Sorbent and method thereof

 

The invention relates to the field of separation of racemates of optically active compounds by chromatography. Proposed sorbent based on derivatives of cyclodextrins, covalently immobilized on carriers at the same time as chiral selectors use per-6-amino derivatives-,or-cyclodextrin or their acetylated counterparts. A method of sorbent. The invention allows to extend the range of the partial substances. 2 S. and 4 C.p. f-crystals, 1 table.

The invention relates to sorbents for the separation of racemates of optically active compounds and can be used for separation of individual isomers of various derivatives of amino acids and coumarin and control of the enantiomeric purity of amino acids, pesticides, biologically active compounds.

Known chromatographic sorbents for the separation of racemic mixtures obtained by immobilization by adsorption on mineral medium hydrophobic derivatives of optically active amino acids (US 4851382, B 01 J 20/22, 1989).

The disadvantage of sorbents is no covalent bond between positories and because the column can only be used in aqueous media and to separate only water-soluble racemate.

For chromatographic separation of optical isomers of pharmaceuticals known sorbent containing media with covalently linked derivatives of chitosan as chiral selectors (A. Senso at al., J. Chromatogr. v. 839, 1999, p. 15-21, "Chitosan derivatives as chiral selectors bonded on allyl silica gel). The method of obtaining the above sorbents involves many stages, including obtaining silica with grafted allyl functional groups, the production of chitosan from 10-undecenol and benzoline or phenylenecarbonyl groups, and, finally, the copolymerization of double bonds of the media and the chiral selector. These sorbents provides separation of optical isomers due to van der Waals and dipole interactions.

The disadvantage of the above sorbents is their relatively low selectivity.

The closest in technical essence and the achieved result is a sorbent containing media and chiral selector based on derivatives-cyclodextrin (-CD), namely-CD, epichlorohydrin crosslinked and modified 2,3-epoxypropyltrimethylammonium chloride. The method of obtaining the known sorbent penned the odd ionic interactions, but without the formation of covalent bonds with the carrier.

Separation of optical isomers of warfarin and some danceline derivatives of amino acids is carried out on the sorbent due to the formation of inclusion complexes of enantiomers with cyclodextrin (n Thuaud et al., J. Chromatogr., v. 555, 1991, p. 53-64, "Retention behavior and chiral recognition of-cyclodextrin-derivative polymer adsorbed on silica for warfarin, structurally related compounds and Dns-amino acids").

The disadvantage of the sorbent again is the gradual loss of carrier chiral selector.

The present invention is to develop a stable sorbent suitable for the separation of a large range of substances.

The problem is solved is described by a sorbent for the separation of racemates of optically active compounds containing media and chiral selector selected from the group of per-6-amino derivatives-,or-cyclodextrin or their acetylated counterparts.

The problem is solved also described a method of producing a sorbent for the separation of racemates of optically active compounds, including covalent immobilization on a carrier derivative of cyclodextrin, which is carried putamen from groups: per-6-amino--cyclodextrin, per-6-amino--cyclodextrin, per-6-amino--cyclodextrin, and then with a metal borohydride. Additionally, the obtained sorbent is subjected to acetylation. Preferably, the medium for use silica, and as the condensing agent is glutaric dialdehyde. Preferably, the interaction is carried out in sodium phosphate buffer solution.

Below are examples of the method of obtaining the sorbent and examples for its use.

Example 1. To 5 g Lichrosorb Si-100 (Merk), suspended in 25 ml of 0.1 M sodium phosphate buffer pH 6.5 add 0.25 ml of 3-aminopropyl-triethoxysilane. The reaction mixture is heated to 95oC and incubated for 2 hours with stirring at the same temperature. Then aminirovanie Lichrosorb Si-100 washed on a glass Frit with water. Received aminirovanie Lichrosorb Si-100 is suspended in 20 ml of 0.01 M sodium phosphate buffer solution with a pH of 7, add 5 ml of 25% glutaric dialdehyde and stirred for 1 hour at 20oS, after which the obtained product 1 is washed with water on a porous filter. 0.2 g amino-cyclodextrin (aminoCD) the e 6,5-7,0). The resulting solution suspicious 5 g of the product 1, conduct the reaction for 16 h under stirring at 20oAnd the resulting sorbent 2 washed with water. The concentration of amino groups in the product 2 is 150 μm to 1 g, which corresponds to 25 μm amino--cyclodextrin 1,

5 g of the product 2 is suspended in 50 ml of 0.3 M sodium phosphate buffer solution with a pH of 6.0 and add 90 mg NaBH4. The reaction is carried out for 6 hours under stirring at 20oC. the resulting sorbent, paramino-cyclodextrine (sorbent A) is separated and washed on a porous filter successively with water, ethanol and acetone and dried.

Example 2. Analogously to example 1 receive sorbent A. After processing NaBH45 g of sorbent And suspended in a mixture of 20 ml of water, 4 ml of methanol and 8 ml of acetic anhydride. The reaction mixture is stirred at 20oWith 8 hours. Separating the obtained sorbent In peracetylated-cyclodextrin and washed with water on a porous filter. Free amino groups in the sorbent was not found.

Example 3. Analogously to example 1 get 1 product. 0.2 g of paramino-CD is dissolved in 50 ml of 0.1 M sodium phosphate buffer pH 6.0 (controlling great 16 hours under stirring at 20oC. the resulting product 3 is filtered using a porous glass filter and washed with water.

5 g of the product 3 is suspended in 50 ml of 0.3 M sodium phosphate buffer solution with a pH of 6.0 and add 90 mg NaBH4. The reaction is carried out for 6 hours under stirring at 20oC. the resulting sorbent with paramino-cyclodextrin (sorbent) is separated and washed on a porous filter successively with water, ethanol and acetone and dried.

Example 4. Get the sorbent as in example 3. After processing NaBH45 g of sorbent suspended in a mixture of 20 ml of water, 4 ml of methanol and 8 ml of acetic anhydride. The reaction mixture is stirred at 20oWith 8 hours. Separating the obtained sorbent D with peracetylated-cyclodextrin and washed with water on a porous filter.

Example 5. Analogously to example 1 get 1 product. 0.2 g of paramino-CD is dissolved in 50 ml of 0.1 M sodium phosphate buffer pH 6.0 (controlling the pH value, which should be in the range of 6.5 to 7.0). In the obtained suspended solution of 5 g of the product 1 and conduct the reaction for 16 hours under stirring at 20oC. the resulting product 4 is filtered through the porous filter and washed in the H4. The reaction is carried out for 6 hours under stirring at 20oC. the resulting sorbent with paramino-cyclodextrine (sorbent (E) is separated and washed on a porous filter successively with water, ethanol and acetone and dried.

Example 6. Analogously to example 5 receive sorbent that is, After processing NaBH4sorbent E is suspended in a mixture of 20 ml of water, 4 ml of methanol and 8 ml of acetic anhydride. The reaction mixture is stirred at 20oWith 8 hours. Separating the obtained sorbent F with peracetylated-cyclodextrin and washed with water on a porous filter.

Thus, the obtained sorbents with covalently immobilized on the carrier TRANS-6-aminocyclohexanone (A, C, E), which is cyclic analogues of chitosan, and with covalently immobilized TRANS-6-acetylaminofluorene (b, D, F), which is cyclic analogues of chitin.

The proposed sorbents allow for the separation of optically active isomers of amino acid derivatives with different structure modifiers amino - 5-dimethylaminonaphthalene-1-sulfonyl (Dansyl), N-9-fluorenylmethoxycarbonyl (FMOC), 2,4-dinitrophenyl (DNP), 3,5-dinitropyridine (DNP), talila (CFT is that coumarin derivatives: warfarin and kumahara (see table). In addition, a new sorbent is separated derivatives of amino acids with butoxycarbonyl that cannot be divided nor sorbent prototype based on cyclodextrin or sorbent equivalent based on chitosan derivatives. The obtained sorbents held chromatographic separation of racemates of various optically active compounds. Some results of the separation of the resulting sorbent (sorbent A) presented in the table.

Thus, the problem of extending the range of the partial connections through the use of new chiral selectors, combining mechanisms for the separation of optical isomers, characteristic of linear and cyclic oligosaccharides, i.e., by combining different mechanisms of separation of optical isomers, namely due to the formation of inclusion complexes and due to van der Waals and dipole interactions. Also solved the problem of stability of the obtained sorbents due to the use as a carrier of silica and covalent immobilization on him chiral selectors.

Claims

1. Sorbent for the separation of racemates of optically active compounds containing chiral media and selector-6-amino derivatives-,- or-cyclodextrin or their acetylated counterparts.

2. A method of producing a sorbent for the separation of racemates of optically active compounds, including covalent immobilization derivatives of cyclodextrins on the carrier, characterized in that the immobilization is carried out by sequential interaction laminirovannogo media with a condensing agent, and then with a reagent selected from groups: per-6-amino--cyclodextrin, per-6-amino--cyclodextrin, per-6-amino--cyclodextrin, and then with a metal borohydride.

3. The method according to p. 2, characterized in that the sorbent is additionally subjected to acetylation.

4. The method according to any of the preceding paragraphs, characterized in that as the carrier used silica.

5. The method according to any of the preceding paragraphs, characterized in that as the condensing agent used glutaric dialdehyde.

6. The method according to any of the preceding paragraphs, characterized in that the interactions are in sodium phosphate buffer solutions.

 

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