Method for preparing phenyl-substituted derivatives of pyridine labeled with tritium

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for preparing N-phenylpicolinium salts and phenyl-substituted picolines labeled with tritium by phenyl ring of the general formula: [CH₃C₅H₄N⁺C₆H^* ₅]BF^- ₄ and CH₃C₆H^* ₅C₅H₃N. Method involves arylation of 2-, 3- and 4-picolines with free phenyl cations obtained in beta-decay of tritium in composition of two-fold labeled benzene in the presence of potassium tetrafluoroborate in the closed system. Method provides improving method of synthesis of labeled benzene and to use ion-molecular reaction of tritium-labeled phenyl cations for simultaneous, simple and a single-step synthesis of N-phenylpicolinium salts and phenyl-substituted picolines labeled with tritium that can be used in investigations of metabolism of biologically active heterocyclic derivatives.

EFFECT: improved method of synthesis.

1 dwg, 1 ex

The present invention relates to the field of chemistry, and in particular to a new process for the preparation of salts of N-phenylpyridinium and phenylsilane pikolines, tritium-labeled in the phenyl ring of General formula:

[CH₃C₅H₄N⁺C₆H₅ ^*]BF₄ ^-and CH₃C₆H₅ ^*C₅H₃N

Six-membered nitrogen-containing heterocyclic compounds, in particular derivatives of pyridine, are a very important object of biological research. 3-Methylpyridin (picoline) is an important synthetic precursor pyridine-3-carboxylic acid (nicotinic acid) - representative group Century Amide of nicotinic acid is a structural component of the coenzymes of adenine dinucleotide (NAD+) (1, R=H) and adenine dinucleotide phosphate (NADP+, R=PO(OH)₂). Last coenzyme (one of the complex of vitamin b₂is part of red blood cells and is involved in important biochemical processes.

Another widespread in nature connection pyridine series - pyridoxine (vitamin b₆, 2, R=CH₂OH) - contains yeast and wheat germ and has great importance as a food Supplement. Connection group is United by a common trivial name of vitamin b₆includes pyridoxal (R=CH) and pyridoxamine (R=CH ₂NH₂). Pyridoxal-5-phosphate is a coenzyme in the decarboxylation and transamination α-amino acids.

There are a number of other derivatives of pyridine, common in nature; the most famous of them the tobacco alkaloid nicotine. Among pyridines used as drugs, the most famous piroxicam, possessing anti-inflammatory activity, nifedipine and amlodipine, used to treat angina, as well as pinacidil - a drug for the treatment of hypertension. Some derivatives of piperizine effective as herbicides, among them the most famous paraquat and Diquat. [Gilchrist So the Chemistry of heterocyclic compounds. M, 1996] For the study of biological processes involving the pyridine ring, as well as for studying drug metabolism in the body is extremely important and promising is the use of labeled compounds. Essentially, what is most important to the chemistry and biochemistry of the elements C, H, O, N - only carbon and hydrogen have long-lived isotopes, but when comparing these isotopes tritium has a number of advantages over organic compounds labelled¹⁴C. the Relatively low value of tritium and treated joints (with the same activity tretirovanie connection many times the dash is Les corresponding compounds with an isotope of carbon), the least radioactive danger and biological toxicity by ingestion of tritium inside the body - all this contributes to the widespread use of tritium as a tracer atom in the chemical, biological and medical research, and stimulates the search process is experimentally simple ways to get very complex and trudnosravnimyh compounds labeled with tritium.

Unfortunately, even inactive synthesis of such derivatives of pyridine is difficult because direct familyromagna data connections impossible. Chemical way of synthesis of N-phenylsilane salts, derivatives of pyridine possible by conversion prelievi salts, but the latter are stable only when there are multiple substituents in ortho - and para-positions, i.e. it does not obtain salts of N-phenylpyridine [Dimroth, K. Angew. Chem. 1960. V.72. R]:

Phenylsilane the pikolines can be obtained only by a specially developed technique reactions Suzuki [Suzuki A. J. were obtained. Chem., 1999. V.576. R]:

The getting labeled derivatives requires the synthesis of tritium-labeled precursors - prelievi salts and galogenarenov. Complicated and multistage syntheses in the presence of isotope labels makes it almost impossible for him the economic way of synthesis of N-phenylpyridine derivatives and phenylsilane pikolines, tritium-labeled in the phenyl ring. Tritium label in the benzene ring is stable and fixed, which is extremely important in biological research.

From the patent literature known nuclear-chemical synthesis difficult Organoelement compounds labeled with tritium (see USSR author's certificate No. 542389, 1981; USSR Author's certificate No. 689196, 1978; USSR Author's certificate 860443, bull. No. 13, 1982; USSR Author's certificate No. 1217861, 1985).

The closest in technical essence to the proposed technical solution is a method for tritium-labeled Portorico phenylsilane niewyk connection elements V1 group of the formula I:

where X is oxygen, sulfur, selenium or tellurium, characterized in that extrativista subjected to interaction with diphenylene derivative of the formula II:

,

where X has the above meaning,

and borftoridov potassium in a closed system at a temperature of -196°÷+25°C for 10-15 days. (A.S. USSR №860443, IPC SS 43/20, bull. No. 13, 1982)

The disadvantages of the method prototype is the impossibility of synthesis phenylsilane derivatives of pyridine, tritium-labeled.

The task of creating the invention to provide an improved method of synthesis of the labeled benzene and application of ion-molecular reactions treated phenyl-cations for simultaneous, simple and one-step synthesis of tritium-labeled salts of N-phenylpyridinium and phenylsilane pikolines that can be used to study the metabolism of biologically active heterocyclic derivatives.

The problem is solved described a new way to produce new tritium-labeled salts of N-phenylpyridinium and phenylsilane pikolines, namely, that 2-, 3-, 4-pikolines are areleaving free tritium-labeled phenyl-cations generated during the beta decay of tritium in the structure of benzene.

The above features make it possible to obtain a technical result - improvement of the method of synthesis of labeled benzene and application of ion-molecular reactions tretiranih phenyl-cations for simultaneous, simple and one-step synthesis of tritium-labeled salts of N-phenylpyridinium and phenylsilane pikolines that can be used to study the metabolism of biologically active heterocyclic derivatives.

The above distinctive features, each separately and all together, are aimed at solving the problem and are significant.

The use of distinctive signs in the prior art was not found, therefore the proposed solution meets the criterion of patents the capacity of "novelty."

One set of new essential features with common, well-known provides a solution to the problem is not obvious to a person skilled in the art and demonstrates compliance of the claimed technical solution to the patentability criterion of "inventive step".

The invention is illustrated by description of a specific but not limiting example of implementation.

Example 1.

In the vacuum system from 5 mg dibromobenzene with 5 CI of tritium in the reaction of hydrogenation catalyst (5% Pd on BaSO₄) for one hour at room temperature was obtained twice tritium-labeled benzene with a specific activity of about 4 CI/ml

The mixture titiraupenga benzene and 4-picoline in a molar ratio of 1:5 was applied to the crystal tetrafluoroborate potassium in a glass ampoule. Then the ampoule was sealed and kept at least 15 days at a temperature of -10°With (benzene is in the solid phase) for accumulation of the products of ion-molecule interactions. After accumulation, the ampoule was opened, and treated unreacted benzene was peremarazhival in a new vial. In a vial was added acetone, and a solution mixture of products, labeled with tritium, were subjected to separation by the method of thin-layer chromatography. Chromatogra the Oia was carried out on glass plates Reverse Phase With 18 silica gel (Fluorescent Indicator) in acetonitrile. Radiochromatography shown in the drawing.

The method of obtaining salts of N-phenylpyridinium and phenylsilane pikolines labeled with tritium on the phenyl ring, the General formula

[CH₃C₅H₄N⁺C₆H₅ ^*]BF₄ ^-and CH₃C₆H₅ ^*C₅H₃N

characterized in that 2-, 3 - and 4-pikolines are areleaving free phenyl-cations, obtained from beta decay of tritium in the composition of the doubly labeled benzene, in the presence of tetrafluoroborate potassium in a closed system.