JPS626709B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a new method for producing 2-alkyl-4-amino-5-aminomethylpyrimidine.

2-Alkyl-4-amino-5-aminomethylpyrimidine is known to be an important synthetic intermediate of vitamin _B1 and its analogues.

Conventional methods for producing 2-alkyl-4-amino-5-aminomethylpyrimidine include, for example, a method of reducing 2-alkyl-4-amino-5-cyanopyrimidine, and a method of reducing 2-alkyl-4-amino-5-acetamidomethylpyrimidine. Methods of hydrolysis are known.

The present inventors have found that if 2-alkyl-4-amino-5-formylpyrimidine is first subjected to a catalytic reaction with ammonia and hydrogen in the presence of a reduction catalyst to undergo reductive amination, yields can be obtained even higher than in known methods. rate of 2-
It was discovered that alkyl-4-amino-5-aminomethylpyrimidine could be produced, and a patent application was filed as Japanese Patent Application No. 1983-22122. However, with this method, the desired product can be produced with a yield of about 80 to 90%, but 2-alkyl-
The problem is that about 10% of 4-amino-5-hydroxymethylpyrimidine and di-(2-alkyl-4-amino-5-pyrimidylmethyl)amine are produced.

The present inventors subsequently conducted extensive research to improve this problem, and found that if a divalent nickel salt is present in the reaction system, the formation of the above-mentioned by-products can be suppressed, resulting in an extremely high yield. The inventors discovered that the desired object could be obtained and completed the present invention.

That is, the present invention is characterized in that 2-alkyl-4-amino-5-formylpyrimidine is catalytically reacted with ammonia and hydrogen in the presence of a divalent nickel salt and a reduction catalyst. A method for producing -amino-5-aminomethylpyrimidine is provided.

The structural formula of 2-alkyl-4-amino-5-formylpyrimidine as a raw material in the present invention is represented by the following general formula.

However, R in the formula can include lower alkyl groups such as methyl, ethyl, propyl, and butyl.

The raw material is, for example, 2-alkyl-4-amino-
It can be easily synthesized by hydrolyzing 5-dialkoxymethylpyrimidine in the presence of an acid. The raw material 2-alkyl-4-amino-5-formylpyrimidine can also be used as a mineral acid salt such as sulfuric acid, nitric acid, hydrochloric acid, or phosphoric acid.

As the reduction catalyst used in the present invention, Raney
Mention may be made of nickel, stabilized nickel, or Group 8 metals such as palladium, platinum, rhodium, ruthenium, gobalt, iron, and metals such as copper and chromium. These metals are usually used in the form of metals, but they can also be used in the form of salts, oxides, or alloys. Among these reduction catalysts, Raney-nickel and stabilized nickel are particularly useful, and Raney-nickel may be developed by conventional methods. These catalysts can be used alone or in combination.
The catalyst may be used as a mixture of more than one species, and the catalyst may be activated with, for example, hydrogen gas prior to use. These catalysts can also be used by being supported on a carrier such as activated carbon, alumina, silica, silicon carbide, diatomaceous earth, pumice, zeolite, or molecular sieve.

These catalysts are 0.001 to 3 gram atoms, preferably 0.002 to 2 gram atoms per mole of raw material 2-alkyl-4-amino-5-formylpyrimidine in terms of metal.
Gram atoms are used.

The divalent nickel salts used in the present invention include nickel chloride, nickel bromide, nickel sulfate, nickel nitrate, nickel phosphate, nickel carbonate, nickel hydroxide, nickel acetate, nickel oxalate, nickel benzoate, and nickel chloride. Examples include ammonium, nickel ammonium sulfate, and nickel potassium sulfate. These divalent nickel salts may be used alone or in combination with
It is also possible to use more than one species in combination. Also, these 2
A nickel salt with crystalline water may be used. The amount used is the raw material 2-alkyl-4
The amount is 0.1 to 5 mol, preferably 0.4 to 1.0 mol, per mol of -amino-5-formylpyrimidine.
When the amount used is less than the lower limit of the above range, 2-alkyl-4-amino-5-hydroxymethylpyrimidine or di-(2-alkyl-
The effect of suppressing by-products such as 4-amino-5-pyrimidylmethyl)amine is not expected to be significant, and on the other hand, if the amount exceeds the upper limit of the above range, the yield of the target product tends to decrease.

Ammonia can be used in the form of liquid ammonia, ammonia gas, or an ammonia aqueous solution, and the amount used is 1 mol or more, preferably 4 to 500 mol per mol of 2-alkyl-4-amino-5-formylpyrimidine as a raw material. It is a mole.

Further, hydrogen is preferably used in an amount of 1 mole or more, preferably 5 to 400 moles, per mole of 2-alkyl-4-amino-5-formylpyrimidine as a raw material.

The reaction can also be carried out in a solvent inert to the reaction. As a solvent, methanol, ethanol,
Examples include lower aliphatic alcohols such as propanol and butanol, ethers such as dioxane, tetrahydrofuran and diethyl ether, hydrocarbons such as benzene, toluene, xylene, hexane and cyclohexane, and water.

The reaction is carried out at a temperature of 0 to 200°C, preferably room temperature to 120°C. Although the reaction proceeds at normal pressure, it proceeds more quickly under increased pressure, so it is usually carried out under a hydrogen partial pressure of 1100 Kg/cm ² G. A reaction time of about 0.5 to 10 hours is sufficient.

As a reaction operation, for example, a method of simultaneously reacting 2-alkyl-4-amino-5-formylpyrimidine with ammonia and hydrogen in the coexistence of a divalent nickel salt and a reduction catalyst, or a method of simultaneously reacting 2-alkyl-4-amino-5-formylpyrimidine with ammonia and hydrogen, or 2-alkyl-4- The reaction can be carried out by first reacting amino-5-formylpyrimidine with ammonia, and then blowing hydrogen into the system to react with hydrogen. Furthermore, a method in which 2-alkyl-4-amino-5-formylpyrimidine and ammonia are first reacted in a divalent nickel salt, and then a reduction catalyst is added to the system and hydrogen is blown into the system to react with hydrogen; This can also be done by

After the completion of the reaction, for example, after cooling the reaction solution and removing insoluble matter such as the catalyst, 2-alkyl-4-amino-5-aminomethylpyrimidine represented by the following general formula is converted into free or mineral acid salt by a conventional method. It can be isolated and obtained in the form of

(However, R in the formula has the same meaning as above).

Next, examples of the present invention and comparative examples will be given.
The yield of the product in each example is based on the 2-alkyl-4-amino-5 raw material used.
- Formylpyrimidine standard.

Example 1 In a stainless steel autoclave with an internal volume of 100 ml, 1.37 g (10 mmol) of 2-methyl-4-amino-5-formylpyrimidine, 24 g of a 20 wt% ammonia methanol solution, and anhydrous nickel chloride were added.
After charging 0.74 g (5.7 mmol) and replacing the inside of the system with nitrogen gas, the temperature was raised while stirring the contents until the temperature reached approx.
It was kept at ℃ for 1 hour. Next, cool it down, open the autoclave, and stabilize the nickel (trade name, N103B; manufactured by JGC Chemical Co., Ltd.; approximately 50 wt% nickel, approximately 50 wt% diatomaceous earth).
After charging 0.46 g of 50 wt%) and purging the system with nitrogen gas, hydrogen gas was injected to a pressure of about 30 kg/cm ² G, and the temperature was raised with stirring to carry out a reaction at about 90°C for 2 hours. .

After the reaction is completed, it is cooled and unreacted gases are depressurized.
The autoclave was opened and the catalyst was removed. The catalyst was washed with methanol and the washing solution was combined with the solution, concentrated under reduced pressure to remove most of the ammonia, and then mixed with 1N HCl.
was added to adjust the pH to approximately 3, and each product was quantitatively analyzed by liquid chromatography using an internal standard method.
The results were as follows.

Yield of 2-methyl-4-amino-5-aminomethylpyrimidine: 94.5% Yield of 2-methyl-4-amino-5-hydroxymethylpyrimidine: 0.3% Di-(2-methyl-4-amino-5 -Yield of pyrimidylmethyl)amine: 2.5% Example 2 In a stainless steel autoclave with an internal volume of 100 ml, 1.37 g (10 mmol) of 2-methyl-4-amino-5-formylpyrimidine, 24 g of a methanol solution of 20 wt% ammonia, and anhydrous chloride were added. Nickel 0.74g
(5.7 mmol) and stabilized Nickel N103B0.46
After purging the inside of the system with nitrogen gas, the temperature of the contents was raised while stirring and maintained at about 90°C for 30 minutes. Next, hydrogen gas was injected under pressure at the same temperature to give a concentration of about 30 kg/cm ² G, and the reaction was carried out at the same temperature for 2 hours, followed by quantitative analysis of each product in the same manner as in Example 1. The results were as follows.

Yield of 2-methyl-4-amino-5-aminomethylpyrimidine: 93.8% Yield of 2-methyl-4-amino-5-hydroxymethylpyrimidine: 0.5% Di-(2-methyl-4-amino-5 -Yield of pyrimidylmethyl)amine: 2.5% Comparative Example 1 An experiment was conducted in the same manner as in Example 2, except that nickel chloride was not used.
The results were as follows.

Yield of 2-methyl-4-amino-5-aminomethylpyrimidine: 88.3% Yield of 2-methyl-4-amino-5-hydroxymethylpyrimidine: 4.1% Di-(2-methyl-4-amino-5 -Yield of pyrimidylmethyl)amine: 5.8% Example 3 In a stainless steel autoclave with an internal volume of 100 ml, 1.37 g (10 mmol) of 2-methyl-4-amino-5-formylpyrimidine, 24 g of a 20 wt% ammonia methanol solution, and acetic acid were added. After charging 1.34 g (5.4 mmol) of nickel tetrahydrate and replacing the inside of the system with nitrogen gas, the temperature was raised while stirring the contents, and the temperature was increased to approx.
After holding at 90°C for 1 hour, the autoclave was cooled and opened. Next, 2.0 g of Raney nickel (nickel content: about 40 wt%) was developed and washed with water in a conventional manner, then water was replaced with methanol (about 6 g of methanol) and the system was replaced with nitrogen gas.
Hydrogen gas was pressurized to about 40 kg/cm ² G, and the temperature was raised with stirring to carry out a reaction at 90° C. for 2 hours. The results were as follows.

Yield of 2-methyl-4-amino-5-aminomethylpyrimidine: 92.9% Yield of 2-methyl-4-amino-5-hydroxymethylpyrimidine: 0.6% Di-(2-methyl-4-amino-5 -Yield of pyrimidylmethyl)amine: 2.5% Comparative Example 2 An experiment was conducted in the same manner as in Example 3, except that nickel acetate tetrahydrate was not used. The results were as follows.

Yield of 2-methyl-4-amino-5-aminomethylpyrimidine: 84.3% Yield of 2-methyl-4-amino-5-hydroxymethylpyrimidine: 5.1% Di-(2-methyl-4-amino-5 -Yield of pyrimidylmethyl)amine: 6.4% Example 4 In Example 1, instead of nickel chloride,
An experiment was conducted in the same manner as in Example 1, except that 0.75 g of NiCO ₃ .Ni(OH) ₂ .4H ₂ O (total amount of nickel salt: 5.3 mmol) was used. The result is
It was as follows.

Yield of 2-methyl-4-amino-5-aminomethylpyrimidine: 93.4% Yield of 2-methyl-4-amino-5-hydroxymethylpyrimidine: 0.4% Di-(2-methyl-4-amino-5 -Yield of pyrimidylmethyl)amine: 2.9% Example 5 Instead of 2-methyl-4-amino-5-formylpyrimidine, 1.51 g (10 mmol) of 2-ethyl-4-amino-5-formylpyrimidine was used as a raw material. , and 20 wt% ammonia in ethanol solution instead of 20 wt% ammonia in methanol solution.
The experiment was conducted in the same manner as in Example 1, except that g was used. The results were as follows.

Yield of 2-ethyl-4-amino-5-aminomethylpyrimidine: 95.1% Yield of 2-ethyl-4-amino-5-hydroxymethylpyrimidine: 1.5% Di-(2-ethyl-4-amino-5 -Yield of pyrimidylmethyl)amine: 2.0%.

Claims (1)

[Claims] 1 2-alkyl-4-amino-, which is characterized by catalytically reacting 2-alkyl-4-amino-5-formylpyrimidine with ammonia and hydrogen in the presence of a divalent nickel salt and a ring catalyst. Method for producing 5-aminomethylpyrimidine.