RU2136672C1 - Tritium high-labeled dimethomorpholine and method of preparation thereof - Google Patents

Abstract

FIELD: organic synthesis. SUBSTANCE: labeled dimethomorpholine derivative with formula I:

Description

 The invention relates to organic chemistry and may find application in biochemistry and medicine.

(The Merc Index an encyclopedia of chemicals, drugs and biologicals. Eleventtn Edition and 12th. 1989-1996. N.J. USA)
Данное производное морфолина обладает физиологической активностью.Known dimethomorpholine or morpholine 2-n-chlorophenyl-2-verotriacrylate of the formula:

(The Merc Index an encyclopedia of chemicals, drugs and biologicals. Eleventtn Edition and 12th. 1989-1996. NJ USA)
This morpholine derivative has physiological activity.

 In biological and biomedical studies, biologically active compounds are widely used in the form of labeled compounds. However, tritium-labeled dimethylomorpholine is not described.

 The problem solved by the present invention is to obtain a new highly labeled physiologically active compound and the recommendation of the conditions for its preparation.

 This problem is solved due to the fact that synthesized highly labeled with tritium dimetomorpholine.

This problem is also solved due to the fact that in the method of producing high-labeled tritium dimethomorpholine, a distinctive feature is that dimethomorpholine is exposed to tritium gas for 10-15 minutes in the presence of rhodium trichloride at a temperature of 120-190 ^o , a pressure of 400-450 hPa and the ratio dimethomorpholine and rhodium trichloride equal to (1-4): 1.

 An additional introduction of a heterogeneous palladium catalyst into the reaction mixture is allowed.

 To obtain tritium-labeled unsaturated compounds, liquid-phase labeling techniques or isotopic exchange with tritium water are usually used.

 The attempts described so far to obtain tritium-labeled unsaturated organic compounds by solid-phase isotopic exchange have been unsuccessful and culminated in the complete hydrogenation of double bonds.

 Our own studies have shown that it is impossible to obtain tritium-labeled dimetomorpholine with molar radioactivity above 0.1 Ci / mmol using liquid-phase labeling or isotope exchange with tritium water. At the level of 0.05-0.2 Ci / mmol, there was a molar radioactivity of tritium-labeled dimetomorpholine and when trying to obtain it by solid-phase isotopic exchange under conditions allowing to maintain the C = C bond. And such a low molar radioactivity is not enough to bring most biological and biomedical experiments.

 In the present invention for the first time it was possible to use the methods of solid-phase isotope exchange for the successful introduction of the label into the unsaturated compound, which is unique.

 Apparently, when carrying out the reaction under the stated conditions, a rhodium complex is formed in the first stage when the rhodium atom is inserted between the aromatic rings of the dimethomorpholine molecule.

 In the second stage, rhodium is restored at an elevated temperature (in the presence of gaseous tritium), which increases the proton mobility in the aromatic ring due to the displacement of the electrons of the benzene rings to the rhodium atom. At the third stage, under the influence of active particles of tritium, an intense isotopic exchange of rhodium for tritium occurs in the aromatic ring (molar radioactivity - 5.2 Ci / mmol). Apparently, the role of the formed rhodium complex is not only to increase the degree of isotope metabolism, but additionally screens the double bond, protecting the drug from destruction.

 The following experimental data support this scheme. The inclusion of the label, although with lower efficiency due to steric factors, occurs when tristriphenylphosphinrodium chloride is used as a catalyst. The molar activity of the tritium-labeled dimethomorpholine obtained in this process reaches 0.7 Ci / mmol.

The additional introduction of heterogeneous palladium catalysts (5% Pd / BaSO ₄ or 5% Pd / CaCO ₃ ) into the reaction mixture, which promote a more active reduction of RhCl ₃ , increases the degree of isotopic exchange (the molar radioactivity of the target product in the case of 5% Pd / BaSO ₄ - 5.8 Ci / mmol, when using 5% Pd / CaCO ₃ - 6.4 Ci / mmol Higher molar radioactivity when using 5% Pd / CaCO ₃ , apparently due to the fact that CaCO ₃ neutralizes hydrogen chloride released during the reduction of rhodium trichloride. in the reaction mixture of rhodium trichloride on heterogeneous palladium catalysts (for example, 5% Pd / BaSO ₄ or 5% Pd / CaCO ₃ ), the double bond of dimethomorpholine is completely restored.

 The following are examples of the implementation of the invention.

Analytical chromatography was performed on a Separon column 7 μm, C ₁₈ , 4x150 mm, v - 0.8 ml / min: in a system of 70% aqueous methanol with 0.1% trifluoroacetic acid, the retention time was 4.96 minutes; in a system of 65% aqueous methanol with 0.1% trifluoroacetic acid, the retention time is 7.88 minutes; in a system of 60% aqueous methanol with 0.1% trifluoroacetic acid, a retention time of 10.63 minutes Preparative chromatography was performed on Separon SGX columns, C ₁₈ , 10x250 mm, v - 2.0 ml / min; in a system of 65% aqueous methanol with 0.1% trifluoroacetic acid, the retention time is 18.58 minutes; Silasorb 13 μm, 10x250 mm, v - 2.0 ml / min; in a system of 65% aqueous methanol with 0.1% trifluoroacetic acid, retention time 25.37 min; in a system of 70% aqueous methanol with 0.1% trifluoroacetic acid, the retention time is 17.61 minutes.

Example 1. A solution of dimethomorpholine (1.4 mg) in 180 μl of methanol was placed in a reaction vial, 35 μl of an aqueous solution of RhCl ₃ (20 mg / ml) was added and evaporated carefully. Then, 7 mg of 5% Pd / BaSO ₄ , 0.1 ml of methanol were added to the ampoule, and the catalyst suspension with the methanol solution of the rhodium complex was carefully evaporated.

The ratio of the outgoing dimethomorphine to rhodium trichloride was 2: 1. 5 mg of heterogeneous rhodium palladium catalyst was taken per 1 mg of rhodium trichloride. The ampoule was evacuated, tritium gas was injected to a pressure of 400 hPa, and the reaction was carried out at 120 ^° C for 15 minutes. Excess tritium was removed by evacuation, the contents of the ampoule were dissolved in 2 ml of methanol, the catalyst was filtered off, labile tritium was removed by evaporation with methanol (3 × 2 ml). The desired product was isolated by chromatographic methods. The yield of labeled metomorpholine was 34%; molar radioactivity, 0.4 Ci / mmol.

Example 2. A solution of dimethomorpholine (1.5 mg) in 200 μl of methanol was placed in a reaction vial, 75 μl of an aqueous solution of RhCl ₃ (20 mg / ml) was added and evaporated carefully. Then, 15 mg of 5% Pd / BaSO ₄ , 0.2 ml of methanol were introduced into the ampoule, and the catalyst suspension with the methanol solution of the rhodium complex was carefully evaporated. The ratio of the starting dimethomorphine and rhodium trichloride was 1: 1. For 1 mg of rhodium trichloride, 10 mg of a heterogeneous palladium catalyst was taken. The ampoule was evacuated, tritium gas was injected to a pressure of 400 hPa, and the reaction was carried out at 160 ^° C for 15 minutes. Further processing was carried out as described in example 1. The yield of labeled dimethomorpholine was 24%, molar radioactivity was 5.6 Ci / mmol.

Example 3. A solution of dimethomorpholine (1.5 mg) in 200 μl of methanol was placed in a reaction vial, 75 μl of an aqueous solution of RhCl ₃ (20 mg / ml) was added and evaporated carefully. The ratio of the starting dimethomorpholine and rhodium trichloride was 1: 1. A heterogeneous palladium catalyst was not introduced into the reaction mixture. The ampoule was evacuated, tritium gas was injected to a pressure of 450 hPa, and the reaction was carried out at 160 ^° C for 15 minutes. Further processing was carried out as described in example 1. The yield of labeled dimethomorpholine was 38%, molar radioactivity was 5.2 Ci / mmol.

Example 4. A solution of dimethomorpholine (1.4 mg) in 200 μl of methanol was placed in a reaction ampoule, 70 μl of an aqueous solution of RhCl ₃ (20 mg / ml) was added and carefully evaporated. Then, 14 mg of 5% Pd / CaCO ₃ , 0.2 ml of methanol were added to the ampoule, and the catalyst suspension with a methanol solution of the rhodium complex was carefully evaporated. The ratio of the starting dimetomorpholine to rhodium trichloride was 1: 1. 10 mg of a heterogeneous palladium catalyst was taken for 1 mg of rhodium trichloride. The ampoule was evacuated, tritium gas was injected to a pressure of 450 hPa, and the reaction was carried out at 160 ^° C for 15 minutes. Further processing was carried out as described in example 1. The yield of labeled dimethomorpholine was 36%, molar radioactivity - 6.4 Ci / mmol.

Example 5. A solution of dimethomorpholine (3.0 mg) in 250 μl of methanol was placed in a reaction vial, 100 μl of an aqueous solution of RhCl ₃ (20 mg / ml) was added and carefully evaporated. Then, 30 mg of 5% Pd / CaCO ₃ , 0.2 ml of methanol were added to the ampoule, and the catalyst suspension with the methanol solution of the rhodium complex was carefully evaporated. The ratio of the starting dimethomorpholine to rhodium trichloride was 1.5: 1. 10 mg of a heterogeneous palladium catalyst was taken for 1 mg of rhodium trichloride. The ampoule was evacuated, tritium gas was injected to a pressure of 400 hPa, and the reaction was carried out at 180 ^° C for 10 minutes. Further processing was carried out as described in example 1. The yield of labeled dimethomorpholine was 12%, molar radioactivity was 6.6 Ci / mmol.

Example 6. A solution of dimethomorpholine (5.0 mg) in 500 μl of methanol was placed in a reaction vial, 100 μl of an aqueous solution of RhCl ₃ (20 mg / ml) was added and evaporated carefully. Then, 50 mg of 5% Pd / CaCO ₃ , 0.5 ml of methanol were added to the ampoule, and the catalyst suspension with the methanol solution of the rhodium complex was carefully evaporated.

The ratio of the starting dimethomorpholine to rhodium trichloride was 4: 1. 24 mg of a heterogeneous palladium catalyst was taken for 1 mg of rhodium trichloride. The ampoule was evacuated, tritium gas was injected to a pressure of 400 hPa, and the reaction was carried out at 190 ^° C for 10 minutes. Further processing was carried out as described in example 1. The yield of labeled dimethomorpholine was 4%, molar radioactivity - 6.8 Ci / mmol.

Example 7. Conducted an isotopic exchange reaction in the claimed conditions, but in the absence of RhCl ₃ (see table 1).

 The molar radioactivity of the target product is low.

 Example 8. A comparative experiment was conducted to replace rhodium trichloride with tris-triphenylphosphinrodinium chloride without using a heterogeneous palladium catalyst. The yield of labeled product is 41%. Molar radioactivity is 0.7 Ci / mmol.

 Example 9. Used known methods of labeling (isotope exchange with tritium water and liquid-phase isotope exchange) in dimethomorpholine. The results are presented in tables 2 and 3 and indicate a low molar radioactivity of the target product.

 Thus, the method according to the invention solved the problem of obtaining a new highly labeled with tritium physiologically active compounds - dimethomorpholine.

Claims (2)

1. Highly labeled tritium dimethomorpholine of formula I:

2. A method of producing high-tritium-labeled dimethomorpholine of formula I, characterized in that dimethoformoline is exposed to tritium gas for 10-15 minutes in the presence of rhodium trichloride at a temperature of 120-190 ^° C, a pressure of 400-450 hPa and a ratio of dimethomorpholine and rhodium trichloride equal to (1 - 4): 1.  3. The method according to p. 2, characterized in that the heterogeneous palladium catalyst is additionally introduced into the reaction mixture in an amount of up to 25 mg per 1 mg of rhodium trichloride.

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