RU2206565C1 - Highly tritium-labeled ethyl-(r)-1-(1-phenethyl)-1h-imidazole-5-carboxylate and method for its preparing - Google Patents

Abstract

FIELD: organic chemistry, chemical technology. SUBSTANCE: invention relates to novel highly tritium-labeled ethyl-(R)-1-(1-phenylethyl)-1H-imidazole-5-carboxylate of the formula (I)

Description

 The invention relates to the field of organic chemistry and can find application in analytical chemistry, bioorganic chemistry, biochemistry and applied medicine.

Данное соединение, содержащее аминобензильную группу, обладает физиологической активностью - снотворным действием и его препарат известен под наименованием "этомидат" (1999 Merck & Co., Inc., Whitehouse Station, NJ, USA., N 3927) [1].Known ethyl (R) -1- (1-phenylethyl) -1H-imidazole-5-carboxylate of the formula I:

This compound containing an aminobenzyl group has physiological activity - hypnotics and its preparation is known as etomidate (1999 Merck & Co., Inc., Whitehouse Station, NJ, USA., N 3927) [1].

 A number of methods for studying physiologically active compounds require the presence of their labeled analogues.

 However, a tritium-labeled analog of this etimidate is not described.

 To obtain high-tritium-labeled analogues of compounds containing an aminobenzyl group, which include a compound of formula I, one has to use expensive precursors, since attempts to produce known methods for introducing a tritium label directly into unlabeled analogues in order to obtain highly-labeled preparations are accompanied by hydrogenolysis of the amine-benzyl bond. Such an outcome is obvious, since the hydrogenolysis of benzylamines is a traditional method for the synthesis of amines (Baltzly R., Buck J. S. // J. Am. Chem. Soc. 1943. Vol.65.1984) [2].

 Neither in the technical nor in the patent literature describes the preparation of uniformly labeled high-tritium-labeled organic compounds containing an aminobenzyl group by the direct introduction of a tritium label into an unlabeled analogue.

 Therefore, the task of finding the conditions for obtaining highly labeled tritium compounds containing an aminobenzyl group by directly introducing labels into their unlabeled analogues is relevant.

 The technical result achieved by the present invention is to obtain a new compound - highly labeled with tritium etimidate by direct introduction of the label into its unlabeled analogue.

Указанный технический результат достигается также тем, что способ получения высокомеченного тритием [³H]-этил(R)-1-(1-фенилэтил)-1Н-имидазол-5-карбоксилата формулы I:

заключается в предварительном нанесении его исходного немеченого аналога на инертный носитель, смешении полученного комплекса с катализатором и проведении реакции изотопного обмена в атмосфере трития при нагревании.This technical result is achieved by the fact that a new highly purified tritium [ ³ H] -ethyl (R) -1- (1-phenylethyl) -1H-imidazole-5-carboxylate of the formula is obtained:

The specified technical result is also achieved by the fact that the method of obtaining highly labeled with tritium [ ³ H] -ethyl (R) -1- (1-phenylethyl) -1H-imidazole-5-carboxylate of the formula I:

consists in preliminary applying its initial unlabeled analog to an inert carrier, mixing the resulting complex with a catalyst and carrying out an isotopic exchange reaction in a tritium atmosphere when heated.

It is recommended that fibrous carbon be used as an inert carrier, 5% Pd / BaSO ₄ as a catalyst, and the isotopic exchange reaction is carried out at 160 ^o C.

 By the example of thisidate, it was shown by our own studies that, during the isotope exchange reaction, the aminobenzyl group does not undergo hydrogenolysis in the organic compounds containing it, if the reaction is not carried out directly on the catalyst, then first put the unlabeled analog onto an inert carrier, then mix it with the catalyst and heat in gaseous tritium atmosphere.

 The following are examples of the implementation of the invention.

Example 1
To a solution of 25 mg of etomidate in 0.75 ml of methanol was added 250 mg of fibrous carbon and evaporated on a rotor. 90 mg of 5% Pd / BaSO ₄ , 0.5 ml of water were added to the residue, evaporated on a rotor and lyophilized for 12 hours. Then, a part of the dried mixture containing 20 mg of etomidate was placed in an ampoule, vacuumized to 0.1 Pa, filled with tritium gas to a pressure of 270 hPa and kept at a temperature of 160 ^o C for 7.5 minutes. Excess tritium was removed by evacuation. After cooling, the reaction products were dissolved in methanol (6 • 1 ml), the catalyst was filtered off, and the filtrates were evaporated several times as a solution in methanol (3 • 3 ml) to remove labile tritium.

The labeled preparation was purified by HPLC on a Kromasil 100C ₁₈ 4 • 150 mm column, 7 μm, v - 1 ml / min, methanol-water-trifluoroacetic acid (50: 50: 0.1) in the system, retention time 5.35 min, and acetonitrile-water-trifluoroacetic acid system (30: 70: 0.1), retention time - 6.44 min. Yield 18–20%, molar activity 23.3 Ci / mmol.

Example 2
Carbon from Norit, alumina, calcium carbonate and fibrous carbon produced by the Resurrection Chemical Plant were studied as an inert carrier. The best radiochemical characteristics of tritium-labeled etomidate were obtained using fibrous carbon, the graphite nanofibers of which consist of graphite layers with a width of 30-500 angstroms laid in highly ordered structures, which leads to greater hydrogen adsorption compared to, for example, activated carbon from Norit.

 Thus, by the method according to the invention, a uniformly labeled high-tritium-labeled compound containing an aminobenzyl group is directly obtained for the first time directly from its unlabeled analogue.

Claims (2)

1. Highly labeled tritium [ ³ H] -ethyl (R) -1- (1-phenylethyl) -1H-imidazole-5-carboxylate of formula I

2. A method of obtaining highly tritiated [ ³ H] -ethyl (R) -1- (1-phenylethyl) -1H-imidazole-5-carboxylate of the formula I

which consists in preliminary applying its initial unlabeled analog to an inert carrier, mixing the resulting complex with a catalyst and carrying out an isotopic exchange reaction in a tritium atmosphere when heated. 3. The method according to claim 2, characterized in that fibrous carbon is used as an inert carrier, 5% Pd / BaSO _{4 is} used as a catalyst, and the isotopic exchange reaction is carried out at 160 ^o C.