) or 32% of water (Example 14) was employed. The yields of 4-hydroxyphenylacetic acid were 94% by As is clear from the results of Comparative Examples, 10 mole (Example 12), 70% by mole (Example 13) and the reaction of phenol and glyoxylic acid at a low tem 68% by mole (Example 14). perature requires a long reaction time of more than one day, and is not industrially practical. EXAMPLES 15 AND 16 EXAMPLES 6 TO 8 The catalytic reduction was carried out in the same 15 manner as in Example 1 except that the water-contain The procedures of Example 1 were repeated except ing acetic acid was employed in an amount of 3 times that in the preparation of 4-hydroxymandelic acid (Example 15) or 8.8 times (Example 16) the weight of monohydrate, the aqueous layer was extracted with 4-hydroxymandelic acid. The yields of 4-hydroxy methyl isobutyl ketone (Example 6), diethyl ether (Ex phenylacetic acid were 78% by mole (Example 15) and ample 7) or n-butyl acetate (Example 8). The yields of 20 95% by mole (Example 16). 4-hydroxymandelic acid monohydrate were 73% by What we claim is: mole (Example 6), 42% by mole (Example 7) and 37% 1. A process for preparing 4-hydroxyphenylacetic by mole (Example 8), respectively. Also, in each Exam acid which comprises reducing, in the presence of a ple, the yield of 4-hydroxyphenylacetic acid to 4 catalyst, 4-hydroxymandelic acid in a reaction medium hydroxymandelic acid was 94% by mole. 25 consisting essentially of a water-containing lower ali When benzene and chloroform were employed as the phatic carboxylic acid containing 5 to 50% by weight of extracting solvent, a trace amount of 4-hydroxyman water, and recovering the resulting 4-hydroxyphenyla cetic acid. delic acid was merely obtained. 2. The process of claim 1, wherein said lower ali COMPARATIVE EXAMPLE 3 30 phatic carboxylic acid is acetic acid. 3. The process of claim 1 or 2, wherein said reaction In a mixture of 480 g. of water and 33.4 g (0.324 medium is employed in an amount of at least 3 times the mole) of conc. sulfuric acid was dissolved 50.0 g (0.269 weight of the 4-hydroxymandelic acid. mole) of 4-hydroxymandelic acid monohydrate, and 4. The process of claim 1, wherein said catalytic re thereto was added 3.7 g of a 5% palladium/carbon 35 duction is carried out in the presence of sulfuric acid. catalyst. The catalytic reduction was carried out at a 5. The process of claim 4, wherein said sulfuric acid is temperature of 90' to 93°C. for 4 hours under a pressure present in an amount of 0.05 to 1 mole per mole of of 4 kg/cm.2 G of hydrogen with stirring. 4-hydroxymandelic acid. After the completion of the reaction, the reaction 6. The process of claim 1, wherein said catalytic re mixture was cooled and the catalyst was filtered. The duction is carried out at a temperature of 50 to 120° C. filtrate was neutralized with an alkali, and the solvent 7. The process of claim 1, wherein said 4-hydroxy was distilled away to dryness to give 135.5 g. of a prod mandelic acid is a crystalline 4-hydroxymandelic acid uct. The product was a mixture of 13.4% of 4-hydroxy obtained by reacting phenol and glyoxylic acid in an phenylacetic acid, 9.7% of the starting material and aqueous medium at a temperature of 40 to 70° C., ex 76.9% of their salts, and the yield of 4-hydroxyphenyla 45 tracting the resulting reaction mixture with an organic cetic acid was low. solvent substantially immiscible with water and remov ing the solvent from the resulting extract. EXAMPLES 9 TO 11 8. The process of claim 7, wherein the reaction of The catalytic reduction was carried out in the same phenol and glyoxylic acid is carried out at a tempera manner as in Example 1 except that conc. sulfuric acid 50 ture of 40° to 65° C. was employed in an amount of 0.30 mole (Example 9), 9. The process of claim 7, wherein said organic sol 0.05 mole (Example 10) or 0.60 mole (Example 11), per vent is a member selected from the group consisting of mole of 4-hydroxymandelic acid. The yields of 4 lower alkyl esters of acetic acid and aliphatic ketones. hydroxyphenylacetic acid were 94% by mole (Example k sk is 55

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