JPH0432824B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION (Field of Industrial Application) The present invention relates to a new method for producing 2,4-diamino-5-formylpyrimidine. 2,4
-Diamino-5-formylpyrimidine and compounds obtained by variously converting the amino groups at the 2 and 4 positions and the formyl group at the 5 position into other functional groups are useful compounds as synthetic intermediates for pharmaceuticals and agricultural chemicals. For example, 2, in which the formyl group at position 5 is reduced by a conventional method,
4-Diamino-5-hydroxymethylpyrimidine can be an intermediate for 2,4-diamino-5-benzylpyrimidine derivatives, which are important as antibacterial and antimalarial agents.

(Prior art) Conventionally, as a method for producing 2,4-diamino-5-formylpyrimidine, 2,4-diamino-5-cyanopyrimidine was heated in a formic acid solvent, and Raney-nickel alloy (Ni/Al=50 /50) (J.Med.Chem.667 (1983)), and a method of reducing the above raw materials with hydrogen using 10% Pd/C in an aqueous hydrochloric acid solution (J.Med.Chem. 1238 (1968)), and the above-mentioned documents include 2,4-diamino-
It is stated that 5-formylpyrimidine was obtained in a crude yield of 76-80%.

(Problems to be Solved by the Invention) These methods require the use of large amounts of expensive reducing agents (catalysts), and both pose problems from an industrial perspective.

(Means for Solving the Problems) The present inventors have conducted extensive studies with the aim of establishing an industrially advantageous method for producing 2,4-diamino-5-formylpyrimidine.

As a result, general formula (I) or () [However, in formulas (I) and (), R ¹ , R ² ,
R ³ , R ⁴ and R ⁵ represent the same or different lower alkyl groups. 2,4-diamino-5-formylpyrimidine can be produced in an extremely industrially advantageous manner by reacting the propanenitrile represented by We have discovered that it can be manufactured, and have arrived at the present invention.

Next, the present invention will be explained in detail.

2-dialkoxymethyl-3,3-dialkoxypropanenitrile represented by the general formula (I), which is a raw material of the present invention, and the general formula ()
2-alkoxymethylene-3,3-
R ¹ , R ² in dialkoxypropanenitrile,
R ³ , R ⁴ and R ⁵ are methyl, ethyl, propyl,
Examples include lower alkyl groups having 1 to 4 carbon atoms such as butyl. These R ¹ , R ² , R ³ , R ⁴ and R ⁵ may all be the same group, may be partially the same group, or may be all different groups.

These raw materials, propanenitrile, are, for example, 3
-Alkoxy-2-propenenitrile or 3,3-dialkoxypropanenitrile is mixed with a formylating agent such as formate or carbon monoxide in the presence of an alkali metal alcoholate at 0 to 100°C.
2-Hydroxymethylene-
By obtaining an alkali metal salt of 3,3-dialkoxypropanenitrile and then reacting the salt with an alkylating agent such as a dialkyl sulfate, an alkyl halide, or with a neutralizing equivalent or more of a mineral acid in an alcohol. Therefore, it can be easily obtained.

In any of the above methods, the propane nitriles obtained are often obtained in the form of a mixture of general formulas (I) and (), but their separation can be carried out by conventional methods such as distillation or column chromatography. I can do it.

In the present invention, the raw material propanenitrile represented by the above general formula (I) or () may be used alone or in the form of a mixture.

In addition, since guanidine, one of the raw materials, is an unstable substance, it is used in the form of a salt with an inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, or carbonic acid, or an organic acid such as acetic acid, and is released in the reaction system. Preferably, guanidine is obtained. Useful bases used to obtain free guanidine in the reaction system include sodium alcoholates, alkali hydroxides, alkali carbonates, alkali bicarbonates, and anion exchange resins. Note that guanidine carbonate may not require a neutralizing base.

The amount of guanidine salt used is preferably 0.5 to 10 mol, particularly 1 to 3 mol, per 1 mol of the propanenitrile represented by the general formula (I) or (). Further, the above-mentioned base is usually used in an amount equivalent to neutralizing the guanidine salt.

By reaction with propanenitrile guanidine represented by general formula (I) or (), 2,
It is believed that 4-diamino-5-dialkoxymethylpyrimidine is produced.

The above reaction may be carried out without a solvent, or in a solvent inert to the reaction. As such a solvent, aliphatic alcohols having 1 to 4 carbon atoms, such as methanol, ethanol, propanol, and butanol, are most preferable, but in addition, dioxane, tetrahydrofuran,
Ether solvents such as dimethoxyethane and diethyl ether; Hydrocarbon solvents such as benzene, toluene, hexane, and cyclohexane; Halogenated hydrocarbon solvents such as methylene chloride, chloroform, carbon tetrachloride, and dichloroethane; Acetonitrile, propionitrile, etc. Nitrile solvents and the like can also be used.

The amount of these solvents used is 1
It is preferable to use 0.3 to 30 parts by weight per part by weight. The reaction is carried out at a temperature of 0 to 130°C under normal pressure to pressurization for 0.5 to 24 hours.

The reaction product is obtained by removing the reaction product from the reaction solution.
Although the reaction product may be isolated by a method known per se such as concentration, extraction, or recrystallization and used in the next hydrolysis reaction, the reaction product may be isolated from the reaction solution and the reaction solution containing the reaction product may be used. Hydrolysis by adding a fixed amount of acid and water is more preferable because the operation can be simplified and there is no loss of reaction products due to isolation operations.

Examples of acids used in the present invention include mineral acids such as hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid, p-toluenesulfonic acid, and cation exchange resins. These acids are preferably used in an amount of 0.5 to 5 mol per mol of propanenitrile. Further, the amount of water used for hydrolysis is not particularly limited, but it is usually preferably used in an amount of 2 to 100 parts by weight per 1 part by weight of the intermediate reaction product.

The conditions for hydrolysis are appropriately selected depending on the concentration of the raw materials, the amount of acid, etc., but the target product, 2,4-diamino-5, is usually - The formylpyrimidine can be obtained in the form of an acid addition salt.

After completion of the reaction, 2,4-diamino-5-formylpyrimidine can be easily isolated and purified by appropriately employing operations such as neutralization, extraction, concentration, filtration, and recrystallization.

(Effects of the Invention) The present invention does not require the use of large amounts of expensive reducing agents, and the target compound can be easily obtained in a high yield of over 90%, and its industrial value is high.

(Example) Next, examples of the present invention will be given.

Example 1 11.6 g (60 mmol) of 28 wt% sodium methylate in methanol and guanidine sulfate
6.48 g (60 mmol) was stirred at room temperature for 30 minutes. Next, 7.85 g (50 mmol) of 2-methoxymethylene-3,3-dimethoxypropanenitrile was added,
The temperature was raised and the mixture was refluxed for 4 hours.

Thereafter, 75 ml of 1N sulfuric acid was added to the residue after concentrating to remove most of the methanol, and the mixture was stirred for 1 hour while maintaining the liquid temperature at 80°C. After the reaction was completed, 35 wt% caustic soda aqueous solution was added little by little to neutralize. After leaving it at room temperature overnight, remove the precipitated crystals and wash with water.
Vacuum drying was performed at °C to obtain 6.60 g of white crystals. The white crystals were quantified by liquid chromatography using an internal standard method. The yield of 2,4-diamino-5-formylpyrimidine was 93.5%.

When the above white crystals were recrystallized from water and the melting point was measured, it was 272-274℃ (decomposition), and NMR,
It was confirmed by MS and IR that it was 2,4-diamino-5-formylpyrimidine.

Example 2 A solution obtained by stirring 10.2 g (52.9 mmol) of a methanol solution of 28 wt% sodium methylate and 4.73 g (49.5 mmol) of guanidine sulfate at room temperature for 30 minutes was mixed with 2-n-butoxymethylene-3,3-di-
After adding 14.2 g (50.2 mmol) of n-butoxypropanenitrile to 40 ml of n-butanol solution, the mixture was heated and stirred at 80° C. for 2 hours.

Then, add 5 ml (58.2 mmol) of concentrated hydrochloric acid to 70 ml of water.
A solution dissolved in was added to the mixture, and stirring was continued for an additional 1 hour and 30 minutes at 80°C. After the reaction was completed, 35 wt% caustic soda aqueous solution was added little by little to neutralize. After standing overnight at room temperature, the precipitated crystals were collected, washed with cold methanol and water, and then vacuum dried at about 50°C to obtain 6.65 g of white crystals. When this white crystal was quantified by liquid chromatography using the internal standard method,
The yield of 2,4-diamino-5-formylpyrimidine was 94.3%.

Example 3 Ethanol solution of 2N-sodium ethylate
30 ml and 5.73 g (60 mmol) of guanidine hydrochloride were stirred at room temperature for 15 minutes.

Next, 10.3 g (60.2 mmol) of 2-ethoxymethylene-3,3-dimethoxypropanenitrile was added, the temperature was raised, and the mixture was refluxed for 3 hours.

Thereafter, 100 ml of 1N hydrochloric acid was added to the residue from which most of the ethanol had been removed by concentration, and stirring was continued for 5 hours while maintaining the liquid temperature at 60°C. After the reaction was completed, the same procedure as in Example was carried out to obtain white crude crystals, which were quantified by liquid chromatography. The yield of 2,4-diamino-5-formylpyrimidine was 92.8%.

Example 4 After dissolving 7.85 g (50 mmol) of 2-methoxymethylene-3,3-dimethoxypropanenitrile in 50 ml of n-butanol, 4.95 g (55 mmol) of guanidine carbonate was added while stirring at room temperature, and the temperature was raised. The mixture was then refluxed for 3 hours. After cooling the above reaction solution, 0.5N−
Add 200ml of hydrochloric acid, keep the liquid temperature at 80℃, and add 1
Stirring was continued for 30 minutes. After the reaction was completed, the mixture was cooled and separated into a butanol layer and an aqueous layer. The washing liquid obtained by washing the butanol layer with water is added to the aqueous layer, and the 2,4
-Diamino-5-formylpyrimidine was determined by liquid chromatography using an internal standard method.
The yield of 2,4-diamino-5-formylpyrimidine was 91.9%.

Example 5 2-n-butoxymethylene-3,3-di-n-
Instead of butoxypropane nitrile, 2-di-
The procedure of Example 2 was repeated except that 17.8 g (49.9 mmol) of n-butoxymethyl-3,3-di-n-butoxypropane nitrile was used to obtain white crude crystals, which were quantified by liquid chromatography.

The yield of 2,4-diamino-5-formylpyrimidine was 91.2%.

When the above white crude crystals were recrystallized from water and the melting point was measured, it was 272-274℃ (decomposition), and NMR,
It was confirmed by MS and IR that it was 2,4-diamino-5-formylpyrimidine.

Claims (1)

[Claims] 1 General formula (I) or () [However, in formulas (I) and (), R ¹ , R ² ,
R ³ , R ⁴ and R ⁵ represent the same or different lower alkyl groups. A method for producing 2,4-diamino-5-formylpyrimidine, which comprises reacting a propanenitrile represented by the following with guanidine, and then hydrolyzing the resulting reaction product in the presence of an acid.