JPS5948464A - Preparation of 2-alkyl-4-amino-5-aminomethylpyrimidine - Google Patents

Abstract

PURPOSE:To prepare the titled compound useful as an important synthetic intermediate of vitamin B1, etc., in high yield, by reacting 2-alkyl-4-amino-5- formylpyrimidine with ammonia, and reducing the reaction product with ammonia, hydrogen and a reduction catalyst. CONSTITUTION:The objective compound of formula II can be prepared by (1) reacting the 2-alkyl-4-amino-5-formylpyrimidine of formula I (R is lower alkyl) with ammonia in an inert solvent (preferably lower aliphatic alcohol) at room temperature -110 deg.C, (2) optionally removing the ammonia insoluble in the inert solvent, (3) adding the reaction solution containing the reaction product to an inert solvent containing ammonia, hydrogen and a reduction catalyst (e.g. Raney Ni, Pd, etc.) and (4) reacting the components at room temperature -120 deg.C thereby reducing the above reaction product. The production of by-product can be suppressed compared with the direct reduction and amination of the compound of formula I .

Description

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

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 1, for example, a method of reducing 2-alkyl-4-amino-5-anopyrimidine; A method of hydrolyzing Migi/ is 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 to form a 2-alkyl-4-amino-5-formylpyrimidine into a reductive amine, the yield is even higher than in the known method. Yield of 2-alkyl-4-amine-5
They discovered that -aminomethylpyrimidine could be produced, and filed a patent application for 4 yen Application No. 57-22122. With this method, the desired product can be produced with a yield of about 80-90%. However, it has the problem that by-products such as 2-alkyl-4-amino-5-methylpyrimidine and di(2-alkyl-4-amino-5-pyrimidylmethyl)amine are produced by about 10%. However, there was still room for improvement from an industrial perspective.

As a result of extensive research into improving vaginal problems, the present inventors found that, rather than directly reducing and aminating 2-alkyl-4-amino-5-formylpyrimidine with ammonia and hydrogen, When a reaction product obtained by previously reacting 2-alkyl-4-amino-5-formylpyrimidine with ammonia in an inert solvent is added to an inert solvent containing ammonia, hydrogen, and a reduction catalyst and reduced. ,
The present invention was completed after discovering that the production of the above-mentioned by-products was suppressed and the target product could be obtained in an extremely high yield.

The present invention is.

2-Argyl-4-amino-5-formylpyrimidine is reacted with ammonia in an inert solvent.

The 2-alkyl-4- The present invention provides an extremely excellent method for producing amino-5-aminemethylpyrimidine.

2-alkyl-4-amino-5- as a raw material in the present invention
The structural formula of formylpyrimidine is represented by the following general formula: In the formula, R can be a lower alkyl group such as methyl, ethyl, propyl, and butyl.

The raw material can be easily synthesized by, for example, hydrolyzing 2-alkyl-4-amino-5-dialkoxy/methylpyrimine 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.In the present invention, these 2-alkyl-4- Amino-5
- Reacting formylpyrimidine with ammonia in an inert solvent.

Ammonia can be used as liquid ammonia, ammonia nonosu, ammonia aqueous solution, or the like.

The amount used is the raw material 2-alkyl-4-amine-5-
The amount is preferably 4 to 500 moles.

Examples of inert solvents include methanol and ethanol.

Lower aliphatic 1M alcohols such as propatool and buknol are preferred, but lower aliphatic alcohols and dioxane,
Hydrocarbons such as ether, diethyl ether, hexane, toluene, xylene, hexane, and nclohexane.

Alternatively, a mixed solvent with water or the like is also useful. Paper used for these solvents 1fJ: + It is preferable to use RO-RO-O chewing portion per 1 part by weight of the raw material 2-methyl-4-amino-5-formylpyrimidine.

Reaction (σ0~1~0°C1 Preferably room temperature~110°
It is carried out at a temperature of C. The reaction also proceeds at normal pressure, but usually the ammonia partial pressure is 1 to 100 kg/2:r.
This is done under an IF direction of /lG. Reaction time is 0.5-10
About an hour is enough.

It is estimated that this reaction converts 2-alkyl-4-amino-5-formylpyrimidine into aldimine represented by the following general formula.

(In formula 1, R has the same meaning as above.) Next, the reaction solution containing the reaction product estimated to be represented by the general formula is optionally mixed with insoluble ammonia in an inert solvent. After removing the components, the reaction product is reduced by adding it into an inert solvent containing ammonia, hydrogen and a reduction catalyst.

The addition is.

Although the reaction solution containing the reaction product may be added all at once, it is preferable to add it gradually and continuously, usually over a period of about 0.5 to 8 hours.

The reduction catalyst used is Raney nickel.

Mention may be made of stabilized nickel or group 8 metals such as palladium, platinum, rhodium, ruthenium, cobalt, v3, and metals such as copper and chromium. These metals are usually used in the metallic state, but can also be used in the form of salts, oxides, or alloys. Among these reduction catalysts, Raney nickel and stabilized nickel are particularly useful. These catalysts are useful and the lye-nickel may be developed by conventional methods.

Each catalyst may be used singly or as a mixture of two or more thereof, and the 2-sized catalyst may be activated with, for example, hydrogen gas before use. These catalysts are activated carbon and alumina.

/Lica, silicon carbide, quartz, pumice, theolite,
It can also be used in combination with a carrier such as a molecular knob.

These catalysts are based on the raw material 2-alkyl-4-a, minnow 5
- o, o in terms of metal per mol of formylpyrimidine
oi~? ) Durham atoms, preferably 0.002 to 2 grano atoms, are used.

Ammonia is liquid ammonia similar to that used in the reaction step of 2-alkyl-4-amino-5-formylpyrimi/no and ammonia.

Ammonia gas or aqueous ammonia solution may be used. The liquid used is the raw material 2-methyl-4-ami7-
The amount is preferably 1 mol or more per mol of 5-formylpyrimidine, preferably 4 to 600 mol.

There is still more than 1 mole of hydrogen per mole of 2-alkyl-4-amino-5-formylpyrimidine as a raw material.

It is preferable to use 5 to 400 moles.

The inert solvent in this step is the 2-alkyl-4
It is preferable to use the same solvent as that used in the reaction step of -amino-5-formylpyrimidine/ and ammonia, and the amount used is 1 1 of the raw material 2-methyl-4-amino-5=formylpyrimidine. 2 to 20 parts by weight
City 1j, department 1. It's so small.

The reaction in this step 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 1 to 1001 -G. It is sufficient to carry out the reaction for about 0.5 to 2 hours after adding the reaction solution containing the reaction product of 2-alkyl-4-amino-5-formylpyrimi/2 and ammonia.

After the completion of the reaction, for example, after cooling the reaction solution and removing insoluble components such as the catalyst, 2-alkyl-4-amino-5-aminomethylpyrimidine represented by the following general formula is prepared using a conventional method.
Unidirectional ILs can be produced in free form or in the form of mineral salts.

(R in the formula has the same meaning as above.) Next, an example of the present invention and a comparative example will be given.

The yield of the product on each side is based on the raw 2-alkyl-4-amino-5-formylpyrimidine used.

Example 1 A stainless steel autoclave with an internal volume of 100 me equipped with a high-pressure foot pump + 20 wt% ammonia/methanol solution 117. Stabilized nickel (trade name, N103Bi manufactured by JGC Chemical Co., Ltd.; approximately 50wt of nickel,
Approximately 50 wt.) 0.672 and hydrogen gas were charged to a temperature of approximately +10Ag, and the temperature was raised while stirring and maintained at 110°C.

Next, in a separate stainless steel autoclave with an internal volume of 100 ml, 2-methyl-4-amino-5-formylpyrimidine 2P (14.6 mmol) and a methanol solution of 20 wt% ammonia 247 were charged in advance. The reaction mixture was stirred at 90°C for 2 hours, then cooled and the autoclave was opened. The total amount of the reaction solution was
The mixture was injected into the solution maintained at 10°C over a period of 2 hours using a high-pressure feed pump, and the reaction was continued for 30 minutes using the same temperature.

After the reaction is complete, cool and depressurize any unreacted gases.

The autoclave was opened and the catalyst was removed. Combine the washing solution from which the catalyst was washed with methanol and solution E, and concentrate under reduced pressure.
After removing ammonia, the pH was adjusted to about 100 ml with 1N-HO2, and each product was softened using liquid chromatography using an internal standard method. The results were as follows.

Yield of 2-methyl-4-amino-5-aminomethylpyrimidine 94.8% Yield of 2-methyl-4-amino-5-hydroxy7methylpyrimidine 06% No(2-methyl-4-amine-5 -Yield of pyrimidylmethyl)amine: 0.9% Comparative Example 1 In a stainless steel autoclave with an internal volume of 100 me, 2
-Methyl-4-amino-5-formylpyrimidine/2y(
z, 6 mmol), 2 wt% ammonia in methanol solution 5g and stabilized nickel N103B0.67F
Add the ingredients and raise the temperature while stirring.

The reaction was carried out at 90°C for 2 hours. Next, hydrogen gas was charged at the same temperature to approximately 7ΔG, and heated to 110°C.
After raising the temperature to , the reaction was carried out for 2 hours and 60 minutes.

The treatment after the completion of the reaction was performed in the same manner as in Example 1.

The results were as follows.

Yield of 2-methyl-4-amino-5-amine methylpyrimidine: 88.1% Yield of 2-methyl-4-amino-5-hydroquinemethylpyrimidine: 2.5% Di(2-methyl-4 -Yield of amino-5-pyrimidylmethyl)amine (near, o%) Example 2 In Example 1, the amount of stabilized nickel N10BB used was changed to 1,362, and 2-methyl-4-amino-5-formylpyrimidine was used. amount of 4 f (29,2 mmol)
, and the time of continuous pressurization using the high-pressure feed pump was changed to 4 hours.

An experiment was conducted in the same manner as in Example 1. The results were as follows.

Yield of 2-methyl-4-amino-5-amine methylpyrimidine: 92.9% Yield of 2-methyl-4-7minor-5-hydroquinemethylpyrimidine 08% Di(2-methyl-4-amino- Yield of 5-pyrimidylmethyl)amine: 1.5% Comparative Example 2 2-Methyl-4-amino-5-formylpyrimidine' was placed in a stainless steel autoclave with an internal volume of 1 o ome.
47 (29.2 mmol), 20W1; methanol solution of ammonia 357. and stabilized nickel N103
B1.33f was charged, the temperature was raised while stirring, and the reaction was carried out at 90°C for 2 hours. Next, at the same temperature, hydrogen gas was charged to about 30 g/crA.

After raising the temperature to 110°C, a reaction was carried out for 4 hours and 30 minutes.

The treatment after the completion of the reaction was performed in the same manner as in Example 1.

The results were as follows.

Yield of 2-methyl-4-amino-5-aminemethylpyrimidine: 76.4% Yield of 2-methyl-4-amino-5-hydroquinemethylpyrimidine/filtration, 3% Di(2-methyl Yield of -4-amino-5-pyrimidylmethyl)amine: 14.6% Example filtration internal volume io fitted with high pressure foot pump.

In a stainless steel autoclave with 1.0 ml of a mixed solvent of methanol and dioxane (heavy phase ratio, 6:4), add 2.2 ml of liquid ammonia. Stabilized nickel BL103B1, roller 7 and hydrogen gas were charged to 20 to give 7βG,
The temperature was raised while stirring and maintained at 110°C. Next, in a separate stainless steel autoclave with an internal volume of 100 m6, 2-methyl-4-amino-5-formylpyrimidine 49 (29.2 mmol) methanol-dioxa/(small 1 FL) 7,6: After reacting the mixed solvent 18'y of 4) and liquid ammonia 257 at 60° C. for 6 hours with stirring, the autoclave was cooled and the autoclave was opened to remove excess ammonia. The total amount of the reaction solution was
After the water was heated to 10°C (it took 4 hours to press into the stored liquid using a high-pressure foot pump)
The reaction was continued for 0 minutes.

Treatment after completion of the reaction d: The same operation as in Example 1 was performed. The results were as follows.

Yield of 2-methyl-4-amino-5-amine methylpyrimidine: 90.4% Yield of 2-methyl-4-amino-5-hydroquinemethylpyrimidine: 1.1% Yield of -amino-5-pyrimidylmethyl)amine: 1.8% Example 4 12 g of a 20 wt% methanol solution of ammonia, stabilized with nickel N 10
”> B (1,67? and hydrogen gas about 6OK7Δ
Prepare the mixture to rhG and raise the temperature to 100°C while stirring.
I kept it there. Next, we installed a glass filter, a gas blowing tube, a gel tube, and a reflux condenser for 100m. In the second flask・2τ Medill−
4-amino-5-formylpyrimidine 42 (29.2 mmol), 2 owt ammonia solution in methanol 26
7 and NH3 gas at 100 mVm while stirring]
After starting the reaction at 40° C. for 10 hours, the mixture was cooled. The entire amount of the reaction solution was placed in the solution kept at 100'C.

After being press-fitted using a high-pressure feed pump for 4 hours,
The reaction was continued for 60 minutes at the same temperature.

The treatment after the completion of the reaction was carried out in the same manner as in Example 1. The results were as follows.

Yield of 2-methyl-4-amino-5-amine methylpyrimidine: 90.5% Yield of 2-methyl-4-amino-5-hydroxymethylpyrimidine: 1,1 dezy(2-methyl-4-amino Yield of -5-pyrimidylmethyl)amine: 1.6% Example 5 In a stainless steel autoclave with an internal volume of 100 yne equipped with a high-pressure feed pump, 2 g of Raney nickel (methyl content: about 40 wt%) was spread in a conventional manner, and washed with water. After that, water was replaced with methanol (methanol approx. 12
f), liquid ammonia Otsu7, and hydrogen nozzle about 6O
Kg/ca G, heated while stirring,
It was kept at 90°C.

2-Methyl-4-amino-5-
Formylpyrimidine 2 y (14,6 mmol) Oyo'U 20 wt% ammonia methanol mW2
87 was charged and allowed to react at 90°C for 2 hours in a stirring vessel, then cooled and the autoclave was opened. The entire amount of the reaction solution was injected into the solution maintained at 90°C using a high-pressure foot pump over a period of 2 nV, and the reaction was continued at the same temperature for 30 minutes.

After the reaction was completed, the same procedure as in Example 1 was carried out.

The results were as follows.

Yield of 2-methyl-4-amino-5-amine methylpyrimidine: 91.7% Yield of 2-methyl-4-amino-5-hydroxymethylpyrimidine, 1.8% Di(2-methyl-4- Yield of 2-methyl-4-amino-5-formylpyrimidine 2y (i 4.6 mmol ), and 2[]wt%
A methanol solution of 377 ml of ammonia was charged, the temperature was raised with stirring, the reaction was carried out at 90°C for 2 hours, and then the autoclave was cooled and opened.

Next, in the autoclave, Raney nickel 27 with a methyl content of about 40 wt% was developed using a conventional method, washed with water, and the water was replaced with methanol (methanol containing about 6 wt%).
7) was charged, hydrogen gas was pressurized to 30 Kg/c#), the temperature was raised with stirring, and the reaction was carried out at 90°C for 2 hours and 30 minutes.

The treatment after the completion of the reaction was performed in the same manner as in Example 1.

The results were as follows.

Yield of 2-methyl-4-amino-5-amine methylpyrimidine: 8,5-2-methyl-4-amino-5-hydrogineYield of methylpyrimidine: 4.1% Di(2-methyl- Yield of 4-amino-5-pyrimidylmethyl)amine (nearly 8%) Patent applicant Ube Industries Co., Ltd. Page 1 continued 0 Inventor Teruhi Inoue Ube Industries Co., Ltd. Central Research Center, 1978 Kogushi, Kogushi, Ube City 0 internal inventions Author: 5 Ube Industries Co., Ltd. Central Research Laboratory, 1978 Kokushi, Omori Kiyuebe City Proceedings Amendment (voluntary amendment) January 2, 1980 Commissioner of the Japan Patent Office 1 Patent application for indication of case 1982 ~158916 No. 2, Name of the invention 2-Argyl-4-amino-5-aminonotylpyrimi 7
Relationship between the manufacturing process and the amendment case Patent applicant postal code 755 1-12'52 Nishihonmachi, Ube City, Yamaguchi Prefecture (020)
Ube Industries Co., Ltd. Telephone: 03 (5B+) 3314 4 Date of amendment order There is no amendment order (voluntary amendment).

5 Number of inventions increased by amendment None 6 Target of amendment 1y Detailed explanation of the invention in Book II Column 7, Contents of amendment (]) Meisho Jusho, page 5, line 10 and 8 page.

In line 8, the description of "2-methyl" is corrected to "2-alkyl."

that's all

Claims (1)

Claims: A 2-alkyl-4-amino-5-formylpyrimidine is reacted with ammonia in an inert solvent. The method is characterized in that the resulting reaction product is then added to an inert solvent containing ammonia, hydrogen, and a reduction catalyst to reduce the reaction product without isolating it from the reaction solution. Method for producing 2-alkyl-4-amine-5-aminemethylpyrimidine.