FI79298B - NOW FOERFARANDE FOER FRAMSTAELLNING AV GLUTAMYLTAURIN. - Google Patents

Description

1 79298

A new process for the preparation of β-glutamyl taurine

The present invention relates to a new process for the preparation of biologically active N-L-glutamyl-5 taurine of formula I

H0N-CH-COOH 2 I

CH- I

I 2 CH ~ I 2

10 CO-NH-CH2-CH2SO2OH

its enantiomer (-D-glutamyl taurine of formula I), a racemic mixture of the two compounds (β-DL-glutamyl taurine of formula 15 I) and pharmacologically acceptable salts thereof. The new synthesis is simpler and more efficient than known methods.

An earlier publication by Chinoin, HU HU 174,114 = DE-A-20 su 2 518 160.0 ^ 7, describes several syntheses for the preparation of β-glutamyl litaurine. Common to these syntheses: is the acylating coupling of taurine after it has been converted to an active derivative, e.g. an active ester derivative. This compound is a γ-pu-25 ester derivative of glutamic acid in which the amino group of glutamic acid is protected, e.g., benzyloxycarbonylglutamic acid oC-benzyl ester.

The present invention relates to a synthetic process by which β-glutamyl taurine can be prepared in a simpler, shorter time and with less chemicals and better yields than known processes.

According to the method of formula II

35 h2n-ch2-ch2-so2oh II

taurine is acylated with phthalylglutamic anhydride of formula III

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O O

c c

(Qj ^ ^^^ N-CH \ 0 III

5 η I I

O CH- C.

From the phthalyl-T'-glutamyltaurine thus obtained having

10 formula IV

O

II

IV

--- ^ N-CH-COOH

15 V

tl '2 O <fH2

C0-NH-CH2-CH2-S020H

The protecting group is removed to give the desired compound of formula I.

The process according to the invention is carried out in such a way that the phthalylglutamic anhydride of the formula III. E. King, D. A. A. Kidd, J. Chem. Soc. (1949) pp. 3315? 25 is reacted in solution with a taurine of formula II. An organic solvent is preferably used as the solvent. When a base is added as an acid scavenger, the reaction proceeds better. The resulting phthalyl-? by ion exchange chromatography and, if desired, converted into a salt.

In the process of the invention, the free amino group of taurine is attached to N-phthalyl-1-glutamyl anhydride.

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For example, J. of Med. Chem. Vol. 25, p. 1019, it is known that the amino groups of amino acids such as 4-aminobutyric acid are more reactive than the amino groups of arylamine derivatives such as e.g. 4-nitro-5 aniline-3-sulfuric acid (cf. DE-A-2 333 798). Therefore, in the process described in the former publication, the amino acids are protected as their trimethylsilyl derivatives before the reaction with N-phthalyl-1-glutamyl anhydride, whereas DE-A 2 333 798, on the other hand, protects 10 4-nitroaniline β-sulfuric acid. Since the taurine used as a starting material in the process of the invention is structurally close to 4-aminobutyric acid, it is unexpected from the prior art of these publications that it can be reacted with N-phthalyl-1-glutamyl anhydride without protection to give the desired product in maximum yield.

The following is a list of the advantages of the new method over methods in which 7 '' L-glutamyl taurine has been previously prepared.

From glutamic acid, a short 4-step synthesis yields γ-glutarine taurine. The previous methods were 6-step or more multi-step syntheses.

The synthesis starting from glutamic acid comprises about *: * 25 half of the number of operations and takes about half the number of working hours as the simplest of the previous methods.

Substantially fewer chemicals are used than in the most economical prior art method.

According to a new synthetic method, glutamic acid is obtained from C-glutamyl taurine in a total yield of 32%. This yield is generally much better than in previous methods based on glutamic acid.

:; Further details are provided in the following pre-. 35 characters without limiting the scope to these examples.

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Example 1 To 3.05 g (11 mmol) of phthalyl-L-glutamic anhydride is added 15 ml of anhydrous acetonitrile. The resulting suspension is cooled to 0 ° C and a solution of 1.25 g (10 mmol) of taurine in 2.56 ml (20 mmol) of tetramethylguanidine and 5 ml of acetonitrile is added dropwise with stirring. . The solution is then stirred for 30 minutes at 0 ° C and for another 30 minutes at 20 ° C. After stirring, the sus-10 suspension clears. To the reaction mixture are added 1.4 ml (20 mmol) of 70% hydrazine hydrate and 10 ml of ethanol. The solution is allowed to stand at room temperature overnight and evaporated under reduced pressure. The residue is dissolved in 50 ml of water and 1.2 ml of glacial acetic acid are added. The separated phthalyl-15 hydrazine is removed by filtration or centrifugation.

The pH of the pure solution is adjusted to 2.5 by adding formic acid. The solution is applied to the H + stage of a 2.2 x 40 cm Dowex 50Wx2 / 100-200 mesh / column pre-equilibrated with a 1: 4: 45 v / v formic acid / acetic acid / water mixture (pH approx. 2.1). Elute with the same formic acid / acetic acid solution. From the very beginning of the sample export, the eluate is collected and stopped after the sample export has been stopped and the eluate has reached 160 ml. The solution is evaporated under reduced pressure. The crystalline residue is dried in a desiccator with lye and recrystallized from an 8: 2 by volume mixture of dimethylformamide and water. The mother liquor is evaporated and the residue thus obtained is also recrystallized.

The two crystalline products are combined. 1.85 g of T-L-glutamyl taurine (73%) are obtained.

Melting point: 222-223 ° C. = + 20.3 ° (water, c 3.6).

Paper electrophoretic mobility at pH 6.5 compared to cysteic acid: 0.73; at pH 2 0.53. Paper chromatographic Rf value: 0.19 (butanol / pyridine / glacial acetic acid / water = 35 15: 10: 3: 12).

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Analysis for C 7 H 14 N 2 O 6 S (254.26) calculated: C 33.07%, H 5.55%, N 11.02%, O 37.75%, S 12.61% found: C 33.11%, H 5.71%, N 10.97%, O 37.58%, δ S 12.76%.

Example 2 3.05 g (11 mmol) of phthalyl-D-glutamic anhydride are reacted according to Example 1 with 1.25 g (10 mmol) of taurine. 1.80 g of N-d-glutamyl taurine (71%) are obtained. Melting point: 220-222 ° C.

-20.4 ° (water, c 5.1).

Example 3 3.05 g (11 mmol) of phthalyl-DL-glutamic anhydride are reacted according to Example 1 with 1.25 g (10 mmol) of taurine. 1.88 g of γ-DL-glutamyvlitaurine (74%) are obtained. Melting point: 209-212 ° C.

Claims (3)

1. A novel process for the preparation of two enantiomers of β-glutamyltaurine of Formula I HoN-CH-C00H 2 in CH CO-NH-CH2-CH2-SO20H of their racemic mixture and their pharmaceutically useful salts, characterized in that taurine of formula II is reacted with h And remove the phthalyl protecting group of the resulting phthalyl-Y-glutamyltaurine of formula IV