JP2011213688A - Mixture of n-((dihydroxyalkyl)2-aminoethyl)ethanolamines, and method for producing 2-hydroxy(alkyl)triethylenediamines using the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for synthesizing hydroxy(alkyl)triethylenediamines and a mixture of N-((dihydroxyalkyl)2-aminoethyl)ethanolamines as a raw material.SOLUTION: The method includes dehydrative intramolecular condensation reaction of a compound of formula (1) and a compound of formula (2). In the formulas, R represents a hydrogen atom or a 1-4C alkyl group; and n is 0 to 6.

Description

  The present invention relates to a mixture of N-((dihydroxyalkyl) 2-aminoethyl) ethanolamine and a method for producing hydroxy (alkyl) triethylenediamine using the same.

  The N-((dihydroxyalkyl) 2-aminoethyl) ethanolamine mixture of the present invention is useful as a raw material for 2-hydroxy (alkyl) triethylenediamines.

  2-Hydroxy (alkyl) triethylenediamines are known to be useful for medical and agricultural intermediates, organic synthesis catalysts, urethane resination catalysts, chemical adsorbents, antibacterial agents and the like.

  As a conventional method for producing 2-hydroxy (alkyl) triethylenediamine, for example, an intermediate hydroxyalkylpiperazine is synthesized from N- (dihydroxyalkyl) ethylenediamine (see, for example, Patent Document 1 and Patent Document 2). ), And then a method for producing an intramolecular condensation reaction of the obtained hydroxyalkylpiperazines as disubstituted hydroxyalkylpiperazines by reaction with alkylene oxide in the presence of an acid catalyst (for example, patent literature). 2).

  However, the above production method has many reaction steps, and a simplified production method has been demanded.

  As another synthesis method, piperazine and ethyl 2,3-dibromopropionate are reacted in an inert solvent such as toluene or benzene to produce 1,4-diazabicyclo [2.2.2] octane-2-carboxylic acid. A two-step synthesis method is known in which ethyl acid is prepared and then the resulting ester is reduced using, for example, lithium aluminum hydride (see, for example, Patent Document 3).

  However, this production method has the disadvantage that the productivity is inferior because piperazine and ethyl 2,3-dibromopropionate need to be reacted at a low substrate concentration. Moreover, in order to perform the next reaction efficiently, the product obtained in the first step had to be isolated and purified. Next, in the second step, lithium aluminum hydride, which has a high risk of ignition, is used as the reducing agent, which is not industrially preferable. Furthermore, piperazine used as a raw material is expensive, and particularly ethyl 2,3-dibromopropionate is very expensive, so it is difficult to say that it is practical.

  As described above, using raw materials that are inexpensive and industrially stable, and without using reducing agents with high risk of ignition, hydroxy (alkyl) triethylenediamines can be efficiently and safely produced with a small number of steps. It was very difficult to synthesize it.

  On the other hand, as a reaction example of N- (2-aminoethyl) ethanolamine and an epoxy compound, a mixture of diethyltriamine mainly composed of N- (2-aminoethyl) ethanolamine, aminoethylpiperazine, and hydroxyethylpiperazine Shows an example in which ethylene oxide is reacted (for example, see Patent Document 4). In addition, it has been reported that triethylenediamine can be obtained from the obtained ethylene oxide addition reaction product by dehydration cyclization within the molecule using a phosphoric acid-supported catalyst.

  Examples of other N- (2-aminoethyl) ethanolamine derivatives include reacting N- (2-aminoethyl) ethanolamine with an alkyl glycidyl ether having 12 to 14 carbon atoms, and then adding sodium chloroacetate. There is an example in which a surfactant is obtained by reaction (see, for example, Patent Document 5).

  However, no examples have been reported so far that have confirmed the production of N-((dihydroxyalkyl) 2-aminoethyl) ethanolamine, which is considered useful for the synthesis of 2-hydroxy (alkyl) triethylenediamines.

Austrian Patent 227,268 International Publication No. 2009/145320 Pamphlet JP 2001-504855 A US Pat. No. 4,757,143 US Pat. No. 4,214,102

  The present invention has been made in view of the above-described background art, and uses a raw material that is inexpensive and industrially stable, and can be easily and safely reduced without using a reducing agent that has a high risk of ignition. It is to provide a method for producing hydroxy (alkyl) triethylenediamine by the number of steps, and to provide a novel N-((dihydroxyalkyl) 2-aminoethyl) ethanolamine mixture as such a raw material.

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

  That is, the present invention relates to an N-((dihydroxyalkyl) 2-aminoethyl) ethanolamine mixture and a method for producing 2-hydroxy (alkyl) triethylenediamine using the same, 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のアルキル基を表し、ｎは０〜６の整数を表す。）
で示される化合物と、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).
And a compound represented by the following formula (2)

（式中、Ｒ、ｎは上記と同じ定義である。）
で示される化合物とを含有することを特徴とするＮ−（（ジヒドロキシアルキル）２−アミノエチル）エタノールアミン類の混合物。

(In the formula, R and n are as defined above.)
And a mixture of N-((dihydroxyalkyl) 2-aminoethyl) ethanolamines, characterized by comprising:

[2] In the above [1], the compound represented by the formula (2) is contained in a ratio of 60:40 to 40:60 (weight ratio) with respect to the compound represented by the formula (1). [3] The following formula (3)

（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のアルキル基を表し、Ｘはハロゲン原子を表し、ｎは０〜６の整数を表す。）
で示されるハロゲン化ジオールと、Ｎ−（２−アミノエチル）エタノールアミンとを反応させることを特徴とする上記［１］又は［２］に記載の混合物の製造方法。

(In the above formula, R represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms, X represents a halogen atom, and n represents an integer of 0 to 6).
The method for producing a mixture according to the above [1] or [2], wherein the halogenated diol represented by the formula (1) is reacted with N- (2-aminoethyl) ethanolamine.

  [4] The mixture according to the above [1] or [2] is subjected to an intramolecular dehydration condensation reaction in the presence of an acid catalyst and / or a Raney metal catalyst to obtain 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、下記式（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)
A compound represented by formula (5):

（式中、Ｒ、ｎは上記と同じ定義である。）
で示される化合物、並びに下記式（６）

(In the formula, R and n are as defined above.)
As well as the following formula (6)

（式中、Ｒ、ｎは上記と同じ定義である。）
で示される化合物からなる群より選択される１種又は２種以上の化合物を得ることを特徴とするジ置換ヒドロキシアルキルピペラジン類の製造方法。

(In the formula, R and n are as defined above.)
A method for producing disubstituted hydroxyalkylpiperazines, characterized in that one or more compounds selected from the group consisting of compounds represented by formula (1) are obtained.

  [5] A disubstituted hydroxyalkylpiperazine obtained by the method described in [4] above is subjected to an intramolecular dehydration condensation reaction in the presence of an acid catalyst.

（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２−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。

(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 of 2-hydroxy (alkyl) triethylenediamine shown by these.

  [6] The production method according to the above [4], wherein the Raney metal catalyst includes a Raney copper catalyst.

  [7] The above [4] to [6], wherein the acid catalyst includes a compound selected from the group consisting of an inorganic phosphorus compound, a metal salt of the inorganic phosphorus compound, and an organic phosphorus compound. The manufacturing method as described.

  According to the production method of the present invention, there is a risk of ignition using a mixture of the above-described N-((dihydroxyalkyl) 2-aminoethyl) ethanolamines as a raw material that is inexpensive and industrially stable. Without using a high reducing agent, hydroxy (alkyl) triethylenediamines can be efficiently synthesized in a simple and safe manner with a relatively small number of steps.

1 is a diagram showing a ¹ H-NMR (solvent D ₂ O, acetic acid-containing product) peak of N- (dihydroxypropyl) N- (2-aminoethyl) ethanolamine (peak 1 compound) obtained in Example 1. FIG. 1 is a diagram showing a ¹ H-NMR (solvent D ₂ O, acetic acid-containing product) peak of N-((N′-dihydroxypropyl) 2-aminoethyl) ethanolamine (peak 2 compound) obtained in Example 1. FIG. . 1 is a diagram showing a ¹³ C-NMR (solvent D ₂ O, acetic acid-containing product) peak of N- (dihydroxypropyl) N- (2-aminoethyl) ethanolamine (peak 1 compound) obtained in Example 1. FIG. It is a diagram showing a ((N'-dihydroxypropyl) aminoethyl) ethanolamine (peak 2 ^compound) 13 C-NMR (solvent _D 2 O, acetic acid product) peak - N obtained in Example 1.

  Hereinafter, the present invention will be described in detail.

A mixture of N-((dihydroxyalkyl) 2-aminoethyl) ethanolamines of the present invention (hereinafter sometimes referred to as “mixture of the present invention”) is a compound represented by the above formula (1), It is characterized by containing a compound represented by the formula (2) In the above formulas (1) and (2), R is a hydrogen atom or a linear or branched alkyl having 1 to 4 carbon atoms. Represents a group. Specific examples include a methyl group, an ethyl group, a propyl group, an isopropyl group, and a butyl group. Of these, a hydrogen atom, a methyl group, and an ethyl group are preferable.

  Moreover, n represents the integer of 0-6 in the said Formula (1) and Formula (2), and the integer of 0-2 is more preferable.

  N-((dihydroxyalkyl) 2-aminoethyl) ethanolamines represented by the above formula (1) or formula (2) are not particularly limited. For example, N-((dihydroxypropyl) 2- Aminoethyl) ethanolamine, N-((dihydroxybutyl) 2-aminoethylethanolamine, N-((dihydroxyhexyl) 2-aminoethylethanolamine, and the like.

  The method for producing the mixture of the present invention is not particularly limited, but for example, by applying a conventional synthesis method, an addition reaction between N- (2-aminoethyl) ethanolamine and an epoxy compound (for example, the United States) Patent No. 4,757,143, International Publication No. 2009/145320 pamphlet), N- (2-aminoethyl) ethanolamine and a trihydroxy compound are subjected to a dehydration condensation reaction in the presence of an acid catalyst. (See, for example, WO-2009 / 145320) and addition reaction between N- (2-aminoethyl) ethanolamine and a halogenated alkyldihydroxy compound (for example, International Publication No. 2009/145320, Journal of the American Chemical Society). (1952) 74, 410 Etc. can be obtained by reference) pp -4103.

  Specifically, the mixture of the present invention is obtained by addition reaction of N- (2-aminoethyl) ethanolamine and glycidol, and N- (2-aminoethyl) ethanolamine and glycerin are dehydrated in the presence of an acid catalyst. It can also be obtained by a condensation reaction. It can also be obtained by reacting N- (2-aminoethyl) ethanolamine with the halogenated diol represented by the above formula (3).

  The mixture of the present invention thus obtained contains a compound represented by the above formula (1) and a compound represented by the above formula (2) in a ratio of usually 60:40 to 40:60 (weight ratio). Contains.

The method for producing 2-hydroxy (alkyl) triethylenediamine represented by the above formula (7) of the present invention is as follows.
(I) The above-described mixture of the present invention is subjected to an intramolecular dehydration condensation reaction in the presence of an acid catalyst and / or a Raney metal catalyst, and the compound represented by the above formula (4) or the above compound (5). And obtaining one or more disubstituted hydroxyalkylpiperazines selected from the group consisting of the compounds represented by the above formula (6), and (ii) the obtained disubstituted hydroxyalkylpiperazines, It is characterized by comprising a step of obtaining a 2-hydroxy (alkyl) triethylenediamine represented by the above formula (7) by intramolecular dehydration condensation reaction in the presence of an acid catalyst.

  In the present invention, the 2-hydroxy (alkyl) triethylenediamine represented by the formula (7) is 2-hydroxytriethylenediamine (when n = 0) or 2-hydroxyalkyltriethylenediamine (n = 1). ~ 6). Such 2-hydroxy (alkyl) triethylenediamines are not particularly limited, and examples thereof include 2-hydroxymethyltriethylenediamine, 2-hydroxyethyltriethylenediamine, 2-hydroxypropyltriethylenediamine, and 2-hydroxybutyltriethylenediamine. Etc.

  First, the step of obtaining the above-mentioned disubstituted hydroxyalkylpiperazines by subjecting the mixture of the present invention to an intramolecular dehydration condensation reaction in the presence of an acid catalyst and / or a Raney metal catalyst will be described.

  In the above step, the acid catalyst is not particularly limited. For example, 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, Group 4B metal oxide condensation catalyst, Group 6B metal-containing condensation catalyst, Bronsted acid, Lewis acid and the like. Of these, phosphorus-containing substances such as metal phosphates and organic phosphorus compounds are particularly preferred.

  Although it does not specifically limit as a metal phosphate, For example, metal salts, such as phosphoric acid, phosphorous acid, hypophosphorous acid, are mentioned. 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.

  The organic phosphorus compound is not particularly limited, but examples thereof include phosphate esters such as methyl phosphate, phosphate diesters such as dimethyl phosphate, phosphate triesters such as triphenyl phosphate, phosphorous acid, Phosphorous esters such as methyl phosphate and phenyl phosphite, phosphorous diesters such as diphenyl phosphite, phosphorous triesters such as phosphorous triphenyl, arylphosphonic acids such as phenylphosphonic acid, methylphosphonic acid, etc. Alkylphosphonic acid such as methylphosphonous acid, arylphosphonous acid such as phenylphosphonic acid, alkylphosphinic acid such as dimethylphosphinic acid, arylphosphinic acid such as diphenylphosphinic acid, phenylmethylphosphinic acid, etc. Alkylarylphosphinic acid, dimethylphosphine Such as alkyl phosphinic acid such as diphenylphosphinic acid, alkylaryl phosphinic acid such as phenylmethylphosphinic acid, acidic phosphorus such as lauryl acid phosphate, tridecyl acid phosphate, stearyl acid phosphate Examples include acid esters and salts of acidic phosphates.

  In the said process, 1 type, or 2 or more types chosen from these acid catalysts can be used.

  Although the usage-amount of an acid catalyst is not specifically limited, 0.01 0.01 normally with respect to the total usage-amount of the compound shown by the said Formula (1) and the compound shown by the said Formula (2) which is a raw material. The range is -20% by weight, preferably 0.1-10% by weight. 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.

  On the other hand, in the said process, although it does not specifically limit as a Raney metal catalyst, For example, Raney copper, metal copper, a copper chromium catalyst, copper phosphate, etc. are mentioned. Of these, Raney copper is particularly preferably included.

  The amount of the Raney metal catalyst used is not particularly limited, but is usually from about 0.1 to the total amount of the compound represented by the above formula (1) and the compound represented by the above formula (2), which are raw materials. The range is 01 to 20% by weight, preferably 0.1 to 10% by weight. 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 above step, an intramolecular dehydration condensation reaction may be performed using an acid catalyst and a Raney metal catalyst in combination.

  In the above step, the reaction is usually performed in a hydrogen atmosphere. The amount of the gas used is usually in the range of 1 to 20 times mol, preferably 2 to 10 times mol, of the total amount of the compound represented by the formula (1) and the compound represented by the formula (2). It is.

  In the above step, the reaction pressure is usually in the range of 1 to 200 atmospheres, preferably 30 to 100 atmospheres. Since the decomposition of the raw material and the product is suppressed when the pressure is 200 atm or less, the selectivity of the disubstituted hydroxyalkylpiperazines is improved, and a sufficient reaction rate is obtained by setting the pressure to 30 atm or more.

  In the above step, the reaction temperature is usually in the range of 150 to 500 ° C, preferably 100 to 400 ° C. When the temperature is 500 ° C. or lower, decomposition of the raw material and the product is suppressed, so that the selectivity of the disubstituted hydroxyalkylpiperazines is improved, and when the temperature is 130 ° C. or higher, a sufficient reaction rate is obtained.

  The disubstituted hydroxyalkylpiperazines obtained by the above steps are prepared by adding 0 to 64 mol of the compound represented by the above formula (4), the compound represented by the above formula (5), and the compound represented by the above formula (6), respectively. In the range of ratio%, 3 to 41 mole ratio%, and 33 to 59 mole ratio% (however, the compound represented by the above formula (4), the compound represented by the above formula (5), and the above formula (6) The total amount of the compounds represented by) does not exceed 100 molar ratio%).

  Next, the step of obtaining the 2-hydroxy (alkyl) triethylenediamine represented by the above formula (7) by subjecting the obtained disubstituted hydroxyalkylpiperazines to an intramolecular dehydration condensation reaction in the presence of an acid catalyst will be described. .

  In the above step, the acid catalyst is not particularly limited. For example, 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, Group 4B metal oxide condensation catalyst, Group 6B metal-containing condensation catalyst, Bronsted acid, Lewis acid and the like. Of these, phosphorus-containing substances such as metal phosphates and organic phosphorus compounds are particularly preferred.

  Although it does not specifically limit as a metal phosphate, For example, metal salts, such as phosphoric acid, phosphorous acid, hypophosphorous acid, are mentioned. 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.

  The organic phosphorus compound is not particularly limited, but examples thereof include phosphate esters such as methyl phosphate, phosphate diesters such as dimethyl phosphate, phosphate triesters such as triphenyl phosphate, phosphorous acid, Phosphorous esters such as methyl phosphate and phenyl phosphite, phosphorous diesters such as diphenyl phosphite, phosphorous triesters such as phosphorous triphenyl, arylphosphonic acids such as phenylphosphonic acid, methylphosphonic acid, etc. Alkylphosphonic acid such as methylphosphonous acid, arylphosphonous acid such as phenylphosphonic acid, alkylphosphinic acid such as dimethylphosphinic acid, arylphosphinic acid such as diphenylphosphinic acid, phenylmethylphosphinic acid, etc. Alkylarylphosphinic acid, dimethylphosphine Such as alkyl phosphinic acid such as diphenylphosphinic acid, alkylaryl phosphinic acid such as phenylmethylphosphinic acid, acidic phosphorus such as lauryl acid phosphate, tridecyl acid phosphate, stearyl acid phosphate Examples include acid esters and salts of acidic phosphates.

  In the said process, 1 type, or 2 or more types chosen from these acid catalysts can be used.

  Although the usage-amount of an acid catalyst is not specifically limited, The compound shown by the said Formula (4), the compound shown by the said Formula (5), and the compound shown by the said Formula (6) which is a raw material is a raw material. It is usually in the range of 0.01 to 20% by weight, preferably in the range of 0.1 to 10% by weight, based on the total amount used. 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 above step, 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 above step, the diluent is a raw material using 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. The disubstituted hydroxyalkylpiperazines can be diluted to allow the reaction to proceed. These diluents can be used in any amount, and the amount used is not particularly limited, but [the compound represented by the above formula (4), the compound represented by the above formula (5), and the above formula ( 6) The total use amount of the compounds represented by 6) / [the use amount of the diluent] (molar ratio) is preferably in the range of 0.01 to 1, more preferably in the range of 0.05 to 0.5. More preferably. When the molar ratio is 0.01 or more, the productivity of hydroxy (alkyl) triethylenediamines represented by the above formula (7) is improved. When the molar ratio is 1 or less, the selectivity of the hydroxy (alkyl) triethylenediamine represented by the above formula (7) is improved.

  In the above step, the diluent may be introduced into the reactor at the same time as the disubstituted hydroxyalkylpiperazines described above, or after dissolving the disubstituted hydroxyalkylpiperazines in the diluent in advance, It may be introduced into the reactor.

  In the above step, 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 1 to 20 with respect to the total amount of the compound represented by the above formula (4), the compound represented by the above formula (5), and the compound represented by the above formula (6). It is in the range of double mole, preferably 2-10 mole.

  In the above step, 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 hydroxy (alkyl) triethylenediamine represented by the above formula (7) is improved, and it is sufficient that the temperature is 150 ° C. or higher Reaction rate can be obtained.

  In the above step, when the reaction is carried out in the gas phase, after completion of the reaction, the reaction mixed gas containing hydroxy (alkyl) triethylenediamine represented by the above formula (7) is dissolved through water or an acidic aqueous solution, A reaction mixture containing hydroxy (alkyl) triethylenediamine represented by the above formula (7) is obtained. And hydroxy (alkyl) triethylenediamine shown by said Formula (7) 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. In addition, the yield of the product in a present Example was confirmed with the gas chromatography.

Analyzer: Shimadzu Corporation GC-17A,
Column: Capillary column manufactured by J & W Scientific, NB-5
Detector: Hydrogen flame ionization detector (FID),
Column temperature condition: temperature rise.

  Further, the molecular weight is confirmed using a gas chromatograph-mass spectrometer (GC-MS, manufactured by JEOL Ltd., GC-MS JMS-K9), and the column is a J & W Scientific capillary column, DB-1, which is performed under temperature rising conditions. It was.

Furthermore, VXR-300S manufactured by Varian was used for ¹ H-NMR and ¹³ C-NMR measurements of the compound.

Example 1 Synthesis of a mixture of N-((dihydroxypropyl) 2-aminoethyl) ethanolamines.
A 200 ml three-necked flask was charged with 41.7 g (0.40 mol) of N- (2-aminoethyl) ethanolamine and 41.7 g of methanol as a solvent, and 3-chloro-1,2-propanediol 11 was added under a nitrogen atmosphere. 0.1 g (0.10 mol) was added dropwise over 0.5 hours. By holding the three-necked flask in an oil bath, the temperature of the reaction solution was kept at 60 to 72 ° C. After completion of dropwise addition of 3-chloropropanediol, the reaction temperature was further maintained at 72 ° C. and the reaction was continued for 14 hours. After the reaction, the mixture was neutralized by adding 13.0 g (0.10 mol) of a 32% aqueous sodium hydroxide solution, and methanol and unreacted N- (2-aminoethyl) ethanol as the solvent in the reaction solution were obtained by simple distillation. The amine was distilled off. Isopropanol was added to the resulting viscous product, followed by filtration and reconcentration to obtain 16.9 g of crude N-((dihydroxypropyl) 2-aminoethyl) ethanolamine. When the concentrated product was analyzed by gas chromatography, two characteristic peaks were observed. The composition ratio (molar ratio) of peak 1 / peak 2 was 28/72. When these were subjected to GC-MS measurement, their molecular weights were all 178, and it was found that the products were two types of N-((dihydroxypropyl) 2-aminoethyl) ethanolamines.

Further, 3.1 g of a crude N-((dihydroxypropyl) 2-aminoethyl) ethanolamine mixture was added to a silica gel column (Wako Gel C-300, manufactured by Wako Pure Chemical Industries, chloroform / methanol / acetic acid = 20/10/1 mixed solvent). And then neutralization treatment, 1.0 g of peak 1 compound and 1.1 g of peak 2 compound could be isolated. The results of measuring ¹ H-NMR and ¹³ C-NMR of each compound are shown in FIGS. 1, 2, 3, and 4.

  From these results, the compound of peak 1 is represented by the following formula (8).

で示されるＮ−（ジヒドロキシプロピル）Ｎ−（２−アミノエチル）エタノールアミン（以下、表現を簡潔にするため、「ＡＥＥＡ−２ＰＤ」と略す。）であることが確認された。これは上記式（２）で示される化合物に該当する。

N- (dihydroxypropyl) N- (2-aminoethyl) ethanolamine (hereinafter abbreviated as “AEEA-2PD” for the sake of brevity). This corresponds to the compound represented by the above formula (2).

  The compound of peak 2 is represented by the following formula (9)

で示されるＮ−（（Ｎ’−ジヒドロキシプロピル）２−アミノエチル）エタノールアミン（以下、表現を簡潔にするため、「ＡＥＥＡ−１ＰＤ」と略す。）であることが確認された。これは上記式（１）で示される化合物に該当する。

N-((N′-dihydroxypropyl) 2-aminoethyl) ethanolamine (hereinafter abbreviated as “AEEA-1PD” for the sake of brevity). This corresponds to the compound represented by the above formula (1).

  In addition, the yield of these 2 types of AEEA-PD sum total was 95% from the measurement by the gas chromatography of a concentrate.

Example 2 Synthesis of N-((dihydroxypropyl) 2-aminoethyl) ethanolamines.
A 20-liter four-necked reactor was charged with 6.9 kg (66.25 mol) of N- (2-aminoethyl) ethanolamine and 5.3 kg of methanol as a solvent, and 98% glycidol 1 under cooling in a nitrogen atmosphere. 0.5 kg (19.84 mol) was added dropwise over 3 hours. The temperature of the reaction solution was kept at 29 to 34 ° C. by holding the four-necked reactor in the cooling bath. After the addition of glycidol, the reaction temperature was kept at 34 ° C. or lower and the reaction was continued for 2 hours. After the reaction, methanol, which is a solvent in the reaction solution, and unreacted N- (2-aminoethyl) ethanolamine are distilled off by simple distillation to obtain crude N-((dihydroxypropyl) 2-aminoethyl) ethanolamine. 2 kg was obtained. The composition ratio (molar ratio) of AEEA-1PD / AEEA-2PD was 66/34 from the measurement by gas chromatography of the concentrated solution, and the total yield was 79%.

Example 3 Synthesis of disubstituted hydroxypropylpiperazines.
18.7 g (0.11 mol) of a mixture of AEEA-1PD and AEEA-2PD obtained in Example 2, 106.3 g of water as a solvent, Raney copper as a catalyst (trade name CDT-60: Kawaken Fine Chemical Co., Ltd.) 1.9 g) was charged into a 200 ml autoclave, purged with nitrogen, and heated to 165 ° C. in a hydrogen atmosphere. The reaction vessel pressure at this time was 8.0 MPa. The reaction time was 6 hours.

  As a result of analyzing the reaction solution by gas chromatography, the conversion rates of AEEA-1PD and AEEA-2PD are 100% and 69%, respectively, and the product has three characteristic peaks (peak 3 to peak 5). It was observed. The composition ratio (molar ratio) of peak 3 / peak 4 / peak 5 was 38/3/59, respectively. When these were measured by GC-MS, the molecular weight of each was 160, and the spectral pattern of GC-MS revealed that the products were three kinds of disubstituted hydroxypropylpiperazines.

  That is, the product of peak 3 is represented by the following formula (10)

で示されるＮ−（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。）であることが確認された。これは、上記式（６）に該当する化合物である。

N- (dihydroxypropyl) piperazine (hereinafter abbreviated as “DHPP” for the sake of brevity). This is a compound corresponding to the above formula (6).

  The compound of peak 4 is represented by the following formula (11)

で示されるＮ−（（ヒドロキシエチル）３−ヒドロキシメチルピペラジン（以下、表現を簡潔にするため、「４−ＨＥ−ＰＩＰＯＨ」と略す。）であることが確認された。これは、上記式（５）に該当する化合物である。

N-((hydroxyethyl) 3-hydroxymethylpiperazine (hereinafter abbreviated as “4-HE-PIPOH” for the sake of brevity of expression). It is a compound corresponding to 5).

  Furthermore, the compound of peak 5 is represented by the following formula (12):

で示されるＮ−（（ヒドロキシエチル）２−ヒドロキシメチルピペラジン（以下、表現を簡潔にするため、「１−ＨＥ−ＰＩＰＯＨ」と略す。）であることが確認された。これは上記式（４）に該当する化合物である。

N-((hydroxyethyl) 2-hydroxymethylpiperazine (hereinafter abbreviated as “1-HE-PIPOH” for the sake of brevity), which was confirmed by the above formula (4 ).

  From the measurement by gas chromatography, the total yield of the three kinds of disubstituted hydroxypropylpiperazines was 49%.

Example 4
3. 37.5 g (0.21 mol) of a mixture of AEEA-1PD and AEEA-2PD obtained in Example 2; 87.5 g of water as a solvent; and 1.9 g of Raney copper as a catalyst. A 200 ml autoclave was filled in the same manner as in Example 3 except that the amount was increased to 8 g, and after purging with nitrogen, it was heated to 165 ° C. in a hydrogen atmosphere. The reaction vessel pressure at this time was 8.0 MPa. The reaction time was 6 hours.

  As a result of analyzing the product by gas chromatography, the conversion rates of AEEA-1PD and AEEA-2PD were 100% and 93%, respectively. As for the selectivity, DHPP / 4-HE-PIPOH / 1-HE-PIPOH was 40/5/55 (molar ratio), respectively, and the total yield was 50%.

Example 5 FIG.
A mixture of AEEA-1PD and AEEA-2PD obtained in Example 2 (37.5 g, 0.21 mol), water as a solvent, 87.5 g, Raney copper as a catalyst (trade name: CDT-60, manufactured by Kawaken Fine Chemical Co., Ltd.) ) 3.8 g was charged into a 200 ml autoclave, purged with nitrogen, and heated to 165 ° C. in a hydrogen atmosphere. The reaction vessel pressure at this time was 8.0 MPa. The reaction time was 6 hours.

  As a result of analyzing the product by gas chromatography, the conversion rates of AEEA-1PD and AEEA-2PD were 97% and 68%, respectively. As for the selectivity, DHPP / 4-HE-PIPOH / 1-HE-PIPOH was 35/5/60 (molar ratio), respectively, and the total yield was 47%.

Example 6
A mixture of 18.7 g (0.11 mol) of AEEA-1PD and AEEA-2PD obtained in Example 2, a two-layer solution of 53.2 g of water and 46.8 g of toluene as a solvent, Raney copper (trade name CDT as a catalyst) -60: Kawaken Fine Chemical Co., Ltd. (1.9 g) was charged in a mixture of 17.5 g (0.11 mol) in a 200 ml autoclave, purged with nitrogen, and heated to 165 ° C. in a hydrogen atmosphere. The reaction vessel pressure at this time was 8.0 MPa. The reaction time was 6 hours.

  As a result of analyzing the product by gas chromatography, the conversion rates of AEEA-1PD and AEEA-2PD were 100% and 70%, respectively. As for the selectivity, DHPP / 4-HE-PIPOH / 1-HE-PIPOH was 38/4/58 (molar ratio), respectively, and the total yield was 44%.

Example 7
37.5 g (0.21 mol) of a mixture of AEEA-1PD and AEEA-2PD obtained in Example 2, 87.5 g of water as a solvent, Raney copper as a catalyst (trade name CDT-60: Kawaken Fine Chemical Co., Ltd.) A 200 ml autoclave was charged in a 200 ml autoclave, purged with nitrogen, heated to 165 ° C. in a hydrogen atmosphere, and the reaction was carried out in the same manner as in Example 3. The reaction vessel pressure at this time was 7.7 MPa. The reaction time was 6 hours.

  As a result of analyzing the product by gas chromatography, the conversion rates of AEEA-1PD and AEEA-2PD were 81% and 38%, respectively. As for the selectivity, DHPP / 4-HE-PIPOH / 1-HE-PIPOH was 33/4/63 (molar ratio), respectively, and the total yield was 39%.

Example 8 FIG.
A mixture of AEEA-1PD and AEEA-2PD obtained in Example 2 (37.5 g, 0.21 mol), water as a solvent, 87.5 g, Raney copper as a catalyst (trade name: CDT-60, manufactured by Kawaken Fine Chemical Co., Ltd.) ) 1.5 g was charged into a 200 ml autoclave, purged with nitrogen, heated to 150 ° C. in a hydrogen atmosphere, and the reaction was carried out in the same manner as in Example 3. The reaction vessel pressure at this time was 7.3 MPa. The reaction time was 10 hours.

  As a result of analyzing the product by gas chromatography, the conversion rates of AEEA-1PD and AEEA-2PD were 53% and 33%, respectively. As for the selectivity, DHPP / 4-HE-PIPOH / 1-HE-PIPOH was 33/3/64 (molar ratio), respectively, and the total yield was 27%.

Example 9
A mixture of AEEA-1PD and AEEA-2PD obtained in Example 2 (37.5 g, 0.21 mol), water as a solvent, 87.5 g, Raney copper as a catalyst (trade name: CDT-60, manufactured by Kawaken Fine Chemical Co., Ltd.) ) 1.5 g was charged into a 200 ml autoclave, purged with nitrogen, heated to 180 ° C. in a hydrogen atmosphere, and the reaction was carried out in the same manner as in Example 3. The reaction vessel pressure at this time was 8.2 MPa. The reaction time was 6 hours.

  As a result of analyzing the product by gas chromatography, the conversion rates of AEEA-1PD and AEEA-2PD were 98% and 79%, respectively. As for the selectivity, DHPP / 4-HE-PIPOH / 1-HE-PIPOH was 38/4/58 (molar ratio), respectively, and the total yield was 41%.

Example 10
1. 21.3 g (0.12 mol) of a mixture of AEEA-1PD and AEEA-2PD obtained in Example 2, 103.8 g of water as a solvent, phosphorous acid as a catalyst (manufactured by Kishida Chemical Co., Ltd., for reagent chemistry) 1 g was charged into a 200 ml autoclave, purged with nitrogen and heated to 250 ° C. The reaction was carried out in the same manner as in Example 3. The reaction vessel pressure at this time was 3.3 MPa. The reaction time was 6 hours.

  As a result of analyzing the product by gas chromatography, the conversion rates of AEEA-1PD and AEEA-2PD were 100% and 99%, respectively. As for the selectivity, DHPP / 4-HE-PIPOH / 1-HE-PIPOH was 62/31/7 (molar ratio), respectively, and the total yield was 9%. At the same time, 4 mol% of 2-hydroxy (methyl) triethylenediamine in which intramolecular dehydration condensation reaction had proceeded was obtained.

Example 11
21.3 g (0.12 mol) of a mixture of AEEA-1PD and AEEA-2PD obtained in Example 2, 103.8 g of water as a solvent, calcium hypophosphite as a catalyst (manufactured by Wako Pure Chemicals, for reagent chemistry) 4.4 g was charged into a 200 ml autoclave, purged with nitrogen, and then heated to 250 ° C. The reaction was carried out in the same manner as in Example 3. The reaction vessel pressure at this time was 4.0 MPa. The reaction time was 6 hours.

  As a result of analyzing the product by gas chromatography, the conversion rates of AEEA-1PD and AEEA-2PD were 100% and 99%, respectively. As for the selectivity, DHPP / 4-HE-PIPOH / 1-HE-PIPOH was 55/40/5 (molar ratio), respectively, and the total yield was 10%. At the same time, 3 mol% of 2-hydroxy (methyl) triethylenediamine having undergone further intramolecular dehydration condensation reaction was obtained.

Example 12
18.1 g (0.10 mol) of a mixture of AEEA-1PD and AEEA-2PD obtained in Example 2; 88.2 g of water as a solvent; 1.8 g of aluminum phosphate (manufactured by Kishida Chemical, for reagent chemistry) Was filled into a 200 ml autoclave, purged with nitrogen and heated to 250 ° C. The reaction was carried out in the same manner as in Example 3. The reaction vessel pressure at this time was 3.2 MPa. The reaction time was 6 hours.

  As a result of analyzing the product by gas chromatography, the conversion rates of AEEA-1PD and AEEA-2PD were 100% and 100%, respectively. As for the selectivity, DHPP / 4-HE-PIPOH / 1-HE-PIPOH was 59/41/0 (molar ratio), respectively, and the total yield was 11%. At the same time, 2 mol% of 2-hydroxy (methyl) triethylenediamine having undergone further intramolecular dehydration condensation reaction was obtained.

Example 13 Synthesis of 2-hydroxy (alkyl) triethylenediamines.
The Raney copper catalyst was filtered and removed from the reaction solution containing the mixture of DHPP, 4-HE-PIPOH, and 1-HE-PIPOH obtained in Example 5, and the concentration (substrate concentration) of these mixtures was 17 wt. %. 125 ml of this solution and 2.1 g of phosphorous acid (manufactured by Kishida Chemical Co., Ltd., for reagent chemistry) were charged into a 200 ml autoclave, purged with nitrogen and heated to 250 ° C. The reaction vessel pressure at this time was 3.6 MPa. The reaction time was 4 hours.

  As a result of analyzing the product by gas chromatography, the conversion rate of the mixture of DHPP, 4-HE-PIPOH, and 1-HE-PIPOH was 88%, and the intramolecular dehydration condensation reaction proceeded, and the corresponding 2- 15 mol% of hydroxy (methyl) triethylenediamine was obtained.

Example 14
The Raney copper catalyst was removed by filtration from the reaction solution containing a mixture of DHPP and 4-HE-PIPOH and 1-HE-PIPOH obtained in Example 7 and Example 9, and the concentration of these mixtures (substrate concentration). Was adjusted to 25% by weight.

A quartz tube (inner diameter: 23 mm, length: 590 mm) filled with 20 ml of commercially available aluminum phosphate (manufactured by Wako Pure Chemical Industries, Ltd., for chemical use) was used as a fixed bed reactor, and the temperature was set to 320 ° C. while flowing nitrogen at a flow rate of 60 ml / min. After the temperature increase, water was circulated at 30 ml / hr ⁻¹ for 1 hour. The cyclization reaction was conducted at a flow rate of 1,616 hr ⁻¹ of the above prepared liquid in a fixed bed reactor at the same temperature and gas space velocity (GHSV: apparent supply rate when solution was gasified and divided by catalyst volume). And the solution distilled from the reactor was received in a flask.

  As a result of analyzing the product by gas chromatography, the conversion ratio of the mixture of DHPP, 4-HE-PIPOH, and 1-HE-PIPOH was 90%, and the intramolecular dehydration condensation reaction proceeded, and the corresponding 2- 29 mol% of hydroxy (methyl) triethylenediamine was obtained.

Comparative Example 1
A mixture of AEEA-1PD and AEEA-2PD obtained in Example 2 (18.7 g, 0.11 mol) and 106.3 g of water as a solvent were charged into a 200 ml autoclave without adding a catalyst, and the example was carried out under a hydrogen atmosphere. The reaction was carried out as in 1. The reaction vessel pressure at this time was 8.0 MPa. The reaction time was 6 hours.

  As a result of analyzing the product by gas chromatography, the conversion of AEEA-1PD and AEEA-2PD was 0%.

Comparative Example 2
A 200 ml autoclave was charged with 18.7 g (0.11 mol) of a mixture of AEEA-1PD and AEEA-2PD obtained in Example 2, 106.3 g of water as a solvent, and 10.0 g of Raney nickel catalyst (dry weight 5.0 g). Then, after purging with nitrogen, it was heated to 165 ° C. under hydrogen pressure. The reaction vessel pressure at this time was 8.0 MPa. The reaction time was 6 hours.

  As a result of analyzing the product by gas chromatography, the conversion of AEEA-1PD and AEEA-2PD was 0%.

Claims (7)

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).
And a compound represented by the following formula (2)

(In the formula, R and n are as defined above.)
And a mixture of N-((dihydroxyalkyl) 2-aminoethyl) ethanolamines, characterized by comprising: 2. The mixture according to claim 1, wherein the compound represented by the formula (2) is contained in a ratio of 60:40 to 40:60 (weight ratio) with respect to the compound represented by the formula (1). Following formula

(In the above formula, R represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms, X represents a halogen atom, and n represents an integer of 0 to 6).
The method for producing a mixture according to claim 1, wherein the halogenated diol represented by the formula (1) is reacted with N- (2-aminoethyl) ethanolamine. The mixture according to claim 1 or 2 is subjected to an intramolecular dehydration condensation reaction in the presence of an acid catalyst and / or a Raney metal catalyst, 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)
A compound represented by formula (5):

(In the formula, R and n are as defined above.)
As well as the following formula (6)

(In the formula, R and n are as defined above.)
A method for producing disubstituted hydroxyalkylpiperazines, characterized in that one or more compounds selected from the group consisting of compounds represented by formula (1) are obtained. A disubstituted hydroxyalkylpiperazine obtained by the method according to claim 4 is subjected to an intramolecular dehydration condensation reaction in the presence of an acid catalyst.

(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 of 2-hydroxy (alkyl) triethylenediamine shown by these. The production method according to claim 4, wherein the Raney metal catalyst includes a Raney copper catalyst. The production method according to any one of claims 4 to 6, wherein the acid catalyst includes a compound selected from the group consisting of an inorganic phosphorus compound, a metal salt of the inorganic phosphorus compound, and an organic phosphorus compound. .

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