JP2007031360A - Method for producing cyclic amine, and method for producing metal catalyst used therefor - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for producing a cyclic amine, by which the cyclic amine can simply be produced in a good yield without using an ammonium salt. <P>SOLUTION: This method for producing the cyclic amine, comprising aminating a cyclic ketone in which at least one of carbon atoms at the α-positions of the carbonyl group is tertiary or quaternary, with hydrogen and ammonia, is characterized by performing the amination in the presence of a metal catalyst comprising a platinum group metal obtained by impregnating activated carbon with a platinum group metal chloride in an atmosphere substantially free from an ammonium salt and then hydrogenating. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to a method for producing a cyclic amine, and more particularly, to a method for producing a cyclic amine in a simple and high yield. The present invention further relates to a metal catalyst used in this method and a method for producing the same.

  An aminosteroid, which is a kind of cyclic amine, is known to have pharmacological effects such as anticoagulant action and anticancer action. For example, 17β-amino steroids are useful as anticancer agents for hormone-dependent tumors, immunomodulators, antiarrhythmic agents, and the like. The following Non-Patent Document 1 discloses a method of synthesizing 17β-amino-1,3,5 (10) -estradien-3-ol by reducing the oxime form of estrone with sodium. The following non-patent document 2 also exists.

However, in this method, when estrone is used as a raw material, the reaction has to be carried out step by step in order to reduce the oxime after being produced, and labor is required. In order to solve this problem, the present inventor has proposed a method for producing a cyclic amine as described in Patent Document 1 below. This method for producing a cyclic amine is a simple method for producing a cyclic amine in a high yield. A functional group (carbonyl group) of a cyclic ketone such as a steroid ketone is used for hydrogen and ammonia using a metal catalyst. In the method of reductive amination with, by adding a metal catalyst containing a platinum group metal or a compound thereof and an ammonium salt, the hydroxylation of ketone, which is a side reaction, is suppressed, and the yield of the amino compound is improved. It is characterized by. Ruthenium, rhodium, palladium, ruthenium-carbon, rhodium-carbon, and palladium-carbon are disclosed as metal catalysts.
Christina Lemini, Elia Cruz-Ramos et al., "A comparative structural study of the steroid epimers: 17β-amino-1,3,5 (10) -estratrien-3-ol, 17α-amino-1,3,5 ( 10) -estratriene-3-ol, and some derivatives by 1HNMR, and X-ray diffraction analysis "Steroids, Elsevier Science Inc. (USA), 1998, vol.63, 556-564 Shinozawa, Hatae, Yada, Takagi, “Selective reductive amination of 5α-cholestan-3-one with a platinum group metal catalyst”, The 81st Annual Meeting of the Chemical Society of Japan 2002 Proceedings I P576 International publication of PCT / JP2004 / 013029

  However, in the method for producing a cyclic amine described in Patent Document 1, since the produced cyclic amine contains an ammonium salt as an impurity after completion of the reaction, the ammonium salt must be separated from the product. There is an inconvenience. Further, in the conventional method for producing a cyclic amine, the produced cyclic amine is an α-form, β-form isomer mixture. Since separation of this isomer is difficult, it has not been sufficient to selectively obtain a useful β-form in the conventional method for producing a cyclic amine.

  Then, this invention aims at providing the method which can manufacture cyclic amines, such as an aminosteroid, purely. Another object of the present invention is to provide a method for producing a cyclic amine, which can produce a cyclic amine with a simple method and in a high yield without using an ammonium salt. Still another object of the present invention is to provide a method capable of selectively producing a β-form of a cyclic amine. Still another object of the present invention is to provide a method for producing a metal catalyst used in the method for producing a cyclic amine.

  As a result of intensive studies to solve the above problems, the present inventors reduced the platinum group metal compound to produce the above-described metal catalyst, which was used to convert a cyclic ketone to an amino acid. As a result, it has been found that a cyclic amine can be produced without using an ammonium salt. As a result, the present invention has been achieved.

  Furthermore, the present inventor does not produce a cyclic amine from a cyclic ketone in one reaction step, but once performs a first reaction step for forming a cyclic imine, and then uses this cyclic imine as a platinum group as a second reaction step. It has been found that a β-form cyclic amine can be produced preferentially by reduction using a metal-containing catalyst, and as a result, the second invention has been achieved.

  In the first invention, a cyclic ketone in which at least one carbon at the α-position of the carbonyl group is tertiary or quaternary is aminated with hydrogen and ammonia, and a platinum group metal compound, particularly a halide is reduced. Using the obtained metal catalyst, a cyclic amine is produced from the cyclic ketone without using an ammonium salt disclosed in Patent Document 1 described above.

  A suitable example of the metal catalyst is a carrier in which a platinum group metal is supported, particularly a carbon-supported platinum group metal. A preferred example of the halogenated platinum group metal compound is chloride. A preferred form of the metal catalyst obtained by reducing the halogenated platinum group metal compound is to mix the halide with carbon, and preferably reduce this to hydrogen in an atmosphere free of halogen ions to obtain carbon. It is a supported platinum group metal. Alternatively, it is a platinum group element supported on carbon, in which a halide is mixed with carbon to make it basic to form a platinum group metal hydroxide, which is reduced with hydrogen. The preferred form for the production of this metal catalyst is to dissolve a platinum group metal chloride in a solvent, add carbon such as activated carbon to this, impregnate the carbon with the platinum group metal chloride for a predetermined time, and then impregnate The thing is to dry and then hydrogen reduce.

  A suitable carbon-supported platinum group metal is ruthenium-carbon or platinum-carbon. A metal catalyst composed of two or more platinum group metals may also be used. The content of the platinum group metal in the carbon-supported platinum group metal catalyst is preferably 3 to 5% by weight. In particular, 4% or its vicinity is preferable. By being in this range, the conversion rate when converting a cyclic ketone (converting to a cyclic amine and a cyclic alcohol) is increased, and particularly at 4% and in the vicinity thereof, the ratio of the cyclic amine to the cyclic alcohol is increased. , Especially getting bigger.

  It is preferable that the atmospheric temperature when impregnating activated carbon with a platinum group metal compound when making a carbon-supported catalyst is 80-85 ° C. The impregnation time is preferably not less than the minimum necessary time and within 60 minutes. Thereby, the activity (the conversion rate described above) of the carbon-supported platinum group metal catalyst can be increased. The drying time when producing the carbon-supported platinum group metal compound is appropriately selected. By appropriately determining the drying time, the activity of the catalyst is increased.

  Next, in the second invention, a cyclic ketone in which at least one carbon at the α-position of the carbonyl group is tertiary or quaternary is aminated with hydrogen and ammonia. A ketone is reacted with the ammonia and ammonium salt to form a cyclic imine, and then in the second step, the cyclic imine is reduced with hydrogen in the presence of a metal catalyst containing a platinum group metal or a compound thereof to form a cyclic amine. It is characterized by that. It does not prevent the metal catalyst from being added in the first step, not in the second step.

  In another form of the second invention, a cyclic ketone in which at least one carbon at the α-position of the carbonyl group is tertiary or quaternary is reacted with ammonia in the presence of the metal catalyst according to the first invention to produce a cyclic imine. And then the cyclic imine is configured to be reduced to a cyclic amine using hydrogen.

  As described above, according to the present invention, a cyclic amine such as an aminosteroid can be produced purely. Furthermore, a cyclic amine can be produced in a high yield by a simple method without using an ammonium salt. Furthermore, a β-form of a cyclic amine can be selectively produced. Furthermore, a metal catalyst suitable for the method for producing the cyclic amine can be provided.

  The platinum group metal is, among elements belonging to groups 8 to 10 of the periodic table, ruthenium (Ru), rhodium (Rh), palladium (Pd), osmium (Os), iridium (Ir), and platinum (Pt). 6 elements. Examples of the platinum group metal compound include halogen compounds such as hydrochloride, bromate and iodate of the platinum group metal, nitrates, sulfates and acetates.

  The metal catalyst is preferably a catalyst in which the platinum group metal or a compound thereof is supported on a carrier such as carbon, silica, alumina, silica-alumina, etc., in particular carbon. Thereby, the conversion rate of a starting material can be improved, and the yield of the amino compound finally obtained can be improved.

  The metal catalyst is preferably ruthenium, rhodium, palladium, ruthenium-carbon (Ru-C), rhodium-carbon (Rh-C), or palladium-carbon (Pd-C), and more preferably rhodium. , Palladium, rhodium-carbon, or palladium-carbon is preferable, and palladium or palladium-carbon is particularly preferable. When such a metal catalyst is used, the yield of the cyclic amine tends to be higher. Further, it is preferable to use a metal catalyst supported on carbon because the conversion rate of the starting material tends to be improved. Further, from the viewpoint of increasing the selectivity of β-form, that is, increasing the yield of β-form, ruthenium, rhodium, palladium, platinum and palladium-carbon are preferable, and palladium, platinum and palladium-carbon are more preferable. Platinum is particularly preferable.

  The production method of the present invention is suitably used for the production of an aminosteroid by amination of a steroid ketone, and in particular, a steroid ketone having a carbonyl group (ketone group) at the C-17 position, specifically, for example, amination of estrone. Is preferably used.

  The amount of the metal catalyst added is 5% by weight or more, preferably 5 to 20% by weight, more preferably 15 to 20% by weight, based on the cyclic ketone, with respect to the amount of platinum group metal or compound thereof added. It is desirable that the amount be determined.

  For example, when the metal catalyst is a catalyst in which 5% of a platinum group metal or a compound thereof is supported on a carrier such as carbon, the amount of the metal catalyst added is preferably 100% by weight or more with respect to the cyclic ketone. Is 100 to 400% by weight, more preferably 300 to 400% by weight.

  When the addition amount of the metal catalyst is below the lower limit, the reaction rate tends to be delayed. Moreover, since the effect by a catalyst does not change even if it exceeds the said upper limit, it is desirable to exist in the said range from a cost viewpoint. The addition amount of the ammonium salt is preferably 30% by weight or more based on the cyclic ketone.

The reaction temperature is, for example, 30 to 100 ° C, preferably 50 to 70 ° C, particularly preferably 60 to 70 ° C. The reaction is preferably carried out under a pressure of 2 to 8 MPa, particularly 4 to 6 MPa.

As the cyclic ketone used in the present invention, for example, a cyclic ketone in which at least one hydrogen at the α-position of the carbonyl group is substituted, that is, at least one adjacent carbon (carbon at the α-position) of the carbonyl group is tertiary or 4 Examples include cyclic ketones that are secondary carbons. More specifically, an alicyclic ketone (steroid ketone) having a steroid skeleton in which at least one hydrogen at the α-position of the carbonyl group is substituted can be mentioned. Here, the steroid skeleton refers to a perhydrocyclopentaphenanthrene skeleton. Further, the substituent for substituting the hydrogen at the α-position is not particularly limited, and examples thereof include an alkyl group (eg, methyl group). The A to D rings in the steroid skeleton may have an unsaturated bond. The production method of the present invention is particularly suitably used for steroid ketones in which the C-17 position is a carbonyl group (ketone group), specifically, for example, estrone represented by the following formula (I).

  In the metal catalyst supported on the carrier, the content of the metal or metal compound in the metal catalyst is preferably 0.1 to 10%, particularly 3 to 5% by weight. Specifically, 5% ruthenium-carbon (5% Ru—C), 5% rhodium-carbon (5% Rh—C), and 5% palladium-carbon (5% Pd—C) are preferable. More preferably, it is 4%, 4% Ru-C, or 4% Pt-C.

  Examples of the ammonium salt used in the present invention include ammonium fluoride, ammonium chloride, ammonium bromide, ammonium iodide, ammonium acetate, and ammonium sulfate. Among these, ammonium halide is preferable, and ammonium chloride is particularly preferable.

  Moreover, it is preferable that the addition amount of ammonium salt is 30 weight% or more with respect to cyclic ketone. When the addition amount of the ammonium salt is in the above range, the amination reaction tends to be efficiently promoted.

  In the present invention, ammonia is used in the amination reaction, and the amount of ammonia used is 1 mol or more, preferably 10 mol or more, more preferably 1 mol with respect to 1 mol of the raw material cyclic ketone (eg, steroid ketone). It is desirable that it is 50 mol or more.

  The reaction temperature during reductive amination is preferably 30 to 100 ° C, more preferably 50 to 70 ° C, and particularly preferably 60 to 70 ° C. When the reaction temperature is within the above range, side reactions do not occur and the yield of cyclic amine (steroid amine) tends to increase.

  Further, the hydrogen pressure is preferably 2 to 8 MPa, particularly 4 to 6 MPa. When the reaction pressure is within the above range, side reactions do not occur and the yield of cyclic amine (steroid amine) tends to increase.

  The reaction solvent used in the present invention is not particularly limited, but a solvent that dissolves ammonia, a cyclic ketone, and an ammonium salt well is preferable. For example, a polar solvent such as methanol, ethanol, or isopropyl alcohol is preferably used. It is done. The amount of the solvent is not particularly limited, but is usually 1 to 1000 times, preferably 10 to 500 times the amount of the cyclic ketone.

  The order of addition of the ammonium salt is not particularly limited, and the ammonium salt may be added almost simultaneously with the metal catalyst to the reaction system containing the cyclic ketone. Further, the ammonium salt may be added in advance before adding the metal catalyst, and then the metal catalyst may be added.

  Next, the expected mechanism of the present invention will be described. In addition, this invention is not limited to this description. In the amination reaction of a ketone using a metal catalyst, hydrogen and ammonia, it is generally considered that the reaction proceeds according to the following scheme.

  As shown in the above Scheme, in the reductive amination reaction using hydrogen, a metal catalyst, and ammonia, a competitive reaction occurs between the alcoholation and the imination of the ketone. According to the manufacturing method described in Patent Document 1 described above, the addition of an ammonium salt facilitates the formation of an imine as a reaction intermediate and promotes the formation of an imine. In addition, since the subsequent amination reaction of imine proceeds rapidly, generation of alcohol (IV) as a by-product is suppressed, and generation of amine (III) as a main product is thereby promoted. Conceivable.

  However, this requires removing the ammonium salt from the reaction product. By using the metal catalyst according to the first invention described above, an amine as a target substance can be obtained from a ketone as a starting material without using an ammonium salt.

  In the second invention, ammonia and an ammonium salt are reacted with a ketone under non-reduction, for example, in a nitrogen gas atmosphere to form imine once (first reaction step). Next, when a metal catalyst is added to the imine and the imine is reduced with hydrogen gas (second reaction step), the β-form amine has an advantage over the alpha-form amine, or the β-pair amine has an advantage over the alpha-form amine. Are selectively generated. Although the metal catalyst can be added to the reaction system of the first reaction, an α-form amine is easily generated. The metal catalyst according to the first invention can be added to the first reaction system, and in this case, the first reaction can proceed without using an ammonium salt.

Example 1
The production of the metal catalyst according to the first invention will be described.
(1) Catalyst example 1
Ru 4 [5% Ru / C]
Ruthenium chloride (RuCl ₃ ) 102 mg (Ru content = 50 mg) is dissolved in 140 ml of distilled water. After dissolution, add 950 mg of activated carbon (Norit "SX Plus"), impregnate the activated carbon with ruthenium chloride for 2 hours at room temperature and stir. Next, this aqueous solution is evaporated to dryness with a rotary evaporator, and then dried overnight in a drier at 110 ° C. Finally, about 1 g of the dried powder is hydrogen-reduced for 2 hours in 50 ml of distilled water using a Squita Pearl medium pressure reduction device.

(2) Catalyst example 2
Ru 5 [5% Ru / C]
Ruthenium chloride (RuCl ₃ ) 102 mg (Ru content = 50 mg) is dissolved in 140 ml of distilled water. After dissolution, add 950 mg of activated carbon, stir the activated carbon impregnated with ruthenium chloride at room temperature for 2 hours. Next, the aqueous solution is heated on a hot water bath at 80-85 ° C. While maintaining the temperature at 80-85 ° C. and stirring with a magnetic stirrer, 10% aqueous sodium hydroxide solution is added dropwise to pH 7.5-8.0, and ruthenium hydroxide is deposited on the activated carbon. The suspension is evaporated to dryness on a rotary evaporator and then dried overnight in a 110 ° C. dryer. Finally, about 1 g of the dried powder is reduced with hydrogen in 50 ml of distilled water for 2 hours using a squita pearl medium pressure reduction device.

(3) Catalyst example 3
Ru 6 [5% Ru / C]
Ruthenium chloride (RuCl ₃ ) 102 mg (Ru content = 50 mg) is dissolved in 140 ml of distilled water, and stirred with a magnetic stirrer, 10% aqueous sodium hydroxide solution is added dropwise to adjust the pH to 7.5-8.0. A ruthenium oxide precipitate is obtained. Leave at room temperature all day long. Next, add 950 mg of activated carbon and stir at room temperature for 2 hours. The suspension is evaporated to dryness on a rotary evaporator and then dried overnight in a drier at 110 ° C. Finally, about 1 g of the dried powder is reduced with hydrogen in 50 ml of distilled water for 2 hours using a squita pearl medium pressure reduction device.

(4) Catalyst example 4
Ru 7 [5% Ru / C]
Ruthenium chloride (RuCl ₃ ) 102 mg (Ru content = 50 mg) is dissolved in 0.1N hydrochloric acid 34 ml. This aqueous solution is added to 950 mg of activated carbon previously impregnated with 95 ml of 0.1N hydrochloric acid and left at room temperature for one day. Next, it is filtered and washed with distilled water, washed until the washing solution has a pH of about 5.0, and vacuum-dried. Finally, about 1 g of the dried powder is reduced with hydrogen in 50 ml of distilled water for 2 hours using a squita pearl medium pressure reduction device.

(5) Catalyst example 5
Pt 4 [4% Pt / C]
After suspending 102 mg of platinum chloride (PtCl ₂ ) (Pt content = 40 mg) in 140 ml of distilled water, 960 mg of activated carbon is added, impregnated at room temperature for 2 hours, and stirred. The suspension is then evaporated to dryness on a rotary evaporator and then dried overnight in a 110 ° C. drier. Finally, about 1 g of the dried powder is reduced with hydrogen in 50 ml of distilled water for 2 hours using a squita pearl medium pressure reduction device.

Example 2
Reductive amination was produced using the metal catalyst produced according to Example 1. The contents of this production are as follows.

20 ml of ethanol in which about 1.0 g (6.0 × 10 ⁻² mol) of ammonia was dissolved, 0.054 g (2.0 × 10 ⁻⁴ mol) of Estrone (I) (manufactured by Wako Pure Chemical Industries, Ltd.), 10 mg (9.9 × 10 ⁻⁵ mol) of the metal catalyst of Example 1-5 was charged into an electromagnetic rotary autoclave (manufactured by Nitto Koatsu Co., Ltd., Start200 Quick), and the hydrogen gas pressure was 6.0 MPa and the reaction temperature was 70 ° C. Time reaction was performed. The obtained crude product was measured by gas chromatography (hereinafter also referred to as GC).

This crude product was purified by silica gel column chromatography (hexane: chloroform: methanol = 5: 4: 1) to determine the yield of the target substance and the like. The confirmation of compound (III) was performed by ¹ H-NMR 270 MHz (C ₆ D ₆ -DMSO, standard substance TMS) and melting point. In the following reaction, the melting point of the target compound (III) was 228 to 230 ° C. The α-form and β-form of the compound obtained as a result of the reaction were confirmed separately.

Result About catalyst example 1-5, the result which manufactured the cyclic amine was put together in the display 1. FIG. In the table, the result of the reaction is defined as follows.
1: Cyclic amine III as a target substance (However, β-NH ₂ )
2: Cyclic amine III (α-NH ₂ ) as the target substance
3: Cyclic alcohol IV as a by-product (β-OH)
4: Cyclic alcohol IV as a by-product (α-OH)
5: Imine (II): Imine
6: Others: Other than the above The numerical values in the table are the weight percent of each compound. The pass-through rate is the sum of (1 + 2 + 3 + 4). The selectivity is a value corresponding to (1 + 2/3 + 4). The conversion rate indicates the ratio of the starting compound (I) converted to amine and alcohol, and the selectivity indicates the ratio of amine to the conversion product.
“Additive: NH ₄ Cl” in the table indicates that NH ₄ Cl was added.

In general, the rate of formation of imine compounds formed by dehydration condensation reaction of carbonyl compounds and amino compounds is related to the hydrogen ion concentration, and it is said that it proceeds easily at a hydrogen ion concentration (pH) of 3-4 depending on the reaction substrate. Yes. In the method described in Patent Document 1, the addition of NH ₄ Cl promotes the dehydration condensation reaction of ketone and ammonia, and facilitates the formation of an intermediate imine. The present inventor has made clear. Furthermore, the present inventor examined ammonium acetate and the like in addition to NH ₄ Cl. However, since the effect was smaller than that of NH ₄ Cl, we thought that a small amount of chloride (halide) might be involved in the selectivity in producing cyclic amines.
Therefore, a small amount of chloride remained, Catalyst Example 1 (Ru4), Catalyst Example 4 (Ru7) in which the amount of residual chloride increased further than Ru4, and chloride completely to compare with Ru4 and Ru7. Catalyst examples 2 and 3 (Ru5, Ru6) prepared for the purpose of removal were prepared, respectively.
All of these Ru / Cs were thoroughly washed until the filtrate became neutral at the end, dried in a desiccator and used for the reductive amination reaction of estrone, and their reactivity was compared. Then, even Ru / C composed of the same components had completely different Ru / C catalytic activity and product selectivity depending on the preparation conditions. When the relationship between the residual chloride amounts of Ru / C was arranged, a curve as shown in FIG. 1 was obtained. In preparation methods that remove residual chloride as much as possible, such as Ru5 and Ru6, the amine / alcohol selectivity is low.However, if the amount of residual chloride is too large, such as Ru7, intermediate imine formation occurs. It is good until promoted, but hydrogenation is hindered.
Therefore, the quantitative balance of chloride remaining on the catalyst surface is an important factor in improving amine selectivity. The amine selectivity improved by Ru4 is thought to be related to the formation of a small amount of ammonium chloride on the catalyst surface by the remaining chloride and ammonia in the reaction system (see FIG. 2). Thus, in the reductive amination reaction of estrone on the catalyst prepared uniquely, in the case of a reaction system in which NH ₄ Cl is added to commercially available 5% Ru / C (Run 1 in Table 1) (Run 2 in Table 1) ), The selectivity to primary amine production was improved (Run 3 in Table 1).
Comparing the total production of amine and alcohol on each prepared catalyst, the catalyst activity was the highest in 97% of the catalyst prepared from hydroxide (Ru5, 6), and then from chloride 52% of the prepared catalyst (Ru4), followed by 2% of the catalyst (Ru7) prepared in aqueous hydrochloric acid. From this, it is considered that the activity of the catalyst is related to the concentration of chloride (chlorine ions) in the impregnation solution. That is, when impregnated in a basic solution, it is considered that the metal adsorption force is strong and the metal particles are well dispersed in the activated carbon.

Example 3 Durability Test Next, it was examined in Catalyst Example 1 (Ru4) whether the selectivity once maintained even if the catalyst once used in the reaction was repeatedly used in the reaction. In the case of a heterogeneous catalyst, the life of the catalyst is also important, and it is difficult to say that the catalyst preparation has been successful from an industrial point of view if the selectivity decreases drastically after being used once. Thus, the catalyst used in the reaction was repeatedly used to investigate whether the activity and selectivity of the catalyst were maintained on the catalyst prepared with Ru4. As a result, the catalyst activity tended to decrease little by little, but the selectivity did not change significantly (Table 2). Therefore, it is unlikely that the selectivity-dominating component is dissolved in the system, and it is considered that the selectivity is controlled on the catalyst surface.

Example 4: Change in impregnation process
The temperature at the time of impregnating activated carbon with metal chloride was examined in the method of preparing Ru4. When the impregnation temperature was increased from room temperature to 80-85 ° C, the catalyst activity could be increased without changing the selectivity (Run 2, 3 in Table 3). This seems to be due to the good dispersion of ruthenium chloride and the high dispersion of ruthenium chloride evenly to the depth of the hole in the activated carbon.

  Next, when the impregnation time was changed, the catalyst activity decreased as the time increased, and hydrogenation became difficult to occur. When impregnated for 60 minutes, 72% of primary amine and alcohol were obtained, but when impregnated for 240 minutes, only 13% were obtained. However, the selectivity of amine / alcohol formation was 3.0-3.8, and no significant change was observed with the impregnation time (Table 3).

  The relationship between the impregnation time, catalyst activity, and selectivity is considered to be related to an increase in the moisture content in the carbon-supported catalyst. The water content in the catalyst is considered to suppress the hydrogenation of imine to amine, promote the reverse reaction from imine to raw material ketone, and cause the catalyst activity to decrease. From these results, it is considered that water adsorption on activated carbon occurs more easily than catalyst adsorption. Furthermore, drying of the prepared catalyst is a major factor in reactivity and selectivity.

Example 5: Changes in the drying process
Based on the conditions of Run 2 in Table 3 in the preparation method of Ru4, the conditions for the drying process during catalyst preparation were examined. After impregnation, if the drying time is extended from 1 day to 3 days in a dryer at 110 ° C, the conversion rate increases from 53% to 88% and the activity of the catalyst increases. At the same time, the primary amine / alcohol selectivity is increased. Improved significantly (about 3 times that of Run1 in Table 4). This is considered to be related to the removal of moisture mixed in the catalyst. When the amount of impregnating liquid in the pores is reduced by evaporation, the liquid inside moves toward the evaporation interface by capillary action. Evaporation takes place preferentially from the large pores in the outer layer of the activated carbon, where the concentration of the active ingredient increases and becomes supersaturated, and eventually the active ingredient precipitates. At that time, it is considered that the active ingredient diffused and redispersed on the surface of the carrier during the drying process (FIG. 3).
However, when the drying time was further extended to 5 days and 9 days, the activity of the catalyst tended to decrease slightly, and the selectivity of amine / alcohol production was the same as that of Run 1 in Table 4. Probably, it is considered that chloride ions present in a trace amount in the catalyst were desorbed from the catalyst as hydrochloric acid, and the chloride in the catalyst was limited by this operation. In general, when the catalytically active component compound is not adsorbed on the support at all or is weakly adsorbed during the impregnation process, the distribution of the active component on the support changes greatly during drying. In the case of the Ru4 catalyst, the amine / alcohol production selectivity was not significantly changed during the impregnation process, but changed greatly during the drying process. This suggests that Ru4 catalyst has weak adsorption of Ru metal on activated carbon.

Example 6: Relationship with metal content relative to support
In the Ru4 preparation method, the amount of metal ruthenium with respect to the support (activated carbon) was examined based on the preparation conditions of Run2 in Table 4. As the amount of metal on the activated carbon support increased to 5% and 10%, the catalytic activity and selectivity decreased (Table 6). The decrease in the catalytic activity is thought to be due to the reduction of the metal surface area due to the agglomeration of the metal. The decrease in selectivity may be due to a slight change in the amount of chloride contained in ruthenium chloride due to the metal percentage.
From the above, the factors governing the selectivity are the relationship between the amount of moisture remaining in the catalyst and the amount of chloride ions, and their quantitative balance. In Ru / C, the most effective for producing primary amines was 88% in Run 3 of Table 5 prepared by the Ru4 preparation method. This catalyst produced a primary amine overwhelmingly than commercially available Ru / C consisting of the same components, and a result comparable to that of commercially available Pd / C was obtained without adding ammonium chloride.

Example 7: Preparation of Pt / C As described in U.S. Patent No. 6,057,055 on a 5% Ru / C, 5% Rh / C, 5% Pd / C catalyst, NH ₄ Cl was added to the primary amine. Although the selectivity was improved, the addition effect of NH ₄ Cl was not observed on the 5% Pt / C catalyst. Therefore, 4% Pt / C (Pt4) was newly prepared according to the preparation conditions of 4% Ru / C used in Run 3 in Table 5 with the highest selectivity to primary amines. Even when ammonium chloride is added, the selectivity to the primary amine has not changed at all, even on the commercially available 5% Pt / C catalyst, the selectivity to the primary amine is about 20 times, The improvement was found (Table 6).

  Next, an embodiment according to the second invention of the present application will be described.

Example 8
20 ml of ethanol in which about 1.0 g (6.0 × 10 ⁻² mol) of ammonia was dissolved, 0.054 g (2.0 × 10 ⁻⁴ mol) of Estrone (I) (manufactured by Wako Pure Chemical Industries, Ltd.) and Ammonium chloride (NH ₄ Cl) 0.20 g (3.7 × 10 ⁻³ mol) was charged into an electromagnetic rotary autoclave (Nitto Koatsu Co., Ltd., Start200 Quick) in a nitrogen gas atmosphere (7 Mpa), and the reaction temperature was 70 ° C. The reaction was carried out for 5 hours. After cooling, the nitrogen gas is removed from the autoclave, the autoclave cover is opened, 9.9 × 10 ⁻⁵ mol of a platinum simple substance (black) catalyst is added, and hydrogen (7 MPa) is supplied to the autoclave. The obtained crude product was measured by gas chromatography (hereinafter also referred to as GC). The crude product was purified by silica gel column chromatography (hexane: chloroform: methanol = 5: 4: 1) Check the cyclic amine III is a target substance was purified by ^{is, 1 H-NMR 270MHz (C} 6 D 6 -DMSO , Standard substance TMS). Further, the same reaction was carried out for the Pd catalyst and the Pt—C catalyst.
Table 7 shows the measurement results. In Table 7, step 1 is a first reaction step performed in a nitrogen gas atmosphere, and step 2 is a second reaction step performed in a hydrogen gas atmosphere.

As shown in Table 7, it was confirmed that in all cases, not only a high conversion rate was obtained, but also the production of β amine was highly selective. When the entire process is performed in one step, the conversion rate is 70% when the catalyst is platinum alone, but 36% of the β-NH ₂ body is produced, whereas 34% of the β-OH body is produced. % Produced. When the catalyst was palladium, a β-NH ₂ isomer was selectively formed, but the conversion was as low as 23%.

Example 9
The same operation as in Example 8 was carried out except that the catalyst was placed in step 1. The results are shown in Table 8.

  In the stage of generating the first stage imine, when Pt catalyst or 5% Pt-C catalyst is first added and reacted, and then nitrogen gas is changed to hydrogen gas and reacted, with 5% Pt-C catalyst, Depending on the gas chromatography detection conditions, α-amine formation was not observed, but when the gas chromatography conditions were changed, approximately 10% α-amine formation was observed. In addition, with the Pt simple substance (black) catalyst, the reaction is complicated, the types of products are large, and the reaction is complicated. After all, when imine is generated first, and then Pt catalyst is added and hydrogenated, β-amine can be obtained with high selectivity and high yield.

The characteristic figure of the amount of chloride which remains on the catalyst surface, and selectivity. Surface model of ruthenium catalyst. Model diagram of activated carbon pore structure.

Claims (19)

In the method for producing a cyclic amine, wherein a cyclic ketone in which at least one carbon at the α-position of the carbonyl group is tertiary or quaternary is aminated with hydrogen and ammonia,
Under an atmosphere where the ammonium salt is substantially absent,
Using a metal catalyst composed of a platinum group metal obtained by reducing a platinum group metal compound,
A method for producing a cyclic amine, wherein the amination is performed.   The method of claim 1, wherein the platinum group metal compound is a halide.   The method according to claim 1, wherein the metal catalyst is a platinum group metal supported on a support.   The metal catalyst is obtained by a first step of supporting a platinum group metal halide on a carrier and a second step of hydrogen reducing the platinum group metal halide supported on the carrier. The method described.   The process according to claim 1, wherein the production of the metal catalyst is carried out in an atmosphere substantially free of halogen ions.   The method of claim 1, wherein the reduction is performed with hydrogen.   The method of claim 3, wherein the carrier is carbon.   The method according to claim 7, wherein the metal catalyst is ruthenium on carbon or platinum on carbon.   The method according to claim 1, wherein a basic salt of the platinum group metal is generated from the metal compound of the platinum group metal, and the basic catalyst is reduced to generate the metal catalyst.   The platinum group metal compound is dissolved in a solvent, carbon is added thereto, the carbon is impregnated with the platinum group metal compound portion for a predetermined time, and then dried at a predetermined temperature for a predetermined time and reduced by hydrogen. 8. A process according to claim 7, wherein a metal catalyst is produced.   4. Process according to claim 3, wherein the content of platinum group metal in the metal catalyst is 3-5% by weight, in particular about 4% by weight.   The method according to claim 10, wherein an atmospheric temperature when impregnating carbon with the platinum group metal compound is 80 to 85 ° C.   The method according to claim 10 or 12, wherein impregnating carbon with the platinum group metal compound is performed within 60 minutes.   A method for producing a carbon-supported platinum group metal catalyst, wherein a platinum group metal halide is supported on carbon and then reduced in an atmosphere substantially free of halogen ions.   A method for producing a carbon-supported platinum group metal catalyst, wherein a platinum group metal chloride is supported on carbon in an atmosphere substantially free of chlorine ions, and then reduced with hydrogen.   A method for producing a carbon-supported platinum group metal catalyst, wherein a platinum group metal halide is supported on carbon, and then the platinum group metal hydroxide is generated in a basic atmosphere and then reduced. .   A method for producing a cyclic amine in which at least one carbon in the α-position of a carbonyl group is a tertiary or quaternary amination with hydrogen and ammonia, wherein the cyclic ketone is subjected to ammonia and ammonia under a non-reducing atmosphere. A first step of reacting with an ammonium salt to form a cyclic imine, and then a second step of reducing the cyclic imine to the cyclic amine with hydrogen in the presence of a metal catalyst containing a platinum group metal or a compound thereof. A method for producing a cyclic amine.   The method according to claim 17, wherein the metal catalyst is used not in the second step but in the first step. A method for producing a cyclic amine, wherein a cyclic ketone in which at least one carbon at the α-position of a carbonyl group is tertiary or quaternary is aminated with hydrogen and ammonia,
The cyclic ketone is reacted with the ammonia and the metal catalyst according to any one of claims 1 to 14 in a non-reducing atmosphere to form a cyclic imine, and then the cyclic imine is reduced with the hydrogen. A method for producing a cyclic amine.