JP4896476B2 - Methyloxymethylaminopyridine derivative and method for producing the same - Google Patents

Description

  The present invention relates to a novel methyloxymethylaminopyridine derivative and a method for producing the same.

  Formula (3):

（式中、Ｘはハロゲン原子を表す）で表されるメチルアミノピリジン誘導体（以下、メチルアミノピリジン誘導体（３）という。）は医薬原料として有用な化合物である（例えば、特許文献１又は２参照）。従来、メチルアミノピリジン誘導体（３）の製造方法としては、１）式（２）：

A methylaminopyridine derivative (hereinafter referred to as methylaminopyridine derivative (3)) represented by the formula (wherein X represents a halogen atom) is a compound useful as a pharmaceutical raw material (see, for example, Patent Document 1 or 2). ). Conventionally, as a method for producing a methylaminopyridine derivative (3), 1) Formula (2):

（式中、Ｘは前記に同じ。）で示されるアミノピリジン誘導体（以下、アミノピリジン誘導体（２）という。）をリチウムジイソプロピルアミンと反応させた後に、反応液にヨウ化メチルを加えて反応させて製造する方法（例えば、特許文献１又は２参照）、２）アミノピリジン誘導体（２）のアミノ基をトシル基で保護した後、ヨウ化メチルを用いてメチル化反応し、次いでトシル基を脱保護して製造する方法が知られている（例えば、非特許文献１参照）。

(In the formula, X is the same as above.) After reacting the aminopyridine derivative (hereinafter referred to as aminopyridine derivative (2)) represented by lithium diisopropylamine, methyl iodide is added to the reaction solution to cause the reaction. 2) Protecting the amino group of the aminopyridine derivative (2) with a tosyl group, followed by a methylation reaction with methyl iodide, and then removing the tosyl group. A method of manufacturing while protecting is known (see, for example, Non-Patent Document 1).

However, since the production method 1) performs the reaction at an ultra-low temperature of -78 ° C., an expensive ultra-low temperature reactor is required. The production method 2) is a complicated method because it is produced from the aminopyridine derivative (2) through three steps. Neither process is yet satisfactory for industrial use.
WO2004 / 106346 WO2001 / 098306 J. et al. Chem. Soc. , 1957, 442-446

  An object of the present invention is to provide a novel intermediate compound capable of industrially easily producing a methylaminopyridine derivative (3) that is useful as an intermediate of a pharmaceutical product.

  As a result of intensive studies by the inventor in order to overcome the above problems, surprisingly, the formula (1):

（式中、Ｘは前記に同じ。）で示される新規なメチルオキシメチルアミノピリジン誘導体（以下、メチルオキシメチルアミノピリジン誘導体（１）という。）を中間体として用いれば、高価な超低温反応装置を用いる必要はなく、さらにアミノピリジン誘導体（２）から２工程で、アミノピリジン誘導体（３）を製造できることを見出し、本発明を完成するに至った。

(In the formula, X is the same as above.) If a novel methyloxymethylaminopyridine derivative (hereinafter referred to as methyloxymethylaminopyridine derivative (1)) represented by It was not necessary to use, and it was found that the aminopyridine derivative (3) can be produced from the aminopyridine derivative (2) in two steps, and the present invention was completed.

  That is, the present invention relates to a methyloxymethylaminopyridine derivative (1) characterized by reacting an aminopyridine derivative (2) with formaldehyde and methanol in the presence of a base. The present invention relates to a production method and a production method of an aminopyridine derivative (3), wherein the methyloxymethylaminopyridine derivative (1) is reduced.

  According to the present invention, the novel methyloxymethylaminopyridine derivative (1) is used as an intermediate, and the methylaminopyridine derivative (3) is used in two steps from the aminopyridine derivative (2) without using an expensive ultra-low temperature reactor. Therefore, the methylaminopyridine derivative (3) can be produced industrially and easily compared with the conventional method, and the industrial utility value is high.

Hereinafter, the present invention will be specifically described.
In the formulas (1), (2) and (3), X represents a halogen atom, and specific examples include chlorine, bromine, iodine and the like.

  Specific examples of the methyloxymethylaminopyridine derivative (1) include 2-chloro-3-methyloxymethylaminopyridine, 2-bromo-3-methyloxymethylaminopyridine, 2-iodo-3-methyloxymethylaminopyridine. Etc.

  Specific examples of the aminopyridine derivative (2) include 3-amino-2-chloropyridine, 3-amino-2-bromopyridine, 3-amino-2-iodopyridine and the like.

  Specific examples of the methylaminopyridine derivative (3) include 2-chloro-3-methylaminopyridine, 2-bromo-3-methylaminopyridine, 2-iodo-3-methylaminopyridine, and the like.

First, a method for producing the methyloxymethylaminopyridine derivative (1) will be described.
The production method of the methyloxymethylaminopyridine derivative (1) of the present invention is carried out by reacting the aminopyridine derivative (2) with formaldehyde and methanol in the presence of a base. The mixing order of the aminopyridine derivative (2), the base, formaldehyde and methanol is not particularly limited, but it is preferable to add the aminopyridine derivative (2) after mixing the base, formaldehyde and methanol.

  Examples of the base include alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and lithium hydroxide, alkaline earth metal hydroxides such as calcium hydroxide and magnesium hydroxide, such as lithium hydride and sodium hydride. Alkali metal hydrides such as potassium hydride, for example, alkali metal methoxides such as lithium methoxide, sodium methoxide, potassium methoxide and the like, preferably alkali metal methoxide, particularly preferably sodium methoxide and potassium methoxy It is. The amount of the base used is usually 0.01 to 1 mol, preferably 0.05 to 0.5 mol, per 1 mol of formaldehyde.

  As the formaldehyde source used in the present invention, there are usually formalin, a methanol solution of formaldehyde, paraformaldehyde and the like, and a methanol solution of formalin and formaldehyde is preferable. The usage-amount of formaldehyde is 1-5 mol normally with respect to 1 mol of aminopyridine derivatives (2), Preferably it is 1-2 mol.

  The amount of methanol used is usually 1 to 20 mol, preferably 1 to 10 mol, relative to 1 mol of aminopyridine derivative (2).

  The reaction temperature is usually 0 ° C to 60 ° C, preferably 0 to 40 ° C.

  When the reaction solution is separated into an aqueous layer and an organic layer after completion of the reaction, the organic layer is separated by liquid separation to obtain a reaction mixture containing the methyloxymethylaminopyridine derivative (1). In addition, when the reaction solution is not separated into an aqueous layer and an organic layer, an appropriate organic solvent (for example, an aliphatic hydrocarbon solvent such as pentane, hexane, cyclohexane, heptane, benzene, toluene, xylene, mesitylene, etc. Extraction with an aromatic hydrocarbon solvent, an ether solvent such as diethyl ether or tert-butyl methyl ether, an ester solvent such as ethyl acetate or butyl acetate), and the organic layer is separated by liquid separation. A reaction mixture containing the methylaminopyridine derivative (1) can be obtained.

  The reaction mixture containing the methyloxymethylaminopyridine derivative (1) from which water is thus obtained can be used as it is as a raw material for the production process of the methylaminopyridine derivative (3) described later. However, since this reaction mixture contains an unreacted aminopyridine derivative (2), a base, formaldehyde, and methanol are added to this reaction mixture and further reacted (this production method is hereinafter reintroduced). The unreacted aminopyridine derivative (2) becomes a methyloxymethylaminopyridine derivative (1), which can be further improved in yield.

  The above-mentioned thing is mentioned as a base and formaldehyde used for a re-reaction process. The amount of base used and the amount of methanol used are also as described above. The reaction temperature is usually 0 ° C to 60 ° C, preferably 0 to 40 ° C.

  When the reaction solution is separated into an aqueous layer and an organic layer after completion of the re-reaction step, the organic layer can be separated by liquid separation to obtain a reaction mixture containing the methyloxymethylaminopyridine derivative (1). . In addition, when the reaction solution is not separated into an aqueous layer and an organic layer, an appropriate organic solvent (for example, an aliphatic hydrocarbon solvent such as pentane, hexane, cyclohexane, heptane, benzene, toluene, xylene, mesitylene, etc. Extraction with an aromatic hydrocarbon solvent, an ether solvent such as diethyl ether or tert-butyl methyl ether, an ester solvent such as ethyl acetate or butyl acetate), and the organic layer is separated by liquid separation. A reaction mixture containing the methylaminopyridine derivative (1) can be obtained. The obtained reaction mixture containing the methyloxymethylaminopyridine derivative (1) can be used as a raw material for the production process of the methylaminopyridine derivative (3) described later.

  The purified methyloxymethylaminopyridine derivative (1) can be obtained by subjecting the reaction mixture obtained from any of the above reaction steps to a desired separation and purification operation such as concentration, recrystallization, column chromatography and the like. Needless to say, the purified methyloxymethylaminopyridine derivative (1) can also be used as a raw material for the production process of the methylaminopyridine derivative (3) described later.

Next, a method for producing the methylaminopyridine derivative (3) will be described.
In order to produce the methylaminopyridine derivative (3), the reaction mixture containing the methyloxymethylaminopyridine derivative (1) or the methyloxymethylaminopyridine derivative (1) may be subjected to a reduction reaction.

  Examples of the reducing agent used in the reduction reaction include a hydride type reducing agent and hydrogen, and a hydride type reducing agent is preferable. When hydrogen is used as a reducing agent, a transition metal catalyst such as platinum, palladium, rhodium, ruthenium, or nickel is usually present.

  Examples of the hydride-type reducing agent include lithium aluminum hydride, sodium aluminum hydride, diisobutylaluminum hydride, sodium borohydride, potassium borohydride, lithium borohydride, zinc borohydride, borane-tetrahydrofuran complex, diborane and the like. And preferably sodium borohydride.

  The usage-amount of a reducing agent is 0.5-10 mol normally with respect to 1 mol of methyloxymethylamino pyridine derivatives (1), Preferably it is 0.5-2 mol.

  A solvent can be used for the reduction reaction. Examples of the solvent include aliphatic hydrocarbon solvents such as pentane, hexane, cyclohexane and heptane, aromatic hydrocarbon solvents such as benzene, toluene, xylene and mesitylene, methylene chloride, chloroform and 1,2-dichloroethane. Halogenated hydrocarbon solvents, ether solvents such as diethyl ether, tetrahydrofuran, tert-butyl methyl ether and dioxane, ester solvents such as ethyl acetate and butyl acetate, nitrile solvents such as acetonitrile and propionitrile, methanol, ethanol And alcohol solvents such as propanol and isopropanol, carboxylic acid solvents such as acetic acid, propionic acid, and butyric acid, and the like. Preferred are aromatic hydrocarbon solvents, ether solvents, and alcohol solvents. Of these, toluene, tetrahydrofuran, methanol, ethanol and isopropanol are particularly preferable. These solvents can be used alone or in admixture of two or more. The amount of the solvent used is 0.2 to 20 times by weight, preferably 0.5 to 10 times by weight, based on the methyloxymethylaminopyridine derivative (1).

  The reaction temperature varies depending on the type of solvent, but is usually in the range of 0 to 150 ° C.

  After completion of the reaction, the methylaminopyridine derivative (3) can be obtained from the reaction mixture by desired separation and purification means such as neutralization, extraction, concentration and distillation.

  Next, the present invention will be specifically described based on examples, but it goes without saying that the present invention is not limited to these examples.

Example 1
Formalin (88.4 g) containing 37% by weight of formaldehyde was gradually added to 35.0 g of 28% by weight sodium methoxide-methanol solution. Thereafter, 100.0 g of 3-amino-2-chloropyridine was slowly added at 20 to 25 ° C., and after completion of the addition, the mixture was reacted at room temperature for 2 hours. After completion of the reaction, the reaction solution was separated to obtain 147.6 g of an organic layer.

Into a mixed solution of 35.0 g of 28% sodium methoxide-methanol solution and 71.1 g of 46% formaldehyde-methanol solution (water content 10% weight), the above organic layer 147.6 g was gradually added at 20-25 ° C. Added to. After reacting at 20-25 ° C. for 3 hours, extraction was performed with toluene. The organic layer was concentrated to obtain 134.6 g of 2-chloro-3-methyloxymethylaminopyridine. ¹ H-NMR data of the obtained 2-chloro-3-methyloxymethylaminopyridine are shown below.

¹ H-NMR (CDCl ₃ ) δ (ppm): 3.33 (3H, s), 4.71 (2H, d), 5.35 (1H, bs), 7.12 (1H, dd), 7 .24 (1H, dd), 7.82 (1H, dd)

Example 2
To a mixed solution of 20.6 g of sodium borohydride, 82.4 g of tetrahydrofuran and 1.7 g of methanol, 134.6 g of 2-chloro-3-methyloxymethylaminopyridine obtained in Example 1 was added at 55 ° C to 65 ° C. The mixture was gradually added, and reacted at 55 ° C. to 65 ° C. for 3 hours after the addition. After completion of the reaction, 303.5 g of a 7.2% by weight aqueous hydrochloric acid solution was added dropwise to the reaction mixture while controlling the internal temperature at 25 ° C. or lower under ice cooling, and further 22. After adding 7 g dropwise, toluene was added. After filtration, the obtained filtrate was separated to obtain an organic layer containing 97.3 g of 2-chloro-3-methylaminopyridine (yield 88%: gas chromatographic quantitative value). This was distilled to obtain 74.2 g of 2-chloro-3-methylaminopyridine. ¹ H-NMR data of the obtained 2-chloro-3-methylaminopyridine are shown below.

¹ H-NMR (CDCl ₃ ) δ (ppm): 2.89 (3H, s), 4.43 (1H, bs), 6.86 (1H, dd), 7.11 (1H, dd), 7 .70 (1H, dd)

Example 3
14.0 g of a 28% sodium methoxide-methanol solution was gradually added to 35.4 g of formalin containing 37% by weight of formaldehyde. Thereafter, 40.0 g of 3-amino-2-chloropyridine was slowly added, and after completion of the addition, the mixture was reacted at room temperature for 2 hours. After completion of the reaction, the reaction solution was separated to obtain 58.9 g of an organic layer.

  To 28.4 g of 46% by weight formaldehyde-methanol solution (water content 10% by weight), 14.0 g of 28% by weight sodium methoxide-methanol solution was gradually added and mixed, and the organic layer components were gradually added. After reacting at room temperature for 3 hours, extraction with toluene was performed, and an organic layer was obtained by liquid separation.

  12.4 g of sodium borohydride was gradually added to the organic layer under water cooling while controlling the internal temperature to 35 ° C. or lower, and reacted at 40 ° C. to 50 ° C. for 3 hours after the addition was completed. To the reaction completion liquid, 182.5 g of a 7.2 wt% hydrochloric acid aqueous solution was dropped while controlling the internal temperature at 25 ° C. or lower under ice cooling, and 13.7 g of a 48 wt% sodium hydroxide aqueous solution was further added at room temperature. It was dripped. The precipitated insoluble matter was separated by filtration, and the obtained filtrate was separated to give 37.3 g of 2-chloro-3-methylaminopyridine, 84% yield, and 0.4 g of 3-amino-2-chloropyridine (gas chromatograph). An organic layer containing a graph quantitative value) was obtained.

Example 4
252.5 g of formalin containing 37% by weight of formaldehyde was gradually added to 100.0 g of a 28% sodium methoxide-methanol solution. Thereafter, 200.0 g of 3-amino-2-chloropyridine was slowly added, and after completion of the addition, the mixture was reacted at 50 ° C. for 2 hours. After completion of the reaction, the reaction solution was separated to obtain 338.6 g of an organic layer.

41.2 g of sodium borohydride, 164.8 g of tetrahydrofuran and 7.0 g of methanol were mixed and the organic layer obtained at 55 ° C. to 65 ° C. was gradually added. After completion of the addition, the reaction was carried out at 55 ° C. to 65 ° C. for 3 hours. I let you. 600.0 g of a 7.2 wt% hydrochloric acid aqueous solution was added dropwise to the reaction completed solution under ice cooling while controlling the internal temperature to 25 ° C. or lower, and 45.0 g of a 48 wt% sodium hydroxide aqueous solution was further added at room temperature. Toluene was added dropwise. The precipitated insoluble matter was filtered off, and the obtained filtrate was separated to obtain 185.3 g of 2-chloro-3-methylaminopyridine, a yield of 85%, and 22.6 g of 3-amino-2-chloropyridine (gas chromatograph). An organic layer containing a graph quantitative value) was obtained.

Claims (3)

Formula (1):

(Wherein X represents a halogen atom)
A methyloxymethylaminopyridine derivative represented by: In the presence of a base, the formula (2):

(Wherein X represents a halogen atom)
The method for producing a methyloxymethylaminopyridine derivative represented by the formula (1) according to claim 1, wherein the aminopyridine derivative represented by formula (1) is reacted with formaldehyde and methanol. Formula (3), wherein the methyloxymethylaminopyridine derivative represented by formula (1) according to claim 1 is subjected to a reduction reaction:

(Wherein X represents a halogen atom)
A process for producing a methylaminopyridine derivative represented by the formula: