1,4-Dimethylpiperazine and its preparation method

Abstract

The present invention provides 1,4-dimethylpiperazine and a preparation method thereof. The preparation method comprises the following steps: (1) reacting N-methyl ethylamine salt to obtain a reactant; (2) purifying the reactant to obtain the 1,4-dimethylpiperazine; the N-methyl ethylamine salt is 2-chloro-N-methyl ethylamine hydrochloride or 2-bromo-N-methyl ethylamine bromate; the process for preparing 1,4-dimethylpiperazine provided by the present invention has high reaction activity, high stability, high selectivity, simple reaction steps, mild reaction conditions, low requirements for reaction equipment, low potential safety hazards in production, and the purity of the 1,4-dimethylpiperazine prepared by the preparation method provided by the present invention can reach 99.5%.

Description

Technical Field

[0001] The present invention belongs to the technical field of chemical synthesis, and particularly relates to 1,4-dimethyl piperazine and a preparation method thereof. Background Art

[0002] 1,4-dimethyl piperazine, with the English name 1,4-dimethyl piperazine, also known as N,N-dimethyl piperazine. The molecular formula is C6H 14 N2, the structural formula, the molecular weight is 114.2, the flash point is 22 °C, and the boiling point is 130 - 133 °C; it is a colorless volatile liquid, soluble in water, ethanol and ether. It is mainly used as a curing agent, catalyst for polyurethane, and intermediate for medicine and surfactant. This substance is flammable, slightly toxic, and has certain corrosiveness.

[0003] In the common synthesis methods of 1-methyl piperazine, in the process of using piperazine as a raw material to obtain 1-methyl piperazine through selective methylation, or using piperazine as a raw material to synthesize 1-methyl piperazine through selective reductive amination, one of the by-products generated is 1,4-dimethyl piperazine. Therefore, a small amount of 1,4-dimethyl piperazine can be obtained thereby.

[0004] Using piperazine and formaldehyde as raw materials, reacting in an aqueous solution, and reducing with zinc and hydrochloric acid to prepare 1,4-dimethyl piperazine; or using piperazine and methanol as raw materials at 160 - 220 °C through a catalyst composed of SiO2 and H3PO4 (90:10), the conversion rate of piperazine is 49.3%, and the weight ratio of the obtained 1-methyl piperazine and 1,4-dimethyl piperazine is 81:15. Using hydrogenation desulfurization catalysts such as Ni-Mo / Al2O3, reacting under normal pressure and high temperature, the product can also be obtained. Transition metal catalysts such as Rh, Ir, Ru can also be used. For example, passing piperazine and methanol through a catalyst composed of IrCl3·3H2O and triphenylphosphine, at a temperature below 100 °C, reacting for 160 h, and separating to obtain 1-methyl piperazine and 1,4-dimethyl piperazine, with the yields being 52% and 13% respectively. ("Synthesis Process Diagram of Methyl and Dimethyl Piperazine", Hu Yuqin et al., Chinese Journal of Pharmaceutical Industry, 1992, 23(6), 284 - 285).

[0005] CN108187679A discloses a method for synthesizing 1,4-dimethyl piperazine using a supported catalyst: using calcined spherical γ-Al2O3 as a carrier, loading active components copper and nickel on the carrier as a supported catalyst, placing the supported catalyst in a fixed-bed reactor, and activating it under the action of hydrogen; feeding the raw material N-methylethanolamine into the vaporization chamber through a feeding pump for vaporization, adjusting the flow rate of the feeding pump to make the volume space velocity in 0.1 - 0.5 h -1; The hydrogen pressure is adjusted so that the reaction pressure is 0.2-2.0MPa, the reaction temperature is 200-300℃, the product flows out from the bottom of the fixed bed reactor, and is collected after condensation in the condenser; 1,4-dimethylpiperazine is obtained by atmospheric distillation. The purity of the obtained 1,4-dimethylpiperazine is 99%, and the yield is 71.1-81.4%. However, the process is complicated, the reaction temperature is high, and heavy metal catalysts are used.

[0006] CN108503608A discloses a method for preparing 1,4-dimethylpiperazine, wherein N-methyldiethanolamine, hydrogen and monomethylamine are used as raw materials, mixed in a certain proportion and then introduced into a tubular fixed bed reactor filled with a catalyst; the raw materials are gasified at high temperature in the reactor; the mixed gas of the raw materials contacts and reacts with the catalyst in the reactor to obtain a reaction mixture containing 1,4-dimethylpiperazine; and then the condensed and collected reaction mixture containing 1,4-dimethylpiperazine is distilled and purified to obtain a high-purity 1,4-dimethylpiperazine product. The method uses a rare earth element modified copper-based composite catalyst as a catalyst for preparing 1,4-dimethylpiperazine from N-methyldiethanolamine, hydrogen and monomethylamine as raw materials. The purity of the obtained 1,4-dimethylpiperazine is 97.5-98.2%.

[0007] CN102796061A discloses a method for synthesizing N,N'-dialkylpiperazine, comprising the following steps: N,N-dialkylethanolamine is preheated and vaporized, and then introduced into a fixed bed reactor filled with a basic molecular sieve as a catalyst, and condensation and amination are carried out under the conditions of normal pressure and a temperature of 250-350°C, wherein the residence time of N,N-dialkylethanolamine in the fixed bed reactor is 30-150 seconds, and the obtained liquid is separated after condensation to obtain N,N'-dialkylpiperazine.

[0008] In summary, the existing processes have the disadvantages of complex process flow, or use of more heavy metal catalysts, or high reaction pressure, or long reaction time. Given that there are few methods for preparing 1,4-dimethylpiperazine, and there are few methods with simple processes, high purity and industrial production, therefore, developing a preparation method with simple reaction process, mild reaction conditions and high product purity is the research focus in this field. Summary of the invention

[0009] In view of the deficiencies in the prior art, the object of the present invention is to provide 1,4-dimethylpiperazine and a method for preparing the same, which has high reactivity, high stability, high selectivity, simple reaction steps, mild reaction conditions, low requirements for reaction equipment, and low safety risks in production.

[0010] In order to achieve the purpose of the invention, the present invention adopts the following technical solutions:

[0011] In a first aspect, the present invention provides a method for preparing 1,4-dimethylpiperazine, and the preparation method includes the following steps:

[0012] (1) React N-methyl ethylamine salt to obtain a reactant;

[0013] (2) Purify the reactant to obtain the 1,4-dimethylpiperazine;

[0014] The N-methyl ethylamine salt has a structure shown in Formula I:

[0015]

[0016] Wherein, X is Cl or Br.

[0017] The process for preparing 1,4-dimethylpiperazine provided by the present invention uses N-methyl ethylamine salt as the main reaction raw material. Under alkaline conditions, the halogen group (Cl or Br) is hydrolyzed into a hydroxyl group, and the hydroxyl group further undergoes a nucleophilic reaction with the amino group to generate 1,4-dimethylpiperazine and water. The product is simple, so the purification process is simple. The whole preparation process has high reaction activity, high stability, high selectivity, simple reaction steps, mild reaction conditions, low requirements for reaction equipment, low potential safety hazards in production, and has high industrial promotion value.

[0018] Preferably, the temperature of the reaction is 0-50 °C, for example, it can be 1 °C, 5 °C, 10 °C, 15 °C, 20 °C, 25 °C, 30 °C, 35 °C, 40 °C or 45 °C, etc., and the reaction time is 1-50 min, for example, it can be 2 min, 5 min, 10 min, 15 min, 20 min, 25 min, 30 min, 35 min, 40 min, 45 min, etc.

[0019] Preferably, the temperature of the reaction is 10-30 °C, for example, it can be 12 °C, 14 °C, 16 °C, 18 °C, 20 °C, 22 °C, 24 °C, 26 °C, 28 °C, etc., and the reaction time is 20-35 min, for example, it can be 22 min, 24 min, 26 min, 28 min, 30 min, 32 min, 34 min, etc.

[0020] Other specific point values within the above numerical ranges can be selected, and will not be elaborated one by one here.

[0021] Preferably, the reaction is carried out under alkaline conditions.

[0022] Preferably, the pH value of the reaction is 10-13, for example, it can be 10.5, 11, 11.5, 12 or 12.5, etc.

[0023] Preferably, an alkaline solution is added during the reaction.

[0024] Preferably, the alkaline solution includes an aqueous sodium hydroxide solution or an aqueous potassium hydroxide solution.

[0025] Preferably, the concentration of the alkaline solution is 0.1 - 100 mmol / L, and for example, it can be 0.5 mmol / L, 1 mmol / L, 5 mmol / L, 10 mmol / L, 20 mmol / L, 30 mmol / L, 40 mmol / L, 50 mmol / L, 60 mmol / L, 70 mmol / L, 80 mmol / L, 90 mmol / L, etc.

[0026] Preferably, the purification is carried out by the method of vacuum distillation.

[0027] Preferably, the pressure of the vacuum distillation is 1100 - 1200 Pa, and for example, it can be 1110 Pa, 1120 Pa, 1130 Pa, 1140 Pa, 1150 Pa, 1160 Pa, 1170 Pa, 1180 Pa or 1190 Pa, etc., and the temperature is 75 - 80 °C, and for example, it can be 76 °C, 77 °C, 78 °C or 79 °C, etc.

[0028] Other specific point values within the above numerical ranges can be selected, and will not be elaborated one by one here.

[0029] Preferably, the preparation method includes the following steps:

[0030] (1) Mix the N - methylethylamine salt with the alkaline solution, adjust the pH value to 10 - 13, and react at 0 - 50 °C for 1 - 50 min to obtain a reactant;

[0031] The alkaline solution includes an aqueous sodium hydroxide solution or an aqueous potassium hydroxide solution, and the concentration of the alkaline solution is 0.1 - 100 mmol / L;

[0032] The N - methylethylamine salt has the structure shown in Formula I:

[0033]

[0034] Wherein, X is Cl or Br;

[0035] (2) Subject the reactant to vacuum distillation at 1100 - 1200 Pa and 75 - 80 °C to obtain the 1,4 - dimethylpiperazine.

[0036] Preferably, the reaction route for the N - methylethylamine salt to react to obtain 1,4 - dimethylpiperazine is as follows:

[0037]

[0038] Second aspect, the present invention provides a 1,4-dimethylpiperazine, which is prepared by the preparation method as described in the first aspect.

[0039] Preferably, the purity of the 1,4-dimethylpiperazine is 99.0 - 99.5%, and can be, for example, 99%, 99.1%, 99.2%, 99.3% or 99.4%, etc.

[0040] Other specific point values within the above numerical ranges can be selected, and will not be elaborated one by one here.

[0041] Compared with the prior art, the present invention has the following beneficial effects:

[0042] The process for preparing 1,4-dimethylpiperazine provided by the present invention uses N-methyl ethylamine salt as the main reaction raw material. Under alkaline conditions, the halogen group is hydrolyzed into a hydroxyl group, and the hydroxyl group further undergoes a nucleophilic reaction with the amino group to generate 1,4-dimethylpiperazine and water. The complexity of the product is low, so the purification process is simple. The whole preparation process has high reaction activity, high stability, high selectivity, simple reaction steps, mild reaction conditions, low requirements for reaction equipment, low potential safety hazards during production, and the purity of the 1,4-dimethylpiperazine prepared by the preparation method provided by the present invention can reach 99.5%. Description of the Drawings

[0043] Figure 1 Mass spectrum obtained in Test Example 1;

[0044] Figure 2 Standard mass spectrum of 1,4-dimethylpiperazine;

[0045] Figure 3 Infrared spectrum obtained in Test Example 2. Detailed Embodiments

[0046] The technical solutions of the present invention will be further described below through specific embodiments. Those skilled in the art should understand that the embodiments are only for helping to understand the present invention and should not be regarded as specific limitations to the present invention.

[0047] As used herein, the terms "comprising", "including", "having", "containing" or any other variation thereof are intended to cover non-exclusive inclusion. For example, a composition, step, method, article or device containing the listed elements is not necessarily limited to those elements, but may also include other elements not explicitly listed or elements inherent to such composition, step, method, article or device.

[0048] "Optional" or "any one" means that the subsequent described matter or event may or may not occur, and this description includes the case where the event occurs and the case where the event does not occur.

[0049] The indefinite articles "a" and "an" before the elements or components of the present invention do not limit the quantity requirements (i.e., the number of occurrences) of the elements or components. Therefore, "a" or "an" should be interpreted as including one or at least one, and the singular form of the elements or components also includes the plural form, unless the quantity clearly refers only to the singular form.

[0050] The descriptions of terms such as "one embodiment", "some embodiments", "exemplarily", "specific example", or "some examples" described in the present invention mean that the specific features, structures, materials, or characteristics described in connection with the embodiment or example are included in at least one embodiment or example of the present invention. In this article, the schematic expressions of the above terms are not necessarily directed to the same embodiment or example.

[0051] Example 1

[0052] This example provides a preparation method of 1,4 - dimethylpiperazine, and the preparation method is as follows:

[0053] (1) Add 1 g of 2 - chloro - N - methylethylamine hydrochloride to the reaction kettle, then add 1 mmol / L of NaOH aqueous solution to adjust the pH to about 12, set the reaction temperature in the reaction kettle to 25 °C, the reaction pressure is normal pressure, react for 30 min, end the reaction, and obtain the reactant;

[0054] (2) Subject the reactant to vacuum distillation. The pressure inside the tower for vacuum distillation is 1132 Pa, the temperature is 80 °C, collect the liquid, which is the 1,4 - dimethylpiperazine product.

[0055] Example 2

[0056] This example provides a preparation method of 1,4 - dimethylpiperazine, and the preparation method is as follows:

[0057] (1) Add 1 g of 2 - chloro - N - methylethylamine hydrochloride to the reaction kettle, then add 0.5 mmol / L of NaOH aqueous solution to adjust the pH to about 11, set the reaction temperature in the reaction kettle to 28 °C, the reaction pressure is normal pressure, react for 25 min, end the reaction, and obtain the reactant;

[0058] (2) Subject the reactant to vacuum distillation. The pressure inside the tower for vacuum distillation is 1140 Pa, the temperature is 78 °C, collect the liquid, which is the 1,4 - dimethylpiperazine product.

[0059] Example 3

[0060] This example provides a preparation method of 1,4 - dimethylpiperazine, and the preparation method is as follows:

[0061] (1) Add 1 g of 2-bromo-N-methylethylamine hydrobromide to the reaction kettle, then add 50 mmol / L aqueous NaOH solution to adjust the pH to 13. Set the reaction temperature in the reaction kettle to 15 °C, and the reaction pressure to atmospheric pressure. React for 30 min, and end the reaction to obtain the reactant;

[0062] (2) Subject the reactant to vacuum distillation. The pressure inside the tower for vacuum distillation is 1130 Pa, and the temperature is 76 °C. Collect the liquid, which is the 1,4-dimethylpiperazine product.

[0063] Example 4

[0064] This example provides a preparation method of 1,4-dimethylpiperazine. The preparation method is as follows:

[0065] The difference from Example 1 is only that in step (1), "adjust the pH to 12" is replaced with "adjust the pH to 9", and other raw materials, dosages, and preparation methods are the same as those in Example 1.

[0066] Example 5

[0067] This example provides a preparation method of 1,4-dimethylpiperazine. The preparation method is as follows:

[0068] The difference from Example 1 is only that in step (1), "adjust the pH to 12" is replaced with "adjust the pH to 14", and other raw materials, dosages, and preparation methods are the same as those in Example 1.

[0069] Example 6

[0070] This example provides a preparation method of 1,4-dimethylpiperazine. The preparation method is as follows:

[0071] The difference from Example 1 is only that in step (1), "set the reaction temperature in the reaction kettle to 25 °C" is replaced with "set the reaction temperature in the reaction kettle to 5 °C", and other raw materials, dosages, and preparation methods are the same as those in Example 1.

[0072] Example 7

[0073] This example provides a preparation method of 1,4-dimethylpiperazine. The preparation method is as follows:

[0074] The difference from Example 1 is only that in step (1), "set the reaction temperature in the reaction kettle to 25 °C" is replaced with "set the reaction temperature in the reaction kettle to 45 °C", and other raw materials, dosages, and preparation methods are the same as those in Example 1.

[0075] Test Example 1

[0076] Mass spectrometry detection

[0077] Test sample: 1,4-dimethylpiperazine prepared in Example 1.

[0078] Detection process: Gas chromatography-mass spectrometry (Agilent Technologies, 8890-5977c), chromatographic column DB-624 (length 30 m, diameter 0.25 mm, film thickness 1.40 μm), inlet temperature 150 °C, split ratio 5:1; source temperature 230 °C, voltage 70 eV. The full scan range is 0-130 m / z. The temperature programming is as follows: hold at 50 °C for 1 min, increase to 250 °C at a rate of 20 °C / min, and hold for 10 min.

[0079] The mass spectrum obtained by mass spectrometry detection of the sample is as shown in Figure 1 Using the qualitative software of the Agilent gas chromatography-mass spectrometry to search the database (NIST library), compare the Figure 1 mass spectrum with the standard mass spectrum of 1,4-dimethylpiperazine (as shown in Figure 2 ), the result shows that the matching degree is 98.6%. Combining the substance structure, reaction mechanism and other characterization test results, it is qualitatively identified as 1,4-dimethylpiperazine.

[0080] Test Example 2

[0081] Infrared spectrum detection

[0082] Test sample: 1,4-dimethylpiperazine prepared in Example 1.

[0083] Detection process: Using an infrared spectrometer (Mettler Toledo Technology Co., Ltd.), directly add the sample to a KBr liquid cell with a specification of 0.5 mm, and scan and measure in the range of 400-4000 cm -1 .

[0084] The infrared spectrum obtained by infrared spectrum detection is as shown in Figure 3 . Compare the Figure 3 infrared spectrum with the standard infrared spectrum of 1,4-dimethylpiperazine, the result shows that the matching degree is 97.9%. Combining the substance structure, reaction mechanism and other characterization test results, it is qualitatively identified as 1,4-dimethylpiperazine.

[0085] Test Example 3

[0086] Perform high performance liquid chromatography detection on the 1,4-dimethylpiperazine products prepared in Examples 1-7, and obtain the yield and purity of the products according to the detection results, as shown in Table 1.

[0087] Table 1

[0088]

[0089]

[0090] According to the table data, it can be seen that when the reaction starts, if the pH value of the reaction system is too low, the yield will decrease significantly. After the pH continues to rise, the yield does not increase accordingly, but instead decreases slightly. Therefore, it is better to control the pH within 10 - 13. When the reaction temperature is controlled within the range of 0 - 50 °C, the reaction temperature has little effect on the reaction. Among them, when the temperature is relatively low or high, the product yield decreases slightly and the purity is hardly affected. Therefore, the reaction effect is better when the temperature is controlled at 10 - 30 °C.

[0091] The applicant declares that the present invention uses the above embodiments to illustrate the process method of the present invention, but the present invention is not limited to the above process steps, that is, it does not mean that the present invention must rely on the above process steps to be implemented. Those skilled in the art should understand that any improvement to the present invention, the equivalent substitution of the raw materials selected for the present invention, the addition of auxiliary components, the selection of specific methods, etc. all fall within the protection scope and the disclosure scope of the present invention.

Claims

1. A method for preparing 1,4-dimethylpiperazine, characterized in that, The preparation method comprises the following steps: (1) Mix the N-methyl ethylamine salt with an alkaline solution, adjust the pH value to 10-13, and react at 0-50°C for 1-50 minutes to obtain a reactant; (2) Subject the reactant to vacuum distillation at 1100-1200 Pa and 75-80°C to obtain the 1,4-dimethylpiperazine; The N-methyl ethylamine salt has the structure shown in Formula I: wherein X is Cl or Br; The alkaline solution comprises an aqueous sodium hydroxide solution or an aqueous potassium hydroxide solution.

2. The preparation method according to claim 1, wherein The temperature of the reaction is 10-30°C, and the reaction time is 20-35 minutes.

3. The preparation method according to claim 1, characterized in that, The concentration of the alkaline solution is 0.1-100 mmol / L.

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