A method for continuously preparing 1-(2-pyrimidinyl)piperazine

Abstract

The invention provides a method for continuously preparing 1-(2-pyrimidinyl) piperazine, belonging to the field of organic synthesis. The present invention adopts 2-chloropyridine and piperazine as raw materials, and prepares 1-(2-pyrimidinyl) piperazine by a continuous flow process, which can ensure that the reaction is completed in a relatively short time, realize a high-throughput target product, and ensure that the raw material conversion is complete by optimizing the process parameters, the ratio of product to impurity is 87:12, and the product purity is high. The present invention is a continuous flow process for one-step synthesis, which is a method for efficiently, environmentally friendly and conveniently obtaining the target product 1-(2-pyrimidinyl) piperazine.

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis, and in particular relates to a method for continuously preparing 1-(2-pyrimidinyl)piperazine. Background Art

[0002] 1-(2-Pyrimidinyl)piperazine is a novel intermediate of azaspirocyclodecane dione antianxiety drug and can be used to produce the antidepressant drugs buspirone and tandospirone.

[0003] The common synthesis method of 1-(2-pyrimidinyl)piperazine is mainly achieved through the nucleophilic substitution reaction between 2-chloropyrimidine and piperazine. In a typical synthesis process, piperazine, potassium carbonate and water are mixed and heated to 60°C, and then 2-chloropyrimidine is added at one time, and the reaction is continued at 60°C for 1 hour, followed by cooling and extraction with chloroform, and finally purification by silica gel column chromatography to obtain the target product.

[0004] Patent CN101250184B discloses a method for synthesizing 1-(2-pyrimidinyl)piperazine, wherein piperazine and 2-chloropyrimidine are reacted under alkaline conditions and a phase transfer catalyst to obtain 1-(2-pyrimidinyl)piperazine. However, this method has the following disadvantages: (1) the reaction time of this method is relatively long, which affects production efficiency and cost; (2) 4-butylammonium bromide is used as a phase transfer catalyst, which has certain toxicity and corrosiveness, and poses risks to the environment and human health; (3) chloroform is used as a solvent in the synthesis process, which increases the cost and also causes pollution to the environment.

[0005] Therefore, it is of great significance to develop an efficient, high-purity, green and safe method for synthesizing 1-(2-pyrimidinyl)piperazine in one step. Summary of the invention

[0006] The object of the present invention is to provide a method for continuously preparing 1-(2-pyrimidinyl)piperazine.

[0007] The present invention provides a method for continuously preparing 1-(2-pyrimidinyl)piperazine. The method is carried out in a continuous flow reaction device. In the continuous flow reaction device, a mixed solution of 2-chloropyrimidine and a solvent is connected to a metering pump 1, a mixed solution of piperazine, a base and a solvent is connected to a metering pump 2, and a mixed solution of a quencher and water is connected to a metering pump 3; the metering pump 1 and the metering pump 2 are simultaneously connected to a continuous flow mixer 1, and then connected to a continuous flow reactor 1, a continuous flow mixer 2, and a continuous flow reactor 2 in sequence, and the metering pump 3 is connected to the continuous flow mixer 2;

[0008] The reaction route of the method is:

[0009]

[0010] The method comprises the following steps: when the continuous flow mixer 1, the continuous flow mixer 2 and the continuous flow reactor 1, the continuous flow reactor 2 reach the circulation temperature, firstly start the metering pump 1, the metering pump 2 to react, and then start the metering pump 3 to quench, so as to obtain 1-(2-pyrimidinyl)piperazine.

[0011] The circulation temperature of the continuous flow mixer 1 is consistent with that of the continuous flow reactor 1 , and the circulation temperature of the continuous flow mixer 2 is consistent with that of the continuous flow reactor 3 .

[0012] Furthermore, the solvent is an organic solvent; the base is an organic base; and the quencher is an ammonium salt.

[0013] Furthermore, the organic solvent is anhydrous methanol; the organic base is triethylamine; and the ammonium salt is ammonium chloride.

[0014] Furthermore, the molar ratio of the 2-chloropyrimidine, piperazine and base is 1:1.2-2.0:1.0-1.5.

[0015] Furthermore, the molar ratio of the 2-chloropyrimidine, piperazine and base is 1:2.0:1.5.

[0016] Furthermore, the circulation temperature of the continuous flow mixer 1 and the continuous flow reactor 1 is 10-60°C; the circulation temperature of the continuous flow mixer 2 and the continuous flow reactor 2 is 5-15°C.

[0017] Furthermore, the circulation temperature of the continuous flow mixer 1 and the continuous flow reactor 1 is 50°C; the circulation temperature of the continuous flow mixer 2 and the continuous flow reactor 2 is 10°C.

[0018] Furthermore, the flow rate of the metering pump 1 is set to 10.0-12.0 ml / min; the flow rate of the metering pump 2 is set to 13.5-16.1 ml / min; the flow rate of the metering pump 3 is set to 12.0-14.0 ml / min, and the operation time of the metering pump 1 and the metering pump 2 is 10-20 min.

[0019] Furthermore, the flow rate of the metering pump 1 is set to 11.5 ml / min; the flow rate of the metering pump 2 is set to 15.0 ml / min; the flow rate of the metering pump 3 is set to 13.0 ml / min, and the operation time of the metering pump 1 and the metering pump 2 is 20 minutes.

[0020] Furthermore, after quenching, the following purification steps are also included: extracting the reaction solution, concentrating the organic phase under reduced pressure and drying, adding dichloromethane to slurry, adding anhydrous methanol to slurry the filtered solid, washing the filtered filter cake, and drying to obtain 1-(2-pyrimidinyl)piperazine.

[0021] The present invention uses 2-chloropyridine and piperazine as raw materials, and prepares 1-(2-pyrimidinyl)piperazine through a continuous flow process. The method can ensure that the reaction is completed in a short time and achieve a high-throughput target product. At the same time, the present invention further optimizes the process conditions of the reaction, and screens and obtains the preferred process conditions shown in Example 1, ensuring that the raw materials are completely converted, the ratio of the product to the impurity is about 87:12, and the product has high purity. The present invention is a one-step synthetic continuous flow process, which is an efficient, environmentally friendly and convenient method for obtaining the target product 1-(2-pyrimidinyl)piperazine.

[0022] Obviously, according to the above contents of the present invention, in accordance with common technical knowledge and customary means in the art, without departing from the above basic technical ideas of the present invention, other various forms of modification, replacement or change may be made.

[0023] The above contents of the present invention are further described in detail below through specific implementation methods in the form of examples. However, this should not be understood as the scope of the above subject matter of the present invention being limited to the following examples. All technologies realized based on the above contents of the present invention belong to the scope of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 It is a process flow chart. DETAILED DESCRIPTION

[0025] The raw materials and equipment used in the present invention are all known products, which are obtained by purchasing commercially available products.

[0026] The "normal temperature" referred to in the present invention is 25±10°C.

[0027] The method for preparing 1-(2-pyrimidinyl)piperazine in the embodiment of the present invention is carried out in a continuous flow reaction device, in which a mixed solution of 2-chloropyrimidine and a solvent is connected to a metering pump 1, a mixed solution of piperazine, a base and a solvent is connected to a metering pump 2, and a mixed solution of a quencher and water is connected to a metering pump 3; metering pumps 1 and 2 are simultaneously connected to a continuous flow mixer 1, and then connected to a continuous flow reactor 1, a continuous flow mixer 2, and a continuous flow reactor 2 in sequence, and metering pump 3 is connected to a continuous flow mixer 2. The schematic diagram is shown in FIG. Figure 1 shown.

[0028] 1-(2-pyrimidinyl)piperazine was prepared according to the following synthetic route:

[0029]

[0030] Example 1

[0031] Add 237.0g of anhydrous methanol and 50g of 2-chloropyrimidine to the reaction bottle, stir at room temperature to dissolve and clarify, and set aside. Connect metering pump 1 and set the flow rate to 11.5ml / min;

[0032] Add 75.2 g of piperazine to 158 g of anhydrous methanol, then add 66.3 g of triethylamine, stir to dissolve and clarify, and set aside; connect metering pump 2 and set the flow rate to 15.0 ml / min;

[0033] Add 35.0 g of ammonium chloride to 250 g of water, stir to dissolve and clarify, and set aside; connect metering pump 3 and set the flow rate to 13.0 ml / min.

[0034] Start the jacket circulation of continuous flow mixer 1 and continuous flow reactor 1; set the circulation temperature to 50°C;

[0035] Start the continuous flow mixer 2 and the jacket circulation of the continuous flow reactor 2; set the circulation temperature to 10°C;

[0036] Metering pumps 1 and 2 were turned on. 20 minutes after the start of operation, metering pump 3 was turned on. The material at the outlet of continuous flow reactor 1 was mixed with the ammonium chloride solution in continuous flow mixer 2 and entered into continuous flow reactor 2 for quenching.

[0037] The mixture was separated and extracted with 250 ml, 100 ml and 100 ml of dichloromethane respectively; the mixture was separated and the organic phases were combined; the organic phases were concentrated and dried under reduced pressure at 40°C.

[0038] Add 75 ml of dichloroethane, cool to about 5°C, stir and slurry for 60 minutes, and filter.

[0039] 100 ml of anhydrous methanol was added to the solid, the temperature was lowered to about 5°C, stirred and slurried for 60 minutes, filtered, and the filter cake was rinsed with 25 ml of methanol; the filter cake was vacuum dried at 25°C to obtain 57.5 g of 1-(2-pyrimidinyl)piperazine with a purity of 99.2%; the total yield was 80%. 1-(2-pyrimidinyl)piperazine is a light yellow to off-white solid (20°C), with a melting point of 32-34°C, and MS+: 165.21.

[0040] NMR data: 1 H NMR (400MHz, DMSO-d6) δ8.88(s,1H),8.43(d,J=4.8Hz,2H),6.75(s,1H),4.02–3.87(m,4H),3.14(s,4H).

[0041] Example 2

[0042] Add 237.0g of anhydrous methanol and 50g of 2-chloropyrimidine to the reaction bottle, stir at room temperature to dissolve and clarify, and set aside. Connect metering pump 1 and set the flow rate to 11.5ml / min;

[0043] Add 45.1 g of piperazine to 158 g of anhydrous methanol, then add 66.3 g of triethylamine, stir to dissolve and clarify, and set aside; connect metering pump 2 and set the flow rate to 13.5 ml / min;

[0044] Add 35.0 g of ammonium chloride to 250 g of water, stir to dissolve and clarify, and set aside; connect metering pump 3 and set the flow rate to 13.0 ml / min.

[0045] Start the jacket circulation of continuous flow mixer 1 and continuous flow reactor 1; set the circulation temperature to 50°C;

[0046] Start the continuous flow mixer 2 and the jacket circulation of the continuous flow reactor 2; set the circulation temperature to 10°C;

[0047] Metering pumps 1 and 2 were turned on. 20 minutes after the start of operation, metering pump 3 was turned on. The material at the outlet of continuous flow reactor 1 was mixed with the ammonium chloride solution in continuous flow mixer 2 and entered into continuous flow reactor 2 for quenching.

[0048] The mixture was separated and extracted with 250 ml, 100 ml and 100 ml of dichloromethane respectively; the mixture was separated and the organic phases were combined; the organic phases were concentrated to dryness under reduced pressure at 40°C.

[0049] Add 75 ml of dichloroethane, cool to about 5°C, stir and slurry for 60 minutes, and filter.

[0050] 100 ml of anhydrous methanol was added to the solid, the temperature was lowered to about 5°C, and the mixture was stirred and slurried for 60 min. The mixture was filtered and the filter cake was rinsed with 25 ml of methanol. The filter cake was vacuum dried at 25°C to obtain 39.7 g of 1-(2-pyrimidinyl)piperazine with a purity of 99.1%; the total yield was 55.3%.

[0051] Example 3

[0052] Add 237.0g of anhydrous methanol and 50g of 2-chloropyrimidine to the reaction bottle, stir at room temperature to dissolve and clarify, and set aside. Connect metering pump 1 and set the flow rate to 11.5ml / min;

[0053] Add 56.4 g of piperazine to 158 g of anhydrous methanol, then add 66.3 g of triethylamine, stir to dissolve and clarify, and set aside; connect metering pump 2 and set the flow rate to 14.0 ml / min;

[0054] Add 35.0 g of ammonium chloride to 250 g of water, stir to dissolve and clarify, and set aside; connect metering pump 3 and set the flow rate to 13.0 ml / min.

[0055] Start the jacket circulation of continuous flow mixer 1 and continuous flow reactor 1; set the circulation temperature to 50°C;

[0056] Start the continuous flow mixer 2 and the jacket circulation of the continuous flow reactor 2; set the circulation temperature to 10°C;

[0057] Metering pumps 1 and 2 were turned on. 20 minutes after the start of operation, metering pump 3 was turned on. The material at the outlet of continuous flow reactor 1 was mixed with the ammonium chloride solution in continuous flow mixer 2 and entered into continuous flow reactor 2 for quenching.

[0058] The mixture was separated and extracted with 250 ml, 100 ml and 100 ml of dichloromethane respectively; the mixture was separated and the organic phases were combined; the organic phases were concentrated to dryness under reduced pressure at 40°C.

[0059] Add 75 ml of dichloroethane, cool to about 5°C, stir and slurry for 60 minutes, and filter.

[0060] 100 ml of anhydrous methanol was added to the solid, the temperature was lowered to about 5°C, and the mixture was stirred and slurried for 60 min. The solid was filtered and the filter cake was rinsed with 25 ml of methanol. The filter cake was vacuum dried at 25°C to obtain 43.8 g of 1-(2-pyrimidinyl)piperazine with a purity of 99.0%; the total yield was 61%.

[0061] Example 4

[0062] Add 237.0g of anhydrous methanol and 50g of 2-chloropyrimidine to the reaction bottle, stir at room temperature to dissolve and clarify, and set aside. Connect metering pump 1 and set the flow rate to 11.5ml / min;

[0063] Add 75.2 g of piperazine to 158 g of anhydrous methanol, then add 66.3 g of triethylamine, stir to dissolve and clarify, and set aside; connect metering pump 2 and set the flow rate to 15.0 ml / min;

[0064] Add 35.0 g of ammonium chloride to 250 g of water, stir to dissolve and clarify, and set aside; connect metering pump 3 and set the flow rate to 13.0 ml / min.

[0065] Start the jacket circulation of continuous flow mixer 1 and continuous flow reactor 1; set the circulation temperature to 50°C;

[0066] Start the continuous flow mixer 2 and the jacket circulation of the continuous flow reactor 2; set the circulation temperature to 10°C;

[0067] Start metering pumps 1 and 2. 10 minutes after the start of operation, start metering pump 3. The material at the outlet of continuous flow reactor 1 is mixed with the ammonium chloride solution in continuous flow mixer 2 and enters continuous flow reactor 2 for quenching.

[0068] The mixture was separated and extracted with 250 ml, 100 ml and 100 ml of dichloromethane respectively; the mixture was separated and the organic phases were combined; the organic phases were concentrated to dryness under reduced pressure at 40°C.

[0069] Add 75 ml of dichloroethane, cool to about 5°C, stir and slurry for 60 minutes, and filter.

[0070] 100 ml of anhydrous methanol was added to the solid, the temperature was lowered to about 5°C, and the mixture was stirred and slurried for 60 min. The mixture was filtered and the filter cake was rinsed with 25 ml of methanol. The filter cake was vacuum dried at 25°C to obtain 36.3 g of 1-(2-pyrimidinyl)piperazine with a purity of 99.0%; the total yield was 50.5%.

[0071] Example 5

[0072] Add 237.0g of anhydrous methanol and 50g of 2-chloropyrimidine to the reaction bottle, stir at room temperature to dissolve and clarify, and set aside. Connect metering pump 1 and set the flow rate to 11.5ml / min;

[0073] Add 75.2 g of piperazine to 158 g of anhydrous methanol, then add 44.2 g of triethylamine, stir to dissolve and clarify, and set aside; connect metering pump 2 and set the flow rate to 13.9 ml / min;

[0074] Add 35.0 g of ammonium chloride to 250 g of water, stir to dissolve and clarify, and set aside; connect metering pump 3 and set the flow rate to 13.0 ml / min.

[0075] Start the jacket circulation of continuous flow mixer 1 and continuous flow reactor 1; set the circulation temperature to 50°C;

[0076] Start the continuous flow mixer 2 and the jacket circulation of the continuous flow reactor 2; set the circulation temperature to 10°C;

[0077] Metering pumps 1 and 2 were turned on. 20 minutes after the start of operation, metering pump 3 was turned on. The material at the outlet of continuous flow reactor 1 was mixed with the ammonium chloride solution in continuous flow mixer 2 and entered into continuous flow reactor 2 for quenching.

[0078] The mixture was separated and extracted with 250 ml, 100 ml and 100 ml of dichloromethane respectively; the mixture was separated and the organic phases were combined; the organic phases were concentrated to dryness under reduced pressure at 40°C.

[0079] Add 75 ml of dichloroethane, cool to about 5°C, stir and slurry for 60 minutes, and filter.

[0080] 100 ml of anhydrous methanol was added to the solid, the temperature was lowered to about 5°C, and the mixture was stirred and slurried for 60 min. The solid was filtered, and the filter cake was rinsed with 25 ml of methanol. The filter cake was vacuum dried at 25°C to obtain 54.0 g of 1-(2-pyrimidinyl)piperazine with a purity of 99.3%; the total yield was 75.2%.

[0081] Example 6

[0082] Add 237.0g of anhydrous methanol and 50g of 2-chloropyrimidine to the reaction bottle, stir at room temperature to dissolve and clarify, and set aside. Connect metering pump 1 and set the flow rate to 11.5ml / min;

[0083] Add 75.2 g of piperazine to 158 g of anhydrous methanol, then add 88.4 g of triethylamine, stir to dissolve and clarify, and set aside; connect metering pump 2 and set the flow rate to 16.1 ml / min;

[0084] Add 35.0 g of ammonium chloride to 250 g of water, stir to dissolve and clarify, and set aside; connect metering pump 3 and set the flow rate to 13.0 ml / min.

[0085] Start the jacket circulation of continuous flow mixer 1 and continuous flow reactor 1; set the circulation temperature to 50°C;

[0086] Start the continuous flow mixer 2 and the jacket circulation of the continuous flow reactor 2; set the circulation temperature to 10°C;

[0087] Metering pumps 1 and 2 were turned on. 20 minutes after the start of operation, metering pump 3 was turned on. The material at the outlet of continuous flow reactor 1 was mixed with the ammonium chloride solution in continuous flow mixer 2 and entered into continuous flow reactor 2 for quenching.

[0088] The mixture was separated and extracted with 250 ml, 100 ml and 100 ml of dichloromethane respectively; the mixture was separated and the organic phases were combined; the organic phases were concentrated to dryness under reduced pressure at 40°C.

[0089] Add 75 ml of dichloroethane, cool to about 5°C, stir and slurry for 60 minutes, and filter.

[0090] 100 ml of anhydrous methanol was added to the solid, the temperature was lowered to about 5°C, and the mixture was stirred and slurried for 60 min. The mixture was filtered and the filter cake was rinsed with 25 ml of methanol. The filter cake was vacuum dried at 25°C to obtain 52.0 g of 1-(2-pyrimidinyl)piperazine with a purity of 99.1%; the total yield was 72.4%.

[0091] Example 7

[0092] Add 237.0g of anhydrous methanol and 50g of 2-chloropyrimidine to the reaction bottle, stir at room temperature to dissolve and clarify, and set aside. Connect metering pump 1 and set the flow rate to 11.5ml / min;

[0093] Add 75.2 g of piperazine to 158 g of anhydrous methanol, then add 66.3 g of triethylamine, stir to dissolve and clarify, and set aside; connect metering pump 2 and set the flow rate to 15.0 ml / min;

[0094] Add 35.0 g of ammonium chloride to 250 g of water, stir to dissolve and clarify, and set aside; connect metering pump 3 and set the flow rate to 13.0 ml / min.

[0095] Start the jacket circulation of continuous flow mixer 1 and continuous flow reactor 1; set the circulation temperature to 10°C;

[0096] Start the continuous flow mixer 2 and the jacket circulation of the continuous flow reactor 2; set the circulation temperature to 10°C;

[0097] Metering pumps 1 and 2 were turned on. 20 minutes after the start of operation, metering pump 3 was turned on. The material at the outlet of continuous flow reactor 1 was mixed with the ammonium chloride solution in continuous flow mixer 2 and entered into continuous flow reactor 2 for quenching.

[0098] The mixture was separated and extracted with 250 ml, 100 ml and 100 ml of dichloromethane respectively; the mixture was separated and the organic phases were combined; the organic phases were concentrated to dryness under reduced pressure at 40°C.

[0099] Add 75 ml of dichloroethane, cool to about 5°C, stir and slurry for 60 minutes, and filter.

[0100] 100 ml of anhydrous methanol was added to the solid, the temperature was lowered to about 5°C, and the mixture was stirred and slurried for 60 min. The mixture was filtered and the filter cake was rinsed with 25 ml of methanol. The filter cake was vacuum dried at 25°C to obtain 18.5 g of 1-(2-pyrimidinyl)piperazine with a purity of 99.0%; the total yield was 25.7%.

[0101] Example 8

[0102] Add 237.0g of anhydrous methanol and 50g of 2-chloropyrimidine to the reaction bottle, stir at room temperature to dissolve and clarify, and set aside. Connect metering pump 1 and set the flow rate to 11.5ml / min;

[0103] Add 75.2 g of piperazine to 158 g of anhydrous methanol, then add 66.3 g of triethylamine, stir to dissolve and clarify, and set aside; connect metering pump 2 and set the flow rate to 15.0 ml / min;

[0104] Add 35.0 g of ammonium chloride to 250 g of water, stir to dissolve and clarify, and set aside; connect metering pump 3 and set the flow rate to 13.0 ml / min.

[0105] Start the continuous flow mixer 1 and the jacket circulation of the continuous flow reactor 1; set the circulation temperature to 60°C;

[0106] Start the continuous flow mixer 2 and the jacket circulation of the continuous flow reactor 2; set the circulation temperature to 10°C;

[0107] Metering pumps 1 and 2 were turned on. 20 minutes after the start of operation, metering pump 3 was turned on. The material at the outlet of continuous flow reactor 1 was mixed with the ammonium chloride solution in continuous flow mixer 2 and entered into continuous flow reactor 2 for quenching.

[0108] The mixture was separated and extracted with 250 ml, 100 ml and 100 ml of dichloromethane respectively; the mixture was separated and the organic phases were combined; the organic phases were concentrated to dryness under reduced pressure at 40°C.

[0109] Add 75 ml of dichloroethane, cool to about 5°C, stir and slurry for 60 minutes, and filter.

[0110] 100 ml of anhydrous methanol was added to the solid, the temperature was lowered to about 5°C, and the mixture was stirred and slurried for 60 min. The solid was filtered and the filter cake was rinsed with 25 ml of methanol. The filter cake was vacuum dried at 25°C to obtain 52.5 g of 1-(2-pyrimidinyl)piperazine with a purity of 99.4%; the total yield was 73%.

[0111] Examples 1-8 are all based on Figure 1 The process flow chart shown in the figure is used to prepare 1-(2-pyrimidinyl)piperazine. Table 1 is the screening condition comparison results of preparing 1-(2-pyrimidinyl)piperazine in Examples 1-8, wherein the impurity represents the by-product 1,4-bis(2-pyrimidine)piperazine, the reaction temperature is the circulation temperature of the continuous flow mixer 1 and the continuous flow reactor 1, and the reaction time (residence time) is the time difference between the operation of metering pump 1 and metering pump 2 and metering pump 3, that is, the total time for the reaction system to flow through the continuous flow mixer 1 and the continuous flow reactor 1:

[0112] Table 1

[0113]

[0114] Comparative Examples 1, 2 and 3, when piperazine is too little, the selectivity is poor and there are more impurities, so the amount of piperazine is selected to be 2.0eq; Comparative Examples 1 and 4, the time is too short and the raw material conversion is incomplete, so the residence time is selected to be 20min; Comparative Examples 1, 5 and 6, the reaction is slow when the amount of alkali is too little, and the selectivity is poor when the amount is too much, so the amount of triethylamine is selected to be 1.5eq; Comparative Examples 1, 7 and 8, the reaction temperature is too low and there are a lot of raw materials remaining, and the selectivity is slightly poor when the reaction temperature is too high, so the reaction temperature is selected to be 50°C.

[0115] Comprehensive comparison of all embodiments shows that embodiment 1 of the present invention is the best reaction condition: that is, the amount of piperazine is 2.0 eq, the residence time is 20 min, the amount of triethylamine is 1.5 eq, and the reaction temperature is 50° C. Under these conditions, 1-(2-pyrimidinyl)piperazine with a purity of 99.2% and a yield of 80% can be obtained.

[0116] In summary, the present invention provides a method for continuously preparing 1-(2-pyrimidinyl)piperazine. The present invention uses 2-chloropyridine and piperazine as raw materials to prepare 1-(2-pyrimidinyl)piperazine through a continuous flow process. The method can ensure that the reaction is completed in a relatively short time and achieve a high-throughput target product. At the same time, by optimizing the process parameters, the raw material conversion is complete, the ratio of product to impurities is about 87:12, and the product purity is high. The present invention is a one-step synthetic continuous flow process, which is an efficient, environmentally friendly and convenient method for obtaining the target product 1-(2-pyrimidinyl)piperazine.

Claims

1. A method for continuously preparing 1-(2-pyrimidinyl)piperazine, characterized in that: The method is carried out in a continuous flow reaction device, in which a mixed solution of 2-chloropyrimidine and a solvent is connected to a metering pump 1, a mixed solution of piperazine, a base and a solvent is connected to a metering pump 2, and a mixed solution of a quencher and water is connected to a metering pump 3; the metering pump 1 and the metering pump 2 are simultaneously connected to a continuous flow mixer 1, and then connected to a continuous flow reactor 1, a continuous flow mixer 2, and a continuous flow reactor 2 in sequence, and the metering pump 3 is connected to the continuous flow mixer 2; The reaction route of the method is: The method comprises the following steps: when the continuous flow mixer 1, the continuous flow mixer 2 and the continuous flow reactor 1, the continuous flow reactor 2 reach the circulation temperature, firstly start the metering pump 1, the metering pump 2 to react, and then start the metering pump 3 to quench, so as to obtain 1-(2-pyrimidinyl)piperazine.

2. The method according to claim 1, characterized in that: The solvent is an organic solvent; the base is an organic base; and the quencher is an ammonium salt.

3. The method according to claim 2, characterized in that The organic solvent is anhydrous methanol; the organic base is triethylamine; and the ammonium salt is ammonium chloride.

4. The method according to any one of claims 1 to 3, characterized in that: The molar ratio of the 2-chloropyrimidine, piperazine and base is 1:1.2-2.0:1.0-1.

5.

5. The method according to claim 4, characterized in that The molar ratio of the 2-chloropyrimidine, piperazine and base is 1:2.0:1.

5.

6. The method according to claim 1, characterized in that The circulation temperature of the continuous flow mixer 1 and the continuous flow reactor 1 is 10-60°C; the circulation temperature of the continuous flow mixer 2 and the continuous flow reactor 2 is 5-15°C.

7. The method according to claim 1, characterized in that The circulation temperature of the continuous flow mixer 1 and the continuous flow reactor 1 is 50°C; the circulation temperature of the continuous flow mixer 2 and the continuous flow reactor 2 is 10°C.

8. The method according to claim 1, characterized in that The flow rate of the metering pump 1 is set to 10.0-12.0 ml / min; the flow rate of the metering pump 2 is set to 13.5-16.1 ml / min; the flow rate of the metering pump 3 is set to 12.0-14.0 ml / min, and the operation time of the metering pump 1 and the metering pump 2 is 10-20 minutes.

9. The method according to claim 8, characterized in that The flow rate of the metering pump 1 is set to 11.5 ml / min; the flow rate of the metering pump 2 is set to 15.0 ml / min; the flow rate of the metering pump 3 is set to 13.0 ml / min, and the operation time of the metering pump 1 and the metering pump 2 is 20 minutes.

10. The method according to claim 1, characterized in that After quenching, the following purification steps are also included: extracting the reaction solution, concentrating the organic phase under reduced pressure and drying, adding dichloromethane to slurry, adding anhydrous methanol to slurry the filtered solid, washing the filtered filter cake, and drying to obtain 1-(2-pyrimidinyl)piperazine.

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