Method for producing 2,5-dialkylpiperazine

Abstract

To provide an efficient method for producing 2,5-dialkylpiperazine from amino alcohols as a raw material, without requiring the addition of hydrogen. [Solution] A method for producing 2,5-dialkylpiperazine, comprising a reaction step of cyclizing and dimerizing an amino alcohol with a ruthenium catalyst having a pincer-type ligand and a base.

Description

Technical Field

[0001] The present invention relates to a method for producing 2,5-dialkylpiperazine.

Background Art

[0002] Piperazine is a compound widely used in fields such as organic synthetic chemistry and pharmaceutical chemistry. Its derivative, 2,5-dialkylpiperazine, is also utilized in these fields. For example, Non-Patent Document 1 discloses that 2,5-dimethylpiperazine is useful as a partial structure of a 17β-hydroxysteroid dehydrogenase type 3 inhibitor.

[0003] The production of 2,5-dialkylpiperazine is achieved by synthesizing 2,5-dialkyldiketopiperazine using an amino acid as a raw material (Non-Patent Document 2) and reducing it with a reducing agent such as lithium aluminum hydride (Non-Patent Document 3). However, in this production method, there were problems such as a long production process and the industrial inaccessibility of reducing agents such as lithium aluminum hydride.

[0004] As a method for producing 2,5-dialkylpiperazine in a short process, Non-Patent Document 4 discloses a method for producing 2,5-dimethylpiperazine by reacting 2-methylethylene glycol and 2-methylethylenediamine using an iridium catalyst. However, this production method cannot be said to be an efficient production method because 2,6-dimethylpiperazine is produced as a by-product.

[0005] As a method for producing 2,5-dialkylpiperazine in which 2,6-dimethylpiperazine is difficult to generate, Patent Document 1 discloses a method of cyclodimerizing 1-amino-2-propanol, which is one type of amino alcohol, using a Raney-Ni catalyst.

Prior Art Documents

Patent Documents

[0006] [Patent Document 1] Chinese Patent Application Publication No. 102002005 Specification [Non-patent literature]

[0007] [Non-Patent Document 1] Poirier et al., Bioorganic Chemistry, 2022, Vol. 129, pp. 106145. [Non-Patent Document 2] Simon et al., Bioorganic & Medicinal Chemistry, 2019, Vol. 27, pp. 2323-2331. [Non-Patent Document 3] Be'rube' et al., Tetrahedron, 2015, Vol. 71, pp. 8077-8084. [Non-Patent Document 4] Lorentz-Petersen et al., European Journal of Organic Chemistry, 2012, p.6752-6759 [Overview of the project] [Problems that the invention aims to solve]

[0008] However, the manufacturing method described in Patent Document 1 requires the use of hydrogen as a reducing agent at a high pressure of 6 MPa, which necessitates special manufacturing equipment, and therefore cannot be considered a suitable manufacturing method for industrial production.

[0009] Therefore, the present invention aims to provide an efficient method for producing 2,5-dialkylpiperazine from amino alcohols as a raw material, without requiring the addition of hydrogen. [Means for solving the problem]

[0010] The present inventors conducted extensive research to solve the above problems and, as a result, discovered that by reacting an amino alcohol with a ruthenium catalyst having a pincer-type ligand and a base, cyclization and dimerization of the amino alcohol proceeds without the addition of hydrogen, producing 2,5-dialkylpiperazine, thus completing the present invention. That is, the present invention provides the following (1) to (5). (1) A method for producing 2,5-dialkylpiperazine represented by general formula (II), comprising a reaction step of cyclizing and dimerizing an amino alcohol represented by general formula (I) with a ruthenium catalyst having a pincer-type ligand and a base. [ka] [ka] (In the formula, R represents an alkyl group having 1 to 5 carbon atoms or a cycloalkyl group having 3 to 6 carbon atoms.) (2) The method for producing the product according to (1) above, wherein the ruthenium catalyst is carbonyl chlorohydride [bis(2-diphenylphosphinoethyl)amino]ruthenium(II) or carbonyl hydride (tetrahydroborato) [bis(2-diphenylphosphinoethyl)amino]ruthenium(II) (3) The method of production according to (1) or (2) above, wherein the base is tert-butoxy potassium, tert-butoxy sodium, potassium hydroxide, or sodium hydroxide. (4) The manufacturing method according to any one of (1) to (3) above, wherein the reaction temperature in the above reaction step is 140 to 200°C. (5) The manufacturing method according to any one of (1) to (4) above, wherein R is a methyl group or an ethyl group. [Effects of the Invention]

[0011] According to the present invention, 2,5-dialkylpiperazine can be produced in a single step using amino alcohol as a raw material without using high-pressure hydrogen. [Modes for carrying out the invention]

[0012] Hereinafter, the present invention will be described in detail.

[0013] The production method of the present invention is a method for producing 2,5-dialkylpiperazine, which comprises a reaction step of cyclodimerizing amino alcohol with a ruthenium catalyst having a pincer-type ligand and a base.

[0014] In the present invention, the amino alcohol is a compound represented by the following general formula (I). [Chemical formula] (In the formula, R represents an alkyl group having 1 to 5 carbon atoms or a cycloalkyl group having 3 to 6 carbon atoms.)

[0015] In the present invention, 2,5-dialkylpiperazine is a compound represented by the following general formula (II). [Chemical formula] (In the formula, R represents an alkyl group having 1 to 5 carbon atoms or a cycloalkyl group having 3 to 6 carbon atoms.)

[0016] The "alkyl group having 1 to 5 carbon atoms" means a linear or branched saturated aliphatic hydrocarbon group having 1 to 5 carbon atoms. Examples of the alkyl group having 1 to 5 carbon atoms include methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group, isopropyl group, sec-butyl group, tert-butyl group, isopentyl group and neopentyl group.

[0017] The "cycloalkyl group having 3 to 6 carbon atoms" means a cyclic saturated aliphatic hydrocarbon group having 3 to 6 carbon atoms. Examples of the cycloalkyl group having 3 to 6 carbon atoms include cyclopropyl group, cyclobutyl group, cyclopentyl group and cyclohexyl group.

[0018] R is preferably a methyl group or an ethyl group.

[0019] The R in general formula (I) and the R in general formula (II) are the same. Specifically, for example, if R in general formula (I) is a methyl group, then R in general formula (II) is also a methyl group.

[0020] A "ruthenium catalyst with pincer-type ligands" refers to a complex in which pincer-type ligands, which coordinate to the metal in a tridental manner from three directions on the same plane, are coordinated to ruthenium. Examples of ruthenium catalysts having pincer-type ligands include carbonyl chlorohydride [bis(2-diphenylphosphinoethyl)amino]ruthenium(II) [Ru-MACHO®], carbonyl hydride (tetrahydroborato) [bis(2-diphenylphosphinoethyl)amino]ruthenium(II) [Ru-MACHO-BH], dichlorotriphenylphosphine [bis(2-(ethylthio)ethyl)amine]ruthenium(II), dichlorotriphenylphosphine [2-(diphenylphosphine)-N-(2-pyridylmethyl)ethaneamine]ruthenium(II), and carbonyl hydride [(Z)-6-((di-tert-butylphosphine)methylene)-6H-[2,2'-bipyridino]ruthenium(II).

[0021] The ruthenium catalyst having a pincer-type ligand is preferably Ru-MACHO or Ru-MACHO-BH, with Ru-MACHO being more preferred.

[0022] Examples of ruthenium catalysts that do not have pincer-type ligands include 1-hydroxytetraphenylcyclopentadienyl(tetraphenyl-2,4-cyclopentadien-1-one)-μ-hydrotetracarbonylzylthenium(II) (Shvo catalyst) and ruthenium(0) dodecacarbonyl / triphenylphosphine [Ru3(CO) 12 Examples include [PPh3] and chloro[(R,R)-N-[2-[2-(4-methylbenzyloxy)ethyl]amino-1,2-diphenylethyl]-p-toluenesulfonamide]ruthenium(II)[(R,R)-Ts-DENEB(registered trademark)].

[0023] The amount of ruthenium catalyst having a pincer-type ligand added in the reaction step is preferably 0.0005 to 0.05 molar equivalents, and more preferably 0.001 to 0.01 molar equivalents, relative to the amino alcohol.

[0024] "Base" refers to a metal alkoxide, inorganic base, or organic base. Examples of bases include tert-butoxypotassium, tert-butoxysodium, potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, sodium hydride, and 1,8-diazabicyclo[5.4.0]-7-undecene.

[0025] The base is preferably tert-butoxy potassium, tert-butoxy sodium, potassium hydroxide, or sodium hydroxide, with tert-butoxy potassium being more preferred.

[0026] The amount of base added in the reaction step is preferably 0.2 to 1 molar equivalent, and more preferably 0.3 to 0.5 molar equivalent, relative to the amino alcohol.

[0027] The reaction temperature in the reaction process is preferably 150 to 210°C, and more preferably 170°C.

[0028] The amino alcohols and 2,5-dialkylpiperazines may have some or all of their constituent atoms replaced by radioactive isotopes. [Examples]

[0029] The present invention will be described in detail below with reference to examples, but the present invention is not limited to these examples.

[0030] (Measurement of 2,5-dialkylpiperazine yield) The yield of 2,5-dialkylpiperazine (2,5-dimethylpiperazine or 2,5-diethylpiperazine) was measured using gas chromatography (GC). A calibration curve for the target peak was prepared in advance, and the yield was calculated from the peak area, sample weight, and total sample weight obtained by GC analysis. The conditions for GC analysis are described below. Equipment: Gas chromatograph (Agilent Technologies, Inc., 7890A) Column: PTA-5 (manufactured by Spelco, 30m length x 0.53mm inner diameter, 3μm film thickness) Oven: Maintain a temperature of 80°C for 3 minutes, then increase the temperature by 5°C per minute to 260°C, and maintain the temperature at 260°C for 11 minutes (total 50 minutes). Carrier gas: Helium (constant flow mode) Average linear velocity: 35cm / sec Split ratio: 80:1 Inlet temperature: 230℃ Detector: Flame ionization detector (FID) Injection volume: 2μL

[0031] (Example 1) Preparation of 2,5-dimethylpiperazine 2-amino-1-propanol (2.0 g), tert-butoxypotassium (0.90 g), and Ru-MACHO (0.016 g) were placed in a 50 mL autoclave, and the autoclave was purged with an argon atmosphere. The mixture was heated to 170 °C and reacted by stirring for 20 hours. After the reaction, the mixture was cooled to room temperature, water (1 mL) was added, and it was extracted with tetrahydrofuran (6 mL). The organic layer was concentrated under reduced pressure to obtain the product (0.82 g). The yield of 2,5-dimethylpiperazine, calculated by GC analysis of the product, was 54%.

[0032] (Example 2) Preparation of 2,5-diethylpiperazine 2-amino-1-butanol (2.9 g), tert-butoxypotassium (1.1 g), and Ru-MACHO (0.019 g) were placed in a 50 mL autoclave, and the autoclave was purged with an argon atmosphere. The mixture was heated to 170 °C and reacted by stirring for 20 hours. After the reaction, the mixture was cooled to room temperature, water (1.4 mL) was added, and the mixture was extracted with tetrahydrofuran (8.5 mL). The organic layer was concentrated under reduced pressure to obtain the product (2.4 g). The yield of 2,5-diethylpiperazine, calculated by GC analysis of the product, was 68%.

[0033] (Example 3 and Comparative Examples 1-3) Comparison of ruthenium catalysts in the production of 2,5-diethylpiperazine Based on the production method of Example 2, 2,5-diethylpiperazine was produced by changing the type of ruthenium catalyst (Example 3 and Comparative Examples 1-3). The differences from Example 2 and the yield of 2,5-diethylpiperazine are shown in Table 1. The yield was calculated by GC analysis of the product.

[0034] [Table 1]

[0035] As shown in Table 1, it was found that among ruthenium catalysts, only ruthenium catalysts having pincer-type ligands could produce 2,5-diethylpiperazine in high yield.

[0036] (Examples 4-6) Comparison of Ru-MACHO addition amounts in the production of 2,5-diethylpiperazine Based on the production method of Example 2, 2,5-diethylpiperazine was produced by changing the amount of Ru-MACHO added (Examples 4-6). The differences from Example 2 and the yield of 2,5-diethylpiperazine are shown in Table 2. The yield was calculated by GC analysis of the product.

[0037] [Table 2]

[0038] As shown in Table 2, it was found that when the amount of ruthenium catalyst having a pincer-type ligand is 0.0005 molar equivalents or more, 2,5-diethylpiperazine can be produced in particularly high yield.

[0039] (Examples 7-9) Comparison of bases in the production of 2,5-diethylpiperazine Based on the production method of Example 2, 2,5-diethylpiperazine was produced by changing the type of base (Examples 7-9). The differences from Example 2 and the results are shown in Table 3. The yield was calculated by GC analysis of the product.

[0040] [Table 3]

[0041] As shown in Table 3, it was revealed that 2,5-diethylpiperazine can be produced even when the base is not tert-butoxy potassium.

[0042] (Examples 10 and 11 and Comparative Example 4) Comparison of reaction temperatures in the production of 2,5-diethylpiperazine Based on the production method of Example 2, 2,5-diethylpiperazine was produced by changing the reaction temperature (Examples 10 and 11 and Comparative Example 4). The differences from Example 2 and the results are shown in Table 4. The yield was calculated by GC analysis of the product.

[0043] [Table 4]

[0044] As shown in Table 4, it was found that 2,5-diethylpiperazine can be produced in particularly high yield when the reaction temperature in the reaction process is 150°C or higher. [Industrial applicability]

[0045] According to the present invention, 2,5-dialkylpiperazine can be efficiently produced without using high-pressure hydrogen, which is an obstacle to industrial production.

Claims

1. A method for producing 2,5-dialkylpiperazine represented by general formula (II), comprising a reaction step of cyclizing and dimerizing an amino alcohol represented by general formula (I) with a ruthenium catalyst having a pincer-type ligand and a base. 【Chemistry 1】 【Chemistry 2】 (In the formula, R represents an alkyl group having 1 to 5 carbon atoms or a cycloalkyl group having 3 to 6 carbon atoms.)

2. The production method according to claim 1, wherein the ruthenium catalyst is carbonyl chlorohydride [bis(2-diphenylphosphinoethyl)amino]ruthenium(II) or carbonyl hydride (tetrahydroborato) [bis(2-diphenylphosphinoethyl)amino]ruthenium(II).

3. The manufacturing method according to claim 1 or 2, wherein the base is tert-butoxy potassium, tert-butoxy sodium, potassium hydroxide, or sodium hydroxide.

4. The manufacturing method according to any one of claims 1 to 3, wherein the reaction temperature in the reaction step is 140 to 170°C.

5. The manufacturing method according to any one of claims 1 to 4, wherein R is a methyl group or an ethyl group.

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