JPS6323981B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a method for isolating p-hydroxymandelic acid. p-Hydroxymandelic acid is an important compound as a starting material for various pharmaceuticals. For example, by aminating p-hydroxymandelic acid,
It is converted into p-hydroxyphenylglycine, which is a raw material for β-lactam antibiotics such as amoxicillin, cephadroxil, and cefatridine, which is converted into p-hydroxyphenylglycine by reduction to p-hydroxyphenylacetic acid, and into p-hydroxybenzaldehyde by oxidative decarboxylation. These include pharmaceuticals, pesticides,
It is an extremely important intermediate for other chemical products. Many methods are known for producing p-hydroxymandelic acid, such as hydrolyzing p-hydroxybenzaldehyde cyanohydrin, diazolyzing p-aminomandelic acid, and reacting phenol with glyoxylic acid. It is being However, since p-hydroxymandelic acid is extremely highly water-soluble, it is difficult to isolate it in a high yield even if the reaction proceeds in a high yield. Since acid (hereinafter referred to as "o-form") is produced as a by-product, in order to selectively isolate p-hydroxymandelic acid, for example, the reaction solution is made weakly acidic, the o-form is extracted and removed with an organic solvent, and then strong acid is added. It has been difficult to selectively and easily isolate p-hydroxymandelic acid in a good yield, as it is necessary to obtain the desired product by extracting it with an organic solvent. Therefore, the present inventors p-
As a result of various studies on methods for selectively and easily isolating hydroxymandelic acid with good yield from an aqueous solvent, we found that calcium of p-hydroxymandelic acid,
It has been found that metal salts such as magnesium, zinc, nickel, copper, or barium are sparingly soluble in water, and their solubility is lower than that of the corresponding o-form metal salts. The present invention was completed based on the above findings. That is, the present invention involves treating an aqueous solution containing p-hydroxymandelic acid with a salt, hydroxide, or oxide of a metal selected from calcium, magnesium, zinc, nickel, copper, and barium, and precipitating p-hydroxymandelic acid. - A method for isolating p-hydroxymandelic acid, which comprises isolating metal salt crystals of hydroxymandelic acid. To carry out the method of the present invention, calcium, magnesium, zinc, nickel,
This is done by treating the salts, hydroxides, oxides, etc. of metals such as copper and barium, and removing the precipitated crystals. The preferred solvent for an aqueous solution is water or a mixed solvent of water and a water-miscible organic solvent. Examples of organic solvents that can be mixed with water include lower alcohols such as methanol, ethanol, and propanol, ketones such as acetone, and methyl ethyl ketone. Examples include ethers such as tetrahydrofuran and dioxane, dimethylformamide, dimethylacetamide, dimethylsulfoxide, acetonitrile, and hexamethylphosphoramide. As the aqueous solution containing p-hydroxymandelic acid, it is usually preferable to use the reaction solution for p-hydroxymandelic acid synthesis as it is, such as a reaction solution obtained by reacting phenol and glyoxylic acid in a basic aqueous medium. can be given. The type and valence of metal salts, hydroxides, and oxides that act on p-hydroxymandelic acid are not particularly limited. Specific typical examples include calcium chloride, calcium nitrate, calcium carbonate, calcium formate, calcium acetate, calcium hydroxide,
Calcium oxide magnesium chloride, magnesium bromide, magnesium sulfate, magnesium nitrate, basic magnesium carbonate, magnesium formate, magnesium acetate, magnesium hydroxide, magnesium oxide, zinc chloride, zinc bromide, zinc sulfate, zinc nitrate, basic zinc carbonate , zinc formate, zinc acetate, zinc hydroxide, zinc oxide, nickel chloride, nickel bromide, nickel sulfate, nickel nitrate, basic nickel carbonate, nickel formate, nickel acetate, nickel hydroxide, cuprous chloride, second chloride copper, cuprous bromide,
Cupric bromide, cupric sulfate, cupric nitrate, basic cupric carbonate, cupric formate, cupric acetate, cupric hydroxide, cuprous oxide, cupric oxide, chloride Examples include barium, barium bromide, barium nitrate, barium carbonate, barium formate, barium acetate, barium hydroxide, barium oxide, and hydrates thereof. In order to cause a metal salt to act on p-hydroxymandelic acid, the metal salt or its aqueous solution is allowed to act on an aqueous solution containing an alkali metal salt such as sodium salt or potassium salt or ammonium salt of p-hydroxymandelic acid. The method is preferred. Metal hydroxide in p-hydroxymandelic acid,
In order to cause the oxide to act, it is preferable to use a method in which a metal hydroxide, oxide, an aqueous solution thereof, or an aqueous suspension thereof is made to act on an aqueous solution of p-hydroxymandelic acid. The temperature at which metal salts, hydroxides, and oxides are applied to p-hydroxymandelic acid can be freely selected between room temperature and the boiling point of the solvent depending on the type and properties of the metal, but it is usually carried out at room temperature. is preferred. Further, the time required for this is usually several minutes to several hours. metal salts for p-hydroxymandelic acid;
The amount of hydroxide and oxide is not particularly limited as long as it is 1 equivalent or more, but 1 to 2 equivalents are preferred. Metal salts of p-hydroxymandelic acid usually precipitate as poorly soluble crystals, while o-hydroxymandelic acid does not precipitate, so it can be taken as is or, if necessary, concentrated or mixed with the aforementioned water-mixed organic solvent. It can be isolated easily and in high yield by adding 100% and collecting the precipitated crystals. The metal salt of p-hydroxymandelic acid, such as a calcium salt, obtained in this way can be used as it is as a raw material for p-hydroxyphenylglycine and p-hydroxybenzaldehyde.
Alternatively, calcium is removed by suspending it in water and adding sulfuric acid, phosphoric acid, oxalic acid, or their water-soluble salts as sulfate, phosphate, oxalate, etc.
High purity p-hydroxymandelic acid can also be obtained by concentrating the liquid. Next, the present invention will be specifically explained using examples. Example 1 A solution of 14.2 g (128 mmol) of calcium chloride dissolved in 30 ml of water was added to 258.3 g of the reaction solution containing p-hydroxymandelic acid produced by the method of Reference Example 1, and the mixture was heated and stirred at 60-70°C for 1 hour. Then, leave it at room temperature overnight, remove the precipitated crystals, wash with water, and leave for 60 minutes.
p-hydroxymandelic acid calcium salt monohydrate by vacuum drying at 70℃

[Formula] 39.7g (yield: 67.5%, recovery rate: 95.7%) was obtained. Here, the recovery rate is calculated by dividing the number of moles of p-hydroxymandelic acid in the extracted salt by the number of moles of p-hydroxymandelic acid produced in the reaction solution.
This is the value multiplied by 100. This crude product is o
- Contains no other impurities except for 0.30 g of hydroxymandelic acid and 0.70 g of a condensate of phenol and two molecules of glyoxylic acid. Structure determination was carried out by taking a part of this crude crystal, suspending it in water, stirring it at room temperature, and collecting it.
-Conducted by measuring the content of hydroxymandelic acid (determined by high performance liquid chromatography), the content of water (determined by Karl Fischer method), and the content of calcium (determined by EDTA) . The results are as follows.

[Table] Example 2-13 Water was added to 258.2 g of the reaction solution containing p-hydroxymandelic acid produced by the method of Reference Example 1.
300.0 g, from which 20 g (containing 2.37 g (14.1 mmol) of p-hydroxymandelic acid) was added, and 8.8 mmol of the metal salt shown in Table 1 was added thereto.
After adjusting the pH with hydrochloric acid as necessary and stirring at room temperature for 3 hours, the precipitated crystals were collected, washed with water, and 60-
A metal salt of p-hydroxymandelic acid was obtained by vacuum drying at 70°C.

[Table] Reference example 1 Add 40% aqueous sodium hydroxide solution to a suspension of 84.6 g (900 mmol) of phenol and 200 ml of water to adjust the pH.
10.5. To this solution, 111.1 g (600 mmol) of a 40% glyoxylic acid aqueous solution, 200 ml of water, and a solution whose pH was adjusted to 10.5 with a 40% aqueous sodium hydroxide solution were added, and the mixture was allowed to react at room temperature for 24 hours. Concentrated hydrochloric acid was added to this reaction solution to adjust the pH to 5, and residual phenol was extracted and removed three times with 140 ml of 1,1,2,2-tetrachloroethane, and the aqueous layer was concentrated under reduced pressure to a total amount of 516.5 g. This solution contained 71.1 g of p-hydroxymandelic acid as determined by high performance liquid chromatography.
(423mmol), o-hydroxymandelic acid 10.5g
(62.4 mmol), condensate of phenol and 2 molecules of glyoxylic acid 18.2 g (75.2 mmol) phenol 2.3
g (24.4 mmol) and trace amounts of side reaction products.

Claims (1)

[Claims] 1 salts of metals selected from calcium, magnesium, zinc, nickel, copper, and barium in an aqueous solution containing p-hydroxymandelic acid;
A method for isolating p-hydroxymandelic acid, which comprises isolating metal salt crystals of p-hydroxymandelic acid precipitated by the action of a hydroxide or oxide.