CS200063B1 - Method of preparing alkylene-n,n'-bis-histidines - Google Patents

Description

The present invention is concerned with the preparation of novel alkylene-Ν, Ν'-bis-histidines.

These compounds are novel complexons based on the natural amino acid histidine. These are newly synthesized substances which have not been described in the literature. Histidine itself is a haterocyclic natural amino acid that contains three nitrogen atoms in the molecule, which under certain conditions are able to potentially enter the condensation reaction, which can occur both on the nitrogen atoms in the imidazole ring (Ν ^% ) and on the nitrogen itself (- The present invention relates to the preparation of alkylene-Ν, Ν'-bis-histidines by condensation on the nitrogen of the α-amino group.

SUMMARY OF THE INVENTION The present invention relates to the preparation of novel alkylene-Ν, Ν'-bis-histidines complexes of the general formula I-CIL-CHCOOH _N / ² 1

NH

IC ^H 2> n

NH ^> - _CH2 -CHC00H (I).

200 063 where n is an integer of 2 to 8, condensation in an aqueous or aqueous alcoholic medium of histidine 8 with an alkylene dihalide in which the alkylene moiety has 2 to 8 carbon atoms, preferably with ethylene bromide, in an alkaline medium under reflux. The reaction proceeds in the pressure range! 1.10 ⁵ to 5.10 ⁶ Pa, preferably 1.10 ⁵ to 5.10 ⁵ Pa, in a molar ratio of amino acid to alkylenedihalogen of 2: 1 to 5: 1, preferably 2: 1.

The condensation of histidine with an alkylenedihalide proceeds according to the equation:

NA || --CH ₂ CHCO ₃ H + X (CH ₂ ) _n X

I ^NH 2

H **

CH _o CHCO 3 H + 2 HX ² I NH 4 ^H 2) n

NH I

CH ₂ CHC00H where X = halogen and »2 to 8

The reaction produces alkylene-N, N'-bis-histidine and hydrogen halide, which is preferably bound by the addition of alkali in the form of the corresponding alkali metal halide, thereby shifting the reaction to the right, favoring the formation of alkylene-Ν, Ν'-bis-histidine .

Condensation in an aqueous medium is accomplished by mixing an aqueous solution of histidine with an alkylene dihalide and an aqueous or aqueous alcoholic (or alcoholic) alkali hydroxide solution, but preferably with a solid alkali or alkaline earth metal carbonate or bicarbonate. The mixture was refluxed for several hours with stirring. Upon cooling and acidification with an inorganic acid, preferably HCl, the crude alkylene-Ν, Ν'-bis-histidine is precipitated, which is recrystallized several times from acetic acid and the crystals obtained are dried under vacuum.

An advantage of the preparation of the alkylene-Ν, Ν'-bis-histidines according to the invention is that the condensation proceeds sufficiently quickly already at atmospheric pressure and with higher yields than with the condensation of lower amino acids.

The novel complexones, alkylene-Ν, Ν'-bis-histidines, could find use as reagents in analytical chemistry, as new types of catalysts and as selective detoxifying agents in health care.

Example 1

In a 250 ml three-necked flask equipped with a reflux condenser, stirrer and dropping funnel, 20 g (0.5 mol) of NaOH in 40 ml of water was added to 77.5 g (0.5 mol) of L-histidine. The solution is heated to boiling and 47 g (0.25 mol) of ethylenedibromide and 34.5 g (0.25 mol) of KgCOg are added simultaneously to bring the pH to 10-11. 10 more hours. After cooling and acidification with concentrated HCl to pH 6-7, a white product precipitates, which is recrystallized three times from acetic acid and the crystals obtained are dried under vacuum. 16 g of ethylene-Ν, Ν'-bie-L-histidine are obtained in 19% yield. Melting point 199-203 ° C. Empirical formula ^C ^ i4 ⁸ 20 6 4 ° · ^s 4 l ^molecular weight 336.35. Elementary analysis:

_T C = 49.90%; _T N = 8.25%; H _t = 6.00%. Found: G = 49.21%; N = 24.82%; H, 5.89%. The obtained material was characterized by an IR spectrum which showed characteristic absorption bands of ethylene-Ν, Ν'-bis-L-histidine bonds (Table 1). IR spectra were measured on a Perkin Elmer Model 337 instrument, KBr-teciinics.

Table 1: Characteristic absorption bands of ethylene-Ν, Ν'-bis-L-histidine

Belt position Characteristics Note / cm H

3350 - 3500 valence vibrations 2840 - 2910 - ^ ch ₂ valence vibrations 1700 - 1750 deformation vibrations 1625 ^ coo valence vibrations 1230 ^ CHg twist vibration 1200 ⁵ C0H deformation vibrations 1060 W ' rocking vibration 1025 ^ C-N valence vibrations 850-875 Al-c valence vibrations

OBJECT OF THE INVENTION

Claims (2)

A process for the preparation of alkylene-Ν, Ν'-bis-histidines of the general formula I NI H H -ch ₂ -chcooh NH CH 2'n (I). -N NNH -chcooh _-CH2 wherein n is an integer from 2 to 8, characterized in that the aqueous or aqueous-alcoholic medium is condensed with histidine alkylendihalogenidem in which the alkylene moiety has 2 to 8 carbon atoms, preferably ethylene dibromide, alkaline medium while boiling the reaction mixture and at pressure range. 1.10 ⁵ to 5.10 ⁶ Pa, preferably 1.10 ⁵ to 5.10 ⁵ Pa, in a molar ratio of histidine to alkylene dihalide of 2: 1 to 5: 1, preferably 2: 1, whereupon the product is isolated by acidifying the aqueous solution with inorganic acid and purified by recrystallization from acetic acid.