RU2363538C1 - Method for preparation of enantioselective sorbent - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention refers to the methods for preparation of sorbents based on metal chelate and used for enantiomer separation. Tne method of enantioselective sorbent preparation includes the applying on the silicagel surface of metal complex compound containing enantioselective fragment with using of γ-substituted acetylacetonate d-metal and residue of amino acid enantiomer selected from the range of L- or D- enantiomers of arginine, valine, triptofane methionine, phenylalanine, threonine.

EFFECT: obtaining of the sorbents efficient for separation of organic compounds enantiomers used as components of medicinal substance and cosmetic preparations.

2 cl, 1 tbl, 1 ex

Description

The invention relates to sorbents for chromatography, in particular to the field of separation of enantiomers and to methods for producing enantioselective sorbents based on metal chelates.

A known sorbent for the separation of isomers of optically active compounds, which as a chiral selector contains a macrocyclic glycopeptide antibiotic eremomycin, vancomycin, ristomycin A, teicoplanin or their analogues, as well as a method for producing this sorbent for chromatography of optical isomers, which includes chemical immobilization of a glycopeptide using an organosilicon modifier on the surface of silica gel. Silica gel in an aqueous buffer solution is treated with 3-glycidoxypropyltrialkoxysilane, and then a macrocyclic glycopeptide antibiotic is inoculated with epoxy-modified silica gel in an alkaline aqueous or aqueous-organic solution. As an antibiotic, eremomycin, ristomycin A, vancomycin, teicoplanin or their aglycones can be used (RF patent 2255802, 7 B01J 20/22, 20/30, 7 G01N 30/48, publ. 2005.07.10).

A disadvantage of the known sorbent based on the surface layers of complex organic molecules is its short life, due to both the destruction of the molecules themselves and the ablation of the surface layer of the mobile phase. The disadvantage of this method is the loss of substance at each stage of processing and, as a consequence, a deviation from the planned composition of the surface phase of the sorbent and the receipt of an uneven surface layer of chiral selectors, as well as an increase in the consumption of the modifier.

A known sorbent for the separation of racemates of optically active compounds and the method for its preparation (RF patent No. 2203730, 7 B01J 20/22, 20/30, 7 B01D 15/08, publ. 2003.05.10), which is selected as a prototype.

Sorbent based on derivatives of cyclodextrins covalently immobilized on supports containing per-6-amino derivatives of α-, β- or γ-cyclodextrin or their acetylated analogues as a chiral selector, has selectivity to a limited range of optically active substances, namely, amino acid derivatives and some coumarin derivatives. A disadvantage of the known sorbent is its selectivity to a limited range of optically active substances, namely derivatives of amino acids and certain derivatives of coumarin. The method for producing this sorbent includes covalent immobilization of cyclodextrin derivatives on a carrier, which is carried out by sequential interaction of the aminated carrier first with a condensing agent, then with a reagent from the group: per-6-amino-α-cyclodextrin, per-6-amino-β- cyclodextrin, per-6-amino-γ-cyclodextrin, and then with metal borohydride. The disadvantage of this method is the complexity of its implementation due to the multi-stage and use of unstable substances, in particular metal borohydride.

The objective of the present invention is to obtain an enantioselective sorbent with high selective properties for the separation of enantiomers of organic compounds, as well as the development of a method for producing an enantioselective sorbent.

The problem is solved in that the enantioselective sorbent containing, like the prototype, nitrogen-containing chiral selectors grafted to an organic carrier molecule, in contrast to the prototype, the carrier molecule is a zirconium, zinc, cobalt, copper and nickel metal acetylacetonate substituted in gamma the position of the fragments of the L- or D-enantiomers of the amino acids arginine, proline and phenylaniline, or fragments of other molecules, including a chiral selector.

A method for producing an enantioselective sorbent, as well as a prototype, involves applying a complex metal compound containing an enantioselective fragment to the surface of an inert carrier, in contrast to the prototype, a gamma-substituted metal acetylacetonate is used as a metal complex, and the amino acid enintiomer residue is used as an enantioselective fragment. It is advisable to use individual L- or D-enantiomers of the amino acids arginine, valine, tryptophan, methionine, phenylalanine, threonine as an enantioselective fragment, since they possess a chiral selector and their grafting to metal acetylacetonate allows one to obtain a molecule with thermal stability up to 150 ° C.

It is preferable to use the L-enantiomers of the amino acids arginine, valine, tryptophan, methionine, phenylalanine, threonine as an enantioselective fragment, since they are less expensive than the properties of D-enantiomers.

Preferably, nickel, copper, iron, aluminum or zirconium are used as the metal. These elements have an unfilled d-orbital, which provides additional donor-acceptor interaction with enantiomers and contributes to their retention on the surface of the sorbent.

The choice of mineral sorbents as objects of modification is determined by a number of their advantages over organopolymers, including resistance to mechanical, chemical and thermal influences. Silipor 075 and Silochrome C80 (0.200-0.250 mm, CEMAPOL Praha, Czechoslovakia) mineral carriers were used to create sorbents. A large specific surface area of 75-105 m ² / g allows sorbents with a large sorption capacity and reliable fixation of the modifying complex to be obtained.

Unlike existing sorbents, the separation is carried out due to weak donor-acceptor interactions, the strength of which can be controlled due to the nature and position of organic ligands in the complex.

Synthesized new enantioselective sorbents with thermal stability up to 150 ° C based on gamma-substituted complexes of metal acetylacetonates of cobalt, copper, nickel and amino acid fragments of arginine, proline and phenylalanine.

Example 1

In order to obtain copper acetylacetonate with a gamma position grafted proline fragment, proline butyl ether was obtained. For this, 0.5 g of the L-enantiomer of proline (L-proline) is placed in 30 ml of butyl alcohol and 1-2 ml of hydrochloric acid is added, after which it is heated to a temperature of 60 ° C for 1-2 hours. The resulting alcoholic ether solution was neutralized with a KOH solution and the liquid phase was distilled off. Then, an alkaline medium is created in the solution (pH = 10-12), 4-5 ml of acetylacetone is added, heated to 50-60 ° C for 1-2 hours and the excess of acetylacetone is distilled off. 0.6 g of Cu (NO ₃ ) _{2 was} added to the resulting solution, and the precipitate formed was washed with water, recrystallized from ethyl alcohol, and dried.

The obtained copper acetylacetonate with a proline fragment grafted in the gamma position (Cu (acac-L-Pro) ₂ ) has the following structure:

The procedure and conditions for the preparation of other gamma-substituted acetylacetonates are similar to the description of Example 1.

The resulting complexes in an amount of 5% by weight of the carrier — silica gel with a specific surface area of at least 60 m ² / g — were applied from a chloroform solution, stirring continuously for uniform phase distribution. Subsequently, the column was subjected to 5-hour conditioning at a temperature of 130 ° C in a stream of inert gas (helium) at a speed of 5 cm ³ / min. Table 1 shows the results on the separation of the enantiomers of amino acids, cyclic ethers and alcohols in the form of selectivity between enantiomers.

From the results it can be seen that the preferred conditions for the inventive method for producing an enantioselective sorbent are selected and the enantioselective sorbent shows the separation of the enantiomers of amino acids, cyclic ethers and alcohols at temperatures above 100 ° C with a selectivity of 1.1.

The creation of composite sorbents based on metal chelates allows one to obtain materials for the selective separation and sorption concentration of a wide range of organic substances for subsequent chromatographic separation. The obtained sorbents are effective for the separation of enantiomers of organic compounds that are components of medical and cosmetic preparations.

Claims (2)

1. A method of producing an enantioselective sorbent, comprising applying to the surface of silica gel a metal complex compound containing an enantioselective fragment, characterized in that a gamma-substituted metal acetylacetonate is used as a metal complex, and an enantiomer of amino acids selected from the series is used as an enantioselective fragment; arginine, valine, tryptophan, methionine, phenylalanine, threonine. 2. The method according to claim 1, characterized in that as the metal acetylacetone, nickel, copper, iron, aluminum or zirconium acetylacetonates are used.