CS271966B1 - Preparation of N-salicylidene-D, L-glutamate-copper trihydrate - Google Patents

Abstract

The solution relates to a method for preparing N-salicylidene-D,L-glutamate trihydrate of the copper (II) formula D, L-Cj^2H1 |OgNCu. 3H2O based on the racemization of an optically active chelate ligand of the formula £" Cu/salal=L-gluH//HjO/2J, where salal-L-glu denotes N-salicylidene-L-glutamate, induced by the action of alkalis on a solution of the complex, prepared by dissolving ECu/salal=L-gluH//H2Q/,7 .H_O or anhydrous Cu/salal=L-gluH/. The final product crystallizes spontaneously from the reacting system after neutralization of the alkaline hydroxide present, and is significant as a compound with superoxide dismutase activity.

Description

The invention relates to a process for the preparation of copper N-salicylidene-D, L-glutamate trihydrate of the formula

D, LC ₁₂ H ₁₁ O ₅ NCu.3H ₂ O based on the racemization of the dianion of the optically active Schiff base, coordinated in the diacva-N-salicylidene-L-glutamate-copper complex, by the action of the base and then such modification of the reactive system that results in spontaneous crystallization of the above compound in good yield.

The advantage of this method of preparation is the replacement of D, L-glutamic acid as the starting amino acid in the syntheses with a more commercially available and significantly cheaper L-glutamic acid.

It is known that by coordinating Cu / II / compounds with dianions of trifunctional Schiff bases (designation: TSB) of the N-salicylidene ci-aminoalkanoate type, they can be prepared in slightly heated reaction systems (t -60 ° C; solvent dilute ethanol, dilute methanol, or water) in which: a / the copper salt of the relevant amino acid and salicylaldehyde, b / copper salicylaldehyde and the appropriate amino acid, c / salicylaldehyde, the appropriate amino acid and a suitable copper salt (usually copper acetate monohydrate) react together.

The chirality of TSB in the Cu / II / coordination compounds thus prepared is analogous to the chirality of the -amino acid used in the syntheses (D-, L-, or D, L).

Copper N-salicylidene-L-glutamate was prepared according to b) as a trihydrate, of formula Cu / salal = L-gluH / .3H ₂ O, where salal = L-gluH · means {oC _g H ₄ .CH = N-CH /COO/.CH ₂ .CH ₂ .COOHj ^. (Y. Nakao, K. Sakurai and A. Nakahara, Bull. Chem. Soc. Japan. 40, 1536 (1967)). The X-ray structure analysis of a compound of the same composition, obtained according to c / has shown that it is a wire pentakooridnovaný / II / complex pyramidal structures of the formula / Cu / Salal = = L-Gluhe // H _2/2 /, H _{2, the} lal = L-gluH is the same as mount. (J. Soldánová, J. KrátsmárSmogrovič, F. Pavelčík, V. Seressová and M. Žemlička, Proc, 11th Conf. Coord. Chem., Smolenice 1987, p. 365.) A very significant superoxide dismutase activity of this complex and its alkali metal salts: N-salicylidene-L-glutamate mesanates (ref. no. AO 271 963). The D, L-forms of these complexes also show similar properties; copper N-salicylidene-D, L-glutamate trihydrate, resp. Alkali metal N-salicylidene-D, L-glutamate mesate (MS AO 271 963).

However, the preparation of N-salicylidene-D, L-glutamate-copper complex trihydrate according to processes a /, b / or c) requires the use of D, L-glutamic acid as the starting amino acid in the synthesis, the commercial cost of which is round five times higher than that of L-glutamic acid. .

It is also known that dianions of optically active N-salicylidene-β-aminoalkanoate-type Schiff bases, coordinated to Cu (II), undergo racemization in solutions by the action of bases (GN Weinstein, MJ O'Connor and RH Holm, Inorg. Chem. £, 2104, 1970; RD Gillard and RS Wooton, J. Chem. Soc. 1970 B, 364; F. Jursík, B. Hájek, Chem. Lists £ 8, 23 (1974) et al.)

However, this finding has not yet been used to prepare N-salicylidene-D, copper glutamate trihydrate by racemization of the L-form of the complex, which is obtained from the affordable L-glutamic acid.

The process according to the invention consists in treating the excess alkali hydroxide with a complex of the formula Z'Cu / salal-L-gluH // H ₂ O / ₂ J (molar ratio 1: 1.5 and more) in aqueous solution or in dilute ethanol, at room or slightly elevated heat (up to 60 ° C). The reaction system is prepared by dissolving a complex of formula Z * Cu / salal-L-gluH / / H ₂ O / ₂ JH ₂ O, or an anhydrous form of the formula Cu / salal = L-gluH /, where salal = L-gluH is the same as in an alkali hydroxide solution.

CS 271 966 Bl

Upon completion of the racemization and neutralization process of the alkali hydroxide in the system, copper N-salicylidene-D, L-glutamate trihydrate crystallizes spontaneously as a green colored microcrystalline product of good purity and in good yield.

The selected examples illustrate but do not limit the method of preparation of the compound obtainable according to the invention.

In addition to the yield and the determined content of elements (C, N, H), the prepared compound is characterized by controlling the disappearance of the optical activity of glutamic acid released from the complex after its decomposition with hydrochloric acid and extraction with salicylaldehyde ether.

Example 1 0.1 mol ("Cu) salal = L-gluH // H ₂ O / ₂ 7.H ₂ 0 / 36.6 g) is dissolved in a 250 cm volumetric solution.

NaOH, or KOH (c = 1M.dm ^-3 ) diluted with 600 cm ^{3 of} water. After standing for 20 minutes (room temperature), the solution was filtered (frit S-4) and the alkali metal hydroxide present was neutralized by adding 250 cm ^{3 of} a standard solution of HCl (c = 1M.dm ^-3 ). After a short time, the reaction product began to crystallize spontaneously in the form of light green acicular crystals. The final product collected on a frit, washed with water and freely dried at room temperature represents an yield of 85.5%. Analysis. For D, LC ₁₂ H _{1; 1} O ₅ NCu.3H ₂ O, M _r = 366.82; calculated / found: 39.29 / 39.7% C, 4.67 / 4.5% H and 3.82 / 3.8% N.

Control of the racemic state of TSB in the complex. The charge (2 g) of Cu / salal = L-gluH / .3H ₂ O was decomposed.

by the action of 3,5 cm of concentrated hydrochloric acid, diluted with 10 cm of water and gentle heating. The released salicylaldehyde was extracted from the cooled mixture with ether. The aqueous layer was quantitatively transferred to a 25 cm ³ volumetric flask, made up to volume with water and examined for optical rotation using a Polamat A / t = 20 ° C polarimeter; λ. = 578 nm /, with a negative result.

Following loading of the solution treated with £ / Salal = L-Gluhe // H _{2 0/2} 0 7 .H ₂ / 2g / showed optical activity, which can be expressed with respect to the amount of L-glutamic acid, liberated from the TSB: 20 Γ2 C = + 31.5 °.

578 nm

Example 2

0.1 mol of anhydrous copper N-salicylidene-L-glutamate was treated in an analogous manner to Example 1. The yield of the final product Cu (salal = D, L-gluH) .3H ₂ o was 85.8% in this case.

Claims (1)

Upon completion of the racemization and neutralization process of the alkali hydroxide in the system, N-salicylidene-D, L-glutamate L-glutamate trihydrate crystallizes spontaneously as a green-colored microcrystalline product of good purity and in good yield. The selected examples illustrate, but do not limit, the method of preparation of the compound of the invention. In addition to the yield and the determined content of the elements (C, N, H), the compound prepared is also characterized by the control of the disappearance of the glutamic acid optical activity released by the complex after its distribution with hydrochloric acid and extraction with salicylaldehyde ether. Example 1 Dissolve 0.1 mole / acu / salal = LgluH / H 2 O/27.H 2 O (36.6 g) in a 250 cm volumetric solution of NaOH or KOH / c = 1M.dm 3 / dilute 600 cm 3 of water. After 20 minutes of standing (room temperature), the solution was filtered (frit S-4) and the alkali metal hydroxide present was neutralized by the addition of 250 cm 3 of HC1 volumetric solution (c = 1M.dm-3). After a short time, the product began to crystallize spontaneously in the form of light green needle crystals. The final product collected on the frit, washed with water and freely dried at room temperature is 85.5% yield. Analysis. For D, L-C 12 H 11 O 5 NCCl 3 H 2 O, M r = 366.82; calculated / found; 39.29 / 39.7% C, 4.67 / 4.5% H and 3.82 / 3.8% N. Control of the racemic state of TSB in the complex. The loading (2 g) of Cu / salal = L-gluH 3 · H 2 O was decomposed with 3.5 cm 3 of concentrated hydrochloric acid, diluted with 10 cm 3 of water and slightly heated. The salicylaldehyde released was extracted with ether from the cooled mixture. The aqueous layer was transferred to a 25 cm 3 volumetric flask, filled with water and examined for optical rotation using a "Polamat A" polarimeter (t = 20 ° C); λ. = 578 nm /, with negative result. In the same manner, the treated solution of β-glucan (L-gluH),, (27) H 2 O (2g) showed an optical activity, which can be expressed with respect to the amount of L-glutamic acid released from TSB: C = + 31.5 °. 578 nm EXAMPLE 2 0.1 mole of anhydrous copper N-salicylidene-L-glutamate was worked up in an analogous manner to that described in Example 1. The yield of the final Cu / salal = D, L-gluH3.3H2obol in this case was 85.8%. OBJECT OF THE INVENTION A process for preparing N-salicylidene-D, L-glutamate trihydrate of formula D, L-C12H11O5NC11.3H2O, characterized in that an optically active chelate ligand of formula (Cu / salal = L-gluH / H2O / 2J) is racemized. where salal = L-gluH denotes N-salicylidene-L-glutamate, (OCgH 2 .CH = N-CH / COO / CH 2 .CH 2 COOH) 3 by treating the solution of this complex by dissolving the compound the formula (Cu / salal = L-gluH 1 H 2 O / 2 J, H 2 O, or the anhydrous compound of the formula Cu / salal = L-gluH), where salal = L-gluH is the same as mount, in water, or diluted ethanol; methanol.