JP6252152B2 - Method for producing bicyclic amine compound - Google Patents

Description

  The present invention relates to a method for producing a bicyclic amine compound by intramolecular dehydration reaction using a hydroxyl group-containing cyclic amine compound.

  Bicyclic amine compounds are known as compounds useful for, for example, pharmaceutical and agrochemical intermediates, organic synthesis catalysts, chemical adsorbents, antibacterial agents, and the like (see, for example, Patent Documents 1 and 2).

  As a method for producing a bicyclic amine compound, in Patent Document 1, after a bicyclic amine compound having an ester group as a substituent is synthesized, the ester group is reduced.

  However, this production method uses lithium aluminum hydride, which has a high risk of ignition, as a reducing agent, and therefore is not preferable for industrial scale-up production. In addition, since an expensive reaction substrate is used, it is not practical.

  For this reason, the applicant of the present invention can obtain the target product in one step and, as a simple and safe production method that does not require excessive high-pressure reaction,

（上記式中、Ｒは水素原子又は直鎖状若しくは分枝状の炭素数１〜４のアルキル基、ｎは０〜６の整数を表す。）
で示されるジヒドロキシアルキルピペラジン類を、酸触媒の存在下で分子内脱水縮合反応させて、二環式アミン化合物を製造する方法について既に特許出願している（特許文献２参照）。

(In the above formula, R represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms, and n represents an integer of 0 to 6)
A patent application has already been filed for a method for producing a bicyclic amine compound by subjecting a dihydroxyalkylpiperazine represented by formula (I) to an intramolecular dehydration condensation reaction in the presence of an acid catalyst (see Patent Document 2).

  The method described in Patent Document 2 is an excellent method in which a multi-step reaction is unnecessary, and a bicyclic amine compound can be easily and safely produced without using a reducing agent having a high risk of ignition. However, since the conversion rate is not sufficient, a recovery step of unreacted raw materials is necessary, and when the acid catalyst in this production method is applied to a gas phase reaction, a sufficient yield cannot be obtained and the reaction side Since organisms may be deposited in the form of tar and clog the reaction tube, there are still problems to be solved in industrial continuous production.

  For this reason, the applicant of the present invention can obtain a bicyclic amine compound easily and in high yield, and a production method capable of suppressing the by-product tar content that hinders continuous production,

（上記式中、Ｒ_１〜Ｒ_８は各々独立して、水素原子、炭素数１〜４のアルキル基、水酸基、ヒドロキシメチル基、又は炭素数１〜４のアルコキシ基を表す。また、Ｘは炭素原子又は窒素原子を表し、Ｙは水素原子、アルキル基、水酸基、又は炭素数１〜４のヒドロキシアルキル基を表す。）
で示される化合物を、固体触媒として下記式

(In the above formula, R _{1 to} R ₈ each independently represents 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. (A carbon atom or a nitrogen atom is represented, Y represents a hydrogen atom, an alkyl group, a hydroxyl group, or a C1-C4 hydroxyalkyl group.)
As a solid catalyst, the compound represented by

［上記式中、ＡはＳｉ、Ａｌ、Ｍｇ、Ｔｉ及びＺｒからなる群より選ばれる１種又は２種以上の元素を表し、Ｍはアルカリ金属元素又はアルカリ土類金属元素を表し、Ｐはリンを表し、Ｏは酸素を表す。添字ａ〜ｄは各元素のモル数を表し、ｂ／ａ＝０．００１〜０．３（モル比）、ｃ／ａ＝０．００１〜０．３（モル比）であって、ｄは各原子の結合状態によって任意に取り得る値を表す。ただし、Ａが２種以上の元素を表す場合には、添字ａはそのモル数が最も大きい元素のモル数を表す。］
で示される無機酸化物の存在下、気相中で分子内脱水させて、二環式アミン化合物を製造する方法について、既に特許出願している（特許文献３参照）。

[In the above formula, A represents one or more elements selected from the group consisting of Si, Al, Mg, Ti and Zr, M represents an alkali metal element or an alkaline earth metal element, and P represents phosphorus. O represents oxygen. 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 a value that can be arbitrarily taken depending on the bonding state of each atom. However, when A represents two or more elements, the subscript a represents 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 dehydration in the gas phase in the presence of an inorganic oxide (see Patent Document 3).

  Patent Document 3 discloses a production method by gas phase reaction, and describes that by-product tar content can be reduced by using a specific solid catalyst. However, since the caulking of the catalyst has not been studied and the long-term operation evaluation has only been conducted for about one week, there is still a problem to be improved in industrial continuous production.

JP 2001-504855 A JP 2010-037325 A JP 2012-149048 A

  This invention is made | formed in view of said background art, The objective is to provide the method which can manufacture a bicyclic amine compound industrially continuously and stably.

  As a result of intensive studies to solve the above-mentioned problems, the present inventors have promoted oxidative degradation of the dihydroxyalkyl group-containing cyclic amine compound as a raw material, and the oxygen dissolved in the solvent in which the reaction is performed. Ascertaining that the selectivity is lowered, the present invention has been completed. That is, this invention is a manufacturing method of the bicyclic amine compound as shown below.

  [1] The following formula (1)

（式中、Ｒ^１〜Ｒ^１０は各々独立して、水素原子、炭素数１〜４のアルキル基、炭素数１〜４のヒドロキシアルキル基、又は水酸基を表し、Ｒ^９、Ｒ^１０のいずれか一方は炭素数１〜４のヒドロキシアルキル基である。Ｘは炭素原子又は窒素原子を表す。）
で示されるジヒドロキシアルキル基含有環状アミン化合物を、固体触媒存在下、気相中で、分子内脱水させて、下記式（２）

(Wherein R ^{1 to} R ¹⁰ each independently represent a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a hydroxyalkyl group having 1 to 4 carbon atoms, or a hydroxyl group, and any one of R ⁹ and R ¹⁰ One is a hydroxyalkyl group having 1 to 4 carbon atoms, X represents a carbon atom or a nitrogen atom.)
A dihydroxyalkyl group-containing cyclic amine compound represented by the formula (2) is subjected to intramolecular dehydration in the gas phase in the presence of a solid catalyst.

（式中、Ｒ^１〜Ｒ^１０及びＸは前記に同じ定義である。）
で表される二環式アミン化合物を製造する際に、当該ジヒドロキシアルキル基含有環状アミン化合物を含み、かつ溶存酸素濃度が３ｍｇ−Ｏ_２／Ｌ以下である原料液を用いることを特徴とする二環式アミン化合物の製造方法。

(Wherein R ^{1 to} R ¹⁰ and X have the same definition as above).
In the production of the bicyclic amine compound represented by formula ( ₂₎ , a raw material solution containing the dihydroxyalkyl group-containing cyclic amine compound and having a dissolved oxygen concentration of 3 mg-O ₂ / L or less is used. A method for producing a cyclic amine compound.

[2] A substitution operation (purging) using an inert gas is performed on the raw material liquid containing the dihydroxyalkyl group-containing cyclic amine compound represented by the general formula (1), and the dissolved oxygen concentration is 3 mg-O ₂ / L or less. The method for producing a bicyclic amine compound as described in [1] above.

  [3] The method for producing a bicyclic amine compound as described in [2] above, wherein the substitution operation is a bubbling method using an inert gas.

  [4] The method for producing a bicyclic amine compound as described in [2] above, wherein the substitution operation is a stripping method using an inert gas.

  [5] The method for producing a bicyclic amine compound as described in [2] to [4] above, wherein the inert gas is nitrogen gas.

[6] In the general formulas (1) and (2), R ^{1 to} R ¹⁰ are each independently a hydrogen atom, a methyl group or a hydroxymethyl group, and any one of R ⁹ and R ¹⁰ is hydroxymethyl. The method for producing a bicyclic amine compound according to any one of the above [1] to [5], which is a group.

[7] The bicyclic amine compound according to any one of [1] to [5], wherein in general formulas (1) and (2), R ^{1 to} R ⁸ are hydrogen atoms. Production method.

  [8] The method for producing a bicyclic amine compound according to any one of the above [1] to [7], wherein in general formulas (1) and (2), X is a nitrogen atom.

  [9] The bicyclic amine compound as described in any one of [1] to [8] above, wherein the solid catalyst is a catalyst having an acid component, a base component, or both supported on a carrier. Manufacturing method.

  [10] The bicyclic amine compound according to any one of [1] to [9] above, wherein the acid component is an inorganic acid and the base component is an alkali metal or an alkaline earth metal Production method.

  According to the production method of the present invention, a bicyclic amine compound can be produced industrially continuously and stably with a higher yield and better reproducibility than conventional methods.

It is a figure which shows the result of Example 4. It is a figure which shows the result (relationship of nitrogen bubbling time and dissolved oxygen) of Example 5. It is a figure which shows the result (relationship of nitrogen bubbling amount and dissolved oxygen) of Example 5.

  Hereinafter, the present invention will be described in detail.

The present invention provides a bicyclic amine represented by the above formula (2) by intramolecular dehydration of a dihydroxyalkyl group-containing cyclic amine compound represented by the above formula (1) in the gas phase in the presence of a solid catalyst. When the compound is produced, a raw material solution containing the dihydroxyalkyl group-containing cyclic amine compound and having a dissolved oxygen concentration of 3 mg-O ₂ / L or less is used. The dissolved oxygen concentration in the raw material liquid is more preferably ₂ mg-O ₂ / L or less.

Here, the unit “mg-O ₂ / L” means the amount (mg) of oxygen dissolved in 1 L of the raw material liquid.

  The raw material liquid only needs to contain the compound represented by the above formula (1) and does not require any other solvent. However, from the viewpoint of suppressing the intermolecular reaction, other solvents may be used. It is preferable to include.

  Here, the solvent is not particularly limited as long as it dissolves the compound represented by the above formula (1). For example, water, alcohol (specifically, methanol, ethanol, 1-propanol) , 2-propanol, etc.), n-hexane, cyclohexane, tetrahydrofuran, 1,4-dioxane and the like. From the viewpoint of compatibility with the solvent and reactivity, water is particularly preferable.

In the present invention, the method for setting the dissolved oxygen concentration in the raw material liquid containing the compound represented by the above formula (1) to 3 mg-O ₂ / L or less, preferably 2 mg-O ₂ / L or less is particularly limited. However, for example, a replacement operation (purging) using an inert gas can be mentioned, and specifically, it is carried out by the methods shown in the following (a) to (e).

  (A) The dissolved oxygen in the raw material liquid is driven out by bubbling the raw material liquid containing the compound represented by the above formula (1) with an inert gas (a bubbling method). From the viewpoint of gas-liquid contact efficiency, it is desirable to reduce the dissolved oxygen by installing a stripper in the process piping and entraining with an inert gas (stripping method).

  (I) After the raw material liquid containing the compound represented by the above formula (1) is pressure-filled with an inert gas in a sealed container, the oxygen partial pressure in the raw material liquid is lowered by lowering the pressure in the sealed container. To expel oxygen in the raw material liquid.

  (C) The dissolved oxygen is driven out by degassing the raw material liquid containing the compound represented by the above formula (1) under reduced pressure. In this degassing, it is preferable to use an ultrasonic device or the like in view of the effect of reducing dissolved oxygen.

  (D) The raw material liquid containing the compound represented by the above formula (1) is once heated to boiling, and then cooled in an inert gas atmosphere to drive out dissolved oxygen in the raw material liquid.

  Among the methods (a) to (d), the methods (a) and (b) are preferable in that production efficiency is good and the load on the facility is small.

  In the method (a), the oxygen dissolved in the raw material liquid is reduced by entraining an inert gas directly in the raw material liquid in the raw material tank or pipe. The amount of the inert gas to be entrained is not particularly limited because it varies depending on conditions such as temperature and amount, but it is 2 to 5 times, preferably 2 to 3 times the amount of dissolved oxygen. Entrain the amount. The dissolved oxygen concentration decreases as the amount of the entrainment increases. However, when the amount exceeds 5 times, the dissolved oxygen concentration does not decrease so much and the efficiency deteriorates.

  In the method (a), the step of lowering the pressure in the sealed container pressurized and filled with the inert gas and then sealing the container and pressurizing and filling the inert gas is preferably performed 2 to 10 times. More preferably, it is repeated 2 to 5 times. The greater the number of repetitions of this step, the lower the dissolved oxygen concentration. However, when the number of repetitions exceeds 10, the dissolved oxygen concentration does not decrease so much and the efficiency deteriorates.

  Here, the inert gas is not particularly limited as long as it does not affect the raw materials and the like, and examples thereof include helium, argon, and nitrogen. Nitrogen gas is particularly preferable from the viewpoints of operability and productivity.

  In the present invention, the dissolved oxygen concentration in the raw material liquid can be easily measured by using, for example, a commercially available dissolved oxygen meter.

In the above formulas (1) and (2), R ^{1 to} R ¹⁰ are not particularly limited as long as they fall under the above definition. For example, a hydrogen atom, an alkyl group having 1 to 4 carbon atoms (ie, A methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group), a hydroxyalkyl group having 1 to 4 carbon atoms (that is, a hydroxymethyl group, 1 -Hydroxyethyl group, 2-hydroxyethyl group, 1-hydroxypropyl group, 2-hydroxypropyl group, 3-hydroxypropyl group, 1-hydroxybutyl group, 2-hydroxybutyl group, 3-hydroxybutyl group, 4-hydroxy Butyl group), hydroxyl group and the like. Preferably, they are a hydrogen atom, a methyl group, and a hydroxymethyl group. Among these, it is more preferable that all of R ^{1 to} R ⁸ are hydrogen atoms.

  Although it does not specifically limit as a compound shown by the said Formula (1), As a preferable compound in case X is a carbon atom, the following compounds (exemplary compound number 3-1 and 3-2) are mentioned, for example. Can be mentioned.

また、上記式（２）で示される二環式アミン化合物としては、特に限定するものではないが、Ｘが炭素原子である場合の好ましい化合物として、例えば、以下の化合物（例示化合物番号４−１及び４−２）を挙げることができる。

In addition, the bicyclic amine compound represented by the above formula (2) is not particularly limited, but preferred compounds when X is a carbon atom include, for example, the following compounds (Exemplary Compound Nos. 4-1 And 4-2).

上記式（１）で示されるヒドロキシル基含有環状アミン化合物のＸが窒素原子である場合の好ましい化合物としては、例えば、以下の化合物（例示化合物番号５−１〜６）を挙げることができる。

As a preferable compound when X of the hydroxyl group-containing cyclic amine compound represented by the above formula (1) is a nitrogen atom, for example, the following compounds (Exemplified Compound Nos. 5-1 to 6) can be exemplified.

また、上記式（２）で示される二環式アミン化合物としては、特に限定するものではないが、Ｘが窒素原子である場合の好ましい化合物として、例えば、以下の化合物（例示化合物番号６−１〜７）を挙げることができる。

In addition, the bicyclic amine compound represented by the above formula (2) is not particularly limited, but preferred compounds when X is a nitrogen atom include, for example, the following compounds (Exemplary Compound No. 6-1). To 7).

また、上記式（１）又は（２）で示される化合物のより好ましい態様としては、Ｘが窒素原子である、ピペラジン誘導体の場合、上記式（１）で示される化合物を含む原料液中の溶存酸素濃度を低減させたときの効果が大きい。

Further, as a more preferable embodiment of the compound represented by the above formula (1) or (2), in the case of a piperazine derivative in which X is a nitrogen atom, dissolution in the raw material liquid containing the compound represented by the above formula (1) Great effect when oxygen concentration is reduced.

  Next, the intramolecular dehydration reaction of the compound represented by the above formula (1) using a solid catalyst will be described.

  In the present invention, the solid catalyst is not particularly limited, but a catalyst having an acid component, a base component, or both supported on a carrier is more preferable.

  As the solid catalyst carrier, for example, an inorganic oxide is used. The inorganic oxide is not particularly limited, and examples thereof include silicon oxide, aluminum oxide, aluminosilicate, zeolite, magnesium oxide, titanium oxide, and zirconium oxide. Among these, silicon oxide, aluminum oxide, and high silica zeolite are preferable. Further, as the silicon oxide, amorphous dry silica or porous silica is particularly preferable.

  As another carrier, for example, a metal phosphate can also be used. The metal phosphate may be a conventionally known metal salt and is not particularly limited, and examples thereof include metal salts such as phosphoric acid, phosphorous acid, hypophosphorous acid and the like. Examples of metals that form salts with phosphoric acid include sodium, potassium, lithium, calcium, barium, magnesium, aluminum, titanium, iron, cobalt, nickel, copper, zinc, zirconium, palladium, silver, tin, and lead. Can be mentioned. More preferably, it is an aluminum phosphate salt.

  A suitable solid catalyst can be prepared by supporting an acid component, a base component, or both on this carrier. More preferably, the base component alone or the acid component and the base component are used in combination.

  It is preferable to use an inorganic acid as the acid component. Although it does not specifically limit as an inorganic acid, For example, phosphoric acid, phosphonic acid, phosphinic acid, phosphine oxide, various phosphates, sulfonic acid, etc. are mentioned as a suitable thing.

  The base component preferably contains an alkali metal or alkaline earth metal element. The alkali metal or alkaline earth metal element is not particularly limited, and examples thereof include Na, K, Rb, Cs, Ca, Sr, and Ba. In order to obtain the target product in a high yield, it is particularly preferable to contain Cs or Rb.

  The raw material for such a base component is not particularly limited, and examples thereof include oxides, hydroxides, halides, carbonates, nitrates, and sulfates thereof. Of these, nitrates and carbonates are preferred.

  In the present invention, the method for preparing the solid catalyst is not particularly limited, but, for example, a generally performed preparation method can be used. Specifically, the above-described solid catalyst raw material (for example, catalyst carrier, acid component raw material, base component raw material, etc.) is dissolved or suspended in water, and after steps such as stirring, heating, concentration, and drying, Examples thereof include a method of forming a solid catalyst through further firing.

  Although it does not specifically limit as a calcination temperature of a solid catalyst, Usually, it is the range of 300-1,100 degreeC, Preferably it is the range of 400-700 degreeC. By setting it as this range, physical properties, such as acid-base intensity | strength of a solid catalyst, and a specific surface area, can be improved, and catalyst activity and a selectivity can be improved more.

  Moreover, although baking of a solid catalyst is not specifically limited, What is necessary is just to perform in air or nitrogen atmosphere.

  In the present invention, the intramolecular dehydration reaction is carried out in the gas phase, but is preferably carried out in a fixed bed flow system.

  The present invention will be described in more detail based on the following reference examples and examples, but the present invention should not be construed as being limited thereto.

  The analytical instruments and measurement methods used in this example are listed below.

[Dissolved oxygen]
Dissolved oxygen meter: DO-5509 manufactured by Mother Tool.

[Elemental analysis]
Element analyzer: Perkin Elmer fully automatic element analyzer 2400II,
Oxygen flask combustion-IC measurement method: Tosoh ion chromatograph IC-2001.

[NMR measurement]
NMR measuring apparatus: VARIAN Gemini-200.

[Quantitative analysis]
Mass spectrometer: JMS-K9, manufactured by JEOL Ltd.
Measuring method: GC-MS analysis.

[Gravimetric analysis]
Muffle furnace: FO810 manufactured by Yamato Scientific Co., Ltd.
Differential heat / thermogravimetry apparatus: EXSTAR TG / DTA6000 manufactured by Seiko Instruments Inc.

Reference Example 1 (Preparation of gas phase reaction catalyst-1).
As a catalyst carrier, 40 g of amorphous dry silica (ox-50, manufactured by Nippon Aerosil Co., Ltd.) is mixed with 200 ml of water to form a slurry solution, and 13.0 g of cesium nitrate and 4.4 g of diammonium hydrogen phosphate are mixed and dispersed. Then, it was evaporated to dryness using an evaporator to obtain a white solid. This solid was compression molded, calcined at 600 ° C. for 4 hours in a muffle furnace under a nitrogen atmosphere, and pulverized to 2.5 to 3.5 mesh to obtain a gas phase reaction catalyst-2.

Reference Example 2 Synthesis of 3- (1′-piperazinyl) -1,2-propanediol (compound represented by Exemplified Compound No. 5-1, hereinafter abbreviated as “DHPP”).
A 50 L reaction kettle was charged with 15.5 kg (180 mol) of piperazine and 15.6 L of methanol as a solvent, adjusted to a liquid temperature of 45 ° C. under a nitrogen atmosphere, and then 3-chloro-1,2-propane. The diol 6.06kg (54.8mol) was dripped over 3 hours. The liquid temperature gradually increased during the dropping, and the liquid temperature at the end was 75 ° C. Thereafter, the reaction temperature was adjusted to 70 ° C., and further aged for 3 hours. The reaction conversion rate was 100%. The reaction solution was allowed to stand overnight and lowered to near room temperature. Then, 4.6 kg (55 mol) of a 48% aqueous sodium hydroxide solution was slowly added dropwise to precipitate a by-product salt. The reaction liquid extracted from the bottom of the kettle was desalted by filtration, and then methanol was distilled off using an evaporator. Further, unreacted piperazine was distilled off by simple distillation, and the target product was isolated by distillation under reduced pressure (white solid, yield 7.9 kg, yield 90%). From GC-MS and NMR analysis, it was confirmed to be DHPP represented by Example Compound 5-1.

  GC-MS: 160.

¹³ C-NMR (CDCl ₃ ): 66.71, 64.97, 61.16, 54.64, 46.04.

Reference Example 3 Synthesis of 3- (3′-methylpiperazin-1′-yl) -1,2-propanediol (compound represented by Exemplified Compound No. 5-3, hereinafter abbreviated as “DHPMP”).
The same procedure as described in Reference Example 4 was used except that 18.0 kg (180 mol) of 2-methylpiperazine was used instead of 15.5 kg (180 mol) of piperazine in Reference Example 2 to obtain a pale yellow oil (yield) 6.5 kg, yield 68%). From the results of GC-MS and NMR, DHPMP and its isomer represented by the following formula (8)

に示される３−（２’−メチルピペラジン−１’−イル）−１，２−プロパンジオールとの混合物であることを確認した。質量分析、ＮＭＲ測定の結果を以下に示す。

It was confirmed that this was a mixture with 3- (2′-methylpiperazin-1′-yl) -1,2-propanediol as shown in FIG. The results of mass spectrometry and NMR measurement are shown below.

  GC-MS: 174.

¹³ C-NMR (CDCl ₃ ): 66.60, 64.95, 62.66, 60.76, 60.67, 60.34, 55.03, 52.76, 50.81, 50.61, 46 05, 45.91, 19.89.

Example 1 Synthesis of Compound represented by Exemplary Compound No. 6-1.
After dissolving DHPP represented by Example Compound No. 5-1 synthesized in Reference Example 3 with water to a concentration of 16% by weight, nitrogen gas was bubbled until the dissolved oxygen concentration finally became 2 mg-O ₂ / L or less. The raw material liquid was prepared. It was 1.9 mg / L when the dissolved oxygen concentration at that time was measured with the dissolved oxygen meter. 20 ml of the gas phase reaction catalyst-1 prepared in Reference Example 1 was filled in the central part of a quartz glass tube having an inner diameter of 18 mm, and a Raschig ring having an outer diameter of 3 mm was filled in the upper and lower parts thereof. The catalyst layer and the Raschig ring layer were kept at 400 ° C. in an electric furnace, and the raw material solution prepared in advance was dropped from above at a rate of 0.5 ml / min, nitrogen, GHSV of about 1,600 Hr ⁻¹ . Nitrogen gas was flowed to such an extent that the reaction liquid flowed from the upper part to the lower part of the reaction tube (this is negligible for GHSV). Three hours after the start of liquid flow, the reaction liquid was collected over 1 hour. During this liquid flow, the inside of the raw material liquid container was placed in a nitrogen atmosphere. As a result of analyzing this reaction liquid by gas chromatography, the conversion was 97%. The obtained component was subjected to GC-MS analysis, distilled and isolated, and then subjected to NMR analysis. As a result, 1,4-diazabicyclo [2.2.2] octane-2-methanol represented by the exemplified compound number 6-1 described above was obtained. I confirmed that there was. The reaction yield was 54%.

Example 2
In Example 1, the method described in Example 1 was followed, except that the raw material liquid subjected to nitrogen bubbling until the dissolved oxygen concentration finally became 1 mg-O ₂ / L or less was used. The dissolved oxygen concentration in that case was measured with a dissolved oxygen meter and found to be 0.8 mg / L. As a result of analyzing the reaction solution by gas chromatography, the conversion rate was 98%, and the reaction yield of Exemplified Compound 6-1 was 58%.

Comparative Example 1 Synthesis of compound represented by Exemplified Compound No. 4-1.
In Example 1, the raw material liquid was used for the reaction without bubbling with nitrogen gas. In this case, the dissolved oxygen concentration was measured with a dissolved oxygen meter and found to be 9.0 mg / L. The reaction solution was collected over 1 hour and analyzed by gas chromatography. As a result, the conversion was 98% and the reaction yield was 46%.

Example 3 Synthesis of compound represented by Exemplified Compound No. 6-3.
In Example 2, it implemented according to the method described in Example 2 except having used DHPMP shown by the example compound number 5-3 synthesize | combined by the reference example 3 instead of DHPP shown by the example compound number 5-1. The dissolved oxygen concentration in that case was measured with a dissolved oxygen meter and found to be 0.9 mg / L. As a result of analyzing this reaction liquid by gas chromatography, the conversion rate was 96%. As a result of GC-MS and NMR analysis of the obtained component, the main product was a mixture of the compound represented by Example Compound No. 6-2 and the compound represented by Example Compound No. 6-3, and their total yield was 41%.

Comparative Example 2
In Example 3, the raw material liquid was used for the reaction without bubbling with nitrogen gas. The dissolved oxygen concentration in that case was measured with a dissolved oxygen meter and found to be 9.3 mg / L. The reaction solution was collected over 1 hour and analyzed by gas chromatography. As a result, the conversion was 95% and the reaction yield was 32%.

Example 4 Change with time of dissolved oxygen concentration in raw material liquid.
500 g of the raw material solution (16 wt% concentration DHPP aqueous solution) having a dissolved oxygen concentration of 0.8 mg / L used in Example 2 was placed in a 1 L round bottom flask (with a stopcock) and allowed to stand at room temperature. The change with time was measured. The results are shown in FIG. The dissolved oxygen concentration in the raw material liquid reached near saturation in about 3 days. Therefore, in an industrial process, it is desirable to keep the dissolved oxygen concentration in the raw material liquid at a constant level by continuously or intermittently introducing an inert gas.

Example 5 Examination of conditions for reducing dissolved oxygen in the raw material liquid.
Changes in dissolved oxygen concentration over time when 400 g of the raw material liquid (16 wt% DHPP aqueous solution) used in Examples 1 and 2 was put into a 1 L round bottom flask (with stopcock) and nitrogen bubbling was performed. It was measured. The results are shown in FIGS. From the viewpoint of contact efficiency with dissolved oxygen, nitrogen bubbling resulted in a higher effect of reducing dissolved oxygen when the nitrogen gas blowing amount per unit time was larger. Moreover, the dissolved oxygen concentration became difficult to decrease at 1 mg / L or less.

  From the above results, it is understood that the productivity of the bicyclic amine compound can be improved by using the production method of the present invention.

Claims (8)

Following formula (1)

(Wherein R ^{1 to} R ¹⁰ each independently represent a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a hydroxyalkyl group having 1 to 4 carbon atoms, or a hydroxyl group, and any one of R ⁹ and R ¹⁰ One is a hydroxyalkyl group having 1 to 4 carbon atoms, X represents a carbon atom or a nitrogen atom.)
In the presence of a solid catalyst carrying at least phosphoric acid and cesium , the dihydroxyalkyl group-containing cyclic amine compound represented by the formula (2)

(Wherein R ^{1 to} R ¹⁰ and X have the same definition as above).
In the production of the bicyclic amine compound represented by formula ( ₂₎ , a raw material solution containing the dihydroxyalkyl group-containing cyclic amine compound and having a dissolved oxygen concentration of 3 mg-O ₂ / L or less is used. A method for producing a cyclic amine compound. The raw material liquid containing the dihydroxyalkyl group-containing cyclic amine compound represented by the general formula (1) is subjected to a substitution operation (purging) using an inert gas so that the dissolved oxygen concentration is 3 mg-O ₂ / L or less. The method for producing a bicyclic amine compound according to claim 1. The method for producing a bicyclic amine compound according to claim 2, wherein the substitution operation is a bubbling method using an inert gas. The method for producing a bicyclic amine compound according to claim 2, wherein the substitution operation is a stripping method using an inert gas. The method for producing a bicyclic amine compound according to claim 2, wherein the inert gas is nitrogen gas. In the general formulas (1) and (2), R ^{1 to} R ¹⁰ are each independently a hydrogen atom, a methyl group or a hydroxymethyl group, and one of R ⁹ and R ¹⁰ is a hydroxymethyl group. A method for producing a bicyclic amine compound according to any one of claims 1 to 5. The method for producing a bicyclic amine compound according to any one of claims 1 to 5, wherein in the general formulas (1) and (2), R ^{1 to} R ⁸ are hydrogen atoms. The method for producing a bicyclic amine compound according to any one of claims 1 to 7, wherein in the general formulas (1) and (2), X is a nitrogen atom.

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