The method of obtaining vysokobarnogo tritium or deuterium in the ethyl radical is 4-ethyl-2,6,7-trioxa-1-phosphabicyclo(2,2, 2)octane-1-oxide

 

(57) Abstract:

The use of the invention: organic chemistry and chemistry of physiologically active compounds may find application in biomedical research. The invention is: to obtain a new vysokobarnogo tritium or deuterium in the ethyl radical substances - 4-ethyl-2,6,7-trioxa-1-phosphabicyclo [2.2.2] octane-1-oxide to its original substance is subjected to the reaction of catalytic solid-phase heterogeneous isotopic exchange between the hydrogens of matter and gaseous tritium. The isotope exchange reaction is conducted for 15 to 25 min at 160 - 180oWith using catalyst 5% Pt/C. the Ratio of catalyst and substance equal to (8 - 12) : 1.

The invention relates to organic chemistry, chemistry of physiologically active compounds and may find application in biomedical research.

Known viscometry tritium on, sawn fragment 4-[2',3'-3H2] propyl-1[4-[(trimethylsilyl)ethinyl] phenyl] -2,6,7-dioxabicyclo[2.2.2]Octan General formula I

< / BR>
(Labelled Compounds and Radiopharmacenticols, 1991, v. XXIX, N 7, p. 829 - 839).

However, the known compound has a low physiological activity and therefore not nasaa objective study of synthetic and natural compounds, capable of interacting with receptors j-aminobutyric acid (GABA) as vertebrates and invertebrates. The main objects and tools for biomedical research of the mechanism of action of substances with GABA-triple activity recognized phosphabicyclononanes (BCF). And as one of the most common methods of investigation of these issues is the radioligand method, the task of obtaining labeled ligands.

Of the General requirements of ligands for these compounds, there arises the necessity of search of labelled compounds with the highest possible affinity to the receptors and the ability to predict the results.

These requirements satisfy tritium-labeled 2,6,7-trioxa-1-phosphabicyclo[2.2.2]octane-1-oxides.

Known 4-[2', 3'-3H] [propyl-2,6,7-trioxa-1-phosphabicyclo [2.2.2]octane-1-oxide of General formula II

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(Martynov, I. C. , Fetisov C. I., Sokolov, C. B. Bicyclic orthoepy of phosphorus acids. - The results of science and technology. A series of "Organic chemistry", T. II Bicyclic areavery acids of phosphorus". - M.: VINITI, 1989, S. 70 - 71).

However, the physiological activity of this vysokobarnogo tritium BCF not high enough.

However, as vysokobarnogo tritium or deuterium in the ethyl radical, this compound is not described.

A method of obtaining vysokobarnogo tritium 4-[2',3'-3H]propyl-2,6,7-trioxa-1-phosphabicyclo[2.2.2] octane-1-oxide of General formula II by reaction accession of tritium to the double bond of the corresponding allyl predecessor

.

However, the known method cannot be used to obtain vysokobarnogo tritium or deuterium in the ethyl radical is 4-ethyl-BSF, because not described corresponding unsaturated predecessor.

The technical result achieved by the invention, is getting a new vysokobarnogo tritium or deuterium highly physiologically active BCF and designing method thereof.

This is achieved by first obtained viscometry tritium or deuterium in the ethyl radical is 4-ethyl-2,6,7-trioxa-1-phosphabicyclo[2.2.2.]octaoxide.

The objective is also achieved by the fact that the method of obtaining vysokobarnogo tritium or deuterium in the ethyl radical is 4-ethyl-2,6,7-trioxa-1-phosphabicyclo[2.2.2. ] octaoxide is the reaction of solid-phase catalytic heterogeneously tritium or deuterium within 15-25 min in the presence of a catalyst 5% Pt/C at 160-180oC and the ratio of catalyst and substance, equal (8-12):1.

The essence of the method consists in carrying out the reaction of isotopic exchange of gaseous tritium with pre-deposited on the catalyst 4-ethyl-2,6,7-trioxa-1-phosphabicyclo[2.2.2.]octane-1-oxide at elevated temperatures. Thus, there is a partial sublimation of material from the catalyst, which is one of the reasons for the fall of molar radioactivity at higher temperatures.

The ratio of catalyst:a substance is also one of the important parameters, which leads to optimization of the conditions of the isotope exchange reaction. Apparently, the larger the ratio of catalyst:a substance, the greater the probability of each molecule organic compounds to be adsorbed on the active center of the catalyst. With further increase with respect to the specified molar ratio of the radioactivity decreases by increasing sublimation, and also due to the growth of irreversible sorption of the substance.

As a catalyst in reactions isotope exchange typically use 5% Pt/C and 10% Pd/C. the Best of them to obtain the target product of the proposed method was 5% Pt/C.

When the source pressure is the maximum pressure (400 hPa), to suppress sublimation of 4-ethyl-BSF with catalyst.

Example 1. In the reaction ampoule of 10 cm3put 1.0 mg of 5% Pt/C, 10 μl of a methanol solution of 4-ethyl-2,6,7-trioxa-1-phosphabicyclo-[2.2.2]octane-1-oxide (10 mg/ml; the ratio of catalyst:a substance is equal to 10:1) and the substance evaporated on a rotary evaporator. Adsorbed on the catalyst substance vacuum to a residual pressure of 110-3hPa. Then the ampoule is filled with gaseous tritium to a pressure of 390 GPa and heated at 170oC within 15 minutes After cooling to room temperature, remove excess tritium labeled and extracted with BCF methanol (4 ml), the catalyst is filtered off. Evaporated reaction mixture with methanol 1-2 times on a rotary evaporator. The reaction products are divided into silicagel plates "Silufol" (Czechoslovakia) in the system of benzene:methanol (2:1). The zone containing the target product (Rf= 0,45), cut, labeled drug elute with methanol, the methanol solution is filtered. Output 4-[1', 2', -3H]-ethyl-2,6,7-trioxa-1-phosphabicyclo[2.2.2.]-octane-1-oxide 50%, molar radioactivity 31,1 CI/mmol. Radiochemical purity established by the method of thin-layer radiochromatography (TSRH) - 95%.

Example 2. In the reaction ampoule volume of the substance is equal to 10:1) and evaporated on a rotary evaporator. Then the operation is carried out as in example 1. The yield of the target product 40 - 60%, radiochemical purity, specific method TSRH - not less than 95%. Molar radioactivity are given in table. 1.

Example 3. To determine the place of occurrence of the label and identification of target tritium-labeled product are isotope exchange reaction with gaseous deuterium. In the reaction ampoule of 20 cm3put 15 mg 5% Pt/C and 150 μl of 4-ethyl-BSP (10 mg/ml; the ratio of catalyst:a substance is 10:1) and evaporated on a rotary evaporator. Adsorbed on the catalyst substance vacuum to a residual pressure of 110-3hPa. Then the ampoule is filled with gaseous deuterium to a pressure of 410 GPa and heated at a temperature of 160oC for 25 minutes After cooling to room temperature, remove excess deuterium and extracted with deuterium labelled 4-ethyl-BCF methanol, the catalyst is filtered off. Then carry out the operation as in example 1. The obtained purified product was analyzed by mass and NMR spectrometers. The analysis showed that deuterium labelled the resulting product contains deuterium in the ethyl radical is 4-ethyl-2,6,7-trioxa-1-phosphabicyclo[2.2.2]octane - 1-oxide.

The proposed method allows for what W 1-2 atoms of deuterium.

Example 4. Studied the dependence of the molar radioactivity vysokobarnogo tritium target product from the reaction temperature of the solid-phase heterogeneous catalytic isotope exchange and from the used catalyst. The catalyst and the substance is taken in the ratio of 10:1. The time of reaction is 20 minutes from the Results in table. 1, show that the best readings are obtained when using catalyst 5% Pt/C and when carrying out the reaction in the range of 160 - 180oC. the Molar radioactivity of the target product, obtained in these conditions is 24.7-31,1 CI/mmol.

The dependence of molar radioactivity 4-ethyl-BZF the ratio of the mass of the catalyst: the mass of the substances used catalyst 5% Pt/C, the reaction was carried out at 170oC for 20 minutes the Results are shown in table. 2, show that the optimal mass ratio of the catalyst and substance equal to (8-12):1. Under these conditions, the molar radioactively the target product is 28,4 - 31,1 CI/mmol, and its molar radioactivity relative maximum is 7.0 and 9.8% (100% is assumed theoretical molar radioactively 4-ethyl-BSF, in the molecule of which all hydrogen atoms are replaced by tritium).

The study is their research.

The method of obtaining vysokobarnogo tritium or deuterium in the ethyl radical is 4-ethyl-2,6,7-trioxa-1-phosphabicyclo(2,2,2)octane-1-oxide, consisting in the reaction of solid-phase heterogeneous catalytic isotope exchange between the hydrogens of ethyl radical 4-ethyl-2,6,7-trioxa-1-phosphabicyclo (2,2,2)octane-1-oxide and gaseous tritium or deuterium for 15 to 25 min in the presence of catalyst, 5 wt.% Pt/C at a temperature of 160 - 180oAnd the mass ratio of the catalyst and the source of the substance 8 to 12 : 1.

 

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