JPS5944364A - Preparation of 2-lakyl-4-amino-5-aminomethylpyrimidine - Google Patents

Abstract

PURPOSE:To prepare the titled compound useful as a synthetic intermediate of vitamin B1, etc., in high yield, by the catalytic reaction of 2-alkyl-4-amino-5- formylpyrimidine with NH3 and H2 in the presence of a bivalent Ni salt using a reduction catalyst. CONSTITUTION:The objective compound of formula II can be prepared in a yield of as high as >=90%, by the catalytic reaction of the 2-alkyl-4-amino-5- formylpyrimidine of formula I (R is lower alkyl such as CH3, C2H5, C3H7, C4H9, etc.) with NH3 and H2 in the presence of a bivalent nickel salt and a reduction catalyst such as Raney Ni, stabilized nickel, etc. in an inert solvent at 0-200 deg.C, preferably room temperature -120 deg.C under an H2-partial pressure of 1-100kg/ cm<2> for 0.5-10hr. The bivalent nickel salt is e.g. NiCl2, NiBr2, NiSO4, Ni(NO3)2, Ni3(PO4)2, Ni(OH)2, NiCO3, nickel acetate, nickel oxalate, nickel benzoate, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a new method for producing 2-argyl-4-amino-5-aminomethylpyrimidine. It is known to be a heavy synthetic intermediate of vitamin B, vitamin B, and its related compounds.

For example, 2-alkyl-4-amino-5-aminomethylpyrimidine can be produced by
Method for reducing 4-amino-5-aneopyrimidine, 2
A method of hydrolyzing -alkyl-4-amino-5-acetamidomethylpyrimidine 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 in the presence of a reduction catalyst to undergo reductive amination, the yield can be obtained even higher than in known methods. 2 = argyl-4-amino-5-
It was discovered that aminomethylpyrimidine could be produced, and a patent application was filed as Japanese Patent Application No. 57-22122. However, with this method, the desired product can be produced with a yield of about 80 to 90%, but as by-products such as 2-alkyl-4-amino-5-hydroginemethylpyrimidine and di(2-alkyl-4- About 10% of amino-5-pyrimidylmethyl)amine is produced. There is a problem with this.

The present inventors have worked diligently to improve the hindlimb problem (υ[
As a result of repeated research, we found that the presence of divalent conokel salt in the reaction system suppresses the formation of the above-mentioned byproducts. 1j11, and found that the target product could be obtained in extremely high yield, leading to the completion of 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. 4-amino-5-
A method for producing amine methylpyrimidine is provided.

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

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

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

The reduction catalyst used in the present invention is Raney nickel, stabilized nickel, or palladium.

Eighth metals such as platinum, rhodium, ruthenium, cobalt, iron, etc.
Group metals, 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, and Raney nickel may be developed by conventional methods. These catalysts may be used singly or as a mixture of two or more, and large catalysts may be activated with, for example, hydrogen gas, before use. These catalysts include activated carbon, alumina, silica, silicon carbide, carbon dioxide, and pumice.

It can also be used by being supported on a carrier such as zeolite or moleki-rap.

These catalysts are 0.001 in terms of metal per mole of raw material 2-alkyl-4-amino-5-formylpyrimidine.
~6 gram atoms are used, preferably 0.002-2 gram atoms.

Examples of divalent nickel salts used in the present invention include di-chloride, nickel bromide, nickel sulfate, nickel nitrate/nickel phosphate, nickel carbonate, nickel hydroxide, nickel acetate, nickel oxalate, and benzoic acid. Examples include nickel, nickel ammonium chloride, nickel ammonium sulfate, nickel potassium sulfate, and the like. These divalent nickel salts are.

Each may be used alone, or two or more types of kneading may be used in combination. In addition, these divalent nickel salts contain 1.
You may use one that has crystallized water.

The amount used is 0.1 to 5 mol, preferably 0.4 to 1.0 mol, per mol of raw material 2-alkyl-4-amino-5-formylpyrimidine. When the amount used is less than the lower limit of the above range, 2-alkyl-4-amino-5-hydroxomethylpyrimidine or di(
The effect of suppressing by-products such as 2-alkyl-4-amino-5-pyriminlmethyl)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 bond 11. Liquid ammonia, anomalous solution, or aqueous ammonia solution can be used.

The amount used is the raw material 2-alkyl-4-amino-5-
The amount is at least 1 mol, preferably from 4 to 500 mol, per mol of formylpyrimidine.

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

The reaction can also be carried out in a solvent inert to the reaction. As a solvent, methanol and ethanol are used.

Examples include propatool, lower aliphatic alcohols such as butanol, dioxane, tetrahydrofuran, diethyl ether natonoether, benzene, toluene, xylene, hexane, cyclohexanna E (D hydrocarbons, or water).

The reaction is carried out at a temperature of 0 to 200°C, preferably room temperature to 120°C. The reaction will proceed even under normal pressure, but it will proceed more quickly under increased pressure.

It is usually carried out under a pressure of 1 to 100 Ky/c+/IG for hydrogen. The reaction time is about 0.5 to 10 hours. - Reaction operations include a method of simultaneously reacting 2-alkyl-4-amino-5-formylpyrimidine with ammonia and hydrogen in the presence of a divalent nickel salt and a reduction catalyst, or -4-Amino-5-formylpyrimidine and ammonia are first reacted, and then hydrogen is blown into the system to react with hydrogen. Furthermore, a method in which 2-argyl-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;
-C can also be performed.

After the completion of the reaction 1. 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 by a conventional method.
It can be isolated and obtained in the form of free salts or mineral salts.

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

Next, nine examples and comparative examples of the present invention are listed.

Note that the yield of the product on each side is based on the raw material 2-argyl-4-amino-5-formylpyrimidine used.

Example 1 In a stainless steel autoclave with an internal volume of 100 m6, 2
-Methyl-4-amino-5-formylpyrimidine 1.6
7y (10 mmol), 2 owt methanol solution of ammonia 247 and anhydrous nickel chloride 0.74F
(5.7 mmol) was charged, and 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 1 hour. Then, cool it down, open the autoclave, and use Stabilized Nickel (trade name).

N10 filter B: Manufactured by JGC Chemical Co., Ltd.; approximately 50 wt% nickel.

After charging approximately 50 wt% (on diatom) with 0.46 Si' and replacing the inside of the system with nitrogen scum, hydrogen gas was heated to approximately 0K.
Press it in so that it becomes qloA U, and raise the temperature while stirring to about 9
The reaction was carried out at 0°C for 2 hours.

After the reaction path R is cooled and unreacted gas etc. is depressurized.

The autoclave was opened and the catalyst was poured out. Combine the washing solution from which the catalyst was washed with methanol and the p solution, and concentrate under reduced pressure (after removing most of the ammonia in step 2, add 1N-HCl and p
H was adjusted to about 6, and each product was quantitatively analyzed using liquid chromatography using an internal standard method.

The results were as follows.

Yield of 2-methyl-4-amino-5-amine methylpyrimidine: 94.5% Yield of 2-methyl-4-amino-5-methylpyrimidine/methylpyrimidine: 0.3% -Amino-5-pyrimidylmethyl)amine yield: 2.5% Example 2 Internal volume 100 m/? 2 in a stainless steel autoclave
-Methyl-4-amino-5-formylpyrimidine/1.3
7f (10 mmol) 2 Owt ammonia in methanol solution 24 g, anhydrous nickel chloride 0.74 g (5,7
mmol) and stabilized nickel N103B0.461
After purging the system with nitrogen gas, the contents were heated while stirring and maintained at about 90°C for 0 minutes. Next, hydrogen gas was injected at the same temperature to a pressure of about 6 OKf/cr/la, 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 result is 9
It was as follows.

Yield of 2-methyl-4-amino-5-aminomethylpyrimidine: 9 filtration, 8 filtration Yield of 2-methyl-4-amino-5-hydroxymethylpyrimidine: 0.5 filtration (2-methyl-4 Yield of -amino-5,-pyrimidylmethyl)amine: 2.5% Comparative Example 1 In Example 2, except that nickel chloride was not used,
An experiment was conducted in the same manner as in Example 2.

The results were as follows.

Yield of 2-methyl-4-amino-5-aminemethylpyrimidine, 884% Yield of 2-methyl-4-amino-5-hytroquinemethylpyrimidine: 4.1% Di(2-methyl- Yield of 4-amino-5-pyrimidylmethyl)amine: 5.8% Example 6 In a stainless steel autoclave with an internal volume of 100 m6, 2
-Methyl-4-amino-5-formylpyrimidine 1. 77 (10 mmol), 2 wt% ammonia in methanol 247 and nickel acetate tetrahydrate 1. Ro4! ? After charging (5.4 mm! J mole) and replacing the inside of the system with nitrogen gas, the contents were heated while stirring, held at about 90° C. for 1 hour, cooled, and the autoclave was opened. Next, Raney nickel 207 containing Nokel; 1 [approximately 4 owt%] was developed by a conventional method, washed with water, and the water was replaced with methanol (methanol approximately 67%).
After filling the system with nitrogen gas and replacing it with hydrogen gas,
Press it in so that it becomes 0Kq/oA a, and stir 1・-
The temperature was raised to 90°C, and the reaction was carried out for 2 hours. The results were as follows.

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

Yield of 2-methyl-4-amino-5-amine methylpyrimidine: 84.3% Yield of 2-methyl-4-amino-5-hydrogyamethylpyrimidine: 5.1 Yield of -4-amino-5-bilimi/lmethyl)amine: 6.4% Example 4 Instead of nickel chloride in Example 1.

Nj, 003・Ni(OH)2・4H200,75y
The experiment was carried out in the same manner as in Example 1, except that 5.3 mmol (5.3 mmol) was used for the Nokel J tray. The result is.

Next No. 1 (! Rita, dada.

2-methyl-4-reminnow 5-aminomethylpyrimi/)
Yield: 9°, 4%; ) Amine yield: 2.9% Example 5 As the raw material 1, 2-methyl-4-amine-5-formylpyrimidine 7 was replaced with 2-ethyl-4-amino-formylpyrimidine 1.51y( 10 mmol), 20w instead of 20wt% ammonia methanol solution
An experiment was conducted in the same manner as in Example 1, except for using an ethanol solution of 307% ammonia, and the results were as follows.

Yield of 2-ethyl-4-amino-5-aminemethylpyrimidine: 95. Yield of 2-ethyl-4-amine-5-hydrogyamethylpyrimidine: 1.5 Yield of 2-ethyl-4-amino-5-pyrimidylmethyl)amine: 2.0'% Patent application Person: Ube Industries, Ltd. (72), Ube Industries, Ltd. Central Research Laboratory, 1978 Oaza Kokushi, Ube City (72) Inventor: Teruhi Inoue, Ube Industries, Ltd. (72), Central Research Laboratory, 1978 Oaza Kogushi, Ube City, Ube City Person: 5 Ube Industries Co., Ltd., Central Research Laboratory, 1978 Kokushi, Omori Kiyuebe City, Supplementary Procedures (Voluntary Amendment) January 20, 1980 Commissioner of the Japan Patent Office, Tono 1, Patent Application for Indication of Cases 1982-154. 661 No. 2 Name of the invention 2 Process for producing argyl-4-amino-5-aminomethylpyrimino Relationship to the case of the person making the amendment Patent applicant postal code 755 1-12-32 Nishihonmachi, Ube City, Yamaguchi Prefecture No. 4 Date of amendment order There is no amendment order (voluntary amendment).

5 Number of inventions increased by the amendment No Column 7 for detailed explanation of the invention in the specification subject to amendment Contents of amendment (1) The statement on page 11, line 16, 120g-1 of the specification is changed to J'2 ．． Correct to OS'J.

Below

Claims (1)

[Claims] % '03 refers to the catalytic reaction of 2-alkyl-4-amine-5-formylpyrimidine with ammonia and hydrogen in the presence of a divalent nickel salt and a reducing catalyst. Method for producing 2-alkyl-4-amino-5-aminomethylpyrimidine.