JP5640332B2 - Process for producing hydroxy (alkyl) triethylenediamines - Google Patents

Description

  The present invention relates to a method for producing hydroxy (alkyl) triethylenediamines. Hydroxy (alkyl) triethylenediamines are useful as intermediates for medicines and agricultural chemicals, catalysts for organic synthesis, chemical adsorbents, antibacterial agents and the like.

  Following formula (2)

（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。）
で示されるヒドロキシ（アルキル）トリエチレンジアミン類の製造方法としては、例えば、ピペラジンと２，３−ジブロモプロパン酸エチルとを反応させて１，４−ジアザビシクロ［２．２．２］オクタン−２−カルボン酸エチルを調製し、次いで得られたエステルを還元して１，４−ジアザビシクロ［２．２．２］オクタン−２−メタノール（ヒドロキシメチルトリエチレンジアミン）を得る方法が知られている（例えば、特許文献１参照）。

(In the 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)
As a method for producing hydroxy (alkyl) triethylenediamines represented by formula (1), for example, piperazine and ethyl 2,3-dibromopropanoate are reacted to produce 1,4-diazabicyclo [2.2.2] octane-2-carboxylic acid. Methods for preparing ethyl acid and then reducing the resulting ester to give 1,4-diazabicyclo [2.2.2] octane-2-methanol (hydroxymethyltriethylenediamine) are known (eg, patents Reference 1).

  However, this production method is not preferable in terms of safety because it requires a multi-step reaction and is complicated and uses lithium aluminum hydride having a high risk of ignition as a reducing agent. In addition, a strong reducing agent such as lithium aluminum hydride is not preferable for industrial use because post-treatment after completion of the reaction needs to be performed carefully.

JP 2001-504855 A

  The present invention has been made in view of the above-described background art, and its purpose is to easily and safely use hydroxy (alkyl) without using a reducing agent that does not require a multistage reaction and has a high risk of ignition. ) To provide a method for producing triethylenediamines.

  As a result of intensive studies to solve the above problems, the present inventors have completed the present invention.

  That is, this invention is a manufacturing method of hydroxy (alkyl) triethylenediamine as shown below.

  [1] The following formula (1)

（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る、下記式（２）

(In the 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 dihydroxyalkyl piperazine represented by the formula (2) is subjected to an intramolecular dehydration condensation reaction in the presence of an acid catalyst.

（式中、Ｒ、ｎは前記に同じ定義である。）
で示されるヒドロキシ（アルキル）トリエチレンジアミン類の製造方法。

(Wherein R and n have the same definitions as above)
The manufacturing method of hydroxy (alkyl) triethylenediamine shown by these.

  [2] The production method according to the above [1], wherein the acid catalyst contains at least a metal phosphate.

  [3] The production method according to the above [1], wherein the acid catalyst contains at least an organic phosphorus compound.

  [4] Dihydroxyalkylpiperazines represented by the above formula (1) are represented by the following formula (3):

で示されるジヒドロキシプロピルピペラジンである上記［１］乃至［３］のいずれかに記載の製造方法。

The manufacturing method in any one of said [1] thru | or [3] which is dihydroxypropyl piperazine shown by these.

  [5] Dihydroxyalkylpiperazines represented by the above formula (1) are piperazine and the following formula (4):

（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。）
で示される化合物との付加反応により得られるジヒドロキシアルキルピペラジン類である上記［１］乃至［３］のいずれかに記載の製造方法。

(In the 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)
The manufacturing method in any one of said [1] thru | or [3] which is dihydroxyalkyl piperazine obtained by addition reaction with the compound shown by these.

  [6] Dihydroxyalkylpiperazines represented by the above formula (1) are piperazine and the following formula (5):

（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。）
で示される化合物を、酸触媒の存在下で脱水縮合反応することにより得られるジヒドロキシアルキルピペラジン類である上記［１］乃至［３］のいずれかに記載の製造方法。

(In the 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)
The manufacturing method in any one of said [1] thru | or [3] which is dihydroxyalkyl piperazine obtained by carrying out the dehydration condensation reaction in the presence of an acid catalyst.

  [7] Dihydroxyalkylpiperazines represented by the above formula (1) are piperazine and the following formula (6):

（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。Ｘはハロゲン原子である。）
で示される化合物との反応により得られるジヒドロキシアルキルピペラジン類である上記［１］」乃至［３］のいずれかに記載の製造方法。

(In the formula, R represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms, n represents an integer of 0 to 6. X represents a halogen atom.)
The manufacturing method in any one of said [1] thru | or [3] which is dihydroxyalkyl piperazine obtained by reaction with the compound shown by these.

  [8] The production method of the above-mentioned [4], wherein the dihydroxypropylpiperazine represented by the formula (3) is dihydroxypropylpiperazine obtained by addition reaction of piperazine and glycidol.

  [9] The production method according to [4], wherein the dihydroxypropylpiperazine represented by the above formula (3) is dihydroxypropylpiperazine obtained by subjecting piperazine and glycerin to a dehydration condensation reaction in the presence of an acid catalyst.

  [10] The production method according to the above [4], wherein the dihydroxypropylpiperazine represented by the formula (3) is dihydroxypropylpiperazine obtained by reaction of piperazine and chloropropanediol.

  According to the production method of the present invention, the target product can be obtained in one step, and since no reducing compound is used, hydroxy (alkyl) triethylenediamines can be obtained easily and safely compared to conventional methods. .

  Hereinafter, the present invention will be described in detail.

  In the production method of the present invention, a dihydroxyalkylpiperazine represented by the above formula (1) is subjected to an intramolecular dehydration condensation reaction in the presence of an acid catalyst to produce a hydroxy (alkyl) triethylenediamine represented by the above formula (2). It is characterized by obtaining.

  In the above formulas (1) and (2), R represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms, specifically a methyl group, an ethyl group, a propyl group, or an isopropyl group. And a butyl group. Of these, a hydrogen atom, a methyl group, and an ethyl group are preferable. Moreover, in said formula (1) and (2), n represents the integer of 0-6, and the integer of 0-2 is more preferable.

  The dihydroxyalkylpiperazines represented by the above formula (1) are not particularly limited, and examples thereof include dihydroxypropylpiperazines, dihydroxybutylpiperazines, dihydroxypentylpiperazines, dihydroxyhexylpiperazines and the like.

  In the production method of the present invention, the dihydroxyalkylpiperazines are not particularly limited. For example, commercially available products may be used, or by addition reaction of piperazine and the compound represented by the above formula (4). The product obtained by the dehydration condensation reaction of piperazine and the compound represented by the above formula (5) in the presence of an acid catalyst, or the reaction of piperazine with the compound represented by the above formula (6) You may use what was obtained.

  Specifically, for example, dihydroxypropylpiperazine represented by the above formula (3) can be obtained by addition reaction of piperazine and glycidol, or can also be obtained by dehydration condensation reaction of piperazine and glycerin in the presence of an acid catalyst. Moreover, the dihydroxypropyl piperazine shown by the said Formula (3) can also be obtained by reacting piperazine and chloropropanediol.

  In the production method of the present invention, the hydroxy (alkyl) triethylenediamine represented by the above formula (2) is hydroxytriethylenediamine (when n = 0) or hydroxyalkyltriethylenediamine (when n = 1 to 6). Means. Such hydroxy (alkyl) triethylenediamines are not particularly limited, and examples thereof include hydroxytriethylenediamine, hydroxymethyltriethylenediamine, hydroxyethyltriethylenediamine, hydroxypropyltriethylenediamine, and hydroxybutyltriethylenediamine.

  In the production method of the present invention, the reaction is carried out by bringing the dihydroxyalkylpiperazine represented by the above formula (1) into contact with an acid catalyst. Examples of the acid catalyst include phosphorus-containing materials such as metal phosphates and organic phosphorus compounds, nitrogen-containing materials, sulfur-containing materials, niobium-containing materials, silica, alumina, silica-alumina, silica-titania, zeolite, heteropolyacid, Examples include Group 4B metal oxide condensation catalysts, Group 6B metal-containing condensation catalysts, Bronsted acids, Lewis acids, and phosphorus amides. Among these, phosphorus-containing materials are particularly preferable.

  In the production method of the present invention, examples of the metal phosphate include metal salts such as phosphoric acid, phosphorous acid, and hypophosphorous acid. The metal that forms a salt with phosphoric acid is not particularly limited. For example, sodium, potassium, lithium, calcium, barium, magnesium, aluminum, titanium, iron, cobalt, nickel, copper, zinc, zirconium, palladium , Silver, tin, lead and the like.

  Further, the organic phosphorus compound may be a conventionally known one, and is not particularly limited. For example, a phosphoric acid ester such as methyl phosphate, a phosphoric acid diester such as dimethyl phosphate, and a triphosphate such as triphenyl phosphate. Ester, phosphorous acid, phosphorous acid ester such as methyl phosphite, phenyl phosphite, phosphorous acid diester such as diphenyl phosphite, phosphorous acid triester such as phosphorous triphenyl, phenylphosphonic acid, etc. Arylphosphonic acid, alkylphosphonic acid such as methylphosphonic acid, alkylphosphonous acid such as methylphosphonous acid, arylphosphonous acid such as phenylphosphonous acid, alkylphosphinic acid such as dimethylphosphinic acid, arylphosphine such as diphenylphosphinic acid Acids, alkylarylphosphinic acids such as phenylmethylphosphinic acid, di Alkyl phosphinic acids such as tilphosphinic acid, aryl phosphinic acids such as diphenylphosphinic acid, alkylaryl phosphinic acids such as phenylmethylphosphinic acid, lauryl acid phosphate, tridecyl acid phosphate, stearyl acid phosphate And the like, and acidic phosphate esters such as acidic phosphate esters.

  In this invention, 1 type, or 2 or more types chosen from these can be used.

  In the production method of the present invention, the amount of the acid catalyst used is not particularly limited, but is usually 0.01 to 20 with respect to the amount of the dihydroxyalkylpiperazine represented by the above formula (1) as the raw material. It is in the range of wt%, preferably in the range of 0.1-10 wt%. If it is less than 0.01% by weight, the reaction may be remarkably slow, and even if it exceeds 20% by weight, it may be economically disadvantageous.

  In the production method of the present invention, the reaction may be performed in a gas phase or a liquid phase. In addition, the reaction can be carried out by batch, semi-batch, continuous, or fixed bed flow type using a suspended bed, but industrially, the fixed bed flow type is advantageous in terms of operation, equipment, and economy.

  In the production method of the present invention, as a diluent, an inert gas such as nitrogen gas, hydrogen gas, ammonia gas, water vapor or hydrocarbon, or an inert solvent such as water or inert hydrocarbon is used as a raw material. A certain dihydroxyalkyl piperazine represented by the above formula (1) can be diluted to allow the reaction to proceed. These diluents can be used in any amount and are not particularly limited, but the molar ratio of dihydroxyalkylpiperazines / diluents represented by the above formula (1) should be in the range of 0.01-1. Preferably, the range is 0.05 to 0.5. When the molar ratio is 0.01 or more, the productivity of hydroxy (alkyl) triethylenediamines represented by the above formula (2) is improved. When the molar ratio is 1 or less, the selectivity of hydroxy (alkyl) triethylenediamine represented by the above formula (2) is improved.

  In the production method of the present invention, the diluent may be introduced into the reactor simultaneously with the dihydroxyalkylpiperazines represented by the above formula (1), or the dihydroxyalkylpiperazines represented by the above formula (1) may be introduced in advance. After dissolving in a diluent, it may be introduced into the reactor as a raw material solution.

  In the production method of the present invention, when the reaction is carried out in the gas phase, it is usually carried out in the presence of a gas inert to the reaction such as nitrogen gas or argon gas. The amount of the gas used is usually in the range of 1 to 20 mol, preferably 2 to 10 mol, per 1 mol of the dihydroxyalkylpiperazines represented by the above formula (1).

  In the production method of the present invention, the reaction temperature is usually in the range of 150 to 500 ° C, preferably 200 to 400 ° C. Since the decomposition of the raw material and the product is suppressed by setting the temperature to 500 ° C. or lower, the selectivity of the hydroxy (alkyl) triethylenediamine represented by the above formula (2) is improved. Reaction rate can be obtained.

  In the production method of the present invention, when the reaction is carried out in the gas phase, after completion of the reaction, the reaction mixed gas containing the hydroxy (alkyl) triethylenediamine represented by the above formula (2) is passed through water or an acidic aqueous solution. To obtain a reaction mixture containing hydroxy (alkyl) triethylenediamine represented by the formula (2). And hydroxy (alkyl) triethylenediamine shown by said Formula (2) can be obtained from the obtained reaction liquid mixture by desired isolation | separation purification operations, such as extraction and concentration. Moreover, it can also obtain as a hydrohalide salt using hydrohalic acid.

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

Reference Example 1 (Synthesis of dihydroxypropylpiperazine).
A 200 ml three-necked flask was charged with 86.1 g (1.0 mol) of piperazine and 100 ml of methanol as a solvent, and 22.2 g (0.3 mol) of glycidol was added dropwise over 4 hours under a nitrogen atmosphere. The temperature of the reaction solution was kept at 60 ° C. by holding the three-necked flask in an oil bath. After completion of the addition of glycidol, methanol as a solvent in the reaction solution and unreacted piperazine were distilled off by simple distillation. The product was vacuum-dried to obtain 45.2 g of a white viscous solid. This substance has the following formula (3)

で示されるジヒドロキシプロピルピペラジン（以下、表現を簡潔にするため、ＤＨＰＰと略す。）であることが、ガスクロマトグラフィー質量分析及び核磁気共鳴分析によって確認された。

It was confirmed by gas chromatography mass spectrometry and nuclear magnetic resonance analysis that it is dihydroxypropylpiperazine (hereinafter abbreviated as DHPP for the sake of brevity).

Reference Example 2 (Synthesis of dihydroxypropylpiperazine).
Piperazine 86.1 g (1.0 mol), glycerin 92.1 g (1.0 mol), aluminum phosphate (made by Wako Pure Chemical Industries, Ltd., for chemical use) 5.0 g as a catalyst, 600 ml of water as a solvent, 1000 ml autoclave And heated to 280 ° C. under a nitrogen atmosphere. The reaction vessel pressure at this time was 6.0 MPa. The reaction time was 2 hours. After completion of the reaction, water as a solvent in the reaction solution and unreacted piperazine, glycerin and by-products were distilled off by distillation to obtain the desired product (white viscous solid 16.4 g). This material was confirmed to be DHPP by gas chromatography mass spectrometry and nuclear magnetic resonance analysis.

Reference Example 3 (Synthesis of dihydroxypropylpiperazine).
Piperazine 86.1 g (1.0 mol), chloropropanediol 55.3 g (0.5 mol), and 200 ml of methanol as a solvent were charged into a 500 ml three-necked flask and heated to 60 ° C. in a nitrogen atmosphere. The reaction vessel pressure at this time was atmospheric pressure. The reaction time was 16 hours. After completion of the reaction, the reaction solution was separated by adding a 5 mol / L sodium hydroxide aqueous solution, and the product contained in the organic layer was extracted with 1-butanol. After distilling off water, which was a solvent in the reaction solution, and unreacted piperazine, by-products, and the like by distillation, the target product (56.1 g of white viscous solid) was obtained. This material was confirmed to be DHPP by gas chromatography mass spectrometry and nuclear magnetic resonance analysis.

Example 1.
A 200 ml autoclave was charged with 16.0 g (0.10 mol) of DHPP obtained in Reference Example 1, 100 ml of water as a solvent, and 5.0 g of aluminum phosphate (manufactured by Wako Pure Chemical Industries, Ltd., chemical) as a catalyst. Heated to 280 ° C. under atmosphere. The reaction vessel pressure at this time was 8.0 MPa. The reaction time was 2 hours.

  As a result of analyzing the product by gas chromatography, the conversion rate of DHPP was 59%, and the selectivity was 85% for hydroxymethyltriethylenediamine and 13% for triethylenediamine produced by elimination of the hydroxymethyl group.

Example 2
The reaction was carried out in the same manner as in Example 1 except that DHPP obtained in Reference Example 2 was used instead of DHPP in Reference Example 1.

  As a result of analyzing the product by gas chromatography, the conversion rate of DHPP was 60%, and the selectivity was 84% for hydroxymethyltriethylenediamine and 14% for triethylenediamine produced by elimination of the hydroxymethyl group.

Example 3
The reaction was carried out in the same manner as in Example 1 except that DHPP obtained in Reference Example 3 was used instead of DHPP in Reference Example 1.

  As a result of analyzing the product by gas chromatography, the conversion rate of DHPP was 61%, and the selectivity was 85% for hydroxymethyltriethylenediamine and 14% for triethylenediamine produced by elimination of the hydroxymethyl group.

Example 4
16.0 g (0.10 mol) of DHPP obtained in Reference Example 1, 100 ml of water as a solvent, and 5.0 g of phenylphosphonic acid (manufactured by Wako Pure Chemical Industries, Ltd., for chemical use) as a solvent were charged into a 200 ml autoclave, and nitrogen was added. Heated to 280 ° C. under atmosphere. The reaction vessel pressure at this time was 8.0 MPa. The reaction time was 2 hours.

  As a result of analyzing the product by gas chromatography, the conversion rate of DHPP was 67%, and the selectivity was 76% for hydroxymethyltriethylenediamine and 24% for triethylenediamine produced by elimination of the hydroxymethyl group.

Comparative Example 1
16.0 g (0.10 mol) of DHPP g obtained in Reference Example 1, 100 ml of water as a solvent, 200 ml of an autoclave was charged without adding a catalyst, and after purging with nitrogen, heated to 280 ° C. The reaction vessel pressure at this time was 8.0 MPa. The reaction time was 2 hours.
As a result of analyzing the product by gas chromatography, the conversion of DHPP was 0%.

Comparative Example 2
16.0 g (0.10 mol) of DHPP obtained in Reference Example 1, 100 ml of water as a solvent, 10.0 g of Raney nickel catalyst (dry weight 5.0 g) were charged into a 200 ml autoclave, and after hydrogen purging, hydrogen was pressurized. To 150 ° C. The reaction vessel pressure at this time was 10.0 MPa. The reaction time was 2 hours.

  As a result of analyzing the product by gas chromatography, the conversion of DHPP was 0%.

Claims (9)

Following formula (1)

(In the 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)
Wherein the dihydroxyalkylpiperazines represented by the formula are subjected to an intramolecular dehydration condensation reaction in the presence of aluminum phosphate or phenylphosphonic acid as an acid catalyst.

(Wherein R and n have the same definitions as above)
The manufacturing method of hydroxy (alkyl) triethylenediamine shown by these. Furthermore, intramolecular dehydration condensation reaction is performed in presence of water, The manufacturing method of Claim 1 characterized by the above-mentioned. The dihydroxyalkylpiperazines represented by the above formula (1) are represented by the following formula (3)

The production method according to claim 1, wherein the production method is dihydroxypropylpiperazine. The dihydroxyalkylpiperazines represented by the above formula (1) are piperazine and the following formula (4)

(In the 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)
The production method according to claim 1 or 2, which is a dihydroxyalkyl piperazine obtained by an addition reaction with a compound represented by formula (1). The dihydroxyalkylpiperazines represented by the above formula (1) are piperazine and the following formula (5)

(In the 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)
The production method according to claim 1 or 2, which is a dihydroxyalkyl piperazine obtained by subjecting the compound represented by the above to dehydration condensation reaction in the presence of an acid catalyst. The dihydroxyalkylpiperazines represented by the above formula (1) are piperazine and the following formula (6)

(In the formula, R represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms, n represents an integer of 0 to 6. X represents a halogen atom.)
The production method according to claim 1 or 2, which is a dihydroxyalkyl piperazine obtained by a reaction with a compound represented by formula (1). The production method according to claim 3, wherein the dihydroxypropyl piperazine represented by the formula (3) is dihydroxypropyl piperazine obtained by addition reaction of piperazine and glycidol. The production method according to claim 3, wherein the dihydroxypropylpiperazine represented by the formula (3) is dihydroxypropylpiperazine obtained by subjecting piperazine and glycerol to a dehydration condensation reaction in the presence of an acid catalyst. . The production method according to claim 3, wherein the dihydroxypropyl piperazine represented by the formula (3) is dihydroxypropyl piperazine obtained by reaction of piperazine and chloropropanediol.