Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acids and salts thereof
Patent
1981-04-09
1983-01-11
Killos, Paul J.
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acids and salts thereof
2605011, C07C 5950
Patent
active
043683347
DESCRIPTION:
BRIEF SUMMARY
This invention relates to a chemical process, and in particular to a process for the isolation of a salt of p-hydroxymandelic acid. It also relates to novel salts which may be isolated by this process.
Salts of p-hydroxymandelic acid are valuable intermediates, for example for the preparation of p-hydroxyphenylglycine, which is useful for the manufacture of the penicillin derivative, amoxycillin.
British Pat. Specification No. 1,377,243 discloses in Example 5(b) thereof the preparation of a solution of the sodium salt of p-hydroxymandelic acid (referred to therein as 4-hydroxyphenylglycolic acid), but this salt is not isolated.
One method for the isolation of the salt is disclosed in Belgium Pat. No. 867,287 which describes a process for the manufacture of solid sodium or potassium p-hydroxymandelate monohydrate which comprises reacting by known means phenol with glyoxylic acid in the presence of, respectively, sodium or potassium hydroxide, followed by adjustment of the pH of the solution to between 5 and 7 and salting out of the desired sodium or potassium salt with respectively, a sodium or potassium salt of a simple acid.
We have now found an advantageous method for the isolation of solid salts of p-hydroxymandelic acid prepared in this way, by precipitation from an organic solution of the acid. This method of isolation produces a higher yield of isolated salt than the method described in Belgium Pat. No. 867,287.
Accordingly the present invention provides a process for the isolation of a solid salt of p-hydroxymandelic acid, which process comprises reacting phenol with glyoxylic acid in the presence of sodium or potassium hydroxide, acidifying to a pH less than 3, extracting the resulting solution with a water-immiscible solvent to provide a solution of p-hydroxymandelic acid and precipitating the salt therefrom.
The reaction between phenol and glyoxylic acid may be carried out in any convenient way. Suitable conditions described in Belgium Pat. No. 867,287 and also in Example 5(b) of British Pat. No. 1,377,243. Suitably the reaction is carried out at a temperature in the range 20.degree.-100.degree. C., suitably 20.degree.-60.degree. preferably 30.degree.-40.degree. C. We have found that it is also preferable to adjust the dilution of the reaction solution so that the concentration of glyoxylic acid is in the range 3 to 9% w/v, preferably 3.5 to 7%, especially 3.5 to 4.5% w/v. The reaction may advantageously be carried out under nitrogen.
The reaction is normally carried out for a time from 3 to 8 hours, suitably about 4 hours.
Suitably the phenol is employed in excess. Preferably the concentration of phenol employed is in the range 13 to 20% w/v. The sodium or potassium hydroxide is employed in a quantity related to the amount of phenol used and is conveniently employed at a concentration of from 5 to 8% w/v in the reaction mixture.
When the reaction is complete excess phenol is removed by conventional means with a solvent and the reaction mixture is then acidified, for example with hydrochloric or sulphuric acid, to a pH of less than 3. Preferably the pH is adjusted to 1 to 2. This acidified reaction mixture is then extracted with a water-immiscible solvent. Examples of suitable solvents include methyl ethyl ketone, methyl isobutyl ketone, ethyl acetate, or methyl acetate, or mixtures of such solvents. A preferred solvent is methyl isobutyl ketone.
This solvent extraction may be carried out in any conventional way, preferably by counter-current technique.
This extraction results in p-hydroxymenadelic acid being extracted into the water-immiscible phase. The aqueous phase is discarded. The required salt is precipitated from the water-immiscible solution by adding a suitable precipitating agent, depending on the particular salt. For preparing the sodium salt, suitable precipitating agents include sodium hydroxide in aqueous or alcoholic solution, or sodium ethyl hexanoate in a suitable organic solvent. A solution of potassium ethyl hexanoate would be a suitable precipitating agent for preparing the p
REFERENCES:
patent: 3725437 (1973-04-01), Nagoya et al.
Beecham Group Limited
Killos Paul J.
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