Preparation method of benzyl-1-piperazine carbonate

Abstract

The invention relates to a preparation method of benzyl-1-piperazine carbonate, and belongs to the technical field of chemical synthesis. The preparation method comprises the following steps: S1, preparation of di (2-chloroethyl) methylamine hydrochloride: reacting in a reaction solvent, diethanol amine and a chlorination reagent under the condition of inert gas, and after the reaction is finished, carrying out post-treatment to obtain the di (2-chloroethyl) methylamine hydrochloride; s2, preparation of benzyl-1-piperazine carbonate: in a solvent, carrying out a reaction on di (2-chloroethyl) methylamine hydrochloride and benzyl carbamate under an alkaline condition, and after the reaction is finished, carrying out post-treatment and purification to obtain the benzyl-1-piperazine carbonate. According to the preparation method of the benzyl-1-piperazine carbonate, the diethanol amine which is low in price and easy to obtain is directly adopted as a raw material, the target product benzyl-1-piperazine carbonate is prepared through chlorination, ring closing and post-treatment methods, the raw material cost is low, operation is easy, and large-scale and continuous industrial production is facilitated.

Description

Technical Field

[0001] This invention relates to a method for preparing benzyl-1-piperazine carbonate, belonging to the field of chemical synthesis technology. Background Technology

[0002] Benzyl-1-piperazine carbonate is an important chemical raw material and pharmaceutical intermediate, widely used in medicine, pesticides, materials science, and chemical analysis. It can also be used to prepare biodegradable pesticide adjuvants, improving pesticide efficacy. Because N-monoacylpiperazine derivatives can be structurally modified and derivatized, they can be used as intermediates in drug synthesis, showing significant applications in anti-inflammatory, antibacterial, and antitumor fields. For example, N-(3,4-dimethoxybenzoyl)-piperazine is a major intermediate in the synthesis of the cardiotonic drug vinarin.

[0003] Since piperazines have two amino groups with identical reactivity, acylation using conventional methods yields a significant amount of diacylated piperazine byproducts. Therefore, the key to synthesizing N-monoacylated piperazines lies in minimizing the formation of diacylated compounds. Common methods involve protecting one amino group before acylation and deprotection, such as formyl protection, ethoxy protection, and salt formation protection. However, these methods involve numerous steps, difficult-to-control reaction conditions, challenging purification, and low yields, hindering large-scale industrial production.

[0004] Existing methods for preparing benzyl-1-piperazine carbonate, such as the patent application with publication number CN116496295A, use piperazine and benzyl chloroformate as raw materials to obtain the target product through a one-step reaction. However, this method easily generates diacylated piperazine byproducts during the reaction, with the content of diacylated piperazine byproducts reaching >60%, ultimately resulting in a low yield of the target product. Even if the content of byproducts can be controlled during the reaction, the control of the reaction process is very high, and these problems make this method difficult to carry out industrial production. Patent applications with publication numbers WO2001042228A1 and CN1923834A report that piperazine is selectively protected with Boc anhydride, then reacted with benzyl chloroformate, and then deprotected. This process also cannot control the two Boc impurities on the piperazine, resulting in a low yield. The patent application with publication number CN1923834A reported the preparation using piperazine and dibenzyl dicarbonate as raw materials. The synthesis process was not reported, but the raw material dibenzyl dicarbonate is not easy to procure. Summary of the Invention

[0005] This invention addresses the shortcomings of traditional methods for synthesizing benzyl-1-piperazine carbonate, such as the generation of numerous diacylated piperazine byproducts, low yields, and high costs. It provides a method for preparing benzyl-1-piperazine carbonate that, without the need to protect the imino group, directly uses readily available and inexpensive diethanolamine as a raw material. Through chlorination and substitution reactions, high-purity benzyl-1-piperazine carbonate is prepared. This preparation method is simple to operate, avoids the generation of diacylated piperazine byproducts, and is suitable for large-scale and continuous production.

[0006] The technical solution of the present invention to solve the above-mentioned technical problems is as follows: a method for preparing benzyl-1-piperazine carbonate, wherein the preparation method is as follows:

[0007] Preparation of S1, di(2-chloroethyl)methylamine hydrochloride:

[0008]

[0009] Under inert gas conditions, diethanolamine and a chlorinating agent are reacted in a reaction solvent. After the reaction is completed, post-treatment yields di(2-chloroethyl)methylamine hydrochloride.

[0010] Preparation of S2, benzyl-1-piperazine carbonate:

[0011]

[0012] In a solvent, di(2-chloroethyl)methylamine hydrochloride and benzyl carbamate react under alkaline conditions. After the reaction is completed, benzyl-1-piperazine carbonate is obtained by post-treatment purification.

[0013] Based on the above technical solution, the present invention can be further improved as follows:

[0014] Furthermore, in step S1, the reaction solvent is dichloroethane.

[0015] Furthermore, in step S1, the chlorinating agent is at least one of thionyl chloride, phosphorus trichloride, phosphorus pentachloride, and phosphorus oxychloride.

[0016] Furthermore, in step S1, the molar ratio of the diethanolamine to the chlorinating reagent is 1:(2.0-2.5); the mass ratio of the diethanolamine to the reaction solvent is 1:(1-3).

[0017] Furthermore, in step S1, the reaction temperature is 60-100℃.

[0018] Furthermore, in step S2, the solvent is at least one of acetonitrile, dioxane, DMF, and NMP.

[0019] Furthermore, in step S2, the reaction temperature is 70-100℃.

[0020] Further, in step S2, the molar ratio of benzyl carbamate to di(2-chloroethyl)methylamine hydrochloride is 1:(1.0-1.2); the molar ratio of benzyl carbamate to alkali is 1:(0.3-1.0).

[0021] Furthermore, in step S2, the alkali is selected from at least one of organic alkali and inorganic alkali;

[0022] The organic base is selected from at least one of organic amines, pyridine, and sodium alkoxide;

[0023] The inorganic base is selected from at least one of potassium carbonate, sodium carbonate, and sodium acetate.

[0024] Furthermore, the organic amine is selected from at least one of triethylamine and diethylisopropylamine.

[0025] The beneficial effects of this invention are:

[0026] The method for preparing benzyl-1-piperazine carbonate described in this invention employs a simple approach. Without protecting the imino group, it directly uses readily available and inexpensive diethanolamine as a raw material, and prepares the target compound benzyl-1-piperazine carbonate through chlorination, cyclization, and post-treatment methods, achieving a GC purity >98%. This method eliminates the generation of diacylated piperazine byproducts. Furthermore, the method uses relatively inexpensive raw materials, resulting in low raw material costs and simple operation, making it more suitable for large-scale and continuous industrial production compared to existing technologies.

[0027] The preparation method described in this invention avoids the generation of diacylated piperazine byproducts, reduces excessive purification operations, and achieves a total yield >75%, thereby lowering raw material costs. This reaction uses diethanolamine and benzyl carbamate as the main raw materials, while existing technologies use piperazine and benzyl chloroformate as the main raw materials. Diethanolamine is significantly cheaper, thus reducing the production cost of this product. Furthermore, the final product of this reaction achieves a purity of 98% without distillation or other purification processes, reducing the operational costs of industrial production. This reaction is a two-step process, simple to operate, and suitable for large-scale and continuous production. Attached Figure Description

[0028] Figure 1 The GC-MS image of the intermediate di(2-chloroethyl)methylamine hydrochloride prepared in Example 1 of this invention;

[0029] Figure 2 The intermediate di(2-chloroethyl)methylamine hydrochloride prepared in Example 1 of this invention 1 H-NMR spectrum;

[0030] Figure 3The intermediate di(2-chloroethyl)methylamine hydrochloride prepared in Example 1 of this invention 13 C-NMR spectrum;

[0031] Figure 4 Here is the GC-MS image of benzyl-1-piperazine carbonate prepared in Example 1 of this invention;

[0032] Figure 5 The benzyl-1-piperazine carbonate prepared in Example 1 of this invention 1 H-NMR spectrum;

[0033] Figure 6 The benzyl-1-piperazine carbonate prepared in Example 1 of this invention 13 C-NMR spectrum;

[0034] Figure 7 for Figure 6 Chemical shifts of 125-160 13 C-NMR spectrum. Detailed Implementation

[0035] To make the above-mentioned objects, features, and advantages of the present invention more apparent and understandable, specific embodiments of the present invention are described in detail below. Many specific details are set forth in the following description to provide a thorough understanding of the present invention. However, the present invention can be practiced in many other ways different from those described herein, and those skilled in the art can make similar modifications without departing from the spirit of the present invention. Therefore, the present invention is not limited to the specific embodiments disclosed below.

[0036] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. The terminology used herein in the description of the invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.

[0037] A method for preparing benzyl-1-piperazine carbonate, wherein the preparation method comprises:

[0038]

[0039] Preparation of S1, di(2-chloroethyl)methylamine hydrochloride:

[0040] Under inert gas conditions, diethanolamine and a chlorinating agent are reacted in a reaction solvent. After the reaction is completed, post-treatment yields di(2-chloroethyl)methylamine hydrochloride.

[0041] Preparation of S2, benzyl-1-piperazine carbonate:

[0042] In a solvent, di(2-chloroethyl)methylamine hydrochloride and benzyl carbamate react under alkaline conditions. After the reaction is completed, benzyl-1-piperazine carbonate is obtained by post-treatment purification.

[0043] Based on the above technical solution, the present invention can be further improved as follows:

[0044] Specifically, in step S1, the reaction solvent is dichloroethane.

[0045] Specifically, in step S1, the chlorination reagent is at least one of thionyl chloride, phosphorus trichloride, phosphorus pentachloride, and phosphorus oxychloride.

[0046] Specifically, in step S1, the molar ratio of diethanolamine to the chlorinating reagent is 1:(2.0-2.5); the mass ratio of diethanolamine to the reaction solvent is 1:(1-3).

[0047] Specifically, in step S1, the reaction temperature is 60-100℃.

[0048] Specifically, in step S2, the solvent is at least one of acetonitrile, dioxane, DMF, and NMP.

[0049] Specifically, in step S2, the reaction temperature is 70-100℃.

[0050] Specifically, in step S2, the molar ratio of benzyl carbamate to di(2-chloroethyl)methylamine hydrochloride is 1:(1.0-1.2); the molar ratio of benzyl carbamate to alkali is 1:(0.3-1.0).

[0051] Specifically, in step S2, the alkali is selected from at least one of organic alkali and inorganic alkali;

[0052] The organic base is selected from at least one of organic amines, pyridine, and sodium alkoxide;

[0053] The inorganic base is selected from at least one of potassium carbonate, sodium carbonate, and sodium acetate.

[0054] Specifically, the organic amine is selected from at least one of triethylamine and diethylisopropylamine.

[0055] More specifically, in step S1, the post-treatment operation is as follows: after the reaction is completed, the heating is turned off and the temperature is lowered. Excess chlorinating reagent and dichloroethane are removed by vacuum distillation to obtain a light yellow solid. 2.0 g / g (based on the light yellow solid) of ethanol is added to the light yellow solid, and the mixture is heated to 60-65°C until it is completely dissolved. Then, the mixture is cooled to -5-0°C and stirred for 0.5 h. It is then filtered and dried at the same temperature to obtain di(2-chloroethyl)methylamine hydrochloride.

[0056] More specifically, in step S2, the post-treatment purification operation is as follows: after the reaction is complete, cool down, add water, extract the aqueous phase twice with ethyl acetate, combine the ethyl acetate extracts, dry them, pass them through a column, elute the column with ethyl acetate, collect the column solution and dry it to obtain benzyl-1-piperazine carbonate.

[0057] Example 1

[0058] A method for preparing benzyl-1-piperazine carbonate, wherein the preparation method comprises:

[0059] 1) Synthesis of the intermediate di(2-chloroethyl)methylamine hydrochloride:

[0060] Under nitrogen protection, 1.0 mol of diethanolamine and dichloroethane were added sequentially to a 1 L three-necked flask, with a mass ratio of diethanolamine to dichloroethane of 1:2. Under mechanical stirring, 2.1 mol of phosphorus trichloride was slowly added dropwise at room temperature. After the addition was complete, the temperature was raised to 75–80 °C and the reaction was stirred for 2 h. The heating was then turned off and the temperature lowered. Excess phosphorus trichloride and dichloroethane were removed by vacuum distillation, yielding a pale yellow solid. Recrystallization once with ethanol yielded di(2-chloroethyl)methylamine hydrochloride, with a yield of 94.95%. The GC-MS chromatogram of the intermediate di(2-chloroethyl)methylamine hydrochloride is shown below. Figure 1 As shown, the intermediate di(2-chloroethyl)methylamine hydrochloride 1 H-NMR spectrum and 13 The C-NMR spectra are as follows: Figure 2 and Figure 3 As shown.

[0061] 2) Synthesis of benzyl-1-piperazine carbonate:

[0062] Under nitrogen protection, 0.5 mol of benzyl carbamate, 0.52 mol of di(2-chloroethyl)methylamine hydrochloride, 0.25 mol of triethylamine, and 200.0 g of DMF were added sequentially to a 500 mL three-necked flask. The mixture was heated to 80–85 °C and stirred for 8 h. After the reaction was complete, the temperature was lowered, water was added, and the mixture was extracted twice with ethyl acetate. The ethyl acetate extracts were combined, dried, and then passed through a column. The residue was eluted with ethyl acetate, collected, and dried to obtain benzyl-1-piperazine carbonate with a GC purity of 98.15% and a yield of 81.9%. The GC-MS chromatogram of benzyl-1-piperazine carbonate is shown below. Figure 4 As shown, benzyl-1-piperazine carbonate 1 H-NMR spectrum as follows Figure 5 As shown, benzyl-1-piperazine carbonate 13 C-NMR spectrum as shown Figure 6 and Figure 7 As shown.

[0063] Example 2

[0064] A method for preparing benzyl-1-piperazine carbonate, wherein the preparation method comprises:

[0065] 1) Synthesis of the intermediate di(2-chloroethyl)methylamine hydrochloride:

[0066] Under nitrogen protection, 1.0 mol of diethanolamine and dichloroethane were added sequentially to a 1 L three-necked flask, with a mass ratio of diethanolamine to dichloroethane of 1:2. Under mechanical stirring, 2.1 mol of thionyl chloride was slowly added dropwise at room temperature. After the addition was complete, the temperature was raised to 75–80 °C and the reaction was stirred for 2 h. The heating was then turned off and the temperature lowered. Excess thionyl chloride and dichloroethane were removed by vacuum distillation to obtain a pale yellow solid. Recrystallization from ethanol yielded di(2-chloroethyl)methylamine hydrochloride, with a yield of 94.95%.

[0067] 2) Synthesis of benzyl-1-piperazine carbonate:

[0068] 0.5 mol benzyl carbamate, 0.52 mol di(2-chloroethyl)methylamine hydrochloride, 0.25 mol sodium carbonate, and 200.0 g dioxane were added sequentially to a 500 mL three-necked flask. The mixture was heated to 80–85 °C and stirred for 10 h. After the reaction was complete, the temperature was lowered to 20–25 °C, and 50.0 g of water was added to quench the reaction. The reaction mixture was then transferred to a single-necked flask and dried under reduced pressure. 50.0 g of water was added to the remaining mixture, and the aqueous phase was extracted twice with ethyl acetate. The ethyl acetate extracts were combined, dried, and passed through a column chromatography column. The column chromatography solution was collected and dried to obtain 89.1 g benzyl-1-piperazine carbonate with a GC purity of 98.80% and a yield of 80.92%.

[0069] Example 3

[0070] A method for preparing benzyl-1-piperazine carbonate, wherein the preparation method comprises:

[0071] 1) Synthesis of the intermediate di(2-chloroethyl)methylamine hydrochloride:

[0072] Under nitrogen protection, 1.0 mol of diethanolamine and dichloroethane were added sequentially to a 1 L three-necked flask, with a mass ratio of diethanolamine to dichloroethane of 1:3. Under mechanical stirring, 2.0 mol of phosphorus pentachloride was added dropwise at room temperature. After the addition was complete, the temperature was raised to 60–65 °C and the reaction was stirred for 2 h. The heating was then turned off and the mixture was cooled to room temperature. The reaction solution was slowly poured into ice water to quench the reaction. The mixture was separated, and the organic phase, dichloroethane, was removed by vacuum distillation to obtain a pale yellow solid. Recrystallization from ethanol yielded di(2-chloroethyl)methylamine hydrochloride, with a yield of 94.69%.

[0073] 2) Synthesis of benzyl-1-piperazine carbonate:

[0074] 0.5 mol benzyl carbamate, 0.5 mol di(2-chloroethyl)methylamine hydrochloride, 0.5 mol pyridine, and 200.0 g acetonitrile were added sequentially to a 500 mL three-necked flask. The mixture was heated to 70–75 °C and stirred for 10 h. After the reaction was complete, water was added, and the mixture was extracted twice with ethyl acetate. The ethyl acetate extracts were combined, dried, and passed through a column. The column chromatography solution was collected and dried to obtain benzyl-1-piperazine carbonate with a GC purity of 99.1% and a yield of 81.08%.

[0075] Example 4

[0076] A method for preparing benzyl-1-piperazine carbonate, wherein the preparation method comprises:

[0077] 1) Synthesis of the intermediate di(2-chloroethyl)methylamine hydrochloride:

[0078] Under nitrogen protection, 1.0 mol of diethanolamine and dichloroethane were added sequentially to a 1 L three-necked flask, with a mass ratio of diethanolamine to dichloroethane of 1:1. Under mechanical stirring, 2.5 mol of phosphorus oxychloride was slowly added dropwise at room temperature. After the addition was complete, the temperature was raised to 70–75 °C and the reaction was stirred for 2 h. The heating was then turned off and the temperature lowered. Excess phosphorus oxychloride and dichloroethane were removed by vacuum distillation, yielding a pale yellow solid. Recrystallization from ethanol yielded di(2-chloroethyl)methylamine hydrochloride in 95.00% yield.

[0079] 2) Synthesis of benzyl-1-piperazine carbonate:

[0080] 0.5 mol benzyl carbamate, 0.6 mol di(2-chloroethyl)methylamine hydrochloride, 0.15 mol sodium acetate, and 200.0 g NMP were added sequentially to a 500 mL three-necked flask. The mixture was heated to 95–100 °C and stirred for 6 h. After the reaction was complete, water was added, and the mixture was extracted twice with ethyl acetate. The ethyl acetate extracts were combined, dried, and passed through a column. The column chromatography solution was collected and dried to obtain benzyl-1-piperazine carbonate with a GC purity of 98.9% and a yield of 82.05%.

[0081] Example 5

[0082] A method for preparing benzyl-1-piperazine carbonate, wherein the preparation method comprises:

[0083] 1) Synthesis of the intermediate di(2-chloroethyl)methylamine hydrochloride:

[0084] Under nitrogen protection, 1.0 mol of diethanolamine and dichloroethane were added sequentially to a 1 L three-necked flask, with a mass ratio of diethanolamine to dichloroethane of 1:2.5. Under mechanical stirring, 2.2 mol of phosphorus trichloride was slowly added dropwise at room temperature. After the addition was complete, the temperature was raised to 60–75 °C and the reaction was stirred for 2 h. The heating was then turned off and the temperature lowered. Excess phosphorus trichloride and dichloroethane were removed by vacuum distillation, yielding a pale yellow solid. Recrystallization from ethanol yielded di(2-chloroethyl)methylamine hydrochloride, with a yield of 95.20%.

[0085] 2) Synthesis of benzyl-1-piperazine carbonate:

[0086] 0.5 mol benzyl carbamate, 0.55 mol di(2-chloroethyl)methylamine hydrochloride, 0.25 mol diethylisopropylamine, and 200.0 g DMF were added sequentially to a 500 mL three-necked flask. The mixture was heated to 90–95 °C and stirred for 7 h. After the reaction was complete, water was added, and the mixture was extracted twice with ethyl acetate. The ethyl acetate extracts were combined, dried, and passed through a column. The column chromatography solution was collected and dried to obtain benzyl-1-piperazine carbonate with a GC purity of 99.0% and a yield of 82.47%.

[0087] Comparative Example 1

[0088] Benzyl-1-piperazine carbonate was prepared using the same method as in Example 1, except that the reaction temperature in step 2) of Comparative Example 1 was 50-55°C, which is lower than the temperature conditions specified in this invention. The specific process is as follows:

[0089] 1) Synthesis of the intermediate di(2-chloroethyl)methylamine hydrochloride:

[0090] Under nitrogen protection, 1.0 mol of diethanolamine and dichloroethane were added sequentially to a 1 L three-necked flask, with a mass ratio of diethanolamine to dichloroethane of 1:2. Under mechanical stirring, 2.1 mol of phosphorus trichloride was slowly added dropwise at room temperature. After the addition was complete, the temperature was raised to 75–80 °C and the reaction was stirred for 2 h. The heating was then turned off and the temperature lowered. Excess phosphorus trichloride and dichloroethane were removed by vacuum distillation, yielding a pale yellow solid. Recrystallization once with ethanol yielded di(2-chloroethyl)methylamine hydrochloride, with a yield of 94.95%.

[0091] 2) Synthesis of benzyl-1-piperazine carbonate:

[0092] Under nitrogen protection, 0.5 mol of benzyl carbamate, 0.52 mol of di(2-chloroethyl)methylamine hydrochloride, 0.25 mol of triethylamine, and 200.0 g of DMF were added sequentially to a 500 mL three-necked flask. The mixture was heated to 50–55 °C and stirred for 8 h. After the reaction was complete, the mixture was cooled, water was added, and the solution was extracted twice with ethyl acetate. The combined ethyl acetate extracts were dried and passed through a column chromatography column. The column chromatography solution was collected and dried to obtain benzyl-1-piperazine carbonate with a GC purity of 93.9% and a yield of 65%.

[0093] A comparison of the experimental results of Comparative Example 1 and Example 1 shows that if the reaction temperature in step 2) is reduced, the yield and purity of the benzyl-1-piperazine carbonate product will decrease. This is because if the reaction temperature in step 2) is too low, the reaction between benzyl carbamate and di(2-chloroethyl)methylamine hydrochloride will be incomplete under the same reaction time, ultimately leading to a decrease in the yield and purity of the benzyl-1-piperazine carbonate product.

[0094] Comparative Example 2

[0095] Benzyl-1-piperazine carbonate was prepared using the same method as in Example 1, except that the reaction temperature in step 2) of Comparative Example 2 was 115-120°C, which is higher than the temperature conditions specified in this invention. The specific process is as follows:

[0096] 1) Synthesis of the intermediate di(2-chloroethyl)methylamine hydrochloride:

[0097] Under nitrogen protection, 1.0 mol of diethanolamine and dichloroethane were added sequentially to a 1 L three-necked flask, with a mass ratio of diethanolamine to dichloroethane of 1:2. Under mechanical stirring, 2.1 mol of phosphorus trichloride was slowly added dropwise at room temperature. After the addition was complete, the temperature was raised to 75–80 °C and the reaction was stirred for 2 h. The heating was then turned off and the temperature lowered. Excess phosphorus trichloride and dichloroethane were removed by vacuum distillation, yielding a pale yellow solid. Recrystallization once with ethanol yielded di(2-chloroethyl)methylamine hydrochloride, with a yield of 94.95%.

[0098] 2) Synthesis of benzyl-1-piperazine carbonate:

[0099] Under nitrogen protection, 0.5 mol of benzyl carbamate, 0.52 mol of di(2-chloroethyl)methylamine hydrochloride, 0.25 mol of triethylamine, and 200.0 g of DMF were added sequentially to a 500 mL three-necked flask. The mixture was heated to 115-120 °C and stirred for 8 h. After the reaction was complete, the mixture was cooled, water was added, and the solution was extracted twice with ethyl acetate. The combined ethyl acetate extracts were dried and passed through a column chromatography column. The column chromatography solution was eluted with ethyl acetate, collected, and dried to obtain benzyl-1-piperazine carbonate with a GC purity of 95.3% and a yield of 72%.

[0100] A comparison of the experimental results of Comparative Example 2 and Example 1 shows that if the reaction temperature of step 2) is increased, the yield and purity of the benzyl-1-piperazine carbonate product will decrease. This is because if the reaction temperature of step 2) is too high, the ester bond in benzyl carbamate or benzyl-1-piperazine carbonate is easily broken, which ultimately leads to a decrease in the purity and yield of the target product. Therefore, the reaction temperature specified in this invention is more conducive to obtaining benzyl-1-piperazine carbonate products with high yield and high purity.

[0101] Comparative Example 3

[0102] Benzyl-1-piperazine carbonate was prepared using the same method as in Example 1, except that the base used in step 2) of Comparative Example 3 was the strong base sodium hydroxide. The specific process is as follows:

[0103] 1) Synthesis of the intermediate di(2-chloroethyl)methylamine hydrochloride:

[0104] Under nitrogen protection, 1.0 mol of diethanolamine and dichloroethane were added sequentially to a 1 L three-necked flask, with a mass ratio of diethanolamine to dichloroethane of 1:2. Under mechanical stirring, 2.1 mol of phosphorus trichloride was slowly added dropwise at room temperature. After the addition was complete, the temperature was raised to 75–80 °C and the reaction was stirred for 2 h. The heating was then turned off and the temperature lowered. Excess phosphorus trichloride and dichloroethane were removed by vacuum distillation, yielding a pale yellow solid. Recrystallization once with ethanol yielded di(2-chloroethyl)methylamine hydrochloride, with a yield of 94.95%.

[0105] 2) Synthesis of benzyl-1-piperazine carbonate:

[0106] Under nitrogen protection, 0.5 mol of benzyl carbamate, 0.52 mol of di(2-chloroethyl)methylamine hydrochloride, 0.25 mol of sodium hydroxide, and 200.0 g of DMF were added sequentially to a 500 mL three-necked flask. The mixture was heated to 80–85 °C and stirred for 8 h. After the reaction was complete, the mixture was cooled, water was added, and the solution was extracted twice with ethyl acetate. The combined ethyl acetate extracts were dried and passed through a column chromatography column. The solution was eluted with ethyl acetate, collected, and dried to obtain benzyl-1-piperazine carbonate with a GC purity of 95.9% and a yield of 79%.

[0107] A comparison of the experimental results of Comparative Example 3 and Example 1 shows that if the inorganic base used in step 2) is a strong base, the yield and purity of the benzyl-1-piperazine carbonate product will decrease. This is because if a strong base is used in step 2), it is easy to cause the ester bond in benzyl carbamate or benzyl-1-piperazine carbonate to break, which will eventually lead to a decrease in the purity and yield of the target product. Therefore, using the inorganic and organic bases specified in this invention is more conducive to obtaining benzyl-1-piperazine carbonate products with high yield and high purity.

[0108] Comparative Example 4

[0109] This comparative example uses a conventional method to prepare benzyl-1-piperazine carbonate using piperazine and benzyl chloroformate as the main raw materials. The specific preparation process is as follows:

[0110] Synthesis of benzyl-1-piperazine carbonate:

[0111] Under nitrogen protection, 1.00 mol of anhydrous piperazine and 688.8 g of methanol were added sequentially to a 2 L three-necked flask, and stirring was started. At an internal temperature of 20–30 °C, 1.00 mol of benzyl chloroformate was added dropwise to the reaction system. After the addition was complete, the reaction was stirred at the same temperature for 2 h. After the reaction was complete, water was added to quench the reaction. The ethanol in the reaction system was removed under reduced pressure and dried. The remaining aqueous phase was extracted with ethyl acetate, and the organic phase was dried to obtain benzyl-1-piperazine carbonate with a GC purity of 35.1%, containing 64.3% of the diacylated piperazine byproduct, with a yield of 65%. Benzyl-1-piperazine carbonate could be obtained by vacuum distillation with a GC purity of 98.21% and a yield of 21.30%.

[0112] A comparison of the experimental results of Comparative Example 4 and Example 1 shows that the conventional method produces a low yield and low purity of 64.3% diacylated piperazine byproduct. The preparation method of this invention employs a two-step reaction, avoiding the generation of diacylated piperazine byproduct and eliminating the need for distillation purification. Furthermore, the overall yield is 77.76%, and the GC purity of the product is 98.15%, thus reducing raw material costs.

[0113] The technical features of the above embodiments can be combined in any way. For the sake of brevity, not all possible combinations of the technical features in the above embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0114] The embodiments described above are merely illustrative of several implementations of the present invention, and while the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the invention patent. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these all fall within the protection scope of the present invention. Therefore, the protection scope of this invention patent should be determined by the appended claims.

Claims

1. A method for preparing benzyl-1-piperazine carbonate, characterized in that, The preparation method is as follows: Preparation of S1, di(2-chloroethyl)methylamine hydrochloride: Under inert gas conditions, diethanolamine and a chlorinating agent are reacted in a reaction solvent. After the reaction is completed, post-treatment yields di(2-chloroethyl)methylamine hydrochloride. Preparation of S2, benzyl-1-piperazine carbonate: In a solvent, di(2-chloroethyl)methylamine hydrochloride and benzyl carbamate react under alkaline conditions. After the reaction is completed, benzyl-1-piperazine carbonate is obtained by post-treatment purification.

2. The method for preparing benzyl-1-piperazine carbonate according to claim 1, characterized in that, In step S1, the reaction solvent is dichloroethane.

3. The method for preparing benzyl-1-piperazine carbonate according to claim 1, characterized in that, In step S1, the chlorination reagent is at least one of thionyl chloride, phosphorus trichloride, phosphorus pentachloride, and phosphorus oxychloride.

4. The method for preparing benzyl-1-piperazine carbonate according to claim 1, characterized in that, In step S1, the molar ratio of the diethanolamine to the chlorination reagent is 1:(2.0-2.5); the mass ratio of the diethanolamine to the reaction solvent is 1:(1-3).

5. The method for preparing benzyl-1-piperazine carbonate according to claim 1, characterized in that, In step S1, the reaction temperature is 60-85℃.

6. The method for preparing benzyl-1-piperazine carbonate according to claim 1, characterized in that, In step S2, the solvent is at least one of acetonitrile, dioxane, DMF, and NMP.

7. The method for preparing benzyl-1-piperazine carbonate according to claim 1, characterized in that, In step S2, the reaction temperature is 70-100℃.

8. The method for preparing benzyl-1-piperazine carbonate according to claim 1, characterized in that, In step S2, the molar ratio of benzyl carbamate to di(2-chloroethyl)methylamine hydrochloride is 1:(1.0-1.2); the molar ratio of benzyl carbamate to alkali is 1:(0.3-1.0).

9. The method for preparing benzyl-1-piperazine carbonate according to claim 1, characterized in that, In step S2, the base is selected from at least one of organic bases and inorganic bases; The organic base is selected from at least one of organic amines, pyridine, and sodium alkoxide; The inorganic base is selected from at least one of potassium carbonate, sodium carbonate, and sodium acetate.

10. The method for preparing benzyl-1-piperazine carbonate according to claim 1, characterized in that, The organic amine is selected from at least one of triethylamine and diethylisopropylamine.

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