Method of preparing 2- and 4-hydroxymandelic acid

Details Method of preparing 2- and 4-hydroxymandelic acid Method of preparing 2- and 4-hydroxymandelic acid

1999-09-15

2002-03-19

Wilson, James O. (Department: 1623)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carboxylic acids and salts thereof

C562S470000

Reexamination Certificate

active

06359172

ABSTRACT:

The invention relates to a method of preparing 2- and 4-hydroxymandelic acid by condensing glyoxylic acid with phenol.
Hydroxymandelic acids are very valuable compounds as they are versatile starting materials for the production of compounds that may be used in various fields such as fine chemicals technology, pharmaceutical chemistry and agricultural chemistry. 4-Hydroxymandelic acid is an intermediate product for the preparation of 4-hydroxybenzyl aldehyde, used in the synthesis of fine chemicals; 4-hydroxyphenyl acetic acid used in the synthesis of the pharmaceutical compound atenolol; 4-hydroxyphenylglycine used in the preparation of the antibiotic amoxycilline, etc. 2-Hydroxymandelic acid is an intermediate product for the preparation of the agrochemical compound ethylene diamine-N,N′-bis(2-hydroxyphenyl acetic acid); 2-hydroxyphenyl acetic acid, used in pharmaceutical compounds; 2-hydroxyphenyl-2-oxoacetic acid methyl ester used in the preparation of fungicides, etc.
The method of preparing 2- and 4-hydroxymandelic acid by condensation of glyoxylic acid with phenol has long been known. Under different conditions glyoxylic acid is condensed with an excess of phenol yielding a mixture of both mandelic acids. The excess of phenol is normally extracted, after acidification of the reaction mixture with a water-immiscible solvent. Subsequently, the 4-hydroxymandelic acid is separated in the form of a salt in the usual manner, while the 2-hydroxymandelic acid is usually not isolated.
The Belgian patent specification 867,287 describes the condensation of glyoxylic acid with phenol in a homogenous system in the presence of sodium or potassium hydroxide. The 4-hydroxymandelic acid is isolated in the form of a salt by adding an inorganic salt to the reaction mixture. Similarly, the U.S. patent specification 4,408,070 describes the homogenous condensation of glyoxylic acid with excess phenol, by using sodium hydroxide. The excess phenol is separated after neutralization by means of steam distillation or extraction with 1,2-dichloroethane, after which the 4-hydroxymandelic acid is precipitated in the presence of sodium acetate. In the known method wherein a salt is added in order to salt out the product, contamination with salt occurs while at the same time a salt-saturated mother liquor is left which is contaminated with by-products formed during the reaction. In the above-mentioned cases the yields of isolated product do not exceed 61%.
The European patent application EP-0,024,181 further describes the condensation of glyoxylic acid with phenol in a homogenous system in the presence of sodium or potassium hydroxide. The reaction mixture is subsequently acidified and the excess of phenol is extracted with methyl isobutyl ketone. The reaction mixture is further acidified and subjected to a second extraction with methyl isobutyl ketone. Subsequently the 4-hydroxymandelic acid is precipitated in a 50-73% yield as a salt from the extract, the remaining part of the organic material, i.e. all the 2-hydroxy isomer and part of the 4-hydroxy isomer, is distributed between the aqueous phase and the solvent phase.
The European patent specification EP-0,368,696 describes the condensation of a glyoxylic acid with phenol in the presence of a water-insoluble amine, to form a 12:84 mixture of 2- and 4-hydroxymandelic acid respectively. Then the excess of phenol is extracted with 1,1-dimethyl-1-methoxypropane. Only 70-74% of the paraisomer, 4-hydroxymandelic acid, is isolated leaving a non-separable mixture of approximately 1:1 2- and 4-hydroxymandelic acid.
Both the methods described in EP-0,024,181 and EP-0,368,696 use two alkaline compounds to obtain the desired mandelic acid; one to perform the reaction and a different one to isolate the product. From a technical and economical point of view, it would be preferable to use only one base, namely the base by means of which the suitable salt of the mandelic acid can be obtained.
Attempts have been made to produce only 2-hydroxymandelic acid. Hoefnagel et al. describe in Recl. Trav. Chim. Pays-Bas 107, 242-247 (1988) the reaction of glyoxylic acid with phenol using metal ion catalysis, to produce 2-hydroxymandelic acid in modest yields together with 4-hydroxymandelic acid. The products were, however, not isolated.
The European patent application EP-0,556,084 also uses trivalent metal ion catalysis but in the presence of insoluble amines, to obtain a solution comprising a mixture of 2- and 4-hydroxymandelic acids, wherein the 2-hydroxymandelic acid is present in excess with yields varying from 59-87%. A water-immiscible solvent is used to extract the excess of phenol, but none of the products is isolated. A disadvantage of these methods is the presence of high-valency metal ions in the final product, and the fact that the catalyst is not reusable. The product was never isolated, possibly due to its extremely high solubility in water, and it is proposed to use the impure solution directly in subsequent reactions.
The solvent extraction of phenol from water, common to all processes, is a problem in itself, as is apparent from the myriad of systems and processes that have been developed for this purpose. Because of its high toxicity, the phenol must be completely eliminated from the effluent stream. Typical examples are the simple extraction with additional salts, polyhydric alcohols or polyglycol ethers; the single or multi solvent counter-current continuous extraction; the two-solvent extraction distillation; the supported-liquid membrane processes; the extraction device with two membranes plus one solvent and a stripping solution; removal by pervaporation, etc. The use of these complicated and specialized systems is necessary because of the high water affinity of phenol. Phenol is best extracted with solvents that also have a high affinity for water, but in that way too much solvent is lost in the aqueous phase. This makes it necessary to add salts or a water-immiscible solvent when phenol is to be extracted with a partially water-soluble solvent. Another general disadvantage of phenol extraction is the necessity of acidifying the mother liquor prior to extraction to avoid to ionized phenoxide form present in the aqueous phase during extraction. This is especially necessary when the mother liquor is alkaline, as with the condensation of glyoxylic acid with phenol.
The above-mentioned methods always result in a mixture of 2- and 4-hydroxymandelic acids the specific formation of only one isomer is not possible. The complete separation of these isomeric mixtures is not realized, and their relative quantities can only be determined by means of analytical methods.
WO 94/14746 discloses a method of separating both isomers by means of the solvent extraction of a solid mixture of 2- and 4-hydroxymandelic acid alkali metal salts. The solid mixture is extracted with one solvent, acetone, to obtain an enriched fraction of sodium 2-hydroxymandelate, and the remaining solid is again extracted with a solvent, this time with ethanol, to obtain an almost pure fraction of sodium 4-hydroxymandelate. It should be pointed out that the hydroxymandelic acids are formed in water, and that this water must be completely eliminated before the separation can be performed. Another disadvantage is that two solvents are used for the separation of both isomers, for which an adequate recovery system must be used. Moreover, the solid-liquid extraction is not at all efficient, as one solid can be incorporated in the other, with the result that it is not subjected to extraction.
It would be advantageous if both isomers could be separated directly from the reaction mixture in which they are formed, thereby avoiding the evaporation of water and the use of flammable and/or toxic solvents.
It is the object of the present invention to provide a method of preparing 2- and 4-hydroxymandelic acid, wherein the above-mentioned disadvantages are effectively removed. To this end the present invention provides a method of preparing 2- and 4-hydroxymandelic acid by condensing glyoxylic acid w

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