GB2101988A - Process for the preparation of 4-alkoxymandelic acids - Google Patents

Abstract

A process for the preparation of a 4-alkoxymandelic acid of the formula: <IMAGE> wherein R is optionally substituted alkyl and each X is independently hydrogen, halogen, lower alkyl or lower alkoxy, which comprises treating an aqueous solution of an alkali metal salt of a 4-hydroxymandelic acid of formula (II): <IMAGE> with an alkyl halide or a dialkyl sulphate at a pH from 9.0 to 13.0, followed by acidification of the reaction mixture to precipitate the 4- alkoxymandelic acid.

Description

SPECIFICATION Process for the preparation of 4-alkoxymandelic acids This invention relates to the preparation of 4alkoxymandelic acids and related compounds.

4-Alkoxymandelic acids are valuable intermediates for the synthesis of dyestuffs, for example, those described in UK Patent Specification No.1568231, and the compounds have usually been prepared from difficultly obtainable, and consequently expensive, 4-alkoxybenzaldehydes via the cyanohydrin and subsequent hydrolysis. This route also has the disadvantages of using highly toxic reagents and complex solvent processes.

It has now been found that 4-alkoxymandelic acids may be prepared by an aqueous process which is suitable for large scale manufacture.

According to the present invention there is provided a process for the preparation of 4alkoxymandelic acids of the formula (I):

wherein R is optionally substituted alkyl and each X is independently hydrogen, halogen, lower alkyl or lower alkoxy, which comprises treating an aqueous solution of an alkali metal salt of a 4-hydroxymandelic acid of formula (11):

with an alkyl halide or a dialkyl sulphate at a pH from 9.0 to 13.0, followed by acidification of the reaction mixture to precipitate the 4alkoxymandelic acid.

Examples of the halogen substituents represented by X are chlorine and bromine.

An example of a lower alkyl substituent represented by X is methyl.

Examples of lower alkoxy substituents represented by X are methoxy and ethoxy.

It is preferred that the optionally substituted alkyl groups represented by R are optionally substituted lower alkyl groups, examples of which are ethyl, propyl, isopropyl and rr butyl.

Examples of the alkali metal salts of the compounds of formula (II) which may be used are the potassium salts and especially the sodium salts.

Examples of the 4-hydroxymandelic acids of formula (II) which may be used are 4-hydroxymandelic acid itself, 3, 5-d imethoxy-4-hydroxy- mandelic acid, 3-chloro-4-hydroxymandelic acid, 3-chloro-4-hydroxy-5methylmandelic acid, 3, 5-dimethyl-4-hydroxymandelic acid and 3-tert. butyl-4-hydroxy-5-methyl mandelic acid.

When the alkylating agent used is an alkyl halide it is preferred that it is an alkyl bromide. Alkyl chlorides may be used, but being less reactive than the bromides their use may entail prolonged reaction times, whilst alkyl iodides, although useable, are much more expensive than the bromides and consequently less commercially attractive. Examples of alkyl halides which may be used are ethyl bromide, rrpropyl bromide, isopropyl bromide and butyl bromide.

Examples of dialkyl sulphates which may be used as alkylating agents are dimethyl sulphate and diethyl sulphate.

In this specification the terms "lower alkyl" and "lower alkoxy" are used to denote alkyl and alkoxy groups respectively which contain from 1 to 4 carbon atoms.

It is preferred to carry out the reaction at a pH from 10.0 to 11.0, conveniently at pH 10.5. Above pH 13.0 excessive hydrolysis of the alkylating agent may occur. Below pH 9.0 the reaction is slow, and below pH 6.0 esterification of the carboxylic acid group may take place.

The process of the invention may be carried out by dissolving the alkali metal salt of the 4hydroxymandelic acid of formula (II) in water and adding sufficient alkali metal hydroxide to bring the pH to a value not exceeding 13.0. If the 4-hydroxymandelic acid is in the form of the free acid then additional alkali metal hydroxide will be required to convert the acid into its alkali-metal salt and bring it into solution. The alkylating agent (alkyl halide or dialkyl sulphate) is then added and the mixture is stirred and heated for several hours to effect the alkylation. An excess of the alkylating agent is used to offset the loss which occurs by hydrolysis, and it is convenient to employ 1.5 mols of alkylating agent per mol of 4-hydroxymandelic acid. Reaction temperatures may be from about 40'C up to the reflux temperature of the mixture.

Hydrolysis of the alkylating agent may be minimised by adding it in two or more portions during the reaction, or by starting the reaction at a pH of approximately 10.5 and maintaining this value by adding an aqueous solution of the alkali metal hydroxide dropwise or portionwise as the reaction proceeds. Yet again, the alkylating agent and the alkali metal hydroxide solution may be added simultaneously to the heated aqueous solution of the alkali metal salt of the 4-hydroxymandelic acid so as to maintain the pH of approximately 10.5.

At the conclusion of the reaction the solution is cooled and acidified to a pH of approximately 1.5, whereupon the free acid form of the 4-alkoxymandelic acid separates out and may be collected, washed with water and dried. The acid employed for the acidification is preferably a strong mineral acid such as hydrochloric acid or sulphuric acid.

The 4-hydroxymandelic acid starting materials of formula (II) may be obtained in known manner, for example, from the reaction between glyoxylic acid and an appropriate phenol. This process is described, for 4-hydroxymandelic acid itself, in UK Patent Specification No.1576331. The reaction gives not only the desired 4-hydroxymandelic acid but also some 2-hydroxymandelic acid and the disubstituted compound of formula (III):

the three compounds being in the approximate proportions: 4-hydroxymandelic acid 75, 2-hydroxymandelic acid 10, di-substituted compound 1 5.

4-Hydroxymandelic acid essentially free from these minor components can be isolated from the crude reaction mixture as the sodium or potassium salt by a salting out technique as described in UK Patent Specification No.1576331, but the process is wasteful, 25% or more of the 4-hydroxymandelic acid being lost. It has been found that by treating the crude reaction mixture with an alkyl halide or a dialkylsulphate at a pH from 9.0 to 13.0 and subsequent acidification, the 4-alkoxymandelic acid can be isolated in high yield and in substantially pure form, the contaminating compounds and/or their derivatives remaining in solution. This process constitutes a further feature of the invention, which is illustrated by the following Examples in which parts and percentages are by weight.

Example 1 Water (200 parts) and aqueous sodium hydroxide solution (32%, 60 parts) are charged to a reaction vessel, followed by 4hydroxymandelic acid sodium salt monohydrate (96 parts at 86% strength, equivalent to 82.6 parts at 100%) and rrpropyl bromide (59 parts). The reaction mixture is heated to 60-65"C over 30 minutes, the pH of the solution at this point being 12.0-12.2.

The solution is stirred at 60-65"C for 1 8 hours, cooled to 55"C, and a further quantity (14.8 parts) of npropyl bromide is added.

The mixture is reheated to 60-65"C and stirred at this temperature for a further 8 hours. The pH at this stage is 8.7. The solution is cooled to 25-30"C and acidified to pH 1.5 by the addition of concentrated hydrochloric acid (approximately 30 parts). 4-n Propoxymandelic acid separates out and is filtered off, washed with cold water (2 x 100 parts) and dried at 50'C. There are obtained 74.7 parts of product, strength 95.5% by HPLC, equivalent to 71.4 parts at 100% (85% of the theoretical yield).

Example 2 Water (200 parts), 4-hydroxymandelic acid sodium salt monohydrate (96 parts at 86% strength, 82.6 parts at 100%) and rrpropyl bromide (73.8 parts) are charged to a reaction vessel. The mixture is heated to 60-65"C and the pH adjusted to 10.5 by the addition of aqueous sodium hydroxide solution (32%, 49 parts). The mixture is stirred at 60-65'C for 30 hours during which time the pH is maintained at 10.5 by the addition of further aqueous sodium hydroxide solution (13 parts).

The mixture is cooled and the pH is adjusted to 1.5 by the addition of concentrated hydrochloric acid (56.6 parts). The precipitated product is filtered off, washed with water, and dried at 50"C.

4-rFpropoxymandelic acid (74.0 parts) is obtained in 88% isolated yield at a strength by HPLC of 99%.

Example 3 226 parts of an aqueous suspension of mixed hydroxymandelic acid isomers (76% 4isomer; 14% compound of formula (111)10% 2-isomer, containing 56.2 parts at 100%) is adjusted to pH 12.0 by the addition of aqueous sodium hydroxide solution (32%; 65 parts). Propyibromide (46.9 parts) is added and the mixture is stirred at 60-65"C for 24 hours when further rrpropylbromide (11.7 parts) is added. Stirring is continued for another 10 hours. The mixture is cooled to room temperature and acidified to pH 1.5 by the addition of concentrated hydrochloric acid (41.3 parts). The precipitated product is fil- tered off and washed with water.

4-nprnpoxymandelic acid (38 parts) is obtained in 72% isolated yield (95% on 4hydroxymandelic acid reacted) at a strength of 96.9% by HPLC containing less than 1 % of each of the other isomers.

Claims (6)

1. A process for the preparation of a 4alkoxymandelic acid of the formula:

wherein R is optionally substituted alkyl and each X is independently hydrogen, halogen, lower alkyl or lower alkoxy, which comprises treating an aqueous solution of an alkali metal salt of a 4-hydroxymandelic acid of formula (11):

with an alkyl halide or a dialkyl sulphate at a pH from 9.0 to 13.0, followed by acidification of the reaction mixture to precipitate the 4alkoxymandelic acid.

2. A process according to Claim 1 wherein each X is hydrogen and R is lower alkyl.

3. A process according to Claim 1 or Claim 2 wherein R is n-propyl.

4. A process according to any one of Claims 1 to 3 wherein the alkyl halide is an alkyl bromide.

5. A process according to any one of claims 1 to 4 performed at a pH from 10.0 to 11.0.

6. A process for the preparation of a 4alkoxymandelic acid as described in any one of the Examples.