JP6665600B2 - Method for producing bicyclic amine compound - Google Patents

Description

  The present invention relates to a method for producing a bicyclic amine compound.

  Bicyclic amine compounds are known as compounds useful as, for example, pharmaceutical and agricultural chemical intermediates, catalysts for organic synthesis, chemical adsorbents, antibacterial agents, and the like (for example, see Patent Document 1).

  As a method for producing a bicyclic amine compound, the present applicant has the following formula

[Wherein, R _{1 to} R ₈ each independently represent a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a hydroxyl group, a hydroxymethyl group, or an alkoxy group having 1 to 4 carbon atoms. X represents a carbon atom or a nitrogen atom; Y represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a hydroxyl group, or a hydroxyalkyl group having 1 to 4 carbon atoms. ]
In the presence of a solid catalyst, a compound represented by

[Wherein, R _{1 to} R ₈ , X, and Y have the same definitions as above. ]
In the method for producing a compound represented by the following, as the solid catalyst,
_{A a} M _b P _c O _d
Wherein A represents one or more elements selected from the group consisting of Si, Al, Mg, Ti and Zr, M represents an alkali metal element, P represents phosphorus, and O represents oxygen. Represent. Subscripts a to d represent the number of moles of each element, b / a = 0.001 to 0.3 (molar ratio), c / a = 0.001 to 0.3 (molar ratio), and d is It represents an arbitrarily possible value depending on the bonding state of each atom. However, when A represents two or more elements, the subscript a indicates the number of moles of the element having the largest number of moles. ]
A patent application has already been filed for a method for producing a bicyclic amine compound by intramolecular cyclization in the gas phase in the presence of an inorganic oxide represented by the following formula (see Patent Document 2).

  Patent Document 2 discloses a production method based on a gas phase reaction, and describes that the use of a specific solid catalyst can reduce tar components. However, by-products including tar are produced in an amount of 20% or more in terms of yield, and the improvement is still insufficient for industrial use, such as blockage of pipes and increased waste.

JP 2010-037325 A JP 2012-149048 A

  An object of the present invention is to provide a method for stably producing a bicyclic amine compound by suppressing the generation of by-products during the production of a bicyclic amine.

  The present inventors have conducted intensive studies to solve the above-mentioned problems, and as a result, by adding an alkaline earth metal element and / or hydroxyapatite to a catalyst comprising an inorganic carrier and an alkali metal phosphate, the above-mentioned problems were solved. Have been solved, and the present invention has been completed. That is, the present invention is a method for producing a bicyclic amine compound as described below.

  [1] The following formula (1)

[Wherein, R _{1 to} R ₈ each independently represent a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a hydroxyl group, a hydroxymethyl group, or an alkoxy group having 1 to 4 carbon atoms. X represents a carbon atom or a nitrogen atom; Y represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a hydroxyl group, or a hydroxyalkyl group having 1 to 4 carbon atoms. ]
From the compound represented by the following formula (2)

[Wherein, R _{1 to} R ₈ , X, and Y have the same definitions as above. ]
In the method for producing a compound represented by the formula (I), a catalyst containing an inorganic carrier and an alkali metal phosphate, and further containing at least 1.5% by weight and less than 15% by weight of an alkaline earth metal hydroxide and / or hydroxyapatite based on the inorganic carrier. A method for producing a bicyclic amine compound, which is used.

  [2] The method for producing a bicyclic amine compound according to the above [1], wherein in the formulas (1) and (2), Y is a hydrogen atom or a hydroxymethyl group.

  [3] The method for producing a bicyclic amine compound according to the above [1] or [2], wherein in the formulas (1) and (2), X is a nitrogen atom.

[4] In Formula (1) and Formula (2), R _{1 to} R ₈ each independently represent a hydrogen atom, a methyl group, an ethyl group, an isopropyl group, or a hydroxymethyl group (provided that R _{1 to} R ₈ are not the same substituents.) The process for producing a bicyclic amine compound according to any one of the above [1] to [3].

  [5] The alkaline earth metal hydroxide is at least one selected from the group consisting of magnesium hydroxide, calcium hydroxide, strontium hydroxide, and barium hydroxide, [1] to [4]. ] The method for producing a bicyclic amine compound according to any one of [1] to [10].

  Hereinafter, the present invention will be described in detail.

  The present invention provides intramolecular dehydration of a hydroxyl group-containing cyclic amine compound represented by the above formula (1) in a gas phase in the presence of a solid catalyst to give a bicyclic amine compound represented by the above formula (2). The feature is to obtain.

  In the present invention, in the above formula (1), X represents a carbon atom or a nitrogen atom, and Y represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a hydroxyl group, or a hydroxyalkyl group having 1 to 4 carbon atoms.

In the present invention, the substituents R _{1 to} R ₈ in the above formula (1) are each independently a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a hydroxyl group, a hydroxymethyl group, or an alkoxy group having 1 to 4 carbon atoms. Represents a group.

  In the present invention, specific examples of the compound represented by the above formula (1) wherein X is a carbon atom include the following compounds (exemplified compound numbers 1 to 6). The invention is not limited to these.

  Further, among the bicyclic amine compounds represented by the above formula (2), specific examples of the compound in which X is a carbon atom include, for example, the following compounds (exemplified compound numbers 7 to 10). However, the present invention is not limited to these.

  Next, the intramolecular dehydration reaction of the hydroxyl group-containing cyclic amine compound of the present invention using a solid catalyst will be described.

  Although the solid catalyst in the present invention is not particularly limited, an inorganic carrier and an alkali metal phosphate, and further, an alkaline earth metal hydroxide and / or hydroxyapatite are added in an amount of 1.5% by weight to 15% by weight based on the inorganic carrier. % Catalyst.

  As the inorganic carrier, for example, inorganic oxides such as silicon dioxide, aluminum oxide, aluminosilicate, zeolite, magnesium oxide, titanium oxide, and zirconium oxide are used.

  Examples of the catalyst component include an alkali metal phosphate, and preferably further include an alkaline earth metal phosphate.

  The alkali metal phosphate is obtained by mixing an oxide, a hydroxide, a halide, a carbonate, a nitrate, a sulfate, or the like of an alkali metal with phosphoric acid, condensed phosphoric acid, phosphonic acid, phosphinic acid, phosphine oxide, or the like. Is obtained.

  Examples of the alkali metal element include lithium, sodium, potassium, rubidium, and cesium.

  Further, alkaline earth metal phosphate may be used, and examples of the alkaline earth metal include magnesium, calcium, strontium, and barium.

  The phosphorus / alkali metal ratio of the alkali metal phosphate is in the range of 0.1 to 1.5, preferably 0.2 to 1.0 in molar ratio.

  The amount of the alkali metal phosphate carried on the inorganic carrier is in the range of 0.1 to 1.0, preferably 0.2 to 0.7, by weight of the alkali metal phosphate / inorganic carrier.

  Furthermore, in the present invention, in order to reduce reaction by-products such as tar, it is essential that the solid catalyst contains an alkaline earth metal hydroxide and / or hydroxyapatite. Examples of the alkaline earth metal hydroxide include calcium hydroxide, magnesium hydroxide, strontium hydroxide, and barium hydroxide, and similar effects can be obtained with similar hydroxyapatite. Regarding the powder physical properties of the alkaline earth metal hydroxide, it is preferable to use one having a high specific surface area in order to obtain a high effect with a small amount.

  In the present invention, the method for preparing the solid catalyst is not particularly limited, and a generally used preparation method can be used. Specifically, a method of dissolving or dispersing the raw material of the solid catalyst in water or an organic solvent, stirring, heating, concentrating, drying, and other steps, molding, and further calcining to obtain a solid catalyst is exemplified. Is done.

  The firing temperature of the solid catalyst is not particularly limited, but is usually in the range of 300 to 1100 ° C, preferably in the range of 400 to 700 ° C. When the content is in this range, physical properties such as the acid-base strength and specific surface area of the solid catalyst can be adjusted, and optimal catalyst characteristics can be obtained.

  The firing of the solid catalyst is not particularly limited, but may be performed in an air or nitrogen atmosphere.

  It is essential that the solid catalyst used in the present invention is a mixture of the inorganic carrier obtained as described above, an alkali metal phosphate, an alkaline earth metal hydroxide and / or hydroxyapatite. The method and order of these additions are not particularly limited, and a method of adding an alkaline earth metal hydroxide as a catalyst component and supporting the same on a carrier, or preliminarily supporting an alkaline earth metal hydroxide on a carrier and then adding other catalyst components Or a method in which a catalyst component is supported on a carrier and then an alkaline earth metal hydroxide is supported. The content of the alkaline earth metal hydroxide and / or hydroxyapatite must be not less than 1.5% by weight and less than 15% by weight with respect to the inorganic carrier. If the effect is not sufficient, the content of the inorganic carrier and the alkali metal phosphate decreases, and the catalytic activity decreases, so that the desired performance cannot be obtained. In addition, in the course of each addition method, baking may be performed for the purpose of improving adhesion.

  In the intramolecular dehydration reaction method of the present invention, a gas phase reaction in a fixed bed flow system is preferably used, and the reaction product of the present invention is obtained mainly from a bicyclic amine and piperazine.

  The by-product in the present invention indicates a high-boiling condensate such as tar or a low-boiling decomposed product, and indicates a component excluding a bicyclic amine and piperazine.

  The production method of the present invention reduces the reaction by-products such as tar by including an alkaline earth metal hydroxide and / or hydroxyapatite in a solid catalyst, and enables industrially continuous production of a bicyclic amine compound. It can be manufactured stably.

  The present invention will be described in more detail based on the following examples, but the present invention is not limited thereto.

Example 1
(Catalyst preparation)
After dissolving 3.15 g of 85% phosphoric acid in 100 ml of pure water, 0.5 g of calcium hydroxide (special grade reagent) was added and dispersed in an aqueous solution to which 6.4 g of cesium carbonate was added. Next, 20.0 g of commercially available aluminum oxide (manufactured by Sumitomo Chemical) as an inorganic carrier was added, and the mixture was evaporated to dryness using an evaporator, and the inorganic carrier, an alkali metal phosphate (P / Cs molar ratio = 0.7) and water were added. A solid catalyst consisting of a mixture of calcium oxide was obtained.
(Gas phase reaction)
As a reaction raw material, Exemplified Compound 6 [N- (2,3-dihydroxypropyl) piperazine] was dissolved in water to prepare a 11.25% by weight aqueous solution. A quartz reaction tube having a diameter of 15 mm was filled with 20 ml of the solid catalyst, and a Raschig ring made of ceramics (3 mm in diameter × 3 mm in length × 1 mm in thickness) so as to have a length of 23 cm above and below the solid catalyst. While maintaining the temperature of the catalyst layer at 400 ° C., the raw material containing Exemplified Compound 6 prepared above was dropped from the upper part at a rate of 0.3 g / min for 24 hours. The obtained reaction mixture gas was cooled by a condenser, and the reaction solution was quantitatively analyzed by gas chromatography. The total yield and byproduct yield of the bicyclic amine (hydroxymethyltriethylenediamine) and piperazine shown in Exemplified Compound 10 were determined by the following formulas, and are shown in Table 1.

By-product yield [%] = 100- (molar yield of bicyclic amine + piperazine [%])
Examples 2 to 4
(Catalyst preparation)
A solid consisting of a mixture of an inorganic carrier, an alkali metal phosphate and an alkaline earth metal hydroxide was obtained in the same manner as in Example 1 except that the type and amount of the alkaline earth metal hydroxide were changed. A catalyst was obtained.
(Gas phase reaction)
Except that the exemplified compounds used as the raw materials were changed, the total yield of bicyclic amine and piperazine and the yield of by-products were determined using the gas phase reaction method of Example 1 and are shown in Table 1.

Example 5
(Preparation of hydroxyapatite)
An aqueous solution obtained by dissolving 22.5 g of diammonium hydrogen phosphate (special grade reagent) in 170 g of pure water was added to a slurry in which 48.5 g of barium hydroxide (special grade reagent) was dispersed in 280 g of pure water while stirring. It was dropped over time. After dropping, the mixture was aged overnight with stirring, and then filtered and washed to synthesize barium-type hydroxyapatite (Ba-Hap).
(Catalyst preparation)
After dissolving 3.15 g of 85% phosphoric acid in 100 ml of pure water, 20.0 g of commercially available aluminum oxide (manufactured by Sumitomo Chemical) as an inorganic carrier was added to an aqueous solution to which 6.4 g of cesium carbonate was added, and then using an evaporator. After evaporation to dryness, a solid catalyst comprising an inorganic carrier and an alkali metal phosphate (P / Cs molar ratio = 0.7) was obtained.

Next, 2 g of Ba-Hap was dispersed in 100 ml of methanol, and the solid catalyst was added. The solid catalyst was evaporated to dryness using an evaporator to obtain a solid catalyst comprising a mixture of an inorganic carrier, an alkali metal phosphate and hydroxyapatite. Was.
(Gas phase reaction)
The total yield of bicyclic amine and piperazine and the yield of by-products were determined using the gas phase reaction method of Example 1 and are shown in Table 1.

Comparative Example 1
(Catalyst preparation)
After dissolving 3.15 g of 85% phosphoric acid in 100 ml of pure water, 20.0 g of commercially available aluminum oxide (manufactured by Sumitomo Chemical) as an inorganic carrier was added to an aqueous solution to which 6.4 g of cesium carbonate was added, and then using an evaporator. After evaporation to dryness, a solid catalyst comprising an inorganic carrier and an alkali metal phosphate (P / Cs molar ratio = 0.7) was obtained.
(Gas phase reaction)
The total yield of bicyclic amine and piperazine and the yield of by-products were determined using the gas phase reaction method of Example 1 and are shown in Table 1.

Comparative Example 2
(Catalyst preparation)
A solid catalyst comprising a mixture of an inorganic carrier, an alkali metal phosphate and an alkaline earth metal hydroxide was prepared in the same manner as in Example 1, except that the amount of the alkaline earth metal hydroxide was changed. Obtained.
(Gas phase reaction)
The total yield of bicyclic amine and piperazine and the yield of by-products were determined using the gas phase reaction method of Example 1 and are shown in Table 1.

Comparative Examples 3 and 4
(Catalyst preparation)
A solid consisting of a mixture of an inorganic carrier, an alkali metal phosphate and an alkaline earth metal carbonate was obtained in the same manner as in Example 1 except that the alkaline earth metal hydroxide was changed to an alkaline earth metal carbonate. A catalyst was obtained.
(Gas phase reaction)
Except that the exemplified compounds used as the raw materials were changed, the total yield of bicyclic amine and piperazine and the yield of by-products were determined using the gas phase reaction method of Example 1 and are shown in Table 1.

The results in Table 1 show that by adding an alkaline earth metal hydroxide or hydroxyapatite to the inorganic carrier and the alkali metal phosphate, generation of by-products is suppressed.

  INDUSTRIAL APPLICABILITY The present invention has a possibility of being used as a method for producing a bicyclic amine compound known as a compound useful as, for example, a pharmaceutical or agricultural chemical intermediate, a catalyst for organic synthesis, a chemical adsorbent, an antibacterial agent, or the like.

Claims (4)

The following equation (1)
[Wherein, R _{1 to} R ₈ each independently represent a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a hydroxyl group, a hydroxymethyl group, or an alkoxy group having 1 to 4 carbon atoms. Further, X represents a nitrogen atom, Y represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a hydroxyl group, or a hydroxyalkyl group having 1 to 4 carbon atoms. ]
From the compound represented by the following formula (2)
[Wherein, R _{1 to} R ₈ , X, and Y have the same definitions as above. ]
In the method for producing a compound represented by the formula (I), a catalyst containing an inorganic carrier and an alkali metal phosphate, and further containing at least 1.5% by weight and less than 15% by weight of an alkaline earth metal hydroxide and / or hydroxyapatite based on the inorganic carrier. A method for producing a bicyclic amine compound, which is used. 2. The method for producing a bicyclic amine compound according to claim 1, wherein in formulas (1) and (2), Y is a hydrogen atom or a hydroxymethyl group. In the formulas (1) and (2), R _{1 to} R ₈ each independently represent a hydrogen atom, a methyl group, an ethyl group, an isopropyl group, or a hydroxymethyl group (provided that R _{1 to} R ₈ are all 3. The method for producing a bicyclic amine compound according to claim 1, wherein the substituents are not the same. Alkaline earth metal hydroxide, magnesium hydroxide, calcium hydroxide, strontium hydroxide, any of claims 1 to 3, characterized in that at least one selected from the group of barium hydroxide The method for producing a bicyclic amine compound according to the above.