JP2008143832A - Method for producing alicyclic amine or saturated heterocyclic amine - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a useful method for easily producing an alicyclic amine or a saturated heterocyclic amine in high yield. <P>SOLUTION: The alicyclic amine or the saturated heterocyclic amine usable as a raw material or the like for a medicine can be produced in a high yield and industrially advantageously by carrying out the hydrogenation reaction of an aromatic nitrile or an unsaturated heterocyclic nitrile in the presence of a noble metal-based catalyst containing palladium and rhodium and/or ruthenium, and an amino alcohol. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to a method for producing a high-purity alicyclic amine or saturated heterocyclic amine. Specifically, a high-purity alicyclic ring used as a raw material for pharmaceuticals or the like by hydrogenating an aromatic nitrile or an unsaturated heterocyclic nitrile in the presence of a catalyst containing at least two precious metals and an amino alcohol solvent. The present invention relates to a method for producing a formula amine or a saturated heterocyclic amine with good yield and industrially advantageous.

There are various known methods for producing alicyclic amines or saturated heterocyclic amines, and one of them is (1) hydrogenation reaction of nitrile groups using aromatic nitriles or heterocyclic nitriles as raw materials. (2) Step of producing aromatic amine or unsaturated heterocyclic amine by hydrogenation Step of hydrogenating double bond in ring of aromatic amine or unsaturated heterocyclic amine Above, known (1) A method is conceivable in which an aromatic amine or an unsaturated heterocyclic amine obtainable by the method is subjected to nuclear hydrogenation in the aromatic ring or heterocyclic ring in the step (2).

  In the hydrogenation reaction of (1) and (2) above, when an attempt is made to efficiently carry out the reaction in order to obtain the target amine from the nitrile compound, a noble metal catalyst such as rhodium, palladium, platinum, ruthenium is used. Methods for catalytic hydrogenation are known.

In the step (1) in which an amine compound is obtained from a nitrile compound using a hydrogenation reaction, a secondary amine and a tertiary amine may be generated simultaneously with the generation of the primary amine. The production ratio of the amine obtained by the hydrogenation reaction varies depending on the reaction conditions such as the catalyst, temperature, pressure, solvent, etc. When primary amines are mainly obtained, it is necessary to select the catalyst and the reaction conditions (Non-Patent Document 1, Patent Document 4).
In addition, in order to suppress an undesirable side reaction even in the hydrogenation reaction of a double bond in an aromatic amine or unsaturated heterocyclic amine ring, it is necessary to select appropriate reaction conditions (Patent Document 5). .

The hydrogenation reaction (Patent Document 1 and Patent Document 3) using ammonia as a hydrogenation reaction solvent may not be industrially preferred from the viewpoint of odor and toxicity.
A method using an acidic solvent such as acetic acid or hydrochloric acid instead of ammonia and an acetylated solvent such as acetic anhydride (Non-Patent Document 1 and Patent Document 6) is also known. May be disadvantageous in terms of cost.

  When the above hydrogenation reaction is carried out without using ammonia, an acidic solvent, or an acetylated solvent, a secondary amine produced as a by-product by the deammonia condensation reaction of the amino group that has been suppressed by using these solvents or The formation of tertiary amine is remarkable, and the yield and purity of the target primary amine are reduced.

When the steps (1) and (2) are carried out to obtain the target amine from the nitrile compound, a purification step is required depending on the purity of the intermediate amines produced in the step (1). It is industrially disadvantageous to carry out the purification at the stage of obtaining an intermediate amine, which complicates the process and causes a decrease in yield. In addition, intermediate amines may cause odor and may be harmful depending on the compound. Therefore, hydrogen can be isolated in one batch without isolating the intermediate from aromatic nitrile or unsaturated heterocyclic nitrile. It is industrially advantageous if an alicyclic amine or a saturated heterocyclic amine can be obtained by carrying out the oxidization reaction.
Although a method for obtaining an alicyclic amine directly from an aromatic nitrile without isolating the intermediate is also known (Patent Document 2), it is necessary to use a special noble metal Raney catalyst, which is disadvantageous in terms of economy. is there. Moreover, the method (Patent Document 6) in which a heterocyclic nitrile is hydrogenated in the presence of an acid to obtain a saturated heterocyclic amine has a yield of the target product obtained in the examples of about 60%. It's hard to say that there is enough.

Japanese Patent Laid-Open No. 5-97776 JP-A-9-66236 JP-A-6-279368 JP 2003-286261 A JP 61-251659 A JP-A-10-273482 Catalytic hydrogenation (application to organic synthesis) J. Am. Chem. Soc., 82, 2386 (1960)

  An object of the present invention is to solve the conventional problems and to provide a method for producing an alicyclic amine or a saturated heterocyclic amine with high purity and high yield and industrially advantageously.

The present invention has found the following knowledge as a result of intensive studies to achieve the above-mentioned problems.
(1) In the hydrogenation reaction of an aromatic nitrile or unsaturated heterocyclic nitrile, by using an amino alcohol as a solvent without using ammonia, an acidic solvent or an acetylated solvent, a secondary amine during the hydrogenation reaction is used. Alternatively, tertiary amine by-products are suppressed, and the desired alicyclic amine or saturated heterocyclic amine can be obtained in high yield.
(2) By performing a hydrogenation reaction of an aromatic nitrile or an unsaturated heterocyclic nitrile using a noble metal catalyst containing palladium as an essential component and further containing rhodium and / or ruthenium as a hydrogenation reaction catalyst. The hydrogenation reaction proceeds in one batch without isolating the amines as intermediates, and the desired alicyclic amine or saturated heterocyclic amine can be obtained efficiently.

  The present invention has been completed on the basis of such findings, and provides the following inventions.

  The confirmed claim is listed last.

  The present invention relates to a method for producing an alicyclic amine or a saturated heterocyclic amine by subjecting an aromatic nitrile or an unsaturated heterocyclic nitrile to a hydrogenation reaction in the presence of a specific noble metal catalyst and an amino alcohol. The saturated heterocyclic amine is a heterocyclic amine having no double bond in the heterocyclic ring. The present invention is described in detail below.

  The starting nitrile compound in the method for producing an alicyclic amine or saturated heterocyclic amine according to the present invention is a compound in which at least one nitrile group is introduced on an aromatic ring or a heterocyclic ring.

<Aromatic nitrile>
The aromatic nitrile according to the present invention has the general formula (1)
R ^1- (CN) n (1)
[Wherein n represents an integer of 1 or 2. In the formula, R ¹ represents an aromatic group having 6 to 30 carbon atoms which may have a substituent. ].

  The number n of nitrile groups in the general formula (1) is 1-2. The aromatic nitrile is selected from the group consisting of a hydroxyl group, a linear or branched alkyl group (having 1 to 10 carbon atoms, preferably 1 to 4 carbon atoms), and a linear or branched acetoxy group. It may have one or two or more selected substituents.

  Specific examples of the aromatic nitrile according to the present invention include 2-cyanotoluene, 3-cyanotoluene, 4-cyanotoluene, 1,2-dicyanobenzene, 1,3-dicyanobenzene, 1,4-dicyanobenzene, 1,4-dicyano-2,3,5,6-tetrafluorobenzene, 1,2-dicyano-3,4,5,6-tetrafluorobenzene, 4-trifluoromethylcyanobenzene, 4-cyano-phenylacetonitrile N- (2-cyano-ethyl) -N-methylaniline, N- (2-cyano-ethyl) -N-ethylaniline, 2-cyanophenol, 3-cyanophenol, 4-cyanophenol, 2-cyanobenzaldehyde 3-cyanobenzyl alcohol, 4-cyanobenzamide, 4-cyanobenzoic acid, methyl 4-cyanobenzoate, 4-sia Nobiphenyl, 2-cyanonaphthalene, 2,3-dicyanonaphthalene, 6-cyano-2-naphthol, α-cyano-3-hydroxycinnamic acid, 4-cyano-4′-hydroxybiphenyl, 4-cyano-4′- Aromatic nitriles such as nitrobiphenyl, 4-cyano-2′-nitrobiphenyl, 2,3-dicyano-hydroquinone, 9-cyanoanthracene, 9-cyanophenanthrene are exemplified.

  Among the above aromatic nitriles, 2-cyanotoluene, 3-cyanotoluene, 4-cyanotoluene, 1,2-dicyanobenzene, 1,3-dicyanobenzene, 1,4-dicyanobenzene, 1,4-dicyano-2 , 3,5,6-tetrafluorobenzene, 1,2-dicyano-3,4,5,6-tetrafluorobenzene, 4-trifluoromethyl-1-cyanobenzene, 4-cyano-phenylacetonitrile, N- ( 2-cyano-ethyl) -N-methylaniline, 2-cyanophenol, 2-cyanonaphthalene, 2,3-dicyanonaphthalene, 6-cyano-2-naphthol, 4-cyano-4′-hydroxybiphenyl, 4-cyano -4'-nitrobiphenyl, 2,3-dicyano-hydroquinone and 9-cyanophenanthrene are preferred.

［式中、ｊは１又は２の整数を表す。Ｘ^１は、−Ｏ−又は−ＮＨ−のいずれかを表す。式中、Ｙ^１及びＺ^１は、同一又は異なって、それぞれ炭素原子又は窒素原子を表す。］
で表される複素環式ニトリル、
一般式（３）

［式中、ｋは１又は２の整数を表す。Ｘ^２、Ｙ^２及びＺ^２は、同一又は異なって、それぞれ炭素原子又は窒素原子を表す。］
で表される複素環式ニトリル、
又は、不飽和縮合二環系複素環式ニトリルである。 <Unsaturated heterocyclic nitrile>
The unsaturated heterocyclic nitrile according to the present invention has the general formula (2),

[Wherein j represents an integer of 1 or 2. X ¹ represents either —O— or —NH—. In the formula, Y ¹ and Z ¹ are the same or different and each represents a carbon atom or a nitrogen atom. ]
A heterocyclic nitrile represented by
General formula (3)

[Wherein, k represents an integer of 1 or 2. X ² , Y ² and Z ² are the same or different and each represents a carbon atom or a nitrogen atom. ]
A heterocyclic nitrile represented by
Or it is an unsaturated condensed bicyclic heterocyclic nitrile.

  In the above general formulas (2) and (3), j and k, which are the number of cyano groups, represent an integer of 1 or 2. The heterocyclic nitrile is selected from the group consisting of a hydroxyl group, a linear or branched alkyl group (having 1 to 10 carbon atoms, preferably 1 to 4 carbon atoms) and a linear or branched acetoxy group. It may have one or two or more selected substituents.

  The above-mentioned unsaturated condensed bicyclic heterocyclic nitriles are indole, isoindole, pyrrolidine, pyridine, indolizine, indazole, purine, quinolidine, quinoline, isoquinoline, naphthyridine, phthalazine, quinoxaline, quinazoline, cinnoline, pteridine, benzofuran. , Chromene, isochromene, coumarin, or chromone, etc., having one or more cyano groups as a substituent in an unsaturated condensed bicyclic heterocyclic compound.

  Specific examples of the unsaturated heterocyclic nitrile according to the present invention include cyanopyrazine, 2,3-dicyanopyrazine, 2-cyanopyrimidine, 3-cyanopyrazole, 3-cyanopyridazine, 4,5-dicyanoimidazole, -Cyanopyrrole, 3-cyanopyrrole, 1- (2-cyanoethyl) pyrrole, 2-cyanopyridine, 3-cyanopyridine, 4-cyanopyridine, 2-cyano-3-hydroxypyridine, 2-cyano-3-methylpyridine , 3-cyano-4,6-dimethyl-2-hydroxypyridine, 2-cyano-1-ethylpyridine, 2,3-dicyanopyridine, 2-pyridineacetonitrile, 3-pyridineacetonitrile and the like.

Specific examples of the unsaturated fused bicyclic heterocyclic nitrile according to the present invention include 3-cyanoindole, 5-cyanoindole, 2-cyanoindole, 3-cyanoisoindole, 5-cyanoisoindole, 2-cyanoindole, Cyanoisoindole, 3-cyanoquinoline, 6-cyanopurine, 3-cyano-4-methylcoumarin, 3-cyano-7-hydroxy-4-methylcoumarin, 3-cyanochromone, 3-cyano-6-isopropylchromone, Examples include 3-cyano-6-ethylchromone.

  Among the above unsaturated heterocyclic nitriles, 2-cyanofuran, 2,5-dicyanofuran, 3-cyanoindole, 5-cyanoindole, 2-cyanoindole, 3-cyanoindole, 5-cyanoindole, 3-cyano Quinoline, 2,3-dicyanopyridine, cyanopyrazine, 2,3-dicyanopyrazine, 2-cyanopyrimidine, 3-hydroxy-2-cyanopyridine, 3-cyano-4-methylcoumarin and 4,5-dicyanoimidazole are preferred. .

<How to obtain raw materials>
As the aromatic nitrile or unsaturated heterocyclic nitrile used for the raw material of the present invention, those which can be obtained for industrial use or those which can be obtained as reagents can be used.
The raw material is preferably a high-purity product and a catalyst poisoning substance with little hydrogenation reaction. Examples of the catalyst poisoning substance include sulfur, phosphorus, and halogen compounds. Moreover, you may refine | purify and use what has low purity or a catalyst poisoning thing by well-known methods, such as distillation, recrystallization, adsorption processing, column separation, solvent extraction.

<Amino alcohol>
In the hydrogenation reaction of the present invention, by using amino alcohol as a solvent, generation of by-products during the hydrogenation reaction is suppressed, and the target amines can be obtained in high yield. Examples of the amino alcohol used in the present invention include 2- (dimethylamino) ethanol, 2- (diethylamino) ethanol, 2- (dibutylamino) ethanol, 2- (diethylamino) propanol, 3- (diethylamino) -1,2 -Propanediol, diethanolamine, N-ethyldiethanolamine, Nn-butyldiethanolamine, triethanolamine and the like are exemplified, and 2- (dimethylamino) ethanol, 2- (diethylamino) ethanol, and 2- (dibutylamino) ethanol are preferable. . Two or more of the above solvents can be used in combination.

The use amount of the amino alcohol solvent according to the present invention is, for example, 100 to 950% by weight and preferably 300 to 900% by weight with respect to 100% by weight of the raw material nitrile compound. As the amount of the solvent used is increased, the side reaction is suppressed and the yield is improved. However, even if the solvent is used in a predetermined amount or more, an effect commensurate with the amount used cannot be obtained.

<Catalyst>
The catalyst used for the hydrogenation reaction of the present invention is a catalyst containing palladium and rhodium and / or ruthenium in a combination of noble metals represented by the following (1) to (3).
(1) Palladium and rhodium (2) Palladium and ruthenium (3) Palladium, rhodium and ruthenium The catalyst is a catalyst in which the noble metal component (palladium, rhodium or ruthenium) is supported on a carrier. Examples of the carrier include carbon, calcium, magnesium, aluminum, silicon, titanium, and oxides thereof. These carriers can be used alone or in combination of two or more.

  The amount of the noble metal supported on the catalyst carrier used in the hydrogenation reaction of the present invention is preferably 0.1 to 20% by weight, more preferably 0.5 to 10% by weight, based on the total amount of the catalyst.

  The amount of catalyst in the hydrogenation reaction of the present invention cannot be determined uniformly because it varies depending on the type of catalyst used and the catalyst performance, but in the case of a batch reaction, the usual amount of catalyst is the total amount of liquid in the reactor. On the other hand, it is 0.1 to 10% by weight, and more preferably about 0.1 to 3% by weight. If the amount of catalyst is less than 0.1% by weight, it is difficult to obtain a practical reaction rate. On the other hand, if the amount of catalyst exceeds 10% by weight, the catalyst cannot be sufficiently diffused and the filtration process is burdened, which is not preferable. There is a case.

  The catalyst used for the hydrogenation reaction of the present invention is a catalyst containing palladium and rhodium and / or ruthenium in an arbitrary ratio, and by using this within the above range of use amount, a nitrile reduction reaction and Nuclear hydrogenation reaction proceeds.

In the case of using a combination of palladium and rhodium and / or ruthenium in the hydrogenation reaction of the present invention, the palladium content is preferably 30% by weight or more, and 40% by weight or more based on the total noble metal content of the catalyst. It is more preferable.

The form of the catalyst is not particularly limited, and is powdery, sponge-like, tablet-like (cylindrical), pellet-like, noodle-like (three-leaf clover-like, four-leaf clover-like, cylindrical) according to the selected form. Etc. are used as appropriate. Specifically, a powdered catalyst is used for batch or continuous suspension reaction, and a tablet catalyst is used for fixed bed reaction.
When a powdery catalyst is used, two or more kinds of powdered noble metal catalysts can be used in combination with the above-mentioned noble metal combinations and ratios.

  The average particle diameter of the powdery catalyst is not particularly limited, but is preferably 1 μm to 200 μm and more preferably 3 μm to 80 μm in view of reactivity and filterability.

The tablet form of the catalyst, ^{10m 2} / g~200m 2 / g is illustrated as its surface ^area, 20m ² / ^g~100m 2 / g are preferred. When the surface area is less than 10 m ² / g, the reaction rate is slow, and when it exceeds 200 m ² / g, the effect of promoting the reaction rate is reduced, the crushing strength is lowered, and the strength retention during the reaction is likely to be lowered.

The size of the tablet-like catalyst is determined by the inner diameter of the reaction tower to be used. The size ranges from 2 to 10 mm in diameter and 2 to 10 mm in height, preferably 2 to 6 mm in diameter and 2 to 6 mm in height. The size of the noodle-shaped catalyst is 1 to 10 mm in diameter, preferably 2 to 6 mm.

<Reaction conditions>
Reaction temperature and reaction time
In the hydrogenation reaction of the present invention, temperature control in the reaction step is important in order to suppress the generation of by-products and advance the reaction efficiently. The reactor in the present invention is recommended to have sufficient cooling performance and easy control of reaction heat. In the hydrogenation reaction of the present invention, it is possible to control the reaction rate and the reaction temperature by controlling the supply amount of hydrogen as necessary during the reaction.
In the hydrogenation reaction of the present invention, a large amount of aromatic nitrile or heterounsaturated heterocyclic nitrile as a raw material exists in the reaction system, and an aromatic amine or unsaturated heterocyclic amine as an intermediate is formed. In particular, side reactions are likely to occur.
When a large amount of aromatic nitrile or heterounsaturated heterocyclic nitrile is present in the reaction system, the generation of secondary amine or tertiary amine can be suppressed by carrying out the reaction at a relatively low temperature. Specific examples of the reaction temperature include 40 to 90 ° C, preferably 50 to 70 ° C. The reaction time in the stage of performing the hydrogenation reaction at a relatively low reaction temperature is usually 0.5 to 10 hours. From the viewpoint of productivity, it is preferable that the reaction at a low temperature has a short reaction time, but from the viewpoint of product quality, the reaction is performed at the above temperature until a reaction time for achieving a raw material conversion of 90% or more, preferably 95% or more. Preferably it is done.

  After performing the reaction for a predetermined reaction time at a relatively low reaction temperature, by raising the reaction temperature, the aromatic nitrile or heterounsaturated heterocyclic nitrile that is an unreacted raw material is substantially lost, Reaction in which the double bond in the ring of the aromatic amine or unsaturated heterocyclic amine as an intermediate is hydrogenated proceeds. As this reaction temperature, 100-250 degreeC is preferable and 100-140 degreeC is more preferable. When the reaction temperature is lower than 100 ° C., the progress of the reaction is delayed from the raw material or the reaction intermediate, and the reaction time becomes longer, resulting in poor productivity. The reaction time of the hydrogenation reaction after raising the temperature is usually 0.5 to 10 hours. The longer the reaction time, the lower the residual amount of aromatic or heterocyclic nitrile as a raw material and aromatic or unsaturated heterocyclic amine as an intermediate. From the viewpoint of product quality, the residual amount of unreacted raw materials and intermediates is preferably 0.5% or less, more preferably 0.1% or less, and particularly preferably 0.05% or less in GC measurement. From the viewpoint of product quality, it is preferable to carry out the reaction until the remaining amount of unreacted raw materials and intermediates is reduced as much as possible, but from the viewpoint of productivity, the reaction time is preferably 2 to 10 hours.

Reaction pressure
The hydrogenation reaction of the present invention can be carried out at a reaction pressure of normal pressure to 30 MPa. The higher the reaction pressure, the higher the reactivity and the better, but 2-10 MPa is preferred from the viewpoint of equipment cost.

Production System As the hydrogenation reaction apparatus used in the present invention, a batch reaction system or a continuous reaction system can be used. In the case of the batch reaction method, a method of performing hydrogenation in the first step and the second step in one batch by raising the temperature in two steps is exemplified. In the case of a continuous reaction system, for example, a suspension bed system or a fixed bed system is exemplified. When performing a continuous reaction in a fixed bed system, a method of performing a hydrogenation reaction using a reaction apparatus including two or more reaction towers having different reaction conditions (catalyst, temperature, pressure) in series is exemplified.

Hydrogen flow rate The hydrogenation reaction of the present invention can also be carried out in a hydrogen flow system. In the case of the suspension bed type, the superficial linear velocity of hydrogen gas is preferably 0.1 to 10 cm / second, more preferably 0.3 to 3 cm / second. In the case of the fixed bed type, the superficial linear velocity of the hydrogen gas is preferably 2 to 40 cm / second, more preferably 8 to 25 cm / second. In the case of the suspension bed type, the superficial linear velocity of hydrogen gas is preferably 2 to 20 cm / second, more preferably 3 to 6 cm / second. When the superficial linear velocity is low, the reaction rate is low, while when it is high, the catalyst tends to be too concentrated.

<Purification method>
The reaction crude obtained after the hydrogenation reaction is separated from the catalyst by a known method such as filtration, distillation, recrystallization, column separation, adsorption treatment, and solvent extraction, and the filtrate is purified. Cyclic amines or saturated heterocyclic amines can be obtained.

  EXAMPLES Hereinafter, although this invention is demonstrated in detail based on an Example, this invention is not limited to these Examples. The hydrogenation conversion rate and purity were measured by gas chromatography analysis.

<GC purity (%): gas chromatography (GC) analysis>
The GC analysis of the target product was performed under the following conditions.
Device: SHIMADZU GC-2010
Column: DB-1701 (GL Science Co., Ltd.) 0.25mm × 30m 0.25μm
Column temperature: 100 ° C → 250 ° C (5 ° C / min)
Flow rate: 1ml / min.
Split: 1/50
Injection temperature: 300 ℃
Detection temperature: 300 ℃

<Conversion rate: GC analysis>
Based on the following formula, the conversion rate of the hydrogenation reaction was calculated.
Conversion rate (%) = 100− (Raw material GC area%)

As the noble metal catalyst, a commercially available 5% palladium alumina powder catalyst (manufactured by NE Chemcat), 5% ruthenium alumina powder catalyst (manufactured by NE Chemcat) and 5% rhodium alumina powder catalyst (manufactured by NT Chemcat) were used.

As the solvent, 2- (dimethylamino) ethanol (manufactured by Nacalai Tesque) was used.

  As the aromatic nitrile or heterocyclic nitrile, those obtained as reagents were used.

[Example 1]
A 500 ml electromagnetically stirred stainless steel autoclave is charged with 30 g of 2-cyanotoluene, 120 g of 2- (dimethylamino) ethanol, 0.3 g of 5 wt% rhodium-alumina powder catalyst and 1.5 g of 5 wt% palladium-alumina powder catalyst. After substituting with nitrogen in the system, hydrogen was introduced to a hydrogen pressure of 2 MPa, and the mixture was stirred for 9 hours at a reaction temperature of 60 ° C. and a hydrogen pressure of 4 MPa. Subsequently, the reaction temperature was raised to 110 ° C., the hydrogen pressure was 5 MPa, and the mixture was stirred for 5 hours. After the reaction, the reaction mixture was cooled to 60 ° C., and then the reaction crude was extracted from the autoclave, and the catalyst was separated by filtration with a vacuum filtration device (filter is No5C filter paper). The crude liquid from which the catalyst was separated by filtration (GC analysis: conversion rate 100%, purity 96.7%) was purified by distillation, and 32.4 g of 2-aminomethyl-1-methylcyclohexane (yield 96.5%, purity 99.99%). 9%).

[Example 2]
A 500 ml electromagnetically stirred stainless steel autoclave was charged with 30 g of 2-cyanotoluene, 120 g of 2- (dimethylamino) ethanol, 0.9 g of 5 wt% ruthenium-alumina powder catalyst and 1.5 g of 5 wt% palladium-alumina powder catalyst. After substituting with nitrogen in the system, hydrogen was introduced to a hydrogen pressure of 2 MPa, and the mixture was stirred for 9 hours at a reaction temperature of 60 ° C. and a hydrogen pressure of 4 MPa. Subsequently, the reaction temperature was raised to 110 ° C., the hydrogen pressure was 5 MPa, and the mixture was stirred for 5 hours. After the reaction, the reaction mixture was cooled to 60 ° C., and the reaction crude product was extracted from the autoclave, the catalyst was filtered and separated with a vacuum filtration device (filter is No5C filter paper), and further the solvent was distilled off to remove 2-aminomethyl-1-methyl. Cyclohexane was obtained (GC analysis: conversion 99.9%, purity 94.8%).

[Example 3]
In a 500 ml electromagnetic stirring stainless steel autoclave, 30 g of 2-cyanotoluene, 120 g of 2- (dimethylamino) ethanol, 0.45 g of 5 wt% ruthenium-alumina powder catalyst, 0.15 g of 5 wt% rhodium-alumina powder catalyst, After charging 1.5 g of a 5 wt% palladium-alumina powder catalyst and replacing with nitrogen in the system, hydrogen was introduced to a hydrogen pressure of 2 MPa, and the mixture was stirred for 9 hours at a reaction temperature of 60 ° C. and a hydrogen pressure of 4 MPa. Subsequently, the reaction temperature was raised to 110 ° C., the hydrogen pressure was 5 MPa, and the mixture was stirred for 5 hours. After the reaction, the reaction mixture was cooled to 60 ° C., and the reaction crude product was extracted from the autoclave, the catalyst was filtered and separated with a vacuum filtration device (filter is No5C filter paper), and further the solvent was distilled off to remove 2-aminomethyl-1-methyl. Cyclohexane was obtained (GC analysis: conversion 99.9%, purity 95.1%).

[Example 4]
In a 500 ml electromagnetically stirred stainless steel autoclave, 30 g of 1,4-dicyanobenzene, 120 g of 2- (dimethylamino) ethanol, 0.3 g of 5 wt% rhodium-alumina powder catalyst, 1.5 g of 5 wt% palladium-alumina powder catalyst Was replaced with nitrogen in the system, hydrogen was introduced to a hydrogen pressure of 2 MPa, and the mixture was stirred at a reaction temperature of 60 ° C. and a hydrogen pressure of 4 MPa for 9 hours. Subsequently, the reaction temperature was raised to 110 ° C., the hydrogen pressure was 5 MPa, and the mixture was stirred for 5 hours. After the reaction, the reaction mixture was cooled to 60 ° C., and the reaction crude product was taken out from the autoclave. The catalyst was filtered and separated with a vacuum filtration device (filter is No5C filter paper), and the solvent was distilled off to further remove 1,4-bis (aminomethyl). ) Cyclohexane was obtained (GC analysis: conversion 100%, purity 94.1%).

[Example 5]
In a 500 ml electromagnetically stirred stainless steel autoclave, 30 g of 1,4-dicyanobenzene, 120 g of 2- (dimethylamino) ethanol, 0.9 g of 5 wt% ruthenium-alumina powder catalyst and 1.5 g of 5 wt% palladium-alumina powder catalyst Was replaced with nitrogen in the system, hydrogen was introduced to a hydrogen pressure of 2 MPa, and the mixture was stirred at a reaction temperature of 60 ° C. and a hydrogen pressure of 4 MPa for 9 hours. Subsequently, the reaction temperature was raised to 110 ° C., the hydrogen pressure was 5 MPa, and the mixture was stirred for 5 hours. After the reaction, the reaction mixture was cooled to 60 ° C., and the reaction crude product was extracted from the autoclave. ) Cyclohexane was obtained (GC analysis: conversion 100%, purity 93.0%).

[Example 6]
In a 500 ml electromagnetically stirred stainless steel autoclave, 30 g of 1,3-dicyanobenzene, 120 g of 2- (dimethylamino) ethanol, 0.3 g of 5 wt% rhodium-alumina powder catalyst, 1.5 g of 5 wt% palladium-alumina powder catalyst Was replaced with nitrogen in the system, hydrogen was introduced to a hydrogen pressure of 2 MPa, and the mixture was stirred at a reaction temperature of 60 ° C. and a hydrogen pressure of 4 MPa for 9 hours. Subsequently, the reaction temperature was raised to 110 ° C., the hydrogen pressure was 5 MPa, and the mixture was stirred for 5 hours. After the reaction, the reaction mixture was cooled to 60 ° C., the reaction crude was extracted from the autoclave, the catalyst was filtered and separated with a vacuum filtration device (filter is No5C filter paper), and further the solvent was distilled off to remove 1,3-bis (aminomethyl). ) Cyclohexane was obtained (GC analysis: conversion 100%, purity 93.8%).

[Example 7]
A 500 ml electromagnetically stirred stainless steel autoclave was charged with 30 g of 2-cyanofuran, 120 g of 2- (dimethylamino) ethanol, 0.3 g of 5 wt% rhodium-alumina powder catalyst, and 1.5 g of 5 wt% palladium-alumina powder catalyst. After substituting with nitrogen in the system, hydrogen was introduced to a hydrogen pressure of 2 MPa, and the mixture was stirred for 9 hours at a reaction temperature of 60 ° C. and a hydrogen pressure of 4 MPa. Subsequently, the reaction temperature was raised to 110 ° C., the hydrogen pressure was 5 MPa, and the mixture was stirred for 5 hours. After the reaction, the reaction mixture is cooled to 60 ° C., and then the reaction crude is taken out from the autoclave, the catalyst is filtered and separated with a vacuum filtration device (filter is No5C filter paper), and further the solvent is distilled off to remove 2-aminomethyltetrahydrofuran. (GC analysis: conversion 100%, purity 92.0%).

[Example 8]
In a 500 ml electromagnetically stirred stainless steel autoclave, 30 g of 2,5-dicyanofuran, 120 g of 2- (dimethylamino) ethanol, 0.3 g of 5 wt% rhodium-alumina powder catalyst, 1.5 g of 5 wt% palladium-alumina powder catalyst Was replaced with nitrogen in the system, hydrogen was introduced to a hydrogen pressure of 2 MPa, and the mixture was stirred at a reaction temperature of 60 ° C. and a hydrogen pressure of 4 MPa for 9 hours. Subsequently, the reaction temperature was raised to 110 ° C., the hydrogen pressure was 5 MPa, and the mixture was stirred for 5 hours. After the reaction, the reaction mixture was cooled to 60 ° C., and the reaction crude product was taken out from the autoclave, the catalyst was filtered and separated with a vacuum filtration device (filter is No5C filter paper), and the solvent was distilled off to remove 2,5-bis (aminomethyl). ) Tetrahydrofuran (conversion 95%, purity 91.8%) was obtained.

[Example 9]
In a 500 ml electromagnetically stirred stainless steel autoclave, 30 g of 1,4-dicyano-2,3,5,6-tetrafluorobenzene, 120 g of 2- (dimethylamino) ethanol, 0.3 g of 5 wt% rhodium-alumina powder catalyst, After charging 1.5 g of a 5 wt% palladium-alumina powder catalyst and replacing with nitrogen in the system, hydrogen was introduced to a hydrogen pressure of 2 MPa, and the mixture was stirred for 9 hours at a reaction temperature of 60 ° C. and a hydrogen pressure of 4 MPa. Subsequently, the reaction temperature was raised to 110 ° C., the hydrogen pressure was 5 MPa, and the mixture was stirred for 5 hours. After the reaction, the reaction mixture was cooled to 60 ° C., and the reaction crude product was taken out from the autoclave. The catalyst was filtered and separated with a vacuum filtration device (filter is No5C filter paper), and the solvent was distilled off to further remove 1,4-bis (aminomethyl). ) -2,3,5,6-tetrafluorocyclohexane (conversion 99.9%, purity 91.6%).

[Example 10]
In a 500 ml electromagnetically stirred stainless steel autoclave, 30 g of 2,3-dicyanonaphthalene, 120 g of 2- (dimethylamino) ethanol, 0.3 g of 5 wt% rhodium-alumina powder catalyst and 1.5 g of 5 wt% palladium-alumina powder catalyst Was replaced with nitrogen in the system, hydrogen was introduced to a hydrogen pressure of 2 MPa, and the mixture was stirred at a reaction temperature of 60 ° C. and a hydrogen pressure of 4 MPa for 9 hours. Subsequently, the reaction temperature was raised to 110 ° C., the hydrogen pressure was 5 MPa, and the mixture was stirred for 5 hours. After the reaction, the reaction mixture was cooled to 60 ° C., and the reaction crude product was taken out from the autoclave, the catalyst was filtered and separated with a vacuum filtration device (filter is No5C filter paper), and the solvent was distilled off to remove 2,3-bis (aminomethyl ) Decahydronaphthalene was obtained (GC analysis: conversion 100%, purity 94.0%).

[Example 11]
A 500 ml electromagnetically stirred stainless steel autoclave was charged with 30 g of 2-cyanophenol, 120 g of 2- (dimethylamino) ethanol, 0.3 g of 5 wt% rhodium-alumina powder catalyst and 1.5 g of 5 wt% palladium-alumina powder catalyst. After substituting with nitrogen in the system, hydrogen was introduced to a hydrogen pressure of 2 MPa, and the mixture was stirred for 9 hours at a reaction temperature of 60 ° C. and a hydrogen pressure of 4 MPa. Subsequently, the reaction temperature was raised to 110 ° C., the hydrogen pressure was 5 MPa, and the mixture was stirred for 5 hours. After the reaction, the reaction mixture is cooled to 60 ° C., and the reaction crude product is taken out from the autoclave, the catalyst is filtered and separated with a vacuum filtration device (filter is No5C filter paper), and the solvent is distilled off to obtain 2-aminomethylcyclohexanol. (GC analysis: conversion 100%, purity 96.5%).

[Example 12]
In a 500 ml electromagnetically stirred stainless steel autoclave, 30 g of 2,3-dicyanopyrazine, 120 g of 2- (dimethylamino) ethanol, 0.3 g of 5 wt% rhodium-alumina powder catalyst, 1.5 g of 5 wt% palladium-alumina powder catalyst Was replaced with nitrogen in the system, hydrogen was introduced to a hydrogen pressure of 2 MPa, and the mixture was stirred at a reaction temperature of 60 ° C. and a hydrogen pressure of 4 MPa for 9 hours. Subsequently, the reaction temperature was raised to 110 ° C., the hydrogen pressure was 5 MPa, and the mixture was stirred for 5 hours. After the reaction, the reaction mixture was cooled to 60 ° C., and the reaction crude product was taken out from the autoclave, the catalyst was filtered and separated with a vacuum filtration device (filter is No5C filter paper), and the solvent was distilled off to remove 2,3-bis (aminomethyl ) Piperazine (conversion 100%, purity 95.7%) was obtained.

[Example 13]
In a 500 ml electromagnetically stirred stainless steel autoclave, 30 g of 6-cyano-2-naphthol, 120 g of 2- (dimethylamino) ethanol, 0.3 g of 5 wt% rhodium-alumina powder catalyst, 5 wt% palladium-alumina powder catalyst After charging 5 g and replacing with nitrogen in the system, hydrogen was introduced to a hydrogen pressure of 2 MPa, and the mixture was stirred for 9 hours at a reaction temperature of 60 ° C. and a hydrogen pressure of 4 MPa. Subsequently, the reaction temperature was raised to 110 ° C., the hydrogen pressure was 5 MPa, and the mixture was stirred for 5 hours. After the reaction, the reaction mixture was cooled to 60 ° C., and the reaction crude product was taken out from the autoclave, the catalyst was filtered and separated with a vacuum filtration device (filter is No5C filter paper), and further the solvent was distilled off to distill off the solvent. Decahydronaphthalene (conversion 100%, purity 96.4%) was obtained.

[Example 14]
A 500 ml electromagnetically stirred stainless steel autoclave is charged with 30 g of 2-cyanopyridine, 120 g of 2- (dimethylamino) ethanol, 0.3 g of 5 wt% rhodium-alumina powder catalyst and 1.5 g of 5 wt% palladium-alumina powder catalyst. After substituting with nitrogen in the system, hydrogen was introduced to a hydrogen pressure of 2 MPa, and the mixture was stirred for 9 hours at a reaction temperature of 60 ° C. and a hydrogen pressure of 4 MPa. Subsequently, the reaction temperature was raised to 110 ° C., the hydrogen pressure was set to 5 MPa, and the mixture was stirred for 5 hours. After the reaction, the reaction mixture was cooled to 60 ° C., and the reaction crude product was extracted from the autoclave. 100%, purity 87.6%).

[Example 15]
A 500 ml electromagnetically stirred stainless steel autoclave was charged with 30 g of 3-cyanopyridine, 120 g of 2- (dimethylamino) ethanol, 0.3 g of 5 wt% rhodium-alumina powder catalyst and 1.5 g of 5 wt% palladium-alumina powder catalyst. After substituting with nitrogen in the system, hydrogen was introduced to a hydrogen pressure of 2 MPa, and the mixture was stirred for 9 hours at a reaction temperature of 60 ° C. and a hydrogen pressure of 4 MPa. Subsequently, the reaction temperature was raised to 110 ° C., the hydrogen pressure was 5 MPa, and the mixture was stirred for 5 hours. After the reaction, the reaction mixture was cooled to 60 ° C., and the reaction crude product was taken out from the autoclave. 100%, purity 87.6%).

[Comparative Example 1]
A 500 ml electromagnetically stirred stainless steel autoclave was charged with 30 g of 1,3-dicyanobenzene, 120 g of ethanol, 0.3 g of 5 wt% rhodium-alumina powder catalyst and 1.5 g of 5 wt% palladium-alumina powder catalyst. After substituting with internal nitrogen, hydrogen was introduced to a hydrogen pressure of 2 MPa, and the mixture was stirred for 9 hours at a reaction temperature of 60 ° C. and a hydrogen pressure of 4 MPa. Subsequently, the reaction temperature was raised to 110 ° C., the hydrogen pressure was 5 MPa, and the mixture was stirred for 5 hours. After the reaction, the reaction mixture was cooled to 60 ° C., and the reaction crude product was extracted from the autoclave. The catalyst was filtered and separated with a vacuum filtration device (filter is No5C filter paper), and further the solvent was distilled off to remove 1,3-diaminomethylcyclohexane Conversion rate 100%, purity 77.5%).

[Comparative Example 2]
A 500 ml electromagnetically stirred stainless steel autoclave was charged with 30 g of 1,3-dicyanobenzene, 120 g of dioxane, 0.3 g of 5 wt% rhodium-alumina powder catalyst and 1.5 g of 5 wt% palladium-alumina powder catalyst, and nitrogen in the system. Then, hydrogen was introduced to a hydrogen pressure of 2 MPa, and the mixture was stirred for 9 hours at a reaction temperature of 60 ° C. and a hydrogen pressure of 4 MPa. Subsequently, the reaction temperature was raised to 110 ° C., the hydrogen pressure was 5 MPa, and the mixture was stirred for 5 hours. After the reaction, the reaction mixture was cooled to 60 ° C., and the reaction crude product was extracted from the autoclave. The catalyst was filtered and separated with a vacuum filtration device (filter is No5C filter paper), and further the solvent was distilled off to remove 1,3-diaminomethylcyclohexane Conversion rate 100%, purity 75.5%).

[Comparative Example 3]
A 500 ml electromagnetically stirred stainless steel autoclave was charged with 30 g of 1,3-dicyanobenzene, 120 g of 2- (dimethylamino) ethanol, 1.5 g of a 5 wt% rhodium-alumina powder catalyst, and replaced with nitrogen in the system. Hydrogen was introduced to 2 MPa, and the mixture was stirred for 9 hours under a reaction temperature of 60 ° C. and a hydrogen pressure of 4 MPa. Subsequently, the reaction temperature was raised to 110 ° C., the hydrogen pressure was 5 MPa, and the mixture was stirred for 5 hours. After the reaction, the reaction mixture was cooled to 60 ° C., and the reaction crude product was taken out from the autoclave, the catalyst was filtered and separated with a vacuum filtration device (filter is No5C filter paper), and further the solvent was distilled off to remove 1,3-diaminomethylcyclohexane ( Conversion 15.6%, purity 8.1%).

[Comparative Example 4]
A 500 ml electromagnetically stirred stainless steel autoclave was charged with 30 g of 1,3-dicyanobenzene, 120 g of 2- (dimethylamino) ethanol, and 3.5 g of a 5 wt% Pd-alumina powder catalyst, and the system was replaced with nitrogen in the system. Hydrogen was introduced to 2 MPa, and the mixture was stirred for 9 hours under a reaction temperature of 60 ° C. and a hydrogen pressure of 4 MPa. Subsequently, the reaction temperature was raised to 110 ° C., the hydrogen pressure was 5 MPa, and the mixture was stirred for 5 hours. After the reaction, the reaction mixture was cooled to 60 ° C., and the reaction crude product was taken out from the autoclave, the catalyst was filtered and separated with a vacuum filtration device (filter is No5C filter paper), and further the solvent was distilled off to remove 1,3-diaminomethylcyclohexane ( Conversion 99.9%, purity 2.3%).

[Comparative Example 5]
A 500 ml electromagnetically stirred stainless steel autoclave was charged with 30 g of 2-cyanotoluene, 120 g of 2- (dimethylamino) ethanol, and 1.5 g of a 5 wt% palladium-alumina powder catalyst. After substituting with nitrogen in the system, up to a hydrogen pressure of 2 MPa. Hydrogen was introduced, and the mixture was stirred for 9 hours under a reaction temperature of 60 ° C. and a hydrogen pressure of 4 MP. The reaction crude was extracted from the autoclave, and the catalyst was separated by filtration with a vacuum filtration device (filter is No5C filter paper) (GC analysis: conversion 99.5%, purity 85.5%). The crude liquid from which the catalyst was separated by filtration was purified by distillation to obtain 25.6 g of 2-aminomethyltoluene (GC area ratio 99.5%, yield 82.6%).
A 500 ml electromagnetically stirred stainless steel autoclave was charged with 25.0 g of 2-aminomethyltoluene obtained in the above step and 100 g of water with 1.5 g of a 5% by weight rhodium-alumina powder catalyst, and replaced with nitrogen in the system. Hydrogen was introduced to a hydrogen pressure of 2 MPa, the reaction temperature was raised to 110 ° C. while stirring, the pressure was increased to 5 MPa, and stirring was carried out for 5 hours. After the reaction, the reaction mixture was cooled to 60 ° C., and then the reaction crude was extracted from the autoclave, and the catalyst was separated by filtration with a vacuum filtration device (filter is No5C filter paper). The crude liquid from which the catalyst was separated by filtration (GC analysis: purity 99.0%) was purified by distillation to obtain 24.6 g of 2-aminomethylcyclohexane (distillation yield 95.0%, GC analysis: purity 99.5%). )
The overall yield from 2-cyanotoluene, the starting aromatic nitrile, to the final product, 2-aminomethylcyclohexane, was 78.5%.

As apparent from Examples 1 to 15, according to the present invention, the desired primary amine was obtained in high yield from the aromatic nitrile or heterocyclic nitrile, and the purity of the obtained primary amine was also good. Met.
As is clear from Comparative Examples 1 and 2, the reaction using no amino alcohol as a solvent resulted in many by-products and low product purity. Moreover, the comparative examples 3 and 4 which used the noble metal catalyst independently were the results of the purity and yield of a final product being low compared with Examples 1-15 which used the noble metal catalyst together. Further, Comparative Example 5 in which a hydrogenation reaction was performed from an aromatic nitrile by a known method, and an aromatic amine, which was an intermediate, was isolated and subjected to nuclear hydrogenation, had a lower yield than the Examples.

The alicyclic amine or saturated heterocyclic amine obtained by the present invention, which is an industrially advantageous method, is particularly useful as a pharmaceutical raw material or a pharmaceutical.

Claims (7)

  An alicyclic amine characterized in that an aromatic nitrile or an unsaturated heterocyclic nitrile is subjected to a hydrogenation reaction in the presence of amino alcohol using palladium and at least one selected from rhodium and ruthenium as a catalyst. Or the manufacturing method of a saturated heterocyclic amine.   The production method according to claim 1, wherein the amino alcohol is an amino alcohol having 1 to 30 carbon atoms.   Amino alcohol is 2- (dimethylamino) ethanol, 2- (diethylamino) ethanol, 2- (dibutylamino) ethanol, 2- (diethylamino) propanol, 3- (diethylamino) -1,2-propanediol, diethanolamine, N- The production method according to claim 1 or 2, which is ethyldiethanolamine, Nn-butyldiethanolamine, or triethanolamine. The aromatic nitrile is represented by the following general formula (1)
R ^1- (CN) _n (1)
[Wherein n represents an integer of 1 or 2. In the formula, R ¹ has at least one substituent selected from the group consisting of a hydroxyl group, a linear or branched alkyl group, and a linear or branched branched acetoxy group. Or an aromatic group having 6 to 30 carbon atoms. ]
The manufacturing method according to any one of claims 1 to 3.   The aromatic nitrile is 2-cyanotoluene, 3-cyanotoluene, 4-cyanotoluene, 1,2-dicyanobenzene, 1,3-dicyanobenzene, 1,4-dicyanobenzene, 1,4-dicyano-2,3. , 5,6-tetrafluorobenzene, 1,2-dicyano-3,4,5,6-tetrafluorobenzene, 4-trifluoromethyl-1-cyanobenzene, 4-cyano-phenylacetonitrile, N- (2- Cyano-ethyl) -N-methylaniline, 2-cyanophenol, 2-cyanonaphthalene, 2,3-dicyanonaphthalene, 6-cyano-2-naphthol, 4-cyano-4′-hydroxybiphenyl, 4-cyano-4 The production method according to claim 4, which is' -nitrobiphenyl, 2,3-dicyano-hydroquinone or 9-cyanophenanthrene. Unsaturated heterocyclic nitrile is represented by the general formula (2)

[Wherein j represents an integer of 1 or 2. X ¹ represents either —O— or —NH—. In the formula, Y ¹ and Z ¹ are the same or different and each represents a carbon atom or a nitrogen atom. ]
A heterocyclic nitrile represented by
General formula (3),

[Wherein, k represents an integer of 1 or 2. X ² , Y ² and Z ² are the same or different and each represents a carbon atom or a nitrogen atom. ]
The manufacturing method in any one of Claims 1-3 which is either the heterocyclic nitrile represented by these, or an unsaturated condensed bicyclic heterocyclic nitrile. The unsaturated heterocyclic nitrile is 2-cyanofuran, 2,5-dicyanofuran, 3-cyanoindole, 5-cyanoindole, 2-cyanoindole, 3-cyanoindole, 5-cyanoindole, 3-cyanoquinoline, It is 2,3-dicyanopyridine, cyanopyrazine, 2,3-dicyanopyrazine, 2-cyanopyrimidine, 3-hydroxy-2-cyanopyridine, 3-cyano-4-methylcoumarin or 4,5-dicyanoimidazole. 6. The production method according to 6.