Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
  • C07C51/42—Separation; Purification; Stabilisation; Use of additives
  • C07C51/48—Separation; Purification; Stabilisation; Use of additives by liquid-liquid treatment
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B57/00—Separation of optically-active compounds
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
  • C07C51/42—Separation; Purification; Stabilisation; Use of additives
  • C07C51/487—Separation; Purification; Stabilisation; Use of additives by treatment giving rise to chemical modification

Definitions

• the invention relates to a method for separating the ortho- and para-isomers of hydroxymandelic acid or a salt thereof, to the ortho- and para-isomers obtained by the practice of the method according to the invention, and to the use of the thus obtained ortho-iso er in the preparation of ⁇ , ⁇ - (1,2-ethanediyldiimino) -bis- [2-hydroxy] -benzeneacetic acid (EDDHA) .
• German patent application 2,944,295 describes a method by the use of which fairly pure para-hydroxymandelic acid (melting range 83-85°C) is obtained in a yield of 70-85%. According to this method, glyoxylic acid is reacted with phenol under alkiline conditions for a relatively short reaction time and at an increased temperature. It has been found (Hoefnagel et al., Reel. Trav. Chim. Pays-Bas 107 (1988) , 242) that by the use of this method, in addition to the para-isomer, 15% ortho-hydroxymandelic acid was formed.
• EP 368,696 describes the preparation of the sodium salt of para-hydroxymandelic acid on industrial scale. For that purpose, a concentrated aqueous solution of glyoxylic acid is added to a six-fold to eight-fold molar excess of phenol in the presence of a tertiary a ine. This amine should be hardly water-soluble, if at all, at room temperature. According to the method described, after a reaction for 345 minutes at 20°C, and utilizing triisooctyl amine, the sodium salt of pure para-hydroxymandelic acid precipitates after a 5% aqueous solution of sodium hydroxide has been added. After washing with diluted isopropanol the product is obtained in a yield of 70%.
• Para-hydroxymandelic acid is an important intermediate in the preparation of antibiotics of the amoxicillin- en cephalosporin-type.
• Ortho-hydroxymandelic acid can be used in the preparation of the above-mentioned EDDHA, which is used Inter alia as a sequestering agent.
• EDDHA which is used Inter alia as a sequestering agent.
• the sodium salt of this isomer is treated with oxygen (in the presence of Pt/Pb as catalyst) to form sodium-2-hydroxy- ⁇ -oxobenzeneacetic acid, which can be converted to_a double Schiff*s base by a reaction with ethylene diamine.
• Reduction of this product with hydrogen and a catalyst or with sodium borohydride, followed by complexing with an iron(III) salt gives the agrochemical EDDHA-FeNa.
• Ortho-hydroxymandelic acid can also be used as monomer in the polymer chemistry. For instance by copolymerization of this isomer in the acid or alkaline form with formaldehyde, polymers with hydroxyl and carboxyl groups can be obtained. Depending on the degree of polymerization, such polymers are water-soluble or not. They can be used for the removal of heavy metal ions. Incidentally, in this polymerization ketal formation between 2-hydroxymandelic acid and formaldehyde should be reckoned with. Water non-soluble polymers carrying carboxyl groups possess mildly catalytic properties for acid- catalyzed reactions and are useful as ion-exchanging resin.
• Catalysis by the use of bivalent metal ions typically results in a reaction product with an ortho/para ratio of 0.2-1.1, while catalysis with cations of a higher valency mainly leads to reaction products with an ortho/para ratio of 1.3-28.
• the method for separating the ortho- and para-isomers of hydroxymandelic acid or a salt thereof is characterized, according to the invention, by (a) starting from a mixture of ortho- and para-isomers in the alkali metal salt form or bringing a mixture of the ortho- and para-isomers into the alkali metal salt form; (b) extracting the mixture of the alkali metal salts with a polar, aprotic, organic solvent; (c) separating the polar, aprotic, organic solvent phase from the other (solid) phase, and (d) optionally recovering the ortho-isomer from the polar, aprotic, organic solvent phase, recovering the para-isomer from the other phase, and/or converting the alkali metal salts into the acid form or into a different salt form.
• step (d) is therefore an optional step.
• Water is the most suitable medium in which hydroxy- mandelic acid can be formed.
• the reaction whereby hydroxymandelic acid is formed can also be carried out in other solvents, for instance ethanol and dichloromethane.
• the ortho- and para-isomers of hydroxymandelic acid must be present in two different phases which can be simply separated.
• a hydrous solvent including the alkali metal salts of both the ortho-isomer and the para-isomer.
• a two-phase system will form rapidly.
• hydroxymandelic acid isomers in the starting mixture are not present in the alkali metal salt form, they can be simply brought into the desired form by treating the mixture with an aqueous alkali metal hydroxide solution.
• the aqueous mixture of alkali metal salts of the isomers of hydroxymandelic acid can be extracted, after evaporation, with a suitable polar, aprotic, organic solvent, for instance acetone or methyl ethyl ketone.
• a suitable polar, aprotic, organic solvent for instance acetone or methyl ethyl ketone.
• the water layer is evaporated as far as possible before method step (b) is carried out.
• a suitable polar, aprotic, organic solvent which can be used in accordance with the invention are acetone, methyl ethyl ketone, tetrahydrofuran and ethyl acetate. These solvents have been enumerated in order of preference.
• a preferred embodiment of the method according to the invention is characterized in that acetone or methyl ethyl ketone is used as the polar, aprotic, organic solvent.
• the mixture of ortho- and para- isomers is preferably obtained by reacting phenol with glyoxylic acid under neutral conditions in the presence of a divalent or trivalent metal ion or an oxide thereof as catalyst.
• a divalent or trivalent metal ion or an oxide thereof as catalyst.
• A1 2 0 3 calcined 0.82 24 5.3 88 0.65 A1 2 0 3 alkaline (Merck) 4.34 25 6.7 81 0.33 ⁇ -Al 2 0 3 4.34 21 6.8 64 0.49 ⁇ -Al 2 0 3 0.65 48 6.7 81 0.20 ⁇ -Al 2 0 3 4.34 21 6.8 77 0.30
• glyoxylic acid is reacted with an excess of phenol.
• An additional advantage of the excess of phenol resides in the fact that in that case disubstitution of the phenol by glyoxylic acid is prevented as well.
• the excess phenol does have to be removed before the starting product is subjected to the separation method. This can be suitably effected by removing the excess phenol from the mixture by the use of extraction with diethyl ether.
• Catalysis of the reaction between phenol and glyoxylic acid with bivalent metal ions typically results in a reaction product with an ortho/para ratio of 0.2-1.1, while catalysis with cations of a higher valence, in particular trivalent metal ions, mainly leads to reaction products with an ortho/para ratio of 1.3-28.
• Al 3+ ions As catalyst, There exists an express preference for this catalyst, based on considerations regarding yield, ortho/para ratio accessibility, cost price and environment.
• the invention also relates to the para-isomer of hydroxymandelic acid or a salt thereof which has been recovered from the phase that remains after the separation of the polar, aprotic, organic solvent phase.
• This isomer can be obtained from the aqueous phase in any of the conventional ways, for instance by acidifying the phase to pH 1.5, removing water, if any, by fractionated distillation under reduced pressure and lixiviating the residue with ethyl acetate or extracting it with diethyl ether. The desired product can subsequently be isolated by removing the ethyl acetate or the ethanol. 10
• the invention further relates to the ortho-isomer of hydroxymandelic acid or a salt thereof, which has been recovered from the polar, aprotic, organic solvent phase obtained from the separation method according to the invention.
• the solvent phase can be evaporated, whereby a voluminous white foam is obtained.
• This white foam which will typically still contain a (minor) amount of solvent, is subsequently dissolved in a small amount of water and the liquid phase is evaporated again. Finally, a hygroscopic product is left.
• EDDHA can be prepared in various ways from ortho-hydroxymandelic acid.
• Ortho-hydroxymandelic acid is often oxidized in a first step, for instance analogously to the disclosure of DE-OS-2,824,407.
• De phenol-free fraction was further processed by acidifying the water layer with-18 N sulfuric acid to a pH of 0.7, adding 25 g sodium chloride, and extracting with three 30 ml portions ethyl acetate. Without drying the ethyl acetate solution was evaporated and after adding 10 ml water the turbid solution was evaporated again to remove the enclosed ethyl acetate and the greater part of the water. The resultant viscous oil, after being dried to constant weight, weighed 12.75 g (76%). HPLC analysis of the viscous residue demonstrated the presence of 14% para-hydroxymandelic acid, 5% dimerec product and 81% ortho-hydroxymandelic acid.
• the HPLC analysis was carried out with the use of a Waters Associates Chromatography Pump M-45, Differential Refractometer Rl 401, Autoinjector Perkin-Elmer ISS 100 and a Spectrophysics SP 4100 Integrator.
• column material C18 Nucleosil® RCM 100 module was employed.
• Methanol/water/trifluoroacetic acid 10/90/0.1 was used as eluent.
• the observed retention times were: 4.7 minutes for 2,6-disubstituted mandelic acid, 5.2 minutes for para-hydroxymandelic acid + 2,4-disubstituted mandelic acid and 7.7 minutes for ortho-hydroxymandelic acid.
• Example l The procedure according to Example l was carried out again, but the further processing was now such that no oligomerization reaction occurred.
• the water layer was evaporated without acidifying with sulfuric acid, which yielded 19.2 g of a light-yellow powder (mixture A) , ⁇ a mixture of sodium salts.
• Mixture A was subsequently extracted with 100 ml 96% ethanol, whereby an insoluble water product was obtained.
• This product, (mixture B) was filtered off and weighed 1.7 g. This mixture was found to contain sodium sulfate and the aluminum complex of ortho- and para-hydroxymandelic acid (1:1) .
• the filtrate obtained gave 17.4 g light-yellow powder (mixture C) .
• Mixture C was introduced into 40 ml 90% acetone, whereafter a precipitate was formed by adding 5 portions of 100 ml acetone. This precipitate consisted of the ortho- and para-isomers in a proportion of about 1:1. Filtering off and extraction with 3 portions of 100 ml acetone yielded 3.2 g ⁇ insoluble product (mixture D) . Evaporation of the two combined acetone-containing filtrates yielded 14.2 g solid residue (mixture E) . In a concentrated solution of mixture E in 50 ml acetone, a precipitate of practically pure ortho-isomer formed after standing for some time at room temperature. Filtering off daily yielded, after 5 days, a total of 3.6 g white powder (product F) , the acetone-insoluble form of the sodium salt of 2-hydroxymandelic acid.
• Example 3 was in essence repeated, utilizing other zinc compounds as catalyst. After evaporation of the water layer and extraction with acetone, the potassium salts of para- and ortho-hydroxymandelic acid are obtained in high purity.
• the table below specifies the catalysts used, the reaction conditions used and the yields of the isolated hydroxymandelic acid salts: Catalyst pH Reaction Reaction Yield Yield time temp. 4-OH 2-OH
• the filtrate contained approximately 35% ethylene diamine-N-2- hydroxybenzeneacetic acid and approximately 15% of the ethylene diamine salt of 2-hydroxymandelic acid. Both products can be added in a second preparation cycle of EDDHA.

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• General Chemical & Material Sciences (AREA)
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Citations (3)

• 1992
  • 1992-12-23 NL NL9202248A patent/NL9202248A/nl not_active Application Discontinuation
• 1993
  • 1993-12-23 WO PCT/NL1993/000277 patent/WO1994014746A1/en active Application Filing
  • 1993-12-23 AU AU58435/94A patent/AU5843594A/en not_active Abandoned

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