IE56419B1 - Process for the preparation of 2-substituted 5-nitroso-4,6-diaminopyrimidines - Google Patents

Abstract

1. A process for producing 2-substituted 5-nitroso-4,6-diamino pyrimidine of the general formula : see diagramm : EP0115325,P5,F1 wherein R is aryl, alkyl, alkylthio, amino, amino substituted by one or two C1 to C4 alkyl groups, or arylalkyl, which comprises the steps of reacting malonic dinitrile with an amidine or guanidine of the general formula : see diagramm : EP0115325,P5,F2 wherein A is Cl, 1/2 SO4 , HSO4 , NO3 , acetate, or 1/3 PO4 , and R has the meaning stated above, in water or alcohol in an acid milieu and in the presence of a nitrite salt to form the respective amidino or guanidino salt of isonitroso-malonitrile, and converting the salt thus obtained in a manner known per se by thermal treatment in dimethyl formamide or a pyridine base in a basic milieu to produce the respective 2-substituted 5-nitroso-4,6-diamino pyrmidine.

Description

The present invention is concerned with a process for the preparation of 2-substituted 5-nitroso4,6-diaminopyrimidines.

If is known that 5-nitroso-2,4,6-triamino5 pyrimidine can be prepared from malodinitrile and a guanidine salt. 2,4,6-Triaminopyrimidine is obtained in moderate yield by the condensation of malodinitrile and guanidine hydrochloride or nitrate in the presence of a sodium alcoholate in alcoholic solution (w. Traube, Ber®, 37, 4544/1904; H« Sato et al., J® Chem® Soc® Japan Pure Chem. Sect®, 7 2, 866/1951; and Chem® Abstr., 47, 5946/1953). This pyrimidine * is then nitrosated with nitrous acid to give 515 nitroso-2,4,6-triaminopyrimidine (M.F0 Mallette & ι et al., J. Am. Chem, Soc., 69, 1814/1947). These processes have the disadvantage that they are too laborious for large-scale preparations and that the maximum1 yield of 5-nitroso-2,4,6-triaminopyrimidine is 75 to 78%, referred to the amount of malodinitrile used* Attempts have been made to simplify this process by. not isolating the intermediate product 2,4,6triaminopyrimidine (see Swiss Patent Specification No. 630,616)* However, this process still has several disadvantages; expensive sodium alcoholate has fo be used, at least two moles of salt (sodium chloride and sodium acetate) are produced per mole of malodinitrile employed, the reaction has to be carried out using relatively dilute solutions (about 2 litres of solvent per mole of product) and, finally, the recovery of the solvent is very difficult because a 4-coraponenf solvent mixture (methanol, ethanol, glacial acetic acid, water and by-products) is present.

Another route for the preparation of 5-nitroso2,4,6-triaminopyrimidine has been described by E.Co Taylor et al. (J. Am. Chem. Soc·, 81, 2442/1959); 5-nitroso-2,4,6-triaminopyrimidine is obtained in 88% yield by heating the potassium salt of isonitroso25 malonitrile with guanidine carbonate in dimethylformamide. Since the potassium salt is prepared from the silver salt of isonifrosomalonifrile, this process is unsuitable for large-scale industrial production.

French Patent Specification No. 1,364,734 describes a process in which malodinitrile in aqueous acetic acid solution is first nitrosated with sodium nitrite and the isonitrosomalonitrile solution formed is then treated with guanidine carbonate, carbon dioxide being evolved and the $ guanidine salt of isonitrosomalonitrile being obtained. This salt suspension is then cooled to about 0°C. and filtered and the guanidine salt of isonitrosomalonitrile is dried. After the addition of potassium carbonate to the salt in dimethylformamide, the mixture is heated under reflux in order to bring about isomerisation to 5-nitroso2,4,6-1 ri ami nopyrimidine.

This process represents a certain degree of progress compared with Taylor0s process but it still has several disadvantages. Thus, the acetic acid has to be used in excess (10%, according to the example). This excess has to bs neutralised with guanidine carbonate in order that the formation of the guanidine salt of isonitrosomalonitrile goes to completion. Cooling the aqueous suspension to about 0°C. involves technical difficulties since a crust <9 of ice is formed on the inside of the reaction vessel.

When the mixture is cooled to temperatures which are not quite so low, the salt is not precipitated completely. From the point of view of safety, drying the guanidine salt of isonitrosomalonitrile involves risks.

In the treatment of crude isonitrosomalonitrile 5 solution with guanidine carbonate, one equivalent of carbon dioxide is formed. Therefore, the reaction mixture has a tendency to foam during this operation so that the capacity of the reaction vessel cannot be optimally utilised.

It is an object of the present invention to avoid these disadvantages and to provide a process which makes it possible to prepare 2-substituted 5nitroso-4,6-diaminopyrimidines in a simple and economical manner and in high yield.

Thus, according to the present invention, there is provided a process for the preparation of 2substituted 5-nitroso-4,6-diaminopyrimidines of the general formula:- NO nh2 wherein R is aryl, alkyl, alkylthio, amino, amino substituted by one or two to C4 alkyl groups, or arylalkyl, wherein malodinitrile is reacted with an amidine of the general formula:- NH · ΝΛ wherein A denotes chlorine 1/2 S04, hydrogen sulphate, nitrate, acetate or 1/3 PO4 and R has the same meaning as above, in water or an alcohol in an acidic medium and in the presence of a nitrite salt to give the corresponding amidine or guanidine salt of isonitrosomalonitrite and the amidine or guanidine salt of the isonitrosomalonitrile is converted into the corresponding 2substituted 5-nitroso-4, 6-diaminopyrimidine by heat · ing in dimethylformamide or a pyridine base in a basic medium.

In the process of the present invention, malodinitrile, in water or an alcohol as solvent, is nitrosated with an amidine or guanidine in an acidic medium in the presence of a nitrite salt, the X5 amidine or guanidine salt of isonitroscpialonitrile being formed directly in aqueous or alcoholic suspension. This salt is not isolated; instead, the reaction mixture is rendered basic and, after dimethylformamide or a pyridine base has been added, the water or the alcohol is distilled off under reduced pressure.

After the water or the alcohol has been virtually completely removed, the reaction mixture is subjected to heat treatment and is advantageously heated under reflux, the corresponding 2-substituted «; .β -nitroso-4,6-diaminopyrimidine thereby being formed.

An acidic medium ie to be understood fo mean one with a pH value of below 6.9 and a basic medium is to be understood to mean one with a pH value of above 7.1.

The reaction which takes place according to the present invention is illustrated by the following equation :10 NC CN NaA wherein A and R have the same meanings as above.

Examples of (1) which can be used include acetamidine hydrochloride, benzamidine hydrochloride, S-methylisothiourea sulphate and guanidine hydrochloride.

According to particular embodiments of the invention, the substituent R in the above formulae preferably has the following meanings: aryl = phenyl; alkyl = C^-C^-alkyl; alkylthio - C^-C4 20 alkylthio? or arylalkyl = phenyl-Ci-C^alkyl. Α Alkali metal and alkaline earth metal nitrites can be used as the nitrite salt, sodium nitrite being preferred.

It is advantageous to use 0.1 to 1.1 mol of 5 nitrite and preferably 1.01 mol of nitrite per mole of malodinitrile.

The amount of solvent used for the first stage of the reaction is not critical, it being advantageous < to use 200 to 2,000 ml. per mole of malodinitrile 10 and preferably 300 to 400 ml. of solvent per mole of malodinitrile® In the second stage of the reaction, with dimethylformamide or a pyridine base as the solvent, 100 to 2,000 ml. and preferably 300 to 500 ml® of solvent can be employed per mole of malodinitrile.

In a preferred embodiment, 5-nitroso-2,4,6triaminopyrimidine is prepared as follows: malodinitrile and guanidine hydrochloride are reacted at a pH of below 6.9 in the presence of sodium 2o nitrite to give the guanidine salt of isonitrosomalonitrile and the guanidine salt of isonitrosomalonitrile is converted to 5-nitroso-2,4/6-triaminopyrimidine by boiling under reflux in dimethylformamide.

According to a particular embodiment of the process of the invention the heat treatment is carried out by heating under reflux. & After the Isomerisation reaction, the red suspension of 5-nitroso-2, 4, 6-triaminopyrimidine in dimethylformamide can be diluted with water and the product can be separated off by filtration or centrifuging and washed with water. For many reactions, the moist product can be used. If necessary, it can be dried by heating in a conventional manner.

-Nitroso-2, 4, 6-triaminopyrimidine is a versatile intermediate product. Thus, for example, it can be used for the preparation of nharmaceuticals, such as triamterene and methotrexate, and for the preparation of dyestuff components, such as 2,4,5,6tetraaminopyrimidine.

The following Examples are given for the purpose of illustrating the present invention :- ' Example 1. ί A solution of 70 g. of sodium nitrite in 120 g. of water was added dropwise at ambient temperature to a suspension of 66 g. of malonitrile and 96 g. of guanidine hydrochloride in 200 g. of water, the pH being kept at 4 by the addition of hydrochloric acid.

After the reaction had continued for 4 hours at ambient temperature, 21 g. of sodium carbonate and 400 g. of dimethylformamide were added and the water was distilled off under reduced pressure. Thereafter, the reaction mixture was heated at 140°C. for 1 hour, isomerisation to 5-nitroso-2,4,6-triaminopyrimidine thereby taking place. After the reaction was complete, 400 ml. of water were added and the product was filtered off and washed with water.

After the product had been dried, 140 g. of pure raspberry-red 5-nitroso-2,4,6-triaminopyrimidine were obtained; m.p. above 340°C.; yield 91% of theory, r Example2.

A A solution of 37.5 g. of sodium nitrite in g. of water was added dropwise to a suspension of 33 g® of malonitrile and 52 g® of acetamidine hydrochloride in 100 g. of water at pH 4 and at ambient temperature. After the reaction had con5 tinued for 4 hours, the reaction mixture was cooled to 0°C. and the product was filtered off. The acetamidine salt of isonitrosomalonitrile (m.p. 142 143°C. (decomposition)), was obtained in virtually quantitative yield (84% isolated).

Example 3.

A solution of 14 g. of sodium nitrite in 25 g. of water was added dropwise to a suspension of 13.2 g. of malonitrile and 32 g. of benzamidine hydrochloride in 25 g. of water at pH 3 to 5 and at °C. After the reaction had continued for 5 hours, the reaction mixture was cooled to 0°C. and the reaction product was filtered off with suction and dried. The benzamidine salt of isonitrosomalonitrile (m.p. 150°C. (decomposition)) was obtained in virtually quantitative yield (94% isolated).

Example 4.

A solution of 35 g. of sodium nitrite in 60 ml. of water was added dropwise to a suspension of 33 g. of malonitrile and 70 g. of S-methylisothiourea sulphate in 100 ml. of water at pH 4 and at ambient temperature. After the reaction had continued for hours, the reaction mixture was cooled to 4°C® and . the product was filtered off. After- the product had been dried, the S-methylisothiouronium salt of isonitrosomalonitrile was obtained in a very high yield (76% isolated): m.p. 123 to 124°C. (decompos5 ition).

A Example 5.

A solution of 70 g. of sodium nitrite in C 120 ml. of water was added dropwise to a suspension of 66 g. of malonxtrile and 97 g. of guanidine hydrochloride in 120 ml. of water at pH 4 and at ambient temperature. After the mixture had been stirred for 4 hours, it was cooled to 0°C. and the product was filtered off. After the product had been dried in vacuo, the guanidine salt of iso15 nitrosomalonitrile waa obtained in virtually quantitative yield (84% isolated); m.pe 160 to 161°C. (decomposition).

Claims (6)

CLAIMS:

1. A process for the preparation of a 2-substituted 5-nitroso-4, 6-diamlnopyrimidine of the general formula:- wherein R is aryl, alkyl, alkylthio, amino, amino substituted by one or two C^ to C 4 alkyl groups, or arylalkyl, which comprises reacting malodinitrile with an amidine of the general formula:.NH . HA —<„ 2 wherein A denotes chlorine, 1/2 SO^, hydrogen sulphate, nitrate, acetate or 1/3 P0 4 and R has the same meaning as above, in water or an alcohol in an acidic medium and in the presence of a nitrite salt to give the corres15 ponding amidine or guanidine salt of isonitrosomalonitrile and converting the salt thus obtained into the corresponding 2-substituted 5-nitroso-4, 6-diaminopyrimidine by heating in dimethylformamide or a pyridine base in a basic medium. 1 41

2. A process according to claim 1, wherein an alkali metal or alkaline earth metal nitrite is used as the nitrite salt.

3. A process according to claim 2, wherein the nitrite salt used is sodium nitrite.

4. A process according to any of the preceding claims for the preparation of 5-nitrosd-2,4,6triaminopyrimidine, wherein malodinitrile is reacted with guanidine hydrochloride in water at a pH of below 6.9 in the presence of sodium nitrite to give the guanidine salt of isonitrosomalonitrile and the guanidine salt of isonitrosomalonitrile is converted in a basic medium into 5-nitroso-2,4,6-triaminopyrimidine by boiling under reflux in a solvent.

5. A Droces3 according to any of the preceding claims for the preparation of 2-substituted 5nitroso-4,6-diaminopyrimidines, substantially as hereinbefore described and exemplified„

6. A 2-substituted 5-nitroso-4, 6-diaminopyrimidine, whenever prepared by the process according to any of claims 1 to 5.