JP2004051491A - Method for manufacturing 2-amino-7-methyl-1,8-naphthyridine - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for industrially manufacturing 2-amino-7-methyl-1,8-naphthyridine with good productivity. <P>SOLUTION: The method for manufacturing 2-amino-7-methyl-1,8-naphthyridine comprises reacting 2,6-diaminopyridine with acetylacetaldehyde dimethyl acetal in the presence of phosphoric acid, diluting a thus obtained reaction solution containing 2-amino-7-methyl-1,8-naphthylidine with a water-soluble organic solvent, subsequently neutralizing it with a neutralizing agent and then separating an inorganic salt from a thus obtained neutralized mixture by filtration. <P>COPYRIGHT: (C)2004,JPO

Description

[0001]
TECHNICAL FIELD OF THE INVENTION
The present invention relates to a method for producing 2-amino-7-methyl-1,8-naphthyridine. More specifically, the present invention relates to a method for producing 2-amino-7-methyl-1,8-naphthyridine, which is useful as an agent for detecting a guanine-guanine mismatch base pair in a nucleic acid, a pharmaceutical intermediate, and the like. 2-amino-7 useful as an agent for detecting a mismatch mutation or single nucleotide polymorphism based on a guanine-guanine mismatch base pair therein, a pharmaceutical intermediate for treating or preventing a disease caused by the mismatch mutation, or the like -Methyl-1,8-naphthyridine.
[0002]
[Prior art]
As a method for producing 2-amino-7-methyl-1,8-naphthyridine, 2,6-diaminopyridine is reacted with acetylacetaldehyde dimethyl acetal in the presence of phosphoric acid to obtain 2-amino-7-methyl-2-naphthyridine. A method is known in which a reaction solution containing methyl-1,8-naphthyridine is neutralized and then extracted with chloroform [Journal of Organic Chemistry (J. Org. Chem.) 30 , 1607 (1965)]. .
[0003]
However, this method has the disadvantage of poor productivity because large amounts of water are required to neutralize and extract 2-amino-7-methyl-1,8-naphthyridine.
[0004]
[Problems to be solved by the invention]
The present invention has been made in view of the above prior art, and has as its object to provide a method capable of industrially producing 2-amino-7-methyl-1,8-naphthyridine with high productivity.
[0005]
[Means for Solving the Problems]
That is, the present invention provides a reaction solution containing 2-amino-7-methyl-1,8-naphthyridine by reacting 2,6-diaminopyridine with acetylacetaldehyde dimethyl acetal in the presence of phosphoric acid. After diluting with a water-soluble organic solvent, neutralizing with a neutralizing agent, and separating an inorganic salt from the resulting neutralized mixture by filtration, characterized in that 2-amino-7-methyl-1,8-naphthyridine is obtained. It relates to a manufacturing method.
[0006]
BEST MODE FOR CARRYING OUT THE INVENTION
In the present invention, first, 2,6-diaminopyridine is reacted with acetylacetaldehyde dimethyl acetal in the presence of phosphoric acid. The reaction of 2,6-diaminopyridine with acetylacetaldehyde dimethyl acetal can be performed, for example, by the method described in Journal of Organic Chemistry (J. Org. Chem.) 30 , 1607 (1965). More specifically, 2,6-diaminopyridine and acetylacetaldehyde dimethyl acetal can be reacted by the following method.
[0007]
The amount of acetylacetaldehyde dimethyl acetal per mol of 2,6-diaminopyridine is usually 0.9 to 1.1 mol, preferably 0.95 to 1.05 mol, from the viewpoint of suppressing side reactions. Is desirable.
[0008]
The amount of phosphoric acid is desirably 10 to 50 mol, preferably 15 to 25 mol, per 1 mol of 2,6-diaminopyridine, from the viewpoint of dehydration and economy.
[0009]
Examples of the phosphoric acid include phosphoric anhydride, polyphosphoric acid, and hydrous phosphoric acid. In the present invention, hydrous phosphoric acid can be preferably used.
[0010]
The reaction between 2,6-diaminopyridine and acetylacetaldehyde dimethyl acetal can be performed by mixing 2,6-diaminopyridine, acetylacetaldehyde dimethyl acetal, and phosphoric acid. The reaction temperature is desirably 50 to 150 ° C, preferably 80 to 100 ° C, from the viewpoint of increasing the reaction rate and suppressing side reactions.
[0011]
The atmosphere for the reaction is not particularly limited and may be air, for example, an inert gas such as nitrogen gas or argon gas.
[0012]
The end point of the reaction can be confirmed by, for example, high performance liquid chromatography, thin layer chromatography, or the like.
[0013]
Thus, a reaction solution containing 2-amino-7-methyl-1,8-naphthyridine formed by the reaction of 2,6-diaminopyridine with acetylacetaldehyde dimethyl acetal is obtained.
[0014]
Next, the obtained reaction solution is diluted with a water-soluble organic solvent. In the present invention, there is one major feature in using this water-soluble organic solvent.
[0015]
In the present invention, since the water-soluble organic solvent is used in the reaction solution before the reaction solution is neutralized as described above, the produced 2-amino-7-methyl-1,8-naphthyridine will be described later. Since the difference in solubility between the reaction solution and the inorganic salt formed by neutralization can be significantly increased as compared with the case where conventional water is used, a solution of 2-amino-7-methyl-1,8-naphthyridine can be used. Unnecessary solid inorganic salts generated after neutralization can be efficiently and easily separated by a simple method such as filtration.
[0016]
Here, the “water-soluble organic solvent” as used herein refers to an organic solvent that can be arbitrarily dissolved in water at 25 ° C.
[0017]
Representative examples of the water-soluble organic solvent include, for example, alcohols and ketones, which may be used alone or in combination of two or more.
[0018]
Preferable examples of the water-soluble organic solvent include aliphatic alcohols and aliphatic ketones having a straight or branched chain having 1 to 8 carbon atoms, and among them, ethanol and isopropanol are preferred.
[0019]
The amount of the water-soluble organic solvent is 300 to 1000 parts by volume, preferably 500 to 500 parts by volume, per 100 parts by volume of the reaction solution, in order to enhance the solubility of the neutralizing agent and to easily stir the resulting slurry. Desirably, it is 600 parts by volume.
[0020]
In addition, the temperature of the reaction solution when adding the water-soluble organic solvent to the reaction solution is preferably 0 to 60 ° C, and more preferably 10 to 40 ° C, in consideration of handling of the water-soluble organic solvent.
[0021]
Next, the diluted reaction solution is neutralized. At the time of neutralization, a neutralizing agent is used. As such a neutralizing agent, those which make it difficult to dissolve the salt formed by the neutralization in the water-soluble organic solvent used in the reaction solution are preferable.
[0022]
Suitable neutralizing agents include alkali metal or alkaline earth metal hydroxides, carbonates and bicarbonates. Of these, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide are more preferred. The neutralizing agent can be used, for example, in a solution dissolved in the above-mentioned water-soluble organic solvent.
[0023]
The amount of the neutralizing agent is desirably 1 to 2 mol, preferably 1 to 1.3 mol, per 1 mol of phosphoric acid used in the reaction.
[0024]
In addition, the liquid temperature at the time of neutralizing the reaction solution is preferably 0 to 60 ° C., and more preferably 10 to 40 ° C. in consideration of handling of the water-soluble snow solvent and heat removal of the heat of neutralization. .
[0025]
The neutralized mixture obtained by neutralizing the reaction solution in this way contains 2-amino-7-methyl-1,8-naphthyridine in its liquid phase, and the inorganic salt precipitated by the neutralization Exists as a solid without being dissolved in a water-soluble organic solvent.
[0026]
Therefore, the 2-amino-7-methyl-1,8-naphthyridine solution can be easily separated from the inorganic salt as impurities only by filtering the neutralized mixture.
[0027]
Next, 2-amino-7-methyl-1,8-naphthyridine is obtained by removing the water-soluble organic solvent from the 2-amino-7-methyl-1,8-naphthyridine solution by means such as distillation under reduced pressure. Can be recovered.
[0028]
【Example】
Next, the present invention will be described in more detail based on examples, but the present invention is not limited to only these examples.
[0029]
Example 1
11 g of 2,6-diaminopyridine, 13 g of acetylacetaldehyde dimethyl acetal, and 188 g of phosphoric acid were mixed and heated at 90 ° C. for 3 hours.
[0030]
After cooling the obtained reaction solution to 20 ° C., 100 mL of ethanol was added to the reaction solution, and neutralized with 518 g of a 25% ethanol solution of potassium hydroxide.
[0031]
The inorganic salt precipitated from the obtained neutralized mixture was separated by filtration, and the filtrate was recovered. Next, this filtrate was dried under reduced pressure at 45 to 50 ° C., and concentrated to dryness to obtain 14.0 g of 2-amino-7-methyl-1,8-naphthyridine (yield: 87%). .
[0032]
It was confirmed by ¹ H-NMR and infrared absorption spectrum that the obtained compound was 2-amino-7-methyl-1,8-naphthyridine 14 g. The results are shown below.
[0033]
(1) Measurement results of ¹ H-NMR
^{1 H-NMR (δppm, CDCl} 3, 300MHz): 2.67 (3H, s, Me), 5.47 (2H, s, NH 2), 6.72 (1H, d, Ar), 7.03 (1H, d, Ar), 7.74 (1H, d, Ar), 7.77 (1H, d, Ar)
[0034]
(2) Measurement result of infrared absorption spectrum IR: 3333 cm ⁻¹ (ν, NH ₂ ), 3151 cm ⁻¹ (ν, CH)
[0035]
Comparative Example 1
11 g of 2,6-diaminopyridine, 13 g of acetylacetaldehyde dimethyl acetal, and 188 g of phosphoric acid were mixed and heated at 90 ° C. for 3 hours.
[0036]
After cooling the obtained reaction solution to 20 ° C., 1,884 g of water was added to the reaction solution, and neutralized with 129.5 g of potassium hydroxide.
[0037]
From the obtained neutralized mixture, 2-amino-7-methyl-1,8-naphthyridine generated with 50 mL of chloroform is extracted eight times, and the obtained extracts are combined and dried at 45 to 50 ° C. under reduced pressure. Thereby, it was concentrated to dryness to obtain 12.6 g of 2-amino-7-methyl-1,8-naphthyridine (yield: 79%).
[0038]
From the above results, in contrast to the production method described in Comparative Example 1, according to the production method of Example 1, a water-soluble organic solvent was used after the reaction between 2,6-diaminopyridine and acetylacetaldehyde dimethyl acetal was completed. Thus, 2-amino-7-methyl-1,8-naphthyridine can be efficiently performed only by performing a simple operation of filtering off by-produced inorganic salts, without performing complicated multiple extraction operations. It can be seen that can be obtained.
[0039]
【The invention's effect】
According to the production method of the present invention, there is an effect that 2-amino-7-methyl-1,8-naphthyridine can be industrially produced with high productivity.

Claims (3)

2,6-Diaminopyridine and acetylacetaldehyde dimethyl acetal are reacted in the presence of phosphoric acid, and the resulting reaction solution containing 2-amino-7-methyl-1,8-naphthyridine is diluted with a water-soluble organic solvent. And then neutralizing the mixture with a neutralizing agent, and separating an inorganic salt from the resulting neutralized mixture by filtration, the method comprising the steps of: The method according to claim 1, wherein the water-soluble organic solvent is ethanol or isopropanol. 3. The method according to claim 1, wherein the neutralizing agent is an alkali metal hydroxide.