JP2011144140A - Method for producing n-(2,3-dihydroxypropyl)piperazine - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for producing N-(2,3-dihydroxypropyl)piperazine simply in a high yield by using glycerol and piperazine being inexpensively and easily obtainable raw materials. <P>SOLUTION: The method for producing N-(2,3-dihydroxypropyl)piperazine includes reacting glycerol and piperazine in the presence of a phosphorus-containing acid catalyst. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

  The present invention relates to a method for producing N- (2,3-dihydroxypropyl) piperazine, which is expected to be used in various applications such as intermediates such as pharmaceuticals and agricultural chemicals, urethane foam catalysts, surfactants and the like. More specifically, the present invention relates to a method for producing N- (2,3-dihydroxypropyl) piperazine in an industrially advantageous manner by reacting piperazine and glycerin using an acid catalyst containing phosphorus. .

  In general, as a production method for obtaining N- (2,3-dihydroxypropyl) piperazine, a method in which piperazine and an epoxy compound glycidol are added in an inert solvent (for example, methanol) is known. (For example, refer nonpatent literature 1). However, in this production method, a large amount of N, N′-di (2,3-dihydroxypropyl) piperazine is by-produced, so that it is difficult to selectively obtain N- (2,3-dihydroxypropyl) piperazine. there were. In addition, glycidol used as a raw material is expensive and industrially difficult to obtain, and thus cannot be said to be a practical production method.

  As another general method for producing N- (2,3-dihydroxypropyl) piperazine, piperazine and 3-chloro-1,2-propanediol are used in an inert solvent (for example, methanol). A method of reacting is known (for example, see Non-Patent Document 2). However, in this production method, it is necessary to neutralize the inorganic salt of the amine produced after the reaction with an alkali such as sodium hydroxide, and there is a problem that inorganic halide is by-produced. Since a desalination treatment facility for removing salt is required, it was not industrially preferable.

  By the way, in recent years, biodiesel is produced as a corresponding carboxylic acid ester by transesterifying oil in vegetable oil such as soybean oil and waste edible oil with alcohol in the presence of a base catalyst, and can be used as an alternative fuel for petroleum. It is spreading.

  On the other hand, it is known that glycerin is by-produced in this production process, and it is desired to effectively use it as a raw material for amine compounds as a chemical utilization of the by-produced glycerin. For example, a reaction in which glycerin is aminated in a hydrogen atmosphere with an aminating agent such as ammonia using a metal catalyst such as nickel, copper, and cobalt has been reported (for example, see Patent Document 1). However, even if glycerin and piperazine were directly reacted according to the method described in the publication, the target product was obtained only in a low yield.

International Publication No. 2009/027248

Zhunal Prikladnoi Kimii (Sank-Peterburg, Russian Federation) (1984), 57 (9), p. 2138 Journal of Pharmacology and Pharmacology (1960), 12, 37.

  The present invention has been made in view of the above-described background art, and an object of the present invention is to use glycerin and piperazine, which are inexpensive and easily available, and easily and efficiently use N- (2,3- It is to provide a process for producing dihydroxypropyl) piperazine.

  As a result of intensive studies to solve the above-mentioned problems, the present inventors have found that a target product can be obtained by reacting in the presence of an acid catalyst containing phosphorus, and have completed the present invention.

  That is, the present invention is a method for producing N- (2,3-dihydroxypropyl) piperazine as shown below.

  [1] The following formula (1), wherein glycerol and piperazine are reacted in the presence of an acid catalyst containing phosphorus.

で示されるＮ−（２，３−ジヒドロキシプロピル）ピペラジンの製造方法。

The manufacturing method of N- (2,3-dihydroxypropyl) piperazine shown by these.

  [2] The phosphorus-containing acid catalyst contains one or more compounds selected from the group consisting of inorganic phosphorus compounds, phosphorous acid or metal salts of hypophosphorous acid, and organic phosphorus compounds. The method for producing N- (2,3-dihydroxypropyl) piperazine as described in [1] above.

  [3] The acid catalyst containing phosphorus is one or two selected from the group consisting of phosphoric acid, phosphorous acid, hypophosphorous acid, sodium hypophosphite, calcium hypophosphite, phenylphosphonic acid, and methylphosphonic acid The method for producing N- (2,3-dihydroxypropyl) piperazine according to the above [1], comprising at least one kind of compound.

  [4] The N according to any one of [1] to [3] above, wherein the amount of phosphorus-containing acid catalyst used is in the range of 0.01 to 20% by weight with respect to glycerin. -Manufacturing method of (2,3-dihydroxypropyl) piperazine.

  According to the production method of the present invention, N- (2,3-dihydroxypropyl) piperazine is easily obtained by reacting glycerol, which is an inexpensive and easily available raw material, with piperazine in the presence of an acid catalyst. And it can manufacture efficiently.

  Hereinafter, the present invention will be described in detail.

  The present invention is characterized in that glycerin and piperazine are reacted in the presence of an acid catalyst containing phosphorus.

  In the present invention, the reaction between glycerin and piperazine is, for example, a method of dropping glycerin into a mixture of an acid catalyst containing phosphorus and piperazine, and conversely, a mixture of an acid catalyst containing phosphorus and glycerin. It is carried out by a method of adding piperazine therein, a method of adding an acid catalyst containing phosphorus in a mixture of piperazine and glycerol, or the like.

  In the present invention, the acid catalyst containing phosphorus is not particularly limited. For example, the acid catalyst is selected from the group consisting of inorganic phosphorus compounds, metal salts of phosphorous acid or hypophosphorous acid, and organic phosphorus compounds. It is preferable to use seeds or two or more compounds.

  In the present invention, preferred examples of the inorganic phosphorus compound include phosphoric acid, phosphorous acid, hypophosphorous acid, condensed phosphoric acid such as pyrophosphoric acid and tripolyphosphoric acid, and metaphosphoric acid.

  In addition, in the metal salt of phosphorous acid or hypophosphorous acid, as the metal that forms a salt with phosphorous acid or hypophosphorous acid, for example, sodium, potassium, lithium, calcium, barium, magnesium, aluminum, titanium, Suitable examples include iron, cobalt, nickel, copper, zinc, zirconium, palladium, silver, tin, lead and the like.

  Furthermore, as the organic phosphorus compound, for example, phosphate esters such as methyl phosphate, phosphate diesters such as dimethyl phosphate, phosphate triesters such as triphenyl phosphate, methyl phosphite, phenyl phosphite, etc. Phosphorous acid esters, phosphorous acid diesters such as diphenyl phosphite, phosphorous acid triesters such as triphenyl phosphite, arylphosphonic acids such as phenylphosphonic acid, alkylphosphonic acids such as methylphosphonic acid, methylphosphonous acid Alkylphosphonous acid such as phenylphosphonous acid, alkylphosphonic acid such as dimethylphosphinic acid, arylphosphinic acid such as diphenylphosphinic acid, alkylarylphosphinic acid such as phenylmethylphosphinic acid, dimethylphosphine Alkylphosphinic acid such as acid Arylphosphinic acids such as diphenylphosphinic acid, alkylarylphosphinic acids such as phenylmethylphosphinic acid, acidic phosphate esters such as lauryl acid phosphate, tridecyl acid phosphate, stearyl acid phosphate, acidic phosphate esters Suitable salts are listed as follows.

  In this invention, 1 type, or 2 or more types of compounds chosen from these can be used. Of these phosphorus-containing compounds, phosphoric acid, phosphorous acid, hypophosphorous acid, sodium hypophosphite, calcium hypophosphite, phenylphosphonic acid, and methylphosphonic acid are particularly preferable.

  In the production method of the present invention, the amount of the acid catalyst containing phosphorus is in the range of 0.01 to 20% by weight, preferably in the range of 0.1 to 15% by weight, with respect to glycerin as the raw material. The amount used in such a range is suitable for obtaining the target product in a high yield. Although the reaction proceeds even when the amount of the acid catalyst containing phosphorus is less than 0.01% by weight relative to the glycerin as a raw material, the reaction is remarkably slow or economically disadvantageous. There is a fear. Moreover, when the usage-amount of the acid catalyst containing phosphorus exceeds 20 weight% with respect to glycerol which is a raw material, a side reaction will be accelerated | stimulated and there exists a possibility that reaction selectivity may fall and a yield may fall. There is.

  In the present invention, the molar ratio of glycerin to piperazine ([glycerin]: [piperazine]) is preferably in the range of 1: 0.1 to 50, and more preferably in the range of 1: 1 to 20. .

  When the amount of piperazine is less than 0.1 mol with respect to 1 mol of glycerin, there is a risk that a large amount of high molecular weight compound in which glycerin is condensed between molecules in the presence of an acid catalyst is by-produced.

  When the amount of piperazine exceeds 50 mol with respect to 1 mol of glycerin, piperazine remains as unreacted, and unreacted piperazine is further a reaction product in the presence of an acid catalyst. May cause a dehydration reaction with N- (2,3-dihydroxypropyl) piperazine, which may reduce the yield and selectivity of N- (2,3-dihydroxypropyl) piperazine represented by the above formula (1). . Moreover, there is a possibility that the operation when separating and purifying the N- (2,3-dihydroxypropyl) piperazine represented by the above formula (1) by extraction, concentration or the like becomes complicated.

  In the present invention, the reaction may be performed in a gas phase or a liquid phase. The reaction can be carried out in 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 present invention, as a diluent, an inert gas such as nitrogen gas, hydrogen gas, ammonia gas, or hydrocarbon, or an inert solvent such as inert hydrocarbon, piperazine as a raw material and glycerin are used. It is also possible to dilute the reaction. These diluents can be used in any amount, and are not particularly limited. However, the total amount of piperazine and glycerin as a raw material and the molar ratio of the diluent ([total amount of piperazine and glycerin] / [diluent] ]) Is preferably in the range of 0.01 to 1, more preferably in the range of 0.05 to 0.5. When the molar ratio is 0.01 or more, the productivity of N- (2,3-dihydroxypropyl) piperazine represented by the above formula (1) is improved, and when the molar ratio is 1 or less, the above formula (1 The selectivity of N- (2,3-dihydroxypropyl) piperazine represented by () is improved.

  In the present invention, when a diluent is used, it may be introduced into the reactor simultaneously with the raw material piperazine and / or glycerin, or the raw material piperazine and / or glycerin is dissolved in the diluent in advance. Later, it may be introduced into the reactor as a raw material solution.

  In 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 piperazine represented by the above formula (1).

  The reaction temperature in this invention is 200-500 degreeC normally, Preferably it is 250-400 degreeC. Since the decomposition of the product is suppressed by setting the temperature to 500 ° C. or lower, the selectivity of N- (2,3-dihydroxypropyl) piperazine represented by the above formula (1) is improved, and is set to 200 ° C. or higher. Can provide a sufficient reaction rate.

  In the present invention, when the reaction is carried out in the gas phase, after completion of the reaction, the reaction mixed gas containing N- (2,3-dihydroxypropyl) piperazine represented by the above formula (1) is converted into water or an acidic aqueous solution. Through the dissolution, a reaction mixture containing N- (2,3-dihydroxypropyl) piperazine represented by the above formula (1) is obtained. Then, N- (2,3-dihydroxypropyl) piperazine represented by the above formula (1) can be obtained from the obtained reaction mixture by a desired separation and purification operation such as extraction and concentration. Moreover, it can also obtain as a hydrohalide salt using hydrohalic acid.

  EXAMPLES Hereinafter, although this invention is demonstrated further in detail based on an Example, this invention is limited to these and is not interpreted.

  The selectivity and purity of the product in this example were confirmed by gas chromatography. Here, the gas chromatography uses an analyzer (manufactured by Shimadzu Corporation, product name: GC-2014), a capillary column (DB-1 manufactured by J & W Scientific), and a detector (FID), and is 10 ° C. from 50 ° C. to 300 ° C. The temperature was raised at / min.

Moreover, the product name: Gemini-200 made from Varian was used for the measurement of < ¹ > H-NMR and < ¹³ > C-NMR of a compound.

Example 1.
Glycerin (manufactured by Kishida Chemical Co., Ltd., reagent special grade) 58.8 g (0.64 mol), piperazine (manufactured by Tokyo Chemical Industry Co., Ltd., reagent special grade) 55.0 g (0.64 mol), 85% phosphoric acid (as acid catalyst) A 200 ml autoclave was filled with 0.69 g of a reagent grade manufactured by Kishida Chemical Co., Ltd., purged with nitrogen, heated to 280 ° C., and held at 280 ° C. for 2 hours.

  As a result of analyzing the obtained reaction liquid by gas chromatography after the completion of the reaction, the selectivity for N- (2,3-dihydroxypropyl) piperazine was 36.5%.

  Further, unreacted piperazine and glycerin were concentrated by distillation under reduced pressure, and then distilled under reduced pressure. As a result, 23.4 g (yield 22.8%) of a distillate having a boiling point of 150 to 152 ° C./40 Pa was obtained. .

The obtained distillate has a purity of 98.8% as analyzed by gas chromatography and is confirmed to be N- (2,3-dihydroxypropyl) piperazine from ¹ H-NMR and ¹³ C-NMR. did it.

¹ H-NMR (CD ₃ OD, 200 MHz)
δ: 3.80 ppm (m, 1H), 3.50 ppm (m, 2H), 3.30 ppm (m, 1H), 2.84 ppm (m, 4H), 2.54 to 2.39 ppm (m, 6H) .
¹³ C-NMR (CD ₃ OD, 200 MHz)
δ: 69.67 ppm (CH), 66.30 ppm (CH ₂ ), 63.23 ppm (CH ₂ ), 55.52 ppm (CH ₂ ), 46.27 ppm (CH ₂ )
The results of Example 1 are shown in Table 1.

実施例２．
グリセリン２６．７ｇ（０．２９モル）、ピペラジン７５．０ｇ（０．８７モル）、酸触媒として８５％−リン酸０．３０ｇを２００ｍｌオートクレーブに充填し、実施例１と同様に反応を行った。実施例２の結果を表１に併せて示す。

Example 2
A 200 ml autoclave was charged with 26.7 g (0.29 mol) of glycerin, 75.0 g (0.87 mol) of piperazine, and 0.30 g of 85% phosphoric acid as an acid catalyst, and the reaction was carried out in the same manner as in Example 1. . The results of Example 2 are also shown in Table 1.

Example 3
A 200 ml autoclave was charged with 8.0 g (0.09 mol) of glycerin, 75.0 g (0.87 mol) of piperazine and 0.09 g of phosphoric acid as an acid catalyst, and the reaction was carried out in the same manner as in Example 1. . The results of Example 3 are also shown in Table 1.

Example 4
A 200 ml autoclave was charged with 8.0 g (0.09 mol) of glycerin, 75.0 g (0.87 mol) of piperazine and 0.03 g of 85% phosphoric acid as an acid catalyst, and the reaction was carried out in the same manner as in Example 1. . The results of Example 4 are also shown in Table 1.

Example 5 FIG.
The reaction was carried out in the same manner as in Example 3 except that 0.08 g of phosphorous acid (made by Kishida Chemical Co., Ltd., reagent grade) was used instead of 85% -phosphoric acid in Example 3. The results of Example 5 are also shown in Table 1.

Example 6
The reaction was conducted in the same manner as in Example 3 except that 0.26 g of 31% -hypophosphorous acid (manufactured by Wako Pure Chemical Industries, Ltd., first grade reagent) was used instead of 85% -phosphoric acid in Example 3. It was. The results of Example 6 are also shown in Table 1.

Example 7
The reaction was performed in the same manner as in Example 3 except that 0.40 g of calcium hypophosphite (manufactured by Wako Pure Chemical Industries, Ltd., reagent chemical) was used instead of 85% -phosphoric acid in Example 3. The results of Example 7 are also shown in Table 1.

Example 8 FIG.
The reaction was performed in the same manner as in Example 3 except that 0.08 g of phenylphosphonic acid (manufactured by Wako Pure Chemical Industries, Ltd., reagent chemical) was used instead of 85% -phosphoric acid in Example 3. The results of Example 8 are also shown in Table 1.

Comparative Example 1
8.0 g (0.09 mol) of glycerin, 75.0 g (0.87 mol) of piperazine, 200 ml autoclave without adding catalyst, purged with nitrogen, heated to 280 ° C., and heated at 280 ° C. for 2 hours Retained.

  As a result of analyzing the reaction solution by gas chromatography, N- (2,3-dihydroxypropyl) piperazine was not detected. The results of Comparative Example 1 are also shown in Table 1.

Comparative Example 2
8.0 g (0.09 mol) of glycerin, 75.0 g (0.87 mol) of piperazine, and H-ZSM-5 zeolite (proton exchange type ZSM-5) having an SiO ₂ / Al ₂ O ₃ ratio of 40 as an acid catalyst ) 0.40 g was charged into a 200 ml autoclave, purged with nitrogen, heated to 280 ° C., and held at 280 ° C. for 2 hours.

  As a result of analyzing the reaction solution by gas chromatography, N- (2,3-dihydroxypropyl) piperazine was not detected. The results of Comparative Example 2 are also shown in Table 1.

Comparative Example 3
According to Patent Document 1, a reaction for aminating glycerin in the presence of a metal catalyst in a hydrogen atmosphere was performed. That is, 16.0 g (0.17 mol) of glycerin, 15.0 g (0.17 mol) of piperazine, 1.5 g of Raney nickel catalyst as a metal catalyst (dry weight 0.75 g, manufactured by Degussa, Type-B 111W), solvent As follows, 85.0 g of water was charged into a 200 ml autoclave, purged with nitrogen, heated to 200 ° C. under hydrogen pressure, and held at 200 ° C. for 2 hours. The reaction vessel pressure at this time was 2.0 MPa.

  After the reaction was completed, the resulting reaction solution was analyzed by gas chromatography. As a result, the selectivity for N- (2,3-dihydroxypropyl) piperazine was as low as 2.4%.

  Further, the solvent water, unreacted piperazine and glycerin were concentrated under reduced pressure and distilled off, followed by distillation under reduced pressure. As a result, 0.2 g of N- (2,3-dihydroxypropyl) piperazine was obtained (yield 0.7%). Only). The results of Comparative Example 3 are also shown in Table 1.

Comparative Example 4
As in Comparative Example 3, instead of using the Raney nickel catalyst in Comparative Example 3, 1.5 g of Raney copper catalyst (dry weight 0.75 g, manufactured by Kawaken Fine Chemical Co., CDT-60), 200 ml of water 85.0 g as a solvent. The autoclave was filled, purged with nitrogen, heated to 200 ° C. under hydrogen pressure, and held at 200 ° C. for 2 hours. The reaction vessel pressure at this time was 2.4 MPa.

After the reaction was completed, the resulting reaction solution was analyzed by gas chromatography. As a result, the selectivity for N- (2,3-dihydroxypropyl) piperazine was as low as 8.8%.
Further, the solvent water, unreacted piperazine and glycerin were concentrated under reduced pressure and evaporated, and then distilled under reduced pressure. As a result, 0.3 g of N- (2,3-dihydroxypropyl) piperazine was obtained (yield 1.%). Only obtained. The results of Comparative Example 4 are also shown in Table 1.

Claims (4)

The following formula (1), wherein glycerin and piperazine are reacted in the presence of an acid catalyst containing phosphorus

The manufacturing method of N- (2,3-dihydroxypropyl) piperazine shown by these. The acid catalyst containing phosphorus contains one or more compounds selected from the group consisting of inorganic phosphorus compounds, metal salts of phosphorous acid or hypophosphorous acid, and organic phosphorus compounds. Item 2. A method for producing N- (2,3-dihydroxypropyl) piperazine according to Item 1. The acid catalyst containing phosphorus is one or more selected from the group consisting of phosphoric acid, phosphorous acid, hypophosphorous acid, sodium hypophosphite, calcium hypophosphite, phenylphosphonic acid, and methylphosphonic acid The method for producing N- (2,3-dihydroxypropyl) piperazine according to claim 1, comprising a compound. 4. The N- (2, wherein the amount of the acid catalyst containing phosphorus is in the range of 0.01 to 20% by weight with respect to glycerin. 5. A process for producing 3-dihydroxypropyl) piperazine.