JP2021161035A - Method for Producing Nitrogen-Containing Alicyclic Compound - Google Patents

Abstract

To provide a method for safely and efficiently producing a nitrogen-containing alicyclic compound containing 2-acetyltetrahydropyridine or the like.SOLUTION: A method for producing a compound (3) includes step A, step B, and step C (final purification) illustrated by the following formulae. In the step A, a compound (1) is reduced. In the step B, a hydroxy group of a compound (2) resulting from the step A is oxidized and an α, β unsaturated bond is formed. In the step C (final purification), the compound (3) resulting from the step B is purified.SELECTED DRAWING: None

Description

The present invention relates to a method for producing a nitrogen-containing alicyclic compound containing 2-acetyltetrahydropyridine and the like.

2-Acetyltetrahydropyridine is known as a flavoring component of foods having the structure (1, 2) shown below. It is understood that the following structures 1 and 2 are in a constant equilibrium state.

Conventional methods for synthesizing 2-acetyltetrahydropyridine are described in G.I. Although the method by Buchi et al. (Non-Patent Document 1) is known, it cannot be said that it is efficient not only in terms of safety and cost but also in the manufacturing process. Specifically, G. The method of Buchi et al. Is a method of synthesizing 2-acetyltetrahydropyridine in two steps using silver carbonate, but in the oxidation reaction of the second step, very expensive silver carbonate is used, and it is suitable for the environment and the human body. There is a drawback that the reaction time is almost one day by refluxing with very harmful benzene (boiling point: 80.1 ° C.). As described above, none of the conventional synthesis methods can be said to be efficient, and there is a problem as a method for industrial production.

J. Org. Chem. , 36 (4), 609-610 (1971)

In light of these circumstances, it is an object of the present invention to provide a safer and more efficient method for producing a nitrogen-containing alicyclic compound containing 2-acetyltetrahydropyridine and the like.

As a result of diligent studies to solve the above problems, the present inventors have succeeded in developing a new production method shown below, and the production method makes the nitrogen-containing alicyclic compound such as 2-acetyltetrahydropyridine more efficient. We have found that we can achieve the provision of a specific synthetic method, and have completed the present invention.

The present invention includes aspects described below.

（式中、Ｒ^１は、水素原子、又は、炭素数１〜３の低級アルキル基、を示す。
ｎは、１〜４の整数を示す。
ｍは、０〜ｎ＋２の整数を示す。
Ｒ^２は、それぞれ独立して、炭素数１〜３の低級アルキル基、炭素数１〜３の低級アルコキシル基、又は、炭素数１〜３の低級アルキルチオ基を示す。ｍが２以上の場合、Ｒ^２は、同一、又は、異なる。ｍが２以上の場合、複数のＲ^２は、共に、炭素数４〜８の環構造を形成していてもよい。）。 [1] Steps A to C represented by the following equation:
Step A: Step of reducing compound (1),
Step B: A step of oxidizing the hydroxyl group of the compound (2) obtained in step A and forming an α and β unsaturated bond, and
Step C: A step of purifying compound (3), (4), or both from a reaction mixture containing compounds (3), (4), or both obtained in step B.
Methods for producing compounds (3), (4), or both, including:

(In the formula, R ¹ represents a hydrogen atom or a lower alkyl group having 1 to 3 carbon atoms.
n represents an integer of 1 to 4.
m represents an integer of 0 to n + 2.
R ² independently represents a lower alkyl group having 1 to 3 carbon atoms, a lower alkoxyl group having 1 to 3 carbon atoms, or a lower alkyl thio group having 1 to 3 carbon atoms. When m is 2 or more, R ² is the same or different. when m is 2 or more, plural R ² are both, they may form a ring structure of 4 to 8 carbon atoms. ).

（式中、Ｒ^１は、水素原子、又は、炭素数１〜３の低級アルキル基、を示す。
ｎは、１〜４の整数を示す。
ｍは、０〜ｎ＋２の整数を示す。
Ｒ^２は、それぞれ独立して、炭素数１〜３の低級アルキル基、炭素数１〜３の低級アルコキシル基、又は、炭素数１〜３の低級アルキルチオ基を示す。ｍが２以上の場合、Ｒ^２は、同一、又は、異なる。ｍが２以上の場合、複数のＲ^２は、共に、炭素数４〜８の環構造を形成していてもよい。）。 [2] Steps A to B represented by the following equation:
Step A: Step of reducing compound (1) and
Step B: A step of oxidizing the hydroxyl group of the compound (2) obtained in step A and forming an α and β unsaturated bond.
Methods for producing compounds (3), (4), or both, including:

(In the formula, R ¹ represents a hydrogen atom or a lower alkyl group having 1 to 3 carbon atoms.
n represents an integer of 1 to 4.
m represents an integer of 0 to n + 2.
R ² independently represents a lower alkyl group having 1 to 3 carbon atoms, a lower alkoxyl group having 1 to 3 carbon atoms, or a lower alkyl thio group having 1 to 3 carbon atoms. When m is 2 or more, R ² is the same or different. when m is 2 or more, plural R ² are both, they may form a ring structure of 4 to 8 carbon atoms. ).

（式中、Ｒ^１は、水素原子、又は、炭素数１〜３の低級アルキル基、を示す。
ｎは、１〜４の整数を示す。
ｍは、０〜ｎ＋２の整数を示す。
Ｒ^２は、それぞれ独立して、炭素数１〜３の低級アルキル基、炭素数１〜３の低級アルコキシル基、又は、炭素数１〜３の低級アルキルチオ基を示す。ｍが２以上の場合、Ｒ^２は、同一、又は、異なる。ｍが２以上の場合、複数のＲ^２は、共に、炭素数４〜８の環構造を形成していてもよい。）。 [3] Steps B to C represented by the following equation:
Step B: A step of oxidizing the hydroxyl group of compound (2) and forming an α and β unsaturated bond, and
Step C: A step of purifying compound (3), (4), or both from a reaction mixture containing compounds (3), (4), or both obtained in step B.
Methods for producing compounds (3), (4), or both, including:

(In the formula, R ¹ represents a hydrogen atom or a lower alkyl group having 1 to 3 carbon atoms.
n represents an integer of 1 to 4.
m represents an integer of 0 to n + 2.
R ² independently represents a lower alkyl group having 1 to 3 carbon atoms, a lower alkoxyl group having 1 to 3 carbon atoms, or a lower alkyl thio group having 1 to 3 carbon atoms. When m is 2 or more, R ² is the same or different. when m is 2 or more, plural R ² are both, they may form a ring structure of 4 to 8 carbon atoms. ).

（式中、Ｒ^１は、水素原子、又は、炭素数１〜３の低級アルキル基、を示す。
ｎは、１〜４の整数を示す。
ｍは、０〜ｎ＋２の整数を示す。
Ｒ^２は、それぞれ独立して、炭素数１〜３の低級アルキル基、炭素数１〜３の低級アルコキシル基、又は、炭素数１〜３の低級アルキルチオ基を示す。ｍが２以上の場合、Ｒ^２は、同一、又は、異なる。ｍが２以上の場合、複数のＲ^２は、共に、炭素数４〜８の環構造を形成していてもよい。）。 [4] Step B represented by the following equation:
Step B: A step of oxidizing the hydroxyl group of compound (2) and forming an α and β unsaturated bond.
Methods for producing compounds (3), (4), or both, including:

(In the formula, R ¹ represents a hydrogen atom or a lower alkyl group having 1 to 3 carbon atoms.
n represents an integer of 1 to 4.
m represents an integer of 0 to n + 2.
R ² independently represents a lower alkyl group having 1 to 3 carbon atoms, a lower alkoxyl group having 1 to 3 carbon atoms, or a lower alkyl thio group having 1 to 3 carbon atoms. When m is 2 or more, R ² is the same or different. when m is 2 or more, plural R ² are both, they may form a ring structure of 4 to 8 carbon atoms. ).

[5] Step C represented by the following equation:
Step C: Purification of compound (3), (4), or both from a reaction mixture containing compounds (3), (4), or both.
A method for producing compounds (3), (4), or both, which comprises.

[6] The production method according to any one of [1] to [4], which comprises manganese dioxide as an oxidizing agent in step B.

[7] In step C, one or more solvents selected from the group consisting of ethylene glycol, propylene glycol, butanediol, benzyl alcohol, triethylcitrate, and triacetin are added to the compounds (3) and (4). The production method according to [1], [3], or [5], which comprises a step of obtaining as an azeotropic distillate solution of, or both of them and the solvent.

[8] The production method according to any one of [1] to [7], wherein ^{R 1 is a methyl group or an ethyl group.}

[9] The production method according to any one of [1] to [8], wherein n is 1 or 2.

The production method according to any one of [1] to [9], wherein [10] m is an integer of 1 to n + 2, and R ^{2 is a methyl group or an ethyl group.}

[11] R ¹ is a methyl group, n is 1 or 2, m is 0 or 1, and R ² is a methyl group, in any of [1] to [7]. The manufacturing method described.

[12] The production method according to any one of [1] to [7], wherein ^{R 1 is a methyl group, n is 2, and m is 0.}

The method for producing a nitrogen-containing alicyclic compound containing 2-acetyltetrahydropyridine or the like of the present invention is safer for the human body and the environment than the conventional method, and the work time and cost in production are significantly reduced. It becomes possible to make it.

Hereinafter, embodiments of the present invention will be described in detail.

（式中、Ｒ^１は、水素原子、又は、炭素数１〜３の低級アルキル基、を示す。
ｎは、１〜４の整数を示す。
ｍは、０〜ｎ＋２の整数を示す。
Ｒ^２は、それぞれ独立して、炭素数１〜３の低級アルキル基、炭素数１〜３の低級アルコキシル基、又は、炭素数１〜３の低級アルキルチオ基を示す。ｍが２以上の場合、Ｒ^２は、同一、又は、異なる。ｍが２以上の場合、複数のＲ^２は、共に、炭素数４〜８の環構造を形成していてもよい。）。 The method for producing the compounds (3), (4), or both of the present invention is:
Steps A to C represented by the following equation:
Step A: Step of reducing compound (1),
Step B: A step of oxidizing the hydroxyl group of the compound (2) obtained in step A and forming an α and β unsaturated bond, and
Step C: A step of purifying compound (3), (4), or both from a reaction mixture containing compounds (3), (4), or both obtained in step B.
including:

(In the formula, R ¹ represents a hydrogen atom or a lower alkyl group having 1 to 3 carbon atoms.
n represents an integer of 1 to 4.
m represents an integer of 0 to n + 2.
R ² independently represents a lower alkyl group having 1 to 3 carbon atoms, a lower alkoxyl group having 1 to 3 carbon atoms, or a lower alkyl thio group having 1 to 3 carbon atoms. When m is 2 or more, R ² is the same or different. when m is 2 or more, plural R ² are both, they may form a ring structure of 4 to 8 carbon atoms. ).

The present invention provides a novel method for producing a nitrogen-containing alicyclic compound represented by the compound (3) or (4), which comprises 2-acetyltetrahydropyridine and the like.

（式中、Ｒ^１は、水素原子、又は、炭素数１〜３の低級アルキル基、を示す。
ｎは、１〜４の整数を示す。
ｍは、０〜ｎ＋２の整数を示す。
Ｒ^２は、それぞれ独立して、炭素数１〜３の低級アルキル基、炭素数１〜３の低級アルコキシル基、又は、炭素数１〜３の低級アルキルチオ基を示す。ｍが２以上の場合、Ｒ^２は、同一、又は、異なる。ｍが２以上の場合、複数のＲ^２は、共に、炭素数４〜８の環構造を形成していてもよい。）。

(In the formula, R ¹ represents a hydrogen atom or a lower alkyl group having 1 to 3 carbon atoms.
n represents an integer of 1 to 4.
m represents an integer of 0 to n + 2.
R ² independently represents a lower alkyl group having 1 to 3 carbon atoms, a lower alkoxyl group having 1 to 3 carbon atoms, or a lower alkyl thio group having 1 to 3 carbon atoms. When m is 2 or more, R ² is the same or different. when m is 2 or more, plural R ² are both, they may form a ring structure of 4 to 8 carbon atoms. ).

In the present invention, R ¹ represents a hydrogen atom or a lower alkyl group having 1 to 3 carbon atoms.

Examples ^{of the lower alkyl group having 1 to 3 carbon atoms represented by R 1} include a methyl group, an ethyl group, an n-propyl group, an isopropyl group and the like.

Further, in the present invention, n represents an integer of 1 to 4.

Further, in the present invention, m represents an integer of 0 to n + 2.

Further, in the present invention, R ² independently represents a lower alkyl group having 1 to 3 carbon atoms, a lower alkoxyl group having 1 to 3 carbon atoms, or a lower alkyl thio group having 1 to 3 carbon atoms. When m is 2 or more, R ² is the same or different. when m is 2 or more, plural R ² are both, they may form a ring structure of 4 to 8 carbon atoms.

Examples ^{of the lower alkyl group having 1 to 3 carbon atoms represented by R 2} include a methyl group, an ethyl group, an n-propyl group, and isopropyl.

Further, ^{as the lower alkoxyl group having 1 to 3 carbon atoms represented by R 2} , for example, a methoxy group, an ethoxy group, an n-propyroxy group, an isoproproxy group and the like can be mentioned.

Further, as the lower alkylthio group having 1 to 3 carbon atoms represented by the R ² (alkylsulfanyl group), for example, methylthio group, ethylthio group, n- propyloxy group, and include a isopropyloxy group.

Further, as the ring structure having 4 to 8 carbon atoms according to the above R ² , for example, a cyclobutyl ring structure, a methylcyclobutyl ring structure, a dimethylcyclobutyl ring structure, a cyclopentyl ring structure, a methylcyclopentyl ring structure, an ethylcyclopentyl ring structure, and a dimethylcyclopentyl. Examples thereof include a ring structure, an ethylmethylcyclopentyl ring structure, a cyclohexyl ring structure, a methylcyclohexyl ring structure, a dimethylcyclohexyl ring structure, a cycloheptyl ring structure, a methylcycloheptyl ring structure, and a cyclooctyl ring structure.

Further, for example, when R ¹ is a methyl group, n is 2, and m is 0, the compound (1) or (2) is 2-acetyltetrahydropyridine. It is understood that the following structures 1 and 2 are in a constant equilibrium state.

Further, for example, when R ¹ is a methyl group, n is 2, m is 1, and R ² is a methyl group at the 3-position, the compound (3) or (4) is. 2-Acetyl-3-methyl-tetrahydropyridine. It is understood that the following structures 3 and 4 are in a constant equilibrium state.

Further, for example, when R ¹ is an ethyl group, n is 2, and m is 0, the compound (5) or (6) is 2-propionyltetrahydropyridine. It is understood that the following structures 5 and 6 are in a constant equilibrium state.

（式中、Ｒ^１は、水素原子、又は、炭素数１〜３の低級アルキル基、を示す。
ｎは、１〜４の整数を示す。
ｍは、０〜ｎ＋２の整数を示す。
Ｒ^２は、それぞれ独立して、炭素数１〜３の低級アルキル基、炭素数１〜３の低級アルコキシル基、又は、炭素数１〜３の低級アルキルチオ基を示す。ｍが２以上の場合、Ｒ^２は、同一、又は、異なる。ｍが２以上の場合、複数のＲ^２は、共に、炭素数４〜８の環構造を形成していてもよい。）。 In addition, the method for producing the compound (3), (4), or both of the compounds (3), (4) of the present invention (hereinafter, may be referred to as “compound (3), etc.”) includes the method represented by the following formula.

(In the formula, R ¹ represents a hydrogen atom or a lower alkyl group having 1 to 3 carbon atoms.
n represents an integer of 1 to 4.
m represents an integer of 0 to n + 2.
R ² independently represents a lower alkyl group having 1 to 3 carbon atoms, a lower alkoxyl group having 1 to 3 carbon atoms, or a lower alkyl thio group having 1 to 3 carbon atoms. When m is 2 or more, R ² is the same or different. when m is 2 or more, plural R ² are both, they may form a ring structure of 4 to 8 carbon atoms. ).

In addition, in the production method of the present invention and each step, even when compound (3), (4), or both ("Compound (3), etc." is described, the above-mentioned 2-acetyltetrahydropyridine In addition to the above-mentioned structures 1 and 2 in the above, which are in a constant equilibrium state, for example, the case where only one of the compounds (3) and (4) can be obtained substantially is included.

The above manufacturing method can be carried out by the following steps (steps) A to C.

（式中、Ｒ^１は、水素原子、又は、炭素数１〜３の低級アルキル基、を示す。
ｎは、１〜４の整数を示す。
ｍは、０〜ｎ＋２の整数を示す。
Ｒ^２は、それぞれ独立して、炭素数１〜３の低級アルキル基、炭素数１〜３の低級アルコキシル基、又は、炭素数１〜３の低級アルキルチオ基を示す。ｍが２以上の場合、Ｒ^２は、同一、又は、異なる。ｍが２以上の場合、複数のＲ^２は、共に、炭素数４〜８の環構造を形成していてもよい。）。 (Step A)

(In the formula, R ¹ represents a hydrogen atom or a lower alkyl group having 1 to 3 carbon atoms.
n represents an integer of 1 to 4.
m represents an integer of 0 to n + 2.
R ² independently represents a lower alkyl group having 1 to 3 carbon atoms, a lower alkoxyl group having 1 to 3 carbon atoms, or a lower alkyl thio group having 1 to 3 carbon atoms. When m is 2 or more, R ² is the same or different. when m is 2 or more, plural R ² are both, they may form a ring structure of 4 to 8 carbon atoms. ).

Step A (step A) is a step of reducing a nitrogen-containing aromatic ring and an aldehyde group or a ketone group, and may include, for example, a site that can be reduced to ^{R 1} or R ^2. As a typical example, a step of obtaining a compound having an NH group in the alicyclic structure and a hydroxy group at the β-position of the N atom as shown as compound (2) by step A (step A). Is.

The reduction in step A can be carried out, for example, by hydrogenation or, as appropriate, using a known reducing agent.

In step A, the reduction can be carried out, for example, in the presence of a solvent. The solvent is not particularly limited as long as the desired reaction proceeds, and for example, alcohols such as water, methanol, ethanol, propanol and butanol; aromatic hydrocarbons such as benzene, toluene and xylene; diethyl ether and diisopropyl. Ethers such as ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; acid amides such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidinone; chloroform, dichloromethane, carbon tetrachloride, 1, Halogenated hydrocarbons such as 2-dichloroethane; sulfoxides such as dimethylsulfoxide; sulfones such as sulfolane; phosphate amides such as hexamethylphosphoramide can be mentioned. These may be used alone or in combination of two or more.

In step A, the reduction can be appropriately carried out using a known catalyst. Examples of the catalyst include catalysts in which palladium, platinum, renium, ruthenium, and rhodium are supported on activated carbon, Raney alloys such as Raney nickel and Raney iron, chromium-free copper catalysts, and rhodium-alumina as an alumina carrier. be able to. These may be used alone or in combination of two or more.

In step A, the pressure of hydrogenation in the reduction is usually an arbitrary pressure of normal pressure to several hundreds of atmospheres. Also, in general, it is possible to accelerate the reaction by increasing the pressure.

In step A, the reaction temperature for the reduction is usually 0 ° C. to 100 ° C., but may be 0 to 50 ° C. The reaction time is usually 1 to 48 hours, but may be 12 to 24 hours. Also, in general, it is possible to accelerate the reaction by raising the temperature.

Further, after completion of the reduction in step A, if necessary, the obtained reaction solution is concentrated under reduced pressure, and then chromatography using silica gel (for example, silica gel fractionated thin layer chromatography, silica gel column chromatography, etc.), distillation, It may be subjected to an arbitrary purification operation such as recrystallization.

In this way, the compound (2) can be obtained from the chemical formula (1) by the step A.

（式中、Ｒ^１は、水素原子、又は、炭素数１〜３の低級アルキル基、を示す。
ｎは、１〜４の整数を示す。
ｍは、０〜ｎ＋２の整数を示す。
Ｒ^２は、それぞれ独立して、炭素数１〜３の低級アルキル基、炭素数１〜３の低級アルコキシル基、又は、炭素数１〜３の低級アルキルチオ基を示す。ｍが２以上の場合、Ｒ^２は、同一、又は、異なる。ｍが２以上の場合、複数のＲ^２は、共に、炭素数４〜８の環構造を形成していてもよい。）。 (Step B)

(In the formula, R ¹ represents a hydrogen atom or a lower alkyl group having 1 to 3 carbon atoms.
n represents an integer of 1 to 4.
m represents an integer of 0 to n + 2.
R ² independently represents a lower alkyl group having 1 to 3 carbon atoms, a lower alkoxyl group having 1 to 3 carbon atoms, or a lower alkyl thio group having 1 to 3 carbon atoms. When m is 2 or more, R ² is the same or different. when m is 2 or more, plural R ² are both, they may form a ring structure of 4 to 8 carbon atoms. ).

In step B (step B), compound (2) (when step A is included, compound (2) obtained in step A can be used, but compound (2) obtained by another method can be used. A step of oxidizing the hydroxyl group and forming an α, β unsaturated bond (in the present specification, the oxidation of the hydroxyl group and the formation of the α, β unsaturated bond are combined to form “oxidation”. It may be called.).

The oxidation used in step B (including the case of including the formation of α and β unsaturated bonds) is carried out, for example, by reacting compound (2) with an oxidizing agent such as a metal reagent having an oxidizing action. be able to.

In step B, the above-mentioned oxidizing agent is not particularly limited as long as it does not adversely affect the reaction, and is known as long as compound (2) forms an α, β unsaturated bond and oxidizes a hydroxyl group. Agents can be used. Examples of the oxidizing agent include manganese dioxide, potassium permanganate, potassium dichromate, chromic acid, pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), dimethylsulfoxide and oxalyl chloride, magnesium oxide and the like. Can be given. Among them, for example, manganese dioxide can be mentioned as a suitable oxidizing agent. These may be used alone or in combination of two or more.

Taking the case of producing 2-acetyltetrahydropyridine as the compounds (3) and (4) as an example, it is particularly preferable to include manganese dioxide as an oxidizing agent in step B. For example, by using manganese dioxide as an oxidant, the target compound can be produced more safely for the human body and the environment than in the conventional method, under milder reaction conditions, and the cost is significantly reduced. It becomes possible to make it. More specifically, even if only the catalyst as an oxidizing agent is taken, according to the commercial product catalog of Fuji Photo Film Wako Pure Chemical Industries, Ltd., the amount of silver carbonate used as an oxidizing agent in the conventional method is 10 g: 5,500 yen. , 500 g: 100,000 yen, whereas manganese dioxide (manganese oxide (IV)) that can be used in the present invention is only 500 g: 2,400 yen, and it can be seen that it can be produced at a very low cost. In addition, the reaction temperature can be lower than that of the conventional method, and the reaction time can be 1/10 or less of that of the conventional method as shown in Examples, which also increases the manufacturing cost. It can be reduced and can be carried out under milder reaction conditions.

In step B, the oxidation can be carried out, for example, in the presence of a solvent. The solvent is not particularly limited as long as the desired reaction proceeds, and is, for example, a fluorine-based solvent such as water, trifluorotoluene, fluorobenzene, and fluorohexane; and aromatic hydrocarbons (for example, benzene, toluene, xylene, and chlorobenzene). , Nitrobenzene, etc.) and hydrocarbon solvents such as aliphatic hydrocarbons (eg, pentane, hexane, heptane, octane, cyclohexane, methylcyclohexane, etc.); 1,2-dioxane, 1,3-dioxane, 1,4-dioxane. , Tetrahydrofuran, tetrahydropyran, dimethyl ether, diethyl ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether and other ether solvents; ethanol, n-propanol, 2-propanol, n-butanol and other alcohol solvents; acetamide, dimethyl acetamide, dimethylformamide, Amid solvents such as diethylformamide and N-methylpyrrolidone; ester solvents such as ethyl acetate, propyl acetate and butyl acetate; nitrile solvents such as acetonitrile and benzonitrile; methyl chloride, dichloromethane, trichloromethane (chloroform), 1, Examples thereof include halogenated hydrocarbons such as 2-dichloroethane, 1,1,1-trichloroethane, 1,1,2-trichloroethane, 1,1,2-trichloroethylene and 1-chlorobutane. These may be used alone or in combination of two or more.

In step B, the reaction temperature in the above oxidation is not particularly limited, but for example, 1 to 80 ° C. can be raised, and 10 to 50 ° C. may be used. The reaction time can be appropriately adjusted according to the reaction temperature and pressure, and is, for example, about 0.5 to 10 hours, preferably 1 to 6 hours, and more preferably 1 to 3 hours.

In step B, the ratio of the oxidizing reagent used in the oxidation is not particularly limited, but is usually 0.1 to 100 equal to 1 mol of compound (2), preferably 0.5 to 50 equal to 1 mol. , More preferably 1 to 10 equal amounts.

Further, after completion of the reduction in step B, if necessary, the obtained reaction solution is concentrated under reduced pressure, and then chromatography using silica gel (for example, silica gel fractionated thin layer chromatography, silica gel column chromatography, etc.), distillation, Although it may be subjected to an arbitrary purification operation such as recrystallization, it is preferable to use purification by step C.

In this way, the reaction mixture containing the compounds (3), (4), or both can be obtained from the chemical formula (2) by the step B.

(Step C)
Step C is the step C represented by the following equation:
Step C: Purification of compound (3), (4), or both from a reaction mixture containing compounds (3), (4), or both.
A method for producing compounds (3), (4), or both, which comprises.

In step C (step C), compounds (3), (4), or both (when step B is included, compound (3) obtained in step B, etc.) can be used, but other methods can be used. The compound (3) and the like obtained in 1) may be used in combination as appropriate. ) This is the refining process.

The reaction mixture containing the compounds (3), (4), or both may be a mixture containing at least one of the compounds (3) and (4). For example, when the reaction mixture contains step B, the reaction product containing the compound (3) or the like obtained in step B may be used as it is, and not only the by-product of compound (2) but also others. It may contain a reaction residue, an impurity component, and the like.

Step C may be performed alone or continuously with step B as appropriate. More specifically, for example, a method of continuously performing the operation of step C on the reaction mixture after the reaction of step B can be mentioned. Further, a known step such as dilution or simple purification operation may be appropriately performed between step B and step C.

In step C, it is preferable to purify by, for example, azeotropic distillation. In the above azeotropic distillation, for example, one or more solvents selected from the group consisting of ethylene glycol, propylene glycol, butanediol, benzyl alcohol, triethylcitrate, and triacetin are added as an azeotropic solvent to compound (3). ), (4), or both of them and the solvent are preferably obtained as an azeotropic distillation solution.

Taking the case of purifying 2-acetyltetrahydropyridine as the compounds (3) and (4) as an example, it is particularly preferable to use, for example, propylene glycol as an example of an azeotropic solvent. This is not intended to limit the rights of the present invention only to the case of the mechanism of action, but the target compound 2-acetyltetrahydropyridine is azeotropically distilled with propylene glycol, although it is unstable at high concentrations and the like. It is presumed that 2-acetyltetrahydropyridine can be efficiently purified and recovered by providing a diluting effect and the like so that the concentration of 2-acetyltetrahydropyridine does not become high even after the azeotropic reaction.

In step C, the azeotropic solvent can be added in an amount of, for example, about 3 to 30 times the total weight of the compounds (3) and (4), and the amount is about 10 to 20 times. You can also.

Further, after completion of purification in step C, if necessary, the obtained reaction solution is concentrated under reduced pressure, and then chromatography using silica gel (for example, silica gel fractionated thin layer chromatography, silica gel column chromatography, etc.) and recrystallization are performed. It may be subjected to any purification operation such as.

In this way, step C can purify compound (3), (4), or both from a reaction mixture containing compounds (3), (4), or both.

(2-Acetyltetrahydropyridine, etc.)
Some nitrogen-containing alicyclic compounds such as 2-acetyltetrahydropyridine thus obtained have a unique aroma depending on the type of the compound, and are useful as an aroma component substance.

The nitrogen-containing alicyclic compound such as 2-acetyltetrahydropyridine obtained by using the production method of the present invention can be used as a flavor composition for foods and drinks. For example, the proportion of 2-acetyl-tetrahydropyridine be incorporated into food or beverage varies depending on the kind and the type of food or drink nitrogen-containing cyclic compound used, for example, the food or beverage composition 100 wt%, 10 ^-12 10 ^{-4 wt% (10 -3 ~10 9 ppb)} , preferably may be mentioned the rate of ¹⁰ -6 ^{to 10 -1} wt% (1~10 ⁵ ppb).

The food and drink that can contain a nitrogen-containing alicyclic compound such as 2-acetyltetrahydropyridine as a fragrance component is not limited, but for example, cold confectionery such as ice cream, ice milk, lacto ice, sherbet, and ice confectionery; milk. Beverages, lactic acid bacteria beverages, soft beverages (including fruit juice), carbonated beverages, fruit juice beverages, vegetable beverages, vegetable / fruit beverages, sports beverages, powdered instant beverages, and other beverages; beer-like effervescent beverages such as non-alcoholic beer-taste beverages. Beverages; Alcoholic beverages such as liqueurs; Tea beverages such as coffee beverages, green tea, tea and herb tea; Soups such as consomme soup and potage soup; Puddings such as custard pudding, milk pudding and fruit juice pudding, jelly, Bavaroa and desserts such as yogurt; syrup, etc .; gums such as chewing gum and balloon gum (plate gum, sugar-coated grain gum); coated chocolate such as marble chocolate, strawberry chocolate, blueberry chocolate, and melon chocolate Chocolates such as chocolates with flavors such as etc .; Hard candy (including bonbons, butterballs, marbles, etc.), soft candy (including caramel, nougat, gummy candy, marshmallows, etc.), drops, toffee and other caramel; Baked confectioneries such as hard biscuits, cookies, okaki, and rice cakes; sauces such as separate dressing, non-oil dressing, ketchup, sauce, and sauces; jams such as strawberry jam, blueberry jam, apple jam, and preservatives; ham, sausage, and grilled pork Processed livestock products such as; fish ham, fish sausage, ground fish meat, fish paste products such as sardines; dairy products such as cheese; noodles; other foods or beverages, confectionery and the like.

Hereinafter, examples and the like that specifically show the configuration and effects of the present invention will be described.

[Example 1]
(Synthesis of 2-acetyltetrahydropyridine)

<Process (A)>
Preparation of 2- (1-hydroxyethyl) piperidine (Compound (2)): Reduction 2-Acetylpyridine (Compound (1), 65.1 g, 0.54 mоL) was dissolved in 53 mL of methanol, followed by 3.38 g. Rhodium-alumina (Rh5%) was added. The above solution was stirred under a hydrogen atmosphere of 5 Mpa at room temperature for 24 hours, and then rhodium-alumina was filtered by Celite filtration. By concentrating the above solution and distilling and purifying the obtained residue under reduced pressure, 2- (1-hydroxyethyl) piperidine (Compound (2), 50.0 g, 0.39 mоL, yield) was obtained as a colorless oily substance. 72%) was obtained.

<Process (B)>
Synthesis of 2-acetyltetrahydropyridine (Compound (3)): Oxidation (including oxidation of hydroxyl groups and formation of α and β unsaturated bonds)
2- (1-Hydroxyethyl) piperidine (Compound (2), 50.0 g, 0.39 mоL) obtained in the above step (A) was dissolved in 2700 mL of acetone. After adding manganese dioxide (manganese oxide (IV)) (336 g, 3.8 mоL) to the above solution, the solution was stirred at 50 ° C. for 1.5 hours. In the above solution, manganese dioxide was filtered off by Celite filtration, and then the solvent was distilled off under reduced pressure to obtain 45 g of a crude product of 2-acetyltetrahydropyridine (compound (3)).

<Final purification>
Purification of 2-Acetyltetrahydropyridine (Compound (3)): Azeotropic Distillation After adding 855 g of propylene glycol to the crude 2-acetyltetrahydropyridine (Compound (3), 45 g) obtained in the above step (B). , The propylene glycol solution was distilled under reduced pressure. 486 g of a propylene glycol solution containing 5.2% of 2-acetyltetrahydropyridine as the main distillate of the above distillation (25.3 g of compound (3), 0.20 mоL, yield 51%) was obtained.

As can be seen from the above examples, in the above step (B), mild temperature conditions can be obtained, and the conventional production method described in Non-Patent Document 1 is similar to benzene in terms of environment. It was possible to obtain 2-acetyltetrahydropyridine at low cost without using harmful substances and without significantly reducing the working time. Further, in the above step (C), it was possible to purify 2-acetyltetrahydropyridine having low stability in good yield. In addition, by using a manufacturing method in which the above-mentioned step (B), the final step, or both, or any one of them is combined with the above-mentioned step (A), the above-mentioned step (B) and / or the above-mentioned step (C) can be performed. It has been found that various production methods having the above effects are possible.

Claims (12)

Steps A to C represented by the following equation:
Step A: Step of reducing compound (1),
Step B: A step of oxidizing the hydroxyl group of the compound (2) obtained in step A and forming an α and β unsaturated bond, and
Step C: A step of purifying compound (3), (4), or both from a reaction mixture containing compounds (3), (4), or both obtained in step B.
Methods for producing compounds (3), (4), or both, including:

(In the formula, R ¹ represents a hydrogen atom or a lower alkyl group having 1 to 3 carbon atoms.
n represents an integer of 1 to 4.
m represents an integer of 0 to n + 2.
R ² independently represents a lower alkyl group having 1 to 3 carbon atoms, a lower alkoxyl group having 1 to 3 carbon atoms, or a lower alkyl thio group having 1 to 3 carbon atoms. When m is 2 or more, R ² is the same or different. when m is 2 or more, plural R ² are both, they may form a ring structure of 4 to 8 carbon atoms. ). Steps A to B represented by the following equation:
Step A: Step of reducing compound (1) and
Step B: A method for producing the compounds (3), (4), or both, which comprises a step of oxidizing the hydroxyl group of the compound (2) obtained in step A and forming an α, β unsaturated bond:

(In the formula, R ¹ represents a hydrogen atom or a lower alkyl group having 1 to 3 carbon atoms.
n represents an integer of 1 to 4.
m represents an integer of 0 to n + 2.
R ² independently represents a lower alkyl group having 1 to 3 carbon atoms, a lower alkoxyl group having 1 to 3 carbon atoms, or a lower alkyl thio group having 1 to 3 carbon atoms. When m is 2 or more, R ² is the same or different. when m is 2 or more, plural R ² are both, they may form a ring structure of 4 to 8 carbon atoms. ). Steps B to C represented by the following equation:
Step B: A step of oxidizing the hydroxyl group of compound (2) and forming an α and β unsaturated bond, and
Step C: A step of purifying compound (3), (4), or both from a reaction mixture containing compounds (3), (4), or both obtained in step B.
Methods for producing compounds (3), (4), or both, including:

(In the formula, R ¹ represents a hydrogen atom or a lower alkyl group having 1 to 3 carbon atoms.
n represents an integer of 1 to 4.
m represents an integer of 0 to n + 2.
R ² independently represents a lower alkyl group having 1 to 3 carbon atoms, a lower alkoxyl group having 1 to 3 carbon atoms, or a lower alkyl thio group having 1 to 3 carbon atoms. When m is 2 or more, R ² is the same or different. when m is 2 or more, plural R ² are both, they may form a ring structure of 4 to 8 carbon atoms. ). Step B shown by the following formula:
Step B: A method for producing the compound (3), (4), or both, which comprises a step of oxidizing the hydroxyl group of the compound (2) and forming an α, β unsaturated bond.

(In the formula, R ¹ represents a hydrogen atom or a lower alkyl group having 1 to 3 carbon atoms.
n represents an integer of 1 to 4.
m represents an integer of 0 to n + 2.
R ² independently represents a lower alkyl group having 1 to 3 carbon atoms, a lower alkoxyl group having 1 to 3 carbon atoms, or a lower alkyl thio group having 1 to 3 carbon atoms. When m is 2 or more, R ² is the same or different. when m is 2 or more, plural R ² are both, they may form a ring structure of 4 to 8 carbon atoms. ). Step C shown by the following formula:
Step C: Purification of compound (3), (4), or both from a reaction mixture containing compounds (3), (4), or both.
A method for producing compounds (3), (4), or both, which comprises. The production method according to any one of claims 1 to 4, wherein in step B, manganese dioxide is contained as an oxidizing agent. In step C, one or more solvents selected from the group consisting of ethylene glycol, propylene glycol, butanediol, benzyl alcohol, triethylcitrate, and triacetin are added to compound (3), (4), or The production method according to claim 1, 3, or 5, which comprises a step of obtaining both of them as an azeotropic distillate solution of the solvent. The production method according to any one of claims 1 to 7, wherein R ^{1 is a methyl group or an ethyl group.} The production method according to any one of claims 1 to 8, wherein n is 1 or 2. The production method according to any one of claims 1 to 9, wherein m is an integer of 1 to n + 2, and R ^{2 is a methyl group or an ethyl group.} The production according to any one of claims 1 to 7, wherein R ¹ is a methyl group, n is 1 or 2, m is 0 or 1, and R ^{2 is a methyl group.} Method. The production method according to any one of claims 1 to 7, wherein R ^{1 is a methyl group, n is 2, and m is 0.}