WO2016199763A1 - Method for producing 1-cyclopropylethylamine or acid addition salt thereof - Google Patents

Method for producing 1-cyclopropylethylamine or acid addition salt thereof Download PDF

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WO2016199763A1
WO2016199763A1 PCT/JP2016/066918 JP2016066918W WO2016199763A1 WO 2016199763 A1 WO2016199763 A1 WO 2016199763A1 JP 2016066918 W JP2016066918 W JP 2016066918W WO 2016199763 A1 WO2016199763 A1 WO 2016199763A1
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cyclopropylethylamine
reaction
addition salt
acid addition
mmol
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PCT/JP2016/066918
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French (fr)
Japanese (ja)
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竜也 日比野
健郷 木津
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石原産業株式会社
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Publication of WO2016199763A1 publication Critical patent/WO2016199763A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/24—Preparation of compounds containing amino groups bound to a carbon skeleton by reductive alkylation of ammonia, amines or compounds having groups reducible to amino groups, with carbonyl compounds
    • C07C209/26—Preparation of compounds containing amino groups bound to a carbon skeleton by reductive alkylation of ammonia, amines or compounds having groups reducible to amino groups, with carbonyl compounds by reduction with hydrogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/33—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C211/34—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of a saturated carbon skeleton
    • C07C211/35—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of a saturated carbon skeleton containing only non-condensed rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B61/00—Other general methods

Definitions

  • the present invention relates to a method for producing 1-cyclopropylethylamine or an acid addition salt thereof useful as an intermediate for pharmaceuticals or agricultural chemicals.
  • Non- Patent Document 1 a method for producing 1-cyclopropylethylamine by reacting cyclopropylmethylketone with ammonia in the presence of a Raney nickel catalyst (non- Patent Document 1) is known, but Raney nickel has a complicated activation method, may spontaneously ignite, and its yield is not sufficient.
  • Non-patent Document 2 a method for producing 1-cyclopentylethylamine from cyclopentylmethylketone using the Leukart reaction. However, this is a reaction at a high temperature, and there are many wastes. Had a problem in terms.
  • Patent Document 1 describes a method for producing a corresponding amine from (3-oxobutyl) benzenes.
  • an example used for reduction of cyclopropyl methyl ketone is not known.
  • 1-Cyclopropylethylamine or an acid addition salt thereof is useful as an intermediate for the production of pharmaceuticals and agricultural chemicals, and is required to be produced more economically by an industrially simple and efficient environmentally friendly method. It was.
  • a production method for obtaining 1-cyclopropylethylamine using a Raney nickel catalyst has already been known. However, Raney nickel usually requires a pretreatment to be activated with an alkali, and easily ignites when dried. It was not satisfactory as a manufacturing method. Further, it is generally known that a cyclopropyl group is easily opened by a transition metal complex.
  • An object of the present invention is to provide a method for producing highly pure 1-cyclopropylethylamine or an acid addition salt thereof in a simple and efficient manner by an environment-friendly technique.
  • the present inventors have obtained the knowledge that high-purity 1-cyclopropylethylamine can be produced under certain conditions, and have completed the present invention. That is, the present invention provides a process for producing 1-cyclopropylethylamine by reacting cyclopropylmethylketone, ammonia and hydrogen in alcohols and / or ethers in the presence of a nickel catalyst supported on an inorganic oxide. Further, the present invention relates to a method for producing an acid addition salt of 1-cyclopropylethylamine by reacting 1-cyclopropylethylamine produced by the method with an acid in a solvent.
  • high-purity 1-cyclopropylethylamine or an acid addition salt thereof can be produced simply and efficiently by an environmentally friendly technique.
  • 1-cyclopropylethylamine can be produced by reacting cyclopropylmethylketone and ammonia in the presence of a nickel catalyst supported on an inorganic oxide as follows.
  • 1-Cyclopropylethylamine has enantiomers (R-form and S-form), but includes both isomers and isomer mixtures.
  • ammonia alcohol solution As the ammonia, ammonia alcohol solution, aqueous ammonia solution, liquefied ammonia or ammonia gas can be used as appropriate.
  • the alcohol in the ammonia alcohol solution include methanol, ethanol, propanol, isopropanol, and butanol.
  • an ammonia alcohol solution When an ammonia alcohol solution is used, it can also be used as a solvent.
  • Ammonia can be used usually in an amount of 1 to 10 times mol, preferably 1 to 2 times mol for 1 mol of cyclopropyl methyl ketone. However, depending on the reaction conditions, an amount outside this range can be used.
  • a nickel catalyst supported on an inorganic oxide is used.
  • the inorganic oxide include diatomaceous earth, silica, alumina, silica alumina, magnesia, calcia, titania, zirconia, niobium oxide, and lanthanum oxide. Among them, diatomaceous earth, silica or alumina is desirable, and diatomaceous earth is more desirable.
  • a nickel catalyst prepared by a generally known method such as a precipitation method or an impregnation method can be used, a commercially available product may be used, and the nickel content in the catalyst is particularly limited.
  • Commercially available products include, for example, stabilized nickel catalyst N-103 (diatomaceous earth supported, nickel content 52.5% by weight) manufactured by JGC Catalysts & Chemicals, and stabilized nickel SN-750 (diatomaceous earth manufactured by Sakai Chemical Industry Co., Ltd.). Support, nickel content of 47% by weight).
  • the nickel catalyst supported on the inorganic oxide is usually used in an amount of 1 to 50% by weight, preferably 5 to 20% by weight, in terms of nickel content, with respect to 100% by weight of cyclopropyl methyl ketone. It can. However, depending on the reaction conditions, an amount outside this range can be used.
  • Hydrogen is usually preferably used in an amount of 1 to 10 times mol per mol of cyclopropyl methyl ketone.
  • the pressure can usually be selected from the range of 0.1 to 10 MPa. In order to perform the reaction efficiently and obtain the target product with high purity and high yield on an industrial scale, the pressure is in the range of 1 to 10 MPa. It is desirable to react with hydrogen while keeping the pressure constant within. However, depending on the reaction conditions, amounts and pressures outside this range can be used.
  • alcohols and / or ethers are used as a solvent used in producing 1-cyclopropylethylamine, but alcohols are preferably used.
  • alcohols having 1 to 6 carbon atoms are desirable, and examples thereof include methanol, ethanol, propanol, isopropanol, and butanol.
  • the ethers are preferably ethers having 1 to 6 carbon atoms, such as diethyl ether, diisopropyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether and the like.
  • the solvent used for producing 1-cyclopropylethylamine is usually used in an amount of 1 to 20 times (V / W), preferably 3 to 15 times (V / W) based on cyclopropyl methyl ketone. be able to. However, depending on the reaction conditions, an amount outside this range can be used.
  • the reaction temperature is usually about 80 to 200 ° C., preferably about 100 to 130 ° C.
  • the reaction time is usually about 1 to 12 hours, preferably about 1 to 6 hours.
  • the acid addition salt of 1-cyclopropylethylamine can be produced by reacting 1-cyclopropylethylamine with an acid in a solvent. This reaction may be carried out without isolating or producing 1-cyclopropylethylamine obtained by the above reaction.
  • Examples of the acid addition salt of 1-cyclopropylethylamine produced by this reaction include salts with inorganic acids such as hydrochloric acid and sulfuric acid, and organic acids such as acetic acid.
  • the acid examples include hydrogen chloride, hydrochloric acid, sulfuric acid, acetic acid and the like.
  • the acid is usually used in an amount of 0.5 to 5 mol, preferably 0.5 to 1.5 mol, per 1 mol of 1-cyclopropylethylamine. However, depending on the reaction conditions, an amount outside this range can be used.
  • the solvent used in producing the acid addition salt of 1-cyclopropylethylamine is one selected from the group consisting of aromatic hydrocarbons, ketones, alcohols, and mixed solvents thereof.
  • aromatic hydrocarbons include benzene, toluene, xylene, chlorobenzene and the like.
  • ketones include acetone and methyl ethyl ketone.
  • alcohols having 1 to 6 carbon atoms are desirable, and examples thereof include methanol, ethanol, propanol, isopropanol, and butanol.
  • the solvent used in preparing the acid addition salt of 1-cyclopropylethylamine is usually 1 to 20 times (V / W), preferably 3 to 15 times (V / W) based on 1-cyclopropylethylamine. / W) Can be used. However, depending on the reaction conditions, an amount outside this range can be used.
  • the reaction temperature is usually 0 to 100 ° C., preferably about 10 to 50 ° C.
  • the reaction time is usually about 1 to 10 hours, preferably about 1 to 3 hours.
  • Oven 50 °C for 12 minutes, 50 °C to 250 °C at 40 °C / min., 250 °C for 3 minutes
  • Inlet 250 °C, split ratio 100: 1, split flow 123 mL / min.
  • Detector FID at 250 °C, Hydrogen flow 40.0 mL / min., Air flow 450 mL / min.
  • Injection volume 3.0 ⁇ L
  • Example 1 500 ml autoclave containing 20 g of cyclopropyl methyl ketone (purity 99%, 238 mmol), 63.6 g (262 mmol) of 7% ammonia methanol solution and 1.96 g (17.0 mmol) of stabilized nickel catalyst N-103 (manufactured by JGC Catalysts & Chemicals)
  • the inside of the reaction vessel was replaced twice with hydrogen gas. After the replacement, the reaction vessel was filled with hydrogen gas to 2.5 MPa and stirred at 120 ° C. for 3 hours. After cooling the reaction mixture to 20 ° C., the inside of the reaction vessel was brought to normal pressure, and insoluble matters were filtered off.
  • the reaction progress rate of the obtained solution was confirmed by gas chromatography (here, “reaction progress rate” means GC-PA% of the above-mentioned CPEA).
  • Example 2 200 ml autoclave containing 10 g of cyclopropyl methyl ketone (purity 99%, 119 mmol), 31.8 g (131 mmol) of 7% ammonia methanol solution and 0.98 g (8.5 mmol) of stabilized nickel catalyst N-103 (manufactured by JGC Catalysts & Chemicals)
  • the inside of the reaction vessel was replaced twice with hydrogen gas. After the replacement, the reaction vessel was filled with hydrogen gas to 2.5 MPa and stirred at 100 ° C. for 3 hours. After cooling the reaction mixture to 20 ° C., the inside of the reaction vessel was brought to normal pressure, and insoluble matters were filtered off. The reaction progress rate of the obtained solution was confirmed by gas chromatography.
  • Example 3 200 ml autoclave containing 10 g of cyclopropyl methyl ketone (purity 99%, 119 mmol), 31.8 g (131 mmol) of 7% ammonia methanol solution and 0.98 g (8.5 mmol) of stabilized nickel catalyst N-103 (manufactured by JGC Catalysts & Chemicals)
  • the inside of the reaction vessel was replaced twice with hydrogen gas. After the replacement, the reaction vessel was filled with hydrogen gas to 3.5 MPa and stirred at 120 ° C. for 3 hours. After cooling the reaction mixture to 20 ° C., the inside of the reaction vessel was brought to normal pressure, and insoluble matters were filtered off. The reaction progress rate of the obtained solution was confirmed by gas chromatography.
  • Example 4 10 g of cyclopropyl methyl ketone (purity 99%, 119 mmol), 31.8 g (131 mmol) of 7% ammonia methanol solution and 1.96 g (17 mmol) of stabilized nickel catalyst N-103 (manufactured by JGC Catalysts & Chemicals) were added to a 200 ml autoclave. The inside of the reaction vessel was replaced twice with hydrogen gas. After the replacement, the reaction vessel was filled with hydrogen gas to 2.5 MPa and stirred at 120 ° C. for 3 hours. After cooling the reaction mixture to 20 ° C., the inside of the reaction vessel was brought to normal pressure, and insoluble matters were filtered off. The reaction progress rate of the obtained solution was confirmed by gas chromatography.
  • Comparative Example 1 10 g of cyclopropyl methyl ketone (purity 99%, 119 mmol), 31.8 g (131 mmol) of 7% ammonia methanol solution and 1 g (0.94 mmol) of 10% palladium on carbon were added to a 200 ml autoclave, and the inside of the reaction vessel was filled with hydrogen gas. Replaced twice. After the replacement, the reaction vessel was filled with hydrogen gas to 2.5 MPa and stirred at 120 ° C. for 3 hours. After cooling the reaction mixture to 20 ° C., the inside of the reaction vessel was brought to normal pressure, and insoluble matters were filtered off. The reaction progress rate of the obtained solution was confirmed by gas chromatography.
  • Comparative Example 2 10 g of cyclopropyl methyl ketone (purity 99%, 119 mmol), 31.8 g (131 mmol) of 7% ammonia methanol solution and 1 g (15.3 mmol) of zinc were added to a 200 ml autoclave, and the inside of the reaction vessel was replaced with hydrogen gas twice. . After the replacement, the reaction vessel was filled with hydrogen gas to 2.5 MPa and stirred at 120 ° C. for 3 hours. After cooling the reaction mixture to 20 ° C., the inside of the reaction vessel was brought to normal pressure, and insoluble matters were filtered off. The reaction progress rate of the obtained solution was confirmed by gas chromatography.
  • Example 1 Comparative Example 1 and Comparative Example 2, the raw material compound CPMK, the target product CPEA and the by-product AP GC-PA% are listed in Table 2, respectively.
  • the CPEA or AP column is “ ⁇ ”, it indicates that the GC could not be detected.
  • Comparative Example 3 20 g of cyclopropyl methyl ketone (purity 99%, 238 mmol), 15.9 g (262 mmol) of 28% aqueous ammonia solution, 62.6 g (3478 mmol) of water and 7.84 g of stabilized nickel catalyst N-103 (manufactured by JGC Catalysts & Chemicals) 68.2 mmol) was added to a 500 ml autoclave, and the inside of the reaction vessel was replaced twice with hydrogen gas. After the replacement, the reaction vessel was filled with hydrogen gas to 2.0 MPa and stirred at 120 ° C. for 6 hours. After cooling the reaction mixture to 20 ° C., the inside of the reaction vessel was brought to normal pressure, and insoluble matters were filtered off. The reaction progress rate of the obtained solution was confirmed by gas chromatography.
  • Example 5 The reaction was conducted in the same manner as in Example 1 except that the stabilized nickel catalyst N-103 (manufactured by JGC Catalysts & Chemicals Co., Ltd.) was already used for the reaction once, and the reaction progress rate was determined by gas chromatography. confirmed.
  • the stabilized nickel catalyst N-103 manufactured by JGC Catalysts & Chemicals Co., Ltd.
  • Example 6 The reaction was conducted in the same manner as in Example 1 except that the stabilized nickel catalyst N-103 (manufactured by JGC Catalysts & Chemicals Co., Ltd.) was used twice for the reaction, and the reaction progress rate was determined by gas chromatography. confirmed.
  • the stabilized nickel catalyst N-103 manufactured by JGC Catalysts & Chemicals Co., Ltd.
  • Example 1 For Example 1, Example 5 and Example 6, GC-PA% of CPMK as the raw material compound and CPEA as the target product are shown in Table 4, respectively.
  • Example 7 13.0 g (367 mmol) of hydrogen chloride gas was introduced into a methanol solution of 1-cyclopropylethylamine obtained according to Example 1, and after stirring at room temperature for 1 hour, 103.8 g (1127 mmol) of toluene was added. Methanol was distilled off from the reaction mixture at 95 ° C. under normal pressure, and then cooled to room temperature to precipitate crystals. The crystals were filtered and dried to obtain 26.8 g of 1-cyclopropylethylamine hydrochloride (purity 90.6%, yield 84.0%, melting point 183.5 ° C.).
  • Example 8 120 g of cyclopropyl methyl ketone (purity 99%, 1427 mmol), 161.4 g of methanol and 11.32 g (102.2 mmol) of stabilized nickel catalyst N-103B (manufactured by JGC Catalysts & Chemicals) were added to a 900 ml autoclave and ammonia (26. 73 g, 1569 mmol) was introduced into the reaction vessel from a gas cylinder. Thereafter, the inside of the reaction vessel was replaced twice with hydrogen gas. After the replacement, the reaction vessel was filled with hydrogen gas to 1.5 MPa and stirred at 80 ° C. When the pressure in the reaction vessel decreased, hydrogen gas was continuously charged to 2.0 MPa again, and stirred at 80 ° C.
  • reaction progress rate of the obtained solution was confirmed by gas chromatography.
  • Table 5 shows GC-PA% of CPMK as a raw material compound and CPEA as a target product for Example 8.
  • Example 9 Hydrogen chloride gas 57.2 g (1569 mmol) was introduced into a methanol solution of 1-cyclopropylethylamine obtained according to Example 8, and the mixture was stirred at room temperature for 1 hour, and then 624.2 g (6764.9 mmol) of toluene was added. . Methanol was distilled off from the reaction mixture under normal pressure at 105 ° C., and then cooled to room temperature to precipitate crystals. The crystals were filtered and dried to obtain 158.6 g of 1-cyclopropylethylamine hydrochloride (purity 99.8%, yield 91.4%, melting point 183.5 ° C.).
  • high-purity 1-cyclopropylethylamine or an acid addition salt thereof can be produced from cyclopropylmethylketone as a raw material under industrially advantageous conditions.

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  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

The present invention pertains to a method for producing 1-cyclopropylethylamine or an acid addition salt thereof. Provided is a method for producing high-purity 1-cyclopropylethylamine or an acid addition salt thereof including reacting cyclopropylmethylketone, ammonia, and hydrogen in alcohols and/or ethers in the presence of an inorganic oxide-supported nickel catalyst.

Description

１－シクロプロピルエチルアミン又はその酸付加塩の製造方法Process for producing 1-cyclopropylethylamine or an acid addition salt thereof
　本発明は、医薬又は農薬の中間体として有用な１－シクロプロピルエチルアミン又はその酸付加塩の製造方法に関する。 The present invention relates to a method for producing 1-cyclopropylethylamine or an acid addition salt thereof useful as an intermediate for pharmaceuticals or agricultural chemicals.
　１－シクロプロピルエチルアミンのようなシクロアルキル基を有する脂肪族アミン類の製造方法としては、例えばシクロプロピルメチルケトンとアンモニアとをラネーニッケル触媒下で反応させて１－シクロプロピルエチルアミンを製造する方法（非特許文献１）が知られているが、ラネーニッケルは活性化方法が煩雑で、自然発火の可能性があり、その収率も十分ではない。またロイカート反応を用いた、シクロペンチルメチルケトンから１-シクロペンチルエチルアミンを製造する方法（非特許文献２）が知られているが、高温での反応であり、廃棄物も多く、これらは工業的製造の面で問題を抱えていた。
　無機酸化物に担持されたニッケル触媒を使用した還元方法としては、例えば、特許文献１に、（３－オキソブチル）ベンゼン類から対応するアミンを製造する方法が記載されている。しかし、シクロプロピルメチルケトンの還元に用いた例は知られていない。 As a method for producing an aliphatic amine having a cycloalkyl group such as 1-cyclopropylethylamine, for example, a method for producing 1-cyclopropylethylamine by reacting cyclopropylmethylketone with ammonia in the presence of a Raney nickel catalyst (non- Patent Document 1) is known, but Raney nickel has a complicated activation method, may spontaneously ignite, and its yield is not sufficient. In addition, a method for producing 1-cyclopentylethylamine from cyclopentylmethylketone using the Leukart reaction is known (Non-patent Document 2). However, this is a reaction at a high temperature, and there are many wastes. Had a problem in terms.
As a reduction method using a nickel catalyst supported on an inorganic oxide, for example, Patent Document 1 describes a method for producing a corresponding amine from (3-oxobutyl) benzenes. However, an example used for reduction of cyclopropyl methyl ketone is not known.
特開昭６３－２５８４４４JP-A 63-258444
　１－シクロプロピルエチルアミン又はその酸付加塩は、医農薬の製造用中間体として有用であり、工業的に簡便かつ効率的に、環境に配慮した手法で、より経済的に製造することが求められていた。ラネーニッケル触媒を用いた１－シクロプロピルエチルアミンを得る製法が既に知られているが、通常ラネーニッケルは、アルカリで活性化させる前処理が必要であり、乾燥すると容易に発火するため、当該製法は工業的製法として満足できるものではなかった。
　また、シクロプロピル基は遷移金属錯体により容易に開環することが一般的に知られている。そのため、シクロプロピル基を有する化合物を、遷移金属錯体を用いて反応させると、副生成物である開環体が生成し、当該副生成物と目的物とを分離させることが容易ではないという課題があった。
　本発明の目的は、簡便かつ効率的に、環境に配慮した手法により、高純度な１－シクロプロピルエチルアミン又はその酸付加塩を製造する方法を提供することにある。 1-Cyclopropylethylamine or an acid addition salt thereof is useful as an intermediate for the production of pharmaceuticals and agricultural chemicals, and is required to be produced more economically by an industrially simple and efficient environmentally friendly method. It was. A production method for obtaining 1-cyclopropylethylamine using a Raney nickel catalyst has already been known. However, Raney nickel usually requires a pretreatment to be activated with an alkali, and easily ignites when dried. It was not satisfactory as a manufacturing method.
Further, it is generally known that a cyclopropyl group is easily opened by a transition metal complex. Therefore, when a compound having a cyclopropyl group is reacted using a transition metal complex, a ring-opened product as a by-product is generated, and it is not easy to separate the by-product from the target product. was there.
An object of the present invention is to provide a method for producing highly pure 1-cyclopropylethylamine or an acid addition salt thereof in a simple and efficient manner by an environment-friendly technique.
　本発明者らは前記課題を解決すべく研究を行った結果、一定の条件において高純度な１－シクロプロピルエチルアミンが製造できるとの知見を得て、本発明を完成した。
　即ち本発明は、シクロプロピルメチルケトン、アンモニア及び水素を、無機酸化物に担持されたニッケル触媒の存在下、アルコール類及び／又はエーテル類中で反応させて、１－シクロプロピルエチルアミンを製造する方法、さらにその方法で製造した１－シクロプロピルエチルアミンと酸とを溶媒中で反応させて、１－シクロプロピルエチルアミンの酸付加塩を製造する方法に関する。 As a result of studies to solve the above problems, the present inventors have obtained the knowledge that high-purity 1-cyclopropylethylamine can be produced under certain conditions, and have completed the present invention.
That is, the present invention provides a process for producing 1-cyclopropylethylamine by reacting cyclopropylmethylketone, ammonia and hydrogen in alcohols and / or ethers in the presence of a nickel catalyst supported on an inorganic oxide. Further, the present invention relates to a method for producing an acid addition salt of 1-cyclopropylethylamine by reacting 1-cyclopropylethylamine produced by the method with an acid in a solvent.
　本発明の製造方法によれば、高純度な１－シクロプロピルエチルアミン又はその酸付加塩を簡便かつ効率的に、環境に配慮した手法で製造することができる。 According to the production method of the present invention, high-purity 1-cyclopropylethylamine or an acid addition salt thereof can be produced simply and efficiently by an environmentally friendly technique.
　本発明において、１－シクロプロピルエチルアミンは、下記のようにしてシクロプロピルメチルケトンとアンモニアとを無機酸化物に担持されたニッケル触媒の存在下で反応させることにより製造することができる。なお、１－シクロプロピルエチルアミンには、鏡像異性体（Ｒ体及びＳ体）が存在するが、各異性体及び異性体混合物の双方が含まれる。 In the present invention, 1-cyclopropylethylamine can be produced by reacting cyclopropylmethylketone and ammonia in the presence of a nickel catalyst supported on an inorganic oxide as follows. 1-Cyclopropylethylamine has enantiomers (R-form and S-form), but includes both isomers and isomer mixtures.
　アンモニアとしては、アンモニアアルコール溶液、アンモニア水溶液、液化アンモニア又はアンモニアガスを適宜用いることができる。アンモニアアルコール溶液におけるアルコールとしてはメタノール、エタノール、プロパノール、イソプロパノール、ブタノールなどが挙げられる。アンモニアアルコール溶液を用いる場合、溶媒として兼用することもできる。 As the ammonia, ammonia alcohol solution, aqueous ammonia solution, liquefied ammonia or ammonia gas can be used as appropriate. Examples of the alcohol in the ammonia alcohol solution include methanol, ethanol, propanol, isopropanol, and butanol. When an ammonia alcohol solution is used, it can also be used as a solvent.
　アンモニアは、シクロプロピルメチルケトン１モルに対して、通常１～１０倍モル、望ましくは１～２倍モル使用することができる。但し、反応条件によっては、この範囲外の量を使用することもできる。 Ammonia can be used usually in an amount of 1 to 10 times mol, preferably 1 to 2 times mol for 1 mol of cyclopropyl methyl ketone. However, depending on the reaction conditions, an amount outside this range can be used.
　触媒としては、無機酸化物に担持されたニッケル触媒を用いられる。無機酸化物としては、例えば、ケイソウ土、シリカ、アルミナ、シリカアルミナ、マグネシア、カルシア、チタニア、ジルコニア、酸化ニオブ、酸化ランタンなどが挙げられる。中でもケイソウ土、シリカ又はアルミナが望ましく、ケイソウ土がさらに望ましい。 As the catalyst, a nickel catalyst supported on an inorganic oxide is used. Examples of the inorganic oxide include diatomaceous earth, silica, alumina, silica alumina, magnesia, calcia, titania, zirconia, niobium oxide, and lanthanum oxide. Among them, diatomaceous earth, silica or alumina is desirable, and diatomaceous earth is more desirable.
　無機酸化物に担持されたニッケル触媒は、好ましくは沈殿法若しくは含浸法といった通常公知の方法により調製したものを用いることができ、市販品を用いてもよく、触媒中のニッケル含有量は特に限定されない。市販品としては、例えば、日揮触媒化成社製の安定化ニッケル触媒Ｎ－１０３（ケイソウ土担持、ニッケル含有量５２．５重量％）、堺化学工業社製の安定化ニッケルＳＮ－７５０（ケイソウ土担持、ニッケル含有量４７重量％）などが挙げられる。 As the nickel catalyst supported on the inorganic oxide, a nickel catalyst prepared by a generally known method such as a precipitation method or an impregnation method can be used, a commercially available product may be used, and the nickel content in the catalyst is particularly limited. Not. Commercially available products include, for example, stabilized nickel catalyst N-103 (diatomaceous earth supported, nickel content 52.5% by weight) manufactured by JGC Catalysts & Chemicals, and stabilized nickel SN-750 (diatomaceous earth manufactured by Sakai Chemical Industry Co., Ltd.). Support, nickel content of 47% by weight).
　無機酸化物に担持されたニッケル触媒は、シクロプロピルメチルケトン１００重量％に対して、ニッケル含有量換算で、通常１重量％～５０重量％、望ましくは５重量％～２０重量％使用することができる。但し、反応条件によっては、この範囲外の量を使用することもできる。 The nickel catalyst supported on the inorganic oxide is usually used in an amount of 1 to 50% by weight, preferably 5 to 20% by weight, in terms of nickel content, with respect to 100% by weight of cyclopropyl methyl ketone. it can. However, depending on the reaction conditions, an amount outside this range can be used.
　水素は、シクロプロピルメチルケトン１モルに対して、通常１～１０倍モル使用するのが望ましい。また、圧力は通常０．１～１０ＭＰａの範囲から選ぶことができるが、反応を効率的に行い、工業的規模で目的物を高純度、高収率で得るためには、１～１０ＭＰａの範囲内で圧力を一定に維持しながら水素と反応させることが望ましい。但し、反応条件によっては、この範囲外の量や圧力を使用することもできる。 Hydrogen is usually preferably used in an amount of 1 to 10 times mol per mol of cyclopropyl methyl ketone. The pressure can usually be selected from the range of 0.1 to 10 MPa. In order to perform the reaction efficiently and obtain the target product with high purity and high yield on an industrial scale, the pressure is in the range of 1 to 10 MPa. It is desirable to react with hydrogen while keeping the pressure constant within. However, depending on the reaction conditions, amounts and pressures outside this range can be used.
　本発明において、１－シクロプロピルエチルアミンを製造する際に使用される溶媒として、アルコール類及び／又はエーテル類を用いるが、アルコール類を用いるのが望ましい。アルコール類としては、炭素数１～６のアルコール類が望ましく、例えばメタノール、エタノール、プロパノール、イソプロパノール、ブタノールなどが挙げられる。また、エーテル類としては、炭素数１～６のエーテル類が望ましく、例えばジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、２－メチルテトラヒドロフラン、エチレングリコールジメチルエーテルなどが挙げられる。なお、反応に影響のない範囲で、上記したもの以外の溶媒を使用してもよい。 In the present invention, alcohols and / or ethers are used as a solvent used in producing 1-cyclopropylethylamine, but alcohols are preferably used. As the alcohols, alcohols having 1 to 6 carbon atoms are desirable, and examples thereof include methanol, ethanol, propanol, isopropanol, and butanol. The ethers are preferably ethers having 1 to 6 carbon atoms, such as diethyl ether, diisopropyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether and the like. In addition, you may use solvents other than what was mentioned above in the range which does not affect reaction.
　１－シクロプロピルエチルアミンを製造する際に使用される溶媒は、シクロプロピルメチルケトンに対して、通常１～２０倍量（Ｖ／Ｗ）、望ましくは３～１５倍量（Ｖ／Ｗ）使用することができる。但し、反応条件によっては、この範囲外の量を使用することもできる。 The solvent used for producing 1-cyclopropylethylamine is usually used in an amount of 1 to 20 times (V / W), preferably 3 to 15 times (V / W) based on cyclopropyl methyl ketone. be able to. However, depending on the reaction conditions, an amount outside this range can be used.
　反応温度は、通常８０～２００℃程度、望ましくは１００～１３０℃程度であり、反応時間は、通常１～１２時間程度、望ましくは１～６時間程度である。 The reaction temperature is usually about 80 to 200 ° C., preferably about 100 to 130 ° C., and the reaction time is usually about 1 to 12 hours, preferably about 1 to 6 hours.
　１－シクロプロピルエチルアミンの酸付加塩は、１-シクロプロピルエチルアミンと酸とを溶媒中で反応させて製造することができる。前記反応によって得られた１－シクロプロピルエチルアミンは単離または生成することなく、本反応を行なってもよい。
　本反応で製造される１－シクロプロピルエチルアミンの酸付加塩としては、塩酸、硫酸のような無機酸、または酢酸のような有機酸との塩などが挙げられる。 The acid addition salt of 1-cyclopropylethylamine can be produced by reacting 1-cyclopropylethylamine with an acid in a solvent. This reaction may be carried out without isolating or producing 1-cyclopropylethylamine obtained by the above reaction.
Examples of the acid addition salt of 1-cyclopropylethylamine produced by this reaction include salts with inorganic acids such as hydrochloric acid and sulfuric acid, and organic acids such as acetic acid.
　酸としては、塩化水素、塩酸、硫酸、酢酸などが挙げられる。酸は、１-シクロプロピルエチルアミン１モルに対して、通常０．５～５モル、望ましくは、０．５～１．５モル使用することができる。但し、反応条件によっては、この範囲外の量を使用することもできる。 Examples of the acid include hydrogen chloride, hydrochloric acid, sulfuric acid, acetic acid and the like. The acid is usually used in an amount of 0.5 to 5 mol, preferably 0.5 to 1.5 mol, per 1 mol of 1-cyclopropylethylamine. However, depending on the reaction conditions, an amount outside this range can be used.
　本発明において、１－シクロプロピルエチルアミンの酸付加塩を製造する際に使用される溶媒としては、芳香族炭化水素類、ケトン類、アルコール類及びこれらの混合溶媒からなる群より選択された１種又は２種以上が望ましく、これらの中でもアルコール類及び／又は芳香族炭化水素類が特に望ましい。芳香族炭化水素類としては、例えばベンゼン、トルエン、キシレン、クロロベンゼンなどが挙げられる。ケトン類としては、例えばアセトン、メチルエチルケトンなどが挙げられる。アルコール類としては、炭素数１～６のアルコール類が望ましく、例えばメタノール、エタノール、プロパノール、イソプロパノール、ブタノールなどが挙げられる。 In the present invention, the solvent used in producing the acid addition salt of 1-cyclopropylethylamine is one selected from the group consisting of aromatic hydrocarbons, ketones, alcohols, and mixed solvents thereof. Alternatively, two or more kinds are desirable, and among these, alcohols and / or aromatic hydrocarbons are particularly desirable. Examples of aromatic hydrocarbons include benzene, toluene, xylene, chlorobenzene and the like. Examples of ketones include acetone and methyl ethyl ketone. As the alcohols, alcohols having 1 to 6 carbon atoms are desirable, and examples thereof include methanol, ethanol, propanol, isopropanol, and butanol.
　１－シクロプロピルエチルアミンの酸付加塩を製造する際に使用される溶媒は、１-シクロプロピルエチルアミンに対して、通常１～２０倍量（Ｖ／Ｗ）、望ましくは３～１５倍量（Ｖ／Ｗ）使用することができる。但し、反応条件によっては、この範囲外の量を使用することもできる。 The solvent used in preparing the acid addition salt of 1-cyclopropylethylamine is usually 1 to 20 times (V / W), preferably 3 to 15 times (V / W) based on 1-cyclopropylethylamine. / W) Can be used. However, depending on the reaction conditions, an amount outside this range can be used.
　反応温度は、通常０～１００℃、望ましくは１０～５０℃程度であり、反応時間は、通常１～１０時間程度、望ましくは１～３時間程度である。 The reaction temperature is usually 0 to 100 ° C., preferably about 10 to 50 ° C., and the reaction time is usually about 1 to 10 hours, preferably about 1 to 3 hours.
　次に、本発明の望ましい実施形態のいくつかを例示するが、これらは本発明を限定するものではない。
（１）シクロプロピルメチルケトン、アンモニア及び水素を、無機酸化物に担持されたニッケル触媒の存在下、アルコール類及び／又はエーテル類中で反応させることを含むことを特徴とする、１－シクロプロピルエチルアミン又はその酸付加塩を製造する方法。
（２）（ｉ）シクロプロピルメチルケトン、アンモニア及び水素を、無機酸化物に担持されたニッケル触媒の存在下、溶媒中で反応させて、１-シクロプロピルエチルアミンを得る第１工程、及び（ii）１-シクロプロピルエチルアミンと酸とを溶媒中で反応させて、１－シクロプロピルエチルアミンの酸付加塩を得る第２工程を含む、（１）に記載の方法。
（３）無機酸化物がケイソウ土、シリカ又はアルミナである（１）又は（２）に記載の方法。
（４）無機酸化物がケイソウ土である（３）に記載の方法。
（５）シクロプロピルメチルケトンに対し、無機酸化物に担持されたニッケル触媒をニッケル含有量換算で１重量％～５０重量％存在させる（１）～（３）に記載の方法。
（６）アルコール類中で反応させる（１）に記載の方法。
（７）０．１～１０ＭＰａの圧力で水素と反応させる（１）～（６）に記載の方法。
（８）１～１０ＭＰａの範囲内で圧力を一定に維持しながら水素と反応させる（７）に記載の方法。
（９）１－シクロプロピルエチルアミンの酸付加塩が塩酸塩、硫酸塩又は酢酸塩である（１）～（８）に記載の方法。
（１０）第２工程の溶媒として、芳香族炭化水素類及び／又はアルコール類を用いる（２）に記載の方法。 The following examples illustrate some of the preferred embodiments of the present invention, but are not intended to limit the present invention.
(1) 1-cyclopropyl characterized by comprising reacting cyclopropylmethylketone, ammonia and hydrogen in alcohols and / or ethers in the presence of a nickel catalyst supported on an inorganic oxide A method for producing ethylamine or an acid addition salt thereof.
(2) (i) a first step of obtaining 1-cyclopropylethylamine by reacting cyclopropylmethylketone, ammonia and hydrogen in a solvent in the presence of a nickel catalyst supported on an inorganic oxide, and (ii) The method according to (1), comprising a second step of reacting 1-cyclopropylethylamine and an acid in a solvent to obtain an acid addition salt of 1-cyclopropylethylamine.
(3) The method according to (1) or (2), wherein the inorganic oxide is diatomaceous earth, silica or alumina.
(4) The method according to (3), wherein the inorganic oxide is diatomaceous earth.
(5) The method according to any one of (1) to (3), wherein a nickel catalyst supported on an inorganic oxide is present in an amount of 1 to 50% by weight in terms of nickel content with respect to cyclopropyl methyl ketone.
(6) The method according to (1), wherein the reaction is performed in alcohols.
(7) The method according to (1) to (6), wherein the reaction is performed with hydrogen at a pressure of 0.1 to 10 MPa.
(8) The method according to (7), wherein the reaction is performed with hydrogen while maintaining the pressure constant within a range of 1 to 10 MPa.
(9) The method according to any one of (1) to (8), wherein the acid addition salt of 1-cyclopropylethylamine is hydrochloride, sulfate or acetate.
(10) The method according to (2), wherein aromatic hydrocarbons and / or alcohols are used as the solvent in the second step.
　本発明をより詳しく述べるために、以下に実施例を記載するが、本発明はこれらに限定して解釈されるものではない。各表中の略号は以下の通りである。
　ＣＰＭＫ：シクロプロピルメチルケトン
　ＣＰＥＡ：１－シクロプロピルエチルアミン
　ＡＰ：２－アミノペンタン（副生成物である開環体）
　各表中のＧＣ－ＰＡ％は、ガスクロマトグラフィー（ＧＣ）で分析したピーク面積百分率（Ｐｅａｋ ａｒｅａ％）を表し、その測定条件は以下の通りである。
Column:J&W社製、DB-1、inner diameter ３２０μｍ、film thickness １．００μｍ、length ３０ｍ
Carrier: Helium, LGV 23 cm/sec.
Oven: 50 ℃ for 12 minutes, 50 ℃ to 250℃ at 40℃/min., 250℃ for 3 minutes
Inlet: 250℃, split ratio 100:1, split flow 123 mL/min.
Detector: FID at 250℃, Hydrogen flow 40.0 mL/min., Air flow 450 mL/min.
Injection volume: 3.0 μL In order to describe the present invention in more detail, examples are described below, but the present invention is not construed as being limited thereto. Abbreviations in each table are as follows.
CPMK: cyclopropyl methyl ketone CPEA: 1-cyclopropylethylamine AP: 2-aminopentane (ring-opening product as a by-product)
GC-PA% in each table represents a peak area percentage (Peak area%) analyzed by gas chromatography (GC), and the measurement conditions are as follows.
Column: J & W, DB-1, inner diameter 320 μm, film thickness 1.00 μm, length 30 m
Carrier: Helium, LGV 23 cm / sec.
Oven: 50 ℃ for 12 minutes, 50 ℃ to 250 ℃ at 40 ℃ / min., 250 ℃ for 3 minutes
Inlet: 250 ℃, split ratio 100: 1, split flow 123 mL / min.
Detector: FID at 250 ℃, Hydrogen flow 40.0 mL / min., Air flow 450 mL / min.
Injection volume: 3.0 μL
実施例１
　シクロプロピルメチルケトン２０ｇ（純度９９％、２３８ｍｍｏｌ）、７％アンモニアメタノール溶液６３．６ｇ（２６２ｍｍｏｌ）及び安定化ニッケル触媒Ｎ－１０３（日揮触媒化成社製）１．９６ｇ（１７．０ｍｍｏｌ）を５００ｍｌオートクレーブに加え、反応容器内を水素ガスにて２回置換した。置換後、反応容器に水素ガスを２．５ＭＰａまで充填し、１２０℃で３時間攪拌した。反応混合物を２０℃に冷却後、反応容器内を常圧にし、不溶解物を濾別した。得られた溶液の反応進行率をガスクロマトグラフィーにて確認した（ここで「反応進行率」とは前記したＣＰＥＡのＧＣ－ＰＡ％を意味する）。 Example 1
500 ml autoclave containing 20 g of cyclopropyl methyl ketone (purity 99%, 238 mmol), 63.6 g (262 mmol) of 7% ammonia methanol solution and 1.96 g (17.0 mmol) of stabilized nickel catalyst N-103 (manufactured by JGC Catalysts & Chemicals) In addition, the inside of the reaction vessel was replaced twice with hydrogen gas. After the replacement, the reaction vessel was filled with hydrogen gas to 2.5 MPa and stirred at 120 ° C. for 3 hours. After cooling the reaction mixture to 20 ° C., the inside of the reaction vessel was brought to normal pressure, and insoluble matters were filtered off. The reaction progress rate of the obtained solution was confirmed by gas chromatography (here, “reaction progress rate” means GC-PA% of the above-mentioned CPEA).
実施例２
　シクロプロピルメチルケトン１０ｇ（純度９９％、１１９ｍｍｏｌ）、７％アンモニアメタノール溶液３１．８ｇ（１３１ｍｍｏｌ）及び安定化ニッケル触媒Ｎ－１０３（日揮触媒化成社製）０．９８ｇ（８．５ｍｍｏｌ）を２００ｍｌオートクレーブに加え、反応容器内を水素ガスにて２回置換した。置換後、反応容器に水素ガスを２．５ＭＰａまで充填し、１００℃で３時間攪拌した。反応混合物を２０℃に冷却後、反応容器内を常圧にし、不溶解物を濾別した。得られた溶液の反応進行率をガスクロマトグラフィーにて確認した。 Example 2
200 ml autoclave containing 10 g of cyclopropyl methyl ketone (purity 99%, 119 mmol), 31.8 g (131 mmol) of 7% ammonia methanol solution and 0.98 g (8.5 mmol) of stabilized nickel catalyst N-103 (manufactured by JGC Catalysts & Chemicals) In addition, the inside of the reaction vessel was replaced twice with hydrogen gas. After the replacement, the reaction vessel was filled with hydrogen gas to 2.5 MPa and stirred at 100 ° C. for 3 hours. After cooling the reaction mixture to 20 ° C., the inside of the reaction vessel was brought to normal pressure, and insoluble matters were filtered off. The reaction progress rate of the obtained solution was confirmed by gas chromatography.
実施例３
　シクロプロピルメチルケトン１０ｇ（純度９９％、１１９ｍｍｏｌ）、７％アンモニアメタノール溶液３１．８ｇ（１３１ｍｍｏｌ）及び安定化ニッケル触媒Ｎ－１０３（日揮触媒化成社製）０．９８ｇ（８．５ｍｍｏｌ）を２００ｍｌオートクレーブに加え、反応容器内を水素ガスにて２回置換した。置換後、反応容器に水素ガスを３．５ＭＰａまで充填し、１２０℃で３時間攪拌した。反応混合物を２０℃に冷却後、反応容器内を常圧にし、不溶解物を濾別した。得られた溶液の反応進行率をガスクロマトグラフィーにて確認した。 Example 3
200 ml autoclave containing 10 g of cyclopropyl methyl ketone (purity 99%, 119 mmol), 31.8 g (131 mmol) of 7% ammonia methanol solution and 0.98 g (8.5 mmol) of stabilized nickel catalyst N-103 (manufactured by JGC Catalysts & Chemicals) In addition, the inside of the reaction vessel was replaced twice with hydrogen gas. After the replacement, the reaction vessel was filled with hydrogen gas to 3.5 MPa and stirred at 120 ° C. for 3 hours. After cooling the reaction mixture to 20 ° C., the inside of the reaction vessel was brought to normal pressure, and insoluble matters were filtered off. The reaction progress rate of the obtained solution was confirmed by gas chromatography.
実施例４
　シクロプロピルメチルケトン１０ｇ（純度９９％、１１９ｍｍｏｌ）、７％アンモニアメタノール溶液３１．８ｇ（１３１ｍｍｏｌ）及び安定化ニッケル触媒Ｎ－１０３（日揮触媒化成社製）１．９６ｇ（１７ｍｍｏｌ）を２００ｍｌオートクレーブに加え、反応容器内を水素ガスにて２回置換した。置換後、反応容器に水素ガスを２．５ＭＰａまで充填し、１２０℃で３時間攪拌した。反応混合物を２０℃に冷却後、反応容器内を常圧にし、不溶解物を濾別した。得られた溶液の反応進行率をガスクロマトグラフィーにて確認した。 Example 4
10 g of cyclopropyl methyl ketone (purity 99%, 119 mmol), 31.8 g (131 mmol) of 7% ammonia methanol solution and 1.96 g (17 mmol) of stabilized nickel catalyst N-103 (manufactured by JGC Catalysts & Chemicals) were added to a 200 ml autoclave. The inside of the reaction vessel was replaced twice with hydrogen gas. After the replacement, the reaction vessel was filled with hydrogen gas to 2.5 MPa and stirred at 120 ° C. for 3 hours. After cooling the reaction mixture to 20 ° C., the inside of the reaction vessel was brought to normal pressure, and insoluble matters were filtered off. The reaction progress rate of the obtained solution was confirmed by gas chromatography.
　実施例１～４につき、原料化合物であるＣＰＭＫ、目的物であるＣＰＥＡのＧＣ－ＰＡ％を各々第１表に記載する。 For Examples 1 to 4, the raw material compound, CPMK, and the target product, CPEA, GC-PA% are listed in Table 1, respectively.
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000001
比較例１
　シクロプロピルメチルケトン１０ｇ（純度９９％、１１９ｍｍｏｌ）、７％アンモニアメタノール溶液３１．８ｇ（１３１ｍｍｏｌ）及び１０％パラジウム炭素１ｇ（０．９４ｍｍｏｌ）を２００ｍｌオートクレーブに加え、反応容器内を水素ガスにて２回置換した。置換後、反応容器に水素ガスを２．５ＭＰａまで充填し、１２０℃で３時間攪拌した。反応混合物を２０℃に冷却後、反応容器内を常圧にし、不溶解物を濾別した。得られた溶液の反応進行率をガスクロマトグラフィーにて確認した。 Comparative Example 1
10 g of cyclopropyl methyl ketone (purity 99%, 119 mmol), 31.8 g (131 mmol) of 7% ammonia methanol solution and 1 g (0.94 mmol) of 10% palladium on carbon were added to a 200 ml autoclave, and the inside of the reaction vessel was filled with hydrogen gas. Replaced twice. After the replacement, the reaction vessel was filled with hydrogen gas to 2.5 MPa and stirred at 120 ° C. for 3 hours. After cooling the reaction mixture to 20 ° C., the inside of the reaction vessel was brought to normal pressure, and insoluble matters were filtered off. The reaction progress rate of the obtained solution was confirmed by gas chromatography.
比較例２
　シクロプロピルメチルケトン１０ｇ（純度９９％、１１９ｍｍｏｌ）、７％アンモニアメタノール溶液３１．８ｇ（１３１ｍｍｏｌ）及び亜鉛１ｇ（１５．３ｍｍｏｌ）を２００ｍｌオートクレーブに加え、反応容器内を水素ガスにて２回置換した。置換後、反応容器に水素ガスを２．５ＭＰａまで充填し、１２０℃で３時間攪拌した。反応混合物を２０℃に冷却後、反応容器内を常圧にし、不溶解物を濾別した。得られた溶液の反応進行率をガスクロマトグラフィーにて確認した。 Comparative Example 2
10 g of cyclopropyl methyl ketone (purity 99%, 119 mmol), 31.8 g (131 mmol) of 7% ammonia methanol solution and 1 g (15.3 mmol) of zinc were added to a 200 ml autoclave, and the inside of the reaction vessel was replaced with hydrogen gas twice. . After the replacement, the reaction vessel was filled with hydrogen gas to 2.5 MPa and stirred at 120 ° C. for 3 hours. After cooling the reaction mixture to 20 ° C., the inside of the reaction vessel was brought to normal pressure, and insoluble matters were filtered off. The reaction progress rate of the obtained solution was confirmed by gas chromatography.
　実施例１、比較例１及び比較例２につき、原料化合物であるＣＰＭＫ、目的物であるＣＰＥＡ及び副生成物であるＡＰのＧＣ－ＰＡ％を各々第２表に記載する。ＣＰＥＡ又はＡＰ欄が「－」の場合は、ＧＣで検知できなかったことを示す。 For Example 1, Comparative Example 1 and Comparative Example 2, the raw material compound CPMK, the target product CPEA and the by-product AP GC-PA% are listed in Table 2, respectively. When the CPEA or AP column is “−”, it indicates that the GC could not be detected.
Figure JPOXMLDOC01-appb-T000002
Figure JPOXMLDOC01-appb-T000002
比較例３
　シクロプロピルメチルケトン２０ｇ（純度９９％、２３８ｍｍｏｌ）、28％アンモニア水溶液１５．９ｇ（２６２ｍｍｏｌ）、水６２．６ｇ（３４７８ｍｍｏｌ）及び安定化ニッケル触媒Ｎ－１０３（日揮触媒化成社製）７．８４ｇ（６８．２ｍｍｏｌ）を５００ｍｌオートクレーブに加え、反応容器内を水素ガスにて２回置換した。置換後、反応容器に水素ガスを２．０ＭＰａまで充填し、１２０℃で６時間攪拌した。反応混合物を２０℃に冷却後、反応容器内を常圧にし、不溶解物を濾別した。得られた溶液の反応進行率をガスクロマトグラフィーにて確認した。 Comparative Example 3
20 g of cyclopropyl methyl ketone (purity 99%, 238 mmol), 15.9 g (262 mmol) of 28% aqueous ammonia solution, 62.6 g (3478 mmol) of water and 7.84 g of stabilized nickel catalyst N-103 (manufactured by JGC Catalysts & Chemicals) 68.2 mmol) was added to a 500 ml autoclave, and the inside of the reaction vessel was replaced twice with hydrogen gas. After the replacement, the reaction vessel was filled with hydrogen gas to 2.0 MPa and stirred at 120 ° C. for 6 hours. After cooling the reaction mixture to 20 ° C., the inside of the reaction vessel was brought to normal pressure, and insoluble matters were filtered off. The reaction progress rate of the obtained solution was confirmed by gas chromatography.
比較例４
　シクロプロピルメチルケトン２０ｇ（純度９９％、２３８ｍｍｏｌ）、28％アンモニア水溶液１５．９ｇ（２６２ｍｍｏｌ）、トルエン６４．０ｇ（６９４．６ｍｍｏｌ）及び安定化ニッケル触媒Ｎ－１０３（日揮触媒化成社製）７．８４ｇ（６８．２ｍｍｏｌ）を５００ｍｌオートクレーブに加え、反応容器内を水素ガスにて2回置換した。置換後、反応容器に水素ガスを２．０ＭＰａまで充填し、１２０℃で６時間攪拌した。反応混合物を２０℃に冷却後、反応器内を常圧にし、不溶解物を濾別した。得られた溶液の反応進行率をガスクロマトグラフィーにて確認した。 Comparative Example 4
6. Cyclopropyl methyl ketone 20 g (purity 99%, 238 mmol), 28% aqueous ammonia solution 15.9 g (262 mmol), toluene 64.0 g (694.6 mmol) and stabilized nickel catalyst N-103 (manufactured by JGC Catalysts & Chemicals) 84 g (68.2 mmol) was added to a 500 ml autoclave, and the inside of the reaction vessel was replaced twice with hydrogen gas. After the replacement, the reaction vessel was filled with hydrogen gas to 2.0 MPa and stirred at 120 ° C. for 6 hours. After the reaction mixture was cooled to 20 ° C., the inside of the reactor was brought to atmospheric pressure, and insoluble matters were filtered off. The reaction progress rate of the obtained solution was confirmed by gas chromatography.
　実施例１、比較例３及び比較例４につき、原料化合物であるＣＰＭＫ及び目的物であるＣＰＥＡのＧＣ－ＰＡ％を各々第３表に記載する。 For Example 1, Comparative Example 3 and Comparative Example 4, GC-PA% of the raw material compound CPMK and the target product CPEA are listed in Table 3, respectively.
Figure JPOXMLDOC01-appb-T000003
Figure JPOXMLDOC01-appb-T000003
実施例５
　安定化ニッケル触媒Ｎ－１０３（日揮触媒化成社製）が、既に１度反応に使用したものであること以外は、前記実施例１と同様に反応を行い、反応進行率をガスクロマトグラフィーにて確認した。 Example 5
The reaction was conducted in the same manner as in Example 1 except that the stabilized nickel catalyst N-103 (manufactured by JGC Catalysts & Chemicals Co., Ltd.) was already used for the reaction once, and the reaction progress rate was determined by gas chromatography. confirmed.
実施例６
　安定化ニッケル触媒Ｎ－１０３（日揮触媒化成社製）が、既に２度反応に使用したものであること以外は、前記実施例１と同様に反応を行い、反応進行率をガスクロマトグラフィーにて確認した。 Example 6
The reaction was conducted in the same manner as in Example 1 except that the stabilized nickel catalyst N-103 (manufactured by JGC Catalysts & Chemicals Co., Ltd.) was used twice for the reaction, and the reaction progress rate was determined by gas chromatography. confirmed.
　実施例１、実施例５及び実施例６につき、原料化合物であるＣＰＭＫ及び目的物であるＣＰＥＡのＧＣ－ＰＡ％を各々第４表に記載する。 For Example 1, Example 5 and Example 6, GC-PA% of CPMK as the raw material compound and CPEA as the target product are shown in Table 4, respectively.
Figure JPOXMLDOC01-appb-T000004
Figure JPOXMLDOC01-appb-T000004
実施例７
　実施例１に準じて得た１－シクロプロピルエチルアミンのメタノール溶液に塩化水素ガス１３．０ｇ（３６７ｍｍｏｌ）を導入し、室温で１時間攪拌した後、トルエン１０３．８ｇ（１１２７ｍｍｏｌ）を加えた。反応混合物を常圧下９５℃でメタノールを留去後、室温に冷却し、結晶を析出させた。結晶をろ過した後乾燥し、１-シクロプロピルエチルアミンの塩酸塩２６．８ｇ（純度９０．６％、収率８４．０％、融点１８３．５℃）を得た。
1H NMR (Solvent：CDCl3/500MHz) : δ(ppm)＝ 8.46(s,2H), 2.62(m,1H), 1.51(d,3H), 1.13(m,1H), 0.64(m,3H), 0.31(m,1H). Example 7
13.0 g (367 mmol) of hydrogen chloride gas was introduced into a methanol solution of 1-cyclopropylethylamine obtained according to Example 1, and after stirring at room temperature for 1 hour, 103.8 g (1127 mmol) of toluene was added. Methanol was distilled off from the reaction mixture at 95 ° C. under normal pressure, and then cooled to room temperature to precipitate crystals. The crystals were filtered and dried to obtain 26.8 g of 1-cyclopropylethylamine hydrochloride (purity 90.6%, yield 84.0%, melting point 183.5 ° C.).
1 H NMR (Solvent: CDCl 3 / 500MHz): δ (ppm) = 8.46 (s, 2H), 2.62 (m, 1H), 1.51 (d, 3H), 1.13 (m, 1H), 0.64 (m, 3H ), 0.31 (m, 1H).
実施例８
　シクロプロピルメチルケトン１２０ｇ（純度９９％、１４２７ｍｍｏｌ）、メタノール１６１．４ｇ及び安定化ニッケル触媒Ｎ－１０３Ｂ（日揮触媒化成社製）１１．３２ｇ（１０２．２ｍｍｏｌ）を９００ｍｌオートクレーブに加え、アンモニア（２６．７３ｇ、１５６９ｍｍｏｌ）をガスボンベから反応容器内に導入した。その後、反応容器内を水素ガスにて２回置換した。置換後、反応容器に水素ガスを１．５ＭＰａまで充填し、８０℃で攪拌した。反応容器内の圧力が低下したら再び水素ガスを２．０ＭＰａまで充填し続け、反応容器内の圧力２．０ＭＰａを保持しながら８０℃で８時間撹拌した。反応混合物を２０℃に冷却後、反応容器内を常圧にし、メタノール１８９．８ｇでかけ洗浄しながら不溶解物を濾別した。得られた溶液の反応進行率をガスクロマトグラフィーにて確認した。 Example 8
120 g of cyclopropyl methyl ketone (purity 99%, 1427 mmol), 161.4 g of methanol and 11.32 g (102.2 mmol) of stabilized nickel catalyst N-103B (manufactured by JGC Catalysts & Chemicals) were added to a 900 ml autoclave and ammonia (26. 73 g, 1569 mmol) was introduced into the reaction vessel from a gas cylinder. Thereafter, the inside of the reaction vessel was replaced twice with hydrogen gas. After the replacement, the reaction vessel was filled with hydrogen gas to 1.5 MPa and stirred at 80 ° C. When the pressure in the reaction vessel decreased, hydrogen gas was continuously charged to 2.0 MPa again, and stirred at 80 ° C. for 8 hours while maintaining the pressure in the reaction vessel at 2.0 MPa. After cooling the reaction mixture to 20 ° C., the inside of the reaction vessel was brought to atmospheric pressure, and insoluble matters were filtered off while washing with 189.8 g of methanol. The reaction progress rate of the obtained solution was confirmed by gas chromatography.
　実施例８、につき、原料化合物であるＣＰＭＫ及び目的物であるＣＰＥＡのＧＣ－ＰＡ％を第５表に記載する。 Table 5 shows GC-PA% of CPMK as a raw material compound and CPEA as a target product for Example 8.
Figure JPOXMLDOC01-appb-T000005
Figure JPOXMLDOC01-appb-T000005
　実施例９
　実施例８に準じて得た１－シクロプロピルエチルアミンのメタノール溶液に塩化水素ガス５７．２ｇ（１５６９ｍｍｏｌ）を導入し、室温で１時間攪拌した後、トルエン６２４．２ｇ（６７７４．９ｍｍｏｌ）を加えた。反応混合物を常圧下１０５℃でメタノールを留去後、室温に冷却し、結晶を析出させた。結晶をろ過した後乾燥し、１-シクロプロピルエチルアミン塩酸塩１５８．６ｇ（純度９９．８％、収率９１．４％、融点１８３．５℃）を得た。
1H NMR (Solvent：CDCl3/500MHz) : δ(ppm)＝ 8.46(s,2H), 2.62(m,1H), 1.51(d,3H), 1.13(m,1H), 0.64(m,3H), 0.31(m,1H). Example 9
Hydrogen chloride gas 57.2 g (1569 mmol) was introduced into a methanol solution of 1-cyclopropylethylamine obtained according to Example 8, and the mixture was stirred at room temperature for 1 hour, and then 624.2 g (6764.9 mmol) of toluene was added. . Methanol was distilled off from the reaction mixture under normal pressure at 105 ° C., and then cooled to room temperature to precipitate crystals. The crystals were filtered and dried to obtain 158.6 g of 1-cyclopropylethylamine hydrochloride (purity 99.8%, yield 91.4%, melting point 183.5 ° C.).
1 H NMR (Solvent: CDCl 3 / 500MHz): δ (ppm) = 8.46 (s, 2H), 2.62 (m, 1H), 1.51 (d, 3H), 1.13 (m, 1H), 0.64 (m, 3H ), 0.31 (m, 1H).
　本発明によれば、シクロプロピルメチルケトンを原料に、工業的に有利な条件で、高純度な１－シクロプロピルエチルアミン又はその酸付加塩を製造することができる。
　なお、２０１５年６月１０日に出願された日本特許出願２０１５－１１７５８８号の明細書、特許請求の範囲、図面、及び要約書の全内容をここに引用し、本発明の明細書の開示として、取り入れるものである。 According to the present invention, high-purity 1-cyclopropylethylamine or an acid addition salt thereof can be produced from cyclopropylmethylketone as a raw material under industrially advantageous conditions.
The entire contents of the specification, claims, drawings, and abstract of Japanese Patent Application No. 2015-117588 filed on June 10, 2015 are cited herein as disclosure of the specification of the present invention. Incorporate.

Claims (9)

  1. 　シクロプロピルメチルケトン、アンモニア及び水素を、無機酸化物に担持されたニッケル触媒の存在下、アルコール類及び／又はエーテル類中で反応させることを含むことを特徴とする、１－シクロプロピルエチルアミン又はその酸付加塩を製造する方法。 Comprising reacting cyclopropylmethylketone, ammonia and hydrogen in alcohols and / or ethers in the presence of a nickel catalyst supported on an inorganic oxide, or 1-cyclopropylethylamine or its A method for producing an acid addition salt.
  2. 　（i）シクロプロピルメチルケトン、アンモニア及び水素を、無機酸化物に担持されたニッケル触媒の存在下、アルコール類及び／又はエーテル類中で反応させて、１－シクロプロピルエチルアミンを得る第１工程、及び
    　（ii）１－シクロプロピルエチルアミンと酸とを溶媒中で反応させて、１－シクロプロピルエチルアミンの酸付加塩を得る第２工程を含む、請求項１に記載の方法。     (I) a first step of obtaining 1-cyclopropylethylamine by reacting cyclopropylmethylketone, ammonia and hydrogen in alcohols and / or ethers in the presence of a nickel catalyst supported on an inorganic oxide; And (ii) reacting 1-cyclopropylethylamine with an acid in a solvent to obtain an acid addition salt of 1-cyclopropylethylamine.
  3. 　無機酸化物がケイソウ土、シリカ又はアルミナである請求項１に記載の方法。 The method according to claim 1, wherein the inorganic oxide is diatomaceous earth, silica or alumina.
  4. 　無機酸化物がケイソウ土である請求項３に記載の方法。 The method according to claim 3, wherein the inorganic oxide is diatomaceous earth.
  5. 　シクロプロピルメチルケトンに対し、無機酸化物に担持されたニッケル触媒をニッケル含有量換算で１重量％～５０重量％存在させる請求項１に記載の方法。 The method according to claim 1, wherein the nickel catalyst supported on the inorganic oxide is present in an amount of 1 to 50% by weight in terms of nickel content with respect to cyclopropyl methyl ketone.
  6. 　アルコール類中で反応させる請求項１に記載の方法。 The method according to claim 1, wherein the reaction is carried out in alcohols.
  7. 　０．１～１０ＭＰａの圧力で水素と反応させる請求項１に記載の方法。 The method according to claim 1, wherein the reaction is conducted with hydrogen at a pressure of 0.1 to 10 MPa.
  8. 　１～１０ＭＰａの範囲内で圧力を一定に維持しながら水素と反応させる請求項７に記載の方法。 The method according to claim 7, wherein the reaction is carried out with hydrogen while maintaining the pressure constant within a range of 1 to 10 MPa.
  9. 　１－シクロプロピルエチルアミンの酸付加塩が塩酸塩、硫酸塩又は酢酸塩である請求項１に記載の方法。 The method according to claim 1, wherein the acid addition salt of 1-cyclopropylethylamine is hydrochloride, sulfate or acetate.
PCT/JP2016/066918 2015-06-10 2016-06-07 Method for producing 1-cyclopropylethylamine or acid addition salt thereof WO2016199763A1 (en)

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