DK159681B - METHOD FOR PREPARING 2-SUBSTITUTED 5-NITROSO-4,6-DIAMINO-PYRIMIDINES - Google Patents

Description

DK 159681 E

The present invention relates to a process for the preparation of 2-substituted 5-nitroso-4,6-diamino-pyrimidines of the general formula NH

X NO

wherein R represents aryl, alkyl, alkylthio, amino, substituted amino or arylalkyl.

It is known to prepare 5-nitroso-2,4,6-triamino-pyrimidine from malonic acid dinitrile and a guanidine salt.

Condensation of malonic acid dinitrile and guanidine hydrochloride or nitrate in the presence of sodium alcoholate in alcoholic solution gives 2,4,6-triamino-pyrimidine in moderate yield, cf. W. Traube, Ber. 3T_, 4544 (1904) and H. Sato et al., J.Chem.Soc.Japan Pure Chem.Sect. 72, 866 (1951), Chem. Abstr. AT_, 5946 (1953). This pyrimidine is then nitrosated to 5-nitroso-2,4,6-triamino-pyrimidine with nitric acid, cf. MF Mallette et al., J.Am.Chem.Soc. 69, 1814 (1947). This process has the disadvantage that it is too cumbersome to produce larger quantities and that the yield of 5-nitroso-2,4,6-triamino-pyrimidine is at most 20 to 75-78%, based on malonic acid dinitrile.

Attempts have been made to simplify this process by failing to isolate the intermediate 2,4,6-triamino-pyrimidine, cf. CH Patent No. 630,616. However, this process is still associated with various drawbacks, as it is necessary to use expensive sodium alcoholate which forms at least 2 moles of salt (NaCl and Na-acetate) per liter. used mole of malonic acid dinitrile, it is necessary to work with relatively dilute reaction solutions (about 2 liters of solvent per mole of product), and finally, the regeneration of the solvent is extremely troublesome as it is a 4-component solvent mixture (methanol, ethanol, glacial acetic acid, water and by-products).

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Another method is known for preparing 5-5 nitroso-2,4,6-triamino-pyrimidine, cf. E.C. Taylor, 0. Vogl and C.C. Cheng, J.Am.Chem.Soc. 81, 2442 (1959). By this process, the potassium salt of isonitroso malonitrile with guanidine carbonate in dimethylformamide 5-nitroso-2,4,6-triamino-pyrimidine is obtained in 88% yield by heating the potassium salt. Since the potassium salt is prepared from the silver salt of isonitroso-malonitrile, this process cannot be used for large-scale production.

FR patent specification No. 1,364,734 also discloses a process in which the malonic acid nitrile is first nitrosated in aqueous acetic acid solution with sodium nitrite, after which the isonitrosomalonitrile solution formed is treated with guanidine carbonate to give off and the guanidine salt of isonititrile . This salt suspension is then cooled to ca. 0 ° C, filtered and the guanidine salt of isonitroso-malonitrile dried. The salt is then heated in dimethylformamide after the addition of 11 CO 2 under reflux to isomerization to 5-nitroso-2,4,6-tri-amino-pyrimidine.

This approach involves some progress over the Taylor method, but still has several drawbacks. Thus, it is necessary to use the acetic acid in excess (10% by example). This excess must be neutralized with guanidine carbonate to obtain complete formation of the guanidine salt of isonitroso-malonitrile.

Cool the aqueous suspension to ca. 0 ° C is technically associated with difficulties as a crust of ice is formed on the inner side of the reaction vessel. When cooled to less low temperatures, the salt does not completely precipitate.

The drying of the guanidine salt of isonitroso-malonitrile is risky for 35 technical reasons.

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When treating the crude isonitroso-malonitrile solution with guanidine carbonate, 1 equivalent of CC 2 is released. The reaction mixture therefore tends to foam during this process so that the reaction vessel cannot be optimally utilized.

It is the object of the present invention to overcome these drawbacks of the known processes and to provide a process which enables simple and economical production of 2-substituted 5-nitroso-4.6-10 diamino-pyrimidines in high yield.

This is achieved by the process of the invention, which is characterized in that malonic acid dinitrile is reacted with an amidine or guanidine of the general formula

<NH. HA

(II) nh 2 wherein A means Cl, 1/2 SO 2, HSO 2, NO 2, acetate or 1/3 phosphate, and R has the meaning given above, in water or alcohol in an acidic environment in the presence of a nitrite salt to formation of the corresponding amidine salt or guanidine salt of isonitrosomalonitrile, which in dimethylformamide in the basic environment by heat treatment is converted to the corresponding 2-substituted 5-nitroso-4,6-diamino-pyrimidine.

In the process of the invention, the malonic acid dinitrile in water or alcohol is reacted as a solvent with an amidine or guanidine in an acidic environment in the presence of a nitrite salt, whereby the amidine salt of isonitroso-malonitrile is formed directly in aqueous or alcoholic suspension. This salt is not isolated, but the mixture is made basic and after the addition of dimethylformamide and optionally a pyridine base, the water or alcohol is distilled off under reduced pressure. After 50 complete removal of the water or alcohol, the reaction mixture is conveniently heated at reflux to give the corresponding 2-substituted 5-nitroso-4.6-4.

DK 159681 B

diamino-pyrimidine is formed. Acidic environment here means a pH value of less than 6.9, and in basic environment a pH value of more than 7.1 is understood.

The process of the invention is illustrated in the following reaction scheme: NH.HA NC. · L N0- H2N +

R - + J + NaN02 - »Y Å + Na A

CN CN E2W R

nh2 yN0

-> AX

R nN ^ NH2 where A means Cl, 1/2 SO ^. HSO4, NO4, acetate or 1/3 phosphate, and R is aryl, alkyl, alkylthio, amino, substituted amino or arylalkyl.

Examples of amidines include acetamidine hydrochloride, benzamidine hydrochloride and S-methyl-isothiourea sulfate.

As nitrite salt can be used alkali metal or alkaline earth metal nitrite, preferably sodium nitrite.

With respect to the amount ratios, 0.1-1.1 moles of nitrite, preferably 1.01 moles of nitrite, are preferably used. mole malonic acid dinitrile.

The amount of solvent in the first reaction step is not critical and is conveniently 200 to 2000 ml per liter. mole of malonic acid dinitrile. Preferably, 300-400 ml of solvent is used per day. mole malonic acid dinitrile.

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In the second reaction step, where dimethylformamide is used and optionally a pyridine base as solvent, 100 to 2000 / preferably 300 to 500 ml of solvent can be used. mole malonic acid dinitrile.

In a preferred embodiment, 5-nitroso-2,4,6-triamino-pyrimidine is prepared by reacting malonic acid dinitrile and guanidine hydrochloride at a pH below 6.9 in the presence of sodium nitrite to the guanidine salt of the isonitroso-malonitrile. and by refluxing in dimethylformamide, the guanidine salt of the isonitroso malonitrile is converted to 5-nitroso-2,4,6-triamino-pyrimidine.

After the isomerization reaction, the red suspension of 5-nitroso-2,4,6-triamino-pyrimidine in dimethylformamide 15 can be diluted with water, the product removed by filtration or centrifugation and washed with water. For many turnovers, the moist product can be used. If necessary, it can be dried by heating in the usual manner. 5-Nitro-so-2,4,6-triamino-pyrimidine is an intermediate with many uses, e.g. for the preparation of drugs such as the triamter and methothrexate and for the preparation of dye components such as 2,4,5,6-tetramino-pyrimidine.

The process of the invention is illustrated in the following examples.

Example 1

To a suspension of 66 g of malonitrile and 96 g of guanidine hydrochloride in 200 g of water is added dropwise at room temperature a solution of 70 g of sodium nitrite in 120 g of water, keeping the pH at 4 by the addition of hydrochloric acid. After 30 further reaction for 4 hours at room temperature, 21 g of sodium carbonate and 400 g of dimethylformamide are added and the water is distilled off under reduced pressure. Then, the reaction mixture is heated for 1 hour at 140 ° C, with isomerization to 5-nitroso-2,4,6-triamino-pyrimidine. After the reaction is complete, 400 ml of water are added and the product is filtered off and washed with water.

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After drying, 140 g of pure raspberry red 5-nitroso-2,4 / 6-triamino-pyrimidine are obtained, m.p. > 340 ° C. Yield: 91%.

Example 2

To a suspension of 33 g of malonitrile and 52 g of acetamidine-5 hydrochloride in 100 g of water is added dropwise at pH 4 and at room temperature a solution of 37.5 g of sodium nitrite in 60 g of water. After further reaction for 4 hours, the reaction mixture is cooled to 0 ° C and the product is filtered off. The acetamidine salt of isonitroso-malonitrile is obtained with m.p. 142-143 ° C (decomposition) in almost quantitative yield (84% isolated).

Example 3

To a suspension of 13.2 g of malonitrile and 32 g of benzamidine hydrochloride in 25 g of water is added dropwise at pH 15 3-5 and at 20 ° C a solution of 14 g of sodium nitrite in 25 g of water. After further reaction for 5 hours and cooling to 0 ° C, the reaction product is suctioned and dried. The benzamidine salt of isonitroso-malonitrile is obtained with m.p. 150 ° C (decomposition) in almost quantitative yield (94% isolated).

Example 4

To a suspension of 33 g of malonitrile and 70 g of S-methyl-isothiourea sulfate in 100 ml of water is added dropwise at pH 4 and at room temperature a solution of 35 g of sodium nitrite in 60 ml of water. After further reaction for 5 hours, the reaction mixture is cooled to 4 ° C and then filtered.

After drying, the S-methylisothiouronium salt of isonitroso-malonitrile is obtained in very high yield (76% isolated), m.p. 123-124 ° C (dec.).

Example 5

To a suspension of 66 g of malonitrile and 97 g of guanidine hydrochloride in 120 ml of water is added dropwise at pH 4 and at room temperature a solution of 70 g of sodium nitrite in 120 ml of water. After stirring for 4 hours, the mixture is cooled

DK 159681 B

7 to 0 ° C and then filtered.

After drying in vacuo at relatively low temperature, the guanidine salt of isonitroso-malonitrile is obtained in almost quantitative yield (84% isolated), m.p. 160-161 ° C (dec.).

The further reaction of these amidine salts of the isonitroso malonitrile prepared according to Examples 2-5 to the corresponding 2-substituted 5-nitroso-4β-diamino-pyrimidines is carried out by heat treatment in dimethylformamide in basic environment as described by E.C. Taylor et al., J. Am. Chem. Soc.

81, 2442 (1959).

Claims (3)

A process for the preparation of 2-substituted 5-nitroso-4,6-diamino-pyrimidines of the general formula NH 2 NO n / v 5 l | Wherein R is aryl, alkyl, alkylthio, amino, substituted amino or arylalkyl, characterized in that malonic acid dinitrile is reacted with an amidine or guanidine of the general formula NH.HA R - (II) Xnh2 wherein A means Cl, 1/2 SC> 4, HSO4, NO3, acetate or 1/3 phosphate and R has the meaning given above, in water or alcohol in an acidic environment in the presence of a nitrite salt to the corresponding amidine salt or guanidine salt of isonotroso-malonitrile, which in dimethylformamide in the basic environment upon heat treatment is converted to the corresponding 2-substituted 5-nitroso-4,6-diamino-pyrimidine. Process according to claim 1, characterized in that alkali metal or alkaline earth metal nitrite, preferably sodium nitrite, is used as nitrite salt. Process according to claims 1-2 for the preparation of 5-nitroso-2,4,6-triamino-pyrimidine, characterized in that malonic acid dinitrile is reacted with guanidine hydrochloride in water at a pH below 6.9 in the presence of sodium. 25 nitrite to the guanidine salt of isonitroso-malonitrile, which in a basic environment when refluxed in dimethylformamide at reflux, is converted to 5 ^ nitroso-2,4,6-triamino-pyrimidine.