JP2005289988A - Method of manufacturing amino compound - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method of manufacturing an amino compound industrially safely. <P>SOLUTION: This is a method of manufacturing an amino compound expressed by formula (2) by reacting an aminocarbonyl compound expressed by formula (1) with a hypohalite. In formula (1), X shows a carbon atom or a nitrogen atom; R<SB>1</SB>shows a hydrogen atom, a 1-8C straight chain or branched chain alkyl group, a 3-8C cycloalkyl group, an alkoxyalkyl group, an alkenyl group, an alkynyl group, an aryl group, or an aralkyl group; R<SB>2</SB>shows a hydrogen atom or an alkyl group. In formula (2), X, R<SB>1</SB>and R<SB>2</SB>are the same as mentioned before. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to formula (1):

（式中、Ｘは炭素原子又は窒素原子を示し、Ｒ_１は水素原子、炭素数１〜８のアルキル基、炭素数３〜８のシクロアルキル基、アルコキシアルキル基、アルケニル基、アルキニル基、アリール基又はアラルキル基を示し、Ｒ_２は水素原子又はアルキル基を示す。）で表されるアミノカルボニル化合物（以下、アミノカルボニル化合物（１）という。）を次亜ハロゲン酸塩と反応させてなる式（２）：

(In the formula, X represents a carbon atom or a nitrogen atom, and R ₁ represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, an alkoxyalkyl group, an alkenyl group, an alkynyl group, aryl. A group or an aralkyl group, and R ₂ represents a hydrogen atom or an alkyl group.) A formula obtained by reacting an aminocarbonyl compound (hereinafter referred to as aminocarbonyl compound (1)) with a hypohalite. (2):

（式中、Ｘ、Ｒ_１及びＲ_２は前記に同じ。）で表されるアミノ化合物（以下、アミノ化合物（２）という。）の製造法に関する。

(Wherein, X, R ₁ and R ₂ are the same as above), and relates to a method for producing an amino compound (hereinafter referred to as amino compound (2)).

The amino compound (2) represented by 1-amino-4-methylpiperazine is useful as a pharmaceutical intermediate. Conventionally, as a method for producing an amino compound (2), for example, a method is known in which piperazines are used as raw materials, reacted with nitrite to obtain nitrosopiperazines as intermediates, and then reduced with thiourea dioxide ( For example, see Patent Document 1).
JP-A-1-224333

However, in the above conventional method, since diethyl ether which is a special flammable substance is used as an extraction solvent and nitrosopiperazines having mutagenic properties are used as an intermediate, it is not necessarily an industrially superior method from the viewpoint of safety. I can't say that.

An object of the present invention is to provide a production method capable of industrially safely obtaining an amino compound using a compound that does not exhibit mutagenicity as a starting material.

The present invention relates to a method for producing an amino compound (2), which comprises reacting an aminocarbonyl compound (1) with a hypohalite in the presence of an alkali.

Since the amino compound (2) can be produced safely by the method of the present invention, the method of the present invention has great industrial applicability.

The present invention is described in detail below.
In the aminocarbonyl compound (1) and the amino compound (2), the alkyl group having 1 to 8 carbon atoms represented by R ₁ represents a linear or branched alkyl group, and includes a methyl group, an ethyl group, and a propyl group. Isopropyl group, butyl group, isobutyl group, tert-butyl group, pentyl group, isopentyl group, hexyl group, isohexyl group, heptyl group, isoheptyl group, octyl group, isooctyl group, etc., preferably methyl group. Examples of the cycloalkyl group having 3 to 8 carbon atoms include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group, and a cyclopentyl group is preferable. Examples of the alkoxyalkyl group include a methoxymethyl group, a methoxyethyl group, a methoxypropyl group, an ethoxymethyl group, an ethoxyethyl group, and an ethoxypropyl group, and a methoxyethyl group is preferable. Examples of the alkenyl group include a vinyl group, a 1-propenyl group, a 2-propenyl group, a 1-butenyl group, a 2-butenyl group, and a 3-butenyl group, and a vinyl group is preferable. Examples of the alkynyl group include an acetylenyl group, a 1-propynyl group, a 2-propynyl group, a 1-butynyl group, a 2-butynyl group, and a 3-butynyl group, and an acetylenyl group is preferable. Examples of the aryl group include a phenyl group, a tolyl group, a naphthyl group, a xylyl group, a mesityl group, and a cumenyl group, and a phenyl group is preferable. Examples of the aralkyl group include a benzyl group, a phenethyl group, a phenylpropyl group, a benzhydryl group, and a trityl group, and a benzyl group is preferable.

R ₂ is a hydrogen atom or an alkyl group, and examples of the alkyl group include a linear or branched alkyl group having 1 to 6 carbon atoms, such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, Examples thereof include an isobutyl group, a tert-butyl group, a pentyl group, an isopentyl group, a hexyl group, an isohexyl group, and preferably a hydrogen atom.

Specific examples of the aminocarbonyl compound (1) include 1-aminocarbonylpiperazine, 1-aminocarbonyl-4-methylpiperazine, 1-aminocarbonyl-4-ethylpiperazine, 1-aminocarbonyl-4-propylpiperazine, 1-aminocarbonylpiperazine, Aminocarbonyl-4-butylpiperazine, 1-aminocarbonyl-4-cyclopentylpiperazine, 1-aminocarbonyl-4-benzylpiperazine, 1-aminocarbonyl-4-phenylpiperazine, 1-aminocarbonyl-2,4-dimethylpiperazine, 1-aminocarbonyl-3,4-dimethylpiperazine, 1-aminocarbonyl-2-methyl-4-ethylpiperazine, 1-aminocarbonyl-3-methyl-4-ethylpiperazine, 1-aminocarbonylpiperidine, 1-aminocarbonyl − -Methylpiperidine, 1-aminocarbonyl-4-ethylpiperidine, 1-aminocarbonyl-4-propylpiperidine, 1-aminocarbonyl-4-butylpiperidine, 1-aminocarbonyl-4-cyclopentylpiperidine, 1-aminocarbonyl-4 -Benzylpiperidine, 1-aminocarbonyl-4-phenylpiperidine, 1-aminocarbonyl-2,4-dimethylpiperidine, 1-aminocarbonyl-3,4-dimethylpiperidine, 1-aminocarbonyl-2-methyl-4-ethyl Examples include piperidine and 1-aminocarbonyl-3-methyl-4-ethylpiperidine.

According to the present invention, amino compounds (2) corresponding to the aminocarbonyl compounds (1) to be used can be produced. Specific examples thereof include 1-aminopiperazine, 1-amino-4-methylpiperazine, 1-amino. -4-ethylpiperazine, 1-amino-4-propylpiperazine, 1-amino-4-butylpiperazine, 1-amino-4-cyclopentylpiperazine, 1-amino-4-benzylpiperazine, 1-amino-4-phenylpiperazine 1-amino-2,4-dimethylpiperazine, 1-amino-3,4-dimethylpiperazine, 1-amino-2-methyl-4-ethylpiperazine, 1-amino-3-methyl-4-ethylpiperazine, 1 -Aminopiperidine, 1-amino-4-methylpiperidine, 1-amino-4-ethylpiperidine, 1-amino 4-propylpiperidine, 1-amino-4-butylpiperidine, 1-amino-4-cyclopentylpiperidine, 1-amino-4-benzylpiperidine, 1-amino-4-phenylpiperidine, 1-amino-2,4-dimethyl Examples include piperidine, 1-amino-3,4-dimethylpiperidine, 1-amino-2-methyl-4-ethylpiperidine, 1-amino-3-methyl-4-ethylpiperidine and the like.

The halogen of the hypohalite used in the reaction may be any of chlorine, bromine and iodine, but usually chlorine or bromine is preferably used. Examples of the cation constituting metal of the hypohalite include alkali metals such as sodium and potassium. The amount of hypohalite used is usually equimolar or more, preferably 1.0 to 4.0 times mol, particularly preferably 1.1 to 2.5 times mol, per mol of aminocarbonyl compound (1). is there.

A conventionally well-known thing can be widely used as an alkali, For example, sodium hydroxide, potassium hydroxide, or calcium hydroxide etc. are mentioned. The amount used is usually 2.0 times mol or more, preferably 2.0 to 6.0 times mol, particularly preferably 2.2 to 4.0 times mol, based on 1 mol of aminocarbonyl compound (1). .

The present invention is usually carried out in water. The amount of water used is usually 2 to 30 parts by weight, preferably 5 to 20 parts by weight, based on 1 part by weight of the aminocarbonyl compound (1). Water as a solvent may be added alone to the reactor, or may be mixed with an alkali first and added as an aqueous alkali solution.

The reaction temperature is important from the viewpoint of the yield of the amino compound (2), and the reaction is carried out at a two-step reaction temperature. That is, the reaction is first carried out at 0 ° C. or less, preferably −30 to 0 ° C., more preferably −30 to −5 ° C., and then 60 ° C. or more, preferably 60 to 100 ° C., more preferably in order to complete the reaction. Perform at 70-90 ° C. In this way, the yield of the amino compound (2) can be improved.

In order to carry out the reaction according to the present invention, aminocarbonylpiperazines are added all at once or dividedly into a mixed solution of water, alkalis and hypohalite at the above-mentioned reaction temperature, usually for 1 hour or more, preferably Stir for 1-5 hours. Thereafter, the reaction mixture is heated to the reaction temperature described above to complete the reaction. In such a heating operation, the reaction mixture may be heated as it is in the same reactor, or may be added with stirring to heated water adjusted to the reaction temperature prepared in another reactor. After completion of the reaction, the reaction mixture is concentrated, and an extraction solvent (aromatic hydrocarbons such as toluene and xylene, alcohols such as methanol and n-butanol, and aliphatic hydrocarbons such as n-hexane and cyclohexane) is used. After extraction, the amino compound (2) can be obtained by purifying the resulting organic layer by a conventional distillation operation.

Moreover, a higher quality amino compound (2) can be obtained by distilling the organic phase after the extraction operation after acid hydrolysis treatment.

As acids used in the acid hydrolysis treatment, mineral acids are usually used, and examples thereof include hydrochloric acid and sulfuric acid. Such acids may be used as they are, or may be used after diluting with a solvent such as water, and the concentration range when diluted with a solvent is not particularly limited. The amount of use is determined by the pH of the extract, and acids are usually added until the pH is 1.0 or less, preferably 0.5 to 1.0.

In order to carry out the acid hydrolysis treatment, after adding a necessary amount of acids at room temperature, the mixture is usually heated to 30 to 80 ° C., preferably 40 to 60 ° C. and stirred. The stirring time is usually 1 hour or longer, preferably 1 to 10 hours, particularly preferably 1 to 5 hours.

After completion of the acid hydrolysis treatment, the mixture is cooled to room temperature, and inorganic bases are added to a pH of 13.5 or more to make the treatment solution basic. Then, the organic layer to be separated is separated, and the organic layer is separated by conventional isolation. A higher-quality amino compound (2) can be obtained by purification by a purification operation (for example, concentration, distillation, recrystallization, chromatography, etc.).

As the inorganic base, an inorganic hydroxide is usually used, and examples thereof include sodium hydroxide, potassium hydroxide, calcium hydroxide, and lithium hydroxide, and sodium hydroxide and potassium hydroxide are preferable. Such inorganic bases may be added alone or diluted with a solvent such as water, and the concentration range when diluted with a solvent is not particularly limited.

EXAMPLES The present invention will be described more specifically with reference to the following examples. However, the present invention is not limited to the following examples.

Example 1
To a flask equipped with a stirrer, 390 g (0.63 mol) of an aqueous sodium hypochlorite solution containing 12% effective chlorine, 76 g (1.35 mol) of potassium hydroxide and 304 g of water were added and cooled to −15 ° C. To this, 80 g (0.56 mol) of 1-aminocarbonyl-4-methylpiperazine powder was added with stirring for about 5 minutes and stirred for 4 hours. In another reaction flask with stirring, 100 g of water was added, the temperature was raised to 80 ° C., the reaction mixture was added dropwise at 80 to 90 ° C. with stirring, and the mixture was heated and stirred for 1 hour. After completion of the reaction, the reaction mixture was concentrated and extracted and separated twice with 260 g of n-butanol to obtain an organic layer. The organic layer was distilled to obtain 58 g of 1-amino-4-methylpiperazine (yield 88.0%, GC purity 98.0%).

Example 2
To a flask equipped with a stirrer was added 1776.5 g (3.34 mol) of an aqueous solution of 14% effective chlorine and sodium hypochlorite, 325.1 g (4.92 mol) of 85% potassium hydroxide and 3268.5 g of water, and cooled to -6 ° C. did. To this, 363.4 g (1.66 mol) of 1-aminocarbonyl-4-benzylpiperazine powder was added in portions over 2 hours with stirring, followed by stirring for 2 hours, followed by heating to 80 ° C. and stirring for 2 hours. After completion of the reaction, the reaction mixture was concentrated and extracted and separated three times with 720 g of toluene to obtain an organic layer. The obtained organic layer was adjusted to pH 1 or lower by adding a 35% aqueous hydrochloric acid solution at room temperature, heated to 50 ° C., stirred for 1 hour, cooled to room temperature, added with a 48% aqueous sodium hydroxide solution to adjust pH 13. Adjust to 5 or higher. The organic layer was separated and concentrated. After distillation, 270 g of 1-amino-4-benzylpiperazine (yield 65.7%, GC purity 99.0%) was obtained.

Example 3
The same procedure as in Example 1 was carried out except that 1-aminocarbonyl-4-cyclopentylpiperazine was used instead of 1-aminocarbonyl-4-methylpiperazine in Example 1, and 1-amino-4-cyclopentylpiperazine (yield) 66.2%, GC purity 98.0%).

Example 4
The same procedure as in Example 1 was carried out except that 1-aminocarbonylpiperidine was used instead of 1-aminocarbonyl-4-methylpiperazine in Example 1, and 1-aminopiperidine (yield 51.3%, GC purity 98 0.0%).

Claims (5)

Formula (1):

(In the formula, X represents a carbon atom or a nitrogen atom, and R ₁ represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, an alkoxyalkyl group, an alkenyl group, an alkynyl group, aryl. A group or an aralkyl group, and R ₂ represents a hydrogen atom or an alkyl group.) And an aminocarbonyl compound represented by the following formula (2): ):

(Wherein X, R ₁ and R ₂ are the same as above). The process according to claim 1, wherein X is a nitrogen atom, and R ₁ is an alkyl group, a cycloalkyl group or an aralkyl group. The production method according to claim 1, wherein R ₂ is a hydrogen atom. The process according to any one of claims 1 to 3, wherein the reaction is first carried out at a reaction temperature of -30 ° C to 0 ° C and then at a reaction temperature of 60 to 100 ° C. It refine | purifies by an acid hydrolysis process, The manufacturing method in any one of Claims 1-4 characterized by the above-mentioned.