HU187472B - Process for preparing purine derivatives - Google Patents

Abstract

PURPOSE:To obtain the titled compound useful as a drug having anticoccidium action in high yield, by benzylating an 6-alkylaminopurine, etc. in the presence of a catalyst transferring between phases in a two-phase system using an inexpensive organic solvent. CONSTITUTION:A compound, e.g., 6-methylaminopurine, shown by the formulaI(R<1> is H, or 1-3C alkyl; R<2> is 1-3C alkyl, aryl) is reacted with a compound, e.g., 2-chloro-6-fluorobenzyl chloride, shown by the formula II(R<3>, R<4>, and X are halogen) in a two-phase system of liquid-liquid or solid-liquid, in the presence of a catalyst transferring between phases (e.g., quaternary ammonium salt, etc.), to give the desired compound shown by the formula III. The reaction is carried out in the presence of a base or using the compound shown by the formulaIas an alkali metal salt, in a two-phase system, e.g., a basic aqueous solution of the compound shown by the formulaIand a solution of the compound shown by the formula II in an organic solvent, an alkali metal powder of the compound shown by the formulaIand the solution of the compound shown by the formula II in the organic solvent, etc.

Description

The present invention relates to a novel process for the preparation of pyridine compounds (VII) and their novel acid addition salts.

Λ In formula VII, R ¹ and R ² are a balogen atom and R ³ is a C 1-3 alkyl group.

German Patent No. 2,836,373 discloses the preparation of purine derivatives identical to those of the present invention from aminopurine dehydrogenase, but not in a biphasic system. This process is disadvantageous in comparison with the biphasic system used in the present invention for commercial production because of:

The known process requires the use of an aprotic solvent such as Ν, Ν-dimethylformamide and N, N-dimethylacetamide, which are expensive and cause problems in their recovery.

- Product isolation is quite difficult.

- Removal of solvent due to its high boiling point is quite difficult.

- The complete removal of solvent from the product isolated by filtration can only be achieved by repeated washing, which obviously means a decrease in yield.

Using an alcohol such as nitromethane or acetonitrile as the solvent mentioned in the cited quotation, without using a two-phase system, the yield of the by-product, such as the 3-isomer, will be higher, the yield of the desired product, i.e. the 9-isomer, will be when using an aprotic solvent.

The preparation of 9-dihalobenzyl-6-alkylaminopurine is described in British Patent 1,534,163. The process differs significantly from the invention and is less advantageous. The process of preparation consists of several steps than the process of the present invention, without the use of a two-phase system, among the reagents used are more expensive than those used in the process of the invention and the yield of the final product is low.

The invention new phenylazo-pyrimidine derivates of formula used as starting material (I) wherein ^R1 is a C1-3, alkyl groups, preferably methyl group - for example, be prepared by (II) phenylazo-malononitrile reacted with a ( III) formamide derivative of the general formula - are reacted and formula (IV) with ammonia - wherein ^R1 is as defined above.

The above reaction is sometimes easier if some or all of the ammonia is used in the form of an acid addition salt such as hydrochloride. Instead of ammonia, formamide and a base (e.g., potassium hydroxide or sodium hydroxide) may be used.

The reaction is generally carried out in a closed reaction system at 120-160 ° C (preferably 150 'Con). 1 to 10, preferably 5 hours.

The following lists give examples of reagents. The ratios given below for each of the related reagents refer to the molar ratio of reagents to be used.

Preparation of 4-Amino-6- (substituted Amino-pyrimidines):

(II) + HCOCHR ³ + NH ₃

1: 1 to 50: 1 to 100 (II) + HCONHj HCONHR + ³ + base

1: 10- 50: 10- 50: 1-10

The compounds of formula (I) thus obtained may be isolated from the reaction mixture or purified by conventional means such as column chromatography, filtration or recrystallization. The compounds of formula (I) may be isolated in the form of salts, such as acid addition salts (e.g., hydrochloride and sulfate).

The novel compounds of formula (I) can be readily converted to the antifungal adenine or various purine derivatives by the novel processes of the present invention (known from U.S. Patent Nos. 3,846,426 and 4,189,485). as intermediates in the preparation of compounds are of great commercial importance.

The processes of Scheme 1 are described in detail below. In the formulas, R ³ is C 1-3 alkyl; X is halogen (e.g., chlorine or bromine); R ¹ and R ² is halogen.

Process A of the process of the invention as described in Scheme 1 may be carried out by reducing a compound of formula I and reacting it with formic acid or a derivative thereof in the presence of a carboxylic acid derivative to give a compound of formula V.

Reduction of the pyrimidine derivative of formula (I) actually yields a compound of formula (VIII) wherein R ³ is as defined above, which is then cyclized in the presence of a carboxylic acid derivative to formate or derivative thereof to give ( V).

Reduction of the compound of formula (I) by catalytic hydrogenation or by reducing agents such as sodium dithionite, sodium sulfide and a variety of other reducing agents such as those described in J. Am. Chem. Soc., 8/3046 (1959). we can do it. The catalytic reduction is carried out in a solvent such as methanol, ethanol, formamide or N-methylformamide. Palladium, palladium on carbon, Raney nickel or the like can be used as the catalyst. The reduction is carried out at room temperature to 150 ° C, or atmospheric

Pressures greater than -2187.472.

It is not always necessary to carry out the reduction and the ring closure in separate steps, the compound of formula (V) may be prepared in a single step, for example by carrying out the ring closure in a reducing environment.

Carboxylic acid derivatives used in the ring closure reaction are carboxylic acid derivatives traditionally used in acylation reactions such as acid anhydrides (e.g. acetic anhydride and formic anhydride) and acid halides (e.g. acetyl chloride and benzoyl chloride). Of these, acetic anhydride is preferably used. The carboxylic acid derivatives promote the ring closure reaction of the amino groups at the 4 and 5 position of the compound of formula VIII and prevent the ring closure in the other direction.

The formic acid derivative is preferably ethyl orthoformate, formamide or ethyl formate, most preferably ethyl orthoformate.

The ring closure is carried out by adding about 2 to 20 parts by weight of formic acid or formic acid derivative and also about 2 to 20 parts by weight of a carboxylic acid derivative to the compound of formula VIII and refluxing for 1 to 5 hours.

The resulting reaction mixture may be heated in an alkaline medium (e.g., by the addition of aqueous sodium hydroxide) and neutralized with an acid (e.g., acetic acid) to precipitate the compound of formula (V).

Process B is carried out by reacting a compound of formula (V) with a compound of formula (VI) in the presence of a base. This benzylation may be carried out in the presence of a phase transfer catalyst in a two-phase liquid-liquid or solid-liquid system. A base may be present in the reaction system or, alternatively, the compound of formula (V) may be used in the form of its alkali metal salt (i.e., as a base). Accordingly, we use the following two-phase systems:

(1) a two-phase system consisting of an aqueous basic phase containing a compound of formula (V) and an organic solvent phase containing a compound of formula (VI);

(2) a two-phase system consisting of a solid (powder) phase comprising a compound of formula (V) and a base and an organic solvent phase containing a compound of formula (VI); and (3) a two-phase system consisting of the solid (powdery) phase of the alkali metal salt of the compound of formula (V) and the organic solvent phase containing the compound of formula (VI).

Bases used in systems (1) and (2) include, for example, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, lithium carbonate, or sodium oxide. The alkali metal salts present in system (3) may be derived from the compound of formula (V) and the bases mentioned above, such as the sodium salt or the potassium salt.

The organic solvents used in the biphasic reaction include hexane, petroleum ether, benzene, toluene, methylene chloride, 1,2-dichloroethane, acetone or acetonitrile. Of these, hexane, acetone and acetonitrile are particularly preferred.

Quaternary ammonium salts, phosphonium salts, crown ethers and the like can be used as phase transfer catalysts in biphasic reactions.

The hydrocarbon side chains of the quaternary ammonium salts are preferably the same or different alkyl groups having from 1 to 20 carbon atoms. Preferably, the anion moiety is halogen. Among the most commonly used quaternary ammonium salts are trioctylmethylammonium chloride, hexadecyltrimethyl-1-ammonium chloride, dodecyltrimethylammonium chloride and tetrabutylammonium bromide.

An example of a phosphonium salt is benzyl triphenylphosphonium chloride.

An example of a crown ether is 18-crown-6 ether.

Among the listed phase transfer catalysts, the quaternary ammonium salts are highlighted.

In each of the aforementioned benzylation reactions, the compound of formula (VI) is used in an equimolar amount or in a slight excess (up to 1 mole excess) of the compound of formula (V). The amount of solvent used is 5-20 times (w / w), the amount of base is 1-2 moles (based on 1 mole of the compound) and the amount of catalyst is about 0.1-20 mole%, preferably 5 mole percent. The reaction is carried out at a temperature between about 0 'C and 120' C, but particularly preferred is room temperature to 70 'C.

It is desirable to use as little water as possible in reaction (1), and this amount is preferably equal to the minimum amount of water required to dissolve the compound of formula (V).

In addition to the desired compound of formula VII, a small amount of its isomer (3-substituted isomer) is formed during the benzylation process. As the 3-isomer is more soluble in dilute acids and unstable in the presence of strong acids, its removal can be accomplished using these properties. For example, the 3-isomer may be removed by boiling the reaction product with dilute nitric acid. A small amount of the remaining 3-isomer can be removed by suspending the dilute acid-insoluble material in toluene by adding concentrated sulfuric acid and heating. This procedure gives the pure product of formula VII. In addition, it has the general formula (V)

-3187.472 starting material can be recovered and reused by subjecting the 3 isomers in the dilute acidic extract to the above procedure.

Among the advantages of the B benzylation process are the following: the reaction can be carried out very efficiently in conventional, inexpensive solvents and by the addition of a phase transfer catalyst without the expensive and difficult to recover aprotic dipolar solvent (e.g. N, N-dimethylformamide) NN-dimethylacetoamide or dimethylsulfoxide) and the desired product (VII) can be obtained in very good yield.

Accordingly, the process of the invention is very advantageous and can be industrially used.

The benzylation process B may be carried out in a conventional inert solvent in the presence of a base. Among the bases which may be used, in addition to those mentioned for the biphasic reaction, are tertiary amines (for example trimethylamine triethylamine and tripropylamine). The amount of base is preferably from about 1 to about 4 molar equivalents per compound of formula (V). Examples of the solvent include: Ν, Ν-dimethylformamide, N, N-dimethylacetamide, acetonitrile, nitromethane, alcohols (e.g. methanol, ethanol and tert-butanol) and the like. The reaction is carried out at room temperature to 150 ° C, preferably at room temperature to 50-100 ° C. The amount of the compound of formula (VI) is preferably from 1 to 4 molar equivalents relative to the compound of formula (V).

The resulting compounds of formula (VII) may be used, for example, as antifouling agents. These compounds are described in U.S. Patent Nos. 3,846,426 and 4,189,485, and Japanese Patent Application Laid-Open Nos. 47-29394 and 54-36292, respectively. Thus, the use of the novel pyrimidine derivatives of formula (I) as intermediates can be carried out in good yield and in an economical manner. The present invention provides processes for the preparation of such lice suppressants. 9-(2-Chloro-6-fluorobenzyl) -6-methylaminopurine, which is a particularly useful intermediate in the production of a known lichen pesticide, may include 4-amino-6-methyl- amino-5-phenylazopyrimidine, as it can be economically converted to said anesthetic agent via 6-methylaminopurine.

The invention is illustrated by the following non-limiting examples.

1. Reference Example

In a autoclave, a mixture of 42.55 g (250 mmol) phenyl azomalononitrile, 245 g (5 mmol) N-methyl form and 345 mL (12.5 mmol) liquid ammonia was stirred at 150 ° C for 5 hours. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in 1 L of chloroform. The solution was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained is purified by chromatography on a column of 900 g of silica gel using chloroform as the eluent and recrystallized from chloroform / petroleum ether. This gave 34 g (60% yield) of 4-amino-6-methylamino-5-phenylazopyrimidine as orange mirror crystals. Melting point. 189 190 'C.

2. Reference Example

A stainless steel autoclave was charged with 850 mg (5 mmol) of phenyl azo-malononitrile and 4.5 g (100 mmol) of formamide, followed by the addition of 6.9 g of 15% ammonia in N-methylformamide and stirred for 5 hours. At 150 ° C. Following the procedure of Example 1, 270 mg (24%) of 4-amino-6-methylamino-5-phenylazopyrimidine are obtained as orange needle crystals.

3. Reference Example

1.68 g (30 mmol) of potassium hydroxide are dissolved in 4.5 g (100 mmol) of formamide and 5.9 g (100 mmol) of n-methylformamide. The solution, together with 850 mg (5 mmol) of phenyl azo-malononitrile, was placed in a stainless steel autoclave and the mixture was stirred at 150 ° C for 5 hours. Following the procedure of Example I, 4-amino-6-methylamino-5-phenylazopyrimidine (184 mg, 16%) was obtained as orange needle crystals.

4. Reference Example

A stainless steel autoclave was charged with 850 mg (5 mmol) of phenyl azo-malononitrile, 675 mg (10 mmol) of methylamine hydrochloride and 5.9 g (100 mmol) of N-methylformamide, and 5.45 g was added. Formamide containing 17% methylamine and the mixture was stirred at 150 ° C for 5 hours. Following the procedure of Example 1, 4-amino-6-methylamino-5-phenylazopyrimidine (610 mg, 53%) was obtained as orange needle crystals.

5. Reference Example

850 mg (5 mmol) of phenyl azo-malononitrile and 675 mg (10 mmol) of methylamine hydrochloride were weighed into a stainless steel autoclave, followed by the addition of 9.3 g of 10% methylamine in formamide and the mixture was stirred for 5 hours. stir at 150 ° C. Next, the procedure of Example 1 was followed to obtain 4-amino-6-methylamino-5-phenylazopyrimidine (405 mg, 36%) as orange needles.

6. Reference example

850 mg (5 mmol) of phenyl azo-malononitrile and 5.9 g (100 mmol) of N-methylformamide were weighed into a stainless steel autoclave and cooled with dry ice / acetone. To this was added 4.25 g (250 mmol) of liquid ammonia. The mixture was stirred for 5 hours at 150 ° C. then concentrated under reduced pressure. The residue was dissolved in chloroform (100 mL), washed with water, water (4)

187,472 free magnesium sulfate) was dried and the solvent was evaporated under reduced pressure. The residue was purified by chromatography on a column of silica gel (30 g) and recrystallized from chloroform / petroleum ether to give 643 mg (56%) of 4-amino-6-melylamino-5-phenylazopyridine as an orange oil. in the form of needle crystals Melting point: 190 191 'C.

/. example

1. To a 1 L autoclave was charged 34.2 g (150 mmol) of 4-amino-6-methylamino-5-phenylazopyrimidine, 3 g of 5% palladium on carbon and 700 mL of methanol, followed by hydrogen gas (initial pressure: 80.0 kg / cm ² ), the reaction was carried out at 7 42 ° C for 3 hours. The catalyst is filtered off and the filtrate is evaporated to dryness under reduced pressure. To the residue was added ethanol / ether (1: 5, 200 mL) and cooled with ice. 17.68 g (85%)

4,5-Diamino-6-methylaminopyrimidine is obtained in crystalline form. Melting point: 180 - 185 'C.

2. Suspend 13.92 g (100 mmol) of 4,5-diamino-6-methylaminopyrimidine in a 1: 1 mixture of ethyl orthoformate and acetic anhydride (250 mL) and stir under reflux for 3 hours. under. After cooling, the mixture is evaporated to dryness under reduced pressure and the residue is recrystallized from ethanol. 14.95 g of a brown crystal are obtained. This product was suspended in 150 ml of 2N sodium hydroxide and refluxed for 1 hour. The reaction mixture was cooled with ice

Glacial acetic acid was added until pH 5 was reached. The precipitated material was collected by filtration and recrystallized from water. This gave 8.42 g (56%) of 6-methylaminopurine as colorless crystals. Melting point:> 300 'C.

Example 2

1. Dissolve 5.966 g (40 mmol) of 6-methylaminopurine in 20 ml of 2N sodium hydroxide and evaporate the solution to dryness under reduced pressure at 50 ° C. The concentrate was dried at 90 ° C under reduced pressure to give 7.305 g (purity: 94%)

The 6-methylaminopurine sodium salt is obtained as a crystalline powder. Melting point:> 300 'C.

2. Sodium salt of 6-methylaminopurine purine (3.65 g, 20 mmol, purity: 94%) was suspended in acetone (30 mL), then 2-chloro-6-fluorobenzyl chloride (3.58 g, 20 mmol) and 404 mg ( (1 mmol) trioctylmethylammonium chloride was dissolved in acetone (15 mL) and the mixture was stirred at reflux for 6 hours. After cooling, the resulting crystals were collected by filtration and washed twice with 10 ml of acetone. The crystals are placed in 30 ml of water and after stirring for 30 minutes, the mixture is filtered to give a crystal of 6-methylaminopurine substituted with 2-chloro-6-fluorobenzyl (4.55, yield: 78%), wherein the isomer 9 is substituted. the proportion of the isomer substituted at the 3-position was 21% according to the ultraviolet assay.

Physical properties of the isomers substituted in positions 3 and 9:

UV spectrum: Isomer 3 _n 0.1 n HCl ¹ max 282 nm (ε = 17,400), Π ^H2 ° max 285 nm (ε = 13,300), 0.1 N NaOH ¹ max 287 nm (ε = 12,100); 9-isomer _n 0.1 n HCl ¹ max 264.5 nm (ε = 19,900), Π ^H2 ° max 267.5 nm (ε = 18,500), π 0.1 n NaOH ¹ max 267.5 nm (ε = 18,500). Proton magnetic resonance spectrum:

Measured on a Varian EM-390 spectrometer (90 MHz) with an internal standard tetramethylsilane, chemical shifts (δ) in ppm.

3-isomer (solvent: CF ₃ COOD)

3.33 (3H, s, CH ₃ ). 5.89 (2H, s, CH 3, 7.0-7.7 (3H, m, Ar-H),

8.44 (1H, s, 2-H or 8-H), 8.73 (1H, s, 8-H or

2 H);

9-isomers (solvent: CDC1 ₃₎

3.18 (3H, J - 4.5 Hz, _CH3), 5.52 (2H, d, J = 2 Hz, CH)

5.87-6.23 (1H, broad NH), 6.94-7.48 (3H, m, Ar-H),

7.65 (1H, s, 2-H or 8-H), 8.47 (1H, s, 8-H or

2 H).

Melting point:

3-isomer 265-266 'C;

9-Isomer 189-190 'C.

Thin layer chromatography

Merck DC-finished plates silica gel 60 F _2J4, layer thickness 0.25 mm, eluent: chloroform: methanol 5: 1 mixture of

3-isomer: _Rf = 0.7;

9 isomer: _Rf = 0.9.

The mother liquor gave 6-methylaminopurine crystals (102% 9-isomer, 4%) in 696 ml (12% yield) of 2-chloro-6-fluorobenzyl-substituted crystals.

3-isomer).

To the crystals obtained in the above procedure (3.5 g, 73% 9-isomer, 21% 3-isomer) were added 50 ml of water and 2.25 ml of 1N nitric acid, and the mixture was refluxed for 2 hours. The insoluble material was collected by filtration of the hot solution, washed with hot water, 28% aqueous ammonium hydroxide and again with hot water to give 2.7 g,

A crystal of 6-methylaminopurine substituted with 2-chloro-6-fluorobenzyl (100% 9-isomer, 3% 3-isomer) is obtained.

2 g of the product obtained are suspended in toluene (4 ml), concentrated sulfuric acid (4 ml) is added with ice-cooling and stirring, and the mixture is stirred at 50-60 ° C for a further 18 hours. After cooling, ice water (15 ml) was added and the mixture was heated to 80-85 ° C. The aqueous layer was separated, washed with hot toluene (2 mL) and filtered. The filtrate was adjusted to pH 10 by addition of 28% aqueous ammonium hydroxide, and the resulting crystalline precipitate was collected by filtration and washed with hot water. This gave 1.84 g (55%) of 9- (2-chloro-6-fluorobenzyl) -6-methylaminopurine as colorless crystals. Melting point: 189-190 ° C.

7. Reference Example

Recovery of 6-methylaminopurine 6-methyl-1-amiflopurine (92% 3-isomer, 9% 9-isomer) substituted with 2-chloro-6-fluorobenzyl (g) was suspended in toluene (2 ml) and ice-cooled. 2 ml of concentrated sulfuric acid are added with stirring and the mixture is stirred for a further 18 hours. The resulting crystals were dissolved by heating and water (6 mL) was added portionwise. After warming to 80 'C, the toluene layer was separated and the aqueous layer was washed with 5 mL of toluene and filtered. The filtrate was adjusted to pH 10 while hot with 28% ammonium hydroxide, filtered once, and adjusted to pH 7 with concentrated hydrochloric acid. After cooling, the resulting crude crystals were collected by filtration and recrystallized from ethanol. 190 mg (40%) of 6-methylaminopurine are obtained in crystalline form. Melting point:> 300 'C.

Example 3

Sodium hydroxide (280 mg, 7 mmol) was dissolved in water (0.28 mL) and acetone (14 mL) and 6-methylaminopurine (1.044 g, 7 mmol) were added. The mixture was stirred at reflux under nitrogen for 1.5 hours. After cooling, a solution of 1.253 g (7 mmol) of 2-chloro-6-fluorobenzyl chloride and 141 mg (0.35 mmol) of trioctylmethylammonium chloride in 5 ml of acetone was added and the mixture was heated under reflux for 6 hours under nitrogen. under refrigeration. The reaction mixture was allowed to stand overnight and the resulting crude crystals were collected by filtration and washed with acetone. The crystals were placed in water (10 mL), stirred for 30 minutes and collected by filtration. This gave 1.595 g (78%) of 6-methylaminopurine substituted with 2-chloro-6-fluorobenzyl.

9-isomer: 65%, 3-isomer: 32%.

After collection of the crude crystals, the mother liquor remaining is evaporated to dryness under reduced pressure, 20 ml of hexane are added to the residue and the crystals are collected by filtration. The crystals were placed in 5 ml of 0.1N sodium hydroxide solution and stirred for 30 minutes. The crystals were collected by filtration and washed with water. Yield: 279 mg (14%) of 6-methylaminopurine substituted with 2-chloro-6-fluorobenzyl. 9-isomer: 84%; 3-isomer: 4%.

Example 4

Sodium hydroxide (280 mg, 7 mmol) was dissolved in 1.4 mL of water and 1.044 g (7 mmol) of 6-methylaminopurine was added. To the resulting solution was then added a solution of 1.253 g (7 mmol) of 2-chloro-6-fluorobenzyl chloride and 141 mg (0.35 mmol) of trioctylmethylammonium chloride in 8.5 mL of hexane. The procedure of Example 3 is then followed. 2.074 g of 6-methylaminopurine substituted with 2-chloro-6-fluorobenzyl are thus obtained. 9-isomer: 56%,

3-isomer: 32%.

Example 5

Sodium hydroxide (280 mg, 7 mmol) was dissolved in water (1.4 mL) and 6-methylaminopurine (1.044 g, 7 mmol) was added. To the resulting solution was added a solution of 1.253 (7 mmol) 2-chlorofluorobenzyl chloride and 141 mg (0.35 mmol) trioctylmethylammonium chloride in 8.5 mL toluene. The resulting mixture was stirred and refluxed for 6 hours under nitrogen. The reaction mixture was then cooled to room temperature and the resulting crude crystals were collected by filtration and washed with toluene. The crystals were placed in 10 ml of 0.1 N sodium hydroxide solution and stirred for 30 minutes. The crystals were collected by filtration and washed with water. This gave 1.790 g (88%) of 6-methylaminopurine substituted with 2-chloro-6-fluorobenzyl. 9-isomer: 50%; 3isomer: 46%.

Example 6

967 mg (7 mmol) of 6-methylaminopurine are dissolved in 2.8 ml of water and the reaction mixture is refluxed under stirring and under a stream of nitrogen for 1.5 hours. After cooling, a solution of 1.253 g (7 mmol) of 2-chloro-6-fluorobenzyl chloride and 141 mg (0.35 mmol) of trioctylmethylammonium chloride in 5 mL of acetone was added. The procedure of Example 21 is then followed. 1.106 g (54% yield) of 2-chloro-6-fluorobenzyl substituted omethylaminopurine are obtained in crystalline form. . 9 isomer:

-6187.472

52%; 3-isomer: 42%.

The mother liquor was worked up as described in Example 19 to give 633 mg (yield; 31%) of 6-methylaninopurine substituted with 2-chloro-6-fluorobenzyl. 9-isomer: 70%; 3-isomer: 15%.

EXAMPLE 7 6-Methylaminopurine (1.044 g, 7 mmol) and potassium carbonate (967 mg, 7 mmol) were suspended in acetonitrile (1 mL) and 2-chloro-6-fluorobenzyl chloride (1.253 g, 7 mmol) was added followed by 141 mg. (0.35 mmol) of trioctylmethylammonium chloride in 10 mL of acetonitrile. Following the procedure of Example 19, 1.687 g (83% yield) of 2-chloro-6-fluorobenzyl was substituted.

6-methylaminopurine is obtained. 9-isomer: 66%.

The mother liquor obtained after collecting the crude crystals is evaporated to dryness under reduced pressure. To the residue was added hexane (10 mL) and water (10 mL), and the mixture was stirred for 30 minutes. The crystals were collected by filtration and washed with a 1: 1 mixture of acetone and water. 162 mg (8%) of 6-methyl-purine substituted with 2-chloro-6-fluorobenzyl are obtained. 9-isomer: 65%, 3-isomer: 13%.

Example 8 1.291 g (7 mmol, 93% purity) of sodium salt of 6-methylaminopurine were suspended in mL of acetone, followed by addition of 1.253 g (7 mmol) of 2-chloro-6-fluorobenzyl chloride and 141 mg (0 (35 mmol) of trioctylmethylammonium chloride in 5 ml of acetone. The reaction mixture was stirred for 6 hours at room temperature. The procedure of Example 22 is then followed. 1.510 g (74% yield),

6-Methyl-purine substituted with 2-chloro-6-fluorobenzyl is obtained. 9-isomer: 80%; 3-isomer: 23%.

From the mother liquor, 313 mg (15%) of 6-methylaminopurine substituted with 2-chloro-6-fluorobenzyl was crystallized. 9isomer: 85%; 3-isomer: 8%.

EXAMPLE 9 Sodium salt of 6-methylaminopurine purine (1.279 g, 7 mmol, 94% purity) was suspended in toluene (mL) and 2-chloro-6-fluorobenzyl chloride (1.253 g, 7 mmol) was added and (35 mmol) of trioctylmethylammonium chloride in 5 mL of toluene. The reaction mixture was heated under reflux for 6 hours with stirring. The procedure of Example 19 is then followed. 1.634 g (80%) of 6-methylaminopurine substituted with 2-chloro-6-fluorobenzyl are obtained in crystalline form. 9-isomer: 50%; 3-isomer: 47%.

8. Reference Example

Removal of 3- (2-chloro-6-fluorobenzyl) -6-melylaminopurine by acetic acid extraction with 500 ml of glacial acetic acid while heating,

6-methylaminopurine (9-isomer: 71%; 3-isomer: 30%) substituted with 2-chloro-6-fluorobenzyl and the small amount of insoluble material was removed by filtration. The filtrate was added with vigorous stirring to 4 ml of water at 90-95 ° C. After stirring for 30 minutes, the reaction mixture was cooled to room temperature. The resulting crystals were collected by filtration and washed with a 1: 4 mixture of glacial acetic acid and water. This gives 343 mg of 6-methylaminopurine substituted with 2-chloro-6-fluorobenzyl as colorless crystals. 9-isomer: 93%; 3-isomer: 2%.

Example 10 Palladium on carbon (200 mg, 5%) was suspended in methanol (ml) and shaken in a stream of hydrogen gas. To this suspension was added 388 mg (1.7 mmol)

A solution of 4-amino-6-methylamino-5-phenylazopyrimidine in methanol (20 mL) was shaken under a stream of hydrogen gas. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethanol and the solution was evaporated to dryness under reduced pressure. Petroleum ether was added to the resulting crystals and the crystals were collected by filtration. The crystals were then placed in a mixture of acetic anhydride (4 ml) and ethyl orthoformate (4 ml), and the mixture was stirred at reflux for 3 hours. The reaction mixture is then concentrated to dryness under reduced pressure. To the residue was added 4 ml of 2N sodium hydroxide and the mixture was refluxed for 1 hour. After cooling, the pH of the mixture was adjusted to 5 with acetic acid and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure and the resulting crude crystals were collected by filtration. The crystals were washed with cold taste and then recrystallized from water. This gave 85 mg (34%) of 6-methylaminopurine as colorless crystals. Melting point:> 300 'C.

Example 11

Preparation of 9- (2-chloro-6-fluorobenzyl) -6- (methylamino) purine hydrochloride 1.0 g of 9- (2-chloro-6-fluorobenzyl) -6- (methylamino) Purine, 20 ml of methanol and 20 ml of hydrochloric acid in ethyl alcohol are stirred at room temperature for 5 hours. The mixture was allowed to stand overnight and concentrated in vacuo. The residue was recrystallized from methyl alcohol to give 1.01 g of 9- (2-chloro-6-fluorobenzyl) -72 in 91% yield.

187.472 of p-methylamino-purine hydrochloride is obtained in the form of colorless crystals. 232-234 ° C.

Analytical results based on the formula C 1, H 1, C 1EN, HCl 5:

Calculated: C _p - 476.58% H = 3.69

N ⁿ "= 21.34% Found: C» 47.70% H, 3.60;

N, 21.22. -IQ

Claims (1)

A patent claim A method (VII) purinszármazé- 15 derivatives of formula - wherein R ^l and R ² is halogen, R ^{3 for the preparation of a C} 13 alkyl group or an acid addition salt thereof by reacting a compound of formula (V) and (VI) - R 1, R ² and R ³ have the meanings given in formula VII, X is halogen, a) a compound of formula I wherein R 'is reduced by catalytic hydrogenation or a reducing agent as defined hereinbefore, then reacted with formic acid or a derivative thereof in the presence of a carboxylic acid derivative, and the resulting compound of formula V and VI the reaction of a compound of formula - are the substituents are as defined above - two-phase, liquid-liquid or solid-liquid phase system is carried out in phase transfer catalyst, or ₂₎ a compound (V) of the formula wherein R ³ is as defined above with sodium or potassium salt with which compound (VI) - wherein ^{R1, R2} and X are as defined above - two-phase, liquid-liquid or solid-liquid phase system is reacted with a phase transfer catalyst and, if desired, the resulting a,) or method ₂₎ compound is converted to the acid addition salt.