DK146801B - PROCEDURE FOR SEPARATING D-P-HYDROXYPHENYLGYLINE FROM A MIXTURE OF D- AND DL-P-HYDROXYPHENYLGYLIN OR ITS ALKYL ESTERS OR MIXTURES THEREOF - Google Patents

Description

in 146801

The invention relates to a process for separating D-p-hydroxyphenylglycine from a mixture containing D- and DL-p-hydroxyphenylglycine or their alkyl esters with 1-10 carbon atoms in the alkyl moiety or mixtures thereof.

D-p-hydroxyphenylglycine is a well-known product used in the synthesis of important β-lactam antibiotics such as [β ~ β- (Ώ-2-amino-2-p-hydroxyphenyl) -acetamido] penicillin

amoxycillin

The preparation of optically homogeneous D-p-hydroxyphenylglycine has previously been carried out by procedures involving the separation of DL-p-hydroxyphenylglycine or derivatives thereof as described e.g. in the descriptions of Belgian patent no.

795 874 and Dutch Patent Application No. 7 311 012.

The present invention relates to a process for separating D-p-hydroxyphenylglycine from a mixture containing D- and DL-p-hydroxyphenylglycine and / or alkyl esters thereof. The principle is based on the novel and surprising fact that the hydrogen bromide salt of DL-p-hydroxyphenylglycine is less soluble in aqueous hydrogen bromide acid than the hydrogen bromide salt of D-p-hydroxyphenylglycine. No solubility differences were found for the corresponding salts with hydrochloric acid or sulfuric acid.

Accordingly, the process of the invention is peculiar to the characterizing part of the claim.

When a mixture of D- and DL-β-hydroxyphenylglycine is stirred in aqueous hydrobromic acid, the hydrogen bromide salt is formed by DL-β-hydroxyphenylglycine, which then crystallizes upon cooling. The hydrogen bromide salt of D A simple filtration at this point results in the separation of the above two products. such as the free amino acid.

When used in the process of the invention, the alkyl esters of D- and DL-β-hydroxyphenylglycine, this process results in simultaneous hydrolysis of the esters and optical separation of the resulting Dβ-hydroxyphenylglycine hydrobromide from DL-β-hydroxyphenylglycine hydrobromide in one operation. without isolation of intermediates.

A mixture containing varying amounts of D- and DL-β-hydroxyphenylglycine is added to a commercially available 48% aqueous solution of hydrobromic acid and heated until a solution is obtained. The amounts of hydrogen bromic acid solution and heat used are not critical, but must be sufficient to produce dissolution of the added p-hydroxyphenylglycine mixture. The hydrobromic acid solution is used in stoichiometric excess, usually in a molar ratio of HBr to 25 p-hydroxyphenylglycine of from 2: 1 to 4: 1. Larger volumes of hydrogen bromic acid solution may undesirably increase the solubility of DL-β-hydroxyphenylglycine hydrobromide. The amount of heat supplied varies with the volume of hydrogen bromide acid solution used and the amount of p-hydroxyphenylglycine mixture added. Temperatures of 100-115 ° C are usually sufficient to rapidly dissolve the added material.

The crystalline product which is separated by cooling to room temperature (20-25 ° C) is removed by filtration or centrifugation. It consists mainly of DL-β-hydroxyphenylglycine hydrobromide as judged by optical rotation. The separated solution containing the hydrobromide salt of D-p-hydroxyphenyl glycine is adjusted with alkali, preferably ammonia water, to pH 4-6, preferably 5.5-5.7. The crystalline free amino acid thus formed or obtained by concentration is separated by filtration or centrifugation. The D-p-hydroxyphenylglycine thus obtained is of approx. 99% purity as determined by optical rotation and thin layer chromatographic examination.

If the process uses a mixture of p-hydroxy-phenylglycine alkyl esters, the ester group is hydrolyzed with anhydrous hydrobromic acid at a temperature of from about 100 to about 115 ° C. The hydrolysis is essentially complete in about 3 hours. The resulting hydrobromide salts of DL-β-hydroxyphenylglycine and D-β-hydroxyphenylglycine are separated as described above. Any alkyl ester whose 15 alkyl moieties contain 1-10 carbon atoms can be used. The methyl esters of the p-hydroxyphenyl glycines are preferred (prepared by the method disclosed in the specification of Belgian Patent No. 795 874).

Of course, it is also possible to separate D-p-hydroxyphenylglycine from mixtures of D- and DL-p-hydroxyphenylglycine and the alkyl esters thereof by the process of the invention.

EXAMPLE 1

A mixture (10 g) containing varying amounts of D- and DL-β-hydroxyphenylglycine (Houben-Weyl 8, 279-284, 1952) and 48% aqueous hydrobromic acid (26.6 ml) was heated to 100-110 ° C. until a solution is formed. It was then allowed to cool to 20-25 ° C. The crystalline product formed was removed by filtration and found to be 90-96% pure DL-β-hydroxy-phenylglycine hydrobromide as judged by optical rotation. The separated filtrate was treated with ammonia water to pH 5.5-30 5.7. The crystalline product thus formed was isolated by filtration and washed with methanol. Examination of this by optical rotation and thin layer chromatography revealed that it was D-p-hydroxyphenylglycine with 98.7-99.3% optical and chemical purity. These results are summarized in Table I.

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A mixture (10 g) containing varying amounts of D and DL-β-hydroxyphenylglycine methyl esters (Belgian Pat.

795 874) and 48% aqueous hydrobromic acid (26.5 nol) were heated to 110-115 ° C for about 3 hours. The reaction mixture was cooled to 20-25 ° C and then filtered. The solid obtained was found to be DL-β-hydroxyphenylglycine with 70-87% purity as determined by optical rotation. The pH of the filtrate was adjusted to pH 5.5-5.7 with ammonia water and the resulting 10 crystalline D-p-hydroxyphenylglycine was recovered by filtration. The determination of optical rotation and thin layer chromatography on the product showed that it was of 96.8-98% optical and chemical purity. These results are summarized in Table II.

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