The method of obtaining water-soluble amino acid derivatives of fullerene

 

(57) Abstract:

The invention relates to an improved method for producing a water-soluble amino acid derivatives of fullerene that can be used in pharmacology and Microbiology. Describes a method of obtaining a water-soluble amino acid derivatives of fullerene General formula I HC60NH(CH2)nCOO-Kt+where60- fullerene core, t+is hydrogen, an ammonium cation or an alkali metal, n= 1, 3, 5, involving the interaction of fullerene with the salt of the amino acids when heated and the subsequent allocation of the target product as a salt of the amino acids is used as a compound of General formula II NH2-(CH2)nSOO-E+Rmwhere R is CqH2q+1, m=3,4, q=2-5, e is a chemical element selected from a Va or VIa group of the Periodic table, then get the compound of General formula III H60-NH-(CH2)nSOO(E+Rm), where R, e, n, m are the specified values, which are subjected to the following reactions: in the case of obtaining the target product of General formula I, where Kt+- hydrogen is affected by the acid solution, and if t+the ammonium cation or an alkali metal - soo is implemented using General chemistry equipment, which leads to simplification of the process and reduce the cost of the target product. 9 C.p. f-crystals.

The invention relates to organic chemistry of fullerene (C60), namely the technology of production on the basis of biologically active compounds, in particular amino acid derivatives of fullerene, which can be used in pharmacology and Microbiology.

Of most interest are the water-soluble amino acid derivatives of fullerene (ACE) inhibitors, which are able to penetrate the lipid membranes to modulate the transport of ions to overcome hematoencephalic barrier, showing biological activity. Conducted numerous studies have shown that water-soluble amino acid or peptide derivatives of fullerenes is able to inhibit a wide range of viral infections, including HIV, have the cytotoxicity and the ability to cleave DNA (Kiselev O. I. and other Antiviral activity of fullerene C60in complex with poly(N-vinyl pyrrolidone). Reports of the Academy of Sciences, 1998, I. 361(4), S. 547-549; Parnes, Z. N. and other Amino acid and peptide derivatives of the fullerene. News of Academy of Sciences, series of chemical, 1998, 2; Andreev, S. M. and other Immunogenic and the Specified properties of the amino acid derivatives of fullerene put the problem of developing efficient technologies for their production and subsequent implementation in an industrial environment.

A method of obtaining water-soluble fullerenes, comprising mixing a pre-dissolved in an organic solvent fullerene polymer matrix in floriforme, evaporation of the mixture under vacuum to remove the solvent, dissolving the obtained complex in phosphate-buffered saline (pH 7.4 and 7.6) followed by treatment of the product by ultrasound (EN 2162819, 02.10.01). At the same time as the water-soluble polymer matrix with the use of membrane Catalina. Receive aqueous suspension of fullerenes, which is treated with ultrasound, which allows to increase the degree of dispersion of the suspension.

The target product is a stable suspension of brown, non-stratifying storage for more than 14 days. The suspension is kept under the rubber stoppers in a nitrogen atmosphere.

Due to the fact that the product is obtained in the form of a suspension, to define clearly its concentration is almost impossible. In addition, the conditions of storage of the final product create significant difficulties when it is received in an industrial environment.

A method of obtaining a symmetrical water-soluble derivatives buckminsterfullerene (C60), in particular derivatives Metropolia AIDS and KS.

New, previously unknown, water-soluble derivatives - methanofullerene get through an intermediate product intermediate (4,4-Bi(N-acetyl-2-amino-ethyl)diphenyl61, the synthesis of which is quite complex and involves several stages. The main component - substituted diphenyldiazomethane, which is used in the synthesis of obtaining the target product, get known techniques of substituted benzophenone hydrazone by oxidation in the presence of Nickel peroxide. Intermediate synthesized by attaching substituted diphenyldiazomethane in tetrahydrofuran to the fullerene C60pre-dissolved in toluene. The resulting mixture is stirred, remove the solvents, and the product purified by known techniques and treated with acetic acid and concentrated aqueous solutions of hydrochloric acid. At this stage receive methanofullerene in the form bi(hydrochloride). For the preparation of water-soluble derivative methanofullerene60to the obtained solution at the previous stage add succinate anhydride in dry pyridine. The reaction mixture is treated with an aqueous solution of hydrochloric acid and isolated by centrifugation precipitate, which is marked with known techniques, PR is foremost ~ 1 mg/ml).

The main disadvantages of the described method of obtaining new derivatives methanofullerenes60are the complexity and the multi-stage process, as well as use at all stages of a large number of solvents, such as tetrahydrofuran, pyridine, o-dichlorobenzene and methyl alcohol. In addition, the target product has low solubility, which limits its use for medical purposes.

The closest analogous solution to the technical essence is a method of obtaining, in particular, filerenameoperations acid HC60NH(CH2)5COOH, described in the patent of the Russian Federation 2124022, which includes several stages.

To a solution of fullerene in o-dichlorobenzene add an aqueous solution of potassium salt of aminocaproic acid and 18-crown-6. The reaction mass is stirred for 6-8 hours at 60oC. Then the solvent is distilled off, the residue is treated with saturated solution of potassium chloride and the remainder of the fullerene derivative is washed with water. The yield of the desired product quantitatively. The obtained N-(monohydro)fullerenechromophor acid is soluble in dimethylsulfoxide, dimethylformamide, pyridine.

The disadvantage of this method is in the process of such a solvent, as o-dichlorobenzene, highly toxic with a strong unpleasant odor. Also used as catalyst 18-crown-6 has a high cost compared to the cost of the fullerene, and is also toxic reagent.

Thus, using the known process of toxic reagents leads to the need for additional purification stages, which significantly complicates the technological process as a whole and increases the cost of the target product.

To eliminate the above disadvantages of the task was to develop a new method of obtaining water-soluble amino acid derivatives of fullerene of the formula I given in the formula of the invention, a highly efficient and cost-effective when implemented in an industrial environment.

The problem is solved by a method of obtaining water-soluble amino acid derivatives of fullerene General formula I HC60NH(CH2)nCOO-Kt+where60- fullerene core, t+is hydrogen, an ammonium cation or an alkali metal, n=1, 3, 5, involving the interaction of fullerene with the salt of the amino acids when heated and the subsequent allocation of the target product, and as salts where R is CqH2q+1n= 1, 3, 5, m=3,4, q=2-5, e is a chemical element selected from a Va or VIa group of the periodic system of elements, with the formation of compounds of General formula III NA60NH(CH2)nSOO(E+Rm), where R, e, n, m have the above values, which are subjected to the following reactions: in the case of obtaining the target product of General formula I, where Kt+- hydrogen is affected by the acid solution, and if Kt+the ammonium cation or an alkali metal - corresponding salt.

Preferred ions of alkali metals in General formula I are ions of sodium or potassium.

The compound of General formula II is a new, previously undescribed in the scientific literature. It is produced by the interaction of amino acids with oneway salt of General formula IV RmE+OR, where R, e and m have the above significance.

Onevia salt of General formula IV can be obtained by known methods and are used in interfacial catalysis. Widely available are such as Quaternary ammonium and postname salts, which are produced by the industry (E. Demlow and other interfacial catalysis, M.: Mir, 1987, S. 80 and 81).

However, they can also be obtained in situ by entries batch is xicom alkali metal in an alcohol solution. Alcohol solution oneway salt is separated from the precipitate and is used to produce the salt of the amino acids of General formula II by introducing aliphatic amino acids, in particular aminocaproic or-aminobutyric. Thus, it is possible to abandon a separate receiving niewyk salts, especially those that are not trading products. As the alkali metal alkoxide is preferably used piperonyl sodium.

The interaction of fullerene with the salt of the amino acids of the formula II is carried out in the presence of an organic solvent, such as toluene, but that does not limit the use of other solvents, such as benzene, acetonitrile, chloronaphthalene.

The use of toluene as an organic solvent is most preferable because it is less toxic compared to other solvents. In addition, the fullerene is highly soluble in toluene and the reaction of interaction with the salt of the amino acids of formula II takes place at a high speed.

The reaction temperature is not higher than 60oC. the Reaction mixture is stirred until complete clarification of the solution. The obtained precipitate was separated and washed with alcohol, for example Atropatene values, which is a solid crystalline substance with high solubility and high reactivity in reactions of metabolism.

To obtain the desired product of General formula I, where Kt+is hydrogen, the compound of General formula III is subjected to interaction with an acid solution, and if Kt+- ammonium or alkali metal, preferably sodium or potassium with the corresponding salt.

The acid can be used inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic carboxylic acids such as acetic acid, propionic acid, salicylic acid, and the like.

The structure of the target products and compounds of General formula III confirmed by amino acid analysis. It is shown that the ratio of the fullerene and the amino acid residue is 1: 1. IR absorption spectra of the synthesized compounds contain bands that are characteristic of the substituted fullerene: 1105 cm-1, 935 cm-1, 845 cm-1; strip asymmetric and symmetric stretching vibrations of carboxylate groups: 1560 cm-1, 1400 cm-1; the bands of stretching vibrations of ineni is also confirmed by UV spectroscopy and HPLC.

Thus, the use as a salt of the amino compounds of General formula II has greatly simplify the process of obtaining water-soluble amino acid derivatives of fullerene General formula I and to exclude from technology use highly toxic solvent and catalyst. This reduces the overall cost of obtaining the target product, which makes the new method is cost effective for implementation in an industrial environment.

The following examples explain the invention.

Example 1. Getting filerenameoperations acid HC60-NH-(CH2)5-COOH.

To a solution 3,22 g (0,01 mol) of tetrabutylammonium bromide in 10 ml of butyl alcohol add alcohol solution of butyl sodium (to 0.23 g of sodium in 5 ml of butyl alcohol). The resulting alcoholic solution oneway tetrabutylammonium salt of butoxide VI4N+JVI-separated from the precipitate of sodium bromide to the solution was added 1.31 g-aminocaproic acid. The alcohol is distilled off, get a solid precipitate tetrabutylammonium salt-aminocaproic acid NH2-(CH2)5COO NBu4that suspension in toluene and added to a solution 0,72 g (0,001 mol) of fullerene, pre-R is fallen precipitate is filtered and washed with ethyl alcohol, get tetrabutylammonium salt filerenameoperations acid of the formula III HC60NH(CH2)5COO-NBu+4that dissolve in water and add 0.1 M Hcl solution. Get gel filerenameoperations acid, centrifuged, washed with water to pH 7 and dried. The yield of the desired product quantitatively.

Example 2. Obtaining sodium salt fullerenelike acid HC60NH(CH2)3COONa.

To a solution of 2.9 g (0,01 mol) tetrabutylphosphonium chloride in 10 ml of ethyl alcohol add alcohol solution of ethoxide sodium (0,23 g Na in 5 ml of dry ethanol). Alcohol solution oneway salt is Tetra-n-butylphosphonium atoxic is separated from the precipitated precipitate of sodium chloride and type of 1.03 g (0,01 mol) -aminobutyric acid. Then the alcohol is distilled off, get a solid precipitate of the salt of the amino acids of the formula II, Tetra-n-butylphosphonium salt-aminobutyric acid NH2-(CH2)3Soori4that suspension in toluene and added dropwise with stirring to a solution to 0.72 g (0,001 mol) of fullerene in 400 ml of toluene. The reaction mass is heated to 60oC and maintained until the complete disappearance of fullerene staining solution. The precipitation hotfil is H(CH2)3COO-PBu+4dissolve in water and add a saturated solution of sodium chloride. The mixture is stirred, evaporated and the solid residue with hot ethyl alcohol is extracted with Et4P+Cl-. The obtained salt is recrystallized from water and dried in vacuum. The yield of the target product quantitative taken by the fullerene.

Example 3. Obtaining potassium salt fullerenelike acid.

The method is carried out analogously to example 2. As alcohol use butyl alcohol. As the corresponding salt at the final stage of obtaining the target product using a saturated aqueous solution of potassium chloride.

Example 4. Obtaining ammonium salt filerenameoperations acid.

The method is carried out analogously to example 2. As the corresponding salt at the final stage of obtaining the target product using a saturated aqueous solution of ammonium chloride.

Thus, in accordance with examples 2, 3, 4 synthesized compounds, which are a water soluble compound of fullerenelike. The IR spectra of salts and their properties show the preservation of the structure H-C60NH(CH2)nCOOKt+

A new method of obtaining the claimed compounds of General formula I are technologically simple, requires no special equipment and its implementation can be done using General chemistry equipment.

1. The method of obtaining water-soluble amino acid derivatives of fullerene General formula I

NA60N(CH2)nSOO-t+,

where C60- fullerene core;

t+is hydrogen, an ammonium cation or an alkali metal;

n= 1, 3, 5,

including the interaction of fullerene with the salt of the amino acids when heated and subsequent selection of the target product, characterized in that as the salt of the amino acids is used as a compound of General formula II

NH2-(CH2)nSOO-E+Rm,

where R-CqH2q+1;

n= 1, 3, 5;

m= 3, 4;

q= 2-5;

E - a chemical element selected from a Va or VIa group of the Periodic table,

you get a connection General formula III

N-C60-NH-(CH2)n-SOO(E+Rm)

where K, e, n, m have the above values,

which is subjected to the following reactions: in the case of obtaining the target proile alkali metal the corresponding salt.

2. The method according to p. 1, characterized in that chemical element used is preferably nitrogen, phosphorus, arsenic, antimony, bismuth, sulfur, selenium or tellurium.

3. The method according to p. 1, characterized in that the cation of the alkali metal is preferably used sodium or potassium.

4. The method according to p. 1, characterized in that the compound of General formula II NH2-(CH2)nSOO-E+Rmproduced by interaction of amino acids with oneway salt of General formula IV RmE+OR, where R, e and m have the above significance.

5. The method according to p. 1, characterized in that the interaction is carried out in the presence of an organic solvent, such as toluene.

6. The method according to p. 1, characterized in that the amino acid use acid aliphatic glad preferred-aminocaproic or-aminobutyric.

7. The method according to p. 1, characterized in that Onyewu salt of General formula IV used in the form of alcohol solution.

8. The method according to p. 2, characterized in that Onyewu salt of General formula IV receive the in situ interaction of halides of the formula LMEs+X, where R, e and m have the above meanings, X - I alkoxide of an alkali metal is preferably used piperonyl sodium.

10. The method according to PP. 1-3, 7 and 8, characterized in that the process is carried out at a temperature not exceeding 60oC.

 

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