PL118655B1 - Method of producing 9-/2,6-dihalogenbenzylo/-adenine - Google Patents

Description

The subject of the invention is a new method for producing 9-(2,6-dihalobenzyl)-adenine. The method according to the invention produces pure 9-(2,6-dihalobenzyl)-adenine, essentially free from the mutagenic isomer presented in item 3. The above adenine derivatives are known are from the patent description St. United Am. No. 3,846,426, as compounds useful in the treatment and prevention of coccidiosis. Coccidiosis is a widespread disease of poultry, caused by infection with protozoa of the genus Himeria, which cause serious intestinal disorders and inflammation of the cecum in poultry. The most important of these species are E. tenella, E. acervulina, E. necatrix, E. brunetti and E. masima. This disease is spread among birds by ingesting infectious microorganisms found in dung on infected litter or soil, or through contaminated food or drinking water. The disease manifests itself by hemorrhages, accumulation of blood in the cecum, blood in the feces, weakness and digestive disorders. The disease often ends in the death of animals, and birds that have experienced a serious infection have a significantly reduced market value as a result of the disease. Coccidiosis is therefore a disease of serious economic importance; Therefore, extensive research has been carried out to find new and improved methods for the prevention and treatment of coccidiosis infections in poultry. by non-selective alkylates, catalyzed by bases, adenine salts in aqueous solvents or aqueous protic organic solvents. These reactions are single-phase and fast, but have the disadvantage that mixtures of isomers substituted in position 3 and in position 9 are obtained, and the mixtures these contain a large amount of the 3-substituted isomer. Screening using Ames tests has shown that the 3-substituted isomer gives a weak positive test and is therefore considered to be putatively mutagenic. Therefore, the presence of a by-product, which is an isomer substituted in position 3 in 9-(2,6-dihalo)-adenine, makes the mixture unsuitable as a coccidiostatic agent due to the problem of residues in poultry meat. To obtain a usable agent, it is necessary to obtain a product essentially free of the 3-substituted isomer, with a content of the latter below the detection level of 100 ppm. By base-catalyzed alkylation of adenine, carried out in aprotic solvents such as dimethylformamide and dimethylsulfoxide, higher the content of the isomer substituted in position 9 in relation to the content of the isomer substituted in position 3, however, the disadvantage of this method is the high cost of solvents. Isolation of the product is also more difficult. The reaction mixture must be cooled rapidly in water and the filtered product washed several times to remove the solvent. This results in a reduction in yield. The product obtained in the alkylation reaction can only be partially purified by conventional methods such as washing with ethanol or water, or by recrystallization from solvents such as acetic acid, aqueous acetic acid, dimethylformamide or dimethylsulfoxide. Shaking the product with dilute nitric acid or tetrafluoroboric acid (HBF4) also provides some purification. The above-mentioned conventional purification methods, such as washing or recrystallization of crude 9-(2,6-dihalobenzyl)-adenine, result in a product containing up to approximately 4% isomer, substituted in the 3-position. Thus, e.g., extraction of crude 9-(2-chloro-6-fluorobenzyl)-deriary containing 20% of the isomer, substituted in the 3-position with a dilute aqueous solution of nitric acid gives 9-(2-chloro- 6-fluorobenzyl)-adenine, containing 3-4% of the 3-substituted isomer, with a recovery of 96-97% of 9-(2-chloro-6-fluorobenzyl)-adenine. Repeating this procedure on a sample enriched with 9-(2-chloro-6-fluorobenzyl)-adenine does not lead to a reaction level of the isomer substituted in position 3 below 0.3-0.5% (3000-5000 ppm). This is due to a clear tendency to produce solid solutions containing both isomers. The same problem arises when removing the 3-substituted isomer by two recrystallizations from acetic acid. The content level of the isomer substituted in the 3-position is of the order of 0.05-0.1% (500-1000 ppm) even though the liquid phase is not saturated with the isomer substituted in the 3-position. The method according to the invention makes it possible, unlike known methods, to obtain very useful 9-(2,6-dihalobenzyl)-adenines, essentially free from the isomer substituted in the 3-position. The admixture of this isomer makes it impossible to use the product as an anti-coccidiosis agent due to its potential carcinogenicity. The method according to the invention, leading to the preparation of 9 -(2,6-dihalobenzyl)-adenine, substantially free of the 3-substituted isomer, is carried out in two steps. The first step involves the alkylation of adenine salts with an alkali or alkaline earth metal in a two-phase system, in the presence of a phase transfer catalyst, which is a quaternary ammonium salt of the general formula 2, where R has the meaning given below. In the first stage, a mixture of isomers is obtained, in which at least 70% by weight is the isomer substituted in the 9-position. The second stage of the method according to the invention consists in the selective dealkylation of the isomer contained in this mixture, substituted in the 3-position, which is an undesirable by-product. This method consists in the mixture of isomers obtained in the first stage being subjected to transalkylation in the presence of concentrated sulfuric acid and a substance that captures carbonium ions. According to the second variant of the method according to the invention, the transalkylation step may be preceded by extraction of the mixture of isomers with diluted mineral acid. Below is a description of preferred embodiments of the method according to the invention. Alkylation of adenine. (2,6-dihalobenzyl)-adenine is prepared by alkylation of adenine salts with 2,6-dihalobenzyl halide in a two-phase solid-liquid system in which the solid phase is the adenine salt and the liquid phase is a solution of the alkylating agent and the quaternary salt ammonium in an organic solvent or in a two-phase liquid-liquid system in which one liquid phase is an aqueous solution of adenine salt, and the other liquid phase contains an alkylating agent and an ammonium salt. The ammonium salt acts as a catalyst for the transport of adenine salt from the solid phase to the organic liquid phase or from the aqueous liquid phase to the organic liquid phase, where alkylation of adenine takes place. Such a process will be generally called "gas transfer catalysis", and the ammonium salt "phase transfer catalyst*4. The compounds produced are presented by the general structural formula 1, in which Xi and X2 denote, independently of each other, a halogen atom, i.e. fluorine, chlorine, bromine or iodine Examples of these compounds are 9-(2,6-dichlorobenzyl)-adenine, 9-(2-chloro-6-fluorobenzyl)-adenine. 9-(2,6-dihalobenzyl)-adenine, produced according to the method of the invention, must be essentially free of positional isomers. The method according to the invention produces primarily 9-(2,6-dihalobenzyl)-adenines containing less than 100 ppm of the isomer substituted in the 3-position, and especially 9-(2-chloro-6-fluorabenzyl)- adenine, containing less than 100 ppm of the isomer substituted in the 3-position. The preferred method of the invention consists in the alkali or alkaline earth metal salt of adenine being alkylated with 2,6-dihalobenzyl halides, obtaining a mixture of (2,6-dihalobenzyl)-adenine isomers , in which at least 70% by weight is 9-(2,6-dihalobenzyl)-adenine, and the alkylation is carried out in a two-phase solid-liquid or liquid-liquid system, where: 118655 3 a) two-phase solid system - the liquid consists of a solid phase, which is a salt of adenine with an alkali or alkaline earth metal, and a liquid phase, which is a solution of 2,6-dihalobenzyl halide and a "phase transfer catalyst", which is a quaternary ammonium salt of the general formula 2, where R is a mixture of normal alkyl radicals with 8-12 C atoms, in an aprotic, water-miscible or water-immiscible organic solvent, wherein the water-miscible solvent contains from 0 to about 5 moles of water per 1 mole of adenine salt. b) the two-phase liquid-liquid system consists of one liquid phase, which is an aqueous solution of adenine salt / alkali metal or alkaline earth, and the second liquid phase, which is a solution of 2,6-dihalobenzyl halide and a phase transfer catalyst, which is a quaternary ammonium salt with general formula 2, wherein R has the meaning given above in an aprotic, water-immiscible organic solvent. “The phase transfer catalyst44 is an onium salt containing alkyl groups attached to nitrogen or phosphorus atoms. Any salt of the above general formula may be used in the process of the invention, provided that the alkyl groups are large enough to solubilize the adenine salt in the selected organic phase, but not so large that an emulsion is formed. Suitable solvent systems for the process of the invention are neutral aprotic solvents, that is, not reacting with the components of the reaction mixture under the maintained reaction conditions. Aprotic solvents are more preferred due to the fact that a higher content of the isomer substituted in position 9 is obtained compared to the isomer substituted in position 3. If the process is carried out in a two-phase solid-liquid system, the aprotic solvent can be either miscible or immiscible with water. It is not critical to maintain water-miscible solvents under anhydrous conditions, but excessive amounts of water tend to increase the proportion of the 3-substituted isomer. When the process is carried out in a two-phase liquid-liquid system, the aprotic organic solvent is limited to immiscible solvents. with water. The amount of water in the aqueous phase is not critical. The alkali or alkaline earth metal adenine salt is represented by the general formula 3, where M+ is the alkali or alkaline earth metal cation, and b and c are integers, with the charge b of moles of anion being neutralized by a positive charge c moles of cation. The salt is suspended in an aprotic organic solvent or dissolved in an aqueous solution. To the above is added a solution containing an alkylating agent of the general formula 4, in which Xi and aprotic. The preferred leaving group is halogen. The substituted toluene is added in an equimolar amount relative to the adenine or in a small excess. The resulting heterogeneous reaction mixture is stirred vigorously until the reaction is completed. According to the method of the invention, adenine is suspended in a suitable aprotic solvent. An equivalent amount of base is added to the suspension. Bases with a pbg higher than 10.5 are preferred, so that adenine is substantially completely converted to the anion. Examples of suitable bases are: carbonates, e.g. alkali metal carbonates such as salt and potassium carbonate, hydroxides, e.g. alkali metal hydroxides such as sodium, potassium or lithium hydroxide, tetraalkyl ammonium hydroxide, and alcoholates, e.g. potassium ethoxide, sodium ethoxide. Generally, suitable bases are all those that exhibit sufficient basicity to produce the adenine anion in the solvent system used. The adenine salt may be prepared in situ by adding an equivalent amount of base or, conveniently, by dissolving adenine in an aqueous solution containing an equivalent amount of strong base, evaporating the water and using the residue containing the hydrate of the adenine salt for alkylation. Preferably, the method of the invention consists in alkylation of the adenine salt with an alkaline earth metal using 2-chloro-6-fluorobenzyl halide or 2,6-4-dichlorobenzyl halide, obtaining a mixture of isomers ( 2-chloro-6-fluorobenzyl)-adenine or (2,6-dichlorobenzyl)-adenine, at least 70% by weight of which is 9-(2-chloro-6-fluorobenzyl)-adenine, or 9-(2,6 -dichlorobenzyl)- adenine. Alkylation is carried out in a two-phase solid-liquid or liquid-liquid system. The solid-liquid two-phase system consists of a solid phase, which is a salt of adenine and an alkaline earth metal, and a liquid phase, which is a solution of 2-chloro-6-fluorobenzyl halide or 2,6-dichlorobenzyl halide, and a phase transfer catalyst, which is a quaternary ammonium salt. , of general formula 2, in which R has the above meaning in an aprotic, water-miscible solvent such as acetone, acetonitrile or hexamethylphosphoramide, the water-miscible solvent may contain 0-5 moles of water per 1 mole of adenine salt, with still obtaining the desired proportion of the 9-substituted isomer. The reaction can also be carried out in an organic solvent immiscible with water, such as hexane, benzene, toluene, methylene chloride, chloroform and petroleum ether. is carried out in a two-phase liquid-liquid system, one liquid phase is an aqueous solution of adenine with an alkaline earth metal, and the second liquid phase is a solution of 2-chloro-6-fluorobenzyl halide or 16-dichlorobenzyl halide and a phase transfer catalyst, which is the fourth ¬ spinal ammonium salt of the general formula 2, where R has the above-mentioned meaning, in a vaprotic, water-immiscible organic solvent such as hexane, benzene, toluene, methylene chloride, chloroform or petroleum ether. The most preferred method is alkylation of sodium adenate with chloride 2 -chloro-6-fluorobenzyl, to provide a mixture of (2-chloro-6-fluorobenzyl)-adenine isomers, wherein at least about 70% by weight is 9-(2-chloro-6-fluorobenzyl)-adenine, wherein the alkylation is carried out in a two-phase solid-liquid or liquid-liquid system, where in the solid-liquid system, the solid phase is sodium adenate and the liquid phase is an acetone solution of 2-chloro-6-fluorobenzyl chloride and a phase transfer catalyst, which is a quaternary salt ammonium of the general formula 2, in which R has the above-mentioned meaning! The above mixture of tetraalkyl ammonium salts of general formula 2, wherein R is primarily the caprylic radical (Cg), is known as Aliauat 336 (manufactured by General Mills, Inc. Chemical Division, 4 620 West 77 th Street, Minneapolis, Minnesota). The reaction mixture does not have to be anhydrous, it may contain 0-5 moles of water per 1 mole of sodium adenate and still give the desired proportion of the isomer substituted in position 9. When the reaction is carried out in a two-phase liquid-liquid system, one liquid phase is an aqueous solution of adenate sodium, and the second liquid phase is a hexane solution of 2-chloro-6-fluorobenzyl chloride and a phase transfer catalyst, which is a quaternary ammonium salt of the general formula 2, in which R has the meaning given above. The ratio of the amount of adenine to the alkylating agent can change relatively a wide range. Reagents can be used in stoichiometric amounts, i.e. equal amounts of moles of reagents, or an excess, e.g. 2-10% or an even greater molar excess of the alkylating agent. Preferably, an excess of about 2 mol% is used. The phase transfer catalyst is preferably used in an amount of 1-10 mol% in relation to adenine. The amount of solvent can also vary over a wide range. The solvent is used in an amount sufficient to keep the heterogeneous reaction mixture stirred so that the reaction can proceed at a moderate rate and so that the reaction product can be more easily isolated. In most cases, the most suitable solution for carrying out the reaction is a 5-15% (by weight) solution of adenine salt in a solvent. The components of the mixture are combined in the reaction medium in any way and in any order. So, for example, a preferred method of combining the components of the reaction mixture is as follows: adenine adds is added to the solution in the reaction mixture, then substituted toluene is added, either neat or in a suitable solvent, and finally the "phase transfer catalyst" is added. Other methods of combining the reactants and catalyst are obvious to the person skilled in the art, but preferably they are combined in such a way that that the adenine anion is produced no later than the addition of the substituted toluene, and preferably earlier. The "phase transfer catalyst" is most preferably added last. The reaction time and temperature conditions are not too critical. However, the reaction time decreases as the reaction temperature increases. The reactions are most preferably carried out at temperatures from about room temperature to about 150°C. However, it is best to carry out the reaction at the boiling point of the selected solvent. When using hexamethylphosphoramide as a solvent, temperatures above 155°C should be avoided because the selectivity of alkylation is reduced at too high temperatures. The reaction can be carried out within 1-24 hours, but alkylation is usually complete after 4-6 hours. Once the reaction is complete, the reaction mixture is cooled to about room temperature to precipitate the solid product. The product is then collected in the usual way, such as by filtering. The second stage of the method according to the invention consists in removing the isomer substituted in the 3-position from the obtained mixture of isomers. The second stage of the method according to the invention, i.e. purification of 9-(2,6-dihalobenzyl)-adenines, is described using, for example, the description of the purification of 9-(2- chloro-6-fluorobenzyl)-adenine. There are two differences of a chemical nature between the isomer substituted in position 9 and the isomer substituted in position 3, on which the purification method according to the invention is based, namely: 1) isomer substituted in position 3 (pKa = 5.6) is 40 times more basic than 9-(2-chloro-6-tluorobenzyl)-adenine, (pKa = 4.0) and 2) the isomer, substituted in the 3-position, is chemically less stable in strong acid solutions than 9-(2-chloro-6-fluorobenzyl)-adenine. It is used in pKa to effect the partial reduction of the 3-substituted isomer contained in the crude reaction mixture by simple extraction of the crude solid product with a dilute mineral acid solution. Thus, extraction of crude 9-(2-chloro-6-fluorobenzyl)-adenine containing 20% of the 3-substituted isomer with a dilute aqueous solution of nitric acid leads to obtaining 9-(2-chloro-6-fluorobenzyl)- adenine, containing 3-4% of the 3-substituted isomer, with a yield of 96-97% of 9-(2-chloro-6-fluorobenzyl)-adenine. The 3-substituted isomer was essentially completely removed (< 100 ppm) by selective chemical decomposition of the 3-substituted isomer, taking advantage of its inherent lower thermodynamic stability. The 3-substituted isomer can be completely and selectively decomposed into adenine and the benzyl polymer by treatment with 96% sulfuric acid without affecting the 9-substituted isomer, according to the reaction shown in Scheme 1, where the compound of formula 5 represents the 9-substituted isomer. 3, and formula 6 represents adenine. Under the same conditions, -(2-chloro-6-fluorobenzyl)-adenine is not reactive. Therefore, treatment of 9-(2-chloro-6-fluorobenzyl)-adenine, containing 3-4% of the 3-substituted isomer, with 96% sulfuric acid gives 96% yield of 9-(2-chloro-6-fluorobenzyl) -adenine, containing < 100ppm of the 3-substituted isomer. It turned out to be very difficult to completely remove the 9-(2-chloro-6-fluorobenzyl)-adenine polymer. This problem was solved by treatment with sulfuric acid in the presence of an appropriate substance that captures carbonate ions. This substance reacts with the carbonium ion and prevents the formation of the polymer. Suitable substances that capture carbonium ions are well known; these are substances such as alkyl sulfide, in which the alkyl groups contain 1-5 C atoms, aryl sulfide, in which the aryl groups contain 6-18 C atoms; benzene, toluene, xylene, a mixture of xylenes, mesitylene, alkoxybenzylene in which the alkyl group contains 1-3 C atoms, such as anisole, thiophene, iodobenzene, naphthalene or triphenylphosphine. Of the many substances tested, toluene and a xylene mixture have proven to be the most suitable for this purpose. Toluene reacts violently with the intermediate carbonium ion to form a transalkylation product according to the reaction shown in Scheme 2, where the compound of formula 7 is an o-, m- or p-transalkylation product; polymerization is thereby prevented. Using the transalkylation process in the presence of toluene, 9-(2~chloro-6-fluorobenzyl)-adenine, containing 3-4% of the 3-substituted isomer, gives 9-(2-chloro-6-fluorobenzyl)-adenine, with a high purity, containing no polymer and < 100ppm of the 3-substituted isomer, with a yield of 97-98%. The crude 9-(2-chloro-6-fluorobenzyl)-adenine containing the 3-isomer in an amount of 20% may be extracted with a dilute mineral acid solution to partially remove the undesirable 3-substituted isomer, especially if necessary , to remove traces of the 7-substituted isomer before treatment with sulfuric acid. The type of mineral acid is not critical, provided that it does not react with the 9-substituted isomer. Suitable mineral acids are hydrochloric, phosphoric or nitric acid, with nitric acid being the most preferred. To avoid excessive loss of the 9-substituted isomer during extraction, it is most preferable to determine the amount of the 3-substituted isomer by the liquid chromatography assay (LC assay) described below under the heading "Assay", with an equimolar (or small excess) addition amount of acid compared to the 3-substituted isomer. Extractions can be carried out between room temperature and about 100° C., preferably at reflux temperature with vigorous stirring. Extraction from about 1 hour to about 5 hours with vigorous stirring is sufficient. .The optimal time is about 2 hours. The hot mixture is collected by filtration and washed with hot water, alkaline water to remove excess acid and finally hot water. The obtained partially purified product, enriched in the 9-substituted isomer, is treated with sulfuric acid in the presence of a scavenging substance carbonium ion, in order to obtain (2-chloro-6-fluorobenzyl)-adenine substituted in position 9. In the method according to the invention, crude 9-(2-chloro-6-fluorobenzyl)-adenine is treated with concentrated sulfuric acid (concentration 96 %), to selectively dealkylate the 3-substituted isomer and recover the adenine. Dealkylation requires at least a two-fold molar excess of sulfuric acid in relation to the amount of the 3-substituted isomer. The concentration of the 3-substituted isomer is determined by a liquid chromatography (or L.C.) test, described below under the heading "Test". excess sulfuric acid is not critical. For example, you can use the equivalent weight of crude 9-(2-chloro-6-fluorobenzyl)-adenine per volume of sulfuric acid or up to ten times the volume of sulfuric acid based on the weight of crude 9-(2-chloro- 6-fluorobenzyl)-adenine. The preferred ratio is 1 g of crude 9-(2-chloro-6-fluorobenzyl)-adenine for every 2 ml of sulfuric acid. The amount of carbonium ion scavenger is not critical, provided that at least equimolar is used amount relative to the 3-substituted isomer. However, a large excess is preferred because it acts both as a reagent and as a solvent. Crude 9-(2-chloro-6-fluorobenzyl))-adenine is treated with concentrated sulfuric acid at temperatures ranging from room temperature to about 90PC. The preferred temperature is room temperature and a final heating period of about 10 minutes at about 80°C to complete the reaction. The reaction time is not critical as long as it is at least 2 hours. After the first 2 hours the reaction is essentially complete and may be stopped at any convenient time. No harmful effects are observed if the process is carried out within 36 hours. A convenient optimal reaction time is about 5 hours on a laboratory scale and about 24 hours on an industrial scale. The aqueous layer is separated from the reaction. Heating to 50-100°C may be necessary, depending on the amount of solvent and acid present, to facilitate separation of the aqueous phase. The aqueous phase is made alkaline by adding a base. Any base that forms a water-soluble sulfate is suitable for this purpose. Preferred bases are sodium hydroxide, potassium hydroxide, ammonium hydroxide and sodium and potassium carbonate, especially sodium hydroxide. After strongly alkalinizing the aqueous phase, the product precipitates, which is collected by filtration, washed with water or an aqueous alcohol solution and dried under reduced pressure. An additional benefit of this process is the fact that adenine can be recovered from the alkaline filtrate by neutralizing the filtrate and filtering off the precipitated adenine. Test: I. Test to determine the percentage (by weight) of the 9-substituted isomer, the 3-substituted isomer and the 7-substituted isomer, when the content of the 3-substituted isomer is more than 1%. The weight percentage of isomers substituted in position 9, 3 and 7 in the product is determined by high-pressure liquid chromatography (LC) and ultraviolet spectra. The weight % of isomers substituted in position 9 and 7 are determined by high-pressure liquid chromatography (L.C), using! A 5 cm column filled with completely porous (5 microns) silica (Du Pont, Zorbax-Sil), eluted with CH3Cl: MeOH (95:5), measuring the absorption of each component at 254nm, with benzyladenine, substituted in position 9, used as an internal standard (accuracy ±0.3%), the weight % of the isomer substituted in the 3-position is determined by ultraviolet examination. The sample is tested at 310 nm, with the 3-substituted isomer showing 2300 at this wavelength, while the 9-substituted isomer does not absorb (accuracy up to +0.1%). II. Test to determine the percentage (by weight) of trace amounts of isomer 3 after treatment with sulfuric acid. The % by weight of the 3-substituted isomer is determined by high-pressure liquid chromatography (L.C.), using a 10 µm, 30 cm, microporous phase column, with an octadecylsilyl bond (Water's Associates Micro Bondapak C-18 No. 27324) and a mobile phase in in the form of a water-methanol solution, phosphate at 35°C. The mobile phase is prepared from 30 parts of methanol and 70 parts of 0.01 molar Na2HP04 adjusted to pH = 7 with H3PO4. Ultraviolet detection at 280nm. The detection limit is 100 ppm. The following examples illustrate the method according to the invention in more detail, without limiting its scope. Example I. Method of alkylation of adenine with α-2-dichloro-6-fluorotoluene in the presence of Aliauat 336 in a hexane-water mixture (Heterogeneous liquid-liquid reaction mixture ). Into a 1-liter, three-necked, round-bottomed flask, equipped with a thermometer, condensers, a nitrogen inlet and a mechanical stirrer at the top, 40 ml of water, 8.0 g of sodium hydroxide (0.20 mol) were successively introduced, and after dissolving the sodium hydroxide, 27.60 g adenine (98% pure, 0.20 mol). After dissolving the adenine, a solution of 39.95 g of α,2-dichloro-6-fluorotoluene (91.5% purity determined by gas chromatography, 0.20 mol plus 2%) and 5.04 g of Aliauat 336 (0.01 mol, 5 mol% ) in 300ml of hexane. (No reaction occurs unless a "phase transfer catalyst" is added). The mixture was stirred under reflux for six hours, cooled to room temperature and the precipitate was collected by filtration. The solid precipitate was washed twice with 100 ml of water and dried under reduced pressure (100° C, overnight) obtaining 52.32 g of (2-chloro-6-fluorobenzyl)-adenine (94%). Ultraviolet test results: (N/10 HC1) Am»x = 264, E% = 535; weight % determined L.C of the 9-substituted isomer = 69.9; ultraviolet weight % of the 3-substituted isomer = 25.0. Purification of crude (2-chloro-6-fluorobenzyl)-adenine. 30 g of the above crude substance was added to 60 ml of hot acid acetic acid (65°C). The temperature was raised to 100°C; at this temperature everything was dissolved. The hot acetic acid solution was filtered through a preheated funnel with crushed glass, and the filtrate was added dropwise over 10 minutes to 240 ml of well-stirred water in 95°C (adding water to the acetic acid solution leads to the formation of a salt of the product with acetic acid, which has a cotton-like form). After cooling the solution to 37°C, most of the product precipitated. After filtration, the product was washed once with 25 ml of acetic acid-water mixture (1:4), twice with 25 ml of water and dried under reduced pressure (95°C for 6 hours), obtaining 20.83 g (2-chloro-6-fluorobenzyl )-adenine, substituted in position 9 (69.5%). % by weight of the 3-substituted isomer, determined by ultraviolet examination = 3.0; % by weight of the 9-substituted isomer, determined by L.C. = 89.118655 7 Example II. Method of alkylation of adenine with α,2-dichloro-6-fluorotoluene in the presence of Aliauat 336 in acetone (solid-liquid reaction mixture). 100 ml of acetone, 6.95 g of adenine (97% purity, 50 mmol) and 4.0 g of sodium hydroxide solution (test: 50%, 50 mmol) were successively introduced into a 250 ml round-bottomed flask, and then the suspension was heated under reflux for 1 1/2 hour. 9.8 g of α,2-dichloro-6-fluoro-toluene (91.4% purity, 50 mmol) and 1.25 g of Aliauat 336 (2.5 mmol, 5 mole%) in 10 ml of acetone were added to the suspension and heated under reflux. stirring vigorously, for six hours. (In the absence of the "phase transfer catalyst" the reaction is 5 times slower. The reaction mixture was cooled to room temperature and the solid product was filtered off, which was washed twice with 15 ml of acetone and then shaken with 50 ml of 0.1N sodium hydroxide solution for 15 minutes (this removes all unreacted adenine and NaCl, produced during alkylation). The solid product was filtered off, washed twice with 20 ml of water and dried under reduced pressure (100°C for 4.5 hours) to obtain 13.12 g (2-chloro-6-fluorobenzyl) - adenine (94.4%). Ultraviolet test: (N/10 HCl) item 3, determined by ultraviolet examination = 20.4. Purification. 10 g of the above-described substance were added to 18 ml of hot glacial acetic acid (~60°C). The mixture was heated to 110°C (the solution was prepared between 60 and 90°C ), was filtered and the filtrate was added to 80 ml of hot water (95°C) over 5 minutes with vigorous stirring (an additional 2 ml of acetic acid was used for rinsing). After the temperature dropped to 37°C, the suspended substances were filtered off, washed once with 10 ml of a 4:1 mixture of H2O: HOAc and twice with 15 ml of water. Drying in an oven under reduced pressure (100°C for 6 hours) gave 7.64g of (2-chloro-6-fluorobenzyl)-adenine, 76.4%. Ultraviolet test: (N/10 HC1) thin-layer chromatography on silica gel in CH3Cl: MeOH (10:1) showed one minor impurity at Rf = 0.57 and a major stain at Rf = 0.86. Exemplary. Method of alkylation of sodium adenate hydrate with a,2-dichloro-6-fluorotoluene in the presence of Aliauat 336 in hexamethylphosphoramide (Solid-liquid reaction mixture). Step 1. Sodium adenate was conveniently prepared by dissolving 1 mole of adenine in 400ml of 2.5M sodium hydroxide (1.0 mole). The solution was concentrated in a rotary evaporator under reduced pressure at steam bath temperature until supersaturation was achieved. The solution was poured into a glass bowl and after sodium adenate crystallized, the substances were dried under reduced pressure overnight at 75°C. The dried product was ground into an easy-flowing powder; KF= 8.3%; equivalent weight (ea.wt.) (HCIO4) = 85.4 (MW = 170.8) (titration of equivalent weight (ea.wt.) with HC1 gave values 172-173). Step 1 Alkylation. 50 ml of hexamethylphosphoramide (HMPA) (without special drying) and 8.55 g (SOmmole) of sodium adenate hydrate (prepared according to Example III, step I) were introduced into a 100 ml flask. After the sodium adenate was uniformly suspended, 9.9 g of c*,2-dichloro-6-fluorotoluene (92.3% pure, 50 mmol plus 2%) were added over a period of 10-15 minutes. The reaction was stirred overnight (four hours was sufficient to achieve complete conversion) and then slowly poured (3 minutes) into 100 ml of water with vigorous stirring (pH = 7.9 after approximately 5 minutes). 0.6 g of sodium hydroxide solution (50% concentration, 7.5 mmol) was added to the suspension to ensure removal of unreacted adenine. After stirring for 15 minutes, the solid precipitate was filtered off, washed twice with 25 ml of water, and dried under reduced pressure for 4 hours at 75°C, obtaining 13.29 g of (2-chloro-6-fluorobenzyl)-adenines ( 95.8%). % by weight of the 3-substituted isomer, determined by ultraviolet = 11.7; % by weight of the 9-substituted isomer, determined by L.C. = 84.8. Stage 3. Cleansing. 10 g of the substance described above was dissolved in 14 ml of acetic acid at 95°C. The solution was filtered while hot and the filtrate was added dropwise over a few minutes to 80 ml of water at 95°C with vigorous stirring (an additional 2 ml of hot acetic acid was used to rinse all the remaining substance into the hot water). After cooling to 37°C, the suspended solid was filtered off, washed once with 10 ml of acetic acid-water solution (1:5), twice with 10 ml of water and dried under reduced pressure (overnight, at 75°C) to obtain 8.45 (2 -chloro-6-fluorobenzyl)-adenine, substituted in position 9 (84.5%). Thin layer chromatography on silica gel in CHCl3:MeOH (10:1) showed a single spot; melting point: 243-245°C; DSC = 0.8 mol% impurities; ultraviolet test:8,118,655 (N/10 HCI) Xmax = 259, E% = 562; % by weight of the 3-substituted isomer, determined by ultraviolet examination = <2. Example IV. Method of alkylation with sodium adenate water using a,2-dioxide! oro-6- fluorotoluene in the presence of Aliauat 336 in acetone (Solid-liquid reaction mixture). 100 ml of acetone and 8.54 g of sodium adenate hydrate (50 mmol, prepared according to example 3, step 1) were introduced into a 250 ml round-bottomed flask. A solution of 9.8 g in 10 ml of acetone was introduced into the suspension and heated to reflux with vigorous stirring for 6 hours. The reaction mixture was cooled to room temperature, then the solid precipitate was filtered off, washed twice with 15 ml of acetone and then shaken with 50 ml of 0.1N sodium hydroxide solution for 15 minutes (removes the remains of unreacted adenine and NaCl produced during alkylation). The solid precipitate was filtered off, washed twice with 20 ml of water and dried under reduced pressure (100°C, 4.5 hours) to obtain 13.2 g of (2-chloro-6-fluorobenzyl)-adenines (95%). Ultraviolet test (N/10HCI) Am»x= 262; E% = 534; % by weight of the 9-substituted isomer, determined by L.C. = 83; % by weight of the 3-substituted isomer, determined by ultraviolet examination = 16. Example V. Method of alkylation of potassium adenate hydrate with a,2-dichloro-6-fluorotoluene in the presence of Aliauat 336 in acetone (solid-liquid reaction mixture). The process was carried out as in Example 4, with the difference that sodium adenate was replaced by an equivalent amount of potassium adenate. Potassium adenate was prepared according to Example 3, step 1, with the difference that instead of sodium hydroxide, an equivalent amount of potassium hydroxide was used. The yield of 2-chloro-6-fluorobenzyl)-adenate is 94.% by weight of the isomer substituted in the position indicated by L.C. 9=82; Weight% of the 3-substituted isomer determined by ultraviolet examination = 18. Example VI. Method of alkylation of sodium adenate hydrate with α-(Y)-2-chloro-6-fluorotoluene in the presence of Aliauat 336 in acetone (Solid-liquid reaction mixture). The process was carried out according to Example IV, with the difference that instead of α,2-dichloro-6-fluorotoluene, an equivalent amount of α-(Y)-2-chloro-6-fluorotoluene was used, in which Y had the meaning listed in Table I. Table I formula 10 Y = formula 11 Y=I Y =S+(CH3)2C1— Y = Yield of (2-chloro-6-fluoro-benzyl)-adenine 85% 85% 31% 85% Ratio of the isomer substituted in position 9 to the isomer substituted in position 3*) 2:1 7:3 3:1 4:1 *) in some cases small amounts, up to 10%, of other products were obtained, which were probably isomers substituted in positions 1 and 7. Example VII. Method of alkylation of sodium adenate hydrate with a,2,6-trichlorotoluene in the presence of Aliauat 336, in acetone (Solid-liquid reaction mixture). 100 ml of acetone and 8.54 g of sodium adenate hydrate (50 mmol, prepared according to example 3, step 1) were introduced into a 250 mg round-bottom flask. We introduce a solution of 10 g of a,2,6-trichlorotoluene (98% pure, 50 mmol) and 125 g of Aliauat 336 (2.5 mmol, 5 mol%) in 10 ml of acetone into the suspension, and then the whole thing is heated under a reflux condenser with vigorous stirring. , within 6 hours. The reaction mixture was cooled to room temperature, the solid precipitate was filtered off, washed twice with 15 ml of acetone and then shaken with 50 ml of 0.1 N sodium hydroxide solution for 15 minutes (removing the remains of unreacted adenine and NaCl, produced during the alkylation). The solid precipitate was filtered off, washed twice with 20 ml of water and dried under reduced pressure (100°C, 4 hours) to obtain 13.8 g of (2,6-dichlorobenzyl)-adenines, (94%). Ultraviolet test (N/10 HCI) A*. ^262, E% = 494; % by weight of the 9-substituted isomer designated by L.C. = 81; % by weight of the 3-substituted isomer, determined under ultraviolet = 17. Example VIII. Method of alkylation of sodium adenate hydrate with a,2,6-trichlorotoluene in the presence of Aliauat 336 in toluene (solid-liquid reaction mixture). 100 ml of toluene and 8.54 g of sodium adenate hydrate (50 mmol, prepared according to Example 3, step 1) were successively introduced into a 250 ml round-bottomed flask. A solution of 10ga,2,6-trichlorotoluene (98% purity, 50 moles) and 1.25g of Aliauat 336 (2.5mmols, 5% moles) in 10ml of toluene were introduced into the suspension and the whole was heated under reflux while stirring vigorously. The mixture was cooled to room temperature, then the solid precipitate was filtered off, washed twice with 15 ml of toluene, and then shaken with 50 ml of 0.1 N sodium hydroxide solution for 15 minutes, thereby removing any remaining unreacted adenine and NaCl produced during alkylation). The solid precipitate was collected by filtration, washed twice with 20 ml of water and dried under reduced pressure (100°C, 4.5 hours) to obtain 10.2 g of (2,6-dichlorobenzyl)-adenine (76%). Ultraviolet test: (N/10 HC1) Xmax= 262, E% = 498; % by weight of the 9-substituted isomer determined by L.C. = 80; % by weight of the substituted isomer determined by ultraviolet examination = 20. Example IX. One-step purification of crude 9-substituted (2-chloro-6-fluorobenzyl)-adenine by treatment with sulfuric acid. For mixed suspension of crude (2-chloro-6-fluorobenzyl)-adenines [2.0 g, wt.% of isomers substituted in positions 9,(3,)7, denoted by L.C. = 79.7(17.8)1.2] concentrated sulfuric acid (96%, 4ml) was added dropwise in xylene (4ml) at room temperature. The mixture was stirred for 12 hours at room temperature and then for a further 10 minutes at 80°C. After cooling the reaction mixture to room temperature, it was poured into ice-cold water (25 ml) containing xylene (10 ml). The resulting mixture was transferred to a steam jacket separator and heated to 85°C to redissolve the precipitate. The aqueous layer was separated and made basic by the addition of concentrated ammonium hydroxide. The resulting solid was filtered off and washed with hot water (2X 10ml). Yield: 1.53 g (95.6% with respect to the obtained isomer substituted in position 9). % of the 9-substituted isomer denoted by - L.C. = 100.07%; no 3-substituted isomer detected (< 100 ppm); isomer substituted in position 7~0.8%. Example crude (2-chloro-6-fluorobenzyladenine (% by weight of isomers substituted in the 9- positions) and 3- (=79.1,/19.3, determined by L.C. test), which corresponds to 31.64g of the isomer substituted in the 9 and 7.72 g of the isomer, substituted in position 3, in 440 ml of water containing 19.0 ml (0.0285 mol) of 1.5 N nitric acid were heated under reflux for 2 hours with vigorous stirring. The mixture was filtered while hot. through a previously heated funnel, washed with hot water (3X 50 ml of sludge), concentrated NH4OH (2X 25 ml) and hot water (3X 50 ml). Steam was sucked dry from the product and finally dried under reduced pressure at 65-70°C for overnight, obtaining 31.67 g (97.1% yield) enriched in the 9-substituted isomer (2-chloro-6-fluorobenzy! o)-adenine. The yield was calculated with respect to the obtained 9-substituted isomer and corrected for purity. The content, determined by L.C, of the isomer substituted in position 9 = 97.2%, and in position 3 = 3.0%. Step B: Dealkylation of 3-substituted (2-chloro-6-fluorobenzyl)-adenine with sulfuric acid. Add to a vigorously stirred suspension 50.0 g (0.18 mol) (2-chloro-6-fluorobenzyl)-adenine, enriched ¬ ne in the isomer, substituted in the 9-position, (% by weight of the isomers, substituted in the 9-position, 3-=96.8 (3,2, denoted by L.C.), corresponding to 48.4 g of the isomer, substituted in the 9-position and l, 6g of the isomer substituted in position 3, in 100ml of toluene (reagent purity grade), 100ml of concentrated sulfuric acid (96.02%) were added dropwise, cooling with ice water so that the temperature was maintained at 50-60°C. The mixture was heated while stirring. at 50-60°C for 18 hours (all solids dissolved in the acid, giving a two-phase system). The whole was cooled to room temperature and poured into ice water (300 ml, where the product precipitated as sulfate. The mixture was transferred to a separatory funnel with a steam jacket , rinsing with hot water and heated to 80-85°C to re-dissolve the precipitate and separate the water layer into the toluene layer. The aqueous layer (650 ml) was separated and washed with 50 ml of hot toluene in the same apparatus. The aqueous layer, still warm, was alkalinized to pH = 10 by carefully adding a concentrated ammonium hydroxide solution. The white solid precipitate was aged with stirring for 1 hour and then collected from the even warmer mixture. The product was washed with hot water (3x100ml) and 50% aqueous methanol solution (2x100ml). After sucking off the steam until dry, the product was dried under reduced pressure at 70°C overnight to obtain pure (2-chloro-6-fluorobenzyl)-adenine, substituted in position 9. The yield was 47.8 g (98.8% with respect to obtained isomer substituted in position 9), melting point 247-248°C. Thin layer chromatography on silica gel in CHCl:MeOH (9:1) showed essentially a single spot, Rr = 0.48. No polymer or other contaminants were detected. Test for 10 118 655 using L.C. showed the content of the isomer substituted in position 9 = 100.68%; 3-substituted isomer was not detected, total yield = 95.9%. Patent claims 1. A method of producing 9-(2,6-dihalobenzyl)-adenine by alkylation of an alkali or alkaline earth metal adenine salt with a 2,5-dihalobenzyl halide, characterized in that the alkylation is carried out in a two-phase solid-state system. a liquid consisting of a solid phase, which is a salt of adenine with an alkali or alkaline earth metal, and a liquid phase, which is a solution of 2,6-dihalobenzyl halide and a phase transfer catalyst, which is a quaternary salt of the general formula 2, where R is a mixture of normal alkyl radicals with 8-12 C atoms, in an aprotic, optionally water-miscible organic solvent, the water-miscible solvent containing from 0 to about 5 moles of water per 1 mole of adenine salt, and then a mixture of isomers is obtained, in which at least at least 70% by weight is 9-(2,6-dihalobenzyl)-adenine, is transalkylated in the presence of concentrated sulfuric acid and a carbonium ion scavenger to obtain 9-(2,6-dihalobenzyl)-adenine, essentially free of the isomer , substituted in position 3. 2. The method according to claim 1, characterized in that in the case of producing 9-(2-chloro-6-fluorobenzyl)-adenine or 9-(2,6-dichlorobenzyl)-adenine, the alkylation is carried out in a two-phase solid-liquid system consisting of a solid phase, constituting an adenine salt with an alkaline earth metal and from the liquid phase, constituting a solution of 2-chloro-6-fluorobenzyl halide or 2,6-dichlorobenzyl halide, and a phase transfer catalyst, constituting a quaternary ammonium salt of the general formula 2, where R is a mixture of normal alkyl radicals with 8-12 C atoms, in an aprotic, water-miscible solvent such as acetone, acetonitrile or hexamethylphosphoramide, the water-miscible solvent containing 0-5 moles of water per 1 mole of adenine salt, or in an organic immiscible with water an organic solvent such as hexane, benzene, toluene, methylene chloride, chloroform or petroleum ether to obtain a mixture of isomers in which at least 70% by weight is 9-(2-chloro-6-fluorobenzyIo)-adenine or 9 -(2,6-dichlorobenzyladenine) is transalkylated in the presence of concentrated sulfuric acid and a carbonium ion scavenger to obtain 9-(2-chloro-6-fluorobenzyl)-adeninc or 9-(2,6-dichlorobenzyladenine). ) substantially free of isomers substituted in the 3-position. 3. The method of claim 1. 1 or 2, characterized in that alkyl sulfide, in which the alkyl radical contains 1-5 C atoms, aryl sulfide, in which the aryl radicals contain 6-18 C atoms, benzene, toluene, xylene, a mixture are used as the carbonium ion-catching substance. xylenes, methylene, alkoxybenzene, in which the alkyl radical contains 1-3 C atoms, thiophene, iodobenzene, naphthalene, or triphenylphosphines. 4. The method according to claim 2, characterized in that the transalkylation is carried out in the presence of an excess of concentrated sulfuric acid and in the presence of toluene or a mixture of xylenes, and the transalkylation is carried out at a temperature between room temperature and about 90°C, within 2-36 hours. 5. A method for producing 9-(2,6-dihalobenzyl)-adenine by alkylation of an alkali or alkaline earth metal adenine salt with a 2,5-dihalobenzyl halide, characterized in that the alkylation is carried out in a two-phase liquid-liquid system consisting of one liquid phase, which is an aqueous solution of an adenine salt of an alkali or alkaline earth metal, and the other liquid phase, which is a solution of 2,6-dihalobenzyl halide and a phase transfer catalyst, which is a quaternary ammonium salt of the general formula 2, in which R is higher given meaning in an aprotic, water-immiscible organic solvent, then obtaining a mixture of isomers in which at least 10% by weight constitutes 9'(2,6) transalkylation in the presence of concentrated sulfuric acid and a substance scavenging carbonium ions, obtaining 9- (2,6-dihalobenzyl)-adenine, substantially free of the isomer substituted in position 3. 6. The process according to claim 5, characterized in that in the case of the preparation of 9-(2-chloro-6-fluorobenzyl)-adenine or 9-(2,6-dichlorobenzyl)-adenine alkylation is carried out in a two-phase liquid-liquid system, consisting of one liquid phase, which is an aqueous solution of adenine salt with an alkaline earth metal, and the second liquid phase, which is a solution of 2-chloro halide -6-fluorobenzyl or 2,6-dichlorobenzyl halide and a phase transfer catalyst consisting of a quaternary ammonium salt of the general formula 2, in which R has the above meaning, in an aprotic, water-immiscible organic solvent such as benzene, hexane, toluene, methylene chloride, chloroform or petroleum ether, and then obtaining a mixture of isomers in which at least 70% by weight is 9-(2~118 655 11 chloro-6-fluorobenzyl)-adenine or 9-(2,6- dichlorobenzyladenine is transalkylated in the presence of concentrated sulfuric acid and a carbonium ion scavenger to obtain 9-(2-chloro-6-fluorobenzyl)-adeninc or 9-(2,6-dichlorobenzyladenine) essentially free of substituted isomers in position 3. 7. Method according to claim. 5 or 6, characterized in that alkyl sulfide, in which the alkyl radical contains 1-5 C atoms, aryl sulfide, in which the aryl radicals contain 6-18 C atoms, benzene, toluene, xylene, a mixture are used as the carbonium ion-catching substance. xylenes, methylene, alkoxybenzene, in which the alkyl radical contains 1-3 C atoms, thiophene, iodobenzene, naphthalene or triphenylphosphine. 8. The method according to claim 6, characterized in that the transalkylation is carried out in the presence of an excess of concentrated sulfuric acid and in the presence of an excess of toluene or a mixture of xylenes, and the transalkylation is carried out at a temperature between room temperature and about 90°C, for 2-36 hours. 9. A method for producing 9-(2,6-dihalobenzyl)-adenine by alkylation of adenine salts with an alkali or alkaline earth metal using a 2,6-dihalogenobenzyl halide, characterized in that the alkylation is carried out in a two-phase solid-liquid system or liquid-liquid, where the two-phase solid-liquid system consists of a solid phase, which is a salt of adenine with an alkali or alkaline earth metal, and a liquid phase, which is a solution of 2,6-dihalobenzyl halide and a phase transfer catalyst, which is a quaternary ammonium salt with general formula 2, in which means a mixture of normal alkyl radicals with 8-12 C atoms in an aprotic organic solvent, miscible or immiscible with water, where the water-miscible solvent contains from 0 to about 5 moles of water per 1 mole of salt adenine, and the two-phase liquid-liquid system consists of one liquid phase, which is an aqueous solution of an adenine salt with an alkali or alkaline earth metal, and the second liquid phase, which is a solution of 2,6-dihalobenzyl halide, and a phase transfer catalyst, which is a quaternary ammonium salt with general formula 2, in which R has the above-mentioned meaning, in an aprotic, water-immiscible organic solvent, and then the obtained mixture of isomers, in which at least 70% by weight is 9-(2,6-dihalobenzyl)-adenine, is subjected to are extracted with dilute mineral acid and then subjected to transalkylation in the presence of concentrated sulfuric acid and a carbonium ion scavenger to obtain 9-(2,6-dihalobenzyl)-adeninc, essentially free of the isomer substituted in the 3-position. 10. The method according to claim 9, characterized in that dilute nitric acid, hydrochloric acid or phosphoric acid is used as the mineral acid. 11. The method according to claim 9, characterized in that the substance capturing carbon ions is alkyl sulfide, in which the alkyl radical contains 1-3 C atoms, aryl sulfide, in which the aryl radicals contain 6-18 C atoms, benzene, toluene, xylene, a mixture of xylenes, mesitylene , alkoxybenzene, in which the alkyl radical contains 1-3 C atoms, thiophene, iodobenzene, naphthalene or triphenylphosphine. 12. The method according to claim 9, characterized in that in the case of preparing 9-(2-chloro-6-fluorobenzyl)-adenine, the mixture of isomers, 70% by weight of which is 9-(2-chloro-6-fluorobenzyladenine), is extracted with dilute nitric acid and transalkylation in the presence of concentrated sulfuric acid and a carbonium ion-catching substance such as toluene or a xylene mixture. 13. A method according to claim 12, characterized in that extraction is carried out with a solution of dilute nitric acid containing an approximately equivalent amount of acid in relation to the isomer, the base ¬ dissolved in position 3, in the temperature range from room to boiling point, with vigorous stirring, and transalkylation is carried out in the presence of an excess of concentrated sulfuric acid and in the presence of an excess of toluene or a mixture of xylenes, in the temperature range from room to 90°C, in 2- 36 hours.118655 NH2 3 X, 9 I carbonium ion polymer 0 (HSO^) FORMULA 7 SCHEME 1118655 © ca ci 0 ""(HSO^ ) FORMULA 7 CH.FORMULA 8 SCHEME 2 CH- Cl CH^ (\ /) F FORMULA 9 Y-cVp FORMULA A a CH2Y FORMULA 10 O O- S -??-CH.O MODEL 11 UPPRL Printing Studio. Print quantity 120 pcs. Price PLN 100 PL PL PL PL PL PL PL

Claims (13)

1. Patent claims 1. A method of producing 9-(2,6-dihalobenzyl)-adenine by alkylation of adenine salts with an alkali or alkaline earth metal using a 2,5-dihalobenzyl halide, characterized in that the alkylation is carried out in a two-phase system solid-liquid consisting of a solid phase, which is a salt of adenine with an alkali or alkaline earth metal, and a liquid phase, which is a solution of 2,6-dihalobenzyl halide and a phase transfer catalyst, which is a quaternary salt of the general formula 2, where R is a mixture of normal alkyl radicals with 8-12 C atoms in an aprotic, optionally water-miscible organic solvent, the water-miscible solvent containing from 0 to about 5 moles of water per 1 mole of adenine salt, and then the resulting mixture of isomers, in of which at least 70% by weight is 9-(2,6-dihalobenzyl)-adenine, is transalkylated in the presence of concentrated sulfuric acid and a carbonium ion scavenger to obtain 9-(2,6-dihalobenzyl)-adenine, essentially free from the isomer substituted in the 3-position. 2. The method according to claim 1, characterized in that in the case of producing 9-(2-chloro-6-fluorobenzyl)-adenine or 9-(2,6-dichlorobenzyl)-adenine, the alkylation is carried out in a two-phase solid-liquid system consisting of a solid phase, constituting an adenine salt with an alkaline earth metal and from the liquid phase, constituting a solution of 2-chloro-6-fluorobenzyl halide or 2,6-dichlorobenzyl halide, and a phase transfer catalyst, constituting a quaternary ammonium salt of the general formula 2, where R is a mixture of normal alkyl radicals with 8-12 C atoms, in an aprotic, water-miscible solvent such as acetone, acetonitrile or hexamethylphosphoramide, the water-miscible solvent containing 0-5 moles of water per 1 mole of adenine salt, or in an organic immiscible with water an organic solvent such as hexane, benzene, toluene, methylene chloride, chloroform or petroleum ether to obtain a mixture of isomers in which at least 70% by weight is 9-(2-chloro-6-fluorobenzyIo)-adenine or 9 -(2,6-dichlorobenzyladenine) is transalkylated in the presence of concentrated sulfuric acid and a carbonium ion scavenger to obtain 9-(2-chloro-6-fluorobenzyl)-adeninc or 9-(2,6-dichlorobenzyladenine). ) substantially free of isomers substituted in the 3-position. 3. The method according to claim 1 or 2, characterized in that alkyl sulfide, in which the alkyl radical contains 1-5 C atoms, aryl sulfide, in which the aryl radicals contain 6-18 C atoms, benzene, toluene, xylene, a mixture are used as the carbonium ion-catching substance. xylenes, methylene, alkoxybenzene, in which the alkyl radical contains 1-3 C atoms, thiophene, iodobenzene, naphthalene, or triphenylphosphines. 4. The method according to claim 2, characterized in that the transalkylation is carried out in the presence of an excess of concentrated sulfuric acid and in the presence of toluene or a mixture of xylenes, and the transalkylation is carried out at a temperature between room temperature and about 90°C, within 2-36 hours. 5. A method for producing 9-(2,6-dihalobenzyl)-adenine by alkylation of alkali metal or alkaline earth metal adenine salts with a 2,5-dihalobenzyl halide, characterized in that the alkylation is carried out in a two-phase liquid-liquid system consisting of consists of one liquid phase, which is an aqueous solution of an adenine salt with an alkali or alkaline earth metal, and a second liquid phase, which is a solution of 2,6-dihalobenzyl halide and a phase transfer catalyst, which is a quaternary ammonium salt of the general formula 2, where R has the above-mentioned meaning in an aprotic, water-immiscible organic solvent, then a mixture of isomers is obtained, in which at least 10% by weight constitutes 9" (2,6) transalkylation in the presence of concentrated sulfuric acid and a substance scavenging carbonium ions, obtaining 9-(2,6-dihalobenzyl)-adenine, substantially free from the 3-position isomer. 6. The method according to claim 5, characterized in that in the case of the preparation of 9-(2-chloro-6-fluorobenzyl)-adenine or 9-(2,6-dichlorobenzyl)-adenine, the alkylation is carried out in a two-phase liquid-liquid system, consisting of one liquid phase , constituting an aqueous solution of an adenine salt with an alkaline earth metal, and the second liquid phase, constituting a solution of 2-chloro-6-fluorobenzyl halide or 2,6-dichlorobenzyl halide, and a phase transfer catalyst, constituting a quaternary ammonium salt of the general formula 2, in wherein R is as defined above, in an aprotic, water-immiscible organic solvent such as benzene, hexane, toluene, methylene chloride, chloroform or petroleum ether, wherein the resulting mixture of isomers is at least 70% by weight of 9- (2~118,655 11 chloro-6-fluorobenzyl)-adenine or 9-(2,6-dichlorobenzyladenine) is transalkylated in the presence of concentrated sulfuric acid and a carbonium ion-catching substance to obtain 9-(2-chloro- 6-fluorobenzyl)-adeninc or 9-(2,6-dichlorobenzyladenine) essentially free of 3-substituted isomers. 7. The method according to claim 5 or 6, characterized in that alkyl sulfide, in which the alkyl radical contains 1-5 C atoms, aryl sulfide, in which the aryl radicals contain 6-18 C atoms, benzene, toluene, xylene, a mixture are used as the carbonium ion-catching substance. xylenes, methylene, alkoxybenzene, in which the alkyl radical contains 1-3 C atoms, thiophene, iodobenzene, naphthalene or triphenylphosphine. 8. The method according to claim 6, characterized in that the transalkylation is carried out in the presence of an excess of concentrated sulfuric acid and in the presence of an excess of toluene or a mixture of xylenes, and the transalkylation is carried out at a temperature between room temperature and about 90°C, for 2-36 hours. 9. A method for producing 9-(2,6-dihalobenzyl)-adenine by alkylation of adenine salts with an alkali or alkaline earth metal using a 2,6-dihalogenobenzyl halide, characterized in that the alkylation is carried out in a two-phase solid-liquid system or liquid-liquid, where the two-phase solid-liquid system consists of a solid phase, which is a salt of adenine with an alkali or alkaline earth metal, and a liquid phase, which is a solution of 2,6-dihalobenzyl halide and a phase transfer catalyst, which is a quaternary ammonium salt with general formula 2, in which means a mixture of normal alkyl radicals with 8-12 C atoms in an aprotic organic solvent, miscible or immiscible with water, where the water-miscible solvent contains from 0 to about 5 moles of water per 1 mole of salt adenine, and the two-phase liquid-liquid system consists of one liquid phase, which is an aqueous solution of an adenine salt with an alkali or alkaline earth metal, and the second liquid phase, which is a solution of 2,6-dihalobenzyl halide, and a phase transfer catalyst, which is a quaternary ammonium salt with general formula 2, in which R has the above-mentioned meaning, in an aprotic, water-immiscible organic solvent, and then the obtained mixture of isomers, in which at least 70% by weight is 9-(2,6-dihalobenzyl)-adenine, is subjected to are extracted with dilute mineral acid and then subjected to transalkylation in the presence of concentrated sulfuric acid and a carbonium ion scavenger to obtain 9-(2,6-dihalobenzyl)-adeninc, essentially free of the isomer substituted in the 3-position. 10. The method according to claim 9, characterized in that dilute nitric acid, hydrochloric acid or phosphoric acid is used as the mineral acid. 11. The method according to claim 9, characterized in that the substance capturing carbon ions is alkyl sulfide, in which the alkyl radical contains 1-3 C atoms, aryl sulfide, in which the aryl radicals contain 6-18 C atoms, benzene, toluene, xylene, a mixture of xylenes, mesitylene , alkoxybenzene, in which the alkyl radical contains 1-3 C atoms, thiophene, iodobenzene, naphthalene or triphenylphosphine. 12. The method according to claim 9, characterized in that in the case of preparing 9-(2-chloro-6-fluorobenzyl)-adenine, the mixture of isomers, 70% by weight of which is 9-(2-chloro-6-fluorobenzyladenine), is extracted with dilute nitric acid and transalkylation in the presence of concentrated sulfuric acid and a carbonium ion scavenger such as toluene or a mixture of xylenes. 13. The method according to claim 12, characterized in that extraction is carried out with a solution of dilute nitric acid containing an approximately equivalent amount of the acid in relation to the isomer substituted in position 3, at temperatures ranging from room temperature to boiling point, with vigorous stirring, and transalkylation is carried out in the presence of excess concentrated sulfuric acid and in the presence of excess toluene or a mixture of xylenes, at temperatures ranging from room to 90°C, for 2-36 hours.118655 NH2 3 X, 9 I X* FORMULA 1 © 0 n-R)3NCH3 CL FORMULA 2 NHL -i 0 N ~ CH. FORMULA 8 SCHEME 2 CH- Cl CH^ (\ /) F FORMULA 9 Y-cVp FORMULA A a CH2Y FORMULA 10 O O- S -??-CH. O WZÓR 11 UPPRL Printing Studio. Circulation: 120 pieces. Price PLN 100 PL PL PL PL PL PL PL