CH636614A5 - Process for preparing 9-(2,6-dihalobenzyl)adenines - Google Patents

Description

The invention relates to a process for the alkylation of an alkali or alkaline earth metal salt of adenine with a 2,6-dihalobenzyl halide and the production of a mixture of isomers of (2,6-dihalobenzyl) adynes which are at least 70% by weight. consist of 9- (2,6-dihalobenzyl) adenines.

Furthermore, the invention relates to new methods for the production and purification of 9- (2,6-dihalogenbenzyl) adenines. The compounds obtained are pure 9- (2,6-dihalobenzyl) adenines, which are practically free of the mutagenic 3-isomer. Such adenines can be used according to US Pat. No. 3,846,426 for the therapy and prophylaxis of coccidiosis.

Coccidiosis is a common poultry disease that is caused by infections with protozoa of the genus Eimeria and leads to serious irregularities in the intestine and appendix. Some of the most important species of the protozoan genus mentioned are E. tenella, E. acervulina, E. necatrix, E. brunetti and E. maxima. Coccidiosis generally spreads by the fact that the poultry absorbs the infectious organism from excrement on soiled barn or soil or through contaminated food or drinking water. The disease is manifested by bleeding, blood accumulation in the appendix, the appearance of blood in the excrement, weakness and indigestion. The disease often causes the animals to die, and the animals surviving severe infections have a considerably reduced market value. Therefore, coccidiosis is a very serious poultry disease from an economic point of view, which is why intensive research has already been carried out to find new or improved means of containing and treating coccidial infections in poultry.

It has been reported that 9- (2,6-dihalobenzyl) adenines, useful for inhibiting and treating coccidial infections, can be prepared by base-catalyzed, non-selective alkylations of an adenine salt in aqueous or aqueous / proton-active organic solvents. The reactions concerned are homogeneous and rapid, but have the defect that they give mixtures of the 3-isomer and 9-isomer with a high proportion of the 3-isomer.

The 3-isomer gave a weakly positive result in the Ames test and is probably mutagenic. The fact that the product mixture contains the 3-isomer as a by-product in addition to the 9- (2,6-dihalobenzyl) adenine means that the mixture is not suitable as a coccidiostat because of the residues remaining in the poultry meat. Usable products should be practically free of 3-isomers, i.e. they should contain this in a proportion below the measurable value of 100 ppm.

Base-catalyzed alkylations of adenine, which are carried out in the presence of aprotic solvents (such as dimethylformamide or dimethyl sulfoxide), give a higher proportion of the 9-isomer compared to the 3-isomer, but have the disadvantage that the solvents mentioned are expensive. Product isolation is also difficult with this method of working. The reaction mixture must be in

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Water is quenched and the filtered product is washed out repeatedly to separate the solvents. This reduces the yield.

The product obtained by the alkylation can only be partially cleaned by conventional methods, such as washing with ethanol or water and recrystallization from solvents (such as acetic acid, aqueous acetic acid, dimethylformamide or dimethyl sulfoxide). Some cleaning can also be achieved by digesting the product with dilute nitric acid or tetrafluoroboric acid (HBF4).

The aforementioned conventional cleaning methods, such as washing or recrystallization of the crude 9- (2,6-dihalobenzyl) adenine, yields a product which contains up to about 4% of 3-isomer. Extraction of crude 9- (2-chloro-6-fluorobenzyl) adenine, which contains 20% 3-isomer, with dilute aqueous nitric acid gives e.g. a 9- (2-chloro-6-fluorobenzyl) adenine with a 3-isomer content of 3 to 4%; the yield of 9- (2-chloro-6-fluorobenzi) adenine thus makes up 96 to 97%. If this process is repeated on the enriched 9- (2-chloro-6-fluoro-benzyl) adenine sample, the content of the s 3 isomer cannot be below about 0.3 to 0.5% (3000 to 5000 ppm). The reason for this is the pronounced tendency towards the formation of solid solutions or mixed crystals of the 9-isomer and 3-isomer. The same problem occurs when trying to separate the 3-isomer by two recrystallizations from acetic acid. The 3-isomer content remains in the range from 0.05 to 0.1% (500 to 1000 ppm), although the liquid phase is not saturated with 3-isomer.

E.C. Taylor et al., J. Org. Chem. 36 (1971), 3211, 15 reported that 9-substituted adenines (2) by reducing cleavage and subsequent cyclization of 7-amidofura-zano [3,4-d] pyrimidines (1) can be prepared according to the following reaction scheme:

(1)

Although a large number of adenine derivatives were produced, the authors were unable to use these pyrimidine derivatives because of the lack of hydrolytic stability of 5-unsubstituted 7-amidofurazano [3,4-d] pyrimidines (1, R = H, Y = Q) To convert 2-unsubstituted adenines (2, R = H).

According to a known alternative method, this conversion was successfully carried out on compounds (1) in which R is a hydrogen atom, Y is a sulfur atom and R 'is a 2,6-dihalobenzyl radical; this gave 9- (2,6-dihalogenbenZod adenines (2) which are not contaminated by positional isomers and in which R represents a hydrogen atom and R 'represents a 2,6-dihalobenzyl radical.

The invention relates to the production of very valuable coccidiostats 9- (2,6-dihalobenzyl) -ade-nine, which are practically free of the 3-isomer, the presence of which would render the mixture unusable due to the potential carcinogenic effect.

It has been found that the 9- (2,6-dihalobenzyl) adenines are obtained in a form which is practically free from the 3-isomer by alkylating a salt of adenine in a two-phase system and in the presence of an onium salt as a phase transfer catalyst and selectively dealkylates the 3-isomer obtained as a by-product with sulfuric acid in the presence of a carbenium ion acceptor (carbenium ion trap).

Optionally, the 9- (2,6-dihalobenzyl) adenines not contaminated by positional isomers are prepared from 4,5,6-triami-nopyrimidine via 7- (N-formyl-N-dihalobenzylamino) - [1,2,5 ] -thiadiazolo [3,4-d] pyrimidines.

The process according to the invention for the alkylation of a 55 alkali metal or alkaline earth metal salt of adenine with a 2,6-dihalobenzyl halide and the production of a mixture of isomers of (2,6-dihalobenzyl) adenines which consist of at least 70% by weight from 9- (2nd , 6-Dihalogenbenzyl) -ad-nines, is characterized in that one carries out the 60 alkylation in a solid / liquid or liquid / liquid two-phase system, whereby a) the solid / liquid two-phase system contains an alkali or alkaline earth metal salt of adenine solid phase «5 and a liquid phase, which comprises a solution of 2,6-dihalobenzyl halide and an onium salt as a phase transfer catalyst with the following general formulas

(R) jNRi Z ° or (Ri) 3PR Z °

wherein R is an alkyl radical with 4 to 18 carbon atoms, Ri is an alkyl radical with 1 to 8 carbon atoms and Z9 is an anion from the group consisting of chlorine, bromine and iodine, in an aprotic, water-miscible or water-immiscible organic solvent, wherein the water-miscible solvent contains 0 to 5 moles of water per mole of adenine salt, and b) the liquid / liquid two-phase system comprises a liquid phase which contains an aqueous solution of an alkali or alkaline earth metal salt of adenine and a second liquid phase which a solution of the 2,6-dihalobenzyl halide and an onium salt as a phase transfer catalyst with one of the formulas below

® 0 0 0

(R) îNRi TJ or (Ri) 3PR To where R, Ri and Z'1 each have the meaning given above, in an aprotic, water-immiscible organic solvent.

According to the invention, 9- (2,6-dihalobenzyl) adenines which are practically free from 3-isomers are obtained by first, as described above, firstly a mixture of isomers of 9- (2,6-dihalobenzyl) adenines produces and then subjected to a transalkylation in the presence of concentrated sulfuric acid and a carbenium ion acceptor.

Another process according to the invention for the preparation of 9- (2,6-dihalobenzyl) adenines which are practically free of 3-isomers is characterized in that, as described above, a mixture of isomers of 9- (2, 6-Dihalogenbenzyl) -adenines and then a) subjecting them to extraction with dilute mineral acid and then b) carrying out a transalkylation in the presence of concentrated sulfuric acid and a carbenium ion acceptor.

Preferred embodiments of the method according to the invention are explained in more detail below:

A) Alkylation of adenine

(2,6-dihalobenzyl) adenines are obtained by alkylating an adenine salt with a 2,6-dihalobenzyl halide in a solid / liquid two-phase system, the solid phase being the adenine salt and the liquid phase being a solution of the alkylating agent and an onium salt in an organic solvent or in a liquid / liquid two-phase system, one liquid phase comprising an aqueous solution of the adenine salt and the second liquid phase containing the alkylating agent and the onium salt. The onium salt, such as an ammonium or phosphonium salt, serves as a catalyst which transfers the adenine salt from the solid phase to the liquid organic phase or from the aqueous liquid phase to the organic liquid phase where the alkylation of the adenine takes place. This process is commonly referred to as "phase transfer catalysis" and the onium salt as "phase transfer catalyst".

The compounds produced have the following general formula:

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KH

1

2nd

CH

in which Xi and X2 each independently represent a halogen atom, i.e. is a fluorine, chlorine, bromine or iodine atom. Specific examples of the compounds of this general formula are 9- (2,6-dichlorobenzyl) adenine and 9- (2-chloro-6-fluorobenzyl) adenine. The 9- (2,6-dihalobenzyl) aadenines which can be prepared according to the invention must be practically free of positional isomers. The invention particularly relates to 9- (2,6-dihalobenzyl) adenines with a 3-isomer content of less than 100 ppm. The invention further relates specifically to the compound 9- (2-chloro-6-fluoro-benzyl) adenine with a 3-isomer content of less than 100 ppm.

The phase transfer catalyst consists of onium salts which have alkyl radicals bonded to nitrogen or phosphorus atoms. Any alkylammonium or phosphonium salts can be used in the process according to the invention, provided that the alkyl radicals are large enough to make the adenine salt soluble in the respective organic phase, but not so large that it forms an emulsion. Suitable alkyl radicals have 1 to 18 carbon atoms.

Suitable solvents for this process according to the invention are aprotic substances which are inert (i.e. non-reactive) to the constituents of the reaction mixture under the reaction conditions. Aprotic solvents are preferred because when they are used, a high quantitative ratio of the 9-isomer to the 3-isomer is achieved. If the reaction is carried out in a solid / liquid two-phase system, the aprotic solvent can either be water-miscible or immiscible. It is not necessary to keep the water-miscible solvents in an anhydrous state; Excessive amounts of water, however, result in a higher proportion of 3-isomer. When using a liquid / liquid two-phase system, only those aprotic organic solvents that are immiscible with water are suitable. The proportion of water in the aqueous phase is not decisive.

The alkali or alkaline earth metal salt of adenine has the general formula:

in which M® is an alkali or alkaline earth metal cation and b

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and c represent such integers that the negative charge of b-mole of the anion is neutralized by c-mole of the cation M®. The salt is preferably suspended in an aprotic organic solvent or dissolved in an aqueous solution. The solution is usually mixed with a solution which is the alkylating agent of the general formula

* 2

in which Xi and X2 each have the meaning given above, and Y is a removable radical in the form of a halogen atom, a dimethylsulfonium halide radical or a tosyl group, and contains an onium salt as phase transfer catalyst in an aprotic solvent. Halogen atoms are preferred as removable substituents. The substituted toluene is preferably used in an equimolar proportion or a slight excess in relation to the adenine. The heterogeneous reaction mixture obtained is stirred rapidly until the end of the reaction.

In the process according to the invention, adenine is usually suspended in a suitable aprotic solvent and an equivalent amount of a base is added to the suspension. Bases with a pKb value of more than 10.5 are preferred, so that the adenine is converted almost completely into its anion. Examples of suitable bases are carbonates, such as alkali metal carbonates (e.g. sodium or potassium carbonate), hydroxides, such as alkali metal hydroxides (e.g. sodium, potassium or lithium hydroxide), tetraalkylammonium hydroxides and alcoholates, such as potassium or sodium ethylate. In general, all those bases are suitable which have a basicity sufficient for the formation of the adenine anion in the solvent system used.

The adenine salt can be prepared in situ by adding an equivalent amount of base. The adenine salt is expediently prepared by dissolving the adenine in an aqueous solution containing an equivalent proportion of a strong base, evaporating the water and using the residue containing the adenine salt hydrate for the alkylation.

According to a preferred embodiment of the process according to the invention, an alkaline earth metal salt of adenine is alkylated with a 2-chloro-6-fluorobenzyl halide or 2,6-dichlorobenzyl halide, a mixture of isomers of (2-chloro-6-fluorobenzyl) adenine or (2 , 6-dichlorobenzyl) adenine, which consists of at least 70% by weight of 9- (2-chloro-6-fluorobenzyl) adenine or 9- (2,6-di chlorobenzyl) adenine. The alkylation is carried out in a solid / liquid or liquid / liquid two-phase system. The solid / liquid two-phase system comprises a solid phase of an alkaline earth metal salt of adenine and a liquid phase in the form of a solution of the 2-chloro-6-fluorobenzyl halide or 2,6-dichlorobenzyl halide and a quaternary ammonium salt as a phase transfer catalyst with the general formula

(R> NRi Z

in which R is an alkyl radical with 4 to 18 carbon atoms, Ri is an alkyl radical with 1 to 8 carbon atoms and Z: 'is an anion from the group consisting of chlorine, bromine or iodine, in an aprotic, water-miscible solvent from the group consisting of Acetone, aceto-nitrile and hexamethylphosphoramide, where the water-miscible solvent can contain 0 to 5 moles of water per mole of adenine salt and the desired proportion of 9-isomer is still achieved. The reaction can also be carried out in a water-immiscible organic solvent from the group consisting of hexane, benzene, toluene, methylene dichloride, chloroform and petroleum ether.

If the reaction is carried out in a liquid / liquid two-phase system, the one liquid phase is usually an aqueous solution of an alkaline earth metal salt of adenine and the second liquid phase is a solution of a 2-chloro-6-fluorobenzyl halide or 2,6-dichlorobenzyl halide. and a quaternary ammonium salt as a phase transfer catalyst with the general formula

® 0 (R) jNRÌ Z ^

in which R, Ri and Z 'each have the meaning given above, in a water-immiscible organic solvent from the group consisting of hexane, benzene, toluene, methylene dichloride, chloroform and petroleum ether.

According to a further preferred embodiment, sodium adeninate is alkylated with 2-chloro-6-fluorobenzyl chloride, a mixture of isomers of (2-chloro-6-fluoro-benzyl) adenine being formed which consists of at least 70% by weight of 9- ( 2-chloro-6-fluorobenzyl) adenine exists. In this method, the alkylation is usually carried out in a solid / liquid or liquid / liquid two-phase system, the solid phase of the solid / liquid reaction system containing sodium adenine and the liquid phase an acetone solution of 2-chloro-6-fluorobenzyl chloride and a quaternary ammonium salt as a phase transfer catalyst having the general formula

® 0

(n-R) 3NCH3 C1U

in which R is a mixture of normal alkanes having 8 to 12 carbon atoms. This mixture of tetraalkylammonium salts, in which R mainly represents a caprylyl group (Cs), is marketed under the name "Aliquat336" (manufacturer: General Mills, Inc., Chemical Division, Minneapolis, Minnesota, V.St.A.) . The reaction mixture need not be anhydrous; it can contain from 0 to about 5 moles of water per mole of sodium adeninate, while still achieving the desired level of 9 isomer.

If the reaction is carried out in a liquid / liquid two-phase system, one liquid phase is an aqueous solution of an alkaline earth metal salt of adenine, while the second liquid phase is a hexane solution of 2-chloro-6-fluorobenzyl chloride and a quaternary ammonium salt as phase transfer Catalyst having the general formula below

® ©

(R) 3NCH.i in which R is an alkyl radical having 8 to 12 carbon atoms and Z0 is an anion from the group consisting of chlorine, bromine and iodine.

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The relative proportions of the adenine and alkylating agent can be varied within a relatively wide range. The reaction components can be used in stoichiometric amounts, i.e. equimolar proportions, or an excess of alkylating agent, e.g. use an excess of 2 to 10 mol% or more. An alkylating agent excess of 2 mol% is preferred. The phase transfer catalyst is also preferably used in a proportion of 1 to 10 mol%, based on the adenine. The proportion of solvent used can also be varied within a wide range. The solvent is usually used in an amount sufficient that the heterogeneous reaction mixture can be stirred in order to achieve a portable reaction rate and to facilitate the isolation of the reaction product. A 5 to 15 percent by weight solution of the adenine salt in the solvent is usually suitable for carrying out the reaction.

The components of the reaction mixture can be combined in the reaction medium in any desired, expedient manner and in any order. A suitable method for combining the components of the reaction mixture is to incorporate the adenine in a solution of the base in the reaction medium, then add the substituted toluene (either as such or in a suitable solvent) and finally add the phase transfer catalyst. Other methods of combining the reaction components and the catalyst will be readily apparent to the person skilled in the art; however, the combination is preferably carried out in such a way that the anion of the adenine does not form later than when the substituted toluene is added (in particular before this time). The phase transfer catalyst is particularly incorporated last.

The response time and temperature are not critical. However, the reaction time decreases as the reaction temperature increases. The reaction is most conveniently carried out in the temperature range from room temperature to 150 ° C. However, the reaction is preferably carried out at the reflux temperature of the particular solvent. When using hexamethylphosphoramide as a solvent, temperatures above 155 ° C should be avoided, since the selectivity of the alkylation decreases at excessive temperatures. The reaction can take place from 1 to 24 hours; however, the alkylation is usually complete after 4 to 6 hours.

s When the reaction has ended, the reaction mixture is generally cooled to about room temperature to precipitate the solid product. Then the product can be isolated in the usual way, e.g. by filtration, and purifies it according to the preferred method described below.

B) Purification of 9- (2,6-dihalobenzyl) adenines

The following preferred statements regarding the purification of 9- (2-chloro-6-fluorobenzyl) adenine also apply to 9- (2,6-dihalobenzyl) adenines.

The 9-isomer and the 3-isomer, which represent the starting point for the cleaning method according to the invention, differ chemically in two ways:

20 1) the 3-isomer (pKa 5.6) has 40 times the basicity of 9- (2-chloro-6-fluorobenzyl) adenine (pKa 4.0); and

2) The 3-isomer has a lower chemical resistance than 9- (2-chloro-6-fluoro-benzyl) adenine in strongly acidic solutions.

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The pKa difference is now used to partially reduce the proportion of 3-isomer in the crude reaction mixture by simply extracting the solid crude product with a dilute mineral acid solution. This extraction of the crude 9- (2-chloro-6-fluorobenzyl) adenine, which contains 20% of the 3-isomer, with dilute aqueous nitric acid gives a 9- (2-chloro-6-fluorobenzyl) adenine a 3-isomer content of 3 to 4% and thus a yield of 9- (2-chloro-6-fluorobenzyl) adenine 35 from 96 to 97%.

A practically complete separation of the 3-isomer (down to <100 ppm) was achieved by selective chemical degradation of the 3-isomer using its lower thermodynamic stability. The 3-isomer can be completely and selectively degraded to adenine and a benzyl polymer by treatment with 96% sulfuric acid according to the following reaction scheme, without the 9-isomer being attacked:

H2SO4

3-isomer

Cabenium ion 1

Polymer

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Under the same conditions, 9- (2-chloro-6-fluorobenzyl) adenine is non-reactive. Treatment of 3 to 4% of 9- (2-chloro-6-fluorobenzyl) adenine containing 3-isomer with 96% sulfuric acid thus gives a 96% yield of 9- (2-chloro-6-fluorobenzyl) ) -adenine with a 3-isomer content of <100 ppm. The complete separation of the polymer from the 9- (2-chloro-6-fluorobenzyl) adenine has proven to be very difficult. This problem is solved by carrying out the sulfuric acid treatment in the presence of a suitable carbenium ion acceptor which reacts with the carbneium ion and prevents the formation of the polymer.

CH,

© "

Cl

+

Suitable carbenium ion acceptors are the known substances of this type, such as dialkyl sulfides each having 1 to 5 carbon atoms in the alkyl radical, diaryl sulfides each having 6 to 18 carbon atoms in the aryl radical, benzene, toluene, xylene, mixed xylenes, mesitylene, alkoxybenzenes with 1 to 3 carbon atoms in the alkyl radical, such as anisole, thiophene, iodobenzene, naphthalene or triphenylphosphine. Of the various substances tested, toluene and mixed xylenes have proven to be the most suitable for the present purpose; Toluene reacts rapidly with the intermediate carbenium ion according to the following equation to the trans-alkylation product (transalkylation product):

CH,

(HSCV)

Toluene which prevents polymerization. In the case of a transalkylation with sulfuric acid in the presence of toluene, 9- (2-chloro-6-fluorobenzyl) adenine containing 3-isomers of 3 to 4% is obtained in high-purity 30 9- (2-chloro-6-fluorobenzyl) - adenine, which contains no polymer and <100 ppm of 3-isomer, in 97-98% yield.

Crude 9- (2-chloro-6-fluorobenzyl) adenine, which contains about 20% 3-isomer, can be used before the treatment with sulfuric acid to partially remove the unwanted 3-isomer and in particular to remove traces of 7- Isomers are extracted with a dilute mineral acid solution.

It is not important which mineral acid 40 is used unless it reacts with the 9 isomer. Specific examples of suitable mineral acids are hydrochloric, phosphoric and nitric acids. Nitric acid is preferred. In order to avoid excessive losses of 9-isomer during extraction, the 45 fraction of the 3-isomer is expediently determined by liquid chromatography (LC analysis) and an equimolar amount (or a slight excess) of acid (based on the 3-isomer) is used ) too. The liquid chromatographic analysis is explained in more detail below. The extraction can be carried out at temperatures from room temperature to about 100 ° C. It is preferable to work at the reflux temperature and with vigorous stirring. Extraction with vigorous stirring for about 1 to about 5 hours is sufficient. The optimal extraction time is about 2 hours. The hot ss mixture is then filtered off and washed out with hot water, with a base to remove excess acid and finally again with hot water. The partially purified, 9-isomer enriched material obtained is then treated with sulfuric acid in the presence of a carbenium acceptor 60 to give pure 9- (2-chloro-6-fluorobenzyl) adenine.

In the preparation of the desired compounds, crude 9- (2-chloro-6-fluorobenzyl) adenine is preferably treated with concentrated (96%) sulfuric acid for the selective dealkylation of the 3-isomer and regeneration 6s of the adenine. For dealkylation, an at least two-fold molar excess of sulfuric acid (based on o-, m- and p-transalkylation product,

the 3-isomer) is required. The concentration of the 3-isomer is determined by liquid chromatography (LC analysis), which is explained in more detail below. The excess sulfuric acid used is not decisive. For example, an equal proportion by weight of crude 9- (2-chloro-6-fluorobenzyl) adenine per part by volume of sulfuric acid or up to 10 times the volume of sulfuric acid per part by weight of crude 9- (2-chloro-6-fluorobenzyl) adenine. A preferred ratio is 1 g of crude 9- (2-chloro-6-fluoro-benzyl) adenine for every 2 ml of sulfuric acid.

The proportion of the carbenium ion acceptor is not critical, provided that there is an at least equimolar proportion with respect to the 3-isomer. However, a high excess of the acceptor is preferably used, since this acts both as a reagent and as a solvent.

The crude 9- (2-chloro-6-fluorobenzyl) adenine is preferably treated with concentrated sulfuric acid at temperatures in the range from room temperature to about 90 ° C. The process is preferably carried out at room temperature, the batch being last heated to about 80 ° C. for about 10 minutes in order to ensure that the reaction proceeds to completion. The response time is not critical if at least two hours have passed. After this period, the implementation is practically complete and can be canceled if necessary. However, even if the reaction is allowed to continue for 36 hours, there are no harmful effects. A convenient, optimal response time is about 5 hours for the laboratory scale and about 24 hours for the industrial scale.

The aqueous layer is usually separated from the reaction mixture. Depending on the solvent and acid content present, heating to temperatures of 50 to 100 ° C may be necessary to facilitate the separation of the aqueous phase. The aqueous phase is then generally made alkaline by adding a base. Any base can be used as long as it forms a water-soluble sulfate. Specific examples of suitable bases are sodium hydroxide, potassium hydroxide, ammonium hydroxide, sodium carbonate and potassium carbonate. Sodium hydroxide is preferred as the base.

9

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After the aqueous phase has been made strongly alkaline, the pure product precipitates and can be filtered off, it is preferably washed out with water or an aqueous alcohol and vacuum-dried.

Another advantage of this method according to the invention is that the expensive adenine can be recovered from the alkaline filtrate by neutralizing and filtering off the precipitated compound.

Liquid chromatography (LC analysis)

I) Determination of the percentage by weight of 9-isomer, 3-isomer and 7-isomer when the 3-isomer is present in a proportion of more than 1%

The percentages by weight of the product in 9-isomer, 3-isomer and 7-isomer are determined by high pressure liquid chromatography (L.C.) and UV spectroscopy. The proportion by weight of the 9-isomer and 7-isomer is determined by high-pressure liquid chromatography using a 15 cm column (DuPont, Zorbax-SIL) charged with completely porous 5 pm-SiCh, with CHCb / methanol (95 : 5) eluted and the absorbance of the components each measured at 254 nm, 9-benzyladenine serving as the internal standard (accuracy ± 0.3%). The weight percentage of the 3-isomer is determined by UV analysis. The sample is analyzed in 0.1 N methanolic base at 310 nm: the 3-isomer has a value of 2300 at this wavelength, while the 9-isomer does not absorb (accuracy ± 0.1%).

II) Determination of the percentages by weight of traces of the 3-isomer after treatment with sulfuric acid

The percentage by weight of the product in 3-isomer is determined by high pressure liquid chromatography (LC), using a 30 cm column (Waters Associates Micro Bondapak C-18 No. 27324) loaded with a microporous, octade-cylsilane-bound phase (10 pm). used as a mobile phase at 35 ° C with a methanolic aqueous phosphate. The mobile phase is prepared from 30 parts of methanol and 70 parts of 0.01 m Na2HPÛ4 while adjusting the pH to 7 with HjPO-i. The UV analysis is carried out at 280 nm. The measurement limit is 100 ppm.

The following examples are intended to explain the invention in greater detail, but without restricting it.

example 1

Alkylation of adenine with a, 2-dichloro-6-fluorotoluene in the presence of Aliquat 336 in hexane / water (heterogeneous liquid / liquid reaction mixture)

A one-liter, three-necked round-bottomed flask equipped with a thermometer, cooler, nitrogen inlet tube and mechanical overhead stirrer is added successively with 40 ml of water, 8 g (0.2 mol) of sodium hydroxide and after dissolving the sodium hydroxide with 27.6 g (0.2 mol) of adenine (98% purity). After the adenine has dissolved, a solution of 39.95 g (0.2 mol plus 2%) <x, 2-dichloro-6-fluorotoluene (degree of purity 91.5% based on the gas chromatographic analysis) and 5.04 g ( 0.01 mol; 5 mol%) of Aliquat 336 in 300 ml of hexane (there is no reaction if the phase transfer catalyst is omitted). The mixture is stirred under reflux for 6 hours and then cooled to room temperature. The solids are then filtered off, washed twice with 100 ml of water each time and vacuum dried at 100 ° C. overnight. This gives 52.32 g (94%) of 2-chloro-6-fluorobenzylated adenines; U.V. (0.1 HCl) Xmnx = 264, E% = 535. Weight percent (L.C.% by weight) of 9-isomer determined by liquid chromatography = 69.9; weight percent (U.V. wt.%) of 3-isomer = 25 determined by UV analysis.

Purification of the crude 2-chloro-6-fluorobenzylated adenine

30 g of the aforementioned crude product are introduced into 60 ml of hot (65 ° C) acetic acid. The batch is heated to 10 ° C., at which temperature all substances go into solution. The hot acetic acid solution is then filtered through a preheated glass frit funnel and the filtrate is added dropwise with good stirring in 240 ml of water at 95 ° C. for 10 minutes (the acetate salt of the product, a cotton-like material, is obtained by adding water to the acetic acid solution). When the solution is cooled to 37 ° C, the majority of the product precipitates. The product is filtered off, washed once with 25 ml of acetic acid / water (1: 4) and twice with 25 ml of water each time and vacuum dried at 95 ° C. for 6 hours. 20.83 g (69.5%) of 9- (2-chloro-6-fluorobenzyl) adenine are obtained; U.V. Wt% 3 isomer = 3.0; L.C. % By weight 9-isomer = 89.

Example 2

Alkylation of adenine with a, 2-dichloro-6-fluorotoluene in the presence of Aliquat 336 in acetone (solid / liquid reaction mixture)

A 250 ml round-bottomed flask is charged in succession with 100 ml of acetone, 6.95 g (50 mmol) of adenine (degree of purity 97%) and 4 g of 50% sodium hydroxide solution (50 mmol) and the suspension obtained is boiled under reflux for 90 minutes. A solution of 9.8 g (50 mmol) of a, 2-dichloro-6-fluorotoluene (degree of purity 91.4%) and 1.25 g of Aliquat 336 (2.5 mmol, 5 mol%) are then added to the suspension. ) in 10 ml acetone. The batch is then boiled under rapid reflux with stirring for 6 hours (in the absence of the phase transfer catalyst, the reaction proceeds about 5 times slower). The reaction mixture is cooled to room temperature. The solids are then filtered off, washed twice with 15 ml of acetone each time and then digested for 15 minutes with 50 ml of 0.1N sodium hydroxide solution, which removes any unreacted adenine and the NaCl formed during the alkylation. The solids are then filtered off, washed twice with 20 ml of water each time and vacuum dried at 100 ° C. for 4 hours. 13.12 g (94.4%) are obtained.

2-chloro-6-fluorobenzylated adenines; U.V. (0.1 in HCl) A. max = 262, E% = 534; L.C. Wt% 9 isomer = 77.4; U.V. % By weight

3-isomer = 20.4.

cleaning

10 g of the aforementioned product are introduced into 18 ml of hot (about 60 ° C) glacial acetic acid. The mixture is heated to 110.degree. C. (the solution is in the range from 60 to 90.degree. C.), filtered and the filtrate is introduced into 80 ml of hot (95.degree. C.) water with rapid stirring within 5 min Acetic acid is used for rinsing). When the temperature has dropped to 37 ° C, the suspended solids are filtered off and washed out once with 10 ml of aqueous acetic acid (H2O / HOAC = 4: 1) and twice with 15 ml of water each. After drying in a vacuum oven (6 hours at 100 ° C.), 7.64 g (76.4%) of 9- (2-chloro-6-fluorobenzyl) adenine are obtained; U.V. (0, In HCl), A.max = 260, E% 570; DSC = 0.5 mol% impurity (5000 ppm), mp (uncorr.) = 244.5 to 246 ° C; thin layer chromatography (TLC) on silica gel in CHCb / methanol (10: 1) shows a slight contamination at Rf = 0.57 and a main spot at Rf = 0.86.

Example 3

Alkylation of sodium adeninate hydrate with cc, 2-dichloro-6-fluorotoluene in the presence of Aliquat 336 in hexamethyl phosphoramide (solid / liquid reaction mixture)

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Step 1:

Sodium adenine hydrate is conveniently prepared by dissolving 1 mole of adenine in 400 ml of 2.5 m sodium hydroxide solution (1 mole), concentrating the solution on a rotary evaporator in vacuo at the temperature of a steam bath to supersaturation and then pouring it into a glass bowl and that crystallized sodium adeninate then vacuum dried at 75 ° C. The dried material is then ground to a free flowing powder; KF = 8.3%; Equivalent weight (HCIO4) = 85.4 (Mgw = 170.8) (titrations with HCl to determine the equivalent weight give values from 172 to 173).

Stage 2 (alkylation);

A 100 ml flask is charged with 50 ml of hexamethylphosphoramide (without special drying) and 8.55 g (50 mmol) of sodium adeninate hydrate (prepared according to Example 3, stage 1). After all of the sodium adeninate has been uniformly suspended, 9.9 g (50 mmol plus 2%) of a, 2-dichloro-6-fluorotoluene (purity 92.3%) are added within 10 to 15 minutes. The reaction mixture is then stirred overnight (4 hours are sufficient for complete conversion) and then poured slowly (with 3 minutes) into 100 ml of water with rapid stirring (pH = 7.9 after about 5 minutes). Then the suspension is mixed with 0.6 g of 50% sodium hydroxide solution (7.5 mol) in order to remove the unreacted adenine. After stirring for 15 minutes, the suspended solids are filtered off, washed twice with 25 ml of water each time and vacuum-dried at 75 ° C. for 4 hours. 13.29 g (95.8%) of 2-chloro-6-fluoro-benzylated adenines are obtained; U.V. Wt% 3-isomer = 11.7; L.C. % By weight 9-isomer = 84.8.

Level 3 (cleaning):

10 g of the aforementioned product are dissolved in 14 ml of acetic acid at 95 ° C. The solution is filtered hot and the filtrate is added dropwise to 80 ml of water at 95 ° C. with rapid stirring within a few minutes (two further ml of hot acetic acid are used to rinse all the remaining material into the hot water). After cooling to 37 ° C., the suspended solids are filtered off, washed once with 10 ml of acetic acid / water (î: 5) and twice with 10 ml of water each and vacuum-dried at 75 ° C. overnight. 8.45 g (84.5%) of 9- (2-chloro-6-fluorobenzyl) adenine are obtained. Thin layer chromatography on silica gel in CHCb / methanol (10: 1) gives a single spot; Mp 243 to 245 ° C; DSC = 0.8 mol% impurity; U.V. (0, In HCl) Lm * = 259, E% = 562; U.V. % By weight of 3-isomer = <2.

Example 4

Alkylation of sodium adeninate hydrate with a, 2-dichloro-6-fluorotoluene in the presence of Aliquat 336 in acetone (solid / liquid reaction mixture)

A 250 ml round-bottomed flask is successively charged with 100 ml of acetone and 8.54 g (50 mmol) of sodium adeninate hydrate (prepared according to Example 3, stage 1). A solution of 9.8 g (50 mmol) of a, 2-dichloro-6-fluorotoluene (degree of purity 91.4%) and 1.25 g (2.5 mmol; 5 mol%) of aliquat is added to the suspension obtained 336 in 10 ml acetone. The reaction mixture is refluxed for 6 hours with rapid stirring and then cooled to room temperature. The solids are filtered off, washed twice with 15 ml of acetone each time and finally digested for 15 minutes with 50 ml of 0.1N sodium hydroxide solution (this removes any unreacted adenine and the NaCl formed during the alkylation). The solids are filtered off, washed twice with 20 ml of water each time and dried for an hour

100 ° C in vacuum. 13.2 g (95%) of 2-chloro-6-fluoro-benzylated adenines are obtained; U.V. (0.1 HCl) im ™ = 262, E% = 534; L.C. Wt% 9 isomer = 83; U.V. % By weight of 3-isomer = 16.

Example 5

Alkylation of potassium adeninate hydrate with a, 2-dichloro-6-fluorotoluene in the presence of Aliquat 336 in acetone (solid / liquid reaction mixture)

The procedure of Example 4 is followed, with the exception that the equivalent amount of potassium adenate is used instead of the sodium adenate. The potassium adenate was prepared according to Example 3, Step 1, with the exception that the equivalent amount of potassium hydroxide was used instead of the sodium hydroxide.

The yield of 2-chloro-6-fluorobenzylated adenines is 94%; L.C. Wt% 9 isomer = 82; U.V. % By weight of 3-isomer = 18.

Example 6

Alkylation of natrimadeninate hydrate with a- (Y) -2-chloro-6-fluorotoluene in the presence of aliquat 336 in acetone (solid / liquid reaction mixture)

The procedure of Example 4 is followed, with the exception that instead of the α, 2-dichloro-6-fluorotoluene, the equivalent amount of an ec- (Y) -2-chloro-6-fluorotoluene (where Y each has the meanings shown in Table II) ) starts.

Table II

Yield at

2-chlorine-6-fluorine ratio of the 9-isomer to the 3-isomer *

Cl benzylated adenines,

CH.

(Tosyl)

Y = J 85 7: 3

© Q

Y = S (CHj) 2CLu 31 3: 1

Y = Br 85 4: 1

* Sometimes there are small amounts (up to 10%) of other products, presumably other isomers (1- and 7-isomers).

Example 7

Alkylation of sodium adeninate hydrate with a, 2,6-tri-chlorotoluene in the presence of Aliquat 336 in acetone (solid / liquid reaction mixture)

A 250 ml round-bottomed flask is charged in succession with 100 ml of acetone and 8.54 g (50 mmol) of sodium adeninate hydrate (prepared according to Example 3, stage 1). A solution of 10 g (50 mmol) of cc, 2,6-trichlorotoluene (degree of purity 98%) and 1.25 g (2.5 mmol; 5 mol%) of Aliquat 336 in 10 ml of acetone is then added to the suspension. The suspension is refluxed for 6 hours with rapid stirring. Then the reaction mixture is cooled to room temperature. The solids are filtered off, washed out twice with in each case 15 ml of acetone and finally digested for 15 minutes with 50 ml of 0.1N sodium hydroxide solution (this removes any unreacted adenine and the NaCl formed during the alkylation). The solids are filtered off, washed twice with 20 ml of water each time and dried in vacuo at 100 ° C. for 4 1/2 hours. 13.8 g (94%) are obtained.

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2,6-dichlorobenzylated adenines; U.V. (0.1 HCl) Xm-.u = 262, E ° / o = 494; L.C. Wt% 9 isomer = 81; U.V. % By weight 3-isomer = 17.

Example 8

Alkylation of sodium adeninate hydrate with a, 2,6-tri-chlorotoluene in the presence of aliquat 336 in toluene (solid / liquid reaction mixture)

A 250 ml round-bottomed flask is charged in succession with 100 ml of toluene and 8.54 g (50 mmol) of sodium adeninate hydrate (prepared according to Example 3, stage 1). A solution of 10 g (50 mmol) of a, 2,6-trichlorotoluene (degree of purity 98% and 1.25 g (2.5 mmol; 5 mol%)) of Aliquat 336 in 10 ml of toluene is then added to the suspension The mixture is boiled under reflux with rapid stirring for 6 hours, then the reaction mixture is cooled to room temperature, the solids are filtered off, washed twice with 15 ml of toluene each time and finally digested for 15 minutes with 50 ml of 0.1N sodium hydroxide solution (this removes any unreacted adenine and the NaCl formed during the alkylation are removed.) The solids are filtered off, washed twice with 20 ml of water each time and dried for 4 hours at 100 ° C. in vacuo. 10.2 g (76%) 2 are obtained. 6-dichlorobenzylated adenines; UV (0, In HCl) A, max = 262, E% = 498; LC wt.% 9-isomer = 80; UV wt.% 3-isomer = 20.

Example 9

One-step purification of crude 9- (2-chloro-6-fluoro-benzyl) adenine by treatment with sulfuric acid

A suspension of 2 g of crude 2-chloro-6-fluorobenzylated adenines (percentages by weight of 9- / 3- / 7-isomer = 79.7 / 17.8 / 1.2 due to liquid chromatography) in 4 ml of xylene is stirred 4 ml of concentrated (96%) sulfuric acid are added dropwise at room temperature. The mixture is stirred for 12 hours at room temperature and then for a further 10 minutes at 80 ° C. After the reaction mixture has cooled to room temperature, it is poured into 25 ml of ice water containing 10 ml of xylene. The mixture obtained is transferred to a separating funnel having a steam jacket and heated to 85 ° C. to dissolve the precipitate. The aqueous layer is separated off and made alkaline with concentrated ammonium hydroxide. The precipitate is filtered off and washed out with hot water (2x 10 ml). 1.53 g of product are obtained (yield 95.6%, based on the 9-isomer available). The liquid chromatographic analysis shows the following proportions: 9-isomer 100.07% by weight; 3-isomer not measurable (<100 ppm); 7 isomer something 0.8% by weight.

Example 10

Two-stage purification of crude 9- (2-chloro-6-fluoro-benzyl) adenine by extraction with dilute nitric acid and treatment with sulfuric acid

Stage A: extraction with dilute nitric acid

A suspension of 40 g (0.144 mol) of crude 2-chloro-6-fluorobenzylated adenines (weight percentages 9- / 3-isomers = 79.1 / 19.3 based on liquid chromatography) corresponding to 31.64 g of 9-isomer and 7.72 g of 3-isomer in 440 ml of water containing 19 ml (0.0285 mol) of 1.5N nitric acid is boiled for 2 hours with vigorous stirring and reflux. The hot mixture is then filtered through a preheated funnel and washed out with hot water (3 x 50 ml slurries), concentrated NH4OH (2x25 ml) and again hot water (3 x 50 ml). The product becomes moist and dry

(damp-dry) and finally vacuum-dried overnight at 65 to 70 ° C. 31.67 g (yield 97.1%) of 9-isomer are obtained, which is enriched with 2-chloro-6-fluorobenzylated adenines. The yield is based on the available 9-isomer and corrected for purity. Liquid chromatography gives 97.2% 9-isomer and 3% 3-isomer.

Step B: Dealkylation of 3- (2-chloro-6-fluorobenzyl) adenine with sulfuric acid

A suspension of 50 g (0.18 mol) of the 9-isomer enriched with 2-chloro-6-fluorobenzylated adenines (percentages by weight 9- / 3-isomers = 96.8 / 3.2 based on liquid chromatography) corresponds to 48.4 g 9-isomer and 1.6 g of 3-isomer in 100 ml of toluene (reagent quality) are added dropwise with 100 ml of concentrated (96.02% strength) sulfuric acid, the temperature being adjusted as required by ice / water cooling in the range from 50 to Holds 60 ° C. The mixture is heated to 50 to 60 ° C. with stirring for 18 hours (all solids dissolve in the acid, a two-phase system being formed). The mixture is then cooled to room temperature and poured into ice / water (300 ml), the product precipitating in the form of the sulfate. The mixture is transferred to a separating funnel having a steam jacket, rinsing with hot water, and the mixture is heated to 80 to 85 ° C. to redissolve the precipitate and separate the aqueous layer from the toluene layer. The aqueous layer (650 ml) is separated off and washed out in the same device with 50 ml of hot toluene. Then make the (still warm) aqueous layer alkaline (pH 10) by carefully adding concentrated ammonium hydroxide. The white precipitate is stirred for 1 hour and then isolated while still warm. The product is washed out with hot water (3 x 100 ml) and 50% aqueous methanol (2x 100 ml). Then the product is vacuum-dried (damp-dry) and finally vacuum-dried overnight at 70 ° C. 47.8 g (98.8%, based on the available 9-isomer) of pure 9- (2-chloro-6-fluoro-benzyl) -adenine of mp 247 to 248 ° C. are obtained. Thin layer chromatography on silica gel in CHCb / methanol (9: 1) essentially gives a single spot (Rr = 0.48). No polymer and no other contamination is found. Liquid chromatography gives the following result: proportion of 9-isomer = 100.68%; Proportion of 3-isomer not measurable. The overall yield is 95.9%.

Example 11

Preparation of 7-amino [1,2,5] thiadiazolo [3,4-d] pyrimidine

A flask is charged with 19.78 g (0.15 mol) of 4,5,6-triaminopyrimidine and 163 g (1.37 mol) of thionyl chloride and the mixture is refluxed with stirring for 18 hours. Then the dark orange colored reaction mixture is evaporated to dryness on a rotary evaporator and the residue is mixed with 500 ml of water and 40 ml of methanol. The solution obtained is adjusted to a pH of 7.5 to 8.0 with saturated sodium bicarbonate solution and boiled under reflux. The hot mixture is filtered and the filtrate is cooled to 0-5 ° C in an ice bath. The solid is collected by filtration, washed twice with 50 ml of ice water and twice with 50 ml of ether. The resulting tan product is dried in vacuo at 70 ° C overnight to form 18.2 g (79%) of mp 247-249 ° C. Thin layer chromatography on silica gel in chloroform / methanol (8: 1) shows a spot with an Rr value of 0.4.

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Example 12

Preparation of 2-chloro-6-fluorobenzylamine An autoclave is charged with 89.0 g (0.5 mol) of 2-chloro-6-fluorobenzyl chloride, 170.0 g (10 mol) of ammonia and 50 ml of benzene. The reaction vessel is closed and the contents are heated to 100 ° C. for 15 hours. Excess ammonia is carefully evaporated from the cooled contents of the autoclave with a stream of nitrogen. The residue is washed with water and, after drying, the organic phase is fractionated with anhydrous MgSC> 4 to give 72.4 g (90%) of product in the form of a clear liquid, bp. 99-100 ° C./20 mm; NMR (CDCh) 8 1.46 (s, 2H); 3.88 (d. 2H); 7.00 (m, 3H).

Example 13

Preparation of 7- (2-chloro-6-fluorobenziamino) [1,2,5] thiadiazolo [3,4-d] pyrimidine

A flask is made with 1.54 g (0.01 mole) of 7-amino [1,2,5] thia-diazolo [3,4-d] pyrimidine, prepared according to the procedure of Example 11, and 4.0 g (0.025 Mol) 2-chloro-6-fluorobenzyl-amine, prepared by the method according to Example 12, charged. The suspension is stirred for 18 hours and heated to 105 ° C. 10 ml of water and 20 ml of hexane are added all at once and the resulting solid is collected by filtration. The cake is washed with hexane and dried at 50 ° C in vacuo to give 2.86 g (97%) of product, mp 224-226 ° C. Thin layer chromatography on silica gel in chloroform / methanol (8: 1) gives a single fluorescent bruise at Rr = 0.8; NMR (DMSO-dt,) 8 4.92 (2H, s); 7.21 (broad s, 3H); 8.44 (s, 1H); 9.45 (s, 1H).

Analysis for C11 H'ClFNsS:

Calculated: C 44.68; H 2.38; N, 23.68. Found: C, 44.36; H 2.38; N 24.24

Example 14

Preparation of 7- (2-chloro-6-fluorobenzylamino) [1,2,5] thiadiazolo [3,4-d] pyrimidine

An autoclave is charged with 1.54 g (0.01 mol) of 7-amino [1,2,5] thiadiazolo [3,4-d] pyrimidine (prepared according to Example 11), 5.1 g (0.3 mol ) Ammonia and 4.48 g (0.025 mol) of 2-chloro-6-fluorobenzyl chloride, seal it and heat the contents to 110 ° C. for 15 hours. After cooling and evaporating the excess ammonia, the solid obtained is filtered off and washed out successively with water and hexane. A product yield of 25% is achieved.

Example 15

Preparation of 7- (N-formyl-N-2-chloro-6-fluorobenzylamino) - [1,2,5] thiadiazolo [3,4-d] pyrimidine

Formic acetic anhydride is prepared by stirring a solution of 18.4 g (0.4 mol) of 98% formic acid and 40.8 g (0.4 mol) of acetic anhydride at 0 to 5 ° C for 1 hour. 40 ml of the solution obtained are then added to 2 g (0.0067 mol) of 7- (2-chloro-6-fluorobenzylamino) [1,2,5] thiadiazolo [3,4-d] pyrimidine (prepared according to Example 13) . The solution is stirred overnight and then any insoluble material is filtered off. The filtrate is evaporated in vacuo at 50 ° C. The solid residue is washed with ether and recrystallized from methanol. 2 g (91%) of the desired compound of mp 133 ° to 135 ° C. are obtained. Thin layer chromatography on silica gel in chloroform / methanol (16: 1) gives a spot with an Rf value of 0.8; IR (CHCb) 1730, 1540, 1120.940 cm- '; NMR (DMSO-dô) 8 5 , 55 (s, 2H); 7.30 (broad, 3H); 911 (s, IH); 1033 (s, IH).

Example 16

Preparation of 9- (2-chloro-6-fluorobenzyl) adenine

A flask is charged with 0.5 g (0.0016 mol) of 7- (N-formyl-N-2-chloro-6-fluorobenzylamino) - [1,2,5] thiadia-zolo [3,4-d] pyrimidine (prepared according to Example 15), 15 ml of ethanol, 15 ml of water and 7 g of Raney nickel. The dark colored suspension is stirred for 2 hours at room temperature, after which the thin layer chromatography indicates the end of the reaction. The reaction mixture is filtered through Celite and the filter cake is washed out with 200 ml of boiling methanol. The clear filtrate is evaporated in vacuo to a white, solid residue which is recrystallized from methanol / water. 0.18 g (40%) of product of mp 245 to 246 ° C. is obtained. Thin layer chromatography on silica gel in chloroform / methanol (16: 1) gives a spot with an Rr value of 0.4; NMR (acetic acid-d-t) 8 5.70 (2H, d); 7.35 (3H, m); 8.15 (1H, s).

Analysis for C12H9CIFN5:

Calc .: C 51.90; H 3.27; N 25.22; Cl 12.77%

Found: C 51.77; H 3.30; N 25.43; Cl 12.49%

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Claims (17)

636 614 1. A process for the alkylation of an alkali or alkaline earth metal salt of adenine with a 2,6-dihalobenzyl halide and the production of a mixture of isomers of (2,6-dihalobenzyl) adenines which are at least 70% by weight 9- (2,6-dihalobenzyl) adenines exist, characterized in that the alkylation is carried out in a solid / liquid or liquid / liquid two-phase system, where a) the solid / liquid two-phase system contains an alkali or alkaline earth metal salt of adenine solid phase and a liquid phase comprising a solution of 2,6-dihalobenzyl halide and an onium salt as a phase transfer catalyst having the general formulas below ® 0 ® 0 (RJ3NR1 or (Ri) jPR To where R is an alkyl radical with 4 to 18 carbon atoms, Ri is an alkyl radical with 1 to 8 carbon atoms and 2. is an anion from the group consisting of chlorine, bromine and iodine, in an aprotic, water-miscible or water-immiscible organic solvent, the water-miscible solvent containing 0 to 5 moles of water per mole of adenine salt, and b) the liquid / liquid two-phase system comprises a liquid phase containing an aqueous solution of an alkali or alkaline earth metal salt of adenine , and a second liquid phase comprising a solution of the 2,6-dihalobenzyl halide and an onium salt as a phase transfer catalyst having one of the formulas below © o © p, (R) jNRi tr or (Ri) aPR ZU wherein R, Ri and Z each have the meaning given above, in an aprotic, water-immiscible organic solvent. 2. The method according to claim 1, wherein an alkaline earth metal salt of adenine is alkylated with a 2-chloro-6-fluorobenzyl halide or 2,6-dichlorobenzyl halide and a mixture of isomers of (2-chloro-6-fluorobenzyl) adenine or ( 2,6-dichlorobenzyl) -adenine produced, which consists of at least 70 wt .-% of 9- (2-chloro-6-fluorobenzyl) -adenine or 9- (2,6-dichlorobenzyl) -adenine, characterized in that the alkylation is carried out in a solid / liquid or liquid / liquid two-phase system, where a) the solid / liquid two-phase system comprises a solid phase containing an alkaline earth metal salt of adenine and a liquid phase which comprises a solution of a 2-chloro-6-fluorine benzyl halide or 2,6-dichlorobenzyl halide and a quaternary ammonium salt as a phase transfer catalyst with the general formula (R) îNRi Z ^ in which R is an alkyl radical with 4 to 18 carbon atoms, Ri is an alkyl radical with 1 to 8 carbon atoms and Z® is an anion from the group consisting of chlorine, bromine and iodine, in an aprotic water-miscible solvent from the group consisting of acetone, Aceto-nitrile and hexamethylphosphoramide, the water-miscible solvent containing 0 to 5 moles of water per mole of adenine salt, or a water-immiscible organic solvent from the group consisting of hexane, benzene, toluene, methylene dichloride, chloroform and petroleum ether, and b ) The liquid / liquid two-phase system comprises a liquid phase which contains an aqueous solution of an alkaline earth metal salt of adenine and a second liquid phase which comprises a solution of a 2-chloro-6-fluorobenzyl halide or 2,6-dichlorobenzyl halide and a quaternary ammonium salt Phase transfer catalyst with the general formula ® 0 (R) iNRi ZU in which R, Ri and z ° each have the meaning given above, in an aprotic, water-immiscible organic solvent from the group consisting of hexane, benzene, toluene, methylene dichloride, chloroform and petroleum ether. 2nd PATENT CLAIMS 3. The method according to claim 1, wherein alkylating sodium adinate with 2-chloro-6-fluorobenzyl chloride and producing a mixture of isomers of (2-chloro-6-fluorobenzyl) adenine which consists of at least 70% by weight from 9 - (2-Chloro-6-fluorobenzyl) adenine, characterized in that the alkylation is carried out in a solid / liquid two-phase system, the solid phase sodium adeninate and the liquid phase a solution of 2-chloro-6- fluorobenzyl chloride and a quaternary ammonium salt as a phase transfer catalyst with the general formula © Q (n-R) 3NCH3 Clu in which R is an n-alkyl radical having 8 to 12 carbon atoms, in acetone containing from 0 to 5 moles of water per mole of sodium adeninate. 4. The method according to claim 2, wherein alkaline earth metalate-ninate is alkylated with 2-chloro-6-fluorobenzyl chloride and a mixture of isomers of (2-chloro-6-fluorobenzyl) -adenine is produced, which consists of at least 70 wt - (2-Chloro-6-fluorobenzyl) adenine, characterized in that the alkylation is carried out in a liquid / liquid two-phase system, a liquid phase being an aqueous solution of an alkaline earth metal salt of adenine and the second liquid phase being a solution of 2-chloro-6-fluorobenzyl chloride and a quaternary ammonium salt as a phase transfer catalyst with the general formula ® © (R) bNCH3 to in which R is an alkyl radical having 8 to 12 carbon atoms and Ze is an anion from the group consisting of chlorine, bromine and iodine, in hexane. 5. A process for the preparation of 9- (2,6-dihalobenzyl) adenines which are practically free from 3-isomers, characterized in that, according to the process of claim 1, a mixture of isomers of 9- (2, 6-Dihalo-genbenzyl) -adenines and then subjected to a transalkylation in the presence of concentrated sulfuric acid and a carbenium ion acceptor. 6. The method according to claim 5, characterized in that the carbenium ion acceptor is a substance from the group consisting of dialkyl sulfides, the alkyl radicals each having 1 to 5 carbon atoms, diaryl sulfides, the aryl radicals each having 6 to 18 carbon atoms 7. The method according to claim 5 for the preparation of 9- (2-chloro-6-fluorobenzyl) -adenine which is practically free from the 3-isomer, characterized in that the transalkylie- tion in the presence of concentrated sulfuric acid and toluene or mixed xylenes as carbenium ion acceptor carries out. 8. The method according to claim 5 for the preparation of 3-isomer practically free 9- (2-chloro-6-fluorobenzyl) adenine, characterized in that the Transalkylie- tion in the presence of excess concentrated sulfuric acid and in the presence of an excess of Toluene or mixed xylenes at temperatures from room temperature to 90 ° C for 2 to 36 hours. 9. 9- (2,6-dihalobenzyl) adenines prepared by the process according to claim 5. 10. 9- (2-chloro-6-fluorobenzyl) adenine as a compound according to claim 9, prepared according to the method according to claim 7. 10th 11. A process for the preparation of 9- (2,6-dihalobenzyl) adenines which are practically free from 3-isomers, characterized in that, according to the process of claim 1, a mixture of isomers of 9- (2, 6-Dihalo-genbenzylj-adenines and then a) subjecting them to extraction with dilute mineral acid and then b) carrying out a transalkylation in the presence of concentrated sulfuric acid and a carbenium ion acceptor. 12. The method according to claim 11, characterized in that the mineral acid used is dilute nitric acid, hydrochloric acid or phosphoric acid. 13. The method according to claim 11, characterized in that the carbenium ion acceptor is a substance from the group consisting of dialkyl sulfides, the alkyl radicals each having 1 to 5 carbon atoms, benzene, toluene, xylene, mixed xylenes, mesitylene, alkoxybenzenes, the alkyl radicals being 1 have up to 3 carbon atoms, thiophene, iodobenzene, naphthalene and triphenylphosphine used. 14. The method according to claim 11 for the preparation of 9- (2-chloro-6-fluorobenzyl) -adenine which is practically free from the 3-isomer, characterized in that a) an extraction with dilute nitric acid and b) a transalkylation in the presence of concentrated Performs sulfuric acid and toluene or mixed xylenes as a carbenium ion acceptor. 15. The method according to claim 11 for the preparation of 9- (2-chloro-6-fluorobenzyl) -adenine which is practically free from the 3-isomer, characterized in that a) an extraction with dilute nitric acid solution which relates an approximately equimolar amount of acid on the 3-isomer, at temperatures from room temperature to the reflux temperature with rapid stirring and b) a transalkylation in the presence of excess concentrated sulfuric acid and in the presence of an excess of toluene or mixed xylenes at temperatures from room temperature to 90 ° C for 2 to 36 Hours. 636614 15 20th 25th 30th 35 40 45 50 SS 60 65 have, benzene, toluene, xylene, mixed xylenes, mesi-tylene, alkoxybenzenes, the alkyl radicals having 1 to 3 carbon atoms, thiophene, iodobenzene, naphthalene and triphenylphosphine used. 16. 9- (2,6-dihalobenzyl) aadenines prepared by the process according to claim 11. 17. 9- (2-chloro-6-fluorobenzyl) adenine as a compound according to claim 16, prepared by the method according to claim 14.