Highly labelled by tritium [methyl-3h]methyltosylate

FIELD: chemistry.

SUBSTANCE: claimed invention relates to highly labelled by tritium [methyl-3H]methyltosylate of formula: . Compound can be used in synthesis of labelled by tritium compounds, which are used in biological research.

EFFECT: obtaining of highly labelled tritium.

5 ex, 4 dwg

 

The invention relates to organic and analytical chemistry and can find application in the synthesis of medical and biological preparations.

It is known that replacement of hydrogen atoms in the organic compound on the atoms of tritium does not change any properties of the original compound (E.A. Evans - Tritium and its compounds London Butterworths, 1974, p.48) [1].

Known metaltail connection formula:

He is a donor metal group and is used for the methylation of organic compounds. B.Pelan, M.Milohnoja, M.Pezdirc U.S. Patent 4145528 03.20, 1979 Process for preparing β-methyldigoxin [2].

However viscometry tritium ([methyl-3H]-H]metaltail) is not described.

The technical result achieved by the present invention, is expanding the range of labeled reagents.

Achieved the specified technical result obtaining vysokobarnogo tritium of metilfenidato formula I:

Figure 1 shows: Distribution of radioactivity in the analysis by HPLC of the reaction mixture formed in the catalytic dehalogenase bromo-derivative of the methoxy group of metilfenidato in the atmosphere of gaseous tritium.

Figure 2 shows: the Distribution of optical density (a) and radioactivity (b) analysis by HPLC of the mixture formed by the reaction between [methyl-3 N]metilfenidato and sodium salt of p-vinylbenzoic acid.

Figure 3 shows: the Distribution of optical density and radioactivity in the analysis by HPLC of the mixture formed by the reaction between [methyl-3H]metilfenidato and potassium phenolate.

Figure 4 shows: (a) Chromatographic mobility of methionine in his analysis by HPLC; (b) the distribution of radioactivity [methyl-3H]methionine in his analysis by HPLC method.

Below are examples of implementation of the invention.

Example 1. The synthesis of the bromo-derivative of the methoxy group of metilfenidato

A mixture of 1.48 g tosilata silver and 0.78 g diiodomethane in 5 ml of dry acetonitrile was heated 3 hours Fell precipitate of iodide of silver, which was discarded, the solution was evaporated, after recrystallization of the resulting sludge from absolute ethanol obtained 1.13 g ditosylate (output - 60%).

A solution of 0.5 g ditosylate in 3 ml of acetone was mixed with a solution of 0.23 g of lithium bromide in 2 ml of acetone, was kept under stirring at 60°C for 5 min and left overnight at room temperature. Then to the reaction mixture was added an equal volume of methylene chloride and the precipitate was centrifuged. The output of the bromo-derivative of the methoxy group of metilfenidato - 50%. After cleaning, the bromo-derivative of the methoxy group of metilfenidato by HPLC on Kromasil column C187 μm, 4.6×150 mm, system: 60% of the ethanol in phosphate buffer (pH 2.8), a flow rate of 1 ml/min, retention time - 5.46 min, the output of the bromo-derivative of the methoxy group of metilfenidato - 42%.

Example 2. Synthesis vysokobarnogo tritium - [methyl-3H]metilfenidato

A solution of 1.5 mg of bromo-derivative of the methoxy group of metilfenidato in 0.2 ml of benzene was introduced into a vial with 30 mg of 5% Pd/caso3. Then, the ampoule was frozen with liquid nitrogen, was evacuated to a pressure of 0.1 PA and filled with gaseous tritium to pressure 333 hPa. The reaction was performed at room temperature for 4 h under stirring. Then the ampoule was again frozen with liquid nitrogen and evacuated. The catalyst was filtered and washed with 0.3 ml of methanol. [methyl-3H]Metaltail was purified by HPLC on a Kromasil column C187 μm, 4.6×150 mm, the system 60% methanol-water-acetic acid (600:399:1), flow rate 0.8 ml/min, retention time - 3.86 min Analysis of the reaction mixture (figure 1) was performed by HPLC on Kromasil column C187 μm, 4.6×150 mm, the system 60% methanol in phosphate buffer (pH 2.8), flow rate 1 ml/min, retention time - 2.72 min, the Eluate was diluted with 10 ml of water and [methyl-3H]metaltail was extracted with fresh ether (3×2 ml). The ether was evaporated and [methyl-3H]metaltail was dissolved in the solvent in which it was planned to hold methylation. Output vysokobarnogo tritium - [methyl-3H]metilfenidato - 50-60%, molar the radioactivity - 15-17 CI/mmol.

Below are examples illustrating the application of vysokobarnogo tritium - [methyl-3H]metilfenidato.

Example 3. Synthesis of [methyl-3H]methyl-p-phenylbenzoate

Sodium salt of p-vinylbenzoic acid was obtained by treatment of a solution of 2 mg of acid in 0.3 ml of methanol and 10 μl of 1 M NaOH. The solution was evaporated and liofilizirovanny.

In the reaction, the ampoule was placed a solution of vysokobarnogo tritium - [methyl-3H]metilfenidato in 0.2 ml of DMFA, and 1.5 mg of sodium salt of p-vinylbenzoic acid. The ampoule was sealed, heated for 10 min at 70°C under stirring and left for 15 h at 20°C. Almost all of the label contained in the formed [methyl-3H]methyl-p-phenylbenzoate. Analysis of the reaction mixture (figure 2) was performed by HPLC on Kromasil column C187 μm, 4.6×150 mm, the system 60% methanol in phosphate buffer (pH 2.8), flow rate 1 ml/min, retention time [methyl-3H]methyl-p-phenylbenzoate - 18.19 min (retention time of p-vinylbenzoic acid - 11.14 min).

Example 4. Synthesis of [methyl-3H]anisole

A solution of phenol (30 mg) in 1.2 ml of DMSO was mixed with 40 mg2CO3within 30 minutes To an aliquot of this mixture (120 ml) was added 0.3 mg vysokobarnogo tritium - [methyl-3N]metilfenidato and heated 10 min at 70°C. Analysis of the reaction mixture (figure 3) was performed by HPLC on Kromasil column C187 μm, 4.6×150 mm, system:60% methanol in phosphate buffer (pH 2.8), a flow rate of 1 ml/min, retention time of anisole - 4.67 min (retention time of phenol - 1.93 min). Almost all of the label contained in the formed [methyl-3H]anisole.

Example 5. Synthesis of (methyl-3H]methionine

In the capsule was introduced a solution of 0.5 mg of homocysteine in a mixture of 125 μl of tetrahydrofuran and 50 ml of water, then add 7 ál of 1 M NaOH and 0.25 mg vysokobarnogo tritium - [methyl-3H]metilfenidato. The ampoule was sealed, heated at 70°C for 10 min, then heating was stopped and after 60 min the solvents were removed by lyophilization. Analysis of the reaction mixture (figure 4) was performed by HPLC on a column (Supelcosil ABZ+Plus 5 μm, 4.6×250 mm, system: 50 mM ammonium phosphate buffer, pH 2.8, flow rate 1 ml/min, retention time of methionine - 4.10 min (retention time of homocysteine - 3.30 min.)

Thus, the resulting new visokomernoe tritium-connection - viscometry tritium - [methyl-3H]metaltail, by which it is possible to synthesize tritium-labeled compounds.

Viscometry tritium - [methyl-3H]metaltail formula:



 

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